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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"2882",leadTitle:null,fullTitle:"New Technologies in the Oil and Gas Industry",title:"New Technologies in the Oil and Gas Industry",subtitle:null,reviewType:"peer-reviewed",abstract:"Oil and gas are the most important non-renewable sources of energy. 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Malignant migrating partial seizures of infancy (MMPSI) is a rare and usually an unrecognized epileptic syndrome of infancy. The International League Against Epilepsy defines this form of epilepsy as follows: seizure onset in the first 6 months of life, occurrence of almost continuous migrating polymorphous focal seizures, combined with multifocal ictal EEG discharges, and progressive deterioration of psychomotor development [1, 2, 3]. Exact criteria of MMPSI are not defined and are being developed. According to the draft of the Classification of the Epilepsies 2001, this syndrome refers to presumably symptomatic neocortical focal epilepsy. In the new Classification of the Epilepsies 2017 (ILAE 2017), MMPSI has not found a separate place, but it is implied that it includes in a group of developmental and epileptic encephalopathy.
This severe form of epilepsy was recently described. The first publication about migrating partial seizures of infancy was presented by Coppola and colleagues in 1995 [1], and then personal observations were done by Gerard et al. [4] and by Okuda et al. [5]. Veneselli et al. summarized previous observations and added three own cases [6]. Coppola et al. in their remarkable report (1995) based on neuropediatric department at the René Descartes University (Paris) presented 14 clinical cases of infants of both sexes with previously undescribed epileptic syndrome characterized by virtually continuous multifocal seizures. According to the classical authors description, the first seizures occurred average at the age of 3 months without any significant previous events. During the period from 1 to 10 months, seizures became very frequent. Seizures were focal and had different clinical characteristics; EEG revealed multiple epileptiform discharges arising independently and with migration during subsequent seizures from one cortical region to another. Patients had regression of psychomotor development, tetraparesis and severe muscular hypotonia of axial muscles. Three of 14 patients died: one at the age of 7 months, and other at the age of 7 and 8 years. Seizures were completely ceased only in two patients. In most cases the cause of the disease was not identified; and there were no family cases [1].
In 2005, Dulac summarized 24 patients’ follow-up (the largest number of verified cases in the world) in the Saint Vincent de Paul Hospital in Paris. Marsh et al. [25] reported another six cases of MMPSI observed in the Philadelphia Children’s Hospital University of Pennsylvania who met the criteria described by Coppola. Presented clinical cases have demonstrated a new epileptic syndrome, different from previously described forms of epileptic encephalopathies of infancy for the whole world epileptology [3].
Synonyms of this epileptic syndrome in the world scientific literature are malignant migrating partial seizures of infancy, migrating partial seizures of infancy, malignant epilepsy of infancy with migrating multifocal seizures, Coppola-Dulac syndrome, and most genetic verified cases, which can be referred to early infantile epileptic encephalopathy type 14 (EIEE14).
In most MMPSI cases, etiology remains unknown; familial cases are rare. In observation by Dulac, relatives in 3 of 24 patients had febrile convulsions, and 4 patients had family history of epilepsy [3]. Multiple tests for inherited metabolism defects had negative results [7].
The first genetic sequencing for identification mutations specific for MMPSI was carried out by Coppola et al. [8]. Was performed automatic sequencing of genes of potassium (KCNQ2, KCNQ3) and sodium (SCN1A, SCN2A) ion channels in three children with MMPSI but no mutation have been found. Mutational screening of chloride (CLCN2) ion channel gene revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three patients. But the same variation has been found in 38 out of 100 control alleles [8].
At present time a number of monogenic mutations were identified in patients with malignant migrating partial seizures of infancy. In catalog of human genes and genetic disorders – Online Mendelian Inheritance in Man (OMIM), we could find the following positions for MMPSI phenotype (Table 1):
Phenotype OMIM classification | Phenotype OMIM number | Gene/locus | Gene OMIM number | Location | Mutation variants | Inheritance | References |
---|---|---|---|---|---|---|---|
Early infantile epileptic encephalopathy type 3 (EIEE3) | 609304 | SLC25A22 | 609302 | 11p15.5 | gly110arg; (.0003) | AR | Poduri et al. [9] |
Early infantile epileptic encephalopathy type 6 (EIEE6) | 607208 | SCN1A | 182389 | 2q24.3 | ala1669gly (.0023) arg862gly (.0024) | AD | Freilich et al. [10] Carranza Rojo et al. [11] |
Early infantile epileptic encephalopathy type 13 (EIEE13) | 614558 | SCN8A | 600702 | 12q13.13 | phe846ser | AD | Ohba et al. [12] |
Early infantile epileptic encephalopathy type 14 (EIEE14) | 614959 | KCNT1 | 608167 | 9q34.3 | arg428glm (.0001) ala934thr (.0002) arg474his (.0003) ile760met (.0004) phe932ile (.0009) gly288ser (.0010) | AD | Barcia et al., [13] Vanderver et al. [14] Ishii et al. [15] |
Early infantile epileptic encephalopathy type 16 (EIEE16) | 615338 | TBC1D24 | 613577 | 16p13.3 | phe229ser (.0005) + cys156ter (.0006) | AR | Milh et al. [18] |
Progressive microcephaly with seizures and cerebral and cerebellar atrophy (MSCCA) | 615760 | QARS | 603727 | 3p21.31 | tyr57his (.0003) + arg515trp (.0004) | AR | Zhang et al. [19] |
Monogenic mutations as etiological factors of malignant migrating partial seizures of infancy
Poduri et al. [9] reported about two sibs (brother and sister), born of consanguineous Saudi Arabian parents, with EIEE3 presenting MMPSI phenotype. EEG showed abnormal spikes in various brain regions. Neurological signs included hypotonia and brisk tendon reflexes; psychomotor development was delayed and subsequently arrested. Brain MRI was normal in the boy but showed delayed myelination and diffuse thinning of the corpus callosum in his sister. Two sibs had polymorphic seizures including bilateral and hemiclonic convulsions, flushing of the face, “staring,” and eventually bilateral eyelid blinking. The seizures in both children were refractory to treatment. The boy developed seizure onset at 1 week of age and died at 14 months; the girl presented first seizures at 2 weeks of age and died at 47 months of age. They also had two healthy brothers. The research team analyzed consanguineous pedigree (parents are cousins) and obtained DNA from affected and unaffected family members, analyzed single nucleotide polymorphism (SNP) 500 K data to identify regions with evidence for linkage, performed whole-exome sequencing, analyzed homozygous variants in regions of linkage to identify a candidate gene, and performed functional studies of the candidate gene SLC25A22. In affected siblings, a homozygous c.328G-C transversion in the SLC25A22 gene was identified, resulting in a gly110-to-arg (G110R; 609302.0003) substitution at a highly conserved residue in the third transmembrane helix [9].
It is a well-known fact that mutation in SCN1A is a leading etiological factor for severe myoclonic epilepsy of infancy (Dravet syndrome). OMIM genetic classification is early infantile epileptic encephalopathy type 6 (607208) with autosomal dominant inheritance. Nevertheless, Freilich et al. [10] have found a novel mutation in the SCN1A gene in the girl with MMPSI who died at the age of 9 months from recurrent status epilepticus (SE). This girl had a severe phenotype, with onset of seizures at age 10 weeks, progression to refractory recurrent seizures by age 5 months, SE of migrating multifocal seizures confirmed by EEG monitoring, progressive microcephaly, and profound psychomotor delay. By sequencing genomic DNA from blood, the heterozygous missense mutation c.C5006C > A transversion in the SCN1A gene, resulting in an ala1669-to-glu (A1669E; 182389.0023), which further was confirmed in brain DNA, was identified. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular linker of domain 4 of the SCN1A sodium channel protein [10].
In a scientific group of Epilepsy Research Centre, Department of Medicine, University of Melbourne, Australia, Carranza Rojo et al. [11] have investigated 15 unrelated children with MMPSI for mutations in genes associated with infantile epileptic encephalopathies (SCN1A, CDKL5, STXBP1, PCDH19, and POLG). One girl with seizure onset at 2 weeks had heterozygous missense mutation de novo 2584C-G transversion in exon 14 of the SCN1A gene, resulting in an arg862-to-gly (R862G; 182389.0024) that affects the sodium channel by substitution in the voltage sensor segment S4 of the second protein domain. She had epilepsy onset of alternative hemiclonic seizures (Dravet-like onset) at the age of 2 weeks with developing status epilepticus of multifocal migrating seizure. Also, the girl had acquired microcephaly, developmental regression, and severe intellectual disability with much more severe phenotype than children with Dravet syndrome. And, another girl who developed MMPSI at the age of 2 months had de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screenings of CDKL5, STXBP1, and PCDH19 and the three common European mutations of POLG were negative [11].
Along with Dravet and MMPSI syndromes, mutation in SCN1A gene has been also associated with generalized epilepsy with febrile seizures plus type 2 (604403), familial febrile seizures type 3A (604403), and familial hemiplegic migraine type 3 (609634). All the diseases have autosomal dominant inheritance.
Ohba et al. [12] identified in seven unrelated patients with early-onset epileptic encephalopathies seven different de novo heterozygous missense mutations in the SCN8A gene, and one of them had MMPSI. In a 5-year-old bedridden severe delayed and profound intellectual disabled Japanese boy by whole-exome sequencing, de novo previously not described mutation in SCN8A gene c.2537 T > C (p.Phe846Ser) was detected. He developed apnea seizures from the age of 2 months and further at 4 months demonstrated migrating hemiclonic convulsions increasing up to status epilepticus of multifocal migrating seizures. MRI has shown mild atrophy of the cerebellum and thin corpus callosum. High-dose combined antiepileptic therapy with phenobarbital, phenytoin, and lamotrigine, ketogenic diet, and vagus nerve stimulator (VNS) implantation are temporarily and partially effective [12].
Voltage-dependent sodium channels, such as SCN8A, are responsible for the initial membrane depolarization that occurs during generation of action potentials in most electrically excitable cells. Mutations in KCNT1 aside from EIEE13 also determine benign familial infantile seizures type 5 (OMIM 617080) and cognitive impairment with or without cerebellar ataxia (OMIM 614306) with autosomal dominant inheritance.
Barcia et al. in 2012 had identified four different de novo heterozygous mutations in the KCNT1 gene (608167.0001–608167.0004) in 6 of 12 unrelated pediatric patients (50%) with clinically manifestation as MMPSI. The gene KCNT1 encodes a sodium-activated potassium channel that is widely expressed at the nervous system. Its activity contributes to the slow hyperpolarization as the neuronal membrane potential that follows repetitive firing. The C-terminal cytoplasmic domain interacts with a protein network, including FMRP (fragile X mental retardation protein), suggesting additional functions [13].
OMIM genetic classification for this type of MMPSI is early infantile epileptic encephalopathy type 14 (614959). At present time, the following allelic variants of KCNT1 gene mutation in patients with MMPSI were identified:
ARG428GLN (608167.0001 KCNT1). It was founded by Barcia et al. [13] in three unrelated patients of French origin and was identified as de novo heterozygous 1283G-A transition in exon 13 of the KCNT1 gene, resulting in an arg428-to-gln substitution at a highly conserved residue in the cytoplasmic C-terminal domain.
ALA934THR (608167.0002 KCNT1). In a child of French origin with MMPSI, Barcia et al. [13] identified a de novo heterozygous 2800G-A transition in exon 24 of the KCNT1 gene, resulting in an ala934-to-thr substitution at a highly conserved residue in the cytoplasmic C-terminal domain. The mutation was shown to cause constitutive activation of the sodium-activated potassium channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C activation.
ARG474HIS (608167.0003 KCNT1). It was identified in a patient of French origin with MMPSI by Barcia et al. [13] as de novo heterozygous 1421G-A transition in exon 15 of the KCNT1 gene, resulting in an arg474-to-his substitution at a highly conserved residue.
ILE760MET (608167.0004 KCNT1). It was also founded by Barcia et al. [13] in a child of Ukrainian origin with early clinical manifestation of MMPSI and was identified as de novo heterozygous 2280C-G transversion in exon 20 of the KCNT1 gene, resulting in an ile760-to-met substitution at a highly conserved residue.
All these mutations were identified by exome sequencing and also were confirmed by Sanger sequencing. Mutations were not found in 200 controls or in several large control databases [13].
PHE932ILE (608167.0009 KCNT1). Vanderver et al. [14] identified in an Australian boy the de novo heterozygous c.2794 T-A transversion in the KCNT1 gene, resulting in a phe932-to-ile substitution at a highly conserved residue in the cytoplasmic C-terminal domain. This mutation was found by whole-exome sequencing, confirmed by Sanger sequencing, and was not present in the 1000 Genomes Project or Exome Sequencing Project databases. Seizure onset was at age of 1 month with refractory myoclonic seizures that progressed to different polymorphic seizure types and status epilepticus. He also had microcephaly and severe developmental stagnation. Brain imaging showed serious delayed myelination, and EEG demonstrated background slowing with multifocal interictal discharges and occasional periods of burst suppression. The patient doesn’t have classical MMPSI characteristics and survived (last observation at the age of 10) with a decrease of pharmacoresistant seizures at the age of 7 [14].
GLY288SER (608167.0010 KCNT1). Ishii et al. in two unrelated Japanese girls with MMPSI identified a de novo heterozygous c.862G-A transition in the KCNT1 gene, resulting in a gly288-to-ser substitution at a highly conserved residue in the pore region of the channel [15].
Kawasaki et al. described three infants with malignant migrating partial seizures with KCNT1 mutations accompanied by massive systemic to pulmonary collateral arteries with life-threatening hemoptysis and heart failure [16].
