Assessment of genetic variability in blackgram (Vigna mungo) under rainfed conditions of Jammu and Kashmir

Analysis of variance for 11 traits under investigation revealed significant variability among the genotypes. This indicated an extensive range of genetic variability existed among the genotypes of blackgram. On the basis of higher mean performance than general mean, genotype PU-19 reported higher seed yield/plant along with higher number of seeds/pod, number of clusters/plant, number of pods/ cluster. Hence, recommended for the enhancement of area under this variety particular in rainfed ecology. On pooled basis seed yield/plant had significant correlation with all yield contributors except plant height. Number of seeds/pod, number of clusters/plant, number of pods/cluster and seed yield/plant signified high heritability as well as high genetic advance as percentage of mean indicated the presence of additive gene action, while plant height and number of pods/ plant exhibited modest heritability as well as modest genetic advance as percentage of mean. Consequently, suggesting the presence of additive gene action and phenotypic selection for such traits may be useful in the future of blackgram improvement programs

Withania somnifera: Progress towards a Pharmaceutical Agent for Immunomodulation and Cancer Therapeutics

Chemotherapy is one of the prime treatment options for cancer. However, the key issues with traditional chemotherapy are recurrence of cancer, development of resistance to chemotherapeutic agents, affordability, late-stage detection, serious health consequences, and inaccessibility. Hence, there is an urgent need to find innovative and cost-effective therapies that can target multiple gene products with minimal adverse reactions. Natural phytochemicals originating from plants constitute a significant proportion of the possible therapeutic agents. In this article, we reviewed the advances and the potential of Withania somnifera (WS) as an anticancer and immunomodulatory molecule. Several preclinical studies have shown the potential of WS to prevent or slow the progression of cancer originating from various organs such as the liver, cervix, breast, brain, colon, skin, lung, and prostate. WS extracts act via various pathways and provide optimum effectiveness against drug resistance in cancer. However, stability, bioavailability, and target specificity are major obstacles in combination therapy and have limited their application. The novel nanotechnology approaches enable solubility, stability, absorption, protection from premature degradation in the body, and increased circulation time and invariably results in a high differential uptake efficiency in the phytochemical\u27s target cells. The present review primarily emphasizes the insights of WS source, chemistry, and the molecular pathways involved in tumor regression, as well as developments achieved in the delivery of WS for cancer therapy using nanotechnology. This review substantiates WS as a potential immunomodulatory, anticancer, and chemopreventive agent and highlights its potential use in cancer treatment

Confounding Factors of Cervical Carcinogenesis and Cervical Cancer Health Disparity

