Aging, oxidative stress and degenerative diseases: mechanisms, complications and emerging therapeutic strategies.

Aging accompanied by several age-related complications, is a multifaceted inevitable biological progression involving various genetic, environmental, and lifestyle factors. The major factor in this process is oxidative stress, caused by an abundance of reactive oxygen species (ROS) generated in the mitochondria and endoplasmic reticulum (ER). ROS and RNS pose a threat by disrupting signaling mechanisms and causing oxidative damage to cellular components. This oxidative stress affects both the ER and mitochondria, causing proteopathies (abnormal protein aggregation), initiation of unfolded protein response, mitochondrial dysfunction, abnormal cellular senescence, ultimately leading to inflammaging (chronic inflammation associated with aging) and, in rare cases, metastasis. RONS during oxidative stress dysregulate multiple metabolic pathways like NF-κB, MAPK, Nrf-2/Keap-1/ARE and PI3K/Akt which may lead to inappropriate cell death through apoptosis and necrosis. Inflammaging contributes to the development of inflammatory and degenerative diseases such as neurodegenerative diseases, diabetes, cardiovascular disease, chronic kidney disease, and retinopathy. The body's antioxidant systems, sirtuins, autophagy, apoptosis, and biogenesis play a role in maintaining homeostasis, but they have limitations and cannot achieve an ideal state of balance. Certain interventions, such as calorie restriction, intermittent fasting, dietary habits, and regular exercise, have shown beneficial effects in counteracting the aging process. In addition, interventions like senotherapy (targeting senescent cells) and sirtuin-activating compounds (STACs) enhance autophagy and apoptosis for efficient removal of damaged oxidative products and organelles. Further, STACs enhance biogenesis for the regeneration of required organelles to maintain homeostasis. This review article explores the various aspects of oxidative damage, the associated complications, and potential strategies to mitigate these effects.

Appraisal of the Possible Role of PPARγ Upregulation by CLA of Probiotic Pediococcus pentosaceus GS4 in Colon Cancer Mitigation.

The prevalence of colon cancer (CC) is increasing at the endemic scale, which is accompanied by subsequent morbidity and mortality. Although there have been noteworthy achievements in the therapeutic strategies in recent years, the treatment of patients with CC remains a formidable task. The current study focused on to study role of biohydrogenation-derived conjugated linoleic acid (CLA) of probiotic Pediococcus pentosaceus GS4 (CLAGS4) against CC, which induced peroxisome proliferator-activated receptor gamma (PPARγ) expression in human CC HCT-116 cells. Pre-treatment with PPARγ antagonist bisphenol A diglycidyl ether has significantly reduced the inhibitory efficacy of enhanced cell viability of HCT-116 cells, suggesting the PPARγ-dependent cell death. The cancer cells treated with CLA/CLAGS4 demonstrated the reduced level of Prostaglandin E2 PGE2 in association with reduced COX-2 and 5-LOX expressions. Moreover, these consequences were found to be associated with PPARγ-dependent. Furthermore, delineation of mitochondrial dependent apoptosis with the help of molecular docking LigPlot analysis showed that CLA can bind with hexokinase-II (hHK-II) (highly expressed in cancer cells) and that this association underlies voltage dependent anionic channel to open, thereby causing mitochondrial membrane depolarization, a condition that initiates intrinsic apoptotic events. Apoptosis was further confirmed by annexin V staining and elevation of caspase 1p10 expression. Taken all together, it is deduced that, mechanistically, the upregulation of PPARγ by CLAGS4 of P. pentosaceus GS4 can alter cancer cell metabolism in association with triggering apoptosis in CC.

Development impact bonds in developing countries: an emerging innovation for achieving social outcomes.

This research focuses on the development of impact bonds (DIBs), a newly emerging alternative financial innovative product for financing social results in developing countries. DIBs are an agreement between several parties working towards a development goal. The idea of DIBs has not been thoroughly investigated. The various dimensions of DIBs, including their structure, evolution, conduct, and performance, are the focus of this research. This study examines the idea of DIBs specifically concerning developing countries based on an analytical review of grey literature. According to our research, when it comes to DIBs, policymakers have prioritised their policies more towards health, followed by employment and training, education, poverty reduction, and agriculture.