Madaan with colleagues from Child Neurology Division, Department of Pediatrics, All India Institutes of Medical Sciences (New Delhi, India), in 2018 identified a child with MMPSI who had a novel heterozygous missense mutation in exon 10 of the KCNT1 gene (chr9:138650308; c.808C > C/G (p.Q270E)). Neither quinidine nor ketogenic diet could control his seizures, and the child succumbed to his illness at 9 months of age [17].
My personal observation consists of two Russian girls with MMPSI having KCNT1 mutations: one with gly288ser (608167.0010 KCNT1) and the other with previously not described mutations c.1066C > T (arg356trp) in exome 12 (chr9:138656907C > T, rs752514808). So, it seems that KCNT1 is a major disease-associated gene for the MMPSI phenotype.
It is interesting that mutations in KCNT1 also determine another form of epilepsy – nocturnal frontal lobe epilepsy type 5. But the mutation is different from the cases of MMPSI and is marked .0005–.0008 (ARG928CYS, TYR796HIS, ARG398GLN, and MET896ILE).
Milh et al. [18] identified compound heterozygosity for two mutations in exon 2 of the TBC1D24 gene (686 T-C transition, resulting in a phe229-to-ser, 613577.0005, and 468C-A transversion, resulting in a cys156-to-ter, 613577.0006) in two sisters with malignant migrating partial seizures of infancy. These girls early developed clonic seizures in the second month of life and subsequently demonstrated prolonged, almost continuous migrating seizures of different types with severe neurologic deterioration and lack of psychomotor development [18].
OMIM genetic classification for this type of MMPSI – early infantile epileptic encephalopathy type 16 (615338). The screening of TBC1D24 in an additional set of eight MMPSI patients observed by Milh and colleagues was negative. The TBC1D24 gene encodes a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins, which coordinates peripheral membrane Rab proteins and other GTPases for the proper transport of intracellular vesicles. Coimmunoprecipitation studies showed that the phe229ser mutation impaired the interaction of TBC1D24 with adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6, 600,464), and overexpression of the mutant protein in primary cortical neurons abolished the ability of TBC1D24 to increase neurite length and arborization, consistent with a loss of function [18].
Mutation in TBC1D24 gene has been also associated to infantile familial myoclonic epilepsy (OMIM 605021, autosomal recessive inheritance), DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome – OMIM 220500) with autosomal recessive inheritance, and also autosomal recessive deafness type 86 (614617), and autosomal dominant deafness type 65 (616044).
Zhang et al. [19] in four patients from two unrelated families with progressive microcephaly, intractable seizures, and cerebral and cerebellar atrophy (MSCCA; 615,760) identified compound heterozygous mutations in the QARS gene (603727.0001–603727.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. QARS (or GLnRS; 603,727) is a class I aminoacyl-tRNA synthetase. Aminoacyl-tRNA synthetases are enzymes that charge tRNAs with their cognate amino acids. The specificity of this reaction determines the fidelity of mRNA translation. At least one synthetase exists in the cytoplasm for each amino acid. QARS is essential for normal brain development. Studies in patient cells and expression of recombinant variants in
On personal observation of MMPSI patients, one Russian boy with clinical and electroencephalographic pattern of mixed form (MMPSI and early myoclonic encephalopathy) had rhizomelic chondrodysplasia punctata type 2 (RCDP2; 222,765) from the group of peroxisomal metabolic diseases [20]. Rhizomelic chondrodysplasia punctata type 2 (RCDP2) is caused by homozygous or compound heterozygous mutation in the DHAPAT gene (GNPAT; 602,744), which encodes acyl-CoA:dihydroxyacetonephosphate acyltransferase, on chromosome 1q42. This peroxisomal disorder is characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, micrognathia, dysplastic external ears, eye abnormalities‑cataract and coloboma, congenital contractures, dwarfism, hypotonia, and severe mental retardation. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective.
At 2010 group of genetics from the Department of Pediatrics, University of Michigan (Ann Arbor, Michigan, USA), has found de novo 598 kb 16p11.2 microduplication in a boy with refractory MMPSI, who has developed seizures in 4 months and also has spastic quadriparesis, severe global developmental delay, hypotonia, and microcephaly [21].
In 2012 Poduri and colleagues from the Department of Neurology of Children’s Hospital Boston (Massachusetts, USA) in a patient, born of consanguineous Palestinian parents, with clinical manifestation as MMPSI, identified a homozygous 486-kb deletion on chromosome 20p12.3 encompassing the promoter region and exons 1, 2, and 3 of the PLCB1 gene. The deletion breakpoints were mapped from 8,094,049–8,094,072 to 8,580,261–8,580,284 (GRCh37). The breakpoints lie within two LINE nuclear elements and likely arose from nonallelic homologous recombination. PLCB1 gene (607,120; locus 20p12.3) is responsible for early infantile epileptic encephalopathy type 12 (EIEE12; 613,722). Phospholipase C-beta (PLCB) catalyzes the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (IP2), a key step in the intracellular transduction of many extracellular signals. The PLCB1 gene encodes a mammalian PLCB isoform that is expressed in cerebral cortex, hippocampus, amygdala, lateral septum, and olfactory bulb [22].
Most cases of MMPSI are considered as unknown etiology (cryptogenic). But also MMPSI had its symptomatic analogs including cases considered as dual pathology [1, 2, 3, 20, 23].
In two of three cases for the first time presented by Coppola et al., neuropathologic brain examination showed marked loss of hippocampal neurons in combination with gliosis in the CA1 sector of hippocampal pyramidal layer [1, 23].
Personal observation of 35 cases with MMPSI contains 12 children with symptomatic clinical-electroencephalographic copies of MMPSI (5 boys and 7 girls). Only two infants had cerebral dysgenesis: lissencephaly-pachygyria in one girl and polymicrogyria in another girl. Other ten children had severe perinatal hypoxic-ischemic CNS disturbances (four of them mixed with perinatal infections‑cytomegalovirus, ureaplasma, chlamydia, herpes type 1) that caused serious brain damage, tetraparetic spastic form of cerebral palsy, and severe retardation in combination with epileptic encephalopathy. Their clinical and video-EEG signs demonstrated MMPSI picture.
At the present time, at least about 100 cases of MMPSI appear to be described in the world literature. However, the number of publications has been steadily growing in recent years. Obviously, this serious disease is more common than diagnosed due to the low clinicians’ awareness. In the structure of patients with onset of status epilepticus before 3 years of age (n = 267), a group of children with MMPSI consisted 4.9% (n = 13), and in the structure of infant with SE (n = 147) – 8.8% [24].
Both sexes are equally susceptible. According to Dulac, 20 children with MMPSI included 9 girls and 11 boys [3]. Disease onset varies in age from 1 week to 7 months of life (average – 3 months) [1, 4]. According to Marsh et al., seizures onset varied from the first days to 3 months (average – 25 days) [25].
In most cases, pattern of the first seizure includes motor component of one limb or half of the body; and 50% of the patients develop secondary generalization. In some cases after seizure onset, their frequency uncontrolled rapidly rises to status epilepticus. However, seizures could have longer duration, but at onset seizures often go unrecognized. Cases with autonomic manifestation (episodes of apnea, short blackouts with cyanosis or redness) are difficult to diagnose [3]. Thus, in observation by Gerard et al. [4], epileptic seizures with diffuse erythema and sweating with subsequent hiccups were reported as gastroesophageal reflux, and only a few weeks later, addition of focal seizures was noted, which made diagnosis obvious [4]. According to observations by Dulac, the initial period of the disease usually lasts from 1 week to 3 months (average – 45 days). During this period, seizures may be quite rare, for example, once a week [3].
In the age of 24 days to 10 months (mean 4.5 months), seizures become very frequent and polymorphic but usually are still focal. Seizures usually get clustered (serial) nature, mental and motor retardation is clear. Clinical manifestation of seizures may include head and eye version, lateralized eyeball twitching, fixed gaze, clonic eyelid twitching, tonic tension or clonic spasms of one limb or hemispasms, axial tonic spasms, chewing or sucking movements, episodes of apnea, flushing, hypersalivation, and secondary generalized seizures. One patient may have multiple different combinations of seizures. Typically, seizure duration is 1–4 minutes, but in some cases, it may persist up to several 1 of minutes, until the status epilepticus development. As far as the disease progresses, secondary generalized seizures became more frequent. Seizures are almost continuous or occur as a series 5–30 times per day, mainly on awakening and when falling asleep. Seizure periods may alternate with clear periods when seizures occur within 2–5 days continuously, and then there are several “light” days (the cyclic course of disease) [1, 2, 3, 26].
It should be considered that many seizures are hardly noticeable visually and often remain unrecognized for parents and medical staff. In particular, these are “volatile” paroxysms, as short episodes of apnea, episodes of eyes closing or eyes deviation, episodes of facial flushing, etc. Only video-EEG monitoring can prove the epileptic genesis of paroxysmal phenomena.
The course of the disease and the severity of clinical symptoms often have undulating pattern: a period of severe illness and permanent seizures may continue for several weeks, and then it is replaced by a relatively favorable period of the temporary seizure regression and some improvement in cognitive and motor functions. This phenomenon generates additional difficulties in controlling the quality of care as it is quite difficult to differentiate in which case the decrease in frequency and severity of seizures is a true response to therapy and in which case it is subject to the course of the disease.
Under personal observation of patients with MMPSI, age of seizure onset ranged from the 1st day of postnatal life up to 6 months of life. MMPSI were characterized by marked polymorphism (Table 2) and high frequency of epileptic seizures and were in fact a special form of infantile status epilepticus (SE) in the form of migrating multifocal SE. All patients had five or more types of epileptic seizures.
Seizure types | Patients (n) | % |
---|---|---|
Tonic versive seizures | 35 | 100 |
Tonic spasms | 33 | 94.3 |
Ophthalmo-tonic seizures | 35 | 100 |
Ophthalmo-clonic seizures | 11 | 31.4 |
Atonic seizures | 23 | 65.7 |
Dialeptic (pseudoabsences) | 19 | 54.3 |
Pharyngo-oral seizures | 18 | 51.4 |
Tongue clonus | 7 | 20 |
Hemiclonic | 19 | 54.3 |
Jacksonian march | 11 | 31.4 |
Automotor | 8 | 22.9 |
Apnea with cyanosis | 14 | 40 |
Autonomic with vomiting | 5 | 14.3 |
Focal myoclonic | 18 | 51.4 |
Bilateral myoclonic | 13 | 37.1 |
Fragmentary “erratic” myoclonus | 5 | 14.3 |
GTCS | 14 | 40 |
Epileptic seizure types in patients with malignant migrating partial seizures of infancy (n=35)
Neurological findings in MMPSI children marked with neurological impairment from birth‑severe central tetraparesis, often with muscular hypotonia in the axial and limb muscles [1], microcephaly, strabismus, and athetoid hyperkinesis [25]‑are common. Many patients in dynamics are unable to walk and sit without support and in severe cases are also unable to control the vertical head position, drink, and swallow. In all cases, there is mental retardation, usually severe, and visual agnosia [3].
Personal patients with MMPSI (n = 35) in neurological status had a high representation of various disorders: high level of stigmatization was observed in 15 patients (42.8%), 13 patients (37.1%) had microcephaly, and optic nerve atrophy was observed in 27 patients (77.1%). Disorders of bulbar innervation were observed in all patients, while in nine children (25.7%), these impairments were bulbar syndrome, and in 26 children (74.3%) – pseudobulbar syndrome. All patients with MMPSI had changes in the muscle tone: 10 children (28.6%) had spastic hypertonus, 16 children (45.7%) had diffuse muscle hypotonia, and 9 children had dystonic changes (25.7%). Severe movement disability with tetraparesis was formed in all of the children with MMPSI. Neurological disorders were expressed at birth (n = 16, 45.7%) or developed with the onset of seizures (n = 19, 54.3%) and tended to a steady progression in all the patients. All children with MMPSI had delay of motor and mental development (n = 35, 100%), up to a complete development stop in 26 infants (74.3%).
Diffuse slowing of the main background activity is typical that is revealed in the first EEG recordings. At first epileptic cause of these EEG phenomena may remain undetected, especially if symptoms include only short autonomic paroxysms. Epileptiform disorders in disease onset are rare. However, in 3 of 14 patients in the observation by Gerard et al. [4], originally normal background EEG was observed; later, slowing with variable asymmetry was recorded in all cases. Often, slow-wave accentuation in one of the EEG recordings is more pronounced in one hemisphere, while the later study may reveal dominating slow-wave lateralization from the opposite side. Multiregional spikes without clear activation during sleep are registered in all cases during development of the disease. However, pathognomonic interictal EEG pattern in MMPSI is absent. During the period relatively free of seizures, stage differentiation in the structure of sleep EEG may persist, but sleep spindles are rare and usually asymmetric [3]. When seizures become very frequent, interictal activity is almost absent.
Ictal EEG patterns involve different areas of the cerebral cortex in the course of successive seizures. Ictal pattern is a rhythmic activity of alpha and theta range, occurring in one region with adjacent regions involvement during seizure, followed by a gradual decrease of the frequency characteristics. Caraballo with colleagues, analyzing 17 infants with MMPSI, had distinguished three different EEG patterns: 8 cases with alternating simple focal motor seizures at onset, and the ictal EEG pattern was characterized by recurrence of rhythmic focal spikes or rhythmic sharp theta or alpha activity in the Rolandic region; 5 cases with complex focal seizures and progressive appearance of polymorphic theta-delta in temporo-occipital regions recurring independently; and 4 cases with focal complex seizures with motor manifestations and ictal EEG with flattening or fast activity in frontotemporal region followed by unilateral fast polyspikes in alternating clusters in both hemispheres. Correlations between these three patterns with severity or prognosis were not found [27]. Electro-clinical seizure patterns last from 1 to 4 minutes. Multiple subclinical ictal EEG patterns lasting from 30 seconds to 1 minute are also typical [1]. Observations show an alternative cortical section of both hemispheres’ involvement in epileptogenesis, which implies the presence of a diffuse pathological process in the cerebral cortex [3].
