Protective factors and resilience strategies.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"7707",leadTitle:null,fullTitle:"A Guide to Small-Scale Energy Harvesting Techniques",title:"A Guide to Small-Scale Energy Harvesting Techniques",subtitle:null,reviewType:"peer-reviewed",abstract:"The use of energy it is argued started about two million years ago when humans started cooking their food using firewood. 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Based on US Census Bureau data Hispanics are the youngest major racial or ethnic group in the United States [1]. About one-third or 17.9 million of the nation’s Hispanic population is younger than 18 and about a quarter or 14.6 million of all Hispanics are millennials (ages 18–33 in 2014). Researchers and practitioners alike recognize the advantages of implementing prevention programming that averts the need for more intensive and costly drug treatments. Advances in prevention science have been highlighted in reports from the Institute of Medicine and National Institute on Drug Abuse (NIDA) among others. The question is whether such advances in scientifically based prevention efforts can also extend to Hispanic/Latino youth including those who are immigrants or non-English speaking. A second question is whether theoretical models used to develop and study drug prevention programs are adequate in terms of addressing core cultural values beliefs and traditions among Hispanic/Latinos. Have prominent and widely used prevention interventions been adapted studied and proven effective with Hispanic/Latino youth? Are culturally tailored evidence-based programs available?
According to the review of literature conducted by Cuijpers [2], prevention programs have different goals, including the following: (a) increasing knowledge about drugs, (b) reducing the use, (c) delaying the onset of first use, (d) reducing abuse, and (e) minimizing the harm caused by the use. Prevention can be understood as any activity designed to avoid substance abuse and reduce its health and social consequences. This broad term can include actions aimed to reduce supply (e.g., based on the principle that the decreased availability of substances reduces the opportunities for abuse and dependence) and actions aimed to reduce demand (i.e., health promotion and disease prevention). In addition, the National Institute on Drug Abuse (NIDA), based on a growing body of prevention science, offers principles concerning prevention which range from the importance of addressing risk and protective factors to implementing and enforcing family and community policies prohibiting substance use [3]. Unfortunately, the NIDA principles do not specifically address the importance of cultural risk or protective factors that may impact substance use among Hispanics. Principle 12 does offer some broad recommendation regarding culture, citing that when communities adapt programs to match their needs, they should still do their best to maintain as close to the original intervention as possible and maintain high fidelity, although this principle is related to program adaptation.
Hispanic adolescents experience health disparities related to substance use, emotional problems, and high-risk sexual behavior. By the 12th grade, Latino students report the highest rates of 30-day use of marijuana, inhalants, ecstasy, cocaine, crack, salvia, Vicodin, methamphetamine, crystal methamphetamine, over-the-counter cough medicines, and tobacco through use of hookah [4]. Additionally, over one-quarter of Latino adolescents report alcohol use in the last 30 days as well as reports of the highest rates of binge and heavy drinking [5]. Suicide ideation is elevated among Latino adolescents as 1 in 7 (16.7%) Latino adolescents report suicidal ideation and 1in 10 (10.2%) report having attempted suicide [6]. In 2012, Latina adolescents had higher rates of teenage pregnancy than any other racial and ethnic minority, with 43.6 births per 1000 females, ages 15–19 years old [7].
The fastest-growing drug problem in the United States is prescription drugs, and it is profoundly affecting the lives of teenagers. According to NIDA DrugFacts, prescription drug misuse and abuse is when someone takes a medication inappropriately (e.g., without a prescription). According to National Survey on Drug Use and Health (NSDUH) data on youth and young adults, more than 5700 youth in 2014 reported using prescription pain relievers without a doctor’s guidance for the first time.
A common misperception is that prescription drugs are safer or less harmful to one’s body than other kinds of drugs. However, there are a range of short- and long-term health consequences for each type of prescription drugs used inappropriately. When concerning opioids, which act on the same parts of the brain as heroin, the consequences of inappropriate use can cause drowsiness, nausea, constipation, and depending on the amount taken, slowed breathing and even respiratory failure [8]. In terms of trends in tobacco use and electronic cigarettes among youth, older students, Hispanics, and Whites are more likely to use e-cigarettes than younger students and Blacks. In the young adult population, males, Hispanics, Whites, and those with lower education are more likely to use e-cigarettes than females, Blacks, and those with higher levels of education [9]. Flavored products marketed as e-cigarettes have gained popularity among youth and adults, while health consequence data continues to highlight the negative health impact of these products.
Factors that drive the substance use behaviors of Hispanic youth may be quite similar to those found in the general population of youth, yet there are unique challenges, stressors, and other risk factors that play a role in the development of substance use among Hispanic/Latino youth [10]. Cultural values and language shifts, pre- and post-migration trauma, ethnic identified problems, and parent–child “acculturation gaps” are implicated in the onset of substance use in this growing population. A body of research on family stress, adaptation, and resilience by McCubbin and colleagues has established that stressors that impact minority groups, including Hispanics, can negatively impact and disrupt the family system [11]. In turn, how the family actively deals with their stressful conditions can strengthen family members, their relationships, and the family unit. Highly stressful conditions can overwhelm family functioning.
Acculturative stressors are a class of adverse conditions that can generate interpersonal, cultural and familial challenges. For example, cultural conflict following immigration can reverberate across generations. Such stressors may comprise chronic adversity that includes clashes between personal and family goals; an increase in individualistic views; a reduced sense of the importance of religion; increased intra-family conflicts; gender role conflict; and increased marital conflict. Families with more acculturative stress and who lack a strong social support system or resilience (i.e., family and friends, spiritual resources, access to public social services) or personal resources (i.e., self-esteem) can show a greater decline in family cohesion.
