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The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1β production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1β resulted in inhibition of TH17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.

Background: Previous randomized controlled trials (RCTs) suggested that gut microbiota-based therapies may be effective in treating autoimmune diseases, but a systematic summary is lacking. Methods: Pubmed, EMbase, Sinomed, and other databases were searched for RCTs related to the treatment of autoimmune diseases with probiotics from inception to June 2022. RevMan 5.4 software was used for meta-analysis after 2 investigators independently screened literature, extracted data, and assessed the risk of bias of included studies. Results: A total of 80 RCTs and 14 types of autoimmune disease [celiac sprue, SLE, and lupus nephritis (LN), RA, juvenile idiopathic arthritis (JIA), spondyloarthritis, psoriasis, fibromyalgia syndrome, MS, systemic sclerosis, type 1 diabetes mellitus (T1DM), oral lichen planus (OLP), Crohn's disease, ulcerative colitis] were included. The results showed that gut microbiota-based therapies may improve the symptoms and/or inflammatory factor of celiac sprue, SLE and LN, JIA, psoriasis, PSS, MS, systemic sclerosis, Crohn's disease, and ulcerative colitis. However, gut microbiota-based therapies may not improve the symptoms and/or inflammatory factor of spondyloarthritis and RA. Gut microbiota-based therapies may relieve the pain of fibromyalgia syndrome, but the effect on fibromyalgia impact questionnaire score is not significant. Gut microbiota-based therapies may improve HbA1c in T1DM, but its effect on total insulin requirement does not seem to be significant. These RCTs showed that probiotics did not increase the incidence of adverse events. Conclusions: Gut microbiota-based therapies may improve several autoimmune diseases (celiac sprue, SLE and LN, JIA, psoriasis, fibromyalgia syndrome, PSS, MS, T1DM, Crohn's disease, and ulcerative colitis). [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effects of general control non-derepressible 2 (GCN2) on osteoarthritis (OA) in vivo and in vitro. First, anterior cruciate ligament transection (ACLT)-induced rat model and interleukin (IL)-1β-induced ATDC5 chondrocyte were established. Hematoxylin and eosin staining and safranin O/fast green staining were employed for analyzing the histological changes in the rat cartilage. In addition, immunohistochemistry, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blot, and immunofluorescence staining were employed for examining cartilage degeneration-, inflammation-, autophagy-, and NLR family pyrin domain containing 3 (NLRP3) inflammasome-associated genes expression. Moreover, 2,7-dichlorodihydrofluorescein acetoacetic acid probe was utilized for examining the intracellular reactive oxygen species. In addition, 5-ethynyl-2′-deoxyuridine assay and flow cytometry were applied for detecting chondrocyte proliferation and apoptosis IL-1β-treated ATDC5 chondrocytes. GCN2 overexpression ameliorated articular cartilage degeneration and inflammation but promoted chondrocyte autophagy in ACLT-induced OA rats. Similarly, we demonstrated that the upregulation of GCN2 could promote chondrocyte proliferation, suppress chondrocyte apoptosis, attenuate chondrocyte inflammation and extracellular matrix degradation, and promote chondrocyte autophagy. Moreover, GCN2 overexpression could inhibit the activation of NLRP3 inflammasome in IL-1β-induced ATDC5 chondrocyte. Furthermore, 3-methyladenine neutralized the protective and autophagy-promoting effects of GCN2 overexpression on ATDC5 chondrocytes. GCN2 could attenuate inflammation and cartilage degeneration, promote chondrocyte autophagy, and inhibit NLRP3 inflammasome activation in OA. [ABSTRACT FROM AUTHOR]

Snakebite in India is a severe problem as it causes a mortality rate of 58,000 and a disability rate of 140,000 every year which is the highest among any other country. Antivenom is the primary therapy for snakebite, and its manufacturing techniques have essentially stayed unaltered for over a century. Indian polyvalent antivenom, a scientifically validated medicine for treating the toxic effects of snakebites, is available against the venom of the so-called Big Four snakes namely Spectacled cobra (Naja naja), Saw-scaled viper (Echis carinatus), Russell's viper (Daboia russelli) and the Common krait (Bungarus caeruleus), responsible for majority of the deaths in India. India hosts many other species of snakes, including cobras, kraits, saw-scaled vipers, sea snakes, and pit vipers, responsible for clinically severe envenomation. Neutralization strategy has been applied to access the efficacy of antivenoms, crucial for reducing snake bite deaths and disabilities. This review aims to conduct a systematic review and meta-analysis on the neutralization efficiency of the Polyvalent Antivenom (PAV) and focus on the factors that may contribute to the poor recognition of the antivenom towards the venom toxins. Reports focusing on the investigation of antivenom efficacy were searched and collected from several databases. Preclinical studies that reported the neutralization efficacy of the commercial antivenom against the medically important snakes of India were included. The articles were screened based on the inclusion criteria and 8 studies were shortlisted for meta-analysis. Pooled proportion was calculated for the antivenom efficacy reported by the studies and was found to be statistically significant with a 95% confidence interval. The heterogenicity in the venom toxicity and neutralization potency of the antivenom was evident in the overall estimate (proportion) and individual data. We provide comprehensive evidence on antivenom efficacy against medically important snakes from various parts of India which may aid in identifying the gaps in snake envenomation therapy and the need for novel potentially improved treatment of snakebites. [ABSTRACT FROM AUTHOR]

Hemophilia B (HB) is an inherited bleeding disorder caused by defects in the FⅨ gene, leading to severe coagulation dysfunction. This study designed eight pairs of primers covering eight exons of the FⅨ gene and used PCR and DNA sequencing to detect FⅨ gene mutations in 31 HB patients. Sequencing results were compared with normal sequences using Chromas software on Blast to identify mutation sites. Findings revealed the CpG dinucleotide region as a mutation hotspot and the 192nd nucleotide (FⅨ192) as a dinucleotide polymorphism site in the Chinese population. Pathogenic mutations included point mutations, deletions, insertions, and mutations affecting amino acids or splicing sites. For cases with only polymorphic sites, further exon sequencing is needed. This study adds new mutation data to the global HB database, supports research on racial differences in FⅨ gene mutations, and contributes to domestic HB statistics. The results aid in understanding the FⅨ gene's role in coagulation, elucidating HB pathogenesis, and providing a basis for future gene therapy. [ABSTRACT FROM AUTHOR]

