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Sunday, April 16, 2017

Health implications of the influence of diet on the gut microbiome


Abstract (as presented by the authors of the scientific work):

"Recent studies have suggested that the intestinal microbiome plays an important role in modulating risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer. At the same time, it is now understood that diet plays a significant role in shaping the microbiome, with experiments showing that dietary alterations can induce large, temporary microbial shifts within 24 h. Given this association, there may be significant therapeutic utility in altering microbial composition through diet. This review systematically evaluates current data regarding the effects of several common dietary components on intestinal microbiota. We show that consumption of particular types of food produces predictable shifts in existing host bacterial genera. Furthermore, the identity of these bacteria affects host immune and metabolic parameters, with broad implications for human health. Familiarity with these associations will be of tremendous use to the practitioner as well as the patient."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusion and future directions (as presented by the authors of the scientific work):

"In conclusion, review of the literature suggests that diet can modify the intestinal microbiome, which in turn has a profound impact on overall health. This impact can be beneficial or detrimental, depending on the relative identity and abundance of constituent bacterial populations. For example, it has been shown that a high-fat diet adversely reduces A. muciniphila and Lactobacillus, which are both associated with healthy metabolic states [53]. This observation provides a good example of how dietary intervention might potentially be used to manage complex diseases, such as obesity and diabetes. Furthermore, advances in microbiome research have suggested novel therapeutic possibilities for diseases that have traditionally been difficult to treat. For example, the fecal microbiota transplant has been used successfully to manage several different conditions, including ulcerative colitis, Clostridium difficile-associated colitis, irritable bowel syndrome, and even obesity [156–160]. It is possible that dermatologic conditions, including psoriasis and atopic dermatitis, may also be observed to benefit from re-engineering the gut microbiota. Recent advances in microbiome research offer exciting new tools to possibly enhance human health. Most of the studies reviewed in this manuscript profiled the microbiome using 16S rRNA amplicon sequencing, which utilizes the hypervariable regions of the bacterial 16S rRNA gene to identify bacteria present in biological samples. 16S rRNA sequencing is the most commonly used method by medical researchers to study microbial composition, due to its low cost and relatively easy workflow for sample preparation and bioinformatic analyses. However, 16S rRNA amplicon sequencing primarily provides information about microbial identity and not function. In order to investigate the microbiome’s functions, many researchers have turned to a shotgun metagenomic approach in which the whole bacterial genome is sequenced. Despite a higher cost and more complicated bioinformatics requirement, shotgun metagenomics provides information about both microbial identity and gene composition. Knowing which genes are encoded by the bacteria present in a sample allows researchers to better understand their roles in human health. With reducing costs of next generation sequencing, improved sample preparation protocols, and more bioinformatic tools available for metagenomic analysis, this technique will be a powerful tool to study microbiome functionality. Performing meta-analyses to correlate the microbiome with host genomes, transcriptomes, and immunophenotypes represents another exciting avenue for investigating human and bacterial interactions.

Precision medicine is another attractive, novel therapeutic approach for many diseases with strong genetic associations. It is important to note that the host genotype also plays a role in shaping the microbiome, and that this host-microbe interaction is crucial for maintaining human health [161]. Therefore, a better understanding of the interplay between genes, phenotypes, and the microbiome will provide important insights into the utility of precision medicine.

The observation that diet can modulate host-microbe interactions heralds a promising future therapeutic approach. Already, the gut microbiome has been found to influence the response to cancer immunotherapy [162, 163]. Indeed, personalized nutrition is an emerging concept that utilizes a machine-learning algorithm to predict metabolic responses to meals [164, 165]. This tool has broad implications for individualized patient care through dietary modification. While this and other technology is in the process of being refined and validated, further research using large, long-term clinical trials to evaluate a greater variety of food components would be helpful in making specific dietary recommendations to patients."


Full-text access of the referenced scientific work:

Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K, Abrouk M, Farahnik B,
Nakamura M, Zhu TH, Bhutani T, Liao W. Influence of diet on the gut microbiome
and implications for human health. J Transl Med. 2017 Apr 8;15(1):73. doi:
10.1186/s12967-017-1175-y. Review. PubMed PMID: 28388917; PubMed Central PMCID:
PMC5385025.
https://www.researchgate.net/publication/315978151_Influence_of_diet_on_the_gut_microbiome_and_implications_for_human_health


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Monday, April 10, 2017

Inflammation regulation by short chain fatty acids


Abstract (as presented by the authors of the scientific work):

"The short chain fatty acids (SCFAs) acetate (C(2)), propionate (C(3)) and butyrate (C(4)) are the main metabolic products of anaerobic bacteria fermentation in the intestine. In addition to their important role as fuel for intestinal epithelial cells, SCFAs modulate different processes in the gastrointestinal (GI) tract such as electrolyte and water absorption. These fatty acids have been recognized as potential mediators involved in the effects of gut microbiota on intestinal immune function. SCFAs act on leukocytes and endothelial cells through at least two mechanisms: activation of GPCRs (GPR41 and GPR43) and inhibiton of histone deacetylase (HDAC). SCFAs regulate several leukocyte functions including production of cytokines (TNF-α, IL-2, IL-6 and IL-10), eicosanoids and chemokines (e.g., MCP-1 and CINC-2). The ability of leukocytes to migrate to the foci of inflammation and to destroy microbial pathogens also seems to be affected by the SCFAs. In this review, the latest research that describes how SCFAs regulate the inflammatory process is presented. The effects of these fatty acids on isolated cells (leukocytes, endothelial and intestinal epithelial cells) and, particularly, on the recruitment and activation of leukocytes are discussed. Therapeutic application of these fatty acids for the treatment of inflammatory pathologies is also highlighted."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusions (as presented by the authors of the scientific work):

"SCFAs present multiple effects in different cells involved in the inflammatory and immune responses. These fatty acids not only affect the function of leukocytes (e.g., production of inflammatory mediators and ability of leukocytes to migrate) but can also induce apoptosis in lymphocytes [96,97], macrophages [98] and neutrophils [99]. The latter effect may be relevant for the outcome of the inflammatory process and the immune response to bacteria that produce these fatty acids.

In general, SCFAs, such as propionate and butyrate, inhibit stimuli-induced expression of adhesion molecules, chemokine production and consequently suppress monocyte/macrophage and neutrophil recruitment, suggesting an anti-inflammatory action. However, there is also evidence in favor of a pro-inflammatory action of SCFAs in some conditions [20,100]. This discrepancy may be in part explained by the ability of SCFAs to induce neutrophil migration. In sites of anaerobic bacteria infection or after loss of intestinal epithelial integrity, high concentrations of SCFAs may lead to neutrophil accumulation and amplification of the inflammatory process. Another possible explanation is the fact that these fatty acids may present divergent effects depending on the cell type (e.g., anti- and pro-inflammatory effects of SCFAs on macrophage and microglial cells have been demonstrated [52,97,101]). Therefore, although SCFAs modulate the function of immune cells, more studies are necessary in order to understand the precise role of SCFAs on the interaction between bacteria and host immune cells in vivo, particularly in the GI tract and in sites of anaerobic infections including the skin, oral cavity and respiratory tract."