When seizures become very frequent, initial zone of ictal pattern shift from one region to another and from one hemisphere to another occurs. As a result, extended, migratory ictal activity, which forms a complex EEG pattern of status epilepticus, develops [1, 2, 3].
Video-EEG monitoring plays the most important role in the MMPSI diagnosis, as it is able to detect a correlation between ictal pattern localization of and clinical characteristics of seizure. Thus, ictal pattern in the frontal region produces clinical signs in the form of tonic tension or clonic spasms in the contralateral limb; ipsilateral automatisms or a versive seizure with alternating tonic phenomena and fencing posture are possible. EEG pattern is localized in perirolandic area and manifests with contralateral clonus of the lips, tongue, facial muscles, and hypersalivation. Temporal EEG patterns clinically manifest with broad “frozen” gaze (“staring” phenomenon) and oro-alimentary automatisms. Ictal EEG patterns originating from occipital cortex correlate with lateralized clonic eyes and head twitching. In the case of parietal pattern, nonspecific motor activity is possible; sometimes, a child seems “listening” to his/her inner feelings. The above phenomena are contrary to a prevailing opinion that there is no clear clinical-electroencephalographic correlation of focal ictal patterns in infants and rather suggest the opposite.
As child grows, the amplitude of ictal activity tends to increase with growing involvement of the frontal lobes; many seizures become secondarily generalized. The phenomenon of secondary bilateral synchronization typically occurs after only a few weeks from the onset [1]. However, Gerard et al. [4] in the last observations found a delay of bilateral synchronization and additional foci of epileptiform activity generation, at least up to 2 months from the onset (possibly as antiepileptic drug effect) [4]. At this stage detection of early drug resistance may result to a wrong decision about surgical treatment. Extended video-EEG monitoring also has a considerable importance in this category of patients, because visualization of seizures originating from the same cortex area does not mean that all seizures originate only from this area [28].
Despite the various topographies, ictal EEG patterns of all episodes are very similar and correspond to rhythmic activity of the alpha or theta range, prone to the spread and involving all large cortex areas [7].
EEG in personal patients (n = 35) was characterized by diffuse slowing of background activity, while in the developed stage, background EEG was almost completely replaced by continuous ictal patterns. In the initial stages of the disease, interictal record revealed regional or multiregional epileptiform discharges with formation of multifocal independent spike foci (MISF) pattern. Most cases of MMPSI (20 patients, 57.1%) initially had MISF with transformation in MMPSI as frequency of epileptic seizures increased and migratory status developed. In seven cases (20%), monofocal epilepsy was initially observed, followed by addition of extra foci, new types of seizures, and increase of multifocal ictal events up to SE. At eight infants (22.9%), the first properly done EEG investigation fixed the multiregional SE pattern with its preservation in dynamic video-EEG studies and negative prognosis for live.
Ictal EEG patterns in the developed stage of MMPSI involved different areas of the cerebral cortex during a series of seizures, which could overlap each other in cases when ictal pattern in one area is not yet over, but the same pattern appeared in other cortical areas. There may be a complex picture, combining postictal changes in one region of the cerebral cortex, initial ictal pattern in another area, and developed ictal pattern in the third. Typical EEG pattern of MMPSI is presented in a series of electroencephalograms (Figures 1–7). In general, ictal pattern demonstrates migration of paroxysmal ictal characteristics from one region to another, without formation of stable interregional relations. Probably, only due to ictal pattern migration, patients are able to stay in SE of focal seizures for a long time without development of life-threatening cerebral edema.
Patient G.E., 1 year old. Diagnosis: Malignant migrating partial seizures of infancy. EEG during status seizures. Emergence of regional ictal EEG pattern in the left frontal region in the form of fast epileptiform activity and transformation to regular activity of theta range with amplitude increase and sharp wave inclusion. In the left parietal, posterior temporal region is seen delta-accentuation after the previous seizure. Manifestation: Right-sided tonic seizure with oro-facial and versive components.
The same patient. Continuation of ictal EEG. Ictal epileptiform activity involves neighboring regions and same areas of the right hemisphere, but with maintenance of left-sided lateralization. Manifestation: Bilateral tonic seizure.
The same patient. Continuation of ictal EEG. Ictal epileptiform activity in the frontal areas changes to the right-sided lateralization. Manifestation: Transformation to asymmetric tonic seizure with left-sided accentuation.
The same patient. Continuation of ictal EEG. Diffuse spread of ictal epileptiform activity with multiple spikes. On this background, emergence of regional accentuation of ictal pattern in the left parietal-posterior temporal region. Manifestation: Transformation to generalized tonic seizure with clonic component.
The same patient. Continuation of ictal EEG. Slowing down of frequency characteristics of the diffuse ictal pattern with transformation to the delta slowing. In the opposite left parietal-posterior temporal region, activation of the regional ictal pattern with regionally accentuated polyspikes and spike-wave complexes is seen. Manifestation: Transformation to asymmetric tonic seizure with right-sided clonic component.
The same patient. Continuation of ictal EEG. Shift of ictal pattern in the left parietal-posterior temporal region to the delta slowing with slow epileptiform complexes. At the same time in the right hemisphere, emergence of a new ictal pattern in the form of low-amplitude fast activity (lafa). Manifestation: Short-term decrease of clinical ictal severity.
The same patient. Continuation of ictal EEG. Ictal pattern in the right hemisphere in the form of regular alpha-theta activity with frontal-central accentuation. Postictal changes in the left hemisphere in the form of depression of the bioelectric activity with delta rhythm dominance. Manifestation: Asymmetrical tonic seizure with left-sided accentuation.
The following variants of ictal patterns have been identified in patients with MMPSI: regional “saw tooth” activity of alpha and theta range; “lafa” runs were obligate ictal patterns and were detected at all patients with MMPSI; frequently runs of fast regular spike-wave complexes were also identified; and runs of slow regular spike-wave complexes (rarely), and diffuse spike- and polyspike-wave discharges.
Along with “classical” EEG pattern of MMPSI, atypical mixed variants were observed in the manner of superposition of continuous migratory multiregional SE pattern to suppression-burst pattern with diffuse polyspike-wave discharges (Figures 8–10). Five of these infants (three boys and two girls) had a special mixed form of epilepsy in the form of MMPSI combination with early myoclonic encephalopathy (EME) with the presence of multiple fragmented “erratic” myoclonus along with migrating focal status seizures.
Patient P.S., age 1 year and 1 month old. Ictal EEG. Diagnosis: Mixed form of MMPSI + EME.
EEG reveals combination of suppression-burst pattern with polyspike waves and focal ictal patterns in the left frontal and right temporal areas independently.
The same patient. Continuation of ictal EEG. EEG reveals combination of suppression-burst pattern and focal ictal patterns in the left centro-parietal area with central sagittal (vertex accent).
The same patient. Continuation of ictal EEG. EEG reveals combination of suppression-burst pattern and focal ictal pattern in right occipital-posterior temporal area.
Such mixed form with transformation of EME into MMPSI was also described by specialists from the Department of Pediatrics of the Taipei City Hospital Zhongxing Branch (Taipei, Taiwan) in a female neonate [29].
According to the world literature, CT and MRI changes are absent, and the majority of MMPSI cases are regarded as cryptogenic. Atrophic changes are nonspecific and further are exacerbated by the constant epileptic seizures [1, 25].
Coppola et al. found left temporal lobe dual pathology in a child with MMRSI, including hippocampal sclerosis and cortical-subcortical blurring [23]. Caraballo et al. reported about mesial temporal lobe sclerosis in 3 of 17 patients [27]. Gross-Tsur et al. presented patients with MMPSI decreased N-acetyl aspartate in the frontal cortex and basal ganglia revealed by MR brain spectroscopy [30].
In cases of cryptogenic MMPSI, minimal or moderate subatrophic changes initially were fixed, sometimes in combination with a moderate delay of myelination, but with progressive cerebral atrophy at 11 children with persistent pharmacoresistant seizures. Dysgenetic brain malformations were found at neuroimaging only in two children with symptomatic analogs of MMPSI in the form of lissencephaly-pachygyria in one girl and polymicrogyria in another girl. Remaining ten patients with symptomatic analogs of MMPSI had a wide range of hypoxic-ischemic CNS lesions in the form of periventricular leukomalacia, parasagittal Chugani necrosis, and diffuse cortical-subcortical atrophy (“walnut” brain).
MMPSI is a drug-resistant epilepsy form with serious prognosis. Treatment approaches are still developing. Baseline, old, and new antiepileptic drugs in various combinations, as well as corticosteroids, are ineffective [1, 2, 3]. However, Dulac observed seizure aggravation during treatment with carbamazepine and vigabatrin in these patients [3]. Perez et al. observed temporary seizure remission in two cases of MMPSI with combination of stiripentol (metabolic drug, inhibitor of several cytochrome P-450 enzymes) and high doses of clonazepam [31]. Hmaimess et al. published about effectiveness of levetiracetam in MMPSI [32]. Okuda et al. [5] reported efficacy of potassium bromide in migrating partial seizures of infancy. A 3-month-old boy and a 4-month-old girl with failure of common antiepileptic drugs reached complete remission of seizures in one case and significant decrease of seizure frequency (95%) in another case due to treatment with potassium bromide 80 mg/kg/day [5]. In all cases of seizure control, gradual improvement in psychomotor development of children was observed that also proves the leading role of epileptiform activity and persistent seizures in the development of epileptic encephalopathy [3].
Chien et al. have stopped erratic myoclonus and suppressive-burst pattern on EEG in a mixed form of EME + MMPSI using dextromethorphan 20 mg/kg [29].
There are different opinions about usefulness of ketogenic diet in MMPSI. So, François et al. proclaimed that seizures in MMPSI are also resistant to ketogenic diet [33]. But specialists from Children’s Neuroscience Centre of Royal Children’s Hospital (Parkville, Victoria, Australia) published data about efficacy of the ketogenic diet in children with this pharmacoresistant form of epilepsy [34].
Surgical treatment of MMPSI is unreasonable because of diffuse nature of brain damage and lack of clear local structural defect [3]. Theoretically, anterior callosotomy may be offered as a palliative intervention; however, there is no such experience in this form of epilepsy.
A group of scientists from the Pediatric Neurology Department of Azienda Ospedaliera Universitaria (Ancona, Italy) have published about positive experience of vagus nerve stimulation (VNS therapy) in three infants with pharmacoresistant MMPSI [35].
Our cases confirmed that MMPSI are resistant to antiepileptic therapy. Monotherapy had no significant effect in all patients. All patients with MMPSI failed to relieve from epileptic seizures. In 14 MMPSI cases, antiepileptic therapy was completely ineffective (56%), reduction of seizures >50% was observed in seven patients (28%), and only in six patients decrease of seizures was >75% (17.16%). Relatively effective combinations of antiepileptic drugs included valproates with barbiturates (phenobarbital and hexamidine) and benzodiazepines. Clobazam 1 mg/kg was most effective among benzodiazepine groups. In two patients positive effect was observed with combination of levetiracetam, and in one case – with combination of benzodiazepine and topiramate. Phenytoin in two cases caused moderate positive effect with “escape effect.” In one patient, frequency of seizures decreased during treatment with potassium bromide (50 mg/kg) but with side effects in the form of hypersomnia. High doses of vitamin B6 in two cases were moderately positive.
Ethosuximide, rufinamide, carbamazepine, and oxcarbazepine have no substantial positive effect. In one case, carbamazepine in cryptogenic focal frontal epilepsy with temporary positive effect caused subsequent aggravation of seizures with appearance of additional foci with clinical and electroencephalographic transformation into MMPSI.
Hormone therapy caused only a temporary moderate positive effect in eight cases and was completely ineffective at other cases.
For emergent relief of SE of hemiconvulsive and secondary generalized tonic-clonic seizures in 15 cases of MMPSI, benzodiazepines (relanium and midazolam) had only a temporary effect in eight or were completely ineffective in seven cases.
Positive effect in SE in MMPSI was observed with sodium oxybate administration at a dose of 100–150 mg/kg, 400 mg/min. This was done in seven cases of hemiconvulsive (n = 3) and secondary generalized tonic-clonic SE (n = 4) resistant to benzodiazepines with a temporary regression (six cases) or a decrease of clinical-EEG paroxysmal events (one case).
In three patients with MMPSI, intravenous valproates caused significant positive effect in relieving SE, especially in cases of tonic-autonomic seizures with episodes of apnea, with aggravation during treatment with benzodiazepines [36]. The recommended dose was 25 mg/kg intravenous over 5 min with the following maintenance infusion – 2 mg/kg/h.
Sodium thiopental (4 mg/kg for 2 min and then infusion of 0.2 mg/kg per minute) is the last chance to stop drug-resistant SE but caused death in one girl due to central inhibition of cardiac activity.
MMPSI is a form of epilepsy with poor prognosis. Within a few months after disease onset, frequency and duration of seizures increase up to the serial seizures and status epilepticus. A number of patients die in the first year of life due to multiple prolonged epileptic seizures, development of respiratory distress syndrome, and decorticate rigidity [30]. Based on the generalized clinical observations, mortality in this syndrome is 28% [3]. The results obtained by Marsh et al. are prognostically more favorable: during the 7-year follow-up, all six patients survived; however, psychomotor retardation with severe muscular hypotonia persisted in three of them, and only one patient reached seizure control for a long time [25].