Clinical studies show that cervical cancer is the most frequently detected cancer in women living with human immunodeficiency virus (HIV), which has been defined as an acquired immunodeficiency syndrome (AIDS). Women living with HIV are 6 times more likely to develop cervical cancer compared to the general population, and an estimated 5% of all cervical cancer cases are attributable to HIV. Studies suggest that several genes are involved in different molecular pathways, which can influence the vulnerability, severity, or advancement of cervical cancer in the presence of HIV and human papillomavirus (HPV) co-infection. Clinical studies have also shown levels of cervical COX-2 are increased in HIV-infected and HIV/HPV-coinfected women. However, the precise molecular-level interactions between HPV and HIV co-infection are not well defined. Further, smoking is well documented among HIV-positive women, but very little is known about the smoking-induced molecular mechanism of HPV-HIV co-infections. In this study, we investigated the interplay between smoking and HIV/HPV co-infection infectivity and their cooperativity. To check the influence of HIV-HPV co-infection at the molecular level, cervical cancer cells, CaSki, were treated with U1(HIV-1-infected U937 cells) cell culture supernatant (UCS) and U937 (HIV-1 noninfected cells) culture supernatant (U9CS) every day for 4 days. To differentiate the U1 cells into macrophages, U1 cells were treated with 100 nM phorbol 12-myristate 13-acetate (PMA) for 3 days. For the treatment of smoking components, both U937 and U1 cells were treated with benzo[a]pyrene (B[a]P) at 100 nM every 24 hours for 4 days. Similarly, we treated HIV-infected (U1) and noninfected (U937) cells were treated with HPV-infected (CasKi) cells supernatant to determine if HPV infection can influence HIV replication-related molecular pathways. Our study demonstrated that HIV-HPV-co-infection and/or B[a]P enhanced cell proliferation colony formation, migration, and invasion as demonstrated by MTS, wound healing, and Boyden chamber assay, respectively, in CaSki cells. HIV-HPV-co-infection and/or B[a]P enhanced also induced the expression of HPV16 E6/E7, HIF-1α, PTGS2, and EMT markers in CaSki cells as determined by qRT-PCR and immunoblotting. Furthermore, our qRT-PCR results demonstrated that cytokine IL-6, IL-8, IP-10, MCP-1, IL-1α, IL-10, MIP-1β TNF-α, IFN-γ and G-CSF were significantly increased in CaSki cell treated with UCS and B[a]P. We have also demonstrated that the supernatant of cervical cancer cells exacerbates HIV-1 replication in differentiated U1 cell lines via transferring CYPs and HPV oncoproteins through extracellular vehicles. Taken together, our results demonstrate that a molecular link between smoking and HIV infections in HPV cooperativity in cervical carcinogenesis might also be responsible for cervical cancer disparity among underserved populations

Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications

Chemotherapy is one of themajor therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an antibody, a cytotoxic payload, and a linker, which can offer selectivity against tumors, anti-cancer activity, and stability in systemic circulation. Therefore, we have reviewed recent updates and principal considerations behind ADC designs, which are not only based on the identification of target antigen, cytotoxic drug, and linker, but also on the drug-linker chemistry and conjugation site at the antibody. Our review focuses on site-specific conjugation methods for producing homogenous ADCs with constant drug-antibody ratio (DAR) in order to tackle several drawbacks that exists in conventional conjugation methods

Integrative transcriptomics data analysis of TRPV1 in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective Ca2+ channel protein that is widely expressed and plays a significant role in cancer initiation and progression. However, the biological significance of TRPV1 in HCC has not been systematically and comprehensively investigated. Using deep data mining and transcriptomics analyses, in this study, we described the significance of TRPV1 expression and its association with HCC prognosis. Methods: TRPV1 mRNA expression in HCC was examined using the Cancer Genome Atlas (TCGA), the Genotype Tissue Expression Atlas (GTEx), the Tumor Immune Estimation Resource (TIMER), and the UALCAN databases to examine the relationship between the expression of TRPV1 and the clinicopathological characteristics of HCC. The genetic alterations and frequency of TRPV1 were analyzed using the cBioPortal and COSMIC databases. The correlations between TRPV1 and tumor-infiltrating immune cells were examined using the TIMER 2.0, TISIDB, and GEPIA databases. The data processing analysis is based on the R language. LinkedOmics was used for TRPV1 co-expression network analysis. Results: TRPV1 mRNA expression was upregulated in HCC samples as compared to normal liver tissues. Kaplan-Meier analysis demonstrated that high expression of TRPV1 is associated with better prognostic significance for overall survival (OS) and disease-free survival (DFS) in HCC patients. The mutation landscape analysis confirms that TRPV1 genetic alterations reached 6%, of which missense substitutions accounted for the highest proportion of 16.16%. The findings of the TIMER analysis indicated a correlation between immune cell infiltration and TRPV1 copy number alterations (CNA). The expression level of TRPV1 was positively correlated with the infiltration level of CD4+ T cells but negatively correlated with CD8+ T cells, B cells, macrophages, and dendritic cell infiltration. Additionally, TRPV1 expression was also found to be associated with certain immunosuppressive cells, chemokines, and receptors. Through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, TRPV1 expression was found to be closely related to some immune pathways, including drug metabolism, PPAR signaling pathway, and chemical carcinogenesis. Conclusion: Our observation demonstrates that TRPV1 was highly expressed in HCC tissues and is linked to prognosis of HCC patients and tumor immune responses

Exploration of potential natural inhibitors against KRAS-G12D in PanCan: Protein centered pharmacophore HTVS approach.

