Products obtained from the biotransformation of artemisinin (1) by different microorganisms.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Microbial transformation is regarded as an enzymatic reaction by using the metabolic activities of microorganisms to modify the chemical structures of bioactive substrates for finding the new chemical derivatives with the potent bioactivities and physical-chemical characteristics. It has a number of advantages over chemical synthesis such as higher stereo- and regioselectivity but is also enantiospecific, allowing the production of chiral products from racemic mixtures. The conditions for biotransformations are mild, and in the majority of cases, they do not require the protection of pre-existing functional groups. Furthermore, some reactions that do not occur when using chemical approaches are easily carried out by microbial transformation. Microbial factories show advantages, for instance, growing rapidly and ease of large-scale production [1, 2, 3].
The use of microorganisms may be a highly efficient method of production of these compounds. The reactions involved in biotransformation of organic compounds by whole cells of various microorganisms include oxidation, reduction, hydroxylation, esterification, methylation, demethylation, isomerization, hydrolysis, glycosylation, and hydrogenation [4, 5].
Biotransformation may be carried out with isolated enzyme systems or with intact organism. Although isolated enzyme systems may be more specific and efficient for certain biotransformation, these reactions may involve isolating the enzyme system, and, for some classes of enzyme-catalyzed reaction, a recycling sequence may be required to regenerate the enzyme [6].
Fungi are playing a prominent role in the catalysis of organic compounds and in the production of commercially and industrially important compounds, because of their ability to catalyze novel reactions [7]. Fungi are commonly used in the industry for production of fermented beverages, foods, physiologically active substances, solvents, organic acids, polysaccharides, antibiotics, etc. Of the zygomycota, Mucor and Rhizopus are commonly used in the industry. Rhizopus strains are important in citric acid production. Mucor strains make a significant number of important lipases and catalyze the hydroxylation of a wide range of chemical compounds [2, 3, 4].
The use of the microbial model offers a number of advantages over the use of animals in metabolism studies, mainly: (1) simple, easy, and can be prepared at low cost; (2) screening for a large number of strains is a simple repetitive process; (3) the large number of metabolites formed allows easier detection, isolation, and structural identification; (4) newer metabolites can be isolated; (5) utilized for synthetic reactions involving many steps; (6) useful in cases where regio- and stereospecificity is required; (7) maintenance of stock cultures of microorganisms is simpler and cheaper than the maintenance of cell or tissue cultures or laboratory animals; (8) ease of setup and manipulation; and (9) more reliable and reproducible [8, 9].
The objective of this review is to highlight the importance of microorganisms or enzymes isolated from them in the biotransformation process of natural products or xenobiotic compounds, according to green chemistry or white biotechnology.
Artemisinin (1), a sesquiterpene lactone endoperoxide and an antimalarial drug, is effective against chloroquine-resistant parasites; but its toxicities and low solubility in water hamper its therapeutical use. Studies on modification of 1 through biological and chemical methodologies have been reported to yield more effective and water-soluble derivatives. A wide array of microbial transformations of 1 involve oxidation, reduction, and degradation reactions by different microorganisms, such as Aspergillus niger, A. flavus, A. adametzi (ATCC 10407), Cunninghamella echinulata, Caenorhabditis elegans, Mucor polymorphous, M. rammanianus, Streptomyces griseus, Penicillium simplicissimum, P. chrysogenum, P. purpuresceus, Pestalotiopsis guepini (P-8), Eurotium amstelodami, Trichoderma viride (T-58), Saccharomyces cerevisiae, and Pichia pastoris. Biotransformation of 1 usually includes the processes such as hydroxylation of methyl, methine and methylene groups, deoxidation reactions, hydration and acetylation reactions, epimerization, and breakdown of heterocyclic rings (Table 1).
Microorganism | Products | Action | Reference |
---|---|---|---|
A. niger | 3β-hydroxy-4,12-epoxy-1-deoxyartemisinin Artemisinin G 3,13-epoxyartemisinin 4α-hydroxy-1-deoxyartemisinin | Epoxidation, hydroxylation C-3β site Endoperoxide function reduction Breakdown of heterocyclic rings Epoxidation C-3 and C-13 Hydroxylation C-4, endoperoxide function reduction | [10] |
A. flavus (MTCC 9167) | 14-hydroxyartemisinin Artemisinin G 4α-hydroxydeoxyartemisinin Deoxyartemisinin | Hydroxylation of C-14 site Breakdown of heterocyclic rings Hydroxylation of C-4α site Endoperoxide function reduction | [11, 12] |
C. elegans (ATCC 9245) | 7β-hydroxy-9α-artemisinin 4α-hydroxy-1-deoxoartemisinin 7β-hydroxyartemisinin 6β-hydroxyartemisinin 7α-hydroxyartemisinin 6β,7α-dihydroxyartemisinin | Hydroxylation C-7β site Epimerization C-9 Hydroxylation C-4α site Hydroxylation C-7β site Hydroxylation C-6β site Hydroxylation C-7α site Hydroxylation C-6β and C-7α sites | [13, 14] |
P. simplicissimum | 9β-acetoxyartimisinin 9α-hydroxyartemisinin | Acetylation of C-9β site Hydroxylation of C-9α site | [15] |
R. stolonifer | Deoxyartemisinin 1α-hydroxyartemisinin 10β-hydroxyartemisinin | Endoperoxide function reduction Hydroxylation of C-1 site | [16] |
S. griseus (ATCC 13273) | 9-artemisitone 9α-hydroxyartemisinin 9β-hydroxyartemisinin 3α-hydroxyartemisinin | Oxidation of C-9 site Hydroxylation of C-9α site Hydroxylation of C-9β site Hydroxylation of C-3α site | [17] |
N. corallina | Deoxyartemisinin | Endoperoxide function reduction | [11] |
Products obtained from the biotransformation of artemisinin (1) by different microorganisms.
Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid, UA, 2), a natural pentacyclic triterpene, is broadly used in food, cosmetics, and biomedical industries. As a ubiquitous constituent in the plant kingdom and the major component of many traditional medicine herbs, ursolic acid remarkably exhibits a lot of biological activities, such as antibacterial, anti-allergic, antioxidative, anti-inflammation, and antitumor activities [18].
Microbial transformation of ursolic acid (2) by Bacillus megaterium CGMCC 1.1741 yielded five metabolites identified as 3-oxo-urs-12-en-28-oic acid (3, 6.2%); 1β,11α-dihydroxy-3-oxo-urs-12-en-28-oic acid (4, 13.5%); 1β-hydroxy-3-oxo-urs-12-en-28,13-lactone (5, 5.0%); 1β,3β,11α-trihydroxy-urs-12-en-28-oic acid (6, 26.9%); and 1β,11α-dihydroxy-3-oxo-urs-12-en-28-O-β-
Biotransformation of UA by S. racemosum (3.2500) yielded five metabolites 3β,7β,21β-trihydroxy-urs-12-en-28-oic acid (22); 3β,21β-dihydroxy-urs-11-en-28-oic acid-13-lactone (23); 1β,3β,21β-trihydroxy-urs-12-en-28-oic acid (24); 3β,7β,21β-trihydroxy-urs-1-en-28-oic acid-13-lactone (25); and 1β,3β-dihydroxy-urs-12-en-21-oxo-28-oic acid (26) which were afforded [22]. Additionally, of the biotransformation of 2 with by S. racemosum compounds 27–30 and 11,26-epoxy-3β-21β-dihydroxy-urs-12-en-28-oic acid were obtained (31), (Figure 1) [23].
Biotransformation products of ursolic acid (2).
The endophytic fungi Pestalotiopsis microspora isolated from medical plant Huperzia serrata can transform 1 to afforded 3-oxo-15β,30-dihydroxy-urs-12-en-28-oic acid (32), 3β,15β-dihydroxy-urs-12-en-28-oic acid (33), 3β,15β,30-trihydroxy-urs-12-en-28-oic acid (34), and 30 [24].
Microbial transformation of ursolic acid by Mucor spinosus AS 3.3450 were isolated and their structures were identified as 9, 22 and 3β,7β-dihydroxy-ursolic acid-28-ethanone (35) (Figure 1) [25].