Campylobacter infections and campylobacteriosis-associated post-infectious sequelae are a significant global health burden that needs to be addressed from a specific African perspective. We conducted a comprehensive literature search on NCBI PubMed to compile a comprehensive narrative review article on Campylobacter infections in Africa, focusing on key aspects in human and veterinary medicine as well as food hygiene. We specifically focused on the epidemiology of enteropathogenic Campylobacter spp. in sub-Saharan and North Africa considering antimicrobial susceptibility. The most significant sequela resulting from molecular mimicry to Campylobacter surface structures is the Guillain-Barré syndrome, which was mainly examined in the context of limited studies conducted in African populations. A dedicated subsection is allocated to the limited research on the veterinary medically important species Campylobacter fetus. There are significant differences in the composition of the gut microbiome, especially in rural areas, which affect the colonization with Campylobacter spp. and the manifestation of campylobacteriosis. There may be a problem of overdiagnosis due to asymptomatic colonization, particularly in the detection of Campylobacter using molecular biological techniques. To reduce the colonization and infection rate of Campylobacter, we propose implementing several control measures and urge further research to improve the current understanding of the peculiarities of campylobacteriosis in Africa. [ABSTRACT FROM AUTHOR]

Hereditary pulmonary veno-occlusive disease (hPVOD) is a severe form of autosomal recessive pulmonary hypertension and is due to biallelic loss of function of the EIF2AK4 gene (alias GCN2) coding for GCN2. GCN2 is a stress kinase that belongs to the integrated stress response pathway (ISR). Three rat lines carrying biallelic Gcn2 mutation were generated and found phenotypically normal and did not spontaneously develop a PVOD-related disease. We submitted these rats to amino acid deprivation to document the molecular and cellular response of the lungs and to identify phenotypic changes that could be involved in PVOD pathophysiology. Gcn2-/- rat lungs were analyzed under basal conditions and 3 days after a single administration of PEG-asparaginase (ASNase). Lung mRNAs were analyzed by RNAseq and single-cell RNAseq (scRNA-seq), flow cytometry, tissue imaging, and Western blots. The ISR was not activated after ASNase treatment in Gcn2-/- rat lungs, and apoptosis was increased. Several proinflammatory and innate immunity genes were overexpressed, and inflammatory cells infiltration was also observed in the perivascular area. Under basal conditions, scRNA-seq analysis of Gcn2-/- rat lungs revealed increases in two T-cell populations, a LAG3þ T-cell population and a proliferative T-cell population. Following ASNase administration, we observed an increase in calprotectin expression involved in TLR pathway activation and neutrophil infiltration. In conclusion, under basal and asparagine and glutamine deprivation induced by asparaginase administration, Gcn2-/- rats display molecular and cellular signatures in the lungs that may indicate a role for Gcn2 in immune homeostasis and provide further clues to the mechanisms of hPVOD development. [ABSTRACT FROM AUTHOR]

Background: Withania somnifera (L.) Dunal, commonly known as ashwagandha, is a small woody shrub whose roots are used traditionally to treat numerous diseases. It is particularly well known for its sedative, sleep-inducing and immunostimulant effects. Materials and Methods: We undertook an extensive search of reviews and primary scientific studies to identify therapeutic uses of W. somnifera and studies that have reported on the phytochemistry and validation of the traditional uses. This information was used to identify gaps in the current research that require further study. Results: Withania somnifera root preparations have widespread uses as sedatives and in the treatment of stress-related conditions. Additionally, there is extensive evidence of the use of W. somnifera to stimulate the immune system to protect against pathogenic disease. Numerous studies have examined the mechanisms of action, which are summarised herein. Conclusion: Despite the widespread usage of W. somnifera roots as a sedative and as an immunostimmulant, the mechanisms of action are not completely understood. Substantial further work is required into the therapeutic mechanism(s) of this useful traditional medicine. [ABSTRACT FROM AUTHOR]

Background: Sepsis is defined as a systemic inflammatory response to microbial infections with multiple organ dysfunction. This study analysed untargeted metabolomics combined with proteomics of serum from patients with sepsis to reveal the underlying pathological mechanisms involved in sepsis. Methods: A total of 63 patients with sepsis and 43 normal controls were enrolled from a prospective multicentre cohort. The biological functions of the metabolome were assessed by coexpression network analysis. A molecular network based on metabolomics and proteomics data was constructed to investigate the key molecules. Results: Untargeted metabolomics analysis revealed widespread dysregulation of amino acid metabolism, which regulates inflammation and immunity, in patients with sepsis. Seventy-three differentially expressed metabolites (|log2 fold change| > 1.5, adjusted P value < 0.05 and variable importance in the projection (VIP) > 1.5) that could predict sepsis were identified. External validation of the hub metabolites was consistent with the derivation results (area under the receiver operating characteristic curve (AUROC): 0.81–0.96/0.62–1.00). The pentose phosphate pathway was found to be related to sepsis-associated encephalopathy. Phenylalanine metabolism was associated with sepsis-associated acute kidney injury. The key molecular alterations of the multiomics network in sepsis compared to normal controls implicate acute inflammatory response, platelet degranulation, myeloid cell activation involved in immune response and phenylalanine, tyrosine and tryptophan biosynthesis, and arginine biosynthesis. Conclusions: Integrated analysis of untargeted metabolomics and proteomics revealed characteristic metabolite and protein alterations in sepsis, which were mainly involved in inflammation-related pathways and amino acid metabolism. This study depicted the pathological characteristics and pathways involved in sepsis and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Main conclusion: Overexpression of a novel geranylgeranyl pyrophosphate synthase gene (WsGGPPS) in planta resulted in increased levels of gibberellic acid and decrease in withanolide content. Withania somnifera (L.) Dunal, the herb from family Solanaceae is one of the most treasured medicinal plant used in traditional medicinal systems owing to its unique stockpile of pharmaceutically active secondary metabolites. Phytochemical and pharmacological studies in this plant were well established, but the genes affecting the regulation of biosynthesis of major metabolites were not well elucidated. In this study cloning and functional characterization of a key enzyme in terpenoid biosynthetic pathway viz. geranylgeranyl pyrophosphate synthase (EC 2.5.1.29) gene from Withania somnifera was performed. The full length WsGGPPS gene contained 1,104 base pairs that encode a polypeptide of 365 amino acids. The quantitative expression analysis suggested that WsGGPPS transcripts were expressed maximally in flower tissues followed by berry tissues. The expression levels of WsGGPPS were found to be regulated by methyl jasmonate (MeJA) and salicylic acid (SA). Amino acid sequence alignment and phylogenetic studies suggested that WsGGPPS had close similarities with GGPPS of Solanum tuberosum and Solanum pennellii. The structural analysis provided basic information about three dimensional features and physicochemical parameters of WsGGPPS protein. Overexpression of WsGGPPS in planta for its functional characterization suggested that the WsGGPPS was involved in gibberellic acid biosynthesis. [ABSTRACT FROM AUTHOR]

