Biology subjects

S, J.

Publications and source records attributed to S, J..

6 recordsLinked to original sources

bioRxiv2025

Evaluating the therapeutic efficacy of the US FDA-designated Orphan drug, uttroside B in impeding hepatocarcinogenesis via induction of immunogenic apoptosis, using a murine model of Aflatoxin B1-induced liver carcinogenesis

The sustained exposure to aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus sp., is one of the fundamental causes of hepatocellular carcinoma (HCC). We have previously documented the exceptional anti-HCC potential and pharmacological safety of uttroside B, a phytosaponin isolated in our lab (Utt-B). The current results indicate that Utt-B mitigates tumor development in mice that have been subjected to AFB1 exposure. Utt-B was found to be cytotoxic towards primary liver cancer cells cultured from mice bearing AFB1-induced liver tumors and the compound effectively prevented the formation of AfBO-DNA adducts in AFB1-induced liver tumors as well as primary liver cancer cells. In vitro studies revealed that treatment with Utt-B resulted in the induction of damage associated molecular patterns such as, ROS, HSP70 and inflammatory cytokines, IL-1{beta} and CXCL-10, suggesting the potential of Utt-B in triggering immunogenic cell death. Mechanistically, treatment with Utt-B enhances the antigen presentation potential, causes blockade of the major immune checkpoint molecules, namely, CTLA-4, PD-1, TIM-3, LAG-3 and TOX, and potentiates immunogenic apoptosis in the hepatic tumor microenvironment of mice pre-exposed to AFB1 via the activation of Zap70/Lck/GRZB signaling axis. Interestingly, it was also observed that Utt-B could abrogate the mutations induced by AFB1 in a concentration dependent manner. Taken together, the findings of the current study attest Utt-B as a propitious drug candidate against HCC.

cancer biology↗

bioRxiv2025

Uttroside B, a US FDA-designated Orphan drug, mitigates thedevelopment of hepatocellular carcinoma and its pulmonary metastasis via EGFR/ERK-mediated inhibition of SREBP-1 and STAT-3

Hepatocellular carcinoma (HCC) is a highly aggressive tumor with rapid propensity for extrahepatic metastasis, which critically limits the long-term clinical benefits of conventional chemotherapeutics and decreases the overall survival rate of patients. Our previous findings on the exceptional anti-HCC potential and pharmacological safety of uttroside B (Utt-B) have gained multiple international patents and the compound has been designated as an Orphan Drug against HCC by the US FDA. The current study substantiates the pharmacodynamics of Utt-B and is the first report to date on the anti-metastatic potential of the compound against HCC. Herein, we demonstrate the role of EGFR/ERK signaling axis and their downstream targets SREBP-1 and STAT-3, the key regulators of HCC development and the pulmonary metastasis, respectively, in orchestrating the anti-HCC and anti-metastatic potential of Utt-B. This is evidenced by the abrogation of the cytotoxic and pro-apoptotic effects of Utt-B upon pharmacological inhibition of this signaling axis. Orthotopic xenograft studies validated that Utt-B treatment restricted the development of tumors via the down-regulation of EGFR/ERK axis. Notably, Utt-B diminishes the migratory and invasive properties of liver cancer cells in vitro and impedes the pulmonary metastasis of HCC, in vivo. Taken together, the current findings attest to the exceptional therapeutic potential of Utt-B against primary and metastatic HCC and highlight its potential as a candidate drug to be evaluated in the clinics for the benefit of HCC patients having limited prognosis and therapeutic options.

cancer biology↗

bioRxiv2025

JNK2 pathway in colonocytes enhances gut barrier integrity in response to microbial acetate.

