The improvement of body's own immune system is considered one of the safest approaches to fight against cancer and several other diseases. Excessive catabolism of the essential amino acid, L-tryptophan (L-Trp) assists the cancer cells to escape normal immune obliteration. The formation of disproportionate kynurenine and other downstream metabolites suppress the T cell functions. Blocking of this immunosuppressive mechanism is considered as a promising approach against cancer, neurological disorders, autoimmunity, and other immune-mediated diseases. Overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme is directly related to the induction of immunosuppressive mechanisms and represents an important therapeutic target. Several classes of small molecule-based IDO1 inhibitors have been already reported, but only few compounds are currently being evaluated in various stages of clinical trials as adjuvants or in combination with chemo- and radiotherapies. In the quest for novel structural class(s) of IDO1 inhibitors, we developed a series of 4,5-disubstituted 1,2,3-triazole derivatives. The optimization of 4,5-disubstituted 1,2,3-triazole scaffold and comprehensive biochemical and biophysical studies led to the identification of compounds, 3i, 4i, and 4k as potent and selective inhibitors of IDO1 enzyme with IC50 values at a low nanomolar level. These potent compounds also showed strong IDO1 inhibitory activities in MDA-MB-231 cells with no/negligible level of cytotoxicity. The T cell activity studies revealed that controlled regulation of IDO1 enzyme activity in the presence of these potent compounds could induce immune response against breast cancer cells. The compounds also showed excellent in vivo antitumor efficacy (of tumor growth inhibition = 79-96%) in the female Swiss albino mice. As a consequence, this study describes the first example of 4,5-disubstituted 1,2,3-triazole based IDO1 inhibitors with potential applications for immunotherapeutic studies.

Soil salinity is one of the major limiting factors for crop productivity across the world. Halophytes have recently been a source of attraction for exploring the survival and tolerance mechanisms at extreme saline conditions. Urochondra setulosa is one of the obligate grass halophyte that can survive in up to 1000 mM NaCl. The de novo transcriptome of Urochondra leaves at different salt concentrations of 300-500 mM NaCl was generated on Illumina HiSeq. Approximately 352.78 million high quality reads with an average contig length of 1259 bp were assembled de novo. A total of 120,231 unigenes were identified. On an average, 65% unigenes were functionally annotated to known proteins. Approximately 35% unigenes were specific to Urochondra. Differential expression revealed significant enrichment (P < 0.05) of transcription factors, transporters and metabolites suggesting the transcriptional regulation of ion homeostasis and signalling at high salt concentrations in this grass. Also, about 143 unigenes were biologically related to salt stress responsive genes. Randomly selected genes of important pathways were validated for functional characterization. This study provides useful information to understand the gene regulation at extremely saline levels. The study offers the first comprehensive evaluation of Urochondra setulosa leaf transcriptome. Examining non-model organisms that can survive in harsh environment can provide novel insights into the stress coping mechanisms which can be useful to develop improved agricultural crops.

Microbial pathogens are known for causing great environmental stress, owing to which emerging challenges like lack of eco-friendly remediation measures, development of drug-resistant and mutational microbial strains, etc., warrants novel and green routes as a stepping stone to serve such concerns sustainably. In the present study, palladium (Pd) doped manganese (II, III) oxide (Mn3O4) nanoparticles (NPs) were synthesized using an aqueous Syzygium aromaticum bud (ASAB) extract. Preliminary phytochemical analysis of ASAB extract indicates the presence of polyphenolics such as phenols, alkaloids, and flavonoids that can act as potential capping agents in NPs synthesis, which was later confirmed in FTIR analysis of pure and Pd-doped Mn3O4 NPs. XRD, Raman, and XPS analyses confirmed the Pd doping in Mn3O4 NPs. FESEM and HRTEM study reveals the mixed morphologies dominated by nanocorns appearance. Zeta potential investigation reveals high stability of the synthesized NPs in colloidal solutions. The developed Pd-doped Mn3O4 NPs were tested against two fungal phytopathogens, i.e., Sclerotinia sclerotiorum and Colletotrichum gloeosporioides, known for causing great economic losses in yield and quality of different plant species. The antifungal activity of synthesized Pd-doped Mn3O4 NPs displayed a dose-dependent response with a maximum of ~92%, and ~72% inhibition was recorded against S. sclerotiorum and C. gloeosporioides, respectively, at 1000 ppm concentration. However, C. gloeosporioides demonstrated higher sensitivity to Pd-doped Mn3O4 NPs upto 500 ppm) treatment than S. sclerotiorum. The prepared NPs also showed significant antibacterial activity against Enterococcus faecalis. The Pd-doped Mn3O4 NPs were effective even at low treatment doses, i.e., 50-100 ppm, with the highest Zone of inhibition obtained at 1000 ppm concentration. Our findings provide a novel, eco-benign, and cost-effective approach for formulating a nanomaterial composition offering multifaceted utilities as an effective antimicrobial agent.