The physical and emotional demands of immigrating to the United States are well documented [12]. New data shows a 117% increase in unaccompanied children ages 12 and under caught at the US-Mexico border in fiscal year 2014 compared to fiscal year 2013. By comparison, the number of apprehensions of children 13–17 years old has by increased 12% in the past year [13]. Parental deportation is an increasingly common hardship experienced by the Hispanic youth. Nearly 33,000 noncitizen youth are in DHS custody each day, representing an over 50% increase from 2001. Chaudry and colleagues found most children of deported undocumented workers remained in the United States with their other parent or relative [14]. The negative consequences of forced family separation because of deportation on child well-being are documented [15, 16, 17, 18]. Children most at risk for negative behavioral or psychological changes are those who witnessed their parents’ arrest; children separated from their parents longer than 30 days; and children whose primary caregiver was deported [19].
The term acculturative stress refers to the distress that individuals experience as a result of tension between maintaining the behaviors and characteristics of their country of origin and concurrently adopting those from the majority culture [20]. Acculturative stressors are not unique to Latino populations and may include pressure from learning a new language, balancing differences in cultural values, and adjusting to new employment expectations [21, 22]. Stress itself is conceptualized as a behavioral and emotional reaction to acute or chronic life-changing events and occurs when the demands of the events exceed the individuals’ perceived personal and social resources to deal with these changes [23]. The stress-illness paradigm offers one way to conceptualize the relationship between social stress and health [24, 25].
Research studies on acculturation and health status have been mixed, with some studies showing a positive relation between acculturation and health, while others demonstrate an inverse effect on health outcomes [26]. Furthermore, there is often considerable variation in these outcomes depending on factors such as country of origin, age, gender, years lived in the United States, education, and income [27]. For example, some research shows differences in health outcomes across a number of Latino/a subpopulations, with some subgroups experiencing higher morbidity and mortality rates, diabetes and hypertension, psychiatric disorders, and substance use disorders [27, 28, 29, 30, 31, 32]. One potential factor driving these different outcomes is experiences of acculturative stress.
Recent work by the authors suggests that acculturation “gaps” between adolescents and their parents can impact healthy emotional development. An additional adversity often faced by Hispanic families involves family member separations due to immigration, such as when parents come to the United States first and children are separated for years. The reunification process can be stressful and painful rather than smooth and joyous. The work by Perreira and colleagues emphasizes how adversity and resilient responses are embedded in social contexts. From an adversities’ perspective, this involves loss of social position and class status, loss of vital extended family resources, loss of peer networks and community support, and economic and social segregation and marginalization. Unfamiliar social contexts, language barriers, and humiliation when confronted by racism and discrimination can further erode individual and family coping and resilience.
Studies also indicate that US-born and more acculturated Mexican origin youth exhibit higher rates of externalizing behavior when compared to their less acculturated, Mexican-born peers. Markers of acculturation are consistently associated with externalizing outcomes like conduct problems, juvenile arrest, and substance use. US-born youth report less investment in education and lower academic aspirations than their Mexican-born peers [33]. Among immigrants, greater length of residence in the United States is associated with lowered academic motivation [34, 35]. Despite the stressful period of adjustment to a new set of cultural and linguistic changes, immigrants show resilience and better behavioral health compared to US-born Latino youth. The immigrant paradox primarily results from the progressive loss of traditional culture and associated negative health consequences associated with increasing generations or time in the United States [36].
Research examining the effects of both acculturation and stress find that stress partially mediates the relationship between acculturation and negative health behaviors. Stress impedes health by limiting access to salutogenic health behaviors and through maladaptive coping [37]. Hispanics under elevated stressor exposure are more likely to deny the stressor or to use maladaptive coping behaviors such as risky sex and substance abuse [38, 39].
Among youth, immigration, and acculturation-related stressors have also been found to predict greater drug use and risky sexual behavior [40, 41]. Recently, Cervantes and colleagues identified eight culturally based stress risk domains commonly experienced by Latino adolescents, ranging from acculturation gaps to family immigration-related stress [42]. Higher scores of cultural stress in these life domains were significantly related to both internalizing and externalizing behavioral health problems in Latino adolescents including polysubstance use [10, 42]. Effective interventions targeting immigration-related stress among Hispanics must promote healthy coping strategies for acculturation- and immigration-based stressors [43].
The implications of immigration and acculturation stressors are likely accentuated in new Hispanic settlement communities. New settlement areas are often hostile towards immigrants, creating a culture of fear where there is a heightened sense of anxiety that likely underlies social interaction and exaggerates possible stressor exposure. Birman and colleagues provide evidence that these hostile contextual conditions can affect the acculturation process and point to contextual factors such as immigrant density, acceptance of cultural diversity, and presence of social capital as core contextual issues [44].
Protective factors are those personal and environmental conditions and experiences that can counteract risk factors for substance use. For example, emphasis on family life is a central core value to most Hispanics and essential for their resilience in achieving normative life aims in the face of adverse social and environmental barriers. The concept of familismo/familism is a core value and belief in the centrality of family in the life of Hispanics. It highlights family loyalty, interdependence over independence, and cooperation over competition. Hispanic cultural values (i.e., familismo, simpatia, power distance, personal space, present time orientation, traditional gender roles) may impact health outcomes and diminish during the acculturation process. Embracing familism as a value contributes to a familial stability, which is linked to better physical health behaviors, higher likelihood of seeking medical help, better psychological health, and lower perceived burden of stress.
