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The SARS-CoV-2 outbreak has posed a plethora of problems for the global healthcare system and socioeconomic burden. Despite valiant efforts to contain the COVID-19 outbreak, the situation has deteriorated to the point that there are no viable preventive therapies to treat this disease. The case count has skyrocketed globally due to the newly evolved variants. Despite vaccination drives, the re-occurrence of recent pandemic waves has reinforced the importance of innovation/utilization of immune-booster to achieve appropriate long-term vaccine protection. Plant-derived immuno-adjuvants, which have multifaceted functions, can impede infections by boosting the immune system. Many previous studies have shown that formulation of vaccines using plant-derived adjuvant results in long-lasting immunity may overcome the natural tendency of coronavirus immunity to wane quickly. Plant polysaccharides, glycosides, and glycoprotein extracts have reportedly been utilized as enticing adjuvants in experimental vaccines, such as Advax, Matrix-M, and Mistletoe lectin, which have been shown to be highly immunogenic and safe. When employed in vaccine formulation, Advax and Matrix-M generate long-lasting antibodies, a balanced robust Th1/Th2 cytokine profile, and the stimulation of cytotoxic T cells. Thus, the use of adjuvants derived from plants may increase the effectiveness of vaccines, resulting in the proper immunological response required to combat COVID-19. A few have been widely used in epidemic outbreaks, including SARS and H1N1 influenza, and their use could also improve the efficacy of COVID-19 vaccines. In this review, the immunological adjuvant properties of plant compounds as well as their potential application in anti-COVID-19 therapy are thoroughly discussed.

The aim of this study is to develop a one-step real-time PCR assay for SARS-CoV-2 detection. A lysis solution was prepared using Tween-20, Triton X-100, EDTA, and tris buffer (pH 7.4) and various parameters were optimised. Adding carrier molecules [Poly (A), glycogen, and linear polyacrylamide] to the lysis solution significantly improved RT-qPCR efficacy. Poly (A) was the most effective of all carriers. Diagnostic potential of this Poly (A) solution was demonstrated using 150 positives and 200 negative swabs, and the sensitivity of the RT-qPCR diagnostic test was estimated to be 98.6 (95%CI; 96.0, 101.17, p

Two new steroidal saponins, named 26-O-β- d -glucopyranosyl-22ξ-hydroxy-(25R)-furost-5-en-3β, 26-diol, 3-O-β [xylopyranosyl (1→3) α- l -rhamnopyranosyl (1→2) β- d -glucopyranoside] (1) and 3-O-β- d -xylopyranosyl (1→3) α- l -rhamnopyranosyl (1→3) β- d -glucopyranoside diosgenin (2), along with protobioside (3), diosgenin (4), β-sitosterol (5) and β-Sitosterol-3-O-β- d -glucopyranoside (6) were isolated from the rhizomes of Polygonatum verticillatum. The structures were elucidated based on physicochemical parameters and spectroscopic analysis. NMR (1 & 2D techniques) was employed to estimate compounds (1-6) in the parent extract (E1) and its fractions (E2 and E4). Cytotoxicity studies of parent extract (E1) and isolates were evaluated against A549 and MCF-7 cell lines. Compounds 1 and 2 exhibited potent cytotoxic activity in both the cell lines and induces apoptosis. These findings will provide two new potent anticancer molecules for the chemical repository.

Background Nutraceuticals often referred as medicinally or nutritionally functional foods has drawn extensive attention in recent years because of their wide array of pharmacological activities. It has been well established that the consumption of nutraceuticals is consistently linked with protection from chronic diseases such as diabetes, heart disease, cancer and neurodegenerative diseases. However, these nutraceuticals are associated with therapeutic limitations because of their poor aqueous solubility, low permeability, short half-lives which ultimately leads to low bioavailability to humans. Therefore, to overcome these issues self-emulsifying formulation approach which compose of oils, surfactants and co-solvents have been demonstrated to be an encouraging approach for augmenting the bioavailability and therapeutic efficacy of the nutraceuticals. Scope and approach In this review, we discuss various key constituents in self-emulsifying formulations and provide recent efforts to generate “solid self-emulsifying formulations” and “supersaturable self-emulsifying formulations” to overcome the problems related with liquid self-emulsifying formulations. We also covered the mechanisms by which self-emulsifying formulations can affect nutraceutical absorption, augment the bioavailability and consequently therapeutic efficacy of nutraceuticals after oral administration. Finally, the potential of this formulation approach for nutraceuticals delivery is critically discussed. Key findings The self-emulsifying formulations have potential to augment the oral bioavailability and consequently therapeutic efficacy of nutraceuticals by various mechanisms such as reduction in intra-enterocyte metabolism by cytochrome P450 enzymes, inhibiting P-glycoprotein (P-gp) efflux transporter and bypass hepatic first-pass metabolism through lymphatic pathway. Conclusion Self-emulsifying formulations have emerged as preferable system for the formulation of nutraceuticals because of their ease of large-scale production, higher loading capacity, better dissolution behaviour of poorly water-soluble nutraceuticals, enhancement of oral bioavailability and their commercial potential.

SARS-CoV-2, like all RNA viruses, evolves over time, and genetic mutations have been linked to increased replication fitness and evolvability. SARS-CoV-2 spreads quickly between countries, resulting in new mutations. SARS-CoV-2 genome sequencing reveals that variants emerge through point mutations, insertions, and deletions. Concerns have been raised about the ability of currently approved vaccines to protect against emerging variants. Viral spike protein is a component of many approved vaccine candidates, and mutations in the S-protein may affect transmission dynamics and the risk of immune escape, resulting this pandemic last-longer in populations. Understanding the evolution of the SARS-CoV-2 virus, as well as its potential relationship with transmissibility, infectivity, and disease severity, may help us predict the consequences of future pandemics. SARS-CoV-2 genome studies have identified a few mutations that could potentially alter the transmissibility and pathogenicity of the SARS-CoV-2 virus. At the moment, it is worth mentioning that a few variants have increased the transmissibility of SARS-CoV-2. The Alpha, Beta, Gamma, Delta, Delta+, and omicron variants are designated as variants of concern (VOCs) by the World Health Organisation and have been linked with an increased risk to the community in terms of transmission, hospitalisation, and mortality. This chapter thoroughly discusses the impact of SARS-CoV-2 mutations, mainly VOCs, on public health by mining many published articles.