Suicide linked to PUBG video gaming: A case report.

PUBG is an online multiplayer battle game played in India. It is causing addiction in teenagers and adolescents and they refuse any kind of interruption while playing. We report a college student who committed suicide by hanging when scolded by his parents for playing PUBG on his mobile phone and whose parents would not provide the internet pack recharge for it. There have been other cases in India, inviting a discussion to prevent addiction with a law to regulate its use.

Probiotic Enterococcus faecalis AG5 mitigated high fat diet induced obesity and produced propionic acid stimulated apoptosis in 3T3-L1 pre-adipocyte.

AIMS: Probiotics and their metabolites (SCFA) can regulate energy homeostasis. The present study thus evaluates the synergistic effect of probiotic Enterococcus faecalis AG5 on HFD induced obesity and the role of propionic acid (PA) in apoptosis induction of 3T3-L1 pre-adipocyte. METHODS: Male Wistar rats (n = 24) were used to develop an HFD induced obesity model for 24 weeks. The effect of the orally administered probiotic AG5 (18th-24th weeks, 1 × 109 CFU/ml) was evaluated using physiological, biochemical, anthropometry, histopathological and serological analyses. Apoptosis in 3T3-L1 pre-adipocyte was assessed using flow cytometry, protein expression of PPARγ, 5-LOX, NF-κB, p-AKT, caspase 10 and detection of caspase 3/7 by Immunofluorescence confirmed the apoptosis induced by PA. KEY FINDINGS: Probiotic AG5 significantly reduced body weight, BMI, serum cholesterol, triglycerides (p < 0.05) and improved HDL, insulin and leptin but lowered LDL and VLDL (p > 0.05). An inflammatory response was reduced as evident by TNF-α IHC. AG5 reduced adipocyte hypertrophy and fatty acid accumulation. Flow cytometry confirmed late apoptosis in PA-AG5 and standard PA treated 3T3-L1 cells. 5-LOX inhibition is associated with apoptosis induction, and increased caspase 1p 10 is related to cell death initiation. The study initially showed a low PPARγ activity inhibiting 5-LOX which may relate to adipose apoptosis. Finally caspase 3/7 detection using immunofluorescence proved the role of PA in adipocyte apoptosis. SIGNIFICANCE: The present study is a novel approach towards obesity mitigation involving adipocyte apoptosis. The role of SCFA in adipocyte apoptosis is very limited which can prove to be novel therapeutic approach in the future.

Cell adherence efficacy of probiotic Pediococcus pentosaceus GS4 (MTCC 12683) and demonstrable role of its surface layer protein (Slp).

The current study examined the cell adherence property of probiotic Pediococcus pentosaceus GS4 (MTCC12683) with the characterization and functionality in adherence of its surface layer protein (GS4-Slp). The Slp of P. pentosaceus GS4 was extracted purified and detected using SDS-PAGE (98 kDa) and size exclusion chromatography. The cell adherence property of probiotic GS4 (Slp+/Slp-) was evaluated on buccal cells and HCT-116. Purified Slp was found neutralized with raised anti-Slp showing reduced adherence to HCT-116 as evident from SEM analysis. The structure of GS4-Slp was determined by MALDI-TOF analysis, CD analysis, atomic force microscopy (AFM), and FT-IR spectrometry. In Silico approach revealed its indirect similarity with cell membrane protein of Helicobacter pylori. Results thus reveal that GS4 has the potential of the production of 98 kDa Slp which facilitates the cell adherence property. This added probiotic attribute will enhance the probiotic potentials of P. pentosaceus GS4 to use it biotechnologically. SIGNIFICANCE: Probiotic Pediococcus pentosaceus GS4 facilitates demonstrable colonization by the elaboration of Slp. This property imparts a value to the strain and claims to be more useful biotechnologically.

Probiotic Enterococcus faecalis AG5 effectively assimilates cholesterol and produces fatty acids including propionate.