Familism and the highly involved parenting practices that often come with familism have been linked to fewer behavior problems in children. The work by Perreira and colleagues has pointed to specific resiliency strategies utilized by Hispanic immigrant parents. These include (1) emphasizing with and respecting adolescents/children (i.e., developing a deep understanding of what they are going through in an unfamiliar context and admiring the strength shown by children in that difficult context); (2) seeking help and fostering social support (i.e., connecting to other Hispanics and building community); (3) developing bicultural coping skills (including teaching children about their heritage and American culture); and (4) improving communication with their children (e.g., speaking honestly about difficult situations and being attentive to the child’s needs). Familismo, the orientation towards putting the needs of the family above that of the individual, family cohesiveness, reciprocity, and honor is a core value in Hispanic/Latino culture [45, 46, 47, 48, 49]. Most studies of psychosocial outcomes related to familismo find favorable psychosocial results for Hispanic children and adolescents [50, 51, 52, 53, 54, 55]. Incorporating Hispanic/Latino family values into early intervention and prevention programs can buffer the impact of weakening connection to traditional family protective factors [56].
Other forms of resilience can be found among Hispanic/Latino youth and families. These resources can be “mobilized” as part of any culturally focused prevention strategy. In one qualitative study of family resilience, Cervantes and Santisteban [57] reported specific, contextual resilience strategies mentioned by Hispanic/Latino families in confronting acculturation stressors (Table 1).
Acculturation risk factors | Suggested resilience strategies |
---|---|
Discrimination |
|
Immigration stress |
|
Family conflicts |
|
Health-related stress |
|
Marital problems |
|
Protective factors and resilience strategies.
Evidence-based drug prevention programming for Hispanic/Latinos does exist, although the number or programs is small. Familias Unidas, Familia Adelante, Strengthening the Bonds of Chicano Youth, and other similar programs will be highlighted here. The Familias Unidas intervention research has been undertaken with various Hispanic/Latino population groups including a study of predominantly Cuban (39%), Central and South Americans (29 and 17%, respectively), and a small proportion of Puerto Rican/Dominican (5%) participants [58]. A more recent study of Familias Unidas included adolescent participants who were predominantly US-born (56.1%) as well as adolescent immigrants from Honduras (26.9%), Cuba (20.4%), and Nicaragua (16.1%) [59]. A study of Strengthening the Bonds of Chicano Youth (El Proyecto de Nuestra Juventud) included 450 high-risk youth in an established, nonimmigrant community setting [60]. Results were generally positive in reducing risk factors for substance use.
Familias Preparando la Nueva Generación (FPNG) is a synchronized culturally grounded parenting component program which involves Latino youth substance abuse prevention [61]. FPNG serves as an addition to the already proven efficacious classroom-based drug abuse prevention intervention, Keepin’ it Real (KIR). One study showed that anti-drug norms were stronger in participants who were enrolled in KIR whose parents also participated in FPNG than in participants who were enrolled in KIR alone. Along with these stronger anti-drug norms, participants whose parents were in FPNG also showed reduced use of cigarettes and alcohol. The findings have shown that adolescent normative beliefs and related behaviors can be changed through synchronized culturally grounded parent and youth interventions.
REAL Groups is a small-group intervention designed to complement the school-based Keepin’ it Real (KIR) prevention program [62]. REAL Groups intervention is the result of a partnership with predominantly Mexican-American schools located in the central city neighborhoods of a southwestern US metropolitan area. The REAL Groups approach was designed as a companion to the larger KIR intervention and takes place over 10 weeks specifically targeting Latino, Hispanic, and Mexican-American children that appear to be more vulnerable to using drugs before entering adolescence. However, the outcomes of the REAL Groups intervention have been mixed and inconclusive, mainly due to the participants of the study being in the fifth grade with low drug use rates.
The mother/daughter intervention (MDI) approach is another program that involves substance abuse prevention strategies for youth [63]. This approach consists of 10 sessions via the internet which are to be completed at a rate of one session per week. In one study the MDI targeted young Black and Latina girls between the ages of 10 and 13 and their mothers. The outcome of the MDI showed that the girls who received the intervention reported lower levels of depression and higher levels of self-efficacy about their ability to avoid cigarette smoking, alcohol consumption, and drug use.
Substance abuse treatment and prevention interventions also exist to address intrafamilial stress in Hispanic families, such as brief strategic family therapy (BSFT) and more recently culturally informed family therapy for adolescents (CIFTA) [64, 65]. Again, these studies have included predominately Cuban or other Caribbean Latino samples yet may prove beneficial when applied to other Hispanic/Latino groups.
As an example of the expanding set of innovative research-based prevention programs for Hispanic/Latino youth, Familia Adelante will be will be discussed in some detail to exemplify one recently developed, culturally focused program. Familia Adelante is a drug prevention program that incorporates promotores as facilitators for this curriculum-based drug prevention program. The first iteration of the Familia Adelante (FA) curriculum showed reductions in family stress and youth behavior problems, enhancing academic and psychosocial coping and decreasing substance use patterns in Latino youth [66]. FA was also tested through in the SAMHSA-funded Blythe Street Prevention Project (BSPP) with youth and their parents, and that study found significant improvements in drug knowledge and drug resistance skills in both youth and parents [67]. FA was then evaluated in 2006 with six cohorts of families in a school-based setting. Findings were positive showing that family and peer communication improved and perceptions of substance use harm increased while social norms around sexual behavior and past-30-day use of marijuana and illegal drugs were reduced [68]. The developers also conducted NIH-supported work to infuse the FA curriculum with reproductive health education and HIV prevention messaging. Based on focus group data, new content was identified by participating youth that was not included in the original FA curriculum (i.e., content on eating disorders) (Table 2).
