Ravichandra Vemuri

Therapeutic interventions for gut dysbiosis and related disorders in the elderly: Antibiotics, probiotics or faecal microbiota transplantation?

Ageing and physiological functions of the human body are inversely proportional to each other. The gut microbiota and host immune system co-evolve from infants to the elderly. Ageing is accompanied by a decline in gut microbial diversity, immunity and metabolism, which increases susceptibility to infections. Any compositional change in the gut is directly linked to gastrointestinal disorders, obesity and metabolic diseases. Increase in opportunistic pathogen invasion in the gut like Clostridium difficile leading to C. difficile infection is more common in the elderly population. Frequent hospitalisation and high prevalence of nosocomial infections with the ageing is also well documented. Long-term utilisation of broad-spectrum antibiotic therapy is being followed in order to control these infections. Nosocomial infections and antibiotic therapy in combination or alone is leading to gastroenteritis followed by Clostridium associated diarrhoea or antibiotic associated diarrhoea. Above all, use of broad-spectrum antibiotics is highly debated all over the world due to growing antimicrobial resistance. The use of narrow spectrum antibiotics could be helpful to some extent. Dietary supplementation of probiotics with prebiotics (synbiotics) or without prebiotics has improved gut commensal diversity and regulated the immune system. The recent emergence of faecal microbiota transplantation has played an important role in treating recurrent Clostridium associated diarrhoea. This review focuses on various therapeutic interventions for gut dysbiosis and gastrointestinal diseases in the elderly. The possible mechanism for antimicrobial resistance and mechanism of action of probiotics are also discussed in detail.

A Review on SIRtuins in Diabetes

BACKGROUND Type-2 Diabetes is a long lasting disease characterized by high glucose concentration in the blood due to insulin resistance. One of the recent treatment strategies is using activators against SIRT-1, which has been in clinical trials. Hence, it is necessary to know the effects of the SIRT-1 modulators against various metabolic pathways. METHODS Many cellular processes, including insulin secretion, cell cycle, and apoptosis are imperatively regulated by a family of mediators called SIRTuins. First known mammalian sirtuin, SIRT1 is a positive regulator of insulin secretion, which triggers glucose uptake and utilization. For the past decade, a major outstanding question is whether SIRT1 activation is a safe therapy for human diseases such as diabetes? RESULTS This review summarizes and discusses the advances of the past decade and the challenges that will brazen out perplexity of this field. We also cover the physiological regulation of sirtuin (SIRT1) activity and how these modes of regulation may be exploited to manipulate SIRT1 activity in cells. Designing of drugs using advanced computational methods that specifically target SIRT1, and also, involvement of advanced biological methods for further understanding of sirtuin1 biology to afford new optimized treatments for diabetes and several age related human diseases. CONCLUSION Hence, this review is a serial perspective of all the above topics.

Gut Microbial Changes, Interactions, and Their Implications on Human Lifecycle: An Ageing Perspective

Gut microbiota is established during birth and evolves with age, mostly maintaining the commensal relationship with the host. A growing body of clinical evidence suggests an intricate relationship between the gut microbiota and the immune system. With ageing, the gut microbiota develops significant imbalances in the major phyla such as the anaerobic Firmicutes and Bacteroidetes as well as a diverse range of facultative organisms, resulting in impaired immune responses. Antimicrobial therapy is commonly used for the treatment of infections; however, this may also result in the loss of normal gut flora. Advanced age, antibiotic use, underlying diseases, infections, hormonal differences, circadian rhythm, and malnutrition, either alone or in combination, contribute to the problem. This nonbeneficial gastrointestinal modulation may be reversed by judicious and controlled use of antibiotics and the appropriate use of prebiotics and probiotics. In certain persistent, recurrent settings, the option of faecal microbiota transplantation can be explored. The aim of the current review is to focus on the establishment and alteration of gut microbiota, with ageing. The review also discusses the potential role of gut microbiota in regulating the immune system, together with its function in healthy and diseased state.

A human origin strain Lactobacillus acidophilus DDS-1 exhibits superior in vitro probiotic efficacy in comparison to plant or dairy origin probiotics