Full-text access of the referenced scientific work:

Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by
short chain fatty acids. Nutrients. 2011 Oct;3(10):858-76. doi:
10.3390/nu3100858. Epub 2011 Oct 14. Review. PubMed PMID: 22254083; PubMed
Central PMCID: PMC3257741.
https://www.researchgate.net/publication/221755956_Regulation_of_Inflammation_by_Short_Chain_Fatty_Acids


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Saturday, April 8, 2017

Dietary constituents with “exercise mimetic'' action


Abstract (as presented by the authors of the scientific work):

"Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has been given to understanding the molecular cues stimulated by endurance exercise that culminate in this adaptive response. In turn, this research has led to the identification of pharmaceutical compounds and small nutritional bioactive ingredients that appear able to amplify exercise-responsive signaling pathways in skeletal muscle. The aim of this review is to discuss these purported exercise mimetics and bioactive ingredients in the context of mitochondrial biogenesis in skeletal muscle. We will examine proposed modes of action, discuss evidence of application in skeletal muscle in vivo and finally comment on the feasibility of such approaches to support endurance-training applications in humans."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusions (as presented by the authors of the scientific work):

"Endurance exercise is a potent stimulus to induce mitochondrial biogenesis in skeletal muscle (Holloszy, 1967; Molé et al., 1971; Oscai and Holloszy, 1971; Hoppeler et al., 1973; Spina et al., 1996). The nutritional approaches described herein could provide a framework to support endurance training via enhancing mitochondrial biogenesis. In this context, we propose that these small molecules should be viewed as exercise enhancers, not mimetics, as they have minimal effect in basal conditions. In the future, it will be interesting to explore the efficacy of using these nutrients in human studies in vivo, to identify the exercise setting in which they may have the most benefit as well as developing optimal supplementation strategies. In this regard, future studies could examine the effect of bioactives during and in recovery from exercise across a variety of intensities, and also examine supplementation during periods of tapering or detraining to shed light on the practical implications of bioactives as regulators of mitochondrial biogenesis in skeletal muscle. In order to achieve this, researchers should perform randomized, placebo-controlled, intervention trials in human subjects (Hasler, 2002), and examine the extent to which the bioactive ingredient in question is absorbed and bioavailable in skeletal muscle (Crowe et al., 2013). Once achieved, it is hoped that bioactives such as those discussed, and derivatives/associated bioactive ingredients yet to be identified may lead to the next-generation of nutritional supplements to specifically enhance mitochondrial adaptations to endurance training."


Full-text access of the referenced scientific work:

Craig DM, Ashcroft SP, Belew MY, Stocks B, Currell K, Baar K, Philp A.
Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial
biogenesis. Front Physiol. 2015 Oct 27;6:296. doi: 10.3389/fphys.2015.00296.
eCollection 2015. Review. PubMed PMID: 26578969; PubMed Central PMCID:
PMC4621424.
https://www.researchgate.net/publication/283451923_Utilizing_small_nutrient_compounds_as_enhancers_of_exercise-induced_mitochondrial_biogenesis


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Thursday, April 6, 2017

Chronic diseases and aging: potential applications of circadian clock-enhancing small molecules


Abstract (as presented by the authors of the scientific work):

"Normal physiological functions require a robust biological timer called the circadian clock. When clocks are dysregulated, misaligned, or dampened, pathological consequences ensue, leading to chronic diseases and accelerated aging. An emerging research area is the development of clock-targeting compounds that may serve as drug candidates to correct dysregulated rhythms and hence mitigate disease symptoms and age-related decline. In this review, we first present a concise view of the circadian oscillator, physiological networks, and regulatory mechanisms of circadian amplitude. Given a close association of circadian amplitude dampening and disease progression, clock-enhancing small molecules (CEMs) are of particular interest as candidate chronotherapeutics. A recent proof-of-principle study illustrated that the natural polymethoxylated flavonoid nobiletin directly targets the circadian oscillator and elicits robust metabolic improvements in mice. We describe mood disorders and aging as potential therapeutic targets of CEMs. Future studies of CEMs will shed important insight into the regulation and disease relevance of circadian clocks."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Future directions and concluding remarks (as presented by the authors of the scientific work):

"Circadian amplitude regulation and pharmacological modifiers are exciting research topics with promising translational potential. The list of CEMs will likely continue to grow, either from phenotypic screening, as in the case of NOB, or from targeted ligand development (14). On the other hand, pharmacological agents shown to target or mimic clock-enhancing pathways such as CR, TRF, and exercise are a rich venue for discovery of additional clock-targeting agents (63, 130, 161, 170). For example, a growing number of small molecules or drugs have been shown to extend life span and health span, including those deliberately designed to mimic CR and other manipulations (170, 171). Future studies should characterize their circadian clock effects and delineate molecular mechanisms.

Besides metabolic diseases, mood disorders, and aging, other chronic diseases such as neurodegenerative diseases (172, 173) have also been shown to correlate with dampened circadian amplitude or clock dysregulation and may represent new venues for studies of clock modifiers. In addition to antidepressive effects, several studies have shown neurological efficacies of NOB using transgenic disease models (Table ​(Table2).2). For example, 11-day oral administration of NOB resulted in an overall memory improvement in olfactory-bulbectomized (OBX) mice based on the step-through passive-avoidance task and the Y-maze test (111). OBX mice share clinical features with both human neurodegenerative diseases and major depression (174). The depression-like phenotype is thought to derive from pathological or compensatory mechanisms within the cortical–hippocampal–amygdala circuit, which typically involve deterioration of spine density and/or synaptic strength changes (175). Future studies are required to determine the specific role of circadian clocks and RORs in disease models.

Significant gaps of knowledge remain regarding circadian amplitude regulation, especially the mechanisms employed by CEMs. At the intracellular level, questions of particular interest include gene expression regulation, such as cofactor recruitment, epigenetic mechanisms, and chromosome dynamics (1). At the intercellular and system levels, other coupling molecules in addition to VIP and the communication between peripheral and central clocks are outstanding questions (50). It is conceivable that CEMs execute distinct mechanistic schemes to restore a robust overall output under disease or aging conditions. Exemplified by the complex and divergent ROR mechanisms when bound by distinct ligands (74, 90, 91), a detailed mechanistic understanding is important to fully exploit the therapeutic potential of individual CEMs.

In conclusion, circadian clocks safeguard physiological health, and dysregulated and dampened clocks can serve as therapeutic targets to mitigate disease symptoms. Exciting functional and mechanistic studies await to develop CEMs as novel preventive and therapeutic agents."