Biotransformation products of 11-keto-b-boswellic acid (36).
The gum resin Boswellia serrata has been used for the treatment of inflammatory and arthritic diseases. Its major active constituents are ursane triterpenoids, which include 11-keto-β-boswellic acid (KBA, 36), β-boswellic acid (BA), and acetyl-β-boswellic acid (ABA). Microbial transformation 36 by Cunninghamella blakesleeana (AS 3.970) yielded ten regioselective transformed products: 7β-hydroxy-11-keto-β-boswellic acid (37), 7β,15α-dihydroxy-11-keto-β-boswellic acid (38), 7β,16β-dihydroxy-11-keto-β-boswellic acid (39), 7β,16α-dihydroxy-11-keto-β-boswellic acid (40), 7β,22β-dihydroxy-11-keto-β-boswellic acid (41), 7β,21β-dihydroxy-11-keto-β-boswellic acid (42), 7β,20β-dihydroxy-11-keto-β-boswellic acid (43), 7β,30-dihydroxy-11-keto-β-boswellic acid (44), 3α,7β-dihydroxy-11-oxours-12-en,24,30-dioic acid (45), and 3α,7β-dihydroxy-30-(2-hydroxypropanoyloxy)-11-oxours-12-en, 24-oic acid (46). Bioconversion of 36 with Bacillus megaterium based on a recombinant cytochrome P450 system yielded regio- and stereoselective 15α-hydroxylation (47) of substrate (Figure 2) [26].
Biotransformation products of 18β-glycyrrhetinic acid (48).
18β-glycyrrhetinic acid (48) is the active form of glycyrrhizin which is the major pentacyclic triterpene found in licorice (Glycyrrhiza glabra L.). Glycyrrhetinic acid has been shown to possess several pharmacological activities, such as antiulcerative, anti-inflammatory, immunomodulating, antitumor, antiviral, antihepatitis effects, and anticancer. Biotransformation 48 with a fungus C. blakesleeana (AS 3.970) yielded 3-oxo-7β-hydroxyglycyrrhetinic acid (49) and 7β-hydroxyglycyrrhetinic acid (50) [27], while of 48 using Absidia pseudocylindrospora (ATCC 24169), Gliocladium viride (ATCC 10097) and Cunninghamella echinulata (ATCC 8688a) afforded seven derivatives: 51, 52, 7β,15α-dihydroxy-18β-glycyrrhetinic acid (53), 15α-hydroxy-18β-glycyrrhetinic acid (54), 1α-hydroxy-18β-glycyrrhetinic acid (55) and 13β-hydroxy-7α,27-oxy-12-dihydro-18β-glycyrrhetinic acid (56), and the epimer of compound 53 on C-17 (Figure 3) [28].
Triterpenic acid: ginsenoside Rb1 (61), oleanolic acid (62), betulinic (63) and betulonic acid (64).
Ginsenoside Rb1 (61) is the most predominant protopanaxadiol-type ginsenoside in Panax species (ginseng). Several microbial transformations of this substrate (Ginsenoside Rb1) have been accomplished with an ample and varied group of microorganisms, all of these having β-glucosidase activities. Deglycosylation appears to be the major transformation pathway, and the intermediate and the final hydrolysis products of 61 depended on the microorganisms used. The biotransformation of various triterpenes, such as 61–64, has been described in the literature. For each triterpenoid, the transforming microorganism together with the type and site of the reaction catalyzed is given in Table 2 (Figure 4) [29].
Triterpenoid | Microorganism | Reaction | Reference |
---|---|---|---|
Ginsenoside Rb1 (61) | A. niger (KTC 6909) | Deglycosylation at the C-3 and C-20 sites | [30] |
A. niger (AS 3.1858) | Deglycosylation at the C-3 and C-20 sites | [30] | |
A. usamii (KTC 6956) | Deglycosylation at the C-3 and C-20 sites | [30] | |
F. sacchari | Deglycosylation at the C-3 and C-20 sites | [31] | |
P. oxalicum | Deglycosylation at the C-3 site | [32] | |
C. lunata (AS 3.1109) | Deglycosylation at the C-20 site, hydration Δ24(25) Formation of tertiary alcohol | [33] | |
R. stolonifer (AS 3.822) | Deglycosylation at the C-3 and C-20 sites | [33] | |
Oleanolic acid (62) | C. blakesleeana | Diverse hydroxylation at the C-1β, C-7β, C-13β sites | [4] |
F. lini | Dehydrogenation C-13 and C-18. oleanderolide formation | [4] | |
P. chrysogenum | Hydroxylation on C-21. Oxidation of the hydroxyl group in C-3 | [4] | |
C. phomoides | Hydroxylation in C-6β | [4] | |
A. ochraceus (NG 1203) | Hydroxylation in C-11α | [4] | |
Chaetomium longirostre | Oxidative ring A cleavage, hydroxylation at the C-21β sites | [34] | |
Nocardia sp. (NRRL 5646) | Methyl esterification of the C-28 carboxyl group | [4] | |
R. miehei (CECT 2749) | Hydroxylation of the C-7β, C-15α and C-30 sites Deshidrogenation Δ9(11) | [35] | |
Betulinic acid (63) | B. megaterium (ATCC 14581) | Dehydrogenation of the C-3 secondary alcohol group, hydroxylation at the C-6α and C-7β sites | [36] |
B. megaterium (ATCC 13368) | Dehydrogenation of the C-3 secondary alcohol group, hydroxylation at the C-7β and C-15α sites | [37] | |
C. elegans (ATCC 9244) | Hydroxylation at the C-1β and C-7β sites | [4] | |
Cunninghamella sp. | Introduction of a β-glucopyranosyl at the C-28 carboxylic acid group | [38] | |
Betulonic acid (64) | B. megaterium (ATCC 13368) | Ketone α-hydroxylation at the C-2 site | [37] |
Ch. longirostris | Oxidative ring A cleavage, hydroxylation, decarboxylation | [39] | |
C. lunata (ATCC 13432) | Hydroxylations at the C-7β and (or) C-15β sites | [4, 40] |
Examples of biotransformed triterpenes (61–64) with different microorganisms.
Biotransformation products of oleanolic acid (62), echnocystic acid (68) and betulinic acid (63).
Biotransformation of oleanolic acid (62) with Bacillus subtilis (ATCC 6633) resulted in five more polar metabolites as 28-O-β-
A C-3 oxidized derivative of oleanolic acid 73 (3-oxoolean-12-en-28-oic acid) was transformed by the Chaetomium longirostre (RF-1095) into 4-hydroxy-3,4-seco-olean-12-ene-3,28-dioic acid (74) and the corresponding 21-hydroxylated derivative (75). Analogous ring-A cleavage oxidation reactions have been observed in the biotransformation of triterpenoid substrates with the fungi Septomyxa affinis ATCC 6737 and Glomerella fusarioides ATCC 9552. (Figure 5) [4, 43].
Diosgenin [(25R)-spirost-5-en-3β-ol, 76] is an important natural starting material in the pharmaceutical industry to produce steroid drugs and hormones since the last century. In recent years, a wide array of new biological activities of 76 has been disclosed. Diosgenin was subjected to several structural modification studies to secure new derivatives via microbial transformation. Several microorganisms have been found to be capable of degrading 76, Bacillus megaterium, Corynebacterium mediolanum, Mycobacterium fortuitum, M. phlei, Nocardia rhodochrous, and F. solani. Three major products were accumulated, diosgenone (77), 1-dehydrodiosgenone (78), androst-4-en-3,17-dione (AD, 79), and androsta-1,4-diene-3,17-dione (ADD, 80) (Table 3) [44, 45]. In addition, two side-chain cleavage intermediates of 76 were produced by C. elegans and Aspergillus nidulans. Microbial transformation of 76 using white-rot fungus Coriolus versicolor afforded eight polyhydroxylated steroids, 7β-hydroxydiosgenin (81), (25R)-spirost-5-en-3β,7β,21-triol (82), (25R)-spirost-5-en-3β,7β,12β-triol (83), (25R)-spirost-5-en-3β,7α,15α,21-tetraol (84), (25R)-spirost-5-en-3β,7β,12β,21-tetraol (85), (25R)-spirost-5-en-3β,7α,12β,21-tetraol (86), and (25R)-spirost-5-en-3β,7β,11α,21-tetraol (87). The 3β-hydroxyl group and double bond in the B-ring of 76 were found to be important structural determinants for their activity [46].