Familia adelante: youth sessions summary | ||
---|---|---|
Session | Lesson | Lesson goal |
1 | Introduction | Have a clear understanding of the Familia adelante curriculum, its purpose, and the need for program evaluation |
2 | Concept building | To define prevention and its application in life, build rapport with group members, acknowledge Hispanic culture as a positive resiliency factor, learn the basic concepts of culture and stress |
3 | Feelings | Explore physical and emotional feelings, explain how feelings affect behavior; how to be assertive in relationships |
4 | Stress overview | What stress is and how it affects physical and emotional health as well as behavior |
5 | Acculturation stress | Hispanic acculturation stress, how to identify the consequences of physical and emotional stress, and what values may hold. Discussion of immigration-related stressors |
6 | School-related stress | Identify the stressors related to school, cultural, and ethnic differences and how this stress affects youth; help youth identify trusted adults to share stressful experiences |
7 | Negative peer pressure | Adaptive ways of coping with stress; how to cope with dating peer pressure around sexual behaviors. |
8 | Family stress | How to identify family stressors; effective ways to deal with cultural stressors, positive and negatives about having sex; explore acculturation gaps |
9 | Gang prevention | Understand Hispanic gangs, violence, and the importance of not becoming members of gangs |
10 | Substance abuse education | Specific drug information, dangers of drug use, other healthy activities, facts about drugs, effects of drugs on a person’s body, cultural pressures to use alcohol and other drugs |
11 | Family communication | Teach families healthy communication skills; revisit acculturation gaps stressors |
12 | Evaluation and celebration | Re-evaluate youth to assess effectiveness of program; certificates of completion awarded to participants |
Familia adelante session summary.
Given the lack of prevention programs that have used a grounded cultural theory or that have incorporated culturally relevant risk and protective factors, there is oftentimes a need to use other evidence-based prevention practices and approaches and to adapt those to the needs of local Hispanic/Latino community. In one literature review comparing cultural adaptations to either no treatment or unadapted treatments, researchers found that cultural adaptations can be more effective than either of these other conditions, especially for clients with a diagnosed mental health disorder [69]. When examined as a whole, the scientific literature on cultural adaptations shows treatment effects to be significant and moderate in size on average [69, 70, 71, 72, 73, 74, 75]. Still, researchers caution that conclusions about the need for cultural adaptations should be reserved until more studies that directly compare adapted and unadapted EBPPs are conducted.
Adapted interventions that address the powerful, everyday stressors experienced by Hispanic/Latino clients are likely to be perceived as more relevant and attractive to clients. Enhancing content of existing EBPPs to reflect the values (e.g., family, religion) and world views of Latino clients will also increase the cultural relevance of the intervention [69, 76]. Finally, there are a number of agency- and provider-level characteristics that must be considered before a decision to adapt an EBP is made. First and foremost is the capacity of a provider organization to systematically undertake an adaptation. Agency capacity refers to the financial and human capital resources, skills, knowledge, and in-kind support that are needed to take on each step of the adaptation process (outlined below). For example, an initial needs assessment may include conducting consumer, staff, and other stakeholder interviews or focus groups. Thus, an agency should be prepared to cover costs related to staffing of these additional activities, paying incentives for participants, offering childcare, providing food and providing transportation for participants, transcription of focus group data, data management, data analysis, and reporting.
Drug prevention science and practice continues to expand, and to some extent the field has made positive impact in the Hispanic/Latino community. Based on the research to date, sufficient evidence exists about culturally specific risk and protective factors associated with the onset of substance use [3, 42]. Additionally, the momentum is gathering for the development and study of culturally focused prevention interventions. Acculturation and related stressors have been shown to precipitate behavioral health problems, and the body of research on acculturation stress can serve as theoretical underpinnings for the development of additional contemporary, culturally sensitive programming. As prevention programming and the evidence base for Hispanic/Latino practices continues to expand, core theoretical considerations will drive effective prevention programming. Latino and other scholars agree that concepts of acculturation, acculturation stress, familismo, respeto, and comunidad (community) must be inherent components, if not core components of prevention strategies for this growing population. Reinforcing positive family and youth identity that incorporates, embraces, and honors cultural history and traditions appears to have most promise.
In addition, there is growing evidence that factors such as acculturation stress, parent–child acculturation gaps, and prolonged discrimination (measured by allostatic load) may all play a role in the development of SUD among Hispanic/Latino youth. Programs such as Familia Adelante, which can be considered a culturally grounded model, address many of the acculturation and stress-related issues that resonate with many Hispanic/Latino youth. The development of prevention service approaches that include family and parent involvement is necessary, not only for the purpose of recruiting and retaining families but also as a way to promote and reinforce familismo. Future research on the impact of immigration policy and enforcement is needed particularly related to how family separations, childhood trauma associated with immigration, and deportation experiences lead to the development of behavioral health problems. The testing of prevention programs that are specific to new immigrants and refugee populations will be needed to address the uncertainties that these youth and families experience and that may not be addressed in existing prevention models.
