Cerebral ischemia-reperfusion (I-R) injury is one of the primary causes of ischemic stroke. Ischemic postconditioning (iPoCo) is evolving as an important adaptive technique to contain I-R injury. Some recent studies have shown neuroprotective effects of iPoCo. However, the neuroprotective mechanism of iPoCo is not clear. So, the present study has been undertaken to investigate the possible role of Sirtinol, a selective class III histone deacetylase (HDAC) inhibitor in the neuroprotective mechanism of iPoCo in mice.

Influenza surveillance is important to identify circulating, emerging/reemerging strains and unusual epidemiological trends. With these objectives, a multisite human influenza surveillance network was initiated in India in 2004.

During the present study on myxozoan parasites infecting gills of cyprinid carps inhabiting Ranjit Sagar Wetland, a new parasite, Myxobolus okamurae sp. nov. infecting gills of Labeo bata has been described based on morphology, histopathology and partial 18S rDNA sequencing. For M. okamurae sp. nov., hundred fish specimens were examined, out of which thirty-three had large cylindrical to round, white plasmodia in gills, each plasmodium measured 0.9-3.0 mm in diameter. The myxospore body was pyriform in shape, measuring 12.25 × 4.93 μm, with a small intercapsular process at the anterior end. The polar capsules were equal and pyriform in shape, measuring 6.06 × 1.45 μm having polar filaments forming coils up to 13-14 in number. The intensity of infection was recorded to be heavy as indicated by gill plasmodium index (GPI = 3). Sequence analysis showed that M. okamurae sp. nov. is 91% similar with M. catlae infecting gills of Catla catla from India followed by M. intimus infecting gills of Leuciscus idus from Hungary. The phylogenetic tree based on the final edited alignment (403 bp) with Maximum-Likelihood showed the high bootstrap value of 75 and formed two major clades involving M. okamurae sp. nov. with M. pendula M. catlae and M. dispar in one clade with a low bootstrap value of 23 and the rest of the species in a separate clade. The plasmodium was located in the gill lamella and typed as "intralamellar vascular type, LV3".

Background. Terminalia arjuna is a popular Indian medicinal plant with its bark been used for over centuries as cardiotonic. The bark has been found to contain several bioactive compounds including saponins and flavonoids. A number of experimental and clinical studies have been conducted to explore therapeutic potential of Terminalia arjuna in cardiovascular ailments specially in patients of coronary heart disease. A number of narrative reviews have been done but no systematic review has been conducted to date. Objective. To systematically review and conduct a meta-analysis on the available literature evaluating the efficacy of Terminalia arjuna in patients of chronic stable angina. Study selection. We included randomised, pseudo-randomized and before-after comparative studies which compared Terminalia arjuna/commercial preparation of Terminalia arjuna with current standard/ conventional treatment regimens in patients with chronic stable angina. Findings. Studies were found to be of poor methodological design. We found no significant difference in the Terminalia arjuna group as compared to control arm in the outcomes for which we were able to pool data and undertake meta-analysis. Conclusions. Currently, the evidence is insufficient to draw any definite conclusions in favour of or against Terminalia arjuna in patients of chronic stable angina. Further, well-controlled multicentric clinical trials need to be conducted in large number of patients to explore the therapeutic potential of Terminalia arjuna if any.

Malarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined.

A myxozoan parasite belonging to the genus Thelohanellus Kudo, 1933 (Cnidaria, Myxosporea, Bivalvulida) was isolated from the fins of Labeo dero inhabiting Ranjit Sagar Wetland, Punjab, India. The plasmodium was 0.5-0.7 mm in diameter each containing 80- 100 number of myxospores. Myxospores were egg shaped to ovoidal in valvular view having bluntly pointed anterior and broad rounded posterior end measuring 8.36x 4.77 µm. Polar capsule was single, broadly pyriform in shape, measuring 4.77x3.98 µm in size containing a polar filament coiled perpendicular to the longitudinal axis of myxospore body making 7-9 turns. Blast analysis of 18S rDNA sequence of the isolate demonstrated 98% homogeneity with Thelohanellus sp. (KU155561, Unpublished), followed by 91% with T. caudatus (KM252684) and Thelohanellus sp. FCO (KR819273). The intensity of infection was recorded to be light as indicated by fin plasmodial index (FPI = 1). In the present study, T. boggoti has been described using 18S rRNA gene and phylogenetic analysis using MEGA.6.