Fungi | Diosgenona (77) | AD (79) | ADD (80) | Progesterone (102) | 16-AD |
---|---|---|---|---|---|
A. nidulans | ++ | ++ | ++ | ++ | |
C elegans | ++ | ++ | |||
F. solani | ++ | ++ | |||
Rhizopus sp. | ++ | ++ | ++ |
The ability of different fungi to transform diosgenin (76).
AD androst-4-ene-3,17-dione; ADD androsta1,4-diene-3,17-dione; 16-AD androst-4-ene-3,16-dione.
Microbial transformation of 76 using Cunninghamella blakesleeana AS 3.970 afforded polyhydroxylated derivatives, such as (25R)-spirost-5-en-3β,7α,12β-triol (88), (25R)-spirost-5-en-3β,7α,12β,15α,21-pentaol (89), (25R)-spirost-5-en-3β,7α,12β,18-tetraol (90), (25R)-spirost-5-en-3β,7α,12β,15α-tetraol (91), (25R)-spirost-5-en-3β,7α,11α,21-tetraol (92), (25R)-spirost-5-en-3β,7β,15α,21-tetraol (93), and (25R)-spirost-5-en-3β,7β,12β,18-tetraol (94) [47], specifically, the hydroxylation, ketonization, and methoxylation by Cunninghamella blakesleeana, C. elegans, Helicostylum piriforme, and Streptomyces virginiae, at C-7, C-9, C-11, C-12, and C-25 positions of 76. Biotransformation of 76 by Syncephalastrum racemosum afforded (25R)-spirost-5-en-3β,7α,9α-triol (95, 1%), (25R)-spirost-5-en-3β,9α,12α-triol-7-one (96, 2%), (25R)-spirost-5-en-3β,9α-diol-7,12-dione (97, 1.5%), (25R)-spirost-4-en-9α,12β,14α-triol-3-one (98, 0.66%), and (25S)-spirost-4-en-9α,14α,25β-triol-3-one (99, 0.66%) [48]. C. echinulata (CGMCC3.2716) metabolized 76 to afford 81 (0.9%), 83 (7.7%), (25R)-spirost-5-en-3β,7β-diol-11-one (100, 7, 1.5%), and (25R)-spirost-5-en-3β,7β,11α-triol (101, 6.2%) (Figure 6) [49].
Biotransformation products of diosgenin (76).
Microorganisms are able to hydroxylate steroids in different positions C-1 to C-21. These represent the most widespread type of steroid bioconversion carried out by fungi. The commercialized microbial process in the steroid field was in the production of 11α-hydroxyprogesterone. This process was realized for the first time by Peterson and Murray (1952), which patented this process of 11α-hydroxylation of progesterone (102) by Rhizopus species [50]. Microbial hydroxylation of 102 by A. griseola produced two hydroxylated pregnane identified as 6β,14α-dihydroxyprogesterone (103) and 7α,14α-dihydroxyprogesterone (104). R. pusillus produced 6β,11α-dihydroxyprogesterone (105) with excellent yield (65.5%) and 7α,14α-dihydroxyprogesterone (106) (Figure 7) [51].
Biotransformation products of progesterone (102).
Industry, which is carried by different microorganisms, such as different species of Curvularia spp., Cunninghamella spp. and fungi Trichoderma hamatum, Cochliobolus lunatus. Structural transformation of steroidal compounds through microorganisms has emerged as an important application in the steroidal drug industry. Microbial conversions of steroids generally involve dehydrogenation, esterification, halogenation, isomerization, methoxylation, and side-chain modification of steroidal skeleton. Recently, Mucor circinelloides lusitanicus transformed 5-en-3β-ol steroids (108 and 109) into di- and trihydroxy products. The compound 108 yielded 3β,7α,11α-trihydroxypregna-5-en-20-one (110, 46.4%), and 109 afforded 111 (3β,7α-dihydroxyandrost-5-en-17-one, 43.6%) (Figure 8) [52].
Biotransformation products of 5-en-3β-ol steroids.
Microbial transformation of (20S)-20-hydroxymethylpregna-1,4-dien-3-one (112) is by four filamentous fungi, Cunninghamella elegans (113–119), Macrophomina phaseolina (115, 117, 120–122), Rhizopus stolonifer (113, 123), and Gibberella fujikuroi (115–117, 123). These metabolites were obtained as a result of biohydroxylation of 112 at C-6β, 7β, 11α, 14α, 15β, 16β, and 17α positions (Figure 9) [53].
Biotransformation products of (20S)-20-hydroxymethylpregna-1, 4-dien-3-one (112).
The 11α-, 11β-, 15α, and 16α-hydroxylations are currently established processes in the steroid industry mainly for the production of adrenal cortex hormones and their analogues. 11α-, 11β-, and 16α-hydroxylations are usually performed using Rhizopus spp. or Aspergillus spp., Curvularia spp. or Cunninghamella spp. and Streptomyces spp., respectively (Figure 10) (Table 4) [54].
The ability of different microorganism to transform progesterone (102).
Hydroxylation sites | Microorganisms | Applications | Reference |
---|---|---|---|
C-7α | Fusarium sp., Gibberella sp., Nigrospora sp., Acremonium sp., Phycomyces sp. | Production of bile acids and drugs for neuropsychiatry and immunology | [55, 56] |
C-7β | Mortierella sp. | Obtaining drugs for prostate cancer | [56, 57] |
11β | Curvularia sp., Absidia sp., Cunninghamella sp., Trichoderma sp., Cochliobolus sp. | Obtaining anti-inflammatory drugs, like hydrocortisone, prednisone acetate, dexamethasone | [56, 57, 58, 59, 60] |
11α | Aspergillus sp., Rhizopus sp. | Obtaining of anti-inflammatory, immunosuppressive, anti-allergic drugs, and production of contraceptive drugs | [56, 61] |
14α | Mucor sp. | [56] | |
15β | Bacillus sp. | [56, 62] | |
16α | Streptomyces sp. | [63, 64] |
Some examples of steroid hydroxylation reactions promoted by microorganisms and their applications.
Boldenone (124) is an important steroid hormone drug which is the derivative of testosterone. Biotransformation of 124 by Arthrobacter simplex and recombinant Pichia pastoris with 17β-hydroxysteroid dehydrogenase from Saccharomyces cerevisiae produces BD (124) from androst-4-ene-3,17-dione (79, AD) efficiently [65]. Many microorganisms such as Mucor racemosus, Nostoc muscorum, and Arthrobacter oxydans can utilize androst-1,4-diene-3,17-dione (80, ADD) as substrate to produce testosterone through 17β-carbonyl reduction reactions (Table 5). The ability of microorganisms to reduce 17-keto- to 17β-hydroxysteroids was evidenced for a wide variety of substrates and microorganisms of different taxonomy: bacteria, fungi, and yeast [54, 56, 57, 66].
Fungi | Yeast | Bacteria | |
---|---|---|---|
Actinomucor elegans Agaricus silvaticus A. pantherina A. spissa Armillaria mellea Corticium centrifugum Fusarium spp. Gibberella saubinetti Mucor spp. Penicillium spp. Aphanocladium album Aspergillus chevalieri A. flavus A. oryzae A. tamarii B. obtusa C. aphidicola Ceratocystis paradoxa C. lunatus Colletotrichum musae C. radicicola Exophiala jeanselmei var. lecaniicorni | Fusarium culmorum F. oxysporum var. cubense F. solani Mucor piriformis M. spinosus P. chrysogenum P. crustosum P. blakesleeanus R. stolonifer Septomyxa affinis T. piriforme Trichoderma viride Zygodesmus sp. | Candida albicans C. pelliculosa C. pseudotropicalis C. robusta C. tropicalis C. utilis Cryptococcus albidus C. laurentii C. tsukubaensis Debaryomyces hansenii D. kloeckeri D. nicotianae D. subglobosus D. vini Hansenula anomala H. califórnica H. schnegii H. suaveolens Kloeckera jensenii Saccharomyces carlsbergensis S. cerevisiae S. fragilis S. lactis S. oviformis S. turbidans S. validus Pichia farinosa P. membranaefaciens Torulopsis spp. Hortaea werneckii Phaeotheca triangularis P. herbarum P. ostreatus Rhodotorula aurantiaca R. mucilaginosa | B. stearothermophilus Bacteroides fragilis Brevibacterium sterolicum Clostridium paraputrificum Comamonas testosteroni Lactobacillus bulgaricus Mycobacterium spp. B. stearothermophilus Bacteroides fragilis Brevibacterium sterolicum Clostridium paraputrificum Comamonas testosteroni (syn. Pseudomonas testosteroni) Lactobacillus bulgaricus Pediococcus cerevisiae Sarcina lutea Staphylococcus aureus Streptomyces globisporus S. sphaeroides S. viridochromogenes S. hydrogenans S. lavendulae |
Reduction of the C-17 carbonyl group of steroids by (17βHSDs) different microorganisms.