Background: As per key statistics of American Cancer Society 2021, Pancreatic Cancer (PanCan) affects around 60,430 persons a year in the U.S. and is tricky to diagnose & treat. Studies revealed that African Americans have a 50–90% higher incidence of PanCan compared to other ethnic groups. Oncogenic KRAS mutation is the signature genetic incident in the progression and development of PDAC. KRAS is the most common protein which is 95% times mutated in PDAC condition. By considering this alarming situation our group is now focused on to develop therapeutic portfolio against KRAS-G12D mutation associated PanCan by using high through-put virtual screening (HTVS) approach. Methodology: In this study, prompt HTVS for vetting the best possible drug candidates from natural compound (NCs) databases has been implemented. Herein, time tested rigorous multi-layered drug screening process to narrow down 66,969 NCs for the identification of potential lead(s) is implemented. Druggability parameters, protein centered pharmacophore-based drug selections & different docking approaches (Rigid & Flexible) were employed in this study. Result: By using different NCs databases around 66,969 NCs were screened based on protein-centered pharmacophore fit score & binding energies. Less than 0.001% of potential NCs were selected against the known & reference KRAS-G12D inhibitor (BI2852). Conclusion: By using HTVS approach we have identified a pool of natural inhibitors against KRAS G12D

Redox-responsive nano-self assemblies for targeted cancer therapeutics

Background: Despite significant advances in cancer therapeutics, it remains one of the leading causes of deaths due to poor response to available treatment modalities and drug resistance. Combination therapy has shown the potential to provide a synergistic therapeutic effect and to overcome drug resistance. However, smart delivery systems that can improve the bioavailability and the delivery of multiple hydrophobic anti-cancer drugs simultaneously at the tumor site without normal organ toxicity could be an effective strategy for cancer treatment. Methods: Here, a PEGylated drug-drug conjugate (CUR-PEG-S-S-CPT) have been successfully synthesized by conjugating two hydrophobic anti-cancer molecules, curcumin and camptothecin through an ester and a redox-sensitive disulfide linkage (-S-S-), respectively, with the PEG chain, via in situ two-step reaction. This amphiphilic polymeric-dual drug conjugate was characterized in the presence and absence of the tannic acid (TA, a physical crosslinker) using various in vitro biophysical, analytical, and functional bioassays. Results: The newly synthesized amphiphilic CUR-PEG-S-S-CPT polymer was found to spontaneously self-assembled in presence of tannic acid into anionic comparatively smaller sized stable nano-assemblies in water in comparison to parent conjugate, where the drug forms hydrophobic core of the particle with negative chirality and left-handed helical arrangement. TA, in addition to help forming stable nano-assemblies in water, it was able produce FRET pair in water between these two anticancer drugs. These nano-assemblies exhibited enhanced cellular uptake and antiproliferative effect in cancer cells (AsPC1 and SW480) in comparison to the individual drugs. Interestingly, our nanoassemblies showed preferential cleavage, breakdown and release of drugs in tumor-relevant redox environment leading to disappearance of the FRET signal, thus can be highly effective for targeted cancer treatment. Conclusions: Our promising in vitro results with novel redox stimuli-responsive (CUR-PEG-S-S-CPT) conjugate system in presence of TA can be a highly useful advanced theranostic platform for effective cancer treatment/management