Evidence suggests that glial cells play a critical role in inflammation in chronic epilepsy, contributing to perpetuation of seizures and cognitive dysfunctions. The present study was designed to evaluate the beneficial effect of curcumin, a polyphenol with pleiotropic properties, on cognitive deficits and inflammation in chronic epilepsy. Kindled model of epilepsy was induced by administering sub-convulsive dose of pentylenetetrazole (PTZ) at 40 mg/kg, i.p. every alternative day for 30 days to Wistar rats. The animals were assessed for cognitive deficits by Morris water maze and inflammatory response in terms of microglial and astrocyte activation. PTZ treated animals had increased escape latency suggesting impaired cognitive functions. Further, an increased expression of astrocyte (GFAP) and microglial (Iba-1) activation markers were observed in terms of mRNA and protein levels in the PTZ treated animals. Concomitantly, mRNA and protein levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokine (MCP-1) were increased in hippocampus and cortex. Immunoreactivity to anti-GFAP and anti-Iba-1 antibodies was also enhanced in hippocampus and cortex suggesting gliosis in PTZ treated animals. However, curcumin administration at a dose of 100 mg/kg to PTZ animals prevented cognitive deficits. A significant decrease in pro-inflammatory cytokines and chemokine expression was observed in hippocampus and cortex of PTZ treated rats supplemented with curcumin. In addition, curcumin also attenuated increased expression of GFAP and Iba-1 in animals with PTZ induced chronic epilepsy. Moreover, immunohistochemical analysis also showed significant reduction in number of activated glial cells on curcumin administration to PTZ treated animals. Taken together, these findings suggest that curcumin is effective in attenuating glial activation and ameliorates cognitive deficits in chronic epilepsy.

Despite numerous studies on major depressive disorder (MDD) susceptibility, the precise underlying molecular mechanism has not been elucidated which restricts the development of etiology-based disease-modifying drug. Major depressive disorder treatment is still symptomatic and is the leading cause of (~30%) failure of the current antidepressant therapy. Here we comprehended the probable genes and pathways commonly associated with antidepressant response and MDD. A systematic review was conducted, and candidate genes/pathways associated with antidepressant response and MDD were identified using an integrative genetics approach. Initially, single nucleotide polymorphisms (SNPs)/genes found to be significantly associated with antidepressant response were systematically reviewed and retrieved from the candidate studies and genome-wide association studies (GWAS). Also, significant variations concerning MDD susceptibility were extracted from GWAS only. We found 245 (Set A) and 800 (Set B) significantly associated genes with antidepressant response and MDD, respectively. Further, gene set enrichment analysis revealed the top five co-occurring molecular pathways (p ≤ 0.05) among the two sets of genes: Cushing syndrome, Axon guidance, cAMP signaling pathway, Insulin secretion, and Glutamatergic synapse, wherein all show a very close relation to synaptic plasticity. Integrative analyses of candidate gene and genome-wide association studies would enable us to investigate the putative targets for the development of disease etiology-based antidepressant that might be more promising than current ones.

RareLSD is a manually curated database of lysosomal enzymes associated with rare diseases that maintains comprehensive information of 63 unique lysosomal enzymes and 93 associated disorders. Each entry provides a complete information on the disorder that includes the name of the disease, organ affected, age of onset, available drug, inheritance pattern, defected enzyme and single nucleotide polymorphism. To facilitate users in designing drugs against these diseases, we predicted and maintained structures of lysosomal enzymes. Our information portal also contains information on biochemical assays against disease-associated enzymes obtained from PubChem. Each lysosomal entry is supported by information that includes disorders, inheritance pattern, drugs, family members, active inhibitors, etc. Eventually, a user-friendly web interface has been developed to facilitate the users in searching and browsing data in RareLSD with a wide range of options. RareLSD is integrated with sequence similarity search tools (e.g. BLAST and Smith-Waterman algorithm) for analysis. It is built on responsive templates that are compatible with most of browsers and screens including smartphones and gadgets (mobile, iPhone, iPad, tablets, etc.).