The oxidation of 17β-hydroxyl group was observed along with hydroxylation of steroids at C5 (Penicillium crustosum, P. chrysogenum), C6 (Bacillus stearothermophilus, B. obtusa, P. blakesleeanus), C7 (α/β) (A. coerulea, Botrytis cinerea, B. obtusa, P. blakesleeanus, Rhizopus stolonifer), C10 (Absidia glauca), C11 (α/β) (A. coerulea, B. obtusa, Cephalosporium aphidicola, R. stolonifer), C12 (A. glauca, B. obtusa), C14 (Bacillus sp.), and C15 (A. glauca, Aspergillus fumigatus, B. obtusa) [54, 56, 57, 67, 68, 69]. The biotransformation of 79 with different microorganisms is shown. Compound 79 is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepiandrosterone (DHEA) [70]. DHEA is an endogenous steroid hormone. It functions as a metabolic intermediate in the biosynthesis of the androgen and estrogen sex steroids. Various microorganisms have had the ability to biotransform steroidal compounds such as AD (79) [54], DHEA (125) [54, 55, 70, 71, 72, 73, 76, 77, 80, 81], testosterone [54, 55, 74, 75, 76, 81], cortexolone (126) [78, 79], and prednisone (127) (Figure 11a–d) [54, 55, 82].
The ability of different fungi to transform DHEA (125), testosterone, cortexolone (126) and prednisone (127). (a) Hydroxilation of 3β-hydroxy-5-androsten-17-one (DHEA) by various microorganisms. (b) Reduction of C-17 and hydroxilation of testosterone by various microorganisms. (c) Hydroxylation of cortexolone (123) by various microorganisms. (d) Reduction and hydroxylation of prednisone (126) microorganisms.
Sclareolide (128) is a natural product isolated from several plant species which displays phytotoxic and cytotoxic activities against several human tumor cells lines. This compound has also been used as starting material for the synthesis of various bioactive products. Regarding the biotransformation of the 128 with different microorganisms, mono- (130, 131, 135, 140–142) and dihydroxylation (132–134, 136, 139, 143, 146), oxidation (129, 144), hydroxylation/oxidation (145), epimerization (137), and cyclization (138) products have been obtained [83]. The microbial transformation of 128 by Curvularia lunata yielded 3-ketoesclareolide (129), 1β-hydroxysclareolide (130), 3β-hydroxysclareolide (131), 1α,3β-dihydroxysclareolide (133), and 1β,3β-dihydroxysclareolide (134) [84]. The incubation of 128 with Cunninghamella elegans afforded 129, 131, 133, and 135–137 [85]. C blakesleeana metabolized 128 to afford 129, 135, 134, and 138–140. Biotransformation of 128 with C. echinulata yielded 5-hydroxysclareolide (141) and 7β-hydroxysclareolide (142) [86]. Fermentation of 148 with A. niger using a nutrient-rich culture medium yielded 141 and 144–146 (Figure 12) [83].
Biotransformation products of sclareolide (128).
As most important phytochemicals in food, the dietary flavonoids exert a wide range of benefits for human health. Recent researches have explored diverse biological and pharmacological activities of natural flavonoids—antioxidant activity, anti-inflammatory activity, anti-Alzheimer’s disease, antibacterial activity, antifungal activity, anti-HIV activity, anticoagulant activity, antileishmanial activity, and anti-obesity activity [87, 88, 89, 90, 91]. Microbial biotransformation strategies for production of flavonoids have attracted considerable interest because they allow yielding novel flavonoids, which do not exist in nature.
The main reactions during microbial biotransformation are hydroxylation, dehydroxylation, O-methylation, O-demethylation, glycosylation, deglycosylation, dehydrogenation, hydrogenation, C ring cleavage of the benzo-γ-pyrone system, cyclization, and carbonyl reduction. Cunninghamella, Penicillium, and Aspergillus strains are very popular to biotransform flavonoids, and they can perform almost all the reactions with excellent yields (Figure 13). Isoflavones are usually hydroxylated at the C-3′ position of the B ring by microorganisms. Chalcones 147-152 were regioselectively cyclized to flavanones (Figure 14). Hydrogenation of flavonoids was only reported on transformation of chalcones to dihydrochalcones (Figure 14) [92, 93].
The main reactions during biotransformation of chalcone whit microorganisms.
Biotransformation products obtained from biotransformation of chalcones 147-152 with A. niger.
Aspergillus niger is one of the most applied microorganisms in the flavonoids’ biotransformation; for example, A. niger can transfer flavanone to flavan-4-ol, 2′-hydroxydihydrochalcone, flavone, 3-hydroxyflavone, 6-hydroxyflavanone, and 4′-hydroxyflavanone. The hydroxylation of flavones by microbes usually happens on the ortho position of the hydroxyl group on the A ring and C-4′ position of the B ring, and microbes commonly hydroxylate flavonols at the C-8 position. Natural flavonoids, such as naringenin (166), hesperetin (167), chrysin (168), apigenin (169), and luteolin (170) were subjected to microbiological transformations by Rhodotorula glutinis (KCh 735). Yeast was able to regioselectively C-8 hydroxylate 167, 168, 169, and 170 to generate 171 (17%), 172 (31%), 173 (12.9%), and 174 (25%), respectively. Naringenin (166) was transformed to carthamidin (175) and isocarthamidin (176) in a ratio of 1:19, respectively (Figure 15) [94].
Biotransformation products of flavanone (166, 167) and flavone (168–170).
The microorganisms tend to hydroxylate flavanones at the C-5, 6, and 4′ positions; however, for prenylated flavanones, dihydroxylation often takes place on the Δ4(5) double bond on the prenyl group (the side chain of A ring), although cyclization of the prenyl group to dihydrofurane derivatives is rather common biotransformation pathway of prenylated flavonoids. Prenylated flavanones are a unique class of naturally occurring flavonoids characterized by the presence of a prenylated side chain (prenyl, geranyl) in the flavonoid skeleton [95]. The prenyl chain generally refers to the 3,3-dimethylallyl substituent (3,3-DMA), geranyl and lavandulyl. It is proposed that the prenyl-moiety makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation brings the flavonoids with enhancement of antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal, as well as estrogenic activities. Figure 16 demonstrated the microbial biotransformation of kurarinone (177) using C. echinulata and C. militaris [96, 97].
Microbial biotransformation of kurarinone (177) using C. echinulate and C. militaris.
Incubation of Absidia coerulea (AM93) with prenylnaringenin (178) led to metabolite 179 (8-prenylnaringenin 7-O-β-
Biotransformation products of prenylnaringenin (178).
Regioselective glycosylation of biologically active flavonoid aglycones catalyzed by microorganisms is an interesting and desired reaction, which significantly increases the water solubility of the compound and, therefore, may improve bioavailability of flavonoids. Absidia glauca AM177, A. coerulea AM93, Rhizopus nigricans UPF701, Beauveria bassiana AM278, and B. bassiana AM446 are able to conjugate sugar moiety to chalcones, flavanones, and isoflavanones with high regioselectivity. Therefore, it is possible to use Beauveria and Absidia for the microbial transformation of simple or prenylated flavonoids by glycosidation reactions [97, 99].