Full-text access of the referenced scientific work:

Gloston GF, Yoo SH, Chen ZJ. Clock-Enhancing Small Molecules and Potential
Applications in Chronic Diseases and Aging. Front Neurol. 2017 Mar 15;8:100. doi:
10.3389/fneur.2017.00100. eCollection 2017. Review. PubMed PMID: 28360884; PubMed
Central PMCID: PMC5350099.
https://www.researchgate.net/publication/315060004_Clock-Enhancing_Small_Molecules_and_Potential_Applications_in_Chronic_Diseases_and_Aging


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Tuesday, April 4, 2017

Avocado: scientific review of possible health benefits


Abstract (as presented by the authors of the scientific work):

"Hass avocados, the most common commercial avocado cultivars in the world, contain a variety of essential nutrients and important phytochemicals. Although the official avocado serving is one-fifth of a fruit (30 g), according to NHANES analysis the average consumption is one-half an avocado (68 g), which provides a nutrient and phytochemical dense food consisting of the following: dietary fiber (4.6 g), total sugar (0.2 g), potassium (345 mg), sodium (5.5 mg), magnesium (19.5 mg), vitamin A (43 μg), vitamin C (6.0 mg), vitamin E (1.3 mg), vitamin K1 (14 μg), folate (60 mg), vitamin B-6 (0.2 mg), niacin (1.3 mg), pantothenic acid (1.0 mg), riboflavin (0.1 mg), choline (10 mg), lutein/zeaxanthin (185 μg), phytosterols (57 mg), and high-monounsaturated fatty acids (6.7 g) and 114 kcals or 1.7 kcal/g. The avocado oil consists of 71% monounsaturated fatty acids (MUFA), 13% polyunsaturated fatty acids (PUFA), and 16% saturated fatty acids (SFA), which helps to promote healthy blood lipid profiles and enhance the bioavailability of fat soluble vitamins and phytochemicals from the avocado or other fruits and vegetables, naturally low in fat, which are consumed with avocados. There are eight preliminary clinical studies showing that avocado consumption helps support cardiovascular health. Exploratory studies suggest that avocados may support weight management and healthy aging."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusions (as presented by the authors of the scientific work):

"In the context of a healthy diet, consumption of avocados can fit into a full range of healthy eating plans (e.g., DASH diet plan). According to NHANES data, the average avocado consumption is one-half fruit, which provides for a nutrient and phytochemical dense food consisting of significant levels of the following: dietary fiber, potassium, magnesium, vitamin A, vitamin C, vitamin E, vitamin K1, folate, vitamin B-6, niacin, pantothenic acid, riboflavin, choline, lutein/zeaxanthin, phytosterols, and MUFA rich oil at 1.7 kcal/g. This caloric density is medium-low because an avocado is about 80% by weight is water (72%) and dietary fiber (6.8%). Unlike the typical fruit, avocados contain a very low sugar content with only about 0.2 g sugar per one-half fruit. There are eight preliminary avocado cardiovascular health clinical studies that have consistently demonstrated positive heart healthy effects on blood lipids profiles. This is primarily because of avocado's low SFA and high-unsaturated fatty acids (MUFA and PUFA) content, but its natural phytosterols and dietary fiber may play potential secondary cholesterol lowering roles. Avocados also have a diverse range of other nutrients and phytochemicals that may have beyond cholesterol vascular health benefits. In particular, avocado's potassium and lutein may help promote normal blood pressure and help to control oxidative/inflammatory stress, respectfully. The consumption of avocados with salads or salsa increases the bioavailability of carotenoids multi-fold, which may add to the potential health benefits. More comprehensive avocado clinical research is underway to significantly expand the scientific understanding of avocados in cardiovascular health, weight management, blood glucose control and healthy living."


Full-text access of the referenced scientific work:

Dreher ML, Davenport AJ. Hass avocado composition and potential health
effects. Crit Rev Food Sci Nutr. 2013;53(7):738-50. doi:
10.1080/10408398.2011.556759. Review. PubMed PMID: 23638933; PubMed Central
PMCID: PMC3664913.
https://www.researchgate.net/publication/236613037_Hass_Avocado_Composition_and_Potential_Health_Effects


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Sunday, April 2, 2017

Recent advances in Parkinson's disease therapy


Abstract (as presented by the author of the scientific work):

"This article summarizes (1) the recent achievements to further improve symptomatic therapy of motor Parkinson's disease (PD) symptoms, (2) the still-few attempts to systematically search for symptomatic therapy of non-motor symptoms in PD, and (3) the advances in the development and clinical testing of compounds which promise to offer disease modification in already-manifest PD. However, prevention (that is, slowing or stopping PD in a prodromal stage) is still a dream and one reason for this is that we have no consensus on primary endpoints for clinical trials which reflect the progression in prodromal stages of PD, such as in rapid eye movement sleep behavior disorder (RBD) -a methodological challenge to be met in the future."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusions (as presented by the author of the scientific work):

"Neurologists have to accept that the majority of patients with PD, even at the very early stage of neurological diagnosis, actually present a late-stage phenotype of an alpha-synucleinopathy. Thus, PD has started at least 20 years before it manifests in the clinic with its motor symptoms. Neurologists will likely have to shift their clinical and diagnostic focus away from the dopaminergic system to symptoms related to different parts of the nervous system, such as the enteric system62, the brainstem with its autonomic control areas, the locus coeruleus57, or even the skin. If the dream of a disease-modifying therapy is to come true, neuroscience, drug development, and physician scientists face at least two challenges. First, drug development will target the aggregation and propagation of alpha-synuclein and of related mechanisms as well as mitochondrial dysfunction; second, a major effort has to be made to enhance the diagnostic methodology in order to identify a primary endpoint for clinical neuroprotective trials, not only in early motor PD but also in the prodromal stages of PD82–84. It has never been so exciting as today to work in the field of PD, and we should share this belief with the patients we diagnose, treat, and care for."


Full-text access of the referenced scientific work:

Oertel WH. Recent advances in treating Parkinson's disease. F1000Res. 2017 Mar
13;6:260. doi: 10.12688/f1000research.10100.1. eCollection 2017. Review. PubMed
PMID: 28357055; PubMed Central PMCID: PMC5357034.
https://f1000research.com/articles/6-260/v1


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Friday, March 31, 2017

What are the effects of essential oils from plants on pathogenic bacteria?


Abstract (as presented by the authors of the scientific work):

"The increasing resistance of microorganisms to conventional chemicals and drugs is a serious and evident worldwide problem that has prompted research into the identification of new biocides with broad activity. Plants and their derivatives, such as essential oils, are often used in folk medicine. In nature, essential oils play an important role in the protection of plants. Essential oils contain a wide variety of secondary metabolites that are capable of inhibiting or slowing the growth of bacteria, yeasts and moulds. Essential oils and their components have activity against a variety of targets, particularly the membrane and cytoplasm, and in some cases, they completely change the morphology of the cells. This brief review describes the activity of essential oils against pathogenic bacteria."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusions (as presented by the authors of the scientific work):

"The action of EOs and their components on bacteria remains a focal area for future research. The study of the synergistic effects among EOs and/or their components could be utilized both to make best use of their antibacterial activity and to reduce their concentrations required to achieve a particular antibacterial effect for food safety and for health purposes."