Cancer cell metastasis and its dissemination are most enigmatic and challenging aspects in the development of its therapeutics. Newcastle disease virus (NDV) is a well-studied avian paramyxovirus frequently isolated from birds and rarely from mammals. Since the first report of its oncolytic property, many NDV strains were studied for its effect in various cancer cells. In the present study, NDV strain Bareilly was characterized for its apoptotic potential and migration inhibition in human oral cancer cells. The NDV mediated apoptosis was confirmed by flow cytometry, DNA laddering, and immunoblotting. Moreover, NDV decreased the mitochondrial membrane potential suggesting an intrinsic pathway of apoptosis in oral cancer cells. NDV infection in oral cancer cells results in migration inhibition by a reduction in levels of MMP-7. MMP-7 is one of the key target genes of β-catenin. While overexpression of MMP-7 reversed the inhibitory effect of NDV mediated migration suggested its possible involvement. Wnt/β-catenin is an essential pathway for cell growth, differentiation, and metastasis. The involvement of the Wnt/β-catenin pathway in NDV infection has never been reported. Our results showed that NDV dysregulates Wnt/β-catenin by down-regulation of p-Akt and p-GSK3β leading to degradation of β-catenin. Furthermore, NDV infection leads to a reduction in cytoplasmic and nuclear levels of β-catenin. The study will provide us with a better insight into the molecular mechanism of NDV mediated oncolysis and the key cellular partners involved in the process.

MicroRNAs as cancer biomarkers in serum, plasma, and other body fluids are often used but analysis of miRNA in urine is limited. We investigated the expression of selected miRNAs in the paired urine, serum, cervical scrape, and tumor tissue specimens from the women with cervical precancer and cancer with a view to identify if urine miRNAs could be used as reliable non-invasive biomarkers for an early diagnosis and prognosis of cervical cancer. Expression of three oncomiRs (miR-21, miR-199a, and miR-155-5p) and three tumor suppressors (miR-34a, miR-145, and miR-218) as selected by database search in cervical pre-cancer, cancer, and normal controls including cervical cancer cell lines were analyzed using qRT-PCR. The expression of miRNAs was correlated with various clinicopathological parameters, including HPV infection and survival outcome. We observed a significant overexpression of the oncomiRs and the downregulation of tumor suppressor miRNAs. A combination of miR-145-5p, miR-218-5p, and miR-34a-5p in urine yielded 100% sensitivity and 92.8% specificity in distinguishing precancer and cancer patients from healthy controls and it well correlates with those of serum and tumor tissues. The expression of miR-34a-5p and miR-218-5p were found to be independent prognostic factors for the overall survival of cervical cancer patients. We conclude that the evaluation of the above specific miRNA expression in non-invasive urine samples may serve as a reliable biomarker for early detection and prognosis of cervical cancer.

Aberrant formation of biomolecular condensates has been proposed to play a role in several cancers. The oncogenic fusion protein BRD4-NUT forms condensates and drives changes in gene expression in Nut Carcinoma. Here we sought to understand the molecular elements of BRD4-NUT and its associated histone acetyltransferase (HAT), p300, that promote these activities. We determined that a minimal fragment of NUT (MIN) in fusion with BRD4 is necessary and sufficient to bind p300 and form condensates. Furthermore, a BRD4-p300 fusion protein also forms condensates and drives gene expression similarly to BRD4-NUT(MIN), suggesting the p300 fusion may mimic certain features of BRD4-NUT. The intrinsically disordered regions, transcription factor-binding domains, and HAT activity of p300 all collectively contribute to condensate formation by BRD4-p300, suggesting that these elements might contribute to condensate formation by BRD4-NUT. Conversely, only the HAT activity of BRD4-p300 appears necessary to mimic the transcriptional profile of cells expressing BRD4-NUT. Our results suggest a model for condensate formation by the BRD4-NUT:p300 complex involving a combination of positive feedback and phase separation, and show that multiple overlapping, yet distinct, regions of p300 contribute to condensate formation and transcriptional regulation.