Background: The health benefits of probiotics are well established and known to be strain-specific. However, the role of probiotics obtained from different origins and their efficacy largely remains unexplored. The aim of this study is to investigate the in vitro efficacy of probiotics from different origins. Methods: Probiotic strains utilized in this study include Lactobacillus acidophilus DDS-1 (human origin), Bifidobacterium animalis ssp. lactis UABla-12 (human origin), L. plantarum UALp-05 (plant origin) and Streptococcus thermophilus UASt-09 (dairy origin). Screening assays such as in vitro digestion simulation, adhesion, cell viability and cytokine release were used to evaluate the probiotic potential. Results: All strains showed good resistance in the digestion simulation process, especially DDS-1 and UALp-05, which survived up to a range of 107 to 108 CFU/mL from an initial concentration of 109 CFU/mL. Two human colonic mucus-secreting cells, HT-29 and LS174T, were used to assess the adhesion capacity, cytotoxicity/viability, and cytokine quantification. All strains exhibited good adhesion capacity. No significant cellular cytotoxicity or loss in cell viability was observed. DDS-1 and UALp-05 significantly upregulated anti-inflammatory IL-10 and downregulated pro-inflammatory TNF-α cytokine production. All the strains were able to downregulate IL-8 cytokine levels. Conclusion: Of the 4 strains tested, DDS-1 demonstrated superior survival rates, good adhesion capacity and strong immunomodulatory effect under different experimental conditions.

Cell stress signaling cascades regulating cell fate.

Initiating anti-apoptotic signaling or triggering cell death depends to a great extent on the nature or source of cellular stress and cell type. Interplay between each stress response eventually determines the fate of stressed cell. Numerous factors induce cell death by a number of pathways including apoptosis, autophagy and necrosis. Not surprisingly, some of the pathways are interrelated to each other through a mediator that could articulate the entire mechanism. The present review attempts to consolidate all the pathways included in intrinsic cellular stress such as oxidative stress and autophagy, endoplasmic reticular stress (ERS) and mitophagy and apoptosis as fate in cell stress. These stress responses are a hallmark of numerous diseases including neurodegenerative diseases, diabetes and cancer. Understanding the cross-talk between different intrinsic cell stress responses will help to develop new therapeutic targets and hence lead to the development of new therapeutics.

Role of Lactic Acid Probiotic Bacteria in IBD

BACKGROUND IBD is considered as one of the major public health concerns worldwide. The pathophysiology and gut microbial alteration during inflammatory bowel disease (IBD) are still not completely understood. Gut microbiota is implicated in most of the gastro-intestinal (GI) diseases including IBD. From the time of gut microbiota establishment and through aging, it undergoes a lot of changes in the composition. METHODS In a healthy state, the composition of beneficial microbes in the gut is comparatively higher and due to factors such as malnutrition, use of antibiotics and any underlying diseases allow the colonization and invasion of pathogens. RESULTS A careful manipulation of gut microbiota during disease conditions such as IBD is required. Probiotics are natural, safe and useful interventions for GI diseases. CONCLUSION Lactic acid probiotic bacteria have shown many beneficial effects in various gastrointestinal and inflammatory disorders. This review focuses on the use of probiotics in IBD and possible mechanism of probiotics in inflammation conditions.

Momordicacharantia: A New Strategic Vision to Improve the Therapy of Endoplasmic Reticulum Stress

BACKGROUND Endoplasmic reticulum is the major site for protein biosynthesis. Any perturbation in the endoplasmic reticulum will compromise its functions and reduce its efficiency in protein biosynthesis. As a result, misfolded proteins are produced and accumulated in the endoplasmic reticulum. This will result in endoplasmic reticulum stress, which reduces the quantity and quality of the functional protein synthesized from the cell. Besides that, the protein biosynthesis is also highly affected by oxidative stress. Oxidative stress is a condition where the cell has excessive exogenous and endogenous radical oxygen species overwhelming the human bodys antioxidant mechanisms. Recent researches have shown that endoplasmic reticulum stress has a strong relationship with oxidative stress and both of them can form a vicious cycle that exacerbates endoplasmic reticulum stress and oxidative stress. Endoplasmic reticulum stress and oxidative stress are harmful to human health since they can disrupt cellular homoeostasis and damage cells. METHOD This work reported several studies that demonstrate that endoplasmic reticulum stress and oxidative stress have a vital role in the pathogenesis of several diseases, such as diabetes and colitis. RESULTS Further research is needed to develop the therapeutic strategies that resolve endoplasmic reticulum stress and oxidative stress in order to treat these diseases. CONCLUSION Currently, Momordicacharantia attracts worldwide attentions due to its various beneficial effects as the functional foods and can possibly help in treating endoplasmic reticulum stress and oxidative stress.