Full-text access of the referenced scientific work:

Nazzaro F, Fratianni F, De Martino L, Coppola R, De Feo V. Effect of essential
oils on pathogenic bacteria. Pharmaceuticals (Basel). 2013 Nov 25;6(12):1451-74.
doi: 10.3390/ph6121451. PubMed PMID: 24287491; PubMed Central PMCID: PMC3873673.
http://www.mdpi.com/1424-8247/6/12/1451/htm


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Tuesday, March 28, 2017

New study points that two-thirds of cancers might be due to unavoidable errors associated with DNA replication, not inheritance or lifestyle


Abstract (as presented by the authors of the scientific work):

"Cancers are caused by mutations that may be inherited, induced by environmental factors, or result from DNA replication errors (R). We studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries throughout the world. The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. The major role of R mutations in cancer etiology was supported by an independent approach, based solely on cancer genome sequencing and epidemiological data, which suggested that R mutations are responsible for two-thirds of the mutations in human cancers. All of these results are consistent with epidemiological estimates of the fraction of cancers that can be prevented by changes in the environment. Moreover, they accentuate the importance of early detection and intervention to reduce deaths from the many cancers arising from unavoidable R mutations."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Concluding paragraph (as presented by the authors of the scientific work):

"As a result of the aging of the human population, cancer is today the most common cause of death in the world (12). Primary prevention is the best way to reduce cancer deaths. Recognition of a third contributor to cancer—R mutations—does not diminish the importance of primary prevention but emphasizes that not all cancers can be prevented by avoiding environmental risk factors (Figs. 2 and 3). Fortunately, primary prevention is not the only type of prevention that exists or can be improved in the future. Secondary prevention, i.e., early detection and intervention, can also be lifesaving. For cancers in which all mutations are the result of R, secondary prevention is the only option."


Full-text access of the referenced scientific work:

Tomasetti C, Li L, Vogelstein B. Stem cell divisions, somatic mutations,
cancer etiology, and cancer prevention. Science. 2017 Mar 24;355(6331):1330-1334.
doi: 10.1126/science.aaf9011. PubMed PMID: 28336671.
http://science.sciencemag.org/content/355/6331/1330.full


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Saturday, March 25, 2017

Cancer acidity and its potential as therapeutic target


Abstract (as presented by the authors of the scientific work):

"The link between cancer metabolism and immunosuppression, inflammation and immune escape has generated major interest in investigating the effects of low pH on tumor immunity. Indeed, microenvironmental acidity may differentially impact on diverse components of tumor immune surveillance, eventually contributing to immune escape and cancer progression. Although the molecular pathways underlying acidity-related immune dysfunctions are just emerging, initial evidence indicates that antitumor effectors such as T and NK cells tend to lose their function and undergo a state of mostly reversible anergy followed by apoptosis, when exposed to low pH environment. At opposite, immunosuppressive components such as myeloid cells and regulatory T cells are engaged by tumor acidity to sustain tumor growth while blocking antitumor immune responses. Local acidity could also profoundly influence bioactivity and distribution of antibodies, thus potentially interfering with the clinical efficacy of therapeutic antibodies including immune checkpoint inhibitors. Hence tumor acidity is a central regulator of cancer immunity that orchestrates both local and systemic immunosuppression and that may offer a broad panel of therapeutic targets. This review outlines the fundamental pathways of acidity-driven immune dysfunctions and sheds light on the potential strategies that could be envisaged to potentiate immune-mediated tumor control in cancer patients."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Concluding remarks and clinical implications (as presented by the authors of the scientific work):

"Many of the known mechanisms of tumor immune escape appear exquisitely and selectively tailored for defined molecular immune pathways, as if tumor cells, through a Darwinian pressure, were forced to lose specific features in order to survive immune attack. A classical example of this process is the loss of tumor or HLA-class I antigens, rendering cancer cells completely invisible to T lymphocytes but at the same time more susceptible to NK cell killing [166]. In a totally opposite trend, tumor acidity could instead be envisaged as a sort of “global protection shield”, by which cancer cells, through a single and relatively simple biochemical pathway, simultaneously wipe out the activity of all antitumor immune effectors and convert regulatory immune cells to protumor allies (Fig. 3). If so, correcting tumor pH should specularly lead to a rebalance of physiological immune responses and the concomitant recovery of multiple antitumor functions.

As a matter of fact, despite research investigating the immunological effects of cancer acidity is still in its infancy, data emerging from preclinical investigations depict a rich scenario of promising candidates for potential immunomodulation in clinical setting. Findings available up to date predict that buffering tumor pH should contribute to a recovery of antitumor T and NK cells and a relief of the detrimental effects exerted by immunosuppressive stroma components. Such an approach might be applied to improve spontaneous cancer immune control, or most likely to potentiate the efficacy of tumor immunotherapy. Contrasting the protumor activity of stromal myeloid cells, by specific immune depletion or blockade of selective signaling pathways, has been convincingly reported to overcome resistance to ICIs at preclinical level [115]. In this view, the hypothesis of introducing an alternative strategy to interrupt cancer/myeloid interaction by antagonizing tumor acidity sounds quite appealing.

Reversion of acidity in the TME might be obtained by systemic buffering with bicarbonate fostering an improved efficacy of PD-1 blockade [43]. The antagonism of cancer acidity is also obtainable by administration of PPIs including omeprazole and analogues. These drugs, recently receiving much attention for their unexpected therapeutic potential in oncology, have shown to reproducibly increase tumor pH in a selective manner, thanks to their nature of prodrugs specifically activated by low-pH of tumor milieu (in addition to gastric environment). PPIs potentiate DC-based cancer vaccines and adoptive T cell transfer in tumor murine models, and synergize with chemotherapy in breast cancer and sarcoma patients [93] ;  [167]. Their safety and accessibility promote omeprazole-related PPIs as promising therapeutic strategy to revert the detrimental effects on antitumor immune responses, simultaneously interfering with autocrine signaling pathways that sustain tumor growth and progression [168]. Indeed, it is established that administration of esomeprazole is associated with increased extracellular tumor pH and this is paralleled by a beneficial effect on antitumor immunity in murine models [41]. Although PPIs have been developed to bind the gastric H,K-ATPase, and definitive data on their actual cross-reactivity with V-ATPase are still scantly [169]; [170] ;  [171].

The possibility to selectively buffer the acidic TME, independently of the underlying molecular mechanisms, underscores the potential role of PPIs as innovative strategy of immunomodulation in cancer patients. Studies focused on the binding and inhibitory activity of PPIs on V-ATPase expressed in tumor or immune cells and the related functional outcomes are encouraged to improve our knowledge about the clinical potential of these promising drugs in cancer.

This could be the case of myeloid cells, which are known to upregulate V-ATPase and CAs under different conditions in response to hypoxic and dysmetabolic stress [172] ;  [173]. Thus, the administration of drugs interfering with the activity of these pumps could help reconditioning the whole immunosuppressive context of the TME, favoring an optimized scenario for conventional T cell activity and antitumor responses. We have collected evidence that esomeprazole can reduce the frequency of MDSCs in melanoma-bearing mice and patients, and this effect is associated with concomitant activation of T cells [Umansky and Rivoltini, unpublished observation]. Interestingly, novel therapeutic tools for blocking V-ATPase function in different pathological conditions are under development, including small molecules, for more selective activity and possibly a better tolerability in clinical setting [174].

Old and novel drugs interfering with TME acidity could thus be envisaged as potential innovative tools of immunomodulation in cancer patients, particularly in synergy with immunotherapeutic strategies. In fact, pH-modulating drugs might represent one possible choice to overcome tumor resistance and potentiate clinical benefit of ICIs. A potential prediction of this synergism may come from the established evidence that cancer patients with high LDH plasma level usually fail to respond to both CTLA-4 and PD-1 blockade [175] ;  [176]."