To explore the role of ChTLR4/MyD88/NF-κB signaling pathway on autophagy induced by selenium (Se) deficiency in the chicken bursa of Fabricius, autophagosome formation in the bursa of Fabricius was observed by transmission electron microscopy. Quantitative real-time PCR (qRT-PCR) and Western blot were used to detect the expression of ChTLR4 and its signaling pathway molecules (MyD88, TRIF, and NF-κB), inflammatory factors (IL-1β, IL-8, and TNF-α), and autophagy-related factors (ATG5, Beclin1, and LC3-II) in the Se-deficient chicken bursa of Fabricius at different ages. The results showed that ChTLR4/MyD88/NF-κB signaling pathway was activated in the chicken bursa of Fabricius and autophagy was induced at the same time by Se deficiency. In order to verify the relationship between the autophagy and ChTLR4/MyD88/NF-κB signaling pathway, HD11 cells were used to establish the normal C group, low Se group, and low Se + TLR4 inhibitor (TAK242) group. The results demonstrated that autophagy could be hindered when the TLR4 signaling pathway was inhibited under Se deficiency. Furthermore, autophagy double-labeled adenovirus was utilized to verify the integrity of autophagy flow induced by Se deficiency in HD11 cells. The results showed that it appeared to form a complete autophagy flow under the condition of Se deficiency and could be blocked by TAK242. In summary, we found that Se deficiency was involved in the chicken bursa of Fabricius autophagy occurring by activating the ChTLR4/MyD88/NF-κB pathway. [ABSTRACT FROM AUTHOR]

Snakebite envenomations (SBEs) are a neglected medical condition of global importance that mainly affect the tropical and subtropical regions. Clinical manifestations include pain, edema, hemorrhage, tissue necrosis, and neurotoxic signs, and may evolve to functional loss of the affected limb, acute renal and/or respiratory failure, and even death. The standard treatment for snake envenomations is antivenom, which is produced from the hyperimmunization of animals with snake toxins. The inhibition of the effects of SBEs using natural or synthetic compounds has been suggested as a complementary treatment particularly before admission to hospital for antivenom treatment, since these alternative molecules are also able to inhibit toxins. Biodiversity-derived molecules, namely those extracted from medicinal plants, are promising sources of toxin inhibitors that can minimize the deleterious consequences of SBEs. In this review, we systematically synthesize the literature on plant metabolites that can be used as toxin-inhibiting agents, as well as present the potential mechanisms of action of molecules derived from natural sources. These findings aim to further our understanding of the potential of natural products and provide new lead compounds as auxiliary therapies for SBEs. [ABSTRACT FROM AUTHOR]

Hemophilia A is an inherited X-linked recessive bleeding disorder caused by deficient activity of blood coagulation factor VIII (FVIII). In addition, hemophilia patients show associated diseases including osteopenia, altered inflammation and vascular fragility which may represent the consequence of recurrent bleeding or may be related to the direct FVIII deficiency. Nowadays, recombinant FVIII is proposed to treat hemophilia patients with no circulating FVIII inhibitor. Initially described as a coenzyme to factor IXa for initiating thrombin generation, there is emerging evidence that FVIII is involved in multiple biological systems, including bone, vascular and immune systems. The present study investigated: (i) the functional activities of recombinant human FVIII (rFVIII) on endothelial cells, and (ii) the impact of rFVIII activities on the functional interactions of human monocytes and endothelial cells. We then investigated whether rFVIII had a direct effect on the adhesion of monocytes to the endothelium under physiological flow conditions. We observed that direct biological activities for rFVIII in endothelial cells were characterized by: (i) a decrease in endothelial cell adhesion to the underlying extracellular matrix; (ii) regulation of the transcriptomic and protein profiles of endothelial cells; (iii) an increase in the vascular tubes formed and vascular permeability in vitro; and (iv) an increase in monocyte adhesion activated endothelium and transendothelial migration. By regulating vascular permeability plus leukocyte adhesion and transendothelial migration, the present work highlights new biological functions for FVIII. [ABSTRACT FROM AUTHOR]

Snakebite envenoming is an important public health problem that threatens the lives of healthy individuals especially in many tropical countries like Nigeria. Antivenins, the only efficient approach for snakebite envenoming, are limited in their efficacy in the neutralization of local tissue damage. Snake venom phospholipase A2 (PLA2), protease, hyaluronidase and l-amino acid oxidase (LAAO) are the major hydrolytic enzymes involve in local tissue damage. Therefore, this study evaluates the inhibitory effect of kolaviron (KV) against Naja n. nigricollis (NNN) snake venom hydrolytic enzymes involved in local tissue damage. Kolaviron was evaluated for its ability to inhibit the hydrolytic enzyme activities of NNN venom phospholipase A2 (PLA2), protease, hyaluronidase and l-amino acid oxidase (LAAO). Present study also deals with the neutralization of NNN venom enzyme(s) induced complications such as myotoxic, edemic, hemolytic and procoagulant effects. Kolaviron inhibited the PLA2, protease, hyaluronidase and LAAO enzyme activities of NNN venom in a dose-dependent manner. Furthermore, myotoxic, edemic, hemolytic and procoagulant effects induced by NNN venom enzyme were neutralized significantly (p<0.05) when different doses of KV were pre-incubated with venom before assays. These findings clearly present kolaviron as a potent inhibitor against NNN venom hydrolytic enzymes involved in local tissue damage and may act by either forming an inhibitor-enzyme complex that restricts the substrate availability to the enzyme or direct binding to the enzyme active site that affects the enzyme activity thereby mitigating venom-induced toxicity. [ABSTRACT FROM AUTHOR]