Picrorhiza kurroa Royle ex Benth. is a high-altitude plant having great medicinal value. However, its medicinal value at the peptide level is still unknown, which limits its utility in the development of peptide-based therapeutics. Here, we identify 65 peptides fromP. kurroa hydrolysate. Sequence analysis suggests that one novel bioactive peptide, ASGLCPEEAVPRR (BP1), has antioxidant potential and shows angiotensin-converting enzyme (ACE) and dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. The molecular docking study showed that BP1 has a lower binding energy and strong affinity toward active pockets of ACE and DPP-IV, which explains its higher ACE [IC50 = 59.90 ± 9.52 μg/mL (43.40 μM)] and DPP-IV [IC50 = 3.04 ± 0.26 μg/mL (2.2 μM)] inhibitory activities. BP1 protects HEK293 cells from H2O2-induced oxidative damage by inhibiting intracellular reactive oxygen species (ROS) and malondialdehyde accumulation and activating the intrinsic antioxidant defense system. Additionally, phase-contrast microscopy studies revealed that pre-treatment of BP1 to HEK293 cells before exposure to H2O2 retains the normal morphology and blocks apoptosis. Furthermore, it also suppresses ROS-induced mitochondrial apoptosis via restoring the mitochondrial membrane potential (ΔΨm) and inhibiting caspase 3/7 activity. Therefore, BP1 has antioxidant potential and ACE and DPP-IV inhibitory activities that could be used for peptide-based formulation(s) in pharmaceuticals to treat diabetes, cardiovascular diseases, and other diseases associated with ROS.

A large body of emerging evidence has revealed the role of p38/MK2 and PI3K/Akt/GSK3β cascades in the orchestrating process of colitis. Rutin, a bioflavonoid present in many fruits and vegetables, has been recognized to offer therapeutic attributes in acute colitis. However, its role in chronic colitic condition has not yet been delineated in reference to p38/MK2 and PI3K/Akt/GSK3β signalling. The present investigation assessed the efficacy and underlying molecular mechanism of rutin in alleviating DSS-induced chronic colitis. The analysis of signalling pathways demonstrated the robust activation of PI3K/Akt/GSK3β/MAPKs/NF-κB and p38/MK2 in DSS-induced colitis in animals, which was efficiently alleviated following the rutin treatment. In silico studies indicated its target specificity with these pathways. Rutin administration markedly improved the disease activity score, colon length, goblet cell loss and compromised colon epithelial integrity in colitic mice. Decreased expression of oxi-inflammatory markers such as IgM, IgE, iNOS, ICAM-1, HO-1 and Th1/IL-10 cytokines ratios after treatment suggests its efficacy in regulating effector, regulatory and B cell homeostasis. Additionally, rutin demonstrated its role in restoring epithelial integrity by modulating the transcript levels of tight junction proteins, mucus-secreting proteins, epithelial cell proliferation and apoptosis. Treg expansion revealed that rutin supplementation also exhibits an immune regulatory potential and suppresses inflammatory aggravation mediated by adaptive immune responses. Overall, results indicate that the modulation of p38/MK2 and PI3K/Akt/GSK3β/NF-κB pathways by rutin represents a novel therapeutic approach in chronic colitis that help to curb dysregulated intestinal integrity, cytokine ratio and splenic Tregs.

Emerging evidence suggests that sustained diabetes-associated factors such as inflammation, hyperinsulinemia, and hyperglycemia are major contributors to aberrant cell proliferation and subsequent neoplastic transformation. Epidemiological studies have also highlighted that diabetes promoting a sedentary lifestyle, with or without the direct involvement of insulin, is frequently linked to cancer. However, our knowledge regarding the molecular mechanisms that correlate hyperglycemia to oncogenic transformations remains limited. In this regard, a recent study has proved that hyperglycemia inactivates AMPK, which results in the destabilization of the TET2 and its tumour-suppressive role ultimately predisposing diabetes mellitus patients to cancer. To the management of hyperglycemia associated with oncogenesis, we need to explore a reverse pharmacology-based ethnopharmacological approach. Botanical-derived natural products are structurally and functionally more diverse with fewer or no side effects on humans. The present review discusses the molecular link between hyperglycemia and cancer progression with the effect of natural products as therapeutic agents on the hyperglycemia-cancer associated signalling pathway.

Background The multifactorial process of aging predisposes elderly to recurring infections and inflammatory disorders which ultimately affect quality of life and longevity. Dietary polyphenols are presently the forerunners for developing nutrition-based pro-longevity interventions due to their documented diverse health beneficial effects. Scope and approach Studies reviewing the accumulating anti-aging effects of polyphenols vis-a-vis our expanding understanding of the aging process are lacking. Therefore, the present review discusses the emerging interrelationship of oxi-inflammatory stress, cellular senescence and immunosenescence as the causal nexus of aging and explores the preventive and therapeutic role of polyphenols in mitigating these disorders. Polyphenols based pro-longevity approaches, targets and mechanisms have been reviewed. Key findings and conclusions Molecular aetiology of aging is governed by the accumulation of senescent cells (SC), chronic oxi-inflammatory stress and immunosenescence. Polyphenols have shown multifaceted effects in attenuating the development and accumulation of SC, cellular oxidative stress as well as immune dysfunctions in several in vitro and in vivo studies. Evidence suggesting polyphenols mediated increase in lifespan through modulation of longevity pathways such as mTOR and calorie restriction are also documented. Although limited, but recent experiments in human setting have confirmed the potential of polyphenols in targeting SC. In addition, amalgamation of polyphenols with probiotics is another promising nutraceutical approach with implications in aging. Together, this review highlights the impact of polyphenols in augmenting lifespan and preventing age-associated disorders and encourages research on novel polyphenols-based strategies and clinical trials for ultimately developing a nutrition oriented holistic anti-aging therapy.

Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the effectiveness of interventions. Asymptomatic breakthrough infections have been a major problem during the ongoing surge of Delta variant globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines used in the higher-income regions. Here, we show for the first time how statistical and machine learning (ML) approaches can discriminate SARS-CoV-2 infection from immune response to an inactivated whole virion vaccine (BBV152, Covaxin, India), thereby permitting real-world vaccine effectiveness assessments from cohort-based serosurveys in Asia and Africa where such vaccines are commonly used. Briefly, we accessed serial data on Anti-S and Anti-NC antibody concentration values, along with age, sex, number of doses, and number of days since the last vaccine dose for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine (SVM) model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, 724 were classified as infected. Since the vaccine contains wild-type virus and the antibodies induced will neutralize wild type much better than Delta variant, we determined the relative ability of a random subset of such samples to neutralize Delta versus wild type strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, Delta variant, was neutralized more effectively than the wild type, which cannot happen without infection. The fraction rose to 71.8% (28 of 39) in subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%-80.2%) over the same period.