Probiotics are known for their health-promoting abilities through the production of various metabolites, and also benefits are membrane associated. Probiotic Enterococcus faecalis AG5 has been previously assessed for its probiotic properties and this study further strengthens that claim. Strain AG5 was inoculated with 0.3% sodium glychocholate (glycine conjugated) and bile salt mixture for different time periods. The percentage assimilation of cholesterol ranged from 14% to 33.1% in the bile salt mixture, but was slightly higher, ranging from 16.55% to 53.1%, in sodium thioglycocholate alone. Similarly, the bile salt hydrolysis activity was measured in terms of cholic acid release at different intervals. The overall range of cholic acid released ranged from 70.4 to 479 µg/mL. Fatty acid production is also an important criterion for a probiotic selection and it was found that the strain produced several long-chain fatty acids (LCFA) such as tetradecanoic acid, hexadecanoic acid, octadecanoic acid and bis(6-methylheptyl) phthalate. Besides LCFA, AG5 produced short-chain fatty acids (SCFA) such as propionic acid, which was estimated comparing liquid chromatography and mass spectrometry with standard SCFA. Thus the ability of deconjugation of bile salt and SCFA production is a value-added property of probiotic AG5, with the promise of being beneficial for human health.

Characterization of Functional, Safety, and Probiotic Properties of Enterococcus faecalis AG5 Isolated From Wistar Rat, Demonstrating Adherence to HCT 116 Cells and Gastrointestinal Survivability.

Gut microbiota remains a prominent source for a diverse range of potential probiotics. In this context, the current study explored the rectal region of experimental Wistar rat for the isolation of potent probiotic. Sixteen lactic acid bacteria (LAB), from rectal swab of Wistar rats, were subjected to evaluation of probiotic properties. Among all, AG5 was found unique with consistent probiotic properties and was further identified as Enterococcus faecalis AG5 (NCBI accession number KT248537) using 16S rDNA sequencing, followed by BLAST analysis. Since the Enterococci strains inhibit various food-borne pathogens efficiently while proving itself as a safe probiotic candidate, the study further evaluated the safety of the strain AG5 using primer specific PCR amplification which revealed the existence of gene encoding gelE, asa1, efaA, ace, vanA, and vanB and negative for cylA, hyl, and esp respectively. SEM analysis confirmed the adherence ability of AG5 to HCT 116 cells. Adherence was found to be non-colonial and scattered manner. Furthermore, the strain demonstrated a significant survivability during simulated gastrointestinal transit. Taken together, the E. faecalis AG5 was found potential probiotic candidate with future implication in both food and health industry.

Obesity: An overview of possible role(s) of gut hormones, lipid sensing and gut microbiota.

Obesity is one of the major challenges for public health in 21st century, with 1.9 billion people being considered as overweight and 600 million as obese. There are certain diseases such as type 2 diabetes, hypertension, cardiovascular disease, and several forms of cancer which were found to be associated with obesity. Therefore, understanding the key molecular mechanisms involved in the pathogenesis of obesity could be beneficial for the development of a therapeutic approach. Hormones such as ghrelin, glucagon like peptide 1 (GLP-1) peptide YY (PYY), pancreatic polypeptide (PP), cholecystokinin (CCK) secreted by an endocrine organ gut, have an intense impact on energy balance and maintenance of homeostasis by inducing satiety and meal termination. Glucose and energy homeostasis are also affected by lipid sensing in which different organs respond in different ways. However, there is one common mechanism i.e. formation of esterified lipids (long chain fatty acyl CoAs) and the activation of protein kinase C δ (PKC δ) involved in all these organs. The possible role of gut microbiota and obesity has been addressed by several researchers in recent years, indicating the possible therapeutic approach toward the management of obesity by the introduction of an external living system such as a probiotic. The proposed mechanism behind this activity is attributed by metabolites produced by gut microbial organisms. Thus, this review summarizes the role of various physiological factors such as gut hormone and lipid sensing involved in various tissues and organ and most important by the role of gut microbiota in weight management.

Delayed presentation and surgical management of a bronchial tear.

Tracheobronchial injuries following blunt trauma to the chest can be life-threatening. However, failure to diagnose can lead to various acute or chronic complications. A delayed presentation is quite rare and its surgical correction is highly challenging. We present here two cases, which came to us after four and six months of trauma respectively. In these patients, successful surgical repair of totally obstructed right main bronchus in the first case and left main bronchus in the other was carried out. The post-operative course was uneventful with improvement in the respiratory status of both the patients. High degree of suspicion and awareness of the possibility of bronchial tear are required for proper management of such cases.