Finally, we have outlined issues related to adapting existing EPBs for use in Hispanic/Latino communities. Research is fairly conclusive that adapting an EBP to the language and cultural characteristics of a particular ethnic community is better than not doing the adaption. Yet, the skills, capacity, and resources available to do good program adaptation must be in place. More specific research on program adaptations of generic prevention programs for Hispanic/Latino communities is needed.
Helicobacter pylori is a Gram-negative microaerophilic helical bacillus equipped with polar flagella as the motility organ. This bacterium colonizes human stomach and causes chronic atrophic gastritis [1]. In addition to gastritis, the patients infected with this pathogen are capable of having various digestive diseases such as gastric ulcer, duodenal ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer [2, 3, 4, 5, 6, 7]. Therefore, the eradication of H. pylori from human stomach is aggressively carried out around the world. Wide-spectrum antibiotics such as amoxicillin, metronidazole, and clarithromycin are used for the treatment for H. pylori infectious diseases. However, the H. pylori strains resistant to the wide-spectrum antibiotics have been increasing year after year [8]. Especially, almost all H. pylori strains clinically isolated from African people have been acquiring the resistance to amoxicillin and metronidazole. In addition, wide-spectrum antibiotics act not only on H. pylori but also on commonplace bacteria inhabiting the mucosa of mouth and intestines. Therefore, the patients infected with H. pylori, who orally take wide-spectrum antibiotics for the treatment, often suffer from side effects such as stomatitis, constipation, and loose bowels resulted from the collapse of the balance of either oral bacterial flora or enterobacterial flora. When the side effects are serious, the patients develop pseudomembranous colitis accompanied with bloody feces and are compelled to discontinue the eradication of H. pylori [9]. To solve the difficult problems on the chemotherapy, we have to develop a novel antibacterial medicine that acts on only H. pylori without affecting the survival of human mucosal bacterial flora.
The assimilation of exogenous cholesterol into the cell membranes is one of the unique biological features of H. pylori. A part of cholesterol assimilated into the cell membranes is modified with a α-glucose at the carbon position-3 of its steroid framework, and the cholesteryl glucosides generated are used as the bacterial cell membrane constituents [10]. A previous study by our group has revealed that H. pylori possesses at least three types of cholesteryl glucosides, cholesteryl-α-D-glucopyranoside (CGL), cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside (CAG), and cholesteryl-6-O-phosphatidyl-α-D-glucopyranoside (CPG) (Figure 1) [11]. In addition to the three cholesteryl glucosides, other researchers have identified the lyso-type of CPG [12]. CGL is synthesized by the catalytic action of cholesterol α-glucosyltransferase (CGT) that localizes to the cytoplasm-side of the inner membrane of H. pylori [13, 14, 15]. CGT transfers a glucose derived from a uridine diphosphate glucose (UDP-Glc) to the cholesterol. Although the enzyme proteins involved in the synthesis of either CAG or CPG remain to be clarified, a recent study by other group has demonstrated that the enzymatic activities for the synthesis of CAG and CPG are detected in H. pylori’s outer membrane and inner membrane, respectively [16]. In addition, both enzymatic activities for the synthesis of CAG and CPG turned out to use phosphatidylethanolamine (PE) as the substrate [16]. In sum, the CGL acyltransferase (CGLAT) transfers a fatty acid derived from PE to the CGL and thereby synthesizes CAG. Meanwhile, the CGL phosphatidyltransferase (CGLPT) transfers a phosphatidyl group derived from PE to the CGL and thereby synthesizes CPG.
Chemical structures of cholesteryl glucosides found in H. pylori cell membranes. In addition to the three types of cholesteryl glucosides, H. pylori possesses the lyso-type of CPG that dissociated a myristic acid. CGL, cholesteryl-α-D-glucopyranoside; CAG, cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside; CPG, cholesteryl-6-O-phosphatidyl-α-D-glucopyranoside; C14, myristic acid; C19, phytomonic acid.
A number of studies, including our own, have revealed that H. pylori assimilates exogenous cholesterol in order to acquire the resistance to the antibacterial actions of antibiotics and lipophilic compounds [17, 18, 19, 20]. Meanwhile, H. pylori glucosylates the assimilated cholesterol to evade the host immune systems and/or to detoxify the toxic steroid compounds with 3β-hydroxyl [12, 21]. The mechanism as for cholesterol uptake of H. pylori, however, remained for many years to be clarified. In a study in 2012, it has been revealed that PE of H. pylori cell membranes functions as a cholesterol-binding lipid [22]. PE is the most predominant glycerophospholipid component composing Gram-negative bacterial cell membranes. The PE of Gram-negative bacteria such as Enterobacteriaceae bacteria and Pseudomonas aeruginosa retains a palmitic acid (C16:0) as the saturated fatty acid side chain, whereas the PE of H. pylori retains a myristic acid (C14:0) as the saturated fatty acid side chain [22, 23, 24, 25, 26]. In sum, the PE molecular species composition of H. pylori turned out to completely differ from that of typical Gram-negative bacteria. A previous study by our group has demonstrated that the PE accounts for greater than 60% in the total lipids (excluding lipopolysaccharide) of H. pylori in the logarithmic growth phase [27]. Moreover, it has been revealed that the PE molecular species (DMPE) with two myristic acids accounts for approximately 30% in the total PE molecular species of H. pylori [22]. Intriguingly, DMPE showed higher binding affinity for cholesterol than for cholesteryl ester (Figure 2). In sum, the selective intermolecular interaction was found between the low-molecular-weight hydrophobic compounds.