Recently, probiotics have gained much attention for their roles against various clinical conditions. Obesity is a worldwide health problem that triggers various other major complications like type 2 diabetes (T2D) and cancers, including colorectal cancer (CRC). Earlier, Kluyveromyces marxianus PCH397 isolated from yak (Bos grunniens) milk has been characterised by us for its efficient β-galactosidase-producing ability, an important probiotic property. In the present study, yeast PCH397 has been evaluated for various parameters for its probiotic use. PCH397 exhibited tolerance to GI tract conditions (low pH, pancreatin, pepsin, and bile salts) with 78 to 99% survivability, possessed around 81% cell surface hydrophobicity, and 96% autoaggregation ability. The cell-free extract (CFE) and cell-free supernatant (CFS) from PCH397 improved insulin sensitisation by enhancing 2-NBDG (a glucose analogue) uptake in 3T3-L1 adipocytes, an approach useful in T2D treatment. They also exhibited lower intracellular lipid accumulation, triglyceride storage, and reactive oxygen species in differentiated adipocytes, indicating their anti-adipogenic ability. Also, CFE and intact cells (ICs) exhibited 73.33 ± 1.11% and 34.88 ± 2.80% DPPH radical scavenging activity, respectively. Furthermore, CFS showed a cytotoxic effect on SW-480 colorectal cancer (CRC) cells and induced the cell cycle phase arrest after 24 h of treatment. In conclusion, these results demonstrate that K. marxianus PCH397 could be used as a potential probiotic yeast and presents a therapeutic potential against obesity, T2D, and colon cancer.

Amplification of oxidative stress can be utilized as a strategy to attenuate cancer progression by instigating apoptosis. However, the duration of positive response to such therapies is limited, as cancer cells eventually develop resistance. The underlying molecular mechanisms of cancer cells to escape apoptosis under high oxidative stress is unknown. Employing big data, and its integration with transcriptome, proteome and network analysis in six cancer types revealed system-level interactions between DNA damage response (DDR), cell cycle and anti-apoptotic proteins. Cancer system biology is used to elucidate mechanisms for cancer progression, but networks defining mechanisms causing resistance is less explored. Using system biology, we identified DDR hubs between G1-S and M phases that were associated with bad prognosis. The increased expression of DDR network was involved in resistance under high oxidative stress. We validated our findings by combining H2O2 induced oxidative stress and DDR inhibitors in human lung cancer cells to conclude the necessity of targeting a ‘disease-causing network’. Collectively, our work provides insights toward designing strategies for network pharmacology to combat resistance in cancer research.

A large body of emerging evidence has revealed the role of p38/MK2 and PI3K/Akt/GSK3β cascades in the orchestrating process of colitis. Rutin, a bioflavonoid present in many fruits and vegetables, has been recognized to offer therapeutic attributes in acute colitis. However, its role in chronic colitic condition has not yet been delineated in reference to p38/MK2 and PI3K/Akt/GSK3β signalling. The present investigation assessed the efficacy and underlying molecular mechanism of rutin in alleviating DSS-induced chronic colitis. The analysis of signalling pathways demonstrated the robust activation of PI3K/Akt/GSK3β/MAPKs/NF-κB and p38/MK2 in DSS-induced colitis in animals, which was efficiently alleviated following the rutin treatment.

Rheumatoid arthritis (RA), a chronic auto-immune disease, is often result of persistent and misdirectional inflammation and cannot be effectually resolved by single-target selective drugs. Present study attempted to uncover anti-arthritic efficacy and governing molecular mechanism of BLFE and its phytoconstituents berberine and rutin, with focus on dysregulated oxi-inflammation and structural integrity during articular damage using Collagen II-CFA-induced RA mice model. NMR-based phytometabolomic analysis revealed presence of phenolics and alkaloids such as berberine and rutin. BLFE, rutin and berberine remarkably mitigated Collagen II-CFA-induced disease severity index, articular damage, immune cells influx and pannus formation. An effective decrease in levels of TNF-α, IL-6, IL-1β, IFN-γ, IL-13, IL-17, MMPs, RORγt, Ob-cadherin, Cox-2, iNOS and enhancement in IL-10, IL-4 and IL-5, BMP-6/7 was observed in BLFE, rutin and berberine treatments. Molecular mechanistic analysis demonstrated reduction in expression of p-STAT-1/3, p-PI3K, p-Akt, p-JNK, p-p38, p-IκB, p-NF-κB and β-catenin via BLFE, rutin and berberine. Furthermore, reduced activation of p-ERK and p-GSK3β and enhanced splenic Tregs was only noticed in BLFE and berberine. Thus, the signifying presence of these phytoconstituents could contribute to the above-mentioned findings. These findings imply that BLFE could be beneficial for assuaging deleterious aspects of RA mediated via perturbed inflammation.

Nonalcoholic fatty liver disease (NAFLD) with growing incidences is a major health concern worldwide. Alteration in cellular redox homeostasis and autophagy plays a critical role in the progression of NAFLD to more severe outcomes. The lack of safe and effective therapy for the disease necessitates the exploration of new therapeutic compounds. Therefore, in the present study, we investigated the potential of phloretin to maintain redox equilibrium and prevent disease progression via modulation of autophagy in NAFLD. Free fatty acid exposed Huh7 cells were used to evaluate the efficacy of phloretin in vitro. Further, phloretin was administered orally to western diet induced NAFLD in C57BL/6J mice at different doses. The chronic exposure to fatty acids and the western diet triggered lipid accumulation in the Huh7 cells and western diet-fed mice liver, respectively. In addition, mitochondrial dysfunction, oxidative stress, inflammation and decreased hepatic autophagy were observed in disease condition. Phloretin encouraged autophagy mediated hepatic lipid clearance and restored mitochondrial membrane potential and redox homeostasis. It also reduced histological injury by reducing hepatic lipogenesis and facilitating fatty acid oxidation. Moreover, findings of the study also revealed the mitigatory effect of phloretin on inflammatory and fibrogenic markers. Altogether, the study suggested that phloretin effectively attenuates NAFLD progression via upregulating autophagy-mediated lipid breakdown and inhibits oxidative damage, hepatic inflammation and fibrosis.

There is a growing interest in developing phytomolecule-based therapies for the management of inflammatory disorders owing to rising cost of treatments and unwarranted effects. The present work attempted to assess the efficacy and mechanisms of Berberis lycium Royle fruit extract (BLFE) in mitigating chemical-induced colitis in mice. Colitis was induced in Balb/C mice using dextran sulphate sodium (DSS) and protective effects of BLFE were examined. Several oxi-inflammatory parameters, histopathological changes, epithelial barrier integrity and activation of NF-κB/c-Jun/MAPKs in colon tissue were determined. Splenic T cell subpopulations were also gauged to evaluate the systemic effects of BLFE in the modulation of immune responses. BLFE treatment effectively improved animal survival rate, DAI score, colon length and structural damage in DSS-exposed mice. Expression of oxi-inflammatory markers such as MPO, IgE, iNOS, ICAM-1, MCP-1 and RANTES as well as Th1/Th2/Th17 cytokines were decreased in BLFE treated animals. On the other hand, an increased mRNA expression of anti-inflammatory cytokines (IL-4/IL-10), tight junction proteins and IgA levels were also observed during BLFE treatment. BLFE appeared to modulate intestinal epithelial cell proliferation (PCNA) and apoptosis (Bcl2/Bax), thereby suggesting its role in the maintenance of intestinal integrity. Analysis of inflammatory signalling pathways indicated robust activation and expression of NF-κB/c-Jun/MAPKs (JNK and p38) in DSS treated animal which was strongly abrogated by BLFE treatment. BLFE supplementation also enhanced the proliferation of CD3+CD4+CD25+ Treg cells indicating suppression of inflammatory activation. These observations provide compelling evidence that BLFE could be considered as a viable natural strategy in the prevention and management of ulcerative colitis.