Bavachinin (182) is one kind compound of flavanones and isolated from the aerial parts and dried fruits of Psoralea corylifolia, and bavachinin displays a broad range of biological activities, such as antioxidant, antibacterial, antifungal, anti-inflammatory, antitumor, anti-pyretic, and analgesic properties [100, 101]. Bavachinin (182) was subject to biotransformation by cultured cells of A. flavus (ATCC 30899); C. elegans (CICC 40250) afforded the same product 183 [(S)-6-((R)-2,3-dihydroxy-3-methylbutyl)-2-(4-hydroxyphenyl)-7-methoxychromen-4-one]. On the other hand, one major product 184 [(2S,4R)-2-(4-hydroxyphenyl)-7-methoxy-6-(3-methylbut-2-en-1-yl)-chromen-4-ol] was obtained by P. raistrickii (ATCC 10490) by the reduction at the position of ketone group of the C-ring (Figure 18) [102].
Biotransformation products of bavachinina (182).
The biotransformation of xanthohumol (185), a prenylated chalcone isolated from hops by selected fungi, Absidia coerulea (AM93), Rhizopus nigricans (UPF701), Mortierella mutabilis (AM404), and Beauveria bassiana (AM446), was investigated. The incubation of A. coerulea with 185 resulted in the isolation of xanthohumol 4′-O-β-
Biotransformation products of xanthohumol (185).
2″-(2″-hydroxyisopropyl)-dihydrofurano-[4″,5″:3′,4′]-4,2′-dihydroxy-6′-methoxychalcone (190), mixture of diastereoisomers of (2S, 2″S) and (2S, 2″R) 2″-(2″-hydroxyisopropyl)-dihydrofurano-[4″,5″:7,8]-4′-hydroxy-5-methoxyflavanone (191), and (Z)-2″-(2″-hydroxyisopropyl)-dihydrofurano-[4″,5″-6,7]-3′,4′-dihydroxy-4-methoxyaurone (192) were obtained by transformation of 185 in Aspergillus ochraceus (AM 465) culture (Figure 19) [106].
Biotransformation products of isoxanthohumol (189).
Incubation of xanthohumol (185) both with Fusarium avenaceum (AM11) and F. oxysporum (AM727) gave a single metabolite 2″-(2″-hydroxyisopropyl)-dihydrofurano-[4″,5″:3′,4′]-4′,2-dihydroxy-6′-methoxy-α,β-dihydrochalcone (193), which turned out to be the product of the prenyl group cyclization and α,β-double bond reduction. F. tricinctum reduced α,β-double bond of 185 to give 4,2′,4′-trihydroxy-6′-methoxy-3-prenyl-α,β-dihydrochalcone (194). Penicillium albidum (AM79) oxidized 185 at the double bond of prenyl group to xanthohumol H (195) [107]. The culture of the yeast, Rhodotorula marina (AM 77), converted 185 and 4-methoxychalcone (196) to α,β-dihydroxanthohumol (197) and 4-methoxydihydrochalcone (198) with the yields of 18% and 20%, respectively [108]. Penicillium albidum (AM79) dihydroxylated the Δ2″(3″) double bond of xanthohumol to produce 3′-[3″-hydroxy-3″-methylbutyl]-4,2′,4′-trihydroxy-6′-methoxychalcone (199, 22.84%) (Figure 19).
Biotransformation products of sylbin (204).
B. bassiana AM278 and Absidia glauca AM177 converted isoxanthohumol (189) into glucoside derivatives (200, 201), whereas Fusarium equiseti AM15 transformed it into (2R)-2-(2-hydroxyisopropyl)-dihydrofurano-[2,3:7,8]-4-hydroxy5-methoxyflavanone (202) (Figure 20) [95, 106].
C. echinulata (ATCC 9244) sulfated silybin (203) to silybin-7-sulfate (204) and 2,3-dehydrosylibin-7-sulfate (205). Sulfonation at the C-7 position of silybin significantly decreased the DPPH free radical scavenging potential; however, further dehydrogenation Δ2(3) to 2,3-dehydrosilbyn-7-sulfate (206) drastically enhanced the DPPH free radical scavenging potential activity [109] (Figure 21).
Enzymes are the most proficient catalysts, offering much more competitive processes than chemical catalysts. A number of enzyme-based processes have been commercialized for producing several valuable products. During the 1980s and 1990s, engineering of enzymes based on structural information allowed extension of their substrate ranges, enabling the synthesis of unusual intermediates. Accordingly, the use of enzymes has been expanded to the manufacture of pharmaceutical intermediates and fine chemicals [110]. Microorganisms and enzymes (biocatalysts) are highly enantio-, chemo-, and regioselective in a wide range of reaction conditions. Selectivity is extremely desirable in the synthesis of different synthesis products, since it offers advantages such as minimizing the side reactions that do not require protection and deprotection steps, which allows for shorter synthesis. Biocatalysis provides a technology that is environmentally safer, and it effectively reduces the level of waste and even eliminates the waste generation rather than remediation and disposal of wastes at the end of the process. In addition to, biocatalysts have many attractive features in the context of green chemistry and sustainable development. Various enzymes used in different industrial processes have been described in the literature. Table 6 indicates some enzymes, their source, and some applications [111, 112, 113].
Microbial enzymes | Microorganism | Application |
---|---|---|
α-Amylase | Bacillus amyloliquefaciens B. stearothermophilus B. licheniformis | Baking, brewing, starch liquefaction Clarification of fruit juice Textile industry Paper industry |
Glucoamylase | Aspergillus niger A. awamori Rhizopus oryzae | Beer production High glucose and high fructose syrups |
Proteases | A. usami | |
Lactase (β-galactosidase) | Kluyveromyces lactis K. fragilis | Lactose intolerance reduction in people Prebiotic food ingredients |
Lipase | Candida antarctica C. cylindraceae Ay30 Helvina lanuginosa Pseudomonas sp. Geotrichum candidum | Cheese flavor development Textile indutry Medicinal applications Use in cosmetics Use as biosensors Use in biodegradation |
Phospholipases | Fusarium oxysporum | Cheese flavor development |
Esterases | Bacillus licheniformis | Enhancement of flavor and fragrance in fruit juice |
Xylanases | Streptomyces sp. Bacillus sp. Pseudomonas sp. | Clarification of fruit juice Beer quality improvement |
Glucose oxidase | A. niger Penicillium glaucum P. adametzzi | Food shelf life important Food flavor improvement |
Laccase | Funalia trogii Bacillus licheniformis Bacillus vallismortis | Polyphenol removal from wine baking |
Pectinases | A. niger A. wentii Rhizopus sp. | Clarification of fruit juice |
Catalase | A. niger Metarhizium anisopliae Psychrobacter piscatorri | Food preservation Removal of H2O2 from milk prior to cheese production |
Peroxidase | Streptomyces viridosporus | Development of flavor, color and nutritional quality of food |
Enzymes, source, and some applications.
A very interesting research area in biology and biotechnology is the of extremophile microorganisms. Extremophiles can be divided into group according to (i) temperature tolerance, (ii) salt concentration, (iii) pH range, or (iv) pressure conditions. Enzymes from extremophilic microorganisms offer versatile tools for sustainable developments in a variety of industrial applications as they show important environmental benefits due to their biodegradability, specific stability under extreme conditions, improved use of raw materials, and decreased amount of waste products. Although major advances have been made in the last decade, our knowledge of the physiology, metabolism, enzymology, and genetics of this fascinating group of extremophilic microorganisms and their related enzymes is still limited [114, 115, 116].
The outstanding properties of thermozymes are suited to industries that employ elevated temperatures, such as the pulp and paper, food, brewing, and feed processing industries. Thermophiles are often highly resistant to harsh conditions such as chemical denaturing agents, wide pH ranges, and/or nonaqueous solvents. Examples of such enzymes are cellulases, xylanases, pectinases, chitinases, amylases, pullulanases, proteases, lipases, glucose isomerases, alcohol dehydrogenases, and esterases. Thermophilic enzymes have played important roles not only at the industrial level but also in pharmaceutical applications requiring use of specific aldolases for the synthesis of enantiopure compounds (Table 7) [118].