Binding affinity of dimyristoyl-phosphatidylethanolamine of H. pylori cell membranes for either cholesterol or cholesteryl ester. Dipalmitoyl-PE with two palmitic acids (C16:0) shows the high binding affinity for both of cholesterol and cholesteryl ester, whereas dimyristoyl-PE (DMPE) with two myristic acids (C14:0) shows the selective high binding affinity only for cholesterol.
Based on a number of studies including our own, the overview from the cholesterol assimilation to the cholesterol glucosylation was partially clarified in H. pylori: (1) cholesterol binds at least to DMPE of the outer membrane of H. pylori and is assimilated into the membranes; (2) a part of cholesterol is glucosylated by the catalytic action of CGT localized to the cytoplasm-side of the inner membrane, and thereby CGL is generated; (3) CGL is next exchanged to CAG and CPG by the enzymatic actions of CGLAT and CGLPT that localize to the outer membrane and the inner membrane, respectively (Figure 3). CGT utilizes an UDP-Glc as the glucose donor of cholesterol. Both enzymes of CGLAT and CGLPT utilize PE (myristoyl-PE) as the acyl group donor and phosphatidyl group donor of CGL, respectively. Incidentally, cholesterol assimilated into H. pylori is distributed to both of the inner and outer membranes, whereas cholesteryl glucosides (CGL, CAG, and CPG) synthesized by H. pylori predominantly localize to the outer membrane [17].
Cholesteryl glucoside synthesis and its enzyme localization in H. pylori cell membranes. CGT, cholesterol α-glucosyltransferase; CGLAT, CGL acyltransferase; CGLPT, CGL phosphatidyltransferase; Cho, cholesterol; MPE, myristoyl phosphatidylethanolamine; LPS, lipopolysaccharide; UDP-Glc, uridine diphosphate-glucose.
As described above, it has been revealed that DMPE is one of the most prevalent lipid components of H. pylori cell membranes and shows the unique interaction not with cholesteryl ester but with cholesterol. Apart from this, previous studies by our group have demonstrated that a steroid hormone, progesterone acts on the cholesterol-binding site in the H. pylori cell membranes and confers the bactericidal action to H. pylori [28, 29]. Although it was unclear as for whether the progesterone shows the selective binding affinity for DMPE, this steroid turned out to destabilize the cell membrane structure of H. pylori and to ultimately induce the bacteriolysis. These findings drove us to the investigations of the low-molecular-weight hydrophobic compounds that induce the serious structure change to the DMPE molecule through the specific interaction. This chapter mentions the bactericidal activity of the indene compounds against H. pylori.
The anti-H. pylori activity of various steroidal compounds was investigated. As a consequence, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of secosteroids turned out to confer the strong bacteriolytic action to H. pylori [30]. However, these vitamin D3 derivatives conspicuously attenuated their bactericidal activity by the nonbiological degradation (Table 1). In contrast, H. pylori did not almost succumb to the bacteriolytic action of vitamin D3. Surprisingly, the nonbiological degradation of vitamin D3 augmented the bactericidal activity of its secosteroid against H. pylori. These results indicated that the vitamin D3 derivatives directly act as bactericidal substances on H. pylori, and that some decomposition product of vitamin D3 possesses potent bactericidal activity against H. pylori. It was, therefore, attempted to extract the anti-H. pylori substance from the decomposition products of vitamin D3. As a consequence, the indene compound species (VDP1), otherwise known as Grundmann’s ketone, was successfully obtained [31, 32]. VDP1 is a low-molecular-weight hydrophobic compound in which the indene consisting of 5- and 6-membered rings of hydrocarbons was modified with alkyl, carbonyl, and methyl (Figure 4). Intriguingly, H. pylori showed high susceptibility to the bacteriolytic action of VDP1, whereas commonplace bacteria such as Enterobacteriaceae bacteria, P. aeruginosa, and Staphylococcus aureus showed insusceptibility to that of VDP1 [30]. In addition, VDP1 conferred the effective bacteriolytic action to H. pylori regardless of the assimilation of cholesterol into the cell membranes. These results indicate the possibility that VDP1 is a beneficial fundamental structure for the development of antibacterial medicines to selectively eradicate H. pylori without collapsing the balance of human mucosal bacterial flora.
Bacteriolytic action of vitamin D3 and its derivatives against H. pylori.
Bacteriolytic action of VDP1 against H. pylori. H. pylori shows high susceptibility to bacteriolytic action of VDP1 derived from decomposition of vitamin D3. Meanwhile, commonplace bacteria such as Escherichia coli and Staphylococcus aureus show insusceptibility to bacteriolytic action of VDP1. VDP1, (1R,3aR,7aR)-1-[(1R)-1,5-dimethylhexyl]octahydro-7a-methyl-4H-inden-4-one.
The collapse induction activity of VDP1 against lipid vesicles was next examined using the unilamellar vesicles prepared with DMPE, dipalmitoyl-PE (DPPE), and dioleoyl-PE (DOPE). Intriguingly, VDP1 turned out to specifically induce the structure collapse of DMPE unilamellar vesicles without affecting the structural stability of either DPPE unilamellar vesicles or DOPE unilamellar vesicles (Figure 5). The structure collapse induction activity of VDP1 against DMPE unilamellar vesicles completely corresponded to the bactericidal activity of the indene compound against H. pylori that abundantly contains DMPE in the cell membranes. Based on these results, VDP1 was considered to specifically interact with the DMPE, to induce the serious structure change to the myristic acid side chain in the PE molecule, and to ultimately disrupt the vesicular conformation of DMPE. In addition, these results strongly suggested that VDP1 exerts the bactericidal effect on H. pylori by targeting at least DMPE of the cell membranes.