Information regarding cellular anti-senescence attributes of probiotic bacteria vis-a-vis modulation of senescence-associated secretory phenotype (SASP) and mTOR signaling is very limited. The present study assessed anti-senescence potential of secretory metabolites of probiotic Lactobacillus fermentum (Lact. fermentum) using H2O2-induced model of senescence in 3T3-L1 preadipocytes. Application of H2O2-induced cellular senescence characterized by increased cell size and SA-β-gal activity, activation of SASP and reactive oxygen species (ROS), DNA damage response and induction of cell cycle inhibitors (p53/p21WAF1/p16INK4a). Further, a robust stimulation of the PI3K/Akt/mTOR pathway and AMPK signaling was also observed in H2O2-treated cells. However, exposure of cells to cell-free supernatant of Lact. fermentum significantly attenuated phosphorylation of PI3K/Akt/mTOR pathway and alleviated senescence markers p53, p21WAF1, SA-β-gal, p38MAPK, iNOS, cox-2, ROS, NF-κB, and DNA damage response. These results provide evidence that secretory metabolites of Lact. fermentum can mitigate the development as well as severity of stress-induced senescence thereby indicating its utility for use as anti-aging or age-delaying agent.

A new N-oxide, Pseudolycorine N-oxide (1) was characterised along with eleven known alkaloids homolycorine (2), O-methylmaritidine (3), 8-O-demethylhomolycorine (4), homolycorine N-oxide (5), lycorine (6), narciclasine (7), pseudolycorine (8), ungeremine (9), 8-O-demethylmaritidine (10), zefbetaine (11) and lycorine N-oxide (12), from Narcissus tazetta. Their structures were established on the basis of spectroscopic data analysis. The extract, fractions and isolated compounds were screened for in vitro cytotoxicity against two human cancer cell lines, human cervical cancer (SiHa) and human epidermoid carcinoma (KB) cells. The study demonstrated the cytotoxic potential of extract and its chloroform and n-butanol fractions. Further, the results revealed the bioactive potential of narciclasine, pseudolycorine and homolycorine alkaloids. However, new N-oxide (1) was not active against these cell lines.

Gliomas are lethal and aggressive form of brain tumors with resistance to conventional radiation and cytotoxic chemotherapies; inviting continuous efforts for drug discovery and drug delivery. Interestingly, small molecule hybrids are one such pharmacophore that continues to capture interest owing to their pluripotent medicinal effects. Accordingly, we earlier reported synthesis of potent Styryl-cinnamate hybrids (analogues of Salvianolic acid F) along with its plausible mode of action (MOA). We explored iTRAQ-LC/MS-MS technique to deduce differentially expressed landscape of native & phospho-proteins in treated glioma cells. Based on this, Protein-Protein Interactome (PPI) was looked into by employing computational tools and further validated in vitro. We hereby report that the Styryl-cinnamate hybrid, an analogue of natural Salvianolic acid F, alters key regulatory proteins involved in translation, cytoskeleton development, bioenergetics, DNA repair, angiogenesis and ubiquitination. Cell cycle analysis dictates arrest at G0/G1 stage along with reduced levels of cyclin D; involved in G1 progression. We discovered that Styryl-cinnamate hybrid targets glioma by intrinsically triggering metabolite-mediated stress. Various oncological circuits alleviated by the potential drug candidate strongly supports the role of such pharmacophores as anticancer drugs. Although, further analysis of SC hybrid in treating xenografts or solid tumors is yet to be explored but their candidature has gained huge impetus through this study. This study equips us better in understanding the shift in proteomic landscape after treating glioma cells with SC hybrid. It also allows us to elicit molecular targets of this potential drug before progressing to preclinical studies.

A new narciclasine glycoside, narciclasine-4-O-β-D-xylopyranoside (1) was characterised along with four known alkaloids pancratistatin (2), 1-O-(3-hydroxybutyryl) pancratistatin (3), vittatine (4), 9-O-demethylgalanthine (5) from Zephyranthes minuta. Their structures were established on the basis of spectroscopic data analysis. The in vitro cytotoxic study of extract, fractions and isolated compounds against two human cancer cell lines (KB and SiHa) indicated the potential activity of extract and n-butanol fraction due to presence of active alkaloids pancratistatin, 1-O-(3-hydroxybutyryl) pancratistatin, lycorine and haemanthamine.

In the present study, we systematically identified and evaluated a synbiotic combination of phytochemical epigallocatechin gallate (EGCG) and probiotic bacteria in amelioration of immunosenescence and oxidative stress in aged mice.Inhibitory effects of EGCG against different bacterial species were evaluated in vitro, followed by analysis to identify potential combination of EGCG and probiotic bacteria against alleviation of oxidative and inflammatory stress ex vivo. The best synbiotic combination, vis-à-vis prebiotic and probiotic supplementation alone, was then evaluated in aged Swiss albino mice for modulation of various immunological and antioxidative parameters.EGCG strongly inhibited the growth of pathogenic microbes as compared to probiotic bacteria. A combination of EGCG with probiotic Lactobacillus fermentum (LF) provided evidence of additive effects in the amelioration of oxidative and inflammatory stress-induced cell death. In vivo study revealed that combined supplementation of LF and EGCG significantly enhanced neutrophil oxidative index, CD3+ cell numbers and activation status, Th1/Th2 cytokines in splenic supernatants as well as liver Nrf-2 expression in comparison with treatments with LF or EGCG alone. The combined application of EGCG and LF did not simply result in additive or synergistic effects in relation with individual treatments.These observations suggest that EGCG could be considered as a potential prebiotic that can offer second generation synbiotic health beneficial effects for the alleviation of some of the deleterious aspects of immunosenescence and aging.