Weaning involves a nutritional shift from fat-rich milk to carbohydrate-based solid food, reshaping metabolism, microbiota, and gut immune tolerance. While dairy remains a component of the human diet beyond weaning, the impact of continued milk supplementation on gut epithelial homeostasis remains poorly understood. Here, using a mouse model, we show that continued milk-based feeding post-weaning promotes intestinal barrier function by enriching the commensal bacterium Dubosiella newyorkensis, which produces acetate to activate epithelial JNK2 signaling. This pathway enhances barrier integrity and suppresses inflammation induced by mild Dextran Sodium Sulphate (DSS) treatment. In contrast, feeding a lard-based high-fat diet or transient pharmacologic inhibition of JNK2 induces epithelial P38 activation, resulting in barrier disruption and inflammation. Importantly, the beneficial effects of milk were observed only if initiated during the weaning period, when the microbiome is in a metastable transitional state. Initiation of the same intervention two weeks after weaning led to P38 activation and inflammatory responses. These findings highlight the microbiome-dependent, stage-specific effects of diet and underscore the importance of early-life nutritional interventions for long-term gut health.

physiology↗

bioRxiv2024

Uttroside B, a US-FDA-Designated Orphan Drug Against Hepatocellular Carcinoma (HCC), Impedes Non-alcoholic Steatohepatitis (NASH) and NASH -Induced HCC

IntroductionNon-alcoholic steatohepatitis (NASH) is characterized by excessive accumulation of fat, accompanied by inflammation and liver injury. NASH can lead to chronic conditions like fibrosis and cirrhosis, and has an elevated risk of progressing to hepatocellular carcinoma (HCC). Currently there are no FDA-approved drugs for the treatment of NASH. ObjectivesOur discovery of Uttroside B (Utt-B), a phytosaponin isolated from Solanum nigrum Linn., which exhibits remarkable anti-HCC potential, has gained global recognition and is currently a US-FDA-designated orphan drug against HCC. The present study highlights Utt-B as an anti-NASH molecule, by utilizing a High-Fat-Diet murine model, and as an inhibitor to the progression of NASH to HCC, using a streptozotocin-induced steatohepatitis-derived HCC animal model, thereby warranting its further validation as a propitious candidate drug molecule against NASH and NASH-induced HCC. MethodsHigh fat diet-induced NASH and streptozotocin-induced steatohepatitis-derived HCC were developed in C57BL/6 mice. Utt-B was administered intraperitoneally. q-PCR, immunoblotting and staining techniques such as Haematoxylin and eosin, Oil Red O, Sirius Red and Massons Trichrome, were performed to assess the therapeutic potency of Utt-B against NASH. Nanostring n-Counter analysis was conducted to verify the anti-fibrotic potential of Utt-B in NASH-induced HCC mouse model. ResultsUtt-B ameliorates the pathological features such as, steatosis, hepatocyte ballooning and inflammation associated with NASH. Utt-B up-regulates the expression of autophagy markers ATG7, Beclin-1 and LC-III and down-regulates the expression of -SMA, the indicator protein for the activation of hepatic stellate cells. Utt-B hinders the development of fibrosis and halts the progression of NASH to HCC in NASH-induced HCC mouse model. ConclusionOur investigation reveals that Utt-B effectively alleviates NASH and abrogates its progression to HCC. As no treatment options are currently available against NASH, our findings are very relevant and strengthen the prospect of developing Utt-B as a potent drug for the treatment of NASH and NASH-induced HCC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/622394v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1d637dcorg.highwire.dtl.DTLVardef@ed6b34org.highwire.dtl.DTLVardef@1195acaorg.highwire.dtl.DTLVardef@197b072_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Exome sequencing identifies variants associated with semen quality in Holstein Friesian and Hallikar bulls.

Effective fertility of bulls is dependent on semen quality, often determined based on standard semen evaluation tests. Here we report Whole Exome Sequencing (WES) of 12 bulls from two breeds Holstien Friesian and Hallikar selected based on Ejaculate Rejection Rate (ERR). We explored the possibility of identifying genetic variants from the conserved protein coding regions of genome. A total of 10,510 SNPs and 10.236 INDELs were identified post alignment against reference genome (ARS-UCD 1.2) and were annotated using SnpEff. The number of variants with high and modifier functional impact detected were 145 and 19,122, respectively. Genetic variants common to