Specific intermolecular interaction between VDP1 and DMPE. Dye-containing unilamellar vesicles were prepared with DMPE, dipalmitoyl-PE (DPPE) or dioleoyl-PE (DOPE) and incubated for 5 minutes in the presence or absence of VDP1. The absorbance (A590 nm) of dye released from the PE unilamellar vesicles was measured (left graph). The data were obtained from the three independent experiments and are denoted with the mean A590 nm ± standard deviation. Statistical significance (P < 0.05) was calculated by the Student’s t-test. N.S. denotes “no statistical significance.” VDP1 induces the selective conformation change to the DMPE unilamellar vesicles. The intermolecular interactions between VDP1 and PE molecular species were simulated by the computational chemistry (right panel). VDP1 induces the conformational change only to a myristic acid side chain in the PE molecule without affecting the conformational stability of a palmitic acid side chain in the PE molecule.
The intermolecular interaction between VDP1, DMPE, and DPPE was, therefore, simulated by the computational chemistry. One of the computer simulations showed that VDP1 induces “the winding-structure change” to a myristic acid side chain in DMPE molecule, while VDP1 induced no structure change to a palmitic acid side chain in DPPE molecule (Figure 5). The alkyl of VDP1 seemed to be crucial conformation for the induction of the structure change of the myristic acid side chain of DMPE. In other words, the slight difference of the length of carbon chain composing the fatty acids in PE molecules appeared to play an important role on the specific interaction between VDP1 and PE molecular species.
As described earlier, VDP1 was considered to confer the bacteriolytic action to H. pylori by the disruption of the cell membranes through the induction of the structure change of DMPE that is one of the most prevalent PE molecular species constructing the bacterial cell membranes. To investigate in detail the crucial conformation of VDP1 for exerting the structure collapse effect on DMPE unilamellar vesicles and for exerting the antibacterial effect on H. pylori, various VDP1 derivatives were chemically synthesized [33]. The structure collapse induction activity of VDP1 against DMPE unilamellar vesicles was already ascertained to almost completely correspond to the bactericidal activity of the indene compound against H. pylori. When the carbonyl of VDP1 was replaced with a hydroxyl, the indene compound (VD3-1) maintained both activities against DMPE unilamellar vesicles and H. pylori (Table 2). As seen in VDP1, VD3-1 turned out to confer no structure collapse induction activity against DPPE unilamellar vesicles. In addition, VD3-1 also had no influence on the viability of commonplace bacteria such as Enterobacteriaceae bacteria, P. aeruginosa, and S. aureus. Intriguingly, VD2-2 that lacks the alkyl chain of VD3-1 was ascertained to induce no structure collapses of either DMPE unilamellar vesicles or DPPE unilamellar vesicles and to completely forfeit the effective bactericidal activity against H. pylori. In combination with the result of computer simulation as for the intermolecular interaction between VDP1 and DMPE, these results indicate that the alkyl structure in the indene compound species plays a crucial role on the induction of the structure change of the myristic acid side chain in DMPE molecule. Moreover, the alkyl structure in the indene compound species turned out to be essential for exerting the effective bacteriolytic action to H. pylori. The functional groups such as carbonyl and hydroxyl of the indene compound species seem to be significant conformation for bonding to the phosphate head in the PE molecules with an electrostatic attraction. Meanwhile, the indene-ring structure is guessed to be significant to stabilize the hydrophobic interaction between the indene compound species and PE molecules.
Relationship between indene compounds, PE unilamellar vesicles and H. pylori.
*Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Salmonella sp., Pseudomonas aeruginosa, and Staphylococcus aureus. VD3-1, (1R,3aR,7aR)-7a-methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-inden-4-ol; VD2-2, (1R,3aR,7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyloctahydro-1H-inden-4-ol.
A recent study by our group has demonstrated that VDP1 confers the antibacterial action not only to H. pylori but also to other Helicobacter species [33]. Especially, Helicobacter felis showed high susceptibility to the bacteriolytic action of VDP1, as similar to H. pylori. H. felis is a Gram-negative microaerophilic spiral bacillus possessing bipolar tufts of flagella. This bacterium is isolated from the gastric mucosa of cats and dogs [34, 35, 36]. As seen in H. pylori, H. felis causes chronic gastritis and gastric MALT lymphoma in mouse when it colonizes the mouse stomach [37, 38]. An earlier study by our group has revealed that a myristic acid accounts for approximately 16% in the fatty acid composition of H. felis PE, and that the PE molecular species retaining a myristic acid and a palmitic acid accounts for approximately 37% in total PE molecular species of the bacteria [39]. Though H. felis completely succumbs to the bacteriolytic action at the same concentration of VDP1 (less than 3 μg/ml) that eradicates H. pylori, this Helicobacter species did not possess DMPE. On this basis, VDP1 is considered to interact not only with DMPE but also with myristoyl-PE that retains a myristic acid as one of the two fatty acid side chains. In addition, H. felis turned out to possess lauryl-PE as the most prevalent PE molecular species. The PE molecular species retaining a lauric acid (C12:0) and a palmitic acid accounted for approximately 40% in total PE molecular species of H. felis. In sum, large parts of PE molecular species of H. felis bind a palmitic acid and either a myristic acid or a lauric acid as the fatty acid side chains. Given that a lauric acid is shorter in the length of carbon chain than a myristic acid, we can assume that VDP1 collapses the vesicular conformation consisting not only of myristoyl-PE but also of lauryl-PE. In the future, it will need to elucidate the hydrophobic interaction between VDP1 and lauryl-PE in addition to myristoyl-PE.