Mortality at personal observed cases was 25.7% (n = 9); however, the expected mortality is higher due to short follow-up (1 year) in more than half of these patients. The oldest of the survived patients with MMPSI is 9 years old; there is gross delay of psychomotor development with unformed verticalization skills, absence of voice activity, spastic tetraparesis, and multiple focal asymmetric tonic, versive, pharyngo-oral, and dialeptic seizures.
Follow-up of patients with MMPSI allowed distinguishing the following subpopulations:
“Classical” form in the form of marked SE of migrating multifocal seizures is pharmacoresistant with a poor prognosis for psychomotor development, seizures, and life (19 cases, 54.3%).
Mixed form (MMPSI + EME) with a combination of electro-clinical MMPSI characteristics but also with the presence of fragmented “erratic” myoclonus and suppression-burst pattern with polyspike-wave discharges on EEG (five cases, 14.3%) with also poor prognosis for mental and motor functions, seizures, and life.
“Moderate” or “mild” form with a consistent evolution from unifocal form to multifocal form with EEG pattern MISF, and then developed expressed MMPSI electro-clinical characteristics, but with a possible regression and decrease in frequency of seizures during combined antiepileptic therapy (six cases, 17.1%).
“Subtle” form, in the form of only “subtle” minimal motor seizures, inhibitory seizures, multiple ictal patterns during sleep, and leading to awakening (five cases, 14.3%). This form causes a rough developmental delay in infants, but without video-EEG monitoring, it remains unrecognized [20].
MMPSI is an independent epileptic syndrome with special clinical-neurophysiological characteristics, distinct from other forms of epilepsy. Diagnosis can be established if there are different types of focal seizures, involving multiple extended EEG and electro-clinical ictal EEG patterns with involvement of several independent areas in both hemispheres. All the patients need complex investigations including dynamic video-EEG monitoring, neuroimaging, and genetic tests (whole-exome sequencing is more preferable).
MMPSI should also be differentiated from the syndrome described by Ohtahara – “severe epilepsy with multiple independent spike foci” (SE-MISF). In the literature, this form is also known as Markand-Blume-Ohtahara syndrome [37]. Unlike MMPSI, this form manifests with predominantly pseudogeneralized seizures: bilateral axial tonic spasms, atypical absences, and myoclonic but focal seizures could also observed. But SE-MISF and MMPSI could have evolutional changes into each other.
Therefore, malignant migrating partial seizures of infancy is the third type of infantile epileptic encephalopathy, along with early encephalopathies with suppression-burst pattern (Aicardi and Ohtahara syndromes) and West syndrome, when the cerebral cortex is more prone to generate epileptic excitation migrating from one area of the cortex to another, without clear interregional organization. This condition is caused by age-dependent features of infant brain with cortex hyperexcitability at a certain stage of evolution [3, 38].
The definition of this syndrome has not been defined in the international classification of epilepsies and epileptic syndromes. The term “malignant migrating partial seizures of infancy” characterizes this form of epilepsy rather as syndrome, so it is proposed to discuss the following title “malignant epilepsy of infancy with migrating multifocal seizures” that may more fully capture the essence of the disease. Taking into account contributions of scientists that first described this form of epilepsy (Coppola) and gave the most detailed description of the clinical and neurophysiological criteria (Dulac), the following definition is proposed: Coppola-Dulac syndrome [39].
I would like to express my special thanks to a veteran of World War II, the world’s famous coryphaeus of neurology and epileptology, Academician and Professor Vladimir Alexeevich Karlov; to an expert in epilepsy, President of the scientific council of the French Epilepsy Research Foundation, leading specialist of Children’s Hospital Necker, Professor Olivier Dulac; to my German teacher and mentor, Professor Hans Holthausen; to my scientific supervisors and epilepsy experts, Professor Konstantin Yurievich Mukhin and Professor Andrey Sergeevich Petrukhin; to the Head of the Department of Neurology, Neurosurgery and Medical Genetics of Pirogov Russian National Research Medical University, Professor Nikolay Nikolaevich Zavadenko; to the Head of the Department of Psychoneurology N2 of the Russian Children Clinical Hospital, Dr. Elena Stepanovna Il’ina; and to all my colleagues. Also, I would like to extend my special thanks to my big family and especially my wife Elena!
No conflict of interest.
Vitamin D plays an important role in calcium and phosphorus metabolism, which are essential for bone health and various biological functions. In vitamin D deficiency, clinical and biochemical rickets characterized by hypocalcemia (irritability, fatigue, muscle cramps, seizures), hypophosphatemia and skeletal manifestations (delayed closure of fontanelles, craniotabes, frontal bossing, bowed legs, enlarged wrists, bone pain, and short stature) in children and adolescents or osteomalacia in adults may occur. Over the past several decades, it has been reported that the efficiency of vitamin D is not limited only to maintaining bone health by managing the calcium homeostasis, but also seems to have anti-inflamatory, immune-modulating and pro-apopitothic properties [1]. There are two different precursor molecules of vitamin D. The first is vitamin D3, or cholecalciferol, which is the main source of vitamin D in the body and is synthesized from the skin by exposure to sun. Vitamin D3 can also be obtained from dietary animal foods (fish, egg yolks) or medicines (vitamin supplements). The second precursor is vitamin D2, or ergocalciferol, which can be used as a source of vitamin D via oral medication or through enriched foods. Vitamin D3 differs in molecular structure from vitamin D2 in that it has a double bond between the 22nd and 23rd carbon atoms and a methyl group on the 24th carbon atom [2]. These structural differences in vitamin D2 affect its catabolism. Compared to vitamin D3, vitamin D2 has a lower affinity for vitamin D-binding protein (VDBP), which leads to its easy removal from the circulation, a reduced formation of 25-hydroxy vitamin D2 (25OHD2) by the 25-hydroxylase enzyme, and increased inactivation by the action of 24-hydroxylase [3, 4, 5]. Although both vitamin D2 and D3 are used as drugs, studies have shown that a higher serum 25OHD2 vitamin level is obtained when vitamin D3 is used in treatment compared to vitamin D2 [6]. In addition, it has been shown that active vitamin D obtained from vitamin D3 has a higher affinity for the vitamin D receptor (VDR) [4]. Despite these differences, vitamins D2 and D3 are both metabolized in substantially the same way and are commonly referred to as vitamin D. Vitamin D is a prohormone and inactive, and to be activated, it must go through a series of enzymatic and non-enzymatic steps.
Formation of vitamin D3, which is the first step of vitamin D synthesis, takes place in the epidermis by a non-enzymatic process (Figure 1). Vitamin D3 is the most important source of vitamin D in the body. 90–95% of vitamin D3 in the human body is produced from the skin with the effect of sunlight. Therefore, sunlight is the main source of vitamin D synthesis, and if there is sufficient exposure to sunlight, there is no need to take additional vitamin D. The mechanism of non-enzymatic photolysis of vitamin D by ultraviolet B (UVB) rays with wavelengths in the range of 290–315 nm involves the breaking of a bond in the B ring of 7-dehydrocholesterol (pro-vitamin D3), resulting in pre-vitamin D3 formation in the epidermis. Subsequently, two different double bonds are formed between the broken carbon atoms in the B ring by thermo-sensitive non-enzymatic process, and the formation of vitamin D3 from pre-vitamin D3 is completed (Figure 2) [7].
Vitamin D metabolism.
Vitamin D3 synthesis from 7-dehydrocholesterol in the epidermis.
The synthesis of vitamin D3 from pro-vitamin D3 in the skin is adjusted according to the needs of the organism. In a period of just fifteen minutes, pre-vitamin D3 is synthesized from pro-vitamin D3 with the effect of ultraviolet light. Conversion from pre-vitamin D3 to vitamin D3 occurs by isomerization in a rather slow and thermo-sensitive manner. In the case of exposure to UV rays or solar radiation for a long period, pre-vitamin D3 converts to a number of photolyzed inactive by-products, such as lumisterol (irreversible) or tachysterol (which can be converted back to pre-vitamin D3). These by-products have no biological effects (Figure 2). In other words, once pre-vitamin D3 is formed in the skin, it turns into either vitamin D3 or inactive metabolites. This is a physiological control mechanism that protects the body from vitamin D intoxication by preventing unnecessary vitamin D synthesis [8, 9].
Some conditions that prevent UVB rays from reaching the skin cause a decrease in vitamin D production. One of these reasons is the ozone (O3) layer surrounding the atmosphere, which reflects some of the sun’s rays, preventing them from reaching the Earth and their harmful carcinogenic effects on the skin. The peak UVB wavelength required for optimal vitamin D synthesis from the skin is 297 (290–315) nm [1, 8]. In addition, air pollution, aerosols, water vapors, and increased nitrogens in the air also play a role in preventing sunlight reaching the Earth, and consequently result in a potential reduced synthesis of vitamin D [8]. Another factor affecting the effectiveness of UVB rays in the synthesis of vitamin D in the skin is the solar zenith angle, which affects how UVB rays reach the world quantifiably. When the sun moves in a path closer to the horizon, which occurs in the northern latitudes in the winter season, vitamin D synthesis is more adversely affected (or reduced). In the summer time in the northern latitudes, a normal biosynthesis is more propitious or favorable. The narrowing of this angle indicates that the sun rays reach the Earth more steeply and intensely. The solar zenith angle is closely related to sunbathing time during the day, the seasons and the geographic region (latitude). Sunlight reaches the Earth most intensely in the “mid-day” when it is summer in the northern latitudes and the weather is clear. Finally, it is thought that sunlight exposure is sufficient for vitamin D synthesis in all geographic regions below 35 degrees north or south latitude all year round. In regions beyond this latitude toward the poles, especially in winter, sunlight is not sufficient for vitamin D synthesis. For example, UVB rays are not sufficient for vitamin D synthesis between October and April in Rome, which is located on 41.9 degrees north latitude, and between November and February in Berlin and Amsterdam, which are located on 52 degrees north latitude. For the reasons mentioned above, it is difficult to predict how much UVB rays reach the skin and how much of this increases serum vitamin D levels. In experimental studies, it has been reported that UVB rays that will cause minimal erythema in 25% of the skin are equivalent to 1000 units of oral vitamin D intake [2, 3, 8].
UVB rays are also affected by the individual’s clothing style, use of sunscreen, and skin colour determined by pigmentation with melanin. In dressing style, especially the type of the clothing fabric used is of great importance [10]. Non-synthetic, light-colored, and linen garments play a less preventive role in UV rays reaching the skin than do garments made of silk, nylon, polyester, and wools. For example, black-dyed cotton clothing prevents 98.6% of UVB rays from reaching the skin compared to white (undyed) cotton clothing, which blocks 47.7% of UVB. Topical sunscreens also prevent UVB rays from reaching the skin by absorbing, reflecting or dispersing them. Topical creams with a sun protection factor of 8 or higher block vitamin D synthesis above 95% [11]. Melanin is a large, opaque polymer synthesized by melanocytes in the skin through the stimulus of exposure to UVB rays. Melanin competes with dehydrocholesterol 7 in the skin to absorb UVB photons and thus inhibits vitamin D synthesis [12]. Individuals with dark skin colour have more melanin pigment in their epidermis than light-skinned individuals and require higher concentrations of sunlight for the same amount of vitamin D synthesis [12]. In addition, the 7-dehydrocholesterol level (provitamin D) in the epidermis can also affect the serum vitamin D concentration. For example, 7-dehydrocholesterol levels in scar tissue caused by the burn are reduced by 42.5% of normal. In these cases, progressive vitamin D deficiency develops, especially if supplemental dietary vitamin D is not provided. Moreover, the content of provitamin D in the skin decreases with age. Skin temperature is also important for vitamin D synthesis. Vitamin D from pre-vitamin D by isomerization whose rate of formation is temperature- dependent. The rate decreases as the skin temperature decreases. In a healthy person, the skin temperature is lower than the central body temperature and varies between 29 and 35 degrees Celcius. When the skin temperature is 37 degrees Celcius, the isomerization of vitamin D from pre-vitamin D occurs within 2.5 hours [13, 14].
Vitamin D3 synthesized in the skin is released into the systemic circulation and all forms are transported by binding to VDBP in serum. A portion of vitamin D, a fat-soluble vitamin, is stored in adipose tissue for use when necessary. The ability of vitamin D to be stored in adipose tissue extends its total half-life in the body up to approximately 2 months. When vitamin D3 is transported to the liver, it is first converted into 25OHD3 by the cytochrome P450 25-hydroxylase enzyme. 25OHD3 is the main circulating form of vitamin D, and it is the parameter that provides the best estimation about the body’s vitamin D pool [15]. Various enzymes that show 25-hydroxylase properties have been described in the body. Among these, the first one is CYP27A1 located in mitochondria, and the second is microsomally located CYP2R1 [1, 6, 16]. CYP27A1 also exerts 27-hydroxylase effect and is involved in bile acid synthesis. Although CYP27A1 is expressed in different tissues of the body, the tissues where it is most commonly found are liver and skeletal muscle tissues [1, 2]. In experimental studies, it was reported that the serum 25OHD3 levels were increased in mice which possess an inactivated CYP27A1 gene, and that rickets did not occur in these mice [17]. Interestingly, in this study, it was shown that CYP2R1 expression increased after CYP27A1 gene inactivation, and consequently 25-hydroxylation activity increased [17]. In addition, individuals with a CYP27A1-inactivating mutation develop a cerebrotendinous xanthomatosis disease with bile and cholesterol synthesis disorders, but without rickets manifestation [18]. Besides CYP27A1, different CYP-450 enzymes with 25-hydroxylase activity (CYP2D25, CYP2J2, CYP2J3, and CYP2C11) have been identified in humans and animals, with the most important one in human being CYP2R1. It is assumed that enzymes other than CYP2R1 have effects only on serum 25OHD3 levels [2].