Therapeutic failure and drug resistance are common sequelae to insulin resistance associated with type 2 diabetes mellitus (T2DM). Consequently, there is an unmet need of alternative strategies to overcome insulin resistance associated complications.To demonstrate whether Kutkin (KT), iridoid glycoside enriched fraction of Picrorhiza kurroa extract (PKE) has potential to increase the insulin sensitivity vis à vis glucose uptake in differentiated adipocytes.Molecular interaction of KT phytoconstituents, picroside-I (P-I)picroside- II (P-II) with peroxisome proliferator-activated receptor gamma (PPARγ), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were analyzed in silico. Cellular viability and adipogenesis were determined by following 3-(4, 5-Dimethylthiazol-2-Yl)-2, 5-Diphenyltetrazolium bromide (MTT) assay and Oil Red-O staining. Further, ELISA kit based triglycerides and diacylglycerol-O-Acyltransferase-1 (DGAT1) were assessed in differentiated adipocytes. ELISA based determination were performed to check the levels of adiponectin and tumor necrosis factor alpha (TNF-α). However, Flow cytometry and immunofluorescence based assays were employed to measure the glucose uptake and glucose transporter 4 (glut4) expression in differentiated adipocytes, respectively. Further to explore the targeted signaling axis, mRNA expression levels of PPARγ, CCAAT/enhancer binding protein α (CEBPα), and glut4 were determined using qRT-PCR and insulin receptor substrate-1 (IRS-1), Insulin receptor substrate-2 (IRS-2), PI3K/Akt, AS160, glut4 followed by protein validation using immunoblotting in differentiated adipocytes.In silico analysis revealed the binding affinities of major constituents of KT (P-IP-II) with PPARγ/PI3K/Akt. The enhanced intracellular accumulation of triglycerides with concomitant activation of PPARγ and C/EBPα in KT treated differentiated adipocytes indicates augmentation of adipogenesis in a concentration-dependent manner. Additionally, at cellular level, KT upregulated the expression of DAGT1, and decreases fatty acid synthase (FAS), and lipoprotein lipase (LPL), further affirmed improvement in lipid milieu. It was also observed that KT upregulated the levels of adiponectin and reduced TNFα expression, thus improving the secretory functions of adipocytes along with enhanced insulin sensitivity. Furthermore, KT significantly promoted insulin mediated glucose uptake by increasing glut4 translocation to the membrane via PI3/Akt signaling cascade. The results were further validated using PI3K specific inhibitor, wortmannin and findings revealed that KT treatment significantly enhanced the expression and activation of p-PI3K/PI3K and p-Akt/Akt even in case of treatment with PI3K inhibitor wortmannin alone and co-treatment with KT in differentiated adipocytes and affirmed that KT as activator of PI3K/Akt axis in the presence of inhibitor as well.Collectively, KT fraction of PKE showed anti-diabetic effects by enhancing glucose uptake in differentiated adipocytes via activation of PI3K/Akt signaling cascade. Therefore, KT may be used as a promising novel natural therapeutic agent for managing T2DMand to the best of our knowledge, this is the first report, showing the efficacy and potential molecular mechanism of KT in enhancing insulin sensitivity and glucose uptake in differentiated adipocytes.

Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the vaccine effectiveness. Asymptomatic breakthrough infections have been a major problem in assessing vaccine effectiveness in populations globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines since whole virion vaccines generate antibodies against all the viral proteins. Here, we show how a statistical and machine learning (ML) based approach can be used to discriminate between SARS-CoV-2 infection and immune response to an inactivated whole virion vaccine (BBV152, Covaxin). For this, we assessed serial data on antibodies against Spike and Nucleocapsid antigens, along with age, sex, number of doses taken, and days since last dose, for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, our ensemble ML model classified 724 to be infected. For method validation, we determined the relative ability of a random subset of samples to neutralize Delta versus wild-type strain using a surrogate neutralization assay. We worked on the premise that antibodies generated by a whole virion vaccine would neutralize wild type more efficiently than delta strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, neutralization against Delta strain was more effective, indicating infection. We found 71.8% subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%-80.2%) over the same period. Our approach will help in real-world vaccine effectiveness assessments where whole virion vaccines are commonly used.

Although Berberis plant species have been advocated as immune modulators, information regarding their mechanism(s) of action is limited. Therefore, in the present study we assessed the efficacy of Berberis lycium Royle fruit extract (BLFE) in the attenuation of lipopolysaccharide (LPS)-induced oxi-inflammatory aggravation and concanavalin A (Con-A)-induced proliferation in murine peritoneal macrophages and lymphocytes, respectively. BLFE strongly suppressed production of the oxidative and inflammatory effector molecules nitric oxide (NO), reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), inflammatory cytokines (TNF-α/IL-6/IL-1β/IFN-γ) as well as chemokines (MCP-1 and RANTES), with a concomitant enhancement in heme oxygenase-1 (HO-1) and IL-10 levels. Subsequent mechanistic analysis revealed that BLFE strongly inhibited the phosphorylation of IκBα as well as MAPKs such as extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun NH2-terminal kinase (JNK), thereby directly resulting in the suppression of nuclear factor-κB (NF-ĸB) and c-Jun activation, ultimately culminating in the observed attenuation of inflammatory molecules. Additionally, BLFE appeared to mitigate Con-A-induced proliferation of Tregs (CD3+ CD4+ CD25+) thereby suggesting its modulatory effects on adaptive immune cells. UPLC-DAD-ESI-QTOF-MS/MS of BLFE revealed the presence of major bioactive phenolics and alkaloids including chlorogenic acid, rutin, catechin and quercetin 3-D-galactoside, berberine and magnoflorine, which could have synergistically contributed to the above findings. Overall, this work provides evidence that BLFE may be effective in the mitigation of inflammatory disorders, especially those associated with NF-κB/MAPK activation.

Cellular senescence is emerging as a major hallmark of aging, and its modulation presents an effective anti-aging strategy. This study attempted to understand the progression of cellular senescence in vivo, and whether it can be mitigated by chronic consumption of green tea catechin epigallocatechin gallate (EGCG). We profiled cellular senescence in various organs of mice at four different time-points of lifespan, and then explored the influence of EGCG consumption in impacting markers of cellular senescence, inflamm-aging, immunosenescence, and gut dysbiosis. We report that visceral adipose and intestinal tissues are highly vulnerable to cellular senescence due to an increase in DNA damage response, activation of cell cycle inhibitors, and senescence-associated secretory phenotype regulators. With advancing age, dysregulation in nutrient signaling mediators (AMPK/AKT/SIRT3/5), and a decrease in autophagy was also observed. Inflamm-aging markers (TNF-α/IL-1β) and splenic CD4/CD8 T cell ratio increased with age, while NK cell population decreased. Metagenomic analyses revealed an age-related decrease in the diversity of microbial species and an increase in the abundance of various pathogenic bacterial species. On the other hand, long-term EGCG consumption significantly attenuated markers of DNA damage, cell cycle inhibitors, senescence-associated secretory phenotype regulators, AMPK/AKT signaling, and enhanced SIRT3/5 expression and autophagy. Systemic inflamm-aging indicators decreased, while early T cell activation increased in EGCG fed animals. EGCG also suppressed the abundance of pathogenic bacteria and preserved microbial diversity. Our results suggest that adipose and intestine tissues are prone to cellular senescence and that chronic consumption of EGCG can attenuate several deleterious aspects of aging which could be implicated in developing anti-aging strategies.