Full-text access of the referenced scientific work:

Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, Tuccitto A,
Tagliabue E, Castelli C, Rivoltini L. Cancer acidity: an ultimate frontier of
tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol.
2017 Mar 3. pii: S1044-579X(17)30036-6. doi: 10.1016/j.semcancer.2017.03.001.
Review. PubMed PMID: 28267587.
http://www.sciencedirect.com/science/article/pii/S1044579X17300366


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Thursday, March 23, 2017

The health-promoting and microbiota-modulating properties of the fermented beverage kefir


Abstract (as presented by the authors of the scientific work):

"Kefir is a complex fermented dairy product created through the symbiotic fermentation of milk by lactic acid bacteria and yeasts contained within an exopolysaccharide and protein complex called a kefir grain. As with other fermented dairy products, kefir has been associated with a range of health benefits such as cholesterol metabolism and angiotensin-converting enzyme (ACE) inhibition, antimicrobial activity, tumor suppression, increased speed of wound healing, and modulation of the immune system including the alleviation of allergy and asthma. These reports have led to increased interest in kefir as a focus of research and as a potential probiotic-containing product. Here, we review those studies with a particular emphasis on the microbial composition and the health benefits of the product, as well as discussing the further development of kefir as an important probiotic product."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusion (as presented by the authors of the scientific work):

"The purpose of this review has been to collate and summarize that which is known about the microbial composition of kefir and how this composition plays a role in the health benefits associated with kefir consumption. Kefir is a dynamic fermented dairy product with many different factors affecting the benefits associated with its consumption. These factors include the variable yeast and bacterial species present, as well as metabolites such as kefiran and other exopolysaccharides. While kefir has been associated with health benefits for 100s of years, the exact form of these benefits has, until recently, not been studied. The use of animal models and other in vitro analyses has allowed for the elucidation of how kefir positively impacts host health. Whole kefir, as well as specific fractions and individual organisms isolated from kefir, provide a multitude of positive effects when consumed. These range from improved cholesterol metabolism and wound healing, to the modulation of the immune system and microbiome, and even the potential alleviation of allergies and cancers. Further studies into the mechanisms behind these effects will allow scientists to better understand exactly how kefir and other fermented dairy products confer these benefits as well as how to harness these traits outside of kefir itself.

The wide range of potential health promoting effects of kefir could lead to a further expansion on the popularity of both traditional fermented kefir and products that are manufactured with kefir fractions or organisms. In order to fully exploit the beneficial characteristics of kefir, a more in-depth understanding of the composition of kefir is critical. With advances in metagenomic analysis through the development of high-throughput sequencing technology, this is a very realistic prospect. Armed with this knowledge, it should be possible to more readily isolate and examine the phenotypic characteristics of individual organisms present in a kefir blend while also providing a greater insight into the evolution of these organisms and how they became specialized to the kefir ecosystem. The additional knowledge gained can also provide crucial information relating to the mechanisms and exact agents responsible for beneficial effects that have been attributed to kefir (Atalan et al., 2003; Rodrigues et al., 2005; Huseini et al., 2012; Rahimzadeh et al., 2014).

The need for further research does not only apply to the mechanisms by which kefir consumption exerts these effects but also which organisms or parts of kefir are responsible for each benefit. By determining which organisms and metabolites are essential for each process, the possibility arises for the commercial manufacturing of kefir that is specifically designed to create the most profound effect in those that consume it. As it stands currently, the highly variable nature of the organisms and metabolites present in traditional kefir requires health claims to be verified individually in each grain and kefir beverage. The ability to combine the best possible strains of the best organisms from multiple sources of kefir would create the potential for greater benefits than have been previously observed, with a measure of control over these effects that has not been possible in traditional kefir."


Full-text access of the referenced scientific work:

Bourrie BC, Willing BP, Cotter PD. The Microbiota and Health Promoting
Characteristics of the Fermented Beverage Kefir. Front Microbiol. 2016 May
4;7:647. doi: 10.3389/fmicb.2016.00647. Review. PubMed PMID: 27199969; PubMed
Central PMCID: PMC4854945.

Traditional use of medicinal plants to combat disease: special journal issue


Submission is open for an ethnopharmacology-focused special issue of the journal Frontiers in Pharmacology (IF=4.4, Q1), guest edited by Atanas G. Atanasov, Judith Maria Rollinger, Judit Hohmann, and Anna Karolina Kiss.

With an emphasis on traditional European medicine, the special issue encourages submissions related to phytochemistry, clinical studies with herbal preparations, bioactivities and mechanism of action studies with natural products, pharmacokinetics and biotransformation of phytochemicals, field and observational studies on the use of local and traditional medicinal plants etc.



The submission of the following article types is particularly encouraged: Original Research, Methods, Protocols, Technology Reports, Reviews, Mini-Reviews, Hypothesis & Theory, Perspectives, Data Reports, General Commentary, Opinions, and Book Reviews.

The full text of the submission call with all further details and requirements can be viewed at:

http://journal.frontiersin.org/researchtopic/6024/ethnopharmacology-in-central-and-eastern-europe-in-the-context-of-global-research-developments



Sunday, March 19, 2017

The novel dietary supplement methylsulfonylmethane (MSM): applications and safety


Abstract (as presented by the authors of the scientific work):

"Methylsulfonylmethane (MSM) has become a popular dietary supplement used for a variety of purposes, including its most common use as an anti-inflammatory agent. It has been well-investigated in animal models, as well as in human clinical trials and experiments. A variety of health-specific outcome measures are improved with MSM supplementation, including inflammation, joint/muscle pain, oxidative stress, and antioxidant capacity. Initial evidence is available regarding the dose of MSM needed to provide benefit, although additional work is underway to determine the precise dose and time course of treatment needed to provide optimal benefits. As a Generally Recognized As Safe (GRAS) approved substance, MSM is well-tolerated by most individuals at dosages of up to four grams daily, with few known and mild side effects. This review provides an overview of MSM, with details regarding its common uses and applications as a dietary supplement, as well as its safety for consumption."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusions (as presented by the authors of the scientific work):

"MSM is a naturally occurring organosulfur compound with broad biological effects. Human absorption and biosynthesis of this compound likely depends heavily on the co-metabolism between microbiota and host. Whether naturally produced or manufactured, MSM exhibits no biochemical differences in its ability to intermediate oxidative stress and inflammation. This micronutrient is well tolerated for arthritis and a number of other conditions related to inflammation, physical function, and performance. Emerging research suggests that MSM may one day aid in the treatment of various types of cancer [49,99,100,101,119,120,121,122,123,125,126,181,184,185,186,194] or metabolic syndromes [195]."


Full-text access of the referenced scientific work:

Butawan M, Benjamin RL, Bloomer RJ. Methylsulfonylmethane: Applications and
Safety of a Novel Dietary Supplement. Nutrients. 2017 Mar 16;9(3). pii: E290.
doi: 10.3390/nu9030290. Review. PubMed PMID: 28300758.
http://www.mdpi.com/2072-6643/9/3/290/htm


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Thursday, March 16, 2017

Stress-induced despair behavior and intestinal microbiota: can eating yogurt combat depression?