Evidence suggests that changes in intestinal microbiota may affect the central nervous system. However, it is unclear whether alteration of intestinal microbiota affects progression of Alzheimer's disease (AD). To understand this, wild-type control (C57BL/6) mice were compared with the AppNL-G-F model of disease. We used probiotic supplementation to manipulate the gut microbiota. Fecal samples were collected for microbiota profiling. To study brain and intestinal inflammation, biochemical and histological analyses were performed. Altered metabolic pathways were examined by quantifying eicosanoid and bile acid profiles in the brain and serum using ultraperformance liquid chromatography-tandem mass spectrometry. We observed that brain pathology was associated with intestinal dysbiosis and increased intestinal inflammation and leakiness in AppNL-G-F mice. Probiotic supplementation significantly decreased intestinal inflammation and gut permeability with minimal effect on amyloid-β, cytokine, or gliosis levels in the brain. Concentrations of several bile acids and prostaglandins were altered in the serum and brain because of AD or probiotic supplementation. Our study characterizes intestinal dysfunction in an AD mouse model and the potential of probiotic intervention to ameliorate this condition.

Hypertension is more prevalent in African Americans (AA) than other ethnic groups. Genome-wide association studies (GWAS) have identified loci associated with hypertension and other cardio-metabolic traits like type 2 diabetes, coronary artery disease, and body mass index (BMI), however the AA population is underrepresented in these studies. In this study, we examined a large AA cohort for the generalizability of 14 Metabochip array SNPs with previously reported European hypertension associations.

Malaria is a life-threatening disease, and Africa is still one of the most affected endemic regions despite years of policy to limit infection and transmission rates. Further, studies into the variable efficacy of the vaccine are needed to provide a better understanding of protective immunity. Thus, the current study is designed to delineate the effect of each dose of vaccine on the transcriptional profiles of subjects to determine its efficacy and understand the molecular mechanisms underlying the protection this vaccine provides. Here, we used gene expression profiles of pre and post-vaccination patients after various doses of RTS,S based on samples collected from the Gene Expression Omnibus datasets. Subsequently, differential gene expression analysis using edgeR revealed the significantly (false discovery rate < 0.005) 158 downregulated and 61 upregulated genes between control vs. controlled human malaria infection samples. Further, enrichment analysis of significant genes delineated the involvement of CCL8, CXCL10, CXCL11, XCR1, CSF3, IFNB1, IFNE, IL12B, IL22, IL6, IL27, etc., genes which found to be upregulated after earlier doses but downregulated after the 3rd dose in cytokine-chemokine pathways. Notably, we identified 13 cytokine genes whose expression significantly varied during three doses. Eventually, these findings give insight into the dual role of cytokine responses in malaria pathogenesis. The variations in their expression patterns after various doses of vaccination are linked to the protection as it decreases the severe inflammatory effects in malaria patients. This study will be helpful in designing a better vaccine against malaria and understanding the functions of cytokine response as well.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and AppNL-G-F. Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and AppNL-G-F mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.

The high mortality rate of hepatocellular carcinoma (HCC) is primarily due to its late diagnosis. In the past, numerous attempts have been made to design genetic biomarkers for the identification of HCC; unfortunately, most of the studies are based on small datasets obtained from a specific platform or lack reasonable validation performance on the external datasets. In order to identify a universal expression-based diagnostic biomarker panel for HCC that can be applicable across multiple platforms, we have employed large-scale transcriptomic profiling datasets containing a total of 2,316 HCC and 1,665 non-tumorous tissue samples. These samples were obtained from 30 studies generated by mainly four types of profiling techniques (Affymetrix, Illumina, Agilent, and High-throughput sequencing), which are implemented in a wide range of platforms. Firstly, we scrutinized overlapping 26 genes that are differentially expressed in numerous datasets. Subsequently, we identified a panel of three genes (FCN3, CLEC1B, and PRC1) as HCC biomarker using different feature selection techniques. Three-genes-based HCC biomarker identified HCC samples in training/validation datasets with an accuracy between 93 and 98%, Area Under Receiver Operating Characteristic curve (AUROC) in a range of 0.97 to 1.0. A reasonable performance, i.e., AUROC 0.91-0.96 achieved on validation dataset containing peripheral blood mononuclear cells, concurred their non-invasive utility. Furthermore, the prognostic potential of these genes was evaluated on TCGA-LIHC and GSE14520 cohorts using univariate survival analysis. This analysis revealed that these genes are prognostic indicators for various types of the survivals of HCC patients (e.g., Overall Survival, Progression-Free Survival, Disease-Free Survival). These genes significantly stratified high-risk and low-risk HCC patients (p-value <0.05). In conclusion, we identified a universal platform-independent three-genes-based biomarker that can predict HCC patients with high precision and also possess significant prognostic potential. Eventually, we developed a web server HCCpred based on the above study to facilitate scientific community (http://webs.iiitd.edu.in/raghava/hccpred/).