Withania somnifera, commonly known as "Ashwagandha" or "Indian ginseng" is an essential therapeutic plant of Indian subcontinent regions. It is regularly used, alone or in combination with other plants for the treatment of various illnesses in Indian Systems of Medicine over the period of 3,000 years. Ashwagandha (W. somnifera) belongs to the genus Withania and family Solanaceae. It comprises a broad spectrum of phytochemicals having wide range of biological effects. W. somnifera has demonstrated various biological actions such as anti-cancer, anti-inflammatory, anti-diabetic, anti-microbial, anti-arthritic, anti-stress/adaptogenic, neuro-protective, cardio-protective, hepato-protective, immunomodulatory properties. Furthermore, W. somnifera has revealed the capability to decrease reactive oxygen species and inflammation, modulation of mitochondrial function, apoptosis regulation and improve endothelial function. Withaferin-A is an important phytoconstituents of W. somnifera belonging to the category of withanolides been used in the traditional system of medicine for the treatment of various disorders. In this review, we have summarized the active phytoconstituents, pharmacologic activities (preclinical and clinical), mechanisms of action, potential beneficial applications, marketed formulations and safety and toxicity profile of W. somnifera. [ABSTRACT FROM AUTHOR]

Background: It has been known for years that the same genetic defects drive breast cancer formation, yet, the onset of breast cancer in different individuals among the same population differs greatly in their life spans with unknown mechanisms. Methods: We used a MMTV-PyMT mouse model with different genetic backgrounds (FVB/NJ vs. C57BL/6J) to generate different cancer onset phenotypes, then profiled and analyzed the gene expression of three tumor stages in both Fvb.B6 and Fvb mice to explore the underlying mechanisms. Results: We found that in contrast with the FVB/N-Tg (MMTV-PyMT) 634Mul mice (Fvb mice), mammary tumor initiation was significantly delayed and tumor progression was significantly suppressed in the Fvb.B6 mice (generated by crossing FVB/NJ with C57BL/6J mice). Transcriptome sequencing and analysis revealed that the differentially expressed genes were enriched in immune-related pathways. Flow cytometry analysis showed a higher proportion of matured dendritic cells in the Fvb.B6 mice. The plasma levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) were significantly reduced in the Fvb.B6 mice. IL-6 also impaired the maturation of bone marrow dendritic cells (BMDCs) of the Fvb mice in vitro. Conclusion: All these findings suggest that immunity levels (characterized by a reduced IL-6 level and intact DC maturation in Fvb.B6 mice) are the key factors affecting tumor onset in a murine mammary cancer model. [ABSTRACT FROM AUTHOR]

Introduction: To explore the ethnobiological wisdom of the tribals of three western districts of West Bengal, India against poisonous and non-poisonous bites and stings, a quantitative approach was adopted. These age-old yet unexplored knowledge can be utilized in finding lead-molecules against poisonous and non-poisonous animal-bites. Further, an evidence-based approach is needed to assess the venom-neutralization ability of plants by experimental studies. Materials and methods: During 2008–2009 and 2012–2017, 11 ethnomedicinal surveys were carried out to explore the use of medicinal flora and fauna via conducting open semi-structured interviews with 47 traditional healers (THs) or informants. The retrieved dataset was statistically evaluated using seven quantitative-indexes: use-value (UV), informants'-consensus-factor (ICF), fidelity-level (FL), relative-importance (RI), cultural importance-index (CI), index of agreement on remedies (IAR) and cultural agreement-index (CAI). Anti-phospholipaseA2 (PLA2) properties of selected plant extracts were also examined. In addition, the cytotoxicity and genotoxicity of the water extract of the plants showing high FL as well as significant PLA2 inhibitory potential were investigated using Allium cepa root tip assay. Results: A total of 41 traditional-formulations (TFs) containing 40 plant species (of 39 genera from 28 families) and 3 animal species were prescribed by the THs. Fabaceae exhibited most number of medicinal plants. Piper nigrum (1.78) and Apis cerana indica and Crossopriza lyoni (both 0.21) exhibited the highest UV among the plants and the animals respectively. Stinging of centipede and dog/cat/hyena bite displayed highest ICF (1.00 each). Among the plants, the maximum RI (0.91) and CI (4.98) values were observed for Aristolochia indica. IAR (1.00) was recorded maximum for Achyranthes aspera, Gloriosa superba, Lycopodium cernuum, Smilax zeylanica and Streblus asper. Maximum CAI value was noted for Piper nigrum (5.5096). Among the animals, Apis cerana indica (0.31) and Crossopriza lyoni (1.52) displayed the highest RI and CI values respectively. Crossopriza lyoni (0.99) and Apis cerana indica (1.3871) exhibited maximum IAR and CAI values respectively. Plants showing higher FL exhibited higher anti-PLA2 activity via selective inhibition of human-group PLA2. In addition, Allium cepa root tip assay has indicated the safety and/or toxicity of the plant parts prescribed by the THs. Root water extracts of Aristolochia indica and Gloriosa superba exhibited significant genotoxicity and cytotoxicity. Conclusions: Three western districts of West Bengal is the natural abode for many tribal and non-tribal communities. A noteworthy correlation was established between the plants used against poisonous-bites and their anti-PLA2 activity. A few plant parts used by the THs also exhibited high toxicity. Such alternative medical practices serve as the only option in these underprivileged and backward areas during medical-exigencies. [ABSTRACT FROM AUTHOR]

The treatment of castration-resistant prostate cancer (CRPC) is always a difficulty in the clinic. Most patients with localized tumor eventually develop CRPC, even if hormone therapy is initially effective. Increasing evidence shows immunotherapy has special advantages compared with traditional therapy in cancer treatment. In this study, we constructed the DC-PC-3 fusion vaccine with B7-1- and GM-CSF-specific modification, and studied its ability to stimulate specific immune response and anti-tumor effect in vitro. The results showed that fusion of DC and tumor cells can improve the expression of associated antigens of DCs. DC-tumor fusion vaccine can strongly promote T cell proliferation and IFN-γ secretion and induce a significant tumor-specific cytotoxic T lymphocyte response. In addition, the B7-1/GM-CSF-modified fusion vaccine showed a more significant anti-tumor effect and greater ability to stimulate the immune response than that without specific modification in vitro. Thus, GM-CSF/B7-1-modified fusion vaccine might be used as a potential therapy strategy for prostate cancer. [ABSTRACT FROM AUTHOR]