Emerging Roles and Potential Applications of Non-Coding RNAs in Cervical Cancer

Cervical cancer (CC) is a preventable disease using proven interventions, specifically prophylactic vaccination, pervasive disease screening, and treatment, but it is still the most frequently diagnosed cancer in women worldwide. Patients with advanced or metastatic CC have a very dismal prognosis and current therapeutic options are very limited. Therefore, understanding the mechanism of metastasis and discovering new therapeutic targets are crucial. New sequencing tools have given a full visualization of the human transcriptome’s composition. Non-coding RNAs (NcRNAs) perform various functions in transcriptional, translational, and post-translational processes through their interactions with proteins, RNA, and even DNA. It has been suggested that ncRNAs act as key regulators of a variety of biological processes, with their expression being tightly controlled under physiological settings. In recent years, and notably in the past decade, significant effort has been made to examine the role of ncRNAs in a variety of human diseases, including cancer. Therefore, shedding light on the functions of ncRNA will aid in our better understanding of CC. In this review, we summarize the emerging roles of ncRNAs in progression, metastasis, therapeutics, chemoresistance, human papillomavirus (HPV) regulation, metabolic reprogramming, diagnosis, and as a prognostic biomarker of CC.We also discussed the role of ncRNA in the tumor microenvironment and tumor immunology, including cancer stem cells (CSCs) in CC.We also address contemporary technologies such as antisense oligonucleotides, CRISPR–Cas9, and exosomes, as well as their potential applications in targeting ncRNAs to manage CC

In silico CD4 + T-cell multiepitope prediction and HLA distribution analysis for Marburg Virus—A strategy for vaccine designing

Marburg, a RNA virus (MRV), is responsible for causing hemorrhagic fever that affects humans and non-human primates. World Health Organization (WHO), National Institutes of Health (NIH) and Centre of Disease Control and Prevention (CDC) considered this as an extremely dangerous virus, thus categorised as risk group 4, category A priority pathogen and category “A” bioterrorism agent, respectively. Despite of all these alarming concerns, no prophylaxis arrangements are available against this virus till date. In fact, the construction of immunogenic vaccine candidates by traditional molecular immunology methods is time consuming and very expensive. Considering these concerns, herein, we have designed CD4 + T Cell multiepitopes against MRV using in silico approach. The pin-point criteria of the screening and selection of potential epitopes are, non-mutagenic, antigenic, large HLAs coverage, non-toxic and high world population coverage. This kind of methodology and investigations can precisely reduce the expenditure and valuable time for experimental planning in development of vaccines in laboratories. In current scenario, researchers are frequently using in silico approaches to speed up their vaccine-based lab studies. The computational studies are highly valuable for the screening of large epitope dataset into smaller one prior to in vitro and in vivo confirmatory analyses

Using network pharmacology to systematically deduce the molecular mechanism of the selective perinucleolar compartment inhibitor ML246

Metarrestin (ML246) is an orally bioavailable synthetic molecule that selectively disrupts the perinucleolar compartment (PNC) structure, and it has showed promise in preclinical studies for metastatic cancer therapy. However, the precise molecular mechanism of ML246 remains poorly understood. We investigated the topological and protein interaction network (PIN) analyses of ML246 to determine the molecular mechanism of ML246. To determine the regulatory effect of ML246 on the rewired PIN of ML246, an intercom was constructed using 25 oncogenic key proteins. These proteins were selected using the reverse pharmacophore matching approach (based on a fit score \u3e 0.502) using the STRING database and Cytoscape tool.ML246-rewired PIN exhibited a scale-free topology and demonstrated substantial connectivity with the biological system. After modularization, the rewired PIN yielded 10 sub- clusters from which the MCODE plugin was able to identify the most critical seed proteins in the intercom; 14 enriched signaling pathways were obtained by using the ClueGO plugin for pathway enrichment. Most of the pathways were associated with human disease groups, like cancer. Finally, identifying major regulatory proteins of the ML246-rewired PIN was finalized by examining topological properties, including bottleneck analysis, GO term/pathways analysis, degree analysis, molecular docking, and dynamics studies. This study suggests a proficient approach to exploring ML246\u27s potential mechanistic actions and paves the way for novel drug development prospects in clinical settings