Endoplasmic reticulum (ER) stress is a major pathology encountered after hypoxic-ischemic (HI) injury. Accumulation of unfolded proteins triggers the unfolded protein response (UPR), resulting in the activation of pro-apoptotic cascades that lead to cell death. Here, we identified Bax inhibitor 1 (BI-1), an evolutionarily conserved protein encoded by the transmembrane BAX inhibitor motif-containing 6 (TMBIM6) gene, as a novel modulator of ER-stress-induced apoptosis after HI brain injury in a neonatal rat pup. The main objective of our study was to overexpress BI-1, via viral-mediated gene delivery of human adenoviral-TMBIM6 (Ad-TMBIM6) vector, to investigate its anti-apoptotic effects as well as to elucidate its signaling pathways in an in vivo neonatal HI rat model and in vitro oxygen-glucose deprivation (OGD) model. Ten-day-old unsexed Sprague Dawley rat pups underwent right common carotid artery ligation followed by 1.5 h of hypoxia. Rat pups injected with Ad-TMBIM6 vector, 48 h pre-HI, showed a reduction in relative infarcted area size, attenuated neuronal degeneration and improved long-term neurological outcomes. Furthermore, silencing of BI-1 or further activating the IRE1α branch of the UPR, using a CRISPR activation plasmid, was shown to reverse the protective effects of BI-1. Based on our in vivo and in vitro data, the protective effects of BI-1 are mediated via inhibition of IRE1α signaling and in part via inhibition of the second stress sensor receptor, PERK. Overall, this study showed a novel role for BI-1 and ER stress in the pathophysiology of HI and could provide a basis for BI-1 as a potential therapeutic target.

Human leukocyte antigen (HLA) are essential components of the immune system that stimulate immune cells to provide protection and defense against cancer. Thousands of HLA alleles have been reported in the literature, but only a specific set of HLA alleles are present in an individual. The capability of the immune system to recognize cancer-associated mutations depends on the presence of a particular set of alleles, which elicit an immune response to fight against cancer. Therefore, the occurrence of specific HLA alleles affects the survival outcome of cancer patients. In the current study, prediction models were developed, using 401 cutaneous melanoma patients, to predict the overall survival (OS) of patients using their clinical data and HLA alleles. We observed that the presence of certain favorable superalleles like HLA-B∗55 (HR = 0.15, 95% CI 0.034-0.67), HLA-A∗01 (HR = 0.5, 95% CI 0.3-0.8), is responsible for the improved OS. In contrast, the presence of certain unfavorable superalleles such as HLA-B∗50 (HR = 2.76, 95% CI 1.284-5.941), HLA-DRB1∗12 (HR = 3.44, 95% CI 1.64-7.2) is responsible for the poor survival. We developed prediction models using key 14 HLA superalleles, demographic, and clinical characteristics for predicting high-risk cutaneous melanoma patients and achieved HR = 4.52 (95% CI 3.088-6.609, p-value = 8.01E-15). Eventually, we also provide a web-based service to the community for predicting the risk status in cutaneous melanoma patients (https://webs.iiitd.edu.in/raghava/skcmhrp/).