Studies have suggested that CYP2R1 is the major enzyme responsible for 25-hydroxylation in the human body. This enzyme is expressed in many tissues, mainly liver, skin, and testis [1, 2, 17]. The 25-hydroxylase encoded by the CYP2R1 gene was first described by Cheng et al. [19]. It was first reported by Chen et al. [20] that homozygous inactivating mutations of this gene lead to clinically observed rickets (vitamin D-dependent rickets type IB) in Nigerian families. It has been reported that these cases gave suboptimal response to standard vitamin D (inactive vitamin D2 or D3 forms) treatment [21]. The CYP2R1 enzyme has equal affinity for the different forms of vitamin D precursors (D2 or D3) [19]. Studies have shown that 25-hydroxylase effect increased in male rats given estrogen, whereas this activity decreased in female rats given testosterone [21]. Despite experimental studies, the effect of sex steroids on 25-hydroxylase enzyme activity in humans is unknown. It has been shown that in CYP2R1-null mice, the level of 25OHD3 decreases by 50%, when both CYP2R1 and CYP27A1 are inactivated, and that serum 25OHD3 levels decrease by 70%, and serum 25OHD3 level remains at a measurable level in both cases [2, 17]. This supports the view that serum vitamin D level is compensated by other enzymes with recruitable 25-hydroxylase enzyme activity.
The final step of active vitamin D formation takes place in the proximal tubules of the kidney, led by the enzyme 1-alpha hydroxylase. 25OHD3, which is bound to VDBP, is taken into tubule cells and metabolized (1-alpha hydroxylation) through megalin and cubilin, which are transmembrane proteins located in renal tubules and act as surface receptors for VDBP in tubules. 25OHD3, which then undergoes 1-alpha hydroxylation [1, 2]. The 1-alpha hydroxylase enzyme hydroxylates the first carbon atom in the A ring of 25OHD3, resulting in the formation of 1,25 (OH) 2D3 [1]. CYP27B1 is the only enzyme that has 1-alpha hydroxylase activity. This enzyme, which belongs to the cytochrome P-450 enzyme system, is located in the inner mitochondrial membrane and carries out electron transport to NADPH via ferrodoxin-ferrodoxin reductase [1, 2]. The gene for the enzyme consists of nine exons and is located 12q14.1 chromosomal region. Four different groups reported the cloning and sequencing of the gene from rats, mice and humans [22, 23, 24, 25, 26]. In biallelic inactivating mutations of this enzyme, which is highly homologous to some mitochondria located cytochrome P-450 enzymes (CYP27A1 and CYP24A1), 25OHD3 cannot be converted to 1.25 (OH) 2D3, which is the active vitamin D form. In this case, the clinical picture of vitamin D-dependent rickets type 1A (also called pseudo-vitamin D deficiency rickets) occurs [23]. This disease is typically characterized by rickets, with clinically observed very low 1.25 (OH) 2D3, low serum calcium/phosphorus, and high parathyroid hormone (PTH) levels. CYP27B1 is expressed mainly in the renal proximal tubules and in the placenta during pregnancy [27]. While the expression of the gene encoding this enzyme increases with the effect of PTH, it decreases with FGF23 (fibroblast growth factor 23) and 1.25 (OH) 2D3. CYP27B1 gene is also expressed in lung, brain, breast and intestinal system epithelial cells, immune system cells (macrophage, T/B lymphocytes and dendritic cells), osteoblasts, chondrocytes, and some tumor cell types [1, 2]. The regulation of the extra-renal localized 1-alpha hydroxylase enzyme differs. In some granulomatous diseases where monocyte/macrophage cells play an important role (sarcoidosis, tuberculosis, Chron’s disease, etc.), with the effect of IL-1, TNF-α, IFN-γ, 1-alpha hydroxylase enzyme activity increases and 1,25 (OH) 2D3 is synthesized in greater quantities than normal, and consequently, hypercalcemia and hypercalciuria emerge [28, 29, 30]. Additionally, since cells in these tissues do not have PTH receptors, it is not yet understood how PTH exerts its enhancing effect on the 1-alpha hydroxylase enzyme activity in these cells. In one study, it has been suggested that this enhancing effect of PTH may have occurred through post-transcriptional effects [31]. Moreover, 1-alpha hydroxylase enzyme in these cells is not inhibited by 1,25 (OH) 2D3 or hypercalcemia, unlike the renal tubules.
The 24-hydroxylase enzyme is located in the mitochondrial inner membrane of the cells located in the proximal kidney and, like CYP27B1, uses the electron transport system that enables electron transport to NADPH via ferrodoxine-ferrodoxin reductase. It is known that CYP24A1, which is the only enzyme showing 24-hydroxylase enzyme activity in humans, can also exhibit 23-hydroxylase enzyme activity [2]. Which enzyme will be more prominent varies according to the species [32]. The 23-hydroxylase, another enzyme that degrades vitamin D, is the first step activity in the conversion of 1,25 (OH) 2D3 to 1,25 (OH) 2D3-23,26-lactone.
The CYP24A1 enzyme, encoded in 20q13 chromosomal region and having 24-hydroxylase enzyme activity, initiates catabolic processes that lead to the inactivation of vitamin D by hydroxylating the 24th carbon atom. This enzyme can use both 25OHD3 and 1.25 (OH) 2D3 as substrates, but has a higher affinity for 1.25 (OH) 2D3. As a result of a series of enzymatic reactions, calcitroic acid is formed, which becomes biologically inactive. On the other hand, it has been suggested that the 1,25 (OH) 2D3-23,26-lactone, which is formed in the 23-hydroxylase pathway, lowers serum calcium level, inhibits bone resorption induced by 1.25 (OH) 2D3, and stimulates the formation of collagen tissue in bone tissue [33]. In addition, it has been suggested that 24,25 (OH) 2D3 is not only a degradation product, but has an important role in bone metabolism, especially in endochondral bone formation [34].
There are two vitamin D response elements (VDRE) in the promoter region of the CYP24A1 gene [35]. When active vitamin D is bound to the these one of VDRE after heterodimerization with various molecules, thus initiates the inactivation process of vitamin D. In addition, it has been shown that CYP24A1 gene expression decreases with the effect of PTH, whereas it increases with increased FGF23 concentrations [1, 32, 36, 37]. Inactivating mutations in CYP24A1 lead to an idiopathic infantile hypercalcemia clinic characterized by hypercalcemia, hypercalciuria, nephrocalcinosis, low PTH, low 24.25 (OH) 2D3 and high 1.25 (OH) 2D3 levels [37]. As a result, CYP24A1 is a critical enzyme that protects the body from excessive accumulation and possible intoxication of vitamin D.
3-epimerase activity was first demonstrated in 2001, with the detection of the 3-epi form of 1,25 (OH) 2D3 in keratinocytes [38]. In the following years, epimer forms of 25OHD3 and other vitamin D metabolites were discovered. However, the enzyme or enzymes involved in epimerization has not yet been identifiedpurified or cloned. This enzyme changes the hydroxyl group in the 3rd carbon of the A ring from the alpha orientation to the beta orientation, causing the three-dimensional structure to change and consequently alter the activity of CYP27B1 and CYP24A1 enzymes on vitamin D metabolism. These epimers can be detected by special liquid chromatography-mass spectroscopy (LC-MC) measurement methods [2]. C-3 epimer forms of 25OHD3 and 1,25 (OH) 2D3 have been shown to have lower affinity for VDR and VDBP compared to non-epimer forms [38]. The C-3 epimer form of 1,25 (OH) 2D3 has been shown to cause PTH suppression similar to the non-epimer form, but its effects on bone tissue are not clear. In addition, epimer forms have also been shown to have non-calcium effects (anti-proliferative effect, surfactant synthesis) [39]. It has been shown that the serum levels of vitamin C-3 epimer forms are found to be 60% higher in the period between the neonatal period and one year old, and decrease after one year of age and decrease to very low levels in adulthood [2, 38]. The reason why epimer forms with limited biological activity are important is that they cause interference and false high results in serum 25OHD3 and 25OHD2 measurement. Therefore, it is important to prefer the method (especially LC–MS / MS) that can exclude this effect of epimer forms that cause serum vitamin D measurement interference. However, the use of LC–MS/MS method in the measurement of vitamin D has not become widespread in the world, and the use of this method is only recommended in selected cases.
The largest part of the circulating vitamin D is in the form of 25OHD3, and its serum concentration is in equilibrium with the level of vitamin D stored in muscle and adipose tissues. The parameter that gives the best information about the whole vitamin D pool in the body is 25OHD3 and its known half-life of 15–20 days. Most of all forms of vitamin D in circulation (85–88%) are transported by binding to VDBP and the remaining part (12–15%) to albumin [2, 40]. The serum concentration of VDBP is 4–8 nM and only 2% of it is bound with vitamin D metabolites [2]. Moreover, the affinity of VDBP to 25OHD3 is 20 times higher than 1.25 (OH) 2D3 [3]. 0.03% of 25OHD3 and 0.4% of 1.25 (OH) 2D3 are in free form [2]. In chronic liver disease or nephrotic syndrome, VDBP and albumin levels and thus total serum 25OHD3 and 1.25 (OH) 2D3 levels decrease, but the levels of free forms are not affected [41]. Likewise, since the VDBP level may decrease during the acute disease period, evaluating the body’s vitamin D pool by measuring the serum 25OHD3 level with standard immunoassays may lead to misinterpretations [42]. In conclusion, while the total levels of vitamin D forms are affected by the VDBP level, there is no relationship between VDBP and free vitamin D forms, which are essential for biological activity. It was shown that both 25OHD3 and 1.25 (OH) 2D3 levels in VDBP-null mice were lower than wild type mice, but serum PTH and calcium levels were similarly normal in both groups [43]. This supports the view that serum vitamin D level measured by the standard method may not be an indicator of biologically active vitamin D pool. In addition, the predisposition of VDBP-null mice to the development of osteomalacia after a vitamin D-restricted diet suggests that VDBP may play a role in maintaining the existing vitamin D pool [44]. In addition, some single nucleotide polymorphisms (GC1F, GC1S, GC2) in the
Vitamin D provides its biological effect in two different ways. The first is by directly affecting gene transcription (genomic effect) as other steroid hormones. This effect is relatively slow and usually occurs within hours or days. The second is the non-genomic pathway whose biological effect is relatively faster (within minutes). Vitamin D exerts its non-genomic effect by directly altering the trans-membrane passage of some ions (Ca, Cl) or by affecting intracellular signaling pathway activities (cAMP, PKA, PLC, PI-3 kinase and MAP kinase) [1, 2]. Genetic studies on vitamin D support that active vitamin D directly or indirectly regulates 0.8–5% of the total genome, suggesting the role of active vitamin D in many actions such as regulation of cellular growth, DNA repair, differentiation, apoptosis, membrane transport, cellular metabolism, adhesion and oxidative stress [1, 2, 3, 47].
The active form of vitamin D displays this effect through the vitamin D receptor (VDR). VDR is a member of the nuclear hormone receptor superfamily, which includes steroid, thyroid hormone, and retinoic acid receptors [48]. The VDR gene located on chromosome 12 consists of 427 amino acids encoded by. The structure of the VDR consists of a relatively short N-terminal domain compared to other nuclear receptors, two zinc-fingers that allow the receptor to bind to DNA, and a highly variable C-terminal region, and the hinge region connecting binding these domains (Figure 3) [2]. The DNA-binding region of the receptor is rich in cysteine, and the sequence of this region is largely conserved between species. The zinc-finger structure close to the C-terminal part of VDR determines the specificity for the VDRE (vitamin D response element), which is the binding site on the DNA. The other zinc-finger structure is involved in the heterodimerization of VDR with RXR (retinoid X receptor) [1, 2]. The ligand-binding part of the receptor consists of 12 α-helix structures (H1-12; the H12 part is also called AF2) and 3 β-sheet structures (S1-3) [49]. The AF-2 region located at the end of the C-terminal is the binding site of co-activator complex structures such as SRC (steroid receptor coactivator) and DRIP (vitamin D receptor interacting protein). Transcription is initiated by binding co-activators to this region [50]. Apart from these functional domains, there are NLS (nuclear localization signal) regions within the DNA binding region of VDR, which are necessary for maintaining transcriptional activity [2]. In addition, there is a hinge region between the ligand-binding and DNA-binding domains of the VDR that ensures molecule stabilization.
The structure of the Vitamin D receptor (VDR).
After active vitamin D crosses the target cell membrane, it interacts with the ligand-binding domain of its own receptor (VDR) in the cytoplasm of the cell. Vitamin D is embedded in the ligand-binding domain, and subsequently, in the H12 alpha-helix H12 (AF-2) region, which is located at the end of the ligand binding part [51]. This critical conformational change of AF-2 facilitates the binding of co-activators in later stages [52]. In the next step, vitamin D-bound VDR binds to RXRα to form a VDR/RXR heterodimer structure that binds to cognate VDR elements (VDRE) in the promoter region in the target genes with a high affinity to initiate gene activation or inhibition. There are many gene-specific VDREs associated with bone metabolism, xenobiotic detoxification, drug resistance, cell growth and differentiation, angiogenesis, mammalian hair growth cycle, lipid synthesis regulation, apoptosis, and immune functions, suggesting that vitamin D has numerous regulatory roles in various organs or tissues in the body [53].