Background: Diabetic Kidney Disease (DKD) is a common complication of diabetes and a leading cause of end-stage renal disease progression. Therefore, therapeutic strategies are desirable to mitigate the progression of disease into more severe consequences. Hypothesis/Purpose: Tinospora cordifolia is a traditionally known antidiabetic plant; however, its effect against DKD remains unexplored. Therefore, in the present study, we assessed the efficacy and mechanism of action of Tinospora cordifolia extract (TC) against DKD. Methods: The molecular interaction of the various phytoconstituents of TC with PPARγ were analyzed in silico. The effect of TC was studied on the viability, cell cycle, and gene expressions (PPARγ, TGFβ, and αSMA) in high glucose treated NRK-52E and SV40 MES13 cells. Further, streptozotocin-induced diabetic rats were treated with TC for eight weeks, and the effects on different biochemical, histological and molecular parameters were studied. Results: In silico analysis revealed the integration of various phytoconstituents of TC with PPARγ. It further increased PPARγ and decreased TGFβ and αSMA expressions in NRK-52E and SV40 MES13 cells. In diabetic rats, TC improved the fasting blood glucose, serum urea, and creatinine levels. It also lowered the urine microalbumin and advanced glycation end products (AGEs) levels. Histopathological studies revealed the preventive effect of TC on degenerative changes, mesangial proliferation and glomerular hypertrophy. Further, it reduced the inflammation and fibrotic changes in the kidney tissue estimated by various markers. The kidney tissue and gene expression analysis revealed the augmented levels of PPARγ after TC treatment. Conclusion: In conclusion, TC exerted the protective effect against DKD by inhibiting inflammation and fibrogenesis through the activation of PPARγ dependent pathways.

Background: India has been amongst the most affected nations during the SARS CoV2 pandemic, with sparse data on country wide spread of asymptomatic infections and antibody persistence. This longitudinal cohort study was aimed to evaluate SARS CoV2 seropositivity rate as a marker of infection and evaluate temporal persistence of antibodies with neutralization capability and to infer possible risk factors for infection. Methods: Council of Scientific and Industrial Research, India (CSIR) with its more than 40 laboratories and centers in urban and semi urban settings spread across the country piloted the pan country surveillance. 10427 adult individuals working in CSIR laboratories and their family members based on voluntary participation were assessed for antibody presence and stability was analyzed over 6 months utilizing qualitative Elecysys SARS CoV2 specific antibody kit and GENScript cPass SARS CoV2 Neutralization Antibody Detection Kit. Along with demographic information, possible risk factors were evaluated through self to be filled online forms with data acquired on blood group type, occupation type, addiction and habits including smoking and alcohol, diet preferences, medical history and transport type utilized. Symptom history and information on possible contact and compliance with COVID 19 universal precautions was also obtained. Findings:1058 individuals (10.14%) had antibodies against SARS CoV2. A follow up on 346 seropositive individuals after three months revealed stable to higher antibody levels against SARS CoV2 but declining plasma activity for neutralizing SARS CoV2 receptor binding domain and ACE2 interaction. A repeat sampling of 35 individuals, at six months, revealed declining antibody levels while the neutralizing activity remained stable compared to three months. Majority of seropositive individuals (75%) did not recall even one of nine symptoms since March 2020. Fever was the most common symptom with one fourth reporting loss of taste or smell. Significantly associated risks for seropositivity (Odds Ratio, 95% CI, p value) were observed with usage of public transport (1.79, 1.43 to 2∙24, 2.81561x10-6), occupational responsibilities such as security, housekeeping personnel etc. (2.23, 1.92 to 2.59, 6.43969x10-26), non smokers (1.52, 1.16 to 1.99, 0.02) and non vegetarianism (1.67, 1.41 to 1.99, 3.03821x10-8). An iterative regression analysis was confirmatory and led to only modest changes to estimates. Predilections for seropositivity was noted with specific ABO blood groups; O was associated with a lower risk. Interpretation: In a first of its kind study from India, we report the seropositivity in a country wide cohort and identify variable susceptible associations for contacting infection. Serology and Neutralizing Antibody response provides much sought for general insights on the immune response to the virus among Indians and will be an important resource for designing vaccination strategies. Funding: Council of Scientific and Industrial Research, India (CSIR)

Camellia sinensis (tea) is an evergreen plant having bioactive compounds associated with various pharmacological effects, including anti-cancerous activity. These phytochemicals are variedly distributed in plant tissues. A detailed study to understand chemical composition within the economically underutilized tea tissues is required to generate value. Therefore, a comprehensive chemical profiling of underutilized C. sinensis parts [coarse leaves, flowers, fruits (immature); n = 9] was performed by NMR techniques. NMR (1D and 2D) spectroscopy ambiguously identified and quantified fifty-seven metabolites (Coarse leaves: 35, flowers; 42, immature fruits; 45). The statistical analysis showed apparent tissue-specific similarities (26 metabolites) and variations. Further, HPLC-DAD revealed absolute quantification of catechins, caffeine and theanine among the different parts of C. sinensis. Moreover, cytotoxicity studies of tea tissues against colorectal cancer cell lines showed anticancer potentials. This chemical information and anticancer activity of underutilized C. sinensis parts will help to develop value added nutraceutical and cosmeceutical products.

Cellular senescence is emerging as the causal nexus of aging, and its potential modulators present an effective strategy to counter age-related morbidity. The current study profiled the extent of cellular senescence in different organs of mice at four different time-points of lifespan, and explored the influence of epigallocatechin gallate (EGCG) consumption in impacting multiple aspects of aging biology. We report that adipose and intestinal tissues are highly vulnerable to cellular senescence as evident by age-associated increase in DNA damage response, activation of cell cycle inhibitors (p53/p21) and induction of SASP (p38MAPK/NF-κB/Cox-2). Further, a distinct modulation of nutrient signaling pathway mediators (AMPK/Akt/SIRT3 and 5), and a decrease in autophagy effectors was also observed in aging animals. Systemic inflamm-aging markers (TNF-α/IL-lβ) and splenic CD4/CD8 ratio increased with age, while NK cell population decreased. Metagenomic analyses revealed age-related decrease in the diversity of microbial species while an increase in the abundance of various pathogenic bacterial genera was also observed. Long term EGCG consumption enhanced lifespan of animals by attenuating markers of DNA damage, cell cycle inhibitors and SASP in adipose, intestine and liver tissue. Mechanistically, EGCG inhibited the activation of AMPK and Akt and enhanced mitochondrial SIRT3 and SIRT5 expression, as well as autophagic response in adipose and intestinal tissues. Systemic presence of inflamm-aging markers decreased while expression of T cell immune response regulator CD69 increased in EGCG fed animals. EGCG also improved age-related decrease in the diversity of microbial species and suppressed the growth of pathogenic microbes. In short, our results provide compelling evidence that post-mitotic adipose tissue is a major site of cellular senescence and SASP activation, and that chronic EGCG consumption can influence several aspects of aging and senescence resulting in improved organismal healthspan and lifespan.