The present study examined the mechanism of a low-protein (LP) diet on hepatic lipid metabolism during gestation and lactation. Timed-pregnant Sprague-Dawley rats were fed a control or an LP diet during gestation and lactation. LP dams had increased hepatic triglyceride accumulation and a significantly higher aspartate/alanine transaminase ratio, accompanied by a decrease in the circulating very low-density/low-density lipoprotein ratio. Microtubuleassociated protein 1 light-chain 3β (LC3B) expression was stimulated in LP dams along with increased histone acetylation. LP diet induced colocalization of the LC3 binding motif interacting proteins apolipoprotein B (APOB) or microsomal triglyceride transfer protein (MTTP) with LC3B, suggesting autophagic degradation. Histone deacetylase 3 (HDAC3) is found necessary to prevent lipid accumulation in response to amino acid deprivation in HepG2 cells. LC3B-mediated APOB protein degradation is related to increases in lipid accumulation. HDAC3 regulated LC3B-induced lipid accumulation potentially through autophagic degradation of APOB and MTTP in response to amino acid limitation caused by a low-protein diet. [ABSTRACT FROM AUTHOR]

Cellular protein homeostasis (proteostasis) depends on the controlled degradation of proteins that are damaged or no longer required by the ubiquitin-proteasome system (UPS). The 26S proteasome is the principal executer of substrate-specific proteolysis in eukaryotic cells and regulates a myriad of cellular functions. Proteasome inhibitors were initially developed as chemical tools to study proteasomal function but rapidly became widely used anticancer drugs that are now used at all stages of treatment for the bone marrow cancer multiple myeloma (MM). Here, we review the mechanisms of action of proteasome inhibitors that underlie their preferential toxicity to MM cells, focusing on endoplasmic reticulum stress, depletion of amino acids, and effects on glucose and lipid metabolism. We also discuss mechanisms of resistance to proteasome inhibition such as autophagy and metabolic rewiring and what lessons we may learn from the success and failure of proteasome inhibition in MM for treating other cancers with proteostasis-targeting drugs. [ABSTRACT FROM AUTHOR]

Therapeutic treatment of bleeds with FVIII can lead to an antibody response that effectively inhibits its function. Herein, we review the factors that contribute to this immunogenicity and possible ways to overcome it. [ABSTRACT FROM AUTHOR]

Venomous snake bites possess significant amount of mortality as well as morbidity in tropical and subtropical regions of the world including India. The snake Russell’s viper (Daboia russelii) is responsible for thousands of deaths in India. Although antivenom are the only treatment available and the effects associated with several side effects. As an alternative, plants have been extensively studied in order to obtain an alternative treatment. The uses of plants against the effects of snake bites have been long recognized more scientific attention has been given since last 20 years. Extracts from plants have been used among traditional healers, especially in tropical areas there are plentiful sources, as therapy for snakebite for a long time. The present study aimed to provide a scientific explanation for the use of Justicia adhatoda plant against snakebite. The acetone extract of Justicia adhatoda leaves were tested for in vitro inhibitory activity on toxic venom enzymes like 5' nucleotidase, L-amino acid oxidase, phosphomonoesterase, phosphodiesterase, acetylcholine esterase and hyaluronidase from the Russell’s viper snake venom. The result showed the potential of plant leaves extract against the enzymes present in the snake venom. Justicia adhatoda inhibits most of the snake venom enzymes like L-amino acid oxidase, phosphomonoesterase, phosphodiestarase and acetylcholine esterase. [ABSTRACT FROM AUTHOR]

Plants have provided a source of inspiration of novel drug compounds, as plant derived medicines have made large contributions to human health and well-being. An estimate of 75-90% of rural population of the world still relies on herbs for their healthcare. Ayurveda, supposed to be the oldest medical system in the world, provides potential leads to find active and therapeutically useful compounds from plants. Epidemiological studies have consistently demonstrated that consumption of plant-derived foods rich in bioactive phytochemicals have a protective effect against different aliments related to human health. Tamarindus indica is having numerous reported activities like antidiabetic, hypolipidemic, hepatoprotective, anti-ulcer, anti-inflammatory, analgesic, antivenom, antimicrobial, antihelmintic and molluscicidal properties. In spite of these medicinal values this plant is also consumed by rural people as vegetable. It also use as flavoring agent to impart flavor to various dishes and beverage. The present comprehensive review is therefore an effort to give detailed information about botanical description, phytochemical, traditional, nutraceutical and pharmacological approaches of Tamarindus indica. [ABSTRACT FROM AUTHOR]

Background: Hemophilia A (HA) and hemophilia B (HB) are rare inherited bleeding disorders. Although causative genetic variants are clinically relevant, in 2012 only 20% of US patients had been genotyped., Objectives: My Life, Our Future (MLOF) was a multisector cross-sectional US initiative to improve our understanding of hemophilia through widespread genotyping., Methods: Subjects and potential genetic carriers were enrolled at US hemophilia treatment centers (HTCs). Bloodworks performed genotyping and returned results to providers. Clinical data were abstracted from the American Thrombosis and Hemostasis Network dataset. Community education was provided by the National Hemophilia Foundation., Results: From 2013 to 2017, 107 HTCs enrolled 11 341 subjects (68.8% male, 31.2% female) for testing for HA (n = 8976), HB (n = 2358), HA/HB (n = 3), and hemophilia not otherwise specified (n = 4). Variants were detected in most male patients (98.2%% HA, 98.1% HB). 1914 unique variants were found (1482 F8, 431 F9); 744 were novel (610 F8, 134 F9). Inhibitor data were available for 6986 subjects (5583 HA; 1403 HB). In severe HA, genotypes with the highest inhibitor rates were large deletions (77/80), complex intron 22 inversions (9/17), and no variant found (7/14). In severe HB, the highest rates were large deletions (24/42). Inhibitors were reported in 27.3% of Black versus 16.2% of White patients., Conclusions: The findings of MLOF are reported, the largest hemophilia genotyping project performed to date. The results support the need for comprehensive genetic approaches in hemophilia. This effort has contributed significantly towards better understanding variation in the F8 and F9 genes in hemophilia and risks of inhibitor formation., (© 2022 International Society on Thrombosis and Haemostasis.)