This study employed subtractive proteomics and immunoinformatics to analyze the Wuchereria bancrofti proteome and identify potential therapeutic targets, with a focus on designing a vaccine against the parasite species. A comprehensive bioinformatics analysis of the parasite's proteome identified 51 probable therapeutic targets, among which "Kunitz/bovine pancreatic trypsin inhibitor domain-containing protein" was identified as the most promising vaccine candidate. The candidate protein was used to design a multi-epitope vaccine, incorporating B-cell and T-cell epitopes identified through various tools. The vaccine construct underwent extensive analysis of its antigenic, physical, and chemical features, including the determination of secondary and tertiary structures. Docking and molecular dynamics simulations were performed with HLA alleles, Toll-like receptor 4 (TLR4), and TLR3 to assess its potential to elicit the human immune response. Immune simulation analysis confirmed the predicted vaccine's strong binding affinity with immunoglobulins, indicating its potential efficacy in generating an immune response. However, experimental validation and testing of this multi-epitope vaccine construct would be needed to assess its potential against W. bancrofti and even for a broader range of lymphatic filarial infections given the similarities between W. bancrofti and Brugia.

Activated microglia have been implicated in the pathogenesis of age-related macular degeneration (AMD), diabetic retinopathy, and other neurodegenerative and neuroinflammatory disorders, but our understanding of the mechanisms behind their activation is in infant stages. With the goal of identifying novel genes associated with microglial activation in the retina, we applied a semiquantitative fundus spot scoring scale to an unbiased, state-of-the-science mouse forward genetics pipeline. A mutation in the gene encoding the E3 ubiquitin ligase Herc3 led to prominent accumulation of fundus spots. CRISPR mutagenesis was used to generate Herc3-/- mice, which developed prominent accumulation of fundus spots and corresponding activated Iba1 + /CD16 + subretinal microglia, retinal thinning on OCT and histology, and functional deficits by Optomotory and electrophysiology. Bulk RNA sequencing identified activation of inflammatory pathways and differentially expressed genes involved in the modulation of microglial activation. Thus, despite the known expression of multiple E3 ubiquitin ligases in the retina, we identified a non-redundant role for Herc3 in retinal homeostasis. Our findings are significant given that a dysregulated ubiquitin-proteasome system (UPS) is important in prevalent retinal diseases, in which activated microglia appear to play a role. This association between Herc3 deficiency, retinal microglial activation and retinal degeneration merits further study.

Synbiotics are employed as feed additives in animal production as an alternate to antibiotics for sustaining the gut microbiota and providing protection against infections. Dairy calves require a healthy diet and management to ensure a better future for the herd of dairy animals. Therefore, the present study was carried out to investigate the effect of synbiotics formulation on growth performance, nutrient digestibility, fecal bacterial count, metabolites, immunoglobulins, blood parameters, antioxidant enzymes and immune response of pre-ruminant Murrah buffalo calves. Twenty-four apparently healthy calves (5 days old) were allotted into four groups of six calves each. Group I (control) calves were fed a basal diet of milk, calf starter and berseem with no supplements. Group II (SYN1) calves were fed with 3 g fructooligosaccharide (FOS) + Lactobacillus plantarum CRD-7 (150 ml). Group III (SYN2) calves were fed with 6 g FOS + L. plantarum CRD-7 (100 ml), whereas calves in group IV (SYN3) received 9 g FOS + L. plantarum CRD-7 (50 ml). The results showed that SYN2 had the highest (P < 0.05) crude protein digestibility and average daily gain compared to the control. Fecal counts of Lactobacilli and Bifidobacterium were also increased (P < 0.05) in supplemented groups as compared to control. Fecal ammonia, diarrhea incidence and fecal scores were reduced in treated groups while lactate, volatile fatty acids and antioxidant enzymes were improved compared to the control. Synbiotic supplementation also improved both cell-mediated and humoral immune responses in buffalo calves. These findings indicated that synbiotics formulation of 6 g FOS + L. plantarum CRD-7 in dairy calves improved digestibility, antioxidant enzymes, and immune status, as well as modulated the fecal microbiota and decreased diarrhea incidence. Therefore, synbiotics formulation can be recommended for commercial use in order to achieve sustainable animal production.