Abstract (as presented by the authors of the scientific work):

"Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice. Restoring intestinal Lactobacillus levels was sufficient to improve the metabolic alterations and behavioral abnormalities. Mechanistically, we identified that Lactobacillus-derived reactive oxygen species may suppress host kynurenine metabolism, by inhibiting the expression of the metabolizing enzyme, IDO1, in the intestine. Moreover, maintaining elevated kynurenine levels during Lactobacillus supplementation diminished the treatment benefits. Collectively, our data provide a mechanistic scenario for how a microbiota player (Lactobacillus) may contribute to regulating metabolism and resilience during stress."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Discussion (as presented by the authors of the scientific work):

"Taken together, our results demonstrate that microbiome homeostasis was robustly altered in animals undergoing UCMS, with a consistent decrease in Lactobacilli. This finding was shared across three strains of mice (C57BL/6J, as BALB/cJ and C57BL/6N). Moreover, our data suggest that the production of H2O2 by Lactobacillus may be protective against the development of despair behavior by direct inhibition of intestinal ido1 expression and decrease in the circulating level of kynurenine, a metabolite associated with depression26.

Our results are in agreement with recent literature demonstrating that microbiome composition is modified with acute and chronic stress20,33,34. Microbiome dysbiosis is also detected in humans affected by major depressive disorders and the transplantation of the biota from these patients in germ free mice can induce despair behavior9. Beyond describing microbiome fluctuation as a consequence of UCMS, we further demonstrated that levels of Lactobacillus correlate with the susceptibility to and severity of despair behaviors. Indeed, animals exhibiting low (i.e. Taconic C57BL/6N mice) intestinal Lactobacillus levels present with a basal despair phenotype, when compared to animals with higher levels of Lactobacillus (i.e. Jackson C57BL/6J mice). Accordingly, therapeutic administration of a probiotic Lactobacillus species during UCMS was sufficient to improve the despair symptoms. Further works will be needed to explore the role of other populations of bacteria affected by UCMS, as well as Lactobacillus strain differences and their abilities to improve behavior.

Recently, members of the Lactobacillus genus have been shown to affect a multitude of aspects of human physiology, as they colonize several sites of the body, including the skin, the vagina, and the entirety of the gastrointestinal tract, starting with the oral cavity35. Perhaps best studied in the vagina, Lactobacilli protect against infection by producing a diversity of antimicrobial factors, including lactic acid, peroxide, bacteriocins, as well as by resource competition35,36,37. Although in a few contexts increased levels of Lactobacilli are associated with pathology, e.g. dental cavities38, the bacteria are largely non-pathogenic or beneficial. From dysbioses or probiotic studies, Lactobacilli are associated with protection against infection, improved recovery after enteric infections, decreased colitis pathology, and better cognitive function25,39,40,41.

While Lactobacilli are able to control other microbial communities through secretion of antimicrobial factors, genetic limitations make them more sensitive to environmental conditions. In particular, many Lactobacillus genus members are unable to synthesize amino acids and purines and thus rely on nutrient rich environments and other bacteria for supply of essential building blocks42,43,44,45. We hypothesize that, in the context of a faster intestinal transit, such as the one observed in stressed animals, fluctuating availability of nutrients and symbiotic bacteria will impact the renewal of the Lactobacillus niche46. Further studies will be able to determine whether there is indeed a causal relationship between increased intestinal motility and microbiota alteration in the context of stress, or rather if the dysbiosis induced during stress causes altered intestinal physiology.

We found that the level of kynurenine is increased after chronic stress, in a manner dependent on Lactobacillus levels. Kynurenine can readily cross the blood-brain barrier to drive depression within the CNS by disrupting neurotransmitter balance and driving neuroinflammation27,47. A recent study by Agudelo et al.26 identified this pathway as also being disrupted in stressed mice using the same model of UCMS. Taken together, these new findings point to disruptions in tryptophan-kynurenine metabolism as an important factor in mediating despair behavior. IDO1 is the main enzyme responsible for conversion of tryptophan to kynurenine outside of the liver, and its expression and activity can be directly inhibited by reactive oxygen species (ROS)32. Members of the Lactobacillus family have the capacity to produce high levels of ROS, as a means of maintaining their niche36,37. In our study, we have shown that decreased levels of ROS in stressed animals correlate with an increase in intestinal ido1 transcripts, thus potentially explaining our observed increase in circulating kynurenine. Moreover, several studies have shown that inhibiting IDO1 activity (such as with the small molecule 1-methyl tryptophan) has potent effects in ameliorating depressive-like behaviors both in chronic stress and inflammation-induced sickness behavior models48,49,50.

The inhibition of IDO1 by Lactobacillus-derived ROS is likely just one of the mechanisms through which Lactobacilli, and L. reuteri in particular, contribute to host physiology and modulate behavior. Our findings are in accordance with the previously reported beneficial effect of L. reuteri administration on despair and anxiety-like behaviors25. Nevertheless, in their study, Bravo and colleagues have shown that L. reuteri can modulate GABA receptor expression in the CNS, via the vagus nerve25. The vagus nerve has been shown to carry peripheral signals and modulate inflammatory and stress reponses51,52,53,54. Whether the two results are connected remains to be investigated. It is possible that intestinal kynurenine can signal on the afferent vagal terminals and modulate its effects in the CNS, including its modulation of the hypothalamus-pituitary adrenal (HPA) axis. To this point, it is important to consider the contribution of liver TDO to peripheral kynurenine levels. TDO expression and activity are increased by glucocorticoids and in response to acute stress, and play a role in glucocorticoid levels homeostasis55,56,57. Whether TDO levels decrease chronically in our long-term stress model (following an expected decrease of corticosterone) or what effect the Lactobacillus administration has remains to be investigated. We have also considered other possible mechanisms for the behavioral effects of L. reuteri supplementation, mediated by the immune system, or other populations of commensals affected by the treatment. Further studies will be necessary to assess the chronological and the hierarchical role of each pathway during despair behavior development, as well as how these pathways affect the CNS.

Altogether, our results indicate that the microbiome can play a causative role in the development and symptomatology of depression. Further studies are needed to prove a causal relationship between intestinal Lactobacillus levels and depressive-like behavior. Moreover, investigation of whether Lactobacilli can play a similar function in human biology and if manipulation of Lactobacillus levels and/or local induction of ROS production in the gut could be used to treat psychiatric disorders is warranted."


Full-text access of the referenced scientific work:
Marin IA, Goertz JE, Ren T, Rich SS, Onengut-Gumuscu S, Farber E, Wu M,
Overall CC, Kipnis J, Gaultier A. Microbiota alteration is associated with the
development of stress-induced despair behavior. Sci Rep. 2017 Mar 7;7:43859. doi:
10.1038/srep43859. PubMed PMID: 28266612; PubMed Central PMCID: PMC5339726.
https://www.researchgate.net/publication/314302451_Microbiota_alteration_is_associated_with_the_development_of_stress-induced_despair_behavior


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At


Monday, March 13, 2017

The stomach in health and disease


Abstract (as presented by the authors of the scientific work):

"The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):






Conclusions (as presented by the authors of the scientific work):

"Healthy stomach: future approach to gastric diseases

The stomach occupies the central role in orchestrating the digestive process, and this is frequently underestimated. Moreover, gastric acid secretion in the last decades has been seen as a ‘bystander’ with little function but with deleterious potential for itself and adjacent organs, the oesophagus and duodenum. As a consequence, the pharmacological approach has been towards the development of more potent drugs for acid inhibition. Due to the increasing awareness of GI functional disorders, the role of the stomach has been revisited in its role as site of origin for dyspeptic symptoms. More recently, attention has focused on the stomach for its control function in food intake and for contributing to maintenance of metabolic balance (figure 10).