In contrast, Helicobacter cinaedi showed low susceptibility to the bacteriolytic action of VDP1, even though the PE molecular species composition in H. cinaedi is similar to the PE molecular species composition in H. felis [39]. H. cinaedi is a Gram-negative rod-like bacillus equipped with bipolar flagella and isolated from the intestinal tracts and livers of various mammals such as human, dog, cat, and hamster [40, 41, 42]. Therefore, this bacterium is classified into the enterohepatic Helicobacter species [43, 44]. Meanwhile, H. pylori and H. felis are classified into the gastric Helicobacter species. Most of the persons infected with H. cinaedi have no clinical symptoms, but some persons suffer from systematic inflammations, namely phlegmone, arthritis, and meningitis, due to the bacteremia [45]. Although it is unclear as for why H. cinaedi is lower in the VDP1-susceptibility than the two Helicobacter species, the involvement of lipopolysaccharide (LPS) is considered as one possibility. LPS is a glycolipid constructed of a long polysaccharide chain and fatty acids and is one of the composition components of the outermost layer of the outer membrane of Gram-negative bacteria [46]. The part of polysaccharide chain in LPS comes into direct contact with the outsides of the bacterial cells and limits the membrane permeability of various lipophilic compounds. The LPS contents in H. cinaedi may be higher than those in H. pylori and H. felis. The membrane permeability of VDP1 through the LPS barrier may be, therefore, stricter in H. cinaedi than in H. pylori and H. felis. Further investigation will be necessary to compare the LPS contents between the Helicobacter species.
Based on the current studies, the following bactericidal mechanism of the indene compounds synthetically derived from vitamin D in H. pylori was proposed: the indene compounds bind to the myristoyl-PE (including DMPE) of H. pylori cell membranes, induce “the winding-structure change” to the myristic acid side chain in the PE molecules, destabilize the membrane conformation, and ultimately confer the bacteriolytic action to H. pylori (Figure 6).
A proposed bactericidal mechanism of the indene compound species for H. pylori. The indene compound species such as VDP1 and VD3-1 bind to the myristoyl-PE of H. pylori cell membranes and induce “the winding-structure change” to the myristic acid side chain of the especially DMPE. H. pylori ultimately lyses via the destabilization of the membrane conformation.
In the case of the cholesterol assimilation in H. pylori, cholesterol is distributed to both membranes of the outer membrane and the inner membrane, and a part of the cholesterol is, thereafter, metabolized to cholesteryl glucosides (CGL, CAG, and CPG), and these metabolites localize to the outer membrane (Figure 7). Cholesterol and cholesteryl glucosides have no influence on the stability of the cell membrane conformation of H. pylori, and rather these steroidal compounds serve to strengthen the membrane lipid barrier of the bacteria on the limitation of the permeability of lipophilic compounds. A recent study by other group has demonstrated that cholesteryl glucosides are responsible for the morphological maintenance of H. pylori, for the acquirement of resistance to antibiotics such as polymyxin B, colistin, and tetracycline, and for the promotion of biofilm formation [47]. This suggests that cholesteryl glucosides of H. pylori play an important role to limit the membrane permeability of various low-molecular-weight compounds. However, VDP1 confers the bacteriolytic action even to H. pylori retaining cholesterol and cholesteryl glucosides. Further investigation will be necessary to clarify the detailed intermolecular interactions between myristoyl-PE and steroidal compounds.
Role of cholesterol and cholesteryl glucosides in H. pylori. Cholesterol (Cho) binds to the myristoyl-PE (MPE) including dimyristoyl-PE (DMPE) of the H. pylori’s cell membranes but has no influence on the stability of the cell membrane conformation. As similar to cholesterol, no cholesteryl glucosides (CGL, CAG, and CPG) affect the cell membrane stability of H. pylori. These steroidal compounds are assimilated as the membrane lipid constituents of H. pylori and serve to strengthen the cell membrane lipid barrier. Incidentally, VDP1 confers the bacteriolytic action to H. pylori regardless of the cholesterol assimilation into the cell membranes.
Almost all hydrophobic drugs are pharmacologically designed to inhibit the functions of either protein molecules or nucleic acids in the target creature species. However, no drugs that target a characteristic lipid molecule in the creatures are discovered for many years. In addition, a number of biochemists on lipid research leave great achievements in the analysis of biosynthetic enzymes of various lipophilic compounds such as fatty acids and complex lipids and in the identification of receptors of various hydrophobic ligands such as steroid hormones and eicosanoids. However, these achievements are not as for lipid itself but as for merely proteins. This chapter described the unique interaction between lipids: the indene compound species specifically disrupt the vesicular conformation consisting of DMPE. These findings will bring the new aspects to the drug discovery research and the lipid biochemistry research.
This work was supported by a Grant-in-Aid from the Adaptable and Seamless Technology Transfer Program through Target-Driven R&A (A-STEP), JSPS KAKENHI (grant number 15 K08006), and JKA promotion funds from KEIRIN RACE.
The authors declare no conflict of interest.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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