In this study GC-MS-based untargeted metabolomics was used to identify the metabolic response of earthworm; Eudrilus eugeniae exposed to sub-lethal concentrations of chlorpyrifos-CHL, cypermethrin-CYP, Glyphosate-GLY, and Combined-C (all three pesticides) at the concentrations of 3, 6, and 12 mg/kg. Principal component analysis of the obtained datasets revealed a clear distinction between the control and treatment groups. The mean weight of the worms in the treated groups decreased significantly (p < 0.05). Among the identified metabolites, oleic acid (~ 93.47%), lysine (~ 92.20%), glutamic acid (~ 91.81%), leucine (~ 90.20%), asparagine (~ 94.20%), methionine (~ 92.27%), malic acid (~ 93.37%), turanose (~ 95.04%), maltose (~ 92.36%), cholesta-3,5-diene (~ 86.11%), galactose (~ 93.20%), cholesterol (~ 91.56%), tocopherol (~ 85.09%), decreased significantly (p < 0.05), whereas myoinositol (~ 83%) and isoleucine (78.09%) increased significantly (p < 0.05) upon exposure to the CHL, CYP, GLY, and C. Overall, the findings suggest that earthworms might be a new entry point for the pesticides into the food chain. The present study highlights that metabolomics can be a reliable approach to understand the effect of different xenobiotics including pesticides on the metabolic response of earthworms.

Nanotechnology appears to be a promising tool to redefine crop nutrition in the coming decades. However, the crucial interactions of nanomaterials with abiotic components of the environment like soil organic matter (SOM) and carbon‒sequestration may hold the key to sustainable crop nutrition, fortification, and climate change. Here, we investigated the use of sugar press mud (PM) mediated ZnO nanosynthesis for soil amendment and nutrient mobilisation under moderately alkaline conditions. The positively charged (+ 7.61 mv) ZnO sheet-like nanoparticles (~ 17 nm) from zinc sulphate at the optimum dose of (75 mg/kg blended with PM (1.4% w/w) were used in reinforcing the soil matrix for wheat growth. The results demonstrated improved agronomic parameters with (~ 24%) and (~ 19%) relative increases in yield and plant Zn content. Also, the soil solution phase interactions of the ZnO nanoparticles with the PM-induced soil colloidal carbon (- 27.9 mv and diameter 0.4864 μm) along with its other components have influenced the soil nutrient dynamics and mineral ecology at large. Interestingly, one such interaction seems to have reversed the known Zn-P interaction from negative to positive. Thus, the study offers a fresh insight into the possible correlations between nutrient interactions and soil carbon sequestration for climate-resilient crop productivity.

De novo lipogenesis, a hallmark for cancers is required for cellular transformation. Further it is believed that resistance to apoptosis and epithelial-to-mesenchymal-transition(EMT) facilitates metastasis via over-expression of anti-apoptotic Bcl-2. Previously we demonstrated that hsa-miR-195 targets BCL2, induces apoptosis and augmented the effect of etoposide in breast cancer cells. However, the mechanism behind its function remains elusive. Herein gene expression profiling was done in presence/absence of hsa-miR-195 in Breast cancer cells. IPA revealed mitochondrial dysfunction, fatty acid metabolism and xenobiotic metabolism signalling among the top processes being affected. For the first time we herein identified ACACA, FASN (the key enzymes of de novo fatty acid synthesis), HMGCR (the key enzyme of de novo cholesterol synthesis) and CYP27B1 as direct targets of hsa-miR-195. We further showed that ectopic expression of hsa-miR-195 in MCF-7 and MDA-MB-231 cells not only altered cellular cholesterol and triglyceride levels significantly but also resulted in reduced proliferation, invasion and migration. We further demonstrated that over expression of hsa-miR-195 decreased the Mesenchymal markers expression and enhanced Epithelial markers. In conclusion we say that hsa-miR-195 targets the genes of de novo lipogenesis, inhibits cell proliferation, migration, and invasion which potentially opens new avenues for the treatment of breast cancer.