Colorectal cancer is a common public health problem and is the leading cause of mortality and morbidity across the globe. Epidemiological, preclinical, and clinical studies have highlighted the critical relationship between the immune system and colon carcinogenesis. This has led to use of immunomodulatory therapy in adjuvant or palliative treatment of colon cancer. Natural products found in fruits, vegetables, and dietary spices have been demonstrated to exhibit protective effects against development of various human diseases including colon cancer. The anticancer effect of these natural products has been linked to their immunomodulatory and anti-inflammatory activity. Natural products are reported to activate a subset of immune cells, inhibit immune checkpoints, and modulate the production of various cytokines and chemokines, thus overall strengthening the immune surveillance. In this chapter, we will discuss the recent advancements in immunomodulatory and anti-inflammatory activities of several natural products which eventually inhibit the development of colon cancer. We will also highlight the chemosensitizing potential of these phytochemicals in combination with standard colon cancer therapies.

Recent progress in understanding the interplay between tumor cells and immune cells has given emergence to a new field called immunotherapy. Tumor cells are dependent upon signals called “immune checkpoints” to escape themselves from immune surveillance. Despite the substantial advances in chemotherapy and radiotherapy, life expectancy of CRC patients has not been achieved successfully. Immunotherapy has recently emerged as a newfangled armor for combating cancer. Several immune checkpoint inhibitors have received approval from FDA for colon cancer treatment in clinical settings. The blocking of these checkpoints such as PD-1 or PDL-1 and CTLA-4 can help the immune system to fight against the tumor cells. Treatment with selective anti-PD-1/PDL-1 and anti-CTLA-4 monoclonal antibodies (mAbs) has revolutionized the therapeutic scenario of different cancer types. Advancements in combination chemotherapy regimens for colorectal cancer have led to significant improvement in disease-free survival. This chapter summarizes the rationale for immune checkpoint inhibitor therapy in colon cancer.

Summary Background & aims Beverages and Non-alcoholic fatty liver disease (NAFLD) both the terms are associated with westernized diet and sedentary lifestyle. Throughout recent decades, dietary changes have boosted demand of beverages to meet the liquid consumption needs, among which rising consumption of several calorie-rich beverages have increased the risk of fatty liver disease. Meanwhile, certain beverages have capacity to deliver many unanticipated health benefits thereby reducing the burden of NAFLD and metabolic diseases. The present review therefore addresses the increasing interconnections between beverages intake among population, dietary patterns and the overall effect of these beverage on the development and prevention of NAFLD. Methods In the present review, some frequently consumed beverage groups have been analyzed in light of their role in the advancement and prevention of NAFLD, including sugar sweetened, hot and alcoholic beverages. The nutritional composition of different beverages makes the progression of NAFLD distinctive. Results The ingestion of sugar-rich beverages has demonstrated the metabolic burden and in all cases, raises the risk of NAFLD, while intake of coffee and tea has decreased this risk without any significant adverse effects. In some cases, low to moderate alcohol intake has been shown to minimize the risk of advanced fibrosis and NAFLD-mortality. Conclusion Together, this review discusses and supports work on new dietary approaches and clinical studies to accomplish nutrition-oriented NAFLD care by improving the drinking habits.

BackgroundTranscriptome profiling has been pivotal in better comprehending the convoluted biology of tumors including head and neck squamous cell carcinoma (HNSCC). Recently, growing evidence has implicated the role of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in many human diseases including tumors. MK2 has been recently reported as a critical regulator of HNSCC that functions via modulating the transcript turnover of crucial genes involved in its pathogenesis. Comprehensive MK2-centric transcriptomic analyses could help the scientific community to delve deeper into MK2-pathway driven mechanisms of tumor progression, but such studies have not yet been reported. Consequently, to delineate the biological relevance of MK2 and its intricate crosstalk in the tumor milieu, an extensive transcriptome analysis of HNSCC was conceptualized and effectuated with MK2 at the nexus.MethodsIn the current study, comprehensive next-generation sequencing-based transcriptome profiling was accomplished to ascertain global patterns of mRNA expression profiles in both in vitro and in vivo models of the HNSCC microenvironment. The findings of the RNA-sequencing analysis were cross-validated via robust validation using nCounter gene expression assays, immunohistochemistry, and real-time quantitative polymerase chain reaction (RT–qPCR).ResultsTranscriptomic characterization followed by annotation and differential gene expression analyses identified certain MK2-regulated candidate genes constitutively involved in regulating HNSCC pathogenesis, and the biological significance of these genes was established by pathway enrichment analysis. Additionally, advanced gene expression assays through the nCounter system in conjunction with immunohistochemical analysis validated the transcriptome profiling outcomes quite robustly. Furthermore, the results obtained from immunohistochemistry and transcript stability analysis indicated the crucial role of MK2 in the modulation of the expression pattern of these genes in HNSCC tumors and cells.ConclusionsConclusively, the findings have paved the way toward the identification of new effective tumor markers and potential molecular targets for HNSCC management. The results have accentuated the importance of certain differentially expressed MK2-regulated genes that are constitutively involved in HNSCC pathogenesis to potentially serve as putative candidates for future endeavors pertaining to diagnosis and therapeutic interventions for HNSCC.

Objective To provide the scientific basis for the utility of rhizome of Trillium govanianum as nutraceutical supplements in managing physiological glycemic levels. Methods The in vitro enzyme inhibitory activity of the extract, fractions, and the isolated steroidal saponins from the rhizome part of T. govanianum was carried out against α-amylase, α-glucosidase, and dipeptidyl peptidase IV. The molecular interactions, binding score, and pharmacokinetic parameters (absorption, distribution metabolism, and excretion) of steroidal saponins were analyzed by the Schrodinger molecular docking software. Key findings Current study explained that the extract, fractions, and isolated steroidal saponins from T. govanianum possess good α-amylase and α-glucosidase inhibitory activity while moderate dipeptidyl peptidase IV inhibitory activity. Moreover, in vitro results revealed that borassoside E (IC50 7.15 ± 1.78 μM), protodioscin (IC50 6.72 ± 0.04 μM), and diosgenin (IC50 12.75 ± 2.70 μM) are most effective in inhibiting the activity of α-amylase, α-glucosidase, and dipeptidyl peptidase IV, respectively. Current in silico and in vitro studies established an association between the steroidal saponins from T. govanianum and their molecular interactions with α-amylase, α-glucosidase, and dipeptidyl peptidase IV. Conclusion The results of this investigation suggest that fractions and steroidal saponins from T. govanianum exhibit good antidiabetic activity which could be used as nutraceutical supplements for the management of systemic glucose level.