Strophanthus hispidus attenuates the Ischemia-Reperfusion induced myocardial Infarction and reduces mean arterial pressure in renal artery occlusion

Background: The myocardium is generally injured in the case of reperfusion injury and arterial damage is caused by hypertension. In reference to these statements, the present study was focused. Cardiac glycosides were said to have protective effects against myocardial infarction and hypertension. Strophanthus hispidus was thus incorporated in the study. Objective: The prime objective of the study was to investigate the protective effects of Strophanthus hispidus against ischemia-reperfusion myocardial Infarction and renal artery occluded hypertension in rats. Materials and Methods: The animal model adopted was surgically-induced myocardial ischemia, performed by means of left anterior descending coronary artery occlusion (LAD) for 30 min followed by reperfusion for another 4 h. Infarct size was assessed by using the staining agent TTC (2,3,5-triphenyl tetrazolium chloride). Hypertension was induced by clamping the renal artery with renal bulldog clamp for 4 h. Results: The study was fruitful by the effect of Strophanthus hispidus on infarction size, which got reduced to 27.2 ± 0.5and 20.0 ± 0.2 by 500 mg/Kg and 1000 mg/Kg ethanolic extracts which was remarkably significant when compared with that of the control group 52.8 ± 4.6. The plant extract did reduce heart rate at various time intervals. There was also a protective effect in the case of mean arterial blood pressure were the 500 mg/Kg and 1000 mg/Kg of the plant extract did reduce the hypertension after 60 minutes was 60.0 ± 4.80 and 50.50 ± 6.80. Conclusion: The results suggest that 500 mg/Kg and 100 mg/Kg ethanolic extract of Strophanthus hispidus was found to possess significant cardiac protective and anti-hypertensive activity.

Lactobacillus acidophilus DDS-1 Modulates the Gut Microbiota and Improves Metabolic Profiles in Aging Mice

Recent evidence suggests that gut microbiota shifts can alter host metabolism even during healthy aging. Lactobacillus acidophilus DDS-1, a probiotic strain, has shown promising probiotic character in vitro, as well as in clinical studies. The present study was carried out to investigate whether DDS-1 can modulate the host metabolic phenotype under the condition of age-affected gut microbial shifts in young and aging C57BL/6J mice. Collected fecal samples were analyzed using 16S rRNA gene sequencing for identifying gut microbiota and untargeted gas chromatography-mass spectrometry (GC-MS) metabolomics analysis. Gut microbial shifts were observed in the control groups (young and aging), leading to an alteration in metabolism. Principal coordinate analysis (PCoA) of microbiota indicated distinct separation in both the DDS-1-treated groups. L. acidophilus DDS-1 increased the relative abundances of beneficial bacteria, such as Akkermansia muciniphila and Lactobacillus spp., and reduced the relative levels of opportunistic bacteria such as Proteobacteria spp. Metabolic pathway analysis identified 10 key pathways involving amino acid metabolism, protein synthesis and metabolism, carbohydrate metabolism, and butanoate metabolism. These findings suggest that modulation of gut microbiota by DDS-1 results in improvement of metabolic phenotype in the aging mice.

Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells

Sustained endoplasmic reticular stress (ERS) is implicated in aggressive metastasis of cancer cells and increased tumor cell proliferation. Cancer cells activate the unfolded protein response (UPR), which aids in cellular survival and adaptation to harsh conditions. Inhibition of apoptosis, in contrast, is a mechanism adopted by cancer cells with the help of the inhibitor of an apoptosis (IAP) class of proteins such as Survivin to evade cell death and gain a proliferative advantage. In this study, we aimed to reveal the interrelation between ERS and Survivin. We initially verified the expression of Survivin in Winnie (a mouse model of chronic ERS) colon tissues by using immunohistochemistry (IHC) and immunofluorescence (IF) in comparison with wild type Blk6 mice. Additionally, we isolated the goblet cells and determined the expression of Survivin by IF and protein validation. Tunicamycin was utilized at a concentration of 10 µg/mL to induce ERS in the LS174T cell line and the gene expression of the ERS markers was measured. This was followed by determination of inflammatory cytokines. Inhibition of ERS was carried out by 4Phenyl Butyric acid (4PBA) at a concentration of 10 mM to assess whether there was a reciprocation effect. The downstream cell death assays including caspase 3/7, Annexin V, and poly(ADP-ribose) polymerase (PARP) cleavage were evaluated in the presence of ERS and absence of ERS, which was followed by a proliferative assay (EdU click) with and without ERS. Correspondingly, we inhibited Survivin by YM155 at a concentration of 100 nM and observed the succeeding ERS markers and inflammatory markers. We also verified the caspase 3/7 assay. Our results demonstrate that ERS inhibition not only significantly reduced the UPR genes (Grp78, ATF6, PERK and XBP1) along with Survivin but also downregulated the inflammatory markers such as IL8, IL4, and IL6, which suggests a positive correlation between ERS and the inhibition of apoptosis. Furthermore, we provided evidence that ERS inhibition promoted apoptosis in LS174T cells and shortened the proliferation rate. Moreover, Survivin inhibition by YM155 led to a comparable effect as that of ERS inhibition, which includes attenuation of ERS genes and inflammatory markers as well as the promotion of programmed cell death via the caspase 3/7 pathway. Together, our results propose the interrelation between ERS and inhibition of apoptosis assigning a molecular and therapeutic target for cancer treatment.