Source | Enzyme | Activity | Bioprocess/industry | Reference |
---|---|---|---|---|
Sulfolobus solfataricus S. acidocaldarius Thermoproteus texas Hyperthermus butylicus | Aldolase | Stereoselective C-C bond formation | Pharmaceutical industry | [117] |
Pyrococcus furiosus | Hydrogenase | Final stage of glucose oxidation by oxidative pentose phosphate cycle | Enhanced production of biohydrogen | [119] |
Geobacillus thermoleovorans | Carboxylesterase | Carboxyl ester hydrolysis | Agriculture, food, and pharmaceutical industries | [120] |
Bacillus pumilus | Acidic thermostable lipase | Degradation of palm oil | Treatment of palm oil-containing wastewater | [121] |
Geobacillus sp. | Lipase | Hydrolysis of diver’s lipid substrates | Biofuel, cosmetics, or perfume production, leather and pulp industries | [122] |
Microbial community from solid-state fermentation reactor | Protease | Degradation of hair waste from tannery | Leather industry | [123] |
Sulfolobus tokodaii | Chitinase | Hydrolysis of β-(1, 4)-glycosidic bonds in chitin | Biomedical, pharmaceutical, food, and environmental | [124] |
Acidothermus cellulolyticus | Endoxylanase | β-(1,4)-xylan cleavage | Biofuel production from lignocellulose | [125] |
Thermotoga neapolitana | Pullulanase | Hydrolysis of α-(1, 6)-glucosidic linkages | Biofuel production | [126] |
Extremophile microorganisms and some applications of their enzymes.
Due to microorganisms’ abundant multienzyme systems, microbial transformation possesses advantages against chemosynthesis of environmental friendliness, mild reaction conditions, and high stereo-, regio, and chemo-selectivities as well as in improving conversion rates and reducing cost. Thus, microbial transformation technique is being increasingly used to structurally modify natural and synthetic compounds.
The hydrolytic and reductive capabilities of microorganisms have been known and are currently used in preparative and industrial reactions. Various classes of bioactive organic compounds have been subjected to enzymatic transformation to obtain more active and less toxic substances or to elucidate their metabolic pathways.
For example, biotransformation-derived steroids are used for a wide range of pharmacotherapeutic purposes, such as anti-inflammatory, immunosuppressive, progestational, diuretic, anabolic, as neurosteroids, and as contraceptive. Researchers continue to discover more useful steroid compounds and to isolate microorganisms that can perform the structural transformations desired. New technologies such as genomics, metanogenomics, gene shuffling, and DNA evolution provide valuable tools for improving or adapting enzyme properties to the desired requirements.
An alternative may be extremophilic microorganisms such as biocatalysts for countless future industrial applications that are more environmentally friendly.
The authors thank Carrera de Biología, FES-Zaragoza, UNAM, Al Departamento de Química Orgánica, FES-Cuautitlán, UNAM.
The authors report no conflicts of interest.
It refers to the discomfort that occurs in the groin area of abdominal wall.
The most common causes of groin pain include:
Pulling on a muscle, tendon, or ligament in the leg
Hernia
Hip joint disease or injury
Less common causes include:
Inflammation of the testicle or epididymis and related structures
Torsion of the spermatic cord attached to the testicle (testicular torsion)
Tumor of the testicle
Kidney stones
Inflammation of the large and small intestine
Skin infection
Swelling of the lymph nodes
Urinary infection
This groin pain is perceived, integrated, transmitted and evaluated by neurons and the nervous system, but we have not yet elucidated how this process takes place. Such is the profuse network of nerves that cover the area, that their involvement is a not uncommon phenomenon (Figure 1).
Nervous system in the groin hernia area (3D 4Medical app).
In fact, the most frequent surgical reason is inguinal pain resistant to conservative treatments. Besides, poor preoperative pain control is a key factor in developing acute and chronic postsurgical pain (CPSP; Figure 2).
Predictability of the appearance of CPSP.
Each patient who develops CPSP has a specific genotype, medical history, previous experiences, beliefs and psychosocial conditions related to their pain; but, in general, there are some common risk factors in the development of chronic pain.
Psychosocial factors: Anxiety, depression and catastrophizing that surround the patient during the perioperative period.
Demographic factors: In some surgeries, age is a determining factor (i.e. young women for mastectomies [1]). In others, the male gender is more prone than the female [2, 3].
Genetic factors: Several authors point to the relationship of different clinical pathologies such as fibromyalgia, migraine, irritable bowel, irritable bladder, Raynaud’s syndrome … as markers of chronic postsurgical pain [4, 5].
Preoperative pain: The presence of preoperative pain has been correlated in different studies with the development of CPSP. Of all the types of surgical interventions, the hernia procedure stands out for its high preoperative pain rates [6, 7, 8, 9].
Surgical factors: Some important surgical factors may be related to the development of CPSP such as:
Duration of the operation (more than 3 h),
Surgical technique (laparoscopy vs. open),
Incision (site and type),
Experience of the surgeon,
Center where the intervention is carried out [10].
Acute postsurgical pain (APSP): Various studies show the importance of optimal APSP control to avoid chronification of postsurgical pain. Among them, surgeries such as groin, breast, hip, knee … are the most identified [11, 12, 13].
However, and despite the fact that there are different studies addressing this issue, the controversy remains dominant. To date, it can only be suggested that they do not play in favor of a better recovery or a lower probability of chronification, in addition to reducing quality of life in the process; but in no case can we establish a universally accepted causal relationship [3, 13, 14, 15, 16].
For the response to a noxious stimulus (be it chemical, thermal, pressure or any other characteristic that can cause pain), there are structures sensitive to those stimuli in the periphery: they are nociceptors [17].
Different classes of afferent nerve fibers are responsible for the communication of nociceptive information and pain:
Type Aβ: with a myelin sheath, are sensitive fibers responsible for touch and pressure.
Type Aδ: with a myelin sheath are responsible for the transmission of localized acute pain, temperature and part of the touch.
C fibers, without myelin sheath are responsible for the transmission of deep diffuse pain, smell, information from some mechanoreceptors, responses of the reflex and postganglionic arcs of the autonomic nervous system.
In a basal state, a noxious stimulus depolarizes a sensory or nociceptor neuron. The stimulation of nociceptors causes the propagation of the nerve stimulus to the dorsal horn of the spinal cord. Control at the spinal level is carried out in the gelatinous substance of Rolando (Rexed plate II) by stimulating inhibitory interneurons (Golgi II type) that cancel or reduce the nociceptive signal towards the lateral spinothalamic tract. In addition, glutamate is released, an excitatory amino acid that binds to a specific receptor, called AMPA and located in a postsynaptic neuron that transmits information to the higher centers of the CNS. Different brain centers are stimulated from the thalamus:
Periaqueductal gray substance (PAGS): Located in the midbrain, it is one of the most important nuclei and its functions are mediated by the opioid system. Its activation allows the inhibition of the painful process. It is connected with brain structures, with the ascending bundles and sends its projections to structures of the pons such as the nuclei of the raphe magnum.
Nuclei of the raphe magno: Located in the protuberance, receives connections from the ascending systems and the PAGS. It sends its axons to the first afferent synapse of the posterior horn and its nature is serotonergic.
Cerulean nucleus: Located on both sides of the fourth ventricle in the bridge. It is noradrenergic in nature.
The prefrontal cortex integrates all the information and the patient feels pain [18]. From these same superior nuclei, descending pathways are set in motion and reach the dorsal horn of the medulla again releasing endogenous inhibitory substances (mainly opioids and GABA). These inhibitory substances act by modulating the transmission of the stimulus: on the one hand, by decreasing the release of glutamate, and on the other, by hyperpolarizing the membrane of the postsynaptic neuron [19]. Inhibitory interneurons also come into play, which by releasing endogenous opioids, mimic and potentiate the inhibitory effect of the descending pathways.
Refers to pain that is associated with actual or threatened damage to non-neural tissue and involves the activation of peripheral nociceptors (IASP Taxonomy, 2015). There are three major forms of nociceptive pain:
Includes all pain originating from non-visceral structures, (i.e. skull, meninges, and teeth) and is the most common cause of consultation for almost all specialties, especially those dedicated to the locomotor system.