After active vitamin D-VDR-RXR-VDRE interaction, the progression of transcription is controlled by co-activator and co-repressors. The best known co-activators are the p160 co-activator family (eg CBP/p300 and p/CAF) and SRC 1,2,3. Both bind to the AF-2 part and have histone acetyl transferase (HAT) activity, which enables the opening of the histone structure and thus facilitates gene expression [54]. The SRC complex has three NR regions that facilitate binding and contain LxxLL (L, leucine; x, any amino acid) motifs. Likewise, the DRIP complex (Mediator) also has NR regions with LxxLL motifs consisting of 15 or more amino acids [55]. Unlike SRC, DRIP complex does not have HAT activity. This suggests the fact that both protein complexes play a complementary role in the initiation of transcription. The mediator multi-protein complex DRIP205/MED1 (also known as MED1) accumulates around RNA polymerase 2of the initiation complex. This complex then interacts with the TATA region in the promoter region and enables transcription to be initiated [56]. Co-repressors (eg SMRT and NCoR) have histone de-acetylase activity and inhibit transcription by preventing unfolding of the histone core.
Some of the hormones that act on the nuclear hormone receptor can also exert their biological effects on the membrane receptor without the need for additional gene regulation [2]. The non-genomic effect occurs through messenger-mediated pathways. Estrogen, progesterone, testosterone, corticosteroids and thyroid hormones have been reported to exert their effects by using both genomic and non-genomic pathways [2]. Vitamin D has been shown to directly regulate the activation or distribution of various ion-transport channel proteins (for calcium and chloride) and of enzymes (protein kinase C and phospholipase C) through the membrane receptor in osteoblast, liver, muscle, and intestinal cells (Figure 4) [57, 58, 59, 60, 61, 62]. In order to demonstrate the non-genomic effect of vitamin D, many studies have been conducted on intestinal calcium absorption. Rapid vesicular calcium absorption (also called transcaltachia) has been shown in the chick intestinal tract [63]. Further experimental studies have shown that intestinal calcium transport cannot be blocked by the administration of actinomycin D (which inhibits the genomic effect) [64], whereas calcium absorption can be blocked by inhibition of voltage-gated L-type calcium channel proteins [65] or by protein kinase C [66].
Representation of the signal transduction pathways where Vitamin D has its non-genomic effect (2). After vitamin D binds to the membrane receptor, GDP in the G protein α-subunit turns into GTP and activation occurs. The α-subunit of the G protein is separated from other subunits and binds to phospholipase C (PLC). The PLC is then activated to convert phosphoinositol bisphosphate (PIP2) to inositol triphosphate (IP3) and diacylglycerol (DAG). Calcium release from the endoplasmic reticulum via the IP3 receptor (IP3R); DAG activates PKC. PKC, on the other hand, provides calcium entry into the cell via the L-type calcium channel in the membrane.
Apart from the intestinal system, it has been suggested that the non-genomic effect also occurs in chondrocytes in the growth plate and keratinocytes in the skin [67, 68]. Vitamin D is believed to exert its non-genomic effects through VDR analog and MARRS (also known as ERp57/GRp58/ERp60) receptors located on the cell membrane [69, 70]. These membrane receptors are located within the caveolar lipid layer [71]. In addition, research findings indicate that VDR is also necessary for the expression of membrane receptors that involve in the emergence of non-genomic effect [1, 2]. In studies evaluating the effects of vitamin D analogs (6-s-cis or 6-s-trans conformations), the 6-s-cis form can activate intestinal rapid calcium entry even though the VDR affinity is very low, whereas the 6-s-trans form has been shown to be ineffective in calcium metabolism [67].
One of the most important functions of vitamin D is to increase calcium absorption from the intestines. Calcium absorption from the intestinal tract occurs trans-cellular and para-cellular processes mediated through genomic and non-genomic effects. Among these, the trans-cellular pathway largely utilized by the intestinal system, which is regulated by vitamin D [2]. The absorption effect of vitamin D with non-genomic effect of calcium occurs directly on the membrane (transcaltachia). The channel-mediated calcium absorption effect of vitamin D occurs more slowly [2].
Calcium enters the epithelian cell by the effect of an electrical and chemical gradient via calcium channel protein TRPV6 (which has significant sequence homology to TRPV5 in the kidney), the transmembrane protein at the lumenal brush border edge of the intestinal epithelial cell. The expression of TRPV6 is activated by vitamin D [72]. Reduced intestinal calcium transport is observed in TRPV6 null mice [73]. Calcium entering the cell binds to calmodulin (CaM), which is bound with myosin 1A (also known as brush border myosin I). This formed complex allows calcium to be transported across the microvilli. Subsequently, the transport of calcium up to the basolateral membrane occurs inside the vesicle via calbindin-D9k (CaBP). The affinity of calcium for calbindinin is greater than for calmodulin, and better facilitates calcium transport inside the cell [74]. The calcium reaching the basolateral membrane is pumped out of the cell to systemic circulation via the Ca-ATPase (PMCA1b) pump located on the membrane [1, 2]. In addition, although it is less important, NCX (sodium/calcium exchanger), located in the basolateral region, also plays a role in excretion of calcium [2, 75]. Vitamin D shows its increasing effect on intestinal calcium absorption by inducing expression of TRPV6, CaBP and PMCAb and increasing the binding affinity of CaM to myosin 1A [1, 2].
Intestinal calcium absorption, serum calcium level and bone mineral content in Kalbindin D9k null mice (regardless of dietary calcium level) have been shown to be similar to normal mice [76]. Intestinal calcium absorption was found to be normal in calbindin D9k and TRPV6 null mice when a diet containing the daily requirement for calcium was given [77]. These findings indicate there is a mechanism other than the genomic effect through which vitamin D exerts its action (a non-genomic effect) in calcium absorption in the intestines when the amount of calcium in the diet is sufficient.
While trans-cellular calcium absorption is effective in compensating for a low-calcium diet, para-cellular calcium transport becomes important with the increase in calcium content in the diet [1]. Paracellular transport occurs through the extracellular space between the layer of the epithelial cells in the intestine. Although it was previously thought that vitamin D does not affect para-cellular calcium absorption, studies conducted in recent years indicate otherwise, with vitamin D still affecting calcium absorption by increasing levels of various transmembrane and adhesion proteins that control the extracellular space between cells [78, 79]. However, it is not clear at what stage of the paracellular pathway these proteins are involved.
Phosphate, another important molecule for bone mineralization, is actively absorbed mostly in the jejunum, with absorption influenced by vitamin D [2]. This absorption is provided by sodium-phosphate co-transporter IIb (NaPi IIb). In experimental studies, it has been shown that phosphate absorption is blocked when cycloheximide, which inhibits protein synthesis, is given [80]. This situation supports that phosphate absorption occurs by genomic effect. Vitamin D increases NaPi-IIb expression and thus phosphate absorption [2].
Most of the calcium that reaches the kidney tubules is absorbed from the proximal and distal tubules and approximately 1–2% of it is excreted through urine. Approximately 65% of calcium absorption in the kidney is passively absorbed para-cellularly from the proximal tubules with the sodium gradient and independent of vitamin D direct action [1]. The rest of the calcium is absorbed from the ascending limb of the loop of Henle (20%), the distal tubules (15–20%), and the collecting ducts (5%) [81]. Vitamin D plays an important role in calcium absorption in the distal tubules and provides active calcium absorption via the trans-cellular pathway with the help of an electrochemical gradient [1]. Calcium is taken into the cell by TRPV5 channel on the surface of the tubular cell and is transported inside the cell by calbindin-D9k and D28k. Transported to the basolateral part of the cell, calcium is released into the systemic circulation by NCX1 (sodium/calcium exchanger) and PMCA1b. This mechanism is similar to that in the intestinal tract. Vitamin D increases the expression of TRPV5, calbindin, NCX and PMCA1b.
Phosphate is reabsorbed by sodium-dependent phosphate carrier proteins (NaPi-IIa and NaPi-IIc) in proximal tubular cells under vitamin D control. In addition, for phosphate reabsorption, a Na/K-ATPase channel located in the basolateral membrane is also needed [1, 2]. The impact of vitamin D on transport channels is not clearly known. While PTH increases the lysosomal degradation of phosphate transport channels, FGF23 causes a decrease in the expression of these channels [1, 2, 82].
Calcium, phosphorus and vitamin D are important molecules for bone metabolism and health. Calcium is one of the most abundant minerals in the body and is obtained entirely from dietary sources. In addition to its various biological effects in the body, it is also essential for bone metabolism [83]. More than 99% of the total body calcium is found in the bone tissue as a calcium-phosphate mineral complex, while the remaining <1% is distributed between the intracellular and extracellular compartments [83]. While 40% of calcium outside bone tissue is bound to protein, 9% forms ionic complexes, and the remaining 51% is found as free ions [84, 85]. Ionized calcium balances the calcium pool in the intracellular-extracellular area and plays an important role in bone metabolism. This balance is provided by the cooperation of various hormones (PTH, vitamin D) and the organs they affect (kidney, bone and intestinal system) [83, 84, 85]. Where there is vitamin D deficiency (nutritional or genetic) or VDR-inactivating mutations, serum levels of calcium and phosphate, which play an important role in bone development and growth, are reduced and thus rickets/osteomalacia emerge. Rickets is a disease characterized by excessive osteoid tissue accumulation and defective mineralization of the epiphyseal plate, which occurs as a result of insufficient mineralization in the epiphyseal plates of growing bones [1, 2]. Osteomalacia is a disease characterized by a deterioration in the mineralization of the newly formed osteoid and a decrease in bone turnover.
There is a continuous remodeling cycle consisting bone tissue resorption and mineralization. When calcium, phosphorus, and vitamin D are sufficient, this cycle continues in a balanced manner. In the case of negative calcium balance caused by insufficient calcium intake with diet or increased renal calcium loss, vitamin D increases bone resorption in osteoblasts through VDR signaling, resulting in calcium passage from bone to blood, which leads to impaired bone mineralization. Vitamin D increases the expression of RANKL (receptor activator of NF-κB ligand), which is an osteoclastogenic factor from osteoblasts [86, 89]. RANKL stimulates osteoclastogenesis and increases osteoclast formation by binding to its related receptor, RANK [87]. In conclusion, in the case of negative calcium balance, vitamin D tries to keep the serum calcium level in a certain balance by increasing resorption and decreasing mineralization [1].
In the case of a positive calcium balance, the osteoblastogenic activity of vitamin D is prominent. In this situation where anti-resorbtive effect is in the predominant, bone mineral density increases. The occurrence of this effect has been associated with a decrease in the RANKL/OPG (osteoproteogerin) ratio and an increase in LRP-5 (LDL receptor related protein 5) expression [1]. LRP-5 is controlled by the VDR and is a necessary co-receptor for the anabolic effect of osteoblasts [88]. In addition, vitamin D plays a role in the proliferation of chondrocytes in the growth plate through genomic action.
Pro-vitamin-D3, pre-vitamin D3 and then vitamin D3 (cholecalciferol) conversion in the skin is under the control of UV radiation. Serum vitamin D concentration reaches its highest level 24–48 hours after exposure to UV radiation and then shows a gradual decrease. The half-life of serum vitamin D is 36–72 hours. Vitamin D, which is a fat-soluble vitamin, is stored in adipose tissue for later use. The ability of vitamin D to be stored in adipose tissue extends its total half-life in the body up to approximately 2 months.
There is little information on how this enzyme is regulated because of the few studies performed. What is known is that serum vitamin D level is inversely related to the rate of 25-hydroxylation in the liver, and the synthesis of 25OHD3 from vitamin D (cholecalciferol) is regulated by the 25-hydroxylase enzyme
Serum active vitamin D levels in healthy adults vary within extremely narrow ranges, so that even in cases of vitamin D intoxication, serum levels may remain normal. 1-alpha hydroxylation activity in the kidney is controlled by PTH, calcium and phosphorus. Hypocalcemia, increased PTH, and hypophosphatemia will stimulate increases in active vitamin D production through renal 1-alpha hydroxylase enzyme activation, while hypercalcemia, FGF-23 secreted from osteoblasts, and active vitamin D itself have an inhibitory effect on active vitamin D synthesis through the renal 1-alpha hydroxylase enzyme. Active vitamin D increases FGF23 synthesis from osteoblasts. FGF23 suppresses the 1-alpha hydroxylase enzyme and increases the activity of 24 hydroxylase enzymes. In addition, hypercalcemia suppressing PTH and hyperphosphatemia by increasing FGF23 levels results in 1-alpha hydroxylase enzyme activity inhbition [1, 2, 3]. It is also suggested that calcium and phosphate have a direct regulatory effect on 1-alpha hydroxylase enzyme [89].
Calcitonin is known to reduce serum calcium levels through osteoclast inhibition. In addition, this hormone has been shown to increase the expression of CYP27B1, the gene encoding the 1-alpha hydroxylase enzyme, in normocalcemic pregnant women due to the increase in calcium need. In this way, active vitamin D synthesis and consequently intestinal calcium absorption is increased [1, 90]. Apart from calcitonin, it has been suggested that prolactin also increases CYP27B1 expression, especially during lactation, and thus contributes to the increased calcium demand of the body [1, 91].
CYP3A4 enzyme in the liver and intestinal system has also been shown to be effective in the inactivation of 25OHD3 and reduction of active vitamin D [92]. Long-term use of drugs such as phenytoin, rifampicin, and carbamazepine may lead to up-regulation of the CYP3A4 enzyme and thus to a decrease in serum 25OHD3 and active vitamin D levels.