The present study aimed at evaluating the role of senescent cell microenvironment as an extrinsic causal factor for altered age-associated macrophage functions, and that whether such changes could be ameliorated by the application of tea catechin epigallocatechin gallate (EGCG). To ascertain this, we analyzed the impact of secretory metabolites of proliferating (P) and senescent (S) preadipocyte cells on the induction of phenotypic and functional characteristics associated with aging in macrophages isolated from young (YM) and old (OM) C57BL/6J mice. The role of EGCG as alleviator of preadipocyte media-induced senescence and inflamm-aging was evaluated in OM. Results revealed strong age-related dysregulation in macrophage functions as evident by decreased CD11b expression, enhanced expression of cytokines (IL-6/TNF-α/IL-1β/IL-10) and cell cycle inhibitors p53/p21WAF1/p16Ink4a, as well as augmentation of M2 phenotype (Arg1/Msr1/Mrc1) and SA-β-gal activity. Ex vivo exposure of macrophages (YM and OM) to secretory factors of preadipocytes induced differential effects, and treatment with S culture media largely showed an augmentation of senescent phenotype, particularly in the YM. Pretreatment with EGCG (10 µM) to OM caused a dramatic reversal of both age-associated and preadipocyte media-induced changes as evident from upregulation of CD11b and ROS levels, inhibition of inflammatory makers, attenuation of p53/p21WAF1/p16Ink4a expression and SA-β-gal activity. Our results indicate vital role of adipose tissue-mediated extrinsic factors in shaping macrophage phenotype and functions during aging. It is also apparent that EGCG is a promising candidate in developing preventive therapies aimed at alleviating macrophage inflamm-aging and senescence that may help curb incidences of inflammatory disorders in elderly.

Probiotic bacteria are increasingly gaining importance in human nutrition owing to their multifaceted health beneficial effects. Studies have also shown that probiotic supplementation is useful in mitigating age-associated oxi-inflammatory stress, immunosenescence, and gut dysbiosis thereby promoting health and longevity. However, our current understanding of the process of aging suggests a strong interrelationship between the accumulation of senescent cells and the development of aging phenotype, including the predisposition to age-related disorders. The present review studies the documented pro-longevity effects of probiotics and highlights how these beneficial attributes of probiotics could be related to the mitigation of cellular senescence. We present a perspective that to fully understand and comprehend the anti-aging characteristics of probiotic bacteria; it is imperative that probiotics or their synbiotic amalgamation with plant polyphenols, be studied under the purview of cellular senescence, that may ultimately help devise probiotic-based anti-senescence strategies.

Context Various factors affect plasma concentrations of antitubercular drugs in different populations so dosing schedule should be adjusted after therapeutic drug monitoring. Aims To study variability in plasma concentrations of Rifampicin and Pyrazinamide with pre and post-meal administration of drugs in tuberculosis patients. Methods and material 52 patients of pulmonary tuberculosis, divided in to two groups, pre and post-meal through systemic randomization. After taking pre-dose sample, drugs were administered according to the group. Samples were withdrawn at 2, 4, 6, and 10 h after drug administration. Analysis of samples was done using HPLC. Results Mean ± 1SD of Cmax of Rifampicin was 7.75 ± 2.82 μg/ml, mean ± 1SD of AUC0–10 was 42.17 ± 17.25 μg h/ml, adjusted Tmax was 4.25 h. In pre-meal samples, the corresponding values were 7.75 ± 2.88 μg/ml, 42.83 ± 18.47 μg h/ml, 3.76 h and in post-meal samples 8.03 ± 2.30 μg/ml, 41.56 ± 16.46 μg h/ml and 4.75 h. Mean ± 1SD of Cmax levels of Pyrazinamide was 54.49 ± 21.86 μg/ml, mean ± 1SD of AUC0–10 was 337.94 ± 124.28 μg h/ml and adjusted Tmax was 3.49 h. In pre-meal samples the corresponding values were 52.00 ± 19.13 μg/ml, 329.96 ± 112.11 μg h/ml, 3.23 h, and in post-meal samples 57.43 ± 23.61 μg/ml, 345.58 ± 136.99 μg h/ml, 3.54 h. Conclusion There is huge variability in the plasma levels of Rifampicin and Pyrazinamide in population of this sub-himalayan region.

Objective The rhizomes of Trillium govanianum have traditionally been used in the Ayurvedic system of medicine to treat inflammation, pain, burn, and reproductive malfunctions. However, the ethanopharmacology and chemical constituents of T. govanianum have not been effusively explored to date. The present study attempted to uncover the phytochemical constituents and quality parameters of T. govanianum rhizomes, along with an evaluation of the anti-inflammatory potential of the extract, fractions, and isolated steroidal saponins. Methods The quality of T. govanianum rhizomes was examined by standard guidelines of the Association of Official Agricultural Chemists (AOAC). The phytochemical composition of rhizomes was estimated by the spectroscopic method. The extract, fractions, and pure molecules were tested for their anti-inflammatory potential using lipopolysaccharide-stimulated RAW 264.7 macrophages. Besides that, computational pharmacokinetics properties of bioactive compounds were screened by using the Schrodinger software. Results The quality control parameters such as moisture content, ash value, pH, heavy metals, alpha toxins, residual pesticides, and microbial load were observed within the permitted limits as per AOAC guidelines, suggesting good quality and safe nature of T. govanianum rhizomes. Phytochemical analysis revealed the presence of steroidal saponins (78.3 ± 0.61 mg/g), phenolics (12.3 ± 2.76 mg/g), flavonoids (3.54 ± 0.24 mg/g), and carbohydrates (473 ± 2.27 mg/g) in the rhizomes. Macrophages cytocompatibility demonstrated that cell viability was not affected at any tested concentration of extract, fractions and pure compounds [diosgenin (1), borassoside D (2), and govanoside B (7)]. The LPS-stimulated macrophages secreted nitric oxide (NO) and pro-inflammatory cytokines (TNFα, IL-1β, and IL-6), which were inhibited by the extract, fractions, and compounds 1, 2, and 7 in a concentration-independent manner. Additionally, in silico pharmacokinetics revealed that compound 1 has good membrane-permeability followed by compound 2, while compound 7 showed the non-membrane permeability. Conclusion This study validates the traditional uses of rhizomes of T. govanianum in the treatment of inflammation, and this activity might be due to the presence of steroidal saponins.