Biogerontological research indicates nutrition as one of the major determinants of healthy aging, due to the role of nutrients in maintaining the dynamic-homeostasis of the organism. In this frame, the importance of proteins and constitutive amino acids (AAs), and in particular of functional AAs is emerging. The ability to sense and respond to changes in AAs availability is mediated by a complex network of dynamic players, crucial for an efficient regulation of their downstream effects. Here, we reviewed the current knowledge about the involvement of AA sensing mechanisms in aging and age-related diseases, focusing our attention on mTORC1 and AA transporters. In this context it is of note that alterations in AA sensors have been reported to be directly implicated in age-related phenotypes, suggesting that their modulation can represent a possible strategy for modulating (and possibly delaying) aging decline. Furthermore, these alterations may influence the effects of AA supplementation, by influencing the individual answer to AA availability. On the whole, evidences support the hypothesis that the efficiency of components of AA sensing network may have important implications for therapy, and their knowledge may be crucial for programming AA supplementation for contrasting age-related phenotypes, opening new opportunities for therapeutic interventions aimed to promote human health span. [ABSTRACT FROM AUTHOR]

Introduction: Factor replacement therapy in treatment of haemophilia A is complicated by the production of neutralising antibodies known as inhibitors. The formation of inhibitors is multifactorial being associated with both genetic and environmental factors. Aim: To document the prevalence of inhibitors in severe haemophilia in the community where most patients receive only infrequent episodic replacement therapy and evaluate the factors which could be contributing to it. Methods: Community based camps were conducted in different parts of the country. Patients were assessed through a structured questionnaire and blood samples were obtained for laboratory evaluation of inhibitors and defined immunological parameters. Results: Inhibitors were present in 87/447 (19.5%) of the evaluated patients. High‐titre inhibitor (>5 Bethesda Units [BU]) was identified in 31 (35.6%) patients. HLA DRB1‐13‐positive cases (RR = 2.04; 95% CI 1.06‐3.911; P = 0.033) had an increased risk of inhibitor formation which was retained in the high‐titre subset. A decreased risk of inhibitor formation was noted with heterozygous IL4‐590 C/T allele (RR = 0.22; 95% CI 0.108‐0.442: P = 0.000). There were no significant correlations between any of the evaluated environmental factors and the development of inhibitors in this study. Conclusion: The overall prevalence of inhibitors in patients with severe haemophilia A is similar to that reported among patients receiving regular replacement therapy. The data from this study, limited by its retrospective and cross‐sectional study design, would suggest that genetic rather than environmental are more likely to impact the development of inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Information from the genes encoding factor VIII (F8) and IX (F9) is used in reproductive planning and to inform inhibitor formation, bleeding severity and response to therapies. Advances in technology and our understanding of the human genome now allows more comprehensive methods to study genomic variation and its impact on haemophilia. Aims: The My Life Our Future (MLOF) programme was begun in 2012 to provide genetic analysis and to expand research in haemophilia through a research repository. Methods: MLOF enrolled haemophilia A and B patients followed at haemophilia treatment centers in the U.S., including, since 2015, known and potential genetic carriers. Initial F8 and F9 DNA analysis was performed utilizing a next generation sequencing approach which allowed simultaneous detection of F8 inversions and other variants. Candidate variants were confirmed using a second method and multiplex ligation‐dependent probe amplification was used to detect structural variants. Results: The initial phase of MLOF completed enrollment in December 2017 with 11,356 patients, genetic carriers, and potential carriers enrolled. In the 9453 subjects in whom analysis is complete, 687 unique previously unreported variants were found. Simultaneous sequencing of the F8 and F9 genes resulted in identification of non‐deleterious variants previously reported as causative in haemophilia. DNA from 5141 MLOF subjects has undergone whole genome sequencing through the NHLBI TOPMed programme of the U.S. NIH. Conclusion: MLOF has provided genetic information for patients and their families to help inform clinical care and has established a repository of data and biospecimens to further advance haemophilia research. [ABSTRACT FROM AUTHOR]

The discovery of numerous genetic variants in the human genome that are associated with inflammatory bowel disease (IBD) has revealed critical pathways that play important roles in intestinal homeostasis. These genetic studies have identified a critical role for macroautophagy/autophagy and more recently, lysosomal function, in maintaining the intestinal barrier and mucosal homeostasis. This review highlights recent work on the functional characterization of IBD-associated human genetic variants in cell type-specific functions for autophagy. [ABSTRACT FROM AUTHOR]

Withania somnifera Dunal, is a commonly used herb in Indian Ayurvedic medicine system. Due to its pharmacological value and an inexhaustible source of novel biologically active compounds, it has been a great interest for researchers. The plant is known to possess anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory and hemopoetic properties. Various withanolides, steroidal lactones, have been isolated from W. somnifera and were known to have high therapeutic value. Based on the differences in the substitution patterns of withanolides the species has been classified into various chemotypes. So far, three different chemotypes have been identified, which have been further classified into ecotypes based on the contents of withanolides. Present review summarizes the phytochemical variability and pharmacological advances reported in literature. [ABSTRACT FROM AUTHOR]