When serum calcium, phosphate and PTH levels are within normal levels, 25OHD3 and 1–25 (OH) 2 D3 are metabolized into biologically inactive forms by activation of 24-alpha hydroxylase enzyme in the kidneys (24–25 dihydroxy vitamin D3 and 1,24, 25 trihydroxy vitamin D3). This enzyme preferably binds to 1–25 (OH) 2 D3, thus limiting the effect of active vitamin D in tissues through inactivation [2]. The low level of 24-hydroxylase enzyme activity leads to high levels of 1–25 (OH) 2D3 and thus hypercalcemia. In addition, it has been suggested that a decrease in this enzyme activity may lead to impairment in intra-membranous bone mineralization [1, 2]. On the other hand, when 1–25 (OH) 2 D3 synthesis decreases, 1-alpha hydroxylase enzyme activity increases and 24-hydroxylase enzyme activity decreases. It is also known that FGF23 increases the activity of 24 hydroxylase enzymes [1, 2].
Numerous studies have shown active vitamin D synthesis by 1-alpha hydroxylase enzyme is not only a renal feature [2, 93]. The gene encoding the 1-alpha hydroxylase enzyme and the vitamin D receptor gene can be expressed in many cells or tissues such as skin, placenta, prostate, parathyroid, bone tissue, colon, lung, breast tissue, monocytes and macrophages, as well as renal cells. It has been reported that active vitamin D synthesized in the aforementioned tissues functions mostly as an intracrine or paracrine factor in the tissues where they are located, and does not contribute to the active vitamin D levels in the circulation, except for some special cases [1, 2]. Since PTH and FGF-23 receptors are not found in these tissues, they are not directly involved in controlling active vitamin D synthesis. However, it is propable that PTH increases the effect of vitamin D through posttranscriptional modification [31]. Unlike in other tissues, in activated macrophages, there is also no negative feedback of active vitamin D on 1-alpha hydroxylase enzyme [91]. Moreover, although the 24-hydroxylase enzyme is expressed in these cells, its function is not fully understood. Cytokines such as IL-1, TNF-α, IFN-γ induce the synthesis of active vitamin D in keratinocytes. Unlike macrophages, keratinocytes have a fully functional 24-hydroxylase enzyme activity and is induced by active vitamin D. In this way, active vitamin D limits its own synthesis in the epidermis through alternative catabolism [1, 2, 93].
Measurement of serum levels of vitamin D, which plays an important role in calcium and phosphorus metabolism and bone mineralization, is routinely performed worldwide. For this, it is preferred to measure the 25OHD level, which has a longer half-life (24–36 hours), can be taken exogenously, and can be synthesized endogenously. The half-life of the 1–25 (OH) 2D3 form is short (4–6 hours), and its serum levels are 1000 times lower than 25OHD. For these reasons, the active form is not preferred for routine measurement. In this section, the measurement methods of 25OHD vitamin are discussed.
To date, many methods have been developed for measuring serum vitamin D levels. These methods are basically divided into two groups. One methodology is the use of competitive binding and immunoassays: radioimmunoassay (RIA), enzyme immunoassay (EIA/ELISA), chemiluminescent immunoassay (CLIA), electrochemiluminescence assay (ECLIA), and competitive protein binding assay. The other methodology involves chemical methods. Chemical methods are based on the non-immunological direct detection methods typically after preparative chromatographic separation. Chemical methods include high performance liquid chromatography (HPLC) and LC/MS (liquid chromatography-mass spectrometer).
The first method used in the measurement of vitamin D is the competitive binding method in which VDBP binds. This method was first reported in 1971 and identifies 25OHD2 and 25OHD3 forms equally [94]. Limitations of this method include the incubation period of 10 days and its inability to separate some polar vitamin D metabolites [24,25(OH)2D, 25,26 (OH)2D ve 25,26 (OH)2D-26,23--lactone] [94]. In the late 1970s, the HPLC method was developed that can exclude the effect of polar vitamin D metabolites causing interference to the chromatographic method [95]. The advantages of this method, which uses a UV absorption technique, include the absence of lipid and polar vitamin D metabolite interference, the ability to measure 25OHD2 and 25OHD3 separated at high resolution, and a high specificity and reliability. Its disadvantages include the use of excess sample amounts, equipment cost, a need for preparative chromatography, and interference by other UV-absorbing compounds, and that the method is somewhat complex and not easily practical. It would not be considered a routine diagnostic test, as it is used in only about 2% of laboratories in the world) [94, 95]. With the later development of the RIA method, the value of quantifying vitamin levels improved. The advantages of this method type are that sample amount can be small and not pre-analytical preparative purification process is required. The assay is economical and easily applicable, and results reliable. As to the disadvantages, chemical and radioactive (with the RIA) waste are issues, and there is cross-reactivity with polar vitamin D metabolites as in the earlier competitive binding type assays. The RIA also is 100% specific for 25OHD3 and 75% specific for 25OHD2, so the final calculation requires an adjustment [94, 96]. Nonetheless automated immunoassay methods are widely used in our country and all over the world (approximately 76% of laboratories in the world) [97]. Requiring less sample volume, not requiring sample preparation, easy equipment supply, easy application, fast results, no cross-reactivity with C3-epimer forms, and low user error are among the reasons why this method is used more widely in the world [97, 98]. Despite its widespread use, this method has some significant disadvantages. In this method, 25OHD2 and 25OHD3 cannot be distinguished and both are measured as total of 25OHD. This may lead to misinterpretation in countries that use ergocalciferol in treatment (eg America) [97]. In addition, automated immunoassay results can be affected by pregnancy, whether sampled from intensive care patients, the presence of chronic disease and liver diseases, all of which affect the amount of VDBP synthesized from the liver [99, 100]. In addition, it has been reported that there is a high probability of interferences involving automated immunoassay measurement methods [97, 101].
Due to the low reliability of immunoassay measurements, this method has begun to be replaced by LC–MS/MS, which is considered to be the “gold standard” method. This method is used in approximately 18% of laboratories around the world, and it is estimated that its prevalence will increase due to its more accurate and precise results [97]. This method provides distinguishing quantitative measurements of both 25OHD2 and 25OHD3 forms in both serum and plasma [102]. Hence, 25OHD2 can be easily monitored in countries where ergocalciferol is widely used. In addition, with this method, C-3 epimer forms of vitamin D, which are present in high levels in serum in the first year, can be separated from other forms, and these metabolites are prevented from causing vitamin D measurement interference [97, 102].
In recent years, instead of measuring the level of vitamin D bound to VDBP, there is a strong belief in the need to measure free vitamin D levels as that is the form that accounts for the principal bioactivity. Routine methods measure the level of 25OHD vitamin bound to VDBP and provide information about the total body pool. In parallel with this, if the total body pool is sufficient, free vitamin D level is estimated to be sufficient. However, the situation is somewhat complex in obese patients, where a negative correlation between the amount of adipose tissue and serum vitamin D levels has been reported. In these cases, it has been reported that serum 25OHD level is lower than those with normal body weight, since large adipose tissue creates a larger pool for vitamin D sequestration [101, 102, 103, 104, 105]. In other words, serum 25OHD level in obese patients may not provide information about the body pool of vitamin D. It is thought that it would be more valuable to measure vitamin D levels that are not bound to binding protein in these cases. However, there is a serious standardization problem in the measurement of free 25OHD [103]. Also, Bikle et al. [106] proposed a method by which free 25OHD vitamin can be calculated. However, studies have shown that the results obtained with this method are not reliable [107]. Finally, direct measurement or indirect calculations of free forms of vitamin D are not yet suitable for routine use.
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\n\nPolicy last updated: 2018-09-11
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These physiological events occur smoothly in normal healthy individual and/or under normal conditions. However, in certain cases, these molecular events are retarded resulting in hard-to-heal or chronic wounds arising from several factors such as poor venous return, underlying physiological or metabolic conditions such as diabetes as well as external factors such as poor nutrition. In most cases, such wounds are infected and infection also presents as another complicating phenomenon which triggers inflammatory reactions, therefore delaying wound healing. There has therefore been recent interests and significant efforts in preventing and actively treating wound infections by directly targeting infection causative agents through direct application of antimicrobial agents either alone or loaded into dressings (medicated). These have the advantage of overcoming challenges such as poor circulation in diabetic and leg ulcers when administered systemically and also require lower amounts to be applied compared to that required via oral or iv administration. This chapter will review and evaluate various antimicrobial agents used to target infected wounds, the means of delivery, and current state of the art, including commercially available dressings. Data sources will include mainly peer-reviewed literature, clinical trials and reports, patents as well as government reports where available.",book:{id:"5290",slug:"wound-healing-new-insights-into-ancient-challenges",title:"Wound Healing",fullTitle:"Wound Healing - New insights into Ancient Challenges"},signatures:"Omar Sarheed, Asif Ahmed, Douha Shouqair and Joshua Boateng",authors:[{id:"183108",title:"Dr.",name:"Joshua",middleName:null,surname:"Boateng",slug:"joshua-boateng",fullName:"Joshua Boateng"},{id:"183399",title:"Dr.",name:"Omar",middleName:null,surname:"Sarheed",slug:"omar-sarheed",fullName:"Omar Sarheed"},{id:"188082",title:"Mr.",name:"Asif",middleName:null,surname:"Ahmed",slug:"asif-ahmed",fullName:"Asif Ahmed"},{id:"188083",title:"Ms.",name:"Douha",middleName:null,surname:"Shouqair",slug:"douha-shouqair",fullName:"Douha Shouqair"}]},{id:"51825",doi:"10.5772/64611",title:"Roles of Matrix Metalloproteinases in Cutaneous Wound Healing",slug:"roles-of-matrix-metalloproteinases-in-cutaneous-wound-healing",totalDownloads:3629,totalCrossrefCites:20,totalDimensionsCites:39,abstract:"Wound healing is a complex process that consists of hemostasis and inflammation, angiogenesis, re-epithelialization, and tissue remodeling. Matrix metalloproteinases (MMPs) play important roles in wound healing, and their dysregulation leads to prolonged inflammation and delayed wound healing. There are 24 MMPs in humans, and each MMP exists in three forms, of which only the active MMPs play a role in the pathology or repair of wounds. The current methodology does not distinguish between the three forms of MMPs, making it challenging to investigate the roles of MMPs in pathology and wound repair. We used a novel MMP-inhibitor-tethered affinity resin that binds only the active form of MMPs, from which we identified and quantified active MMP-8 and active MMP-9 in a murine diabetic model with delayed wound healing. We showed that up-regulation of active MMP-9 plays a detrimental role whereas active MMP-8 is involved in repairing the wound in diabetic mice. These studies identified MMP-9 as a novel target for therapeutic intervention in the treatment of chronic wounds. A selective inhibitor of MMP-9 that leaves MMP-8 unaffected would provide the most effective therapy and represents a promising strategy for therapeutic intervention in the treatment of diabetic foot ulcers.",book:{id:"5290",slug:"wound-healing-new-insights-into-ancient-challenges",title:"Wound Healing",fullTitle:"Wound Healing - New insights into Ancient Challenges"},signatures:"Trung T. Nguyen, Shahriar Mobashery and Mayland Chang",authors:[{id:"183405",title:"Prof.",name:"Mayland",middleName:null,surname:"Chang",slug:"mayland-chang",fullName:"Mayland Chang"},{id:"191152",title:"Mr.",name:"Trung",middleName:null,surname:"Nguyen",slug:"trung-nguyen",fullName:"Trung Nguyen"},{id:"191153",title:"Prof.",name:"Shahriar",middleName:null,surname:"Mobashery",slug:"shahriar-mobashery",fullName:"Shahriar Mobashery"}]},{id:"63675",doi:"10.5772/intechopen.81208",title:"Wound Healing: Contributions from Plant Secondary Metabolite Antioxidants",slug:"wound-healing-contributions-from-plant-secondary-metabolite-antioxidants",totalDownloads:1331,totalCrossrefCites:7,totalDimensionsCites:20,abstract:"Plants by their genetic makeup possess an innate ability to synthesize a wide variety of phytochemicals that help them to perform their normal physiological functions and/or to protect themselves from microbial pathogens and animal herbivores. The synthesis of these phytochemicals presents the plants their natural tendency to respond to environmental stress conditions. These phytochemicals are classified either as primary or secondary metabolites. The secondary metabolites have been identified in plants as alkaloids, terpenoids, phenolics, anthraquinones, and triterpenes. These plant-based compounds are believed to have diverse medicinal properties including antioxidant properties. Plants have therefore been a potential source of antioxidants which have received a great deal of attention since increased oxidative stress has been identified as a major causative factor in the development and progression of several life-threatening diseases, including neurodegenerative and cardiovascular diseases and wound infection. Consequently, many medicinal plants have been cited and known to effect wound healing and antioxidant properties. This chapter briefly reviews antioxidant properties of medicinal plants to highlight the important roles medicinal plants play in wound healing.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Victor Y.A. Barku",authors:[{id:"261027",title:"Prof.",name:"Victor Y. A.",middleName:null,surname:"Barku",slug:"victor-y.-a.