Extremely frequent, although in many cases it is not diagnosed as such. It is a neuromuscular dysfunction with a tendency to chronicity. It consists of a regional pain disorder, which affects the muscles and fasciae, so that the muscles involved have trigger points as essential components. In addition, regional and segmental autonomous alterations may coexist.
Dull, diffuse and poorly localized pain, referred to an area of the body surface, being frequently accompanied by an intense motor and autonomic (sympathetic) reflex response. The stimuli that can produce visceral pain are: spasm of the smooth muscle (hollow viscera), distension and ischemia.
Sometimes there is no relationship between the painful stimulus and the response that it originates in the CNS: it is then when a very important amplification of the nociceptive signal occurs, and this phenomenon is known as neuronal sensitization or neuropathy, so that the information transmitted to the brain causes a disproportionate pain reaction. This derangement occurs both at the peripheral and central levels.
Persistent pain becomes a pathological state that includes a series of elements that facilitate its generation and persistence over time. For this reason, any process that injures nerve tissues or causes neuronal dysfunction can produce neuropathic pain (NP). NP is qualitatively characterized by the absence of a causal relationship between injury and pain. Its etiology is very diverse and the relationship between etiology, pathophysiological mechanisms and symptoms is complex. NP differs from nociceptive pain in several aspects (Table 1).
Nociceptive (somatic / visceral) | Neuropathic | |
---|---|---|
Official definition | Pain caused by activation of peripheral / visceral nociceptors | Pain caused by PNS / CNS dysfunction |
Mechanism | Natural physiological transduction (nociceptor) | Ectopic pulse generation |
Symptom location | Local pain + referred | Territory of innervation of the affected nerve pathway |
No neurological topography | ||
Quality of symptoms | Common painful sensations of daily life - easy verbal description (i.e. Head ache, belly ache…) | New, unfamiliar, aberrant sensations: difficult verbal description (i.e. burning, electrical…) |
Normal neurological examination: response and aggression correspond | Hypo / hypersensitivity: response and aggression do not correspond | |
Treatment | Effective: conventional analgesia | Partially effective: antiepileptics, antidepressants |
Differences between nociceptive and neuropathic pain.
Adapted from Serra Catafau, Treatise on neuropathic pain (Adapted from SGADOR Handbook).
The balance between arousal and inhibition of the somatosensory system is dynamic and is influenced by context, behaviors, emotions, expectations, and pathology. In NP this equilibrium is broken and a loss in inhibitory currents has been demonstrated, with dysfunction in the mechanisms of production and release of GABA, a decrease in μ-opioid receptors in the dorsal root ganglia, and less receptivity to opioids in the spinal neurons. In summary, the neuronal pathological process changes in the course of injury and its pathophysiological mechanisms are evolutionary. The mechanisms that trigger NP produce:
Local inflammation
Glia cell activation
Changes in neuronal plasticity of nociceptive pain-transmitting pathways
Acute pain is an experience, usually of sudden onset, of short duration in time and with remission parallel to the cause that produces it. There is a close temporal and causal relationship with tissue injury or nociceptive stimulation caused by disease. Its duration ranges from a few minutes to several weeks. Acute pain has been attributed a “protective” function, its presence acts by preventing the individual from developing behaviors that may increase the injury or leads him to adopt those that minimize or reduce its impact. The fundamental emotional response is anxiety, with less involvement of other psychological components. Its characteristics offer important help in establishing the etiological diagnosis and selecting the most appropriate treatment. Its presence follows a classic treatment scheme such as Pain-Symptom. The most common causes of acute pain are:
Visceral pain
Gastrointestinal
Biliary
Urological
Cardiovascular
Pulmonary
Nervous system
Pancreatic
Gynecological
Muscle Skeletal Pain
Arthropathies
Chest wall pain
Fractures
Costochondritis
Tendinitis
Oral pain
Burn pain
Postoperative pain
Chronic pain extends beyond the tissue injury or organic involvement with which, initially, there was a relationship. It can also be related to the persistence and repetition of episodes of acute pain, with the progression of the disease, with the appearance of complications thereof and with degenerative changes in bone and musculoskeletal structures. Examples of this are cancer, secondary pathological fractures, osteoarthritis, postherpetic neuralgia, etc.
Chronic pain does not prevent or avoid damage to the body. Both their nature and their intensity show great variability over time, in many cases the complaints are perceived as disproportionate to the underlying disease. The most frequent repercussions in the psychological sphere involve anxiety, anger, fear, frustration or depression, which, in turn, contribute to further increasing pain perception. The socio-family, labor and economic repercussions are multiple and generate important changes in the lives of the people who suffer from it and their families: disability and dependency. The need to use drugs to relieve pain becomes a potential risk factor for use, abuse and self-prescription, not only of analgesics, but also tranquilizers, antidepressants and other drugs.
In its management, in addition to the physical aspects of pain, the other components, emotional, affective, behavioral and social, must be taken into account. The treatment scheme is complicated, we are facing the Pain-Syndrome (Table 2).
Acute Pain | Chronic pain | |
---|---|---|
Purpose | Initial-biological | Initial-destructive |
Duration | Temporary | Persistent |
Generator mechanism | Unifactorial | Multifactorial |
Affected component | Organic+++Psychic+ | Organic+Psychic+++ |
Organic response | Adrenergic: raise in heart rate, arterial hypertension, sweating, pupillary dilation | Vegetative: anorexy, constipation, less lybid, insomnia |
Affective component | Anxiety | Depression |
Physical exhaustion | No | Yes |
Therapeutic goal | Cure | Relief and adaptation |
Differences between acute and chronic pain.
All surgical intervention is associated with acute postsurgical pain (APSP) whose intensity decreases during the first days and weeks, in parallel with the tissue repair process. However, sometimes this pain lasts longer than is reasonable in relation to the surgical procedure. This fact can lead to the appearance of severe and disabling chronic pain syndromes, frequently associated with certain surgical procedures.
The definition of chronic postoperative pain (CPSP) does not find a consensus among the different authors in the literature reviewed. The most commonly used definition continues to be that of McRae [20, 21] based on the following aspects:
pain with a minimum duration of two months after a surgical procedure
after excluding other etiologies of pain
ruled out any pre-existing cause of pain (Figure 3).
Temporal evolution of postsurgical pain (adapted from Woolf and salter, science 2000; 288: 1765 [22]).
CPSP originates from the injury to the nerves and tissues inherent in the surgical process. During the immediate postsurgical period appears the breakthrough pain limited to the surgical site and its vicinity and develops through the direct activation of nociceptors, the inflammatory process and, in some cases, of direct nerve injury [23]. For this reason, the patient will present pain in the area of the surgical scar (primary hyperalgesia) and around it (secondary hyperalgesia). These changes are usually reversible and the normal sensitivity of the nociceptive system will then be restored. This type of pain, APSP, has a known beginning and an end in direct relation to tissue repair. In addition, it responds effectively to non-steroidal anti-inflammatory drugs, paracetamol, and minor or major opioids.
In the event of nerve injury during surgery, the neuropathic component of pain can immediately develop and persist in the absence of any noxious peripheral stimuli or ongoing peripheral inflammation [24]. The prerequisite for the development of CPSP is an injury to the major nerves that run through the surgical site. However, in a small group of patients, an ongoing inflammatory response may help maintain inflammatory pain and lead to a CPSP, such as that occurs after inguinal mesh hernia repair [25]. During progression from APSP to CPSP after inguinal hernia surgery:
7% of patients present severe acute pain the first 24 h;
14% of patients present subacute pain that could last until 8 weeks after surgery;
12% of patients present CPSP that could last until 12 months after surgery (80% of whom present Neuropathic component)
The incidence of chronic pain after inguinal hernia surgery rates from 5–63%, with an estimated incidence of severe chronic pain (VAS > 4) between 2% and 4%.
Inguinal hernia surgery can trigger a post-herniorrhaphy chronic inguinal pain syndrome, which can occur in up to 10% of the interventions performed [21].