The tumor microenvironment is profoundly immunosuppressive. This creates a major barrier for attempts to combine immunotherapy with conventional chemotherapy or radiation, because the tumor antigens released by these cytotoxic agents are not cross-presented in an immunogenic fashion. In this Focused Research Review, we focus on mouse preclinical studies exploring the role of immunosuppressive Tregs expressing the PTEN lipid phosphatase, and the links between PTEN+ Tregs and the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO has received attention because it can be expressed by a variety of human tumor types in vivo, but IDO can also be induced in host immune cells of both humans and mice in response to inflammation, infection or dying (apoptotic) cells. Mechanistically, IDO and PTEN+ Tregs are closely connected, with IDO causing activation of the PTEN pathway in Tregs. Genetic ablation or pharmacologic inhibition of PTEN in mouse Tregs destabilizes their suppressive phenotype, and this prevents transplantable and autochthonous tumors from creating their normal immunosuppressive microenvironment. Genetic ablation of either IDO or PTEN+ Tregs in mice results in a fundamental defect in the ability to maintain tolerance to antigens associated with apoptotic cells, including dying tumor cells. Consistent with this, pharmacologic inhibitors of either pathway show synergy when combined with cytotoxic agents such as chemotherapy or radiation. Thus, we propose that IDO and PTEN+ Tregs represent closely linked checkpoints that can influence the choice between immune activation versus tolerance to dying tumor cells. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is foremost among the non-reversible fatal ailments where exposure to tobacco/biomass-smoke and aging are the major risk factors for the initiation and progression of the obstructive lung disease. The role of smoke-induced inflammatory-oxidative stress, apoptosis and cellular senescence in driving the alveolar damage that mediates the emphysema progression and severe lung function decline is apparent, although the central mechanism that regulates these processes was unknown. To fill in this gap in knowledge, the central role of proteostasis and autophagy in regulating chronic lung disease causing mechanisms has been recently described. Recent studies demonstrate that cigarette/nicotine exposure induces proteostasis/autophagy-impairment that leads to perinuclear accumulation of polyubiquitinated proteins as aggresome-bodies, indicative of emphysema severity. In support of this concept, autophagy inducing FDA-approved anti-oxidant drugs control tobacco-smoke induced inflammatory-oxidative stress, apoptosis, cellular senescence and COPD-emphysema progression in variety of preclinical models. Hence, we propose that precise and early detection of aggresome-pathology can allow the timely assessment of disease severity in COPD-emphysema subjects for prognosis-based intervention. While intervention with autophagy-inducing drugs is anticipated to reduce alveolar damage and lung function decline, resulting in a decrease in the current mortality rates in COPD-emphysema subjects. [ABSTRACT FROM AUTHOR]

In both underwater and semi-aquatic environments, the gut microbiota is of particular physiological importance for amphibious animals, given that the gut tract is among those organs in direct communication with the external environment. In this study, we examined the effects of these contrasting environments on the dominant bacteria in the guts of the amphibious mudskipper Boleophthalmus pectinirostris. Compared with the guts of normal mudskippers, in which the dominant bacteria were identified as Vibrio and Faecalibacterium, we found that Acinetobacter, Shigella, and Bacillus predominated in their guts after exposure to the semi-aquatic environment, whereas Escherichia, Bacteroides, and Bacillus were more prevalent in the guts in the underwater environment. The total number of cultured gut bacteria decreased significantly in the semi-aquatic environment. In semi-aquatic mudskippers, we also detected reductions and increases in the length and width of gut villi, respectively, whereas the width of gut villi declined and the number of goblet cells increased significantly in mudskippers maintained underwater. The mRNA expression of multiple gut transporters for glucose, long-chain fatty acids, and amino acids was found to increase markedly in both underwater and semi-aquatic environments, with the expression of most transporters being significantly higher in those mudskippers exposed to an underwater environment. Furthermore, we detected significant increases in the mRNA expression of pro-inflammatory cytokine transcripts in the guts of both underwater and semi-aquatic mudskippers on days 2, 4, and 6 of exposure, whereas the expression of IL-10 and TGFβ mRNA was more pronounced on days 4 and 8, respectively. Comparatively, we found that expression levels of cytokines in the guts of underwater mudskipper were substantially higher than those in the guts of semi-aquatic mudskippers. Collectively, our findings revealed notable differences in the gut microbiota and energy metabolism requirements of mudskippers exposed to underwater and semi-aquatic conditions, thereby providing a theoretical basis explaining the maintenance of a homeostatic state in mudskippers that constantly transition between these contrasting amphibious habitats.

Traditional genetic studies of single traits may be unable to detect the pleiotropic effects involved in complex diseases. To detect the correlation that exists between several phenotypes involved in the same biological process, we introduce an original methodology to analyze sets of correlated phenotypes involved in the coagulation cascade in genome-wide association studies. The methodology consists of a two-stage process. First, we define new phenotypic meta-variables (linear combinations of the original phenotypes), named metaphenotypes, by applying Independent Component Analysis for the multivariate analysis of correlated phenotypes (i.e. the levels of coagulation pathway–related proteins). The resulting metaphenotypes integrate the information regarding the underlying biological process (i.e. thrombus/clot formation). Secondly, we take advantage of a family based Genome Wide Association Study to identify genetic elements influencing these metaphenotypes and consequently thrombosis risk. Our study utilized data from the GAIT Project (Genetic Analysis of Idiopathic Thrombophilia). We obtained 15 metaphenotypes, which showed significant heritabilities, ranging from 0.2 to 0.7. These results indicate the importance of genetic factors in the variability of these traits. We found 4 metaphenotypes that showed significant associations with SNPs. The most relevant were those mapped in a region near the HRG, FETUB and KNG1 genes. Our results are provocative since they show that the KNG1 locus plays a central role as a genetic determinant of the entire coagulation pathway and thrombus/clot formation. Integrating data from multiple correlated measurements through metaphenotypes is a promising approach to elucidate the hidden genetic mechanisms underlying complex diseases. [ABSTRACT FROM AUTHOR]

Background: The General Control Nonderepressible 2 (GCN2) kinase is a conserved member of the integrated stress response (ISR) pathway that represses protein translation and helps cells to adapt to conditions of nutrient shortage. As such, GCN2 is required for longevity and stress resistance induced by dietary restriction (DR). IMPACT is an ancient protein that inhibits GCN2. Results: Here, we tested whether IMPACT down-regulation mimics the effects of DR in C. elegans. Knockdown of the C. elegans IMPACT homolog impt-1 activated the ISR pathway and increased lifespan and stress resistance of worms in a gcn-2-dependent manner. Impt-1 knockdown exacerbated DR-induced longevity and required several DR-activated transcription factors to extend lifespan, among them SKN-1 and DAF-16, which were induced during larval development and adulthood, respectively, in response to impt-1 RNAi. Conclusions: IMPACT inhibits the ISR pathway, thus limiting the activation of stress response factors that are beneficial during aging and required under DR. [ABSTRACT FROM AUTHOR]