-barku",fullName:"Victor Y. A. Barku"}]},{id:"66793",doi:"10.5772/intechopen.85020",title:"The Impact of Biofilm Formation on Wound Healing",slug:"the-impact-of-biofilm-formation-on-wound-healing",totalDownloads:1434,totalCrossrefCites:7,totalDimensionsCites:16,abstract:"Chronic wounds represent an important challenge for wound care and are universally colonized by bacteria. These bacteria can form biofilm as a survival mechanism that confers the ability to resist environmental stressors and antimicrobials due to a variety of reasons, including low metabolic activity. Additionally, the exopolymeric substance (EPS) contained in biofilm acts as a mechanical barrier to immune system cells, leading to collateral damage in the surrounding tissue as well as chronic inflammation, which eventually will delay healing of the wound. This chapter will discuss current knowledge on biofilm formation, its presence in acute and chronic wounds, how biofilm affects antibiotic resistance and tolerance, as well as the wound healing process. We will also discuss proposed methods to eliminate biofilm and improve wound healing despite its presence, including basic science and clinical studies regarding these matters.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Rafael A. Mendoza, Ji-Cheng Hsieh and Robert D. Galiano",authors:[{id:"253607",title:"M.D.",name:"Rafael",middleName:null,surname:"Mendoza",slug:"rafael-mendoza",fullName:"Rafael Mendoza"},{id:"254018",title:"Dr.",name:"Robert",middleName:null,surname:"Galiano",slug:"robert-galiano",fullName:"Robert Galiano"},{id:"271116",title:"Mr.",name:"Ji-Cheng",middleName:null,surname:"Hsieh",slug:"ji-cheng-hsieh",fullName:"Ji-Cheng Hsieh"}]},{id:"63086",doi:"10.5772/intechopen.80215",title:"Medicinal Plants in Wound Healing",slug:"medicinal-plants-in-wound-healing",totalDownloads:2901,totalCrossrefCites:7,totalDimensionsCites:15,abstract:"Wound healing process is known as interdependent cellular and biochemical stages which are in trying to improve the wound. Wound healing can be defined as stages which is done by body and delayed in wound healing increases chance of microbial infection. Improved wound healing process can be performed by shortening the time needed for healing or lowering the inappropriate happens. The drugs were locally or systemically administrated in order to help wound healing. Antibiotics, antiseptics, desloughing agents, extracts, etc. have been used in order to wound healing. Some synthetic drugs are faced with limitations because of their side effects. Plants or combinations derived from plants are needed to investigate identify and formulate for treatment and management of wound healing. There is increasing interest to use the medicinal plants in wound healing because of lower side effects and management of wounds over the years. Studies have shown that medicinal plants improve wound healing in diabetic, infected and opened wounds. The different mechanisms have been reported to improve the wound healing by medicinal plants. In this chapter, some medicinal plants and the reported mechanisms will be discussed.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Mohammad Reza Farahpour",authors:[{id:"253340",title:"Prof.",name:"Mohammadreza",middleName:null,surname:"Farahpour",slug:"mohammadreza-farahpour",fullName:"Mohammadreza Farahpour"}]}],mostDownloadedChaptersLast30Days:[{id:"55736",title:"Haemodynamic Monitoring in the Intensive Care Unit",slug:"haemodynamic-monitoring-in-the-intensive-care-unit",totalDownloads:3369,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Monitoring is a cognitive aid that allows clinicians to detect the nature and extent of pathology and helps assessment of response to therapy. The cardiovascular system is the most commonly monitored organ system in the critical care setting. It helps identify the presence and nature of shock and guides response to resuscitation by detection of cardiac rate and rhythm, evaluation of volume state, cardiac contractility and systemic vascular resistance. Newer technologies allow greater assessment of oxygen delivery to vulnerable tissues. We discuss the nature, history, modalities and interpretation of the most commonly available haemodynamic monitoring methods in clinical use currently.",book:{id:"5756",slug:"intensive-care",title:"Intensive Care",fullTitle:"Intensive Care"},signatures:"Mainak Majumdar",authors:[{id:"86678",title:"Dr.",name:"Mainak",middleName:null,surname:"Majumdar",slug:"mainak-majumdar",fullName:"Mainak Majumdar"}]},{id:"51825",title:"Roles of Matrix Metalloproteinases in Cutaneous Wound Healing",slug:"roles-of-matrix-metalloproteinases-in-cutaneous-wound-healing",totalDownloads:3628,totalCrossrefCites:20,totalDimensionsCites:37,abstract:"Wound healing is a complex process that consists of hemostasis and inflammation, angiogenesis, re-epithelialization, and tissue remodeling. Matrix metalloproteinases (MMPs) play important roles in wound healing, and their dysregulation leads to prolonged inflammation and delayed wound healing. There are 24 MMPs in humans, and each MMP exists in three forms, of which only the active MMPs play a role in the pathology or repair of wounds. The current methodology does not distinguish between the three forms of MMPs, making it challenging to investigate the roles of MMPs in pathology and wound repair. We used a novel MMP-inhibitor-tethered affinity resin that binds only the active form of MMPs, from which we identified and quantified active MMP-8 and active MMP-9 in a murine diabetic model with delayed wound healing. We showed that up-regulation of active MMP-9 plays a detrimental role whereas active MMP-8 is involved in repairing the wound in diabetic mice. These studies identified MMP-9 as a novel target for therapeutic intervention in the treatment of chronic wounds. A selective inhibitor of MMP-9 that leaves MMP-8 unaffected would provide the most effective therapy and represents a promising strategy for therapeutic intervention in the treatment of diabetic foot ulcers.",book:{id:"5290",slug:"wound-healing-new-insights-into-ancient-challenges",title:"Wound Healing",fullTitle:"Wound Healing - New insights into Ancient Challenges"},signatures:"Trung T. Nguyen, Shahriar Mobashery and Mayland Chang",authors:[{id:"183405",title:"Prof.",name:"Mayland",middleName:null,surname:"Chang",slug:"mayland-chang",fullName:"Mayland Chang"},{id:"191152",title:"Mr.",name:"Trung",middleName:null,surname:"Nguyen",slug:"trung-nguyen",fullName:"Trung Nguyen"},{id:"191153",title:"Prof.",name:"Shahriar",middleName:null,surname:"Mobashery",slug:"shahriar-mobashery",fullName:"Shahriar Mobashery"}]},{id:"63086",title:"Medicinal Plants in Wound Healing",slug:"medicinal-plants-in-wound-healing",totalDownloads:2898,totalCrossrefCites:7,totalDimensionsCites:15,abstract:"Wound healing process is known as interdependent cellular and biochemical stages which are in trying to improve the wound. Wound healing can be defined as stages which is done by body and delayed in wound healing increases chance of microbial infection. Improved wound healing process can be performed by shortening the time needed for healing or lowering the inappropriate happens. The drugs were locally or systemically administrated in order to help wound healing. Antibiotics, antiseptics, desloughing agents, extracts, etc. have been used in order to wound healing. Some synthetic drugs are faced with limitations because of their side effects. Plants or combinations derived from plants are needed to investigate identify and formulate for treatment and management of wound healing. There is increasing interest to use the medicinal plants in wound healing because of lower side effects and management of wounds over the years. Studies have shown that medicinal plants improve wound healing in diabetic, infected and opened wounds. The different mechanisms have been reported to improve the wound healing by medicinal plants. In this chapter, some medicinal plants and the reported mechanisms will be discussed.",book:{id:"7046",slug:"wound-healing-current-perspectives",title:"Wound Healing",fullTitle:"Wound Healing - Current Perspectives"},signatures:"Mohammad Reza Farahpour",authors:[{id:"253340",title:"Prof.",name:"Mohammadreza",middleName:null,surname:"Farahpour",slug:"mohammadreza-farahpour",fullName:"Mohammadreza Farahpour"}]},{id:"67217",title:"Nursing Implications in the ECMO Patient",slug:"nursing-implications-in-the-ecmo-patient",totalDownloads:2528,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Effective care and positive outcomes of the extracorporeal membrane oxygenation (ECMO) patient necessitate optimal interdisciplinary management from the healthcare team, including expert care from specially trained registered nurses (RNs). It is incumbent upon the RN caring for the ECMO patient to excel in both time management and assessment skills, as this population often demands care delivery at the pinnacle of intensive care unit (ICU) acuity. Astute and nuanced monitoring of neurological status, bleeding risk with potential (often massive) transfusions, poor hemodynamics, and integrity of the ECMO pump itself are only the few specialized areas of focus that must share priority with traditional nursing considerations involving the critically ill, such as prevention of pressure injuries and bloodstream infections. These high-intensity medical foci must be balanced with ethical considerations, as the ultimate goal of returning the patient to their normal life is not always possible. These demands highlight the dynamic proficiency of the RN caring for the ECMO patient. The following chapter will highlight the importance of specialized nursing care in the critically ill patient supported with ECMO.",book:{id:"7878",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",title:"Advances in Extracorporeal Membrane Oxygenation",fullTitle:"Advances in Extracorporeal Membrane Oxygenation - Volume 3"},signatures:"Alex Botsch, Elizabeth Protain, Amanda R. Smith and Ryan Szilagyi",authors:[{id:"298623",title:"Mr.",name:"Alexander",middleName:null,surname:"Botsch",slug:"alexander-botsch",fullName:"Alexander Botsch"}]},{id:"66239",title:"Echocardiography Evaluation in ECMO Patients",slug:"echocardiography-evaluation-in-ecmo-patients",totalDownloads:2184,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Extracorporeal membrane oxygenation (ECMO) is a special form of organ support for selected cases of cardiovascular and severe respiratory failure. Echocardiography is a diagnostic and monitoring tool widely used in all aspects of ECMO support. The pathophysiology of ECMO, and its distinct effects on cardiorespiratory physiology, requires an echocardiographer with high skills to understand the interaction between the ECMO and the patient. In this chapter, we present the main application of echocardiography in ECMO patients and some general concepts on the ECMO working. ECMO, such as the standard cardiopulmonary bypass employed in cardiac surgery, V-V (veno-venous), can support the insufficient respiratory system by oxygenating and removing carbon dioxide from the blood. VA-ECMO (venous-arterial) can support haemodynamics by providing mechanical circulatory assistance. Today, ECMO can be used as bridge to decision, waiting for the development of the clinical conditions to support with other devices the evolution of cardiorespiratory failure or stop the assistance. Echocardiography (transthoracic (TTE) or transoesophageal (TOE)) can be used primarily to take decisions regarding appropriateness of ECMO support, therefore to control cannula insertion and confirm final position, to modify number and position of the cannulae in case of malfunctioning of these, and, finally, to assess clinical progress and suitability for weaning from ECMO.",book:{id:"7878",slug:"advances-in-extracorporeal-membrane-oxygenation-volume-3",title:"Advances in Extracorporeal Membrane Oxygenation",fullTitle:"Advances in Extracorporeal Membrane Oxygenation - Volume 3"},signatures:"Luigi Tritapepe, Ernesto Greco and Carlo Gaudio",authors:[{id:"284893",title:"Prof.",name:"Luigi",middleName:null,surname:"Tritapepe",slug:"luigi-tritapepe",fullName:"Luigi Tritapepe"},{id:"294005",title:"Prof.",name:"Ernesto",middleName:null,surname:"Greco",slug:"ernesto-greco",fullName:"Ernesto Greco"},{id:"294006",title:"Prof.",name:"Carlo",middleName:null,surname:"Gaudio",slug:"carlo-gaudio",fullName:"Carlo Gaudio"}]}],onlineFirstChaptersFilter:{topicId:"173",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:332,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:142,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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His present research includes organic synthesis, drug discovery and development, biochemistry, nanoscience, and nanotechnology.",institutionString:"Visiting Scientist at Lipid Nanostructures Laboratory, Centre for Smart Materials, School of Natural Sciences, University of Central Lancashire",institution:null},{id:"428125",title:"Dr.",name:"Vinayak",middleName:null,surname:"Adimule",slug:"vinayak-adimule",fullName:"Vinayak Adimule",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428125/images/system/428125.jpg",biography:"Dr. Vinayak Adimule, MSc, Ph.D., is a professor and dean of R&D, Angadi Institute of Technology and Management, India. He has 15 years of research experience as a senior research scientist and associate research scientist in R&D organizations. He has published more than fifty research articles as well as several book chapters. He has two Indian patents and two international patents to his credit. Dr. Adimule has attended, chaired, and presented papers at national and international conferences. He is a guest editor for Topics in Catalysis and other journals. He is also an editorial board member, life member, and associate member for many international societies and research institutions. His research interests include nanoelectronics, material chemistry, artificial intelligence, sensors and actuators, bio-nanomaterials, and medicinal chemistry.",institutionString:"Angadi Institute of Technology and Management",institution:null},{id:"284317",title:"Prof.",name:"Kantharaju",middleName:null,surname:"Kamanna",slug:"kantharaju-kamanna",fullName:"Kantharaju Kamanna",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284317/images/21050_n.jpg",biography:"Prof. K. Kantharaju has received Bachelor of science (PCM), master of science (Organic Chemistry) and Doctor of Philosophy in Chemistry from Bangalore University. He worked as a Executive Research & Development @ Cadila Pharmaceuticals Ltd, Ahmedabad. He received DBT-postdoc fellow @ Molecular Biophysics Unit, Indian Institute of Science, Bangalore under the supervision of Prof. P. Balaram, later he moved to NIH-postdoc researcher at Drexel University College of Medicine, Philadelphia, USA, after his return from postdoc joined NITK-Surthakal as a Adhoc faculty at department of chemistry. Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a scientist and Principal Investigator at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering the lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via artificial intelligence-based analyses of exosomal Raman signatures. Dr. Paul also works on spatial multiplex immunofluorescence-based tissue mapping to understand the immune repertoire in lung cancer. Dr. Paul has published in more than sixty-five peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award and the 2022 AAISCR-R Vijayalaxmi Award for Innovative Cancer Research. He is a senior member of the Institute of Electrical and Electronics Engineers (IEEE) and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. 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