The future approach to gastric diseases (box 3) is directed to maintaining a healthy stomach, which is free from discomfort, ulceration and the risk of complications and malignancy. The main challenge remains the elimination of H. pylori infection from individual patients and from populations. An estimated 20% of H. pylori-infected people will continue to suffer from overt clinical upper GI symptoms and complications over their lifetime, and some may develop extra-digestive diseases. The individual outcome of anyone infected with H. pylori cannot be predicted. Therefore, a public health approach should be directed towards ‘screen and treat’ strategies that will have to be adapted to the needs of different populations according to the prevalence of H. pylori infection and gastric cancer risk stratification. Gastric disease prevention programmes should be integrated with more comprehensive GI prevention strategies. The combination of H. pylori screening and eradication programmes with colorectal cancer screening is an initiative promoted and coordinated by the Healthy Stomach Initiative (HSI) (http://www.hsinitiative.org).

Gastric cancer is still a major challenge worldwide, and because detection is frequently made only at an advanced stage, mortality has remained high.216 ,217 Gastric cancer prevention programmes by H. pylori eradication have been shown of benefit in high-risk populations.193 The best results from gastric cancer prevention strategies are obtained when H. pylori eradication is performed before advanced atrophic gastritis with pre-neoplastic changes becomes established and thus implementation of H. pylori screening and treatment in early adulthood is required. Secondary prevention by H. pylori eradication following endoscopic resection of early gastric cancer has major limitations.218 With pre-neoplastic conditions such as atrophy and IM already present, carcinogenic pathways are more likely to progress in spite of the eradication of H. pylori infection. Future research will need to focus on unravelling mechanisms involved in progression from pre-neoplastic lesions to cancer.

The recent definition of H. pylori gastritis as an infectious disease by the Kyoto global consensus conference, January 2014, is expected to raise concern and engender support from regulatory authorities towards the global elimination of H. pylori infection and its serious sequelae.150

Despite these important indications and calls for a widespread approach to the eradication of H. pylori infection, there remain substantial challenges. The first includes achieving the ideal effective therapy without significant side effects and no antibiotic resistance. Such an ideal therapy is not yet available, and therefore, H. pylori eradication therapy, beyond the established specific clinical indications, should embark on selected screen and treat strategies. For the time being, these strategies will have to address populations with a high to moderate incidence of gastric cancer. The search for a ‘golden treatment bullet’ continues to remain one option while the second option is an intensified search for a vaccine.

Second, H. pylori infection may confer some benefits to those who do not have gastroduodenal symptoms, nor present with gastroduodenal disease or complications. The reduced prevalence of atopic diseases, such as asthma in patients infected with H. pylori up to young adulthood, requires intensive investigation to understand the mechanism of this phenomenon. Epidemiological and experimental evidence is still limited and cannot yet offer any conclusions about a causal relationship.93 ,219 ,220 Studies on the relationship of H. pylori gastritis will lead to better understanding of both local and systemic immune responses and their impact on gastric diseases.

In addition to the initiatives and strategies to eradicate H. pylori infection, studies are required to better understand the role of the stomach in food intake, accommodation, pre-digestion and the delivery of nutrient for intestinal digestion.38 Research should focus on ways to modulate gastric functions and their role as ‘weight watcher’ and their integration in the balance of hunger and satiety. Studies will need to address to what extent gastric acid should be inhibited and for how long during the 24 h period in patients who suffer from acid-related diseases. Moreover, it will be important to define just how much acid is required to preserve a ‘healthy’ gut microbiome. The role of the gastric microbiota in the presence and absence of H. pylori infection on the diversity of microbiota in the small bowel will be of enormous relevance in understanding and tackling gastric, hepatic and intestinal diseases.221–223

Last, but by no means least, education with effective presentation of new knowledge to the general public to ensure gastric health and prevent disease is a major task to be accomplished and the creation of the HSI for public awareness is a step in this direction."


Full-text access of the referenced scientific work:

Hunt RH, Camilleri M, Crowe SE, El-Omar EM, Fox JG, Kuipers EJ, Malfertheiner P, McColl KE, Pritchard DM, Rugge M, Sonnenberg A, Sugano K, Tack J. The stomach in health and disease. Gut. 2015 Oct;64(10):1650-68. doi:10.1136/gutjnl-2014-307595. Review. PubMed PMID: 26342014; PubMed Central PMCID: PMC4835810.
https://www.researchgate.net/publication/281510130_The_stomach_in_health_and_disease


Webmaster:

Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At



Sunday, March 12, 2017

How beneficial is Silymarin/Silybin use in chronic liver disease?


Abstract (as presented by the authors of the scientific work):

"
Silymarin is the extract of Silybum marianum, or milk thistle, and its major active compound is silybin, which has a remarkable biological effect. It is used in different liver disorders, particularly chronic liver diseases, cirrhosis and hepatocellular carcinoma, because of its antioxidant, anti-inflammatory and antifibrotic power. Indeed, the anti-oxidant and anti-inflammatory effect of silymarin is oriented towards the reduction of virus-related liver damages through inflammatory cascade softening and immune system modulation. It also has a direct antiviral effect associated with its intravenous administration in hepatitis C virus infection. With respect to alcohol abuse, silymarin is able to increase cellular vitality and to reduce both lipid peroxidation and cellular necrosis. Furthermore, silymarin/silybin use has important biological effects in non-alcoholic fatty liver disease. These substances antagonize the progression of non-alcoholic fatty liver disease, by intervening in various therapeutic targets: oxidative stress, insulin resistance, liver fat accumulation and mitochondrial dysfunction. Silymarin is also used in liver cirrhosis and hepatocellular carcinoma that represent common end stages of different hepatopathies by modulating different molecular patterns. Therefore, the aim of this review is to examine scientific studies concerning the effects derived from silymarin/silybin use in chronic liver diseases, cirrhosis and hepatocellular carcinoma."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusions (as presented by the authors of the scientific work):

"
The “marriage of many years” that links silymarin/silybin to liver diseases, derives from the progressive evidence that, with the passing of time, has led to investigation of, firstly empirically and then scientifically, the mechanisms through which they act in carrying out the therapeutic effect. The studies of pharmacokinetics and pharmacodynamics on silymarin have improved, in the last few years, its applicability in different pathologies, especially liver diseases, allowing, through the use of conjugates compounds, a more efficient application. Through the analysis of literature, it has been demonstrated that silymarin has an effect that allows its use in all of the most frequent causes of liver damage. Indeed, silymarin has three important activities: anti-inflammatory, antioxidant and pro-apoptotic, which represent the “functional triad” that allows for antagonizing the onset and the progression of mechanisms of damage that are responsible for the progression of hepatitis to cirrhosis and HCC. However, it is clear that, also in the end stages of liver pathologies, silymarin can act by limiting de-novo fibrogenesis and antagonizing procarcinogenic mechanisms that cause HCC. Nevertheless, the treatment with silymarin/silybin in routine clinical practice is strongly limited, since it is necessary to obtain scientific data deriving from well-structured trials based on large populations of patients, and to achieve a standardization of methods used for evaluating the therapeutic efficacy, especially in an NAFLD context, that is particularly promising."