The ability to predict how different individuals will respond to vaccination and to understand what best protects individuals from infection greatly facilitates developing next-generation vaccines. It facilitates both the rapid design and evaluation of new and emerging vaccines and identifies individuals unlikely to be protected by vaccine. We describe a general-purpose machine-learning framework, DAMIP, for discovering gene signatures that can predict vaccine immunity and efficacy. DAMIP is a multiple-group, concurrent classifier that offers unique features not present in other models: a nonlinear data transformation to manage the curse of dimensionality and noise; a reserved-judgment region that handles fuzzy entities; and constraints on the allowed percentage of misclassifications. Using DAMIP, implemented results for yellow fever demonstrated that, for the first time, a vaccine's ability to immunize a patient could be successfully predicted (with accuracy of greater than 90 percent) within one week after vaccination. A gene identified by DAMIP, EIF2AK4, decrypted a seven-decade-old mystery of vaccination. Results for flu vaccine demonstrated DAMIP's applicability to both live-attenuated and inactivated vaccines. Results in a malaria study enabled targeted delivery to individual patients. Our project's methods and findings permit highlighting and probabilistically prioritizing hypothesis design to enhance biological discovery. Moreover, they guide the rapid development of better vaccines to fight emerging infections, and improve monitoring for poor responses in the elderly, infants, or others with weakened immune systems. In addition, the project's work should help with universal flu-vaccine design. [ABSTRACT FROM AUTHOR]

Background: Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant cutaneous disorder caused by the mutations of adenosine deaminase acting on RNA1 (ADAR1) gene. We present a clinical and genetic study of seven unrelated families and two sporadic cases with DSH for mutations in the full coding sequence of ADAR1 gene. Methods: ADAR1 gene was sequenced in seven unrelated families and two sporadic cases with DSH and 120 controls. Functional significance of the observed ADAR1 mutations was analyzed using PolyPhen 2, SIFT and DDIG-in. Results: We describe six novel mutations of the ADAR1 gene in Chinese patients with DSH including a nonstop mutation p.Stop1227R, which was firstly reported in ADAR1 gene. In silico analysis proves that all the mutations reported here are pathogenic. Conclusion: This study is useful for functional studies of the protein and to define a diagnostic strategy for mutation screening of the ADAR1 gene. A three-generation family exhibiting phenotypic variability with a single germline ADAR1 mutation suggests that chilblain might aggravate the clinical phenotypes of DSH. [ABSTRACT FROM AUTHOR]

Viper envenomation results in inflammation at the bitten site as well as target organs. Neutrophils and other polymorphonuclear leukocytes execute inflammation resolving mechanism and will undergo apoptosis after completing the task. However, the target specific toxins induce neutrophil apoptosis at the bitten site and in circulation prior to their function, thus reducing their number. Circulating activated neutrophils are major source of inflammatory cytokines and leakage of reactive oxygen species (ROS)/other toxic intermediates resulting in aggravation of inflammatory response at the bitten/target site. Therefore, neutralization of venom induced neutrophil apoptosis reduces inflammation besides increasing the functional neutrophil population. Therefore, the present study investigates the venom induced perturbances in isolated human neutrophils and its neutralization by crocin ( Crocus sativus) a potent antioxidant carotenoid. Human neutrophils on treatment with venom resulted in altered ROS generation, intracellular Ca mobilization, mitochondrial membrane depolarization, cyt-c translocation, caspase activation, phosphatidylserine externalization and DNA damage. On the other hand significant protection against oxidative stress and apoptosis were evidenced in crocin pre-treated groups. In conclusion the viper venom induces neutrophil apoptosis and results in aggravation of inflammation and tissue damage. The present study demands the necessity of an auxiliary therapy in addition to antivenin therapy to treat secondary/overlooked complications of envenomation. [ABSTRACT FROM AUTHOR]

Objectives: Snakebite envenoming is an important public health problem that threatens the lives of healthy individuals especially in many tropical countries like Nigeria. Antivenins, the only efficient approach for snakebite envenoming, are limited in their efficacy in the neutralization of local tissue damage. Snake venom phospholipase A 2 (PLA 2 ), protease, hyaluronidase and l-amino acid oxidase (LAAO) are the major hydrolytic enzymes involve in local tissue damage. Therefore, this study evaluates the inhibitory effect of kolaviron (KV) against Naja n. nigricollis (NNN) snake venom hydrolytic enzymes involved in local tissue damage., Methods: Kolaviron was evaluated for its ability to inhibit the hydrolytic enzyme activities of NNN venom phospholipase A 2 (PLA 2 ), protease, hyaluronidase and l-amino acid oxidase (LAAO). Present study also deals with the neutralization of NNN venom enzyme(s) induced complications such as myotoxic, edemic, hemolytic and procoagulant effects., Results: Kolaviron inhibited the PLA 2 , protease, hyaluronidase and LAAO enzyme activities of NNN venom in a dose-dependent manner. Furthermore, myotoxic, edemic, hemolytic and procoagulant effects induced by NNN venom enzyme were neutralized significantly (p<0.05) when different doses of KV were pre-incubated with venom before assays., Conclusions: These findings clearly present kolaviron as a potent inhibitor against NNN venom hydrolytic enzymes involved in local tissue damage and may act by either forming an inhibitor-enzyme complex that restricts the substrate availability to the enzyme or direct binding to the enzyme active site that affects the enzyme activity thereby mitigating venom-induced toxicity., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Withania somnifera, also called 'Indian ginseng', is an important medicinal plant of the Indian subcontinent. It is widely used, singly or in combination, with other herbs against many ailments in Indian Systems of Medicine since time immemorial. Withania somnifera contains a spectrum of diverse phytochemicals enabling it to have a broad range of biological implications. In preclinical studies, it has shown anti-microbial, anti-inflammatory, anti-tumor, anti-stress, neuroprotective, cardioprotective, and anti-diabetic properties. Additionally, it has demonstrated the ability to reduce reactive oxygen species, modulate mitochondrial function, regulate apoptosis, and reduce inflammation and enhance endothelial function. In view of these pharmacologic properties, W. somnifera is a potential drug candidate to treat various clinical conditions, particularly related to the nervous system. In this review, we summarize the pharmacologic characteristics and discuss the mechanisms of action and potential therapeutic applications of the plant and its active constituents. [ABSTRACT FROM AUTHOR]