Urinary tract infections (UTIs) are a serious health concern worldwide. Treatment of UTIs is becoming a challenge as uropathogenic Escherichia coli (UPEC), which is the most common etiological agent, has developed resistance to the main classes of antibiotics. Small molecules that interfere with metabolic processes rather than growth are attractive alternatives to conventional antibiotics. Repurposing of already known drugs for treating infectious diseases could be an attractive avenue for finding novel therapeutics against infections caused by UPEC. Virtual screenings enable the rapid and economical identification of target ligands from large libraries of compounds, reducing the cost and time of traditional drug discovery. Moreover, the drugs that have been approved by the FDA have low cytotoxicity and good pharmacological characteristics. In this work, we targeted the HisC enzyme of the histidine biosynthetic pathway as enzymes of this pathway are absent in humans. We screened the library of FDA-approved drugs against HisC via molecular docking, and four hits (Docetaxel, Suramin, Digitoxin, and Nystatin) showing the highest binding energy were selected. These were further tested for antibacterial activity, which was observed only for Docetaxel (MIC value of 640 μg/ml); therefore, Docetaxel was further tested for its efficacy in vivo in murine catheter UTI model and antibiofilm activity using crystal violet staining and scanning electron microscopy. Docetaxel inhibited biofilm formation and reduced the bacterial load in urine, kidney, and bladder. Docking studies revealed that Docetaxel acts by blocking the binding site of HisC to the native substrate by competitive inhibition. Docetaxel may be a potential new inhibitor for UPEC with antibacterial and antibiofilm capability.

Understanding the drivers for care-seeking among those who present with symptoms of TB is crucial for early diagnosis of TB and prompt treatment, which will in turn halt further TB transmission. While TB is a challenge among the tribal population, little is known about the care-seeking behaviour and the factors influencing care-seeking behaviour among the tribal population across India.

The tapeworms of Moniezia spp. are heteroxenous parasites and their adult forms occur in ruminants' alimentary tract. They steal a significant portion of hosts' nourishment initiating monieziasis, thereby inflicting economic losses in animal rearing. Despite their high economic importance, the molecular characterization and taxonomic status of these parasites have remained poorly understood. In the present study, cestodes were isolated from the sheep and goats' intestines and were stained with Gower's carmine. Upon careful evaluation of morphological characters, 2 species Moniezia denticulata and Moniezia expansa were identified. The genomic DNA was extracted and polymerase chain reaction (PCR) amplified targeting regions of mitochondrial cytochrome c oxidase subunit 1 (cox1), small subunit ribosomal RNA (SSU rRNA) and internal transcribed spacer 1–5.8S rRNA (ITS1–5.8S rRNA) genes followed by sequencing. The partial sequences of cox1, SSU rRNA and ITS1–5.8S rRNA genes of M. denticulata generated in the present study revealed that even though they share high similarities with M. benedeni (93.2% cox1; 92.6% SSU rRNA; 84.70% ITS1–5.8S rRNA) and M. expansa (88.85% cox1; 92.27% SSU rRNA; 81.70% ITS1–5.8S rRNA), they are not identical to them. In the maximum likelihood phylogenetic trees, M. denticulata and M. expansa consistently appeared as distinct species from each other. The high values of pairwise divergence between these 2 species collected in the present study confirmed their separate identity. The present study reports the first molecular characterization of M. denticulata with reference to M. expansa infecting sheep and goats in India.

Several probiotic-derived factors have been identified as effectors of probiotics for exerting beneficial effects on the host. However, there is a paucity of studies to elucidate mechanisms of their functions. p40, a secretory protein, is originally isolated from a probiotic bacterium, Lactobacillus rhamnosus GG. Thus, this study aimed to apply structure-functional analysis to define the functional peptide of p40 that modulates the epigenetic program in intestinal epithelial cells for sustained prevention of colitis. In silico analysis revealed that p40 is composed of a signal peptide (1-28 residues) followed by a coiled-coil domain with uncharacterized function on the N-terminus, a linker region, and a β-sheet domain with high homology to CHAP on the C-terminus. Based on the p40 three-dimensional structure model, two recombinant p40 peptides were generated, p40N120 (28-120 residues) and p40N180 (28-180 residues) that contain first two and first three coiled coils, respectively. Compared to full-length p40 (p40F) and p40N180, p40N120 showed similar or higher effects on up-regulating expression of Setd1b (encoding a methyltransferase), promoting mono- and trimethylation of histone 3 on lysine 4 (H3K4me1/3), and enhancing Tgfb gene expression and protein production that leads to SMAD2 phosphorylation in human colonoids and a mouse colonic epithelial cell line. Furthermore, supplementation with p40F and p40N120 in early life increased H3K4me1, Tgfb expression and differentiation of regulatory T cells (Tregs) in the colon, and mitigated disruption of epithelial barrier and inflammation induced by DSS in adult mice. This study reveals the structural feature of p40 and identifies a functional peptide of p40 that could maintain intestinal homeostasis.