Full-text access of the referenced scientific work:

Federico A, Dallio M, Loguercio C. Silymarin/Silybin and Chronic Liver
Disease: A Marriage of Many Years. Molecules. 2017 Jan 24;22(2). pii: E191. doi: 
10.3390/molecules22020191. Review. PubMed PMID: 28125040.
http://www.mdpi.com/1420-3049/22/2/191


Webmaster:


Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At



Thursday, March 9, 2017

Role of intestinal microbiota and metabolites in human diseases


Abstract (as presented by the authors of the scientific work):

"
BACKGROUND:
A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health.
METHODS:
This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA).
RESULTS:
In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction.
CONCLUSIONS:
A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment."


Covered topics (the letter size corresponds to the frequency of mentioning in the text):



Conclusions (as presented by the authors of the scientific work):

"
Intestinal microbiota is normally indispensable for shaping host gut immune system and thus contributing to gut homeostasis maintenance, and is also a key mediator in keeping metabolic functions in the peripheral tissues including liver and pancreas. Accumulating evidence has indicated that intestinal microbiota not only induces and reinforces pro-inflammatory immune responses but also elicits immunosuppressive responses. Abnormal microbial-elicited immunosuppression may result in dysregulation in host metabolism and/or impairment in anti-cancer immunity.

Data with regard to commensal bacteria have integrated, which leads up to a conclusion that a number of microbes are fluctuating on the boundary of virulence. B. fragilis is a representative of this phenomenon. This bacterium is able to improve the development of the host adaptive immune system while being confined to the lumen of the intestinal tract, but becomes enterotoxigenic while it contingently traverses the gut epithelial mucosa. Mazmanian et al [103] showed that during colonization of B. fragilis in animals, a bacterial polysaccharide A (PSA) was presented by DCs, which could direct and promote the maturation of the developing immune system [103]. Subsequent work by the same group substantiated the above finding and further explored the mechanisms of its immunomodulatory effects [129]. Not belonging to dominant members of the gut microbiota, B. fragilis is normally absent in conventionally raised SPF mice. Inoculation with B. fragilis has been found to protect mice from colitis in the T-cell-transferred and TNBS-treated animal models. It appeared that the purified B. fragilis PSA was sufficient to act on host analogous to the live bacterium, including the initiation of IL-10 production by Tregs, suppression of Th17 cell production, disease protection from colitis, and colonization of the host [129, 200]. On the other hand, B. fragilis is capable of producing Bft (Bacteriodes fragilis toxin), which acts indirectly by eliciting high levels of ROS and the ensuing damage of host DNA [201]. Sustained high-leveled ROS, once exceeding the host’s DNA repair capacity, may lead to DNA damage and thereby culminating in cell death or oncogenic mutations [202]. Thus B. fragilis is considered to be a risky factor for colorectal cancer in mammals. Such example also illustrates that a subtle balance is maintained between mammal hosts and microbial kingdom [203].

Mucosal surface barriers are essential for host-microbial symbiosis, the former of which are vulnerable to persistent microbial insults and dietary antigenic components, and must be repaired to re-establish homeostasis. Compromised flexibility of the host or microbiota may place itself on a “death tunnel” to malignancy [202]. In addition, manifestations that immunotherapies are displaying efficacy in malignancies of organs such as melanoma, bladder, renal and lung cancers rather than cancer of the colon, the latter being highly-populated by microbes, have garnered extensive attention as to whether and how the microbiota influences immunotherapy’s efficacy [202]. So the interplays of microbiota and immunotherapy efficacy/toxicity need further investigation.

Among the metabolic disorders, NAFLD, which is characteristic of hepatic triglyceride (TG) accumulation rather than being arisen from alcohol abuse, is linked up with ectopic fat accumulation, especially in the liver. T2D is characterized by persistent hyperglycemia. Pathophysiologic mechanisms of NAFLD and T2D in common are believed to be relevant to insulin resistance, lipotoxicity, and inflammation [171]. Insulin resistance is a multi-organ manifestation as observed at the level of the liver, muscle and adipose tissues. Moreover, adipose tissues and the liver can secrete proinflammatory cytokines. In addition to insulin resistance and inflammation, other risk factors may contribute to the elevated incidence of metabolic diseases including lifestyle (high-fat/sugar diets and poor physical activity), gut microbiota alterations and environmental pollutants.

Based on data heretofore, it is hypothesized that the gut microbiota may mediate the influence of lifestyle factors triggering development of NAFLD and T2D [171]. A metagenome-wide association study on 345 Chinese patients with T2D versus healthy individuals has revealed that T2D sufferers exhibited a moderate degree of gut microbial dysbiosis, referring to a dearth of some butyrate-producing bacteria and an elevation in some opportunistic pathogens [204]. As afore-described in Section of “Liver diseases”, an increased prevalence of Firmicutes, a representation of dysbiosis, is found to be linked to NAFLD [168, 169, 205]. Of particular interest, these two metabolic disorders, NAFLD and T2D, to some extent, share similar mechanisms of etiology: being associated with dysbiosis. These novel findings would broaden our knowledge about metabolic influences of a shifted intestinal microbiota beyond the gut and thus benefit our exploration of therapeutic targets for metabolic diseases.

Close to the completion of this manuscript, an interesting paper has been published demonstrating the link of atherosclerosis etiology with abnormal gut microbiota [206]. Studies with low-density lipoprotein receptor (LDLR) −/− mice, an atherosclerotic murine model, revealed that 12-week supplementation of high-fat diet could lead to evident aortic lesions, macrophage infiltration, and collagen level increase, concurrent with an up-regulation of inflammatory factors [206]. This finding suggests that gut microbiota, combined with metabolisms of fatty acids and vitamin B3, could play a profound role in the onset and development of atherosclerosis [206] (Fig. 3).

A growing body of novel “omics” technologies based on next-generation sequencing, nuclear magnetic resonance (NMR) spectroscopy and gas chromatography coupled with flame ionization detector/mass spectrometry (GC–FID/MS) is gaining wide popularity in the field of cardiometabolic diseases in association with microbiota dysbiosis. The integration and comparison of omics-mode data and molecular biological data would offer comprehensive insight into the mechanisms by which microbiota and metabolites thereof influence host immunity and metabolism. Commensal microbiota in the intestine may serve as a consortium with immunologic and endocrine-like activities to modulate the epigenetic status of host cells. Owing to the advances in genome-wide epigenetic analysis, for instance, chromatin immunoprecipitation sequencing (CHIP-Seq), researchers can determine and analyze these epigenetic modifications, thereby deciphering the intrinsic intestinal microbiota–host interactions and unraveling the impacts of microbiota within and beyond the gut such as liver, cardiovascular system, and even CNS."


Full-text access of the referenced scientific work:

Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut
homeostasis and human diseases. BMC Immunol. 2017 Jan 6;18(1):2. doi:
10.1186/s12865-016-0187-3. Review. PubMed PMID: 28061847; PubMed Central PMCID:
PMC5219689.
https://www.researchgate.net/publication/312145121_Role_of_intestinal_microbiota_and_metabolites_on_gut_homeostasis_and_human_diseases


Webmaster:


Prof. Atanas G. Atanasov (Dr. habil., PhD)
https://about.me/Atanas_At