The symptoms of postherniorrhaphy neuropathic inguinodynia consist of pain, paresthesias, allodynia (sensation of pain in the presence of non-harmful stimuli such as touch or pressure), pain radiating to the scrotal area, labia majora of the vagina and Scarpa’s triangle. This symptomatology also worsens with walking or hyperextension of the hip and decreases with decubitus and flexion of the thigh. These last aspects of the symptomatology make us see that the affectation of the nervous tract is the main actor of the chronic pain postherniorrhaphy [26].
There are three types of causes for the appearance of this painful syndrome:
Non-neuropathic
Reaction of the periosteum of the pubis
Keloid scar formation
Direct pressure exerted by bent or wrinkled prosthetic material (mesh) [27].
Neuropathic
Fibrosis of the perineurium of the nerves that run along the inguinal path (ilioinguinal nerve and genital branch of the genitofemoral nerve)
Compression of these by suture material, staples or prosthetic material
Direct injury to the nervous tract in a complete or incomplete manner. It can be produced by traction, direct cutting with a scalpel, or excessive thermocoagulation.
Peripheral sensitization involves lowering the discharge threshold from the peripheral terminal of the nociceptor. The molecules released in response to tissue damage and the activation of cells in the environment such as keratinocytes, mast cells, lymphocytes, platelets or the nociceptor itself, are called inflammatory soup (Substance P, calcitonin gene receptor protein [CGRP], quinines, amines, prostaglandins, growth factors, chemokines, cytokines, ATP, protons, etc.). These molecules induce morphological and functional changes in the neuron, which consequently generate an increase in the expression of structures such as the Na2+ channels and transient receptor potential cation channel subfamily V member 1 [TRPV1]; or molecules such as neuropeptides, or brain-derived neurotrophic factor [BDNF]. The interaction of these molecules with the different membrane receptors initiates an activation cascade of intracellular second messengers that modify the firing capacity of the cell, the final consequence being a greater capacity to respond to stimuli. This circumstance translates clinically into the following processes: hyperalgesia, allodynia, and spontaneous pain.
Spontaneous pain can be caused by:
An abnormal response to stimuli that normally do not cause harm (arterial heartbeat, increased temperature)
Ectopic discharges from the damaged nociceptor itself
Those produced by surrounding healthy fibers in response to the release of TNFα by damaged Schwann cells
At present, it is proposed a new state of the nociceptor, called “priming”, in which, a sensitized nociceptor, after a few hours will have a normal response to physiological stimuli, but will have an increased response to stimuli derived from inflammation. This state lasts for weeks and the hyperalgesic response to inflammatory agents is greater, which could be a possible explanation for the maintenance of chronic pain.
In a situation in which nociceptive information continues to be sent from the periphery to the dorsal horn of the spinal cord, the nociceptive neuron itself sends, from its soma (without the need for external stimulation) substance P and peptide related to the calcitonin gene (PRCG). These substances bind to neutrophils, mast cells and basophils, and release pro-inflammatory molecules: cytosines, bradykinins, histamines, cyclooxygenases, prostaglandins, eicosanoids and nerve growth factor (NGF). All this “inflammatory soup” produces changes in pH, release of ATP from injured cells, synthesis and release of nitric oxide (NO), etc., which induces amplification of the signal towards the spinal cord and higher centers and causes what is known as peripheral sensitization, which contributes in a very important manner to the maintenance of chronic pain.
If the nociceptive impulses are of great intensity or are sustained over time, plastic changes occur in the neurons of the posterior horn that facilitate the transmission of the nociceptive impulse. These changes in functionality are called central sensitization and cause specific clinical manifestations. It may represent the anatomical and physiological substrate to the fact of persistence of pain in the absence of peripheral nociceptive impulses in chronic pain, since the state of hyper-reactivity of the system would allow to explain the autonomous activity of the system in the absence of peripheral stimulus. In general terms, the following changes can be considered, which can all occur simultaneously or simply manifest some of them:
Disinhibition of the N-methyl-D-aspartate (NMDA) receptor by release of the Mg2+ ion at the first medullary synapse
Access of peripheral Aβ fibers to the nociceptive system. It is one of the causes of the phenomenon of allodynia
Dysregulation of the GABAergic system of inhibitory interneurons, which finally produces an alteration in the current of the Cl− channel.
Activation of the glia with the release of pro-analgesic substances
Alteration of the regulatory capacity of the downstream system
There is also the release of glutamate, which binds to specific receptors, which are not expressed in situations of acute pain. When activated, they contribute not only to depolarize the postsynaptic neuron, but also to generate a series of intracellular changes, which will increase the nociceptive signal. In response to peripheral sensitization, the primary afferent pathways also release substance P, resulting in an increase in signal. In situations of chronic pain there is also a reorganization of the neuronal structure: axonal collateral branches appear that increase the amount of nociceptive afferent signal.
On the other hand, a loss of efficacy of the inhibition produced by the descending pathways has been described, with a decrease in the release of endogenous opioids, and even cellular degeneration of those descending neurons, which indirectly also increases the nociceptive signal that is send to higher centers.
All these changes greatly amplify and sustain the nociceptive signal produced in the dorsal horn of the spinal cord, producing what is known as central sensitization.
The main clinical manifestations of nervous sensitization are hyperalgesia and allodynia phenomena, with the consequent increase in the extension of the painful area.
The presence of sensitization leads to the appearance of vicious circles in which there is a continuous sending of the afferent signal from the periphery to the brain centers in the absence of stimuli that generate them. This sustained stimulation leads to adaptive changes in the brain, such that the brain remains active even in the absence of noxious peripheral stimulus.
This continuous brain overexcitation conditions the effectiveness of the integrative pain response of the higher centers and the inhibitory descending pathway, in such a way that there is no inhibition proportional to the ascending amplified stimulus and the pain becomes chronic. This “centralizing” effect of the neuronal sensitization of nociceptors is one of the most relevant chronifying factors in the postoperative period of surgeries that present moderate to severe acute pain, that is not adequately controlled.
The type of pain, its location, duration and intensity determine the pharmacological approach (Figure 4).
Drugs that target peripheral sensitization: such as topical capsaicin (i.e. 8% capsaicin patch); topical lidocaine (i.e. 5% lidocaine patch); NSAIDs; paracetamol and local anesthetics.
Drugs that target central sensitization: such as serotonin reuptake inhibitors (SSRIs); tapentadol; tramadol; opioids; calcium channel ligands; adjuvants; tricyclic antidepressants; anticonvulsants and COX-2.
Pharmacological approach to chronic pain.
Blocking the pain signal before it reaches the central nervous system prior to surgery will prevent the development of central sensitization. The times that include the first consultation, the referral to the specialist, the decision of surgical treatment, the pre-anesthetic consultation and the appointment for surgery would favor peripheral and central sensitization if pain is not controlled, making the pain chronic and making it independent of the injury.
Using aggressive perioperative analgesia (antihyperalgesics, regional blocks, and multimodal analgesia) during the peri-surgical period could reduce the incidence of CPSP (Figure 5).
Perioperative analgesia.
Chronic pain is common after hernia surgery. Patients with pain before the operation benefit from surgery, but some patients who have no pain before hernia repair surgery develop significant groin pain later. Watchful waiting has proven to be safe [28] and profitable [29] in patients with asymptomatic inguinal hernia. It is a theme of debate whether surgery is appropriate in asymptomatic hernias and possibly in some other interventions as well.
CPSP is a common entity in interventional procedures today. Progress continues in the standardization of prevention and treatment strategies for this delicate problem in the technical and organizational sphere.
The improvement efforts aim to:
Early identification of patients with preoperative pain who need intervention.
Avoid delaying this intervention as far as possible, and if there is a delay, provide adequate pain management until the time of surgery.
At the time of the intervention, determine the least invasive and most appropriate surgical technique for the pathology.
Implement the most appropriate perioperative anesthetic and analgesic techniques for the patient.
Once intervened, individualize postoperative analgesia so that APSP is as low as possible, thus avoiding, as far as possible, chronic pain.
Thanks to Merche and Eduardo, for giving me the opportunity to study without worrying about anything else. To Monica, for her patience in preparing this chapter and to Alaitz and Inhar, for their fun distractions.
I declare that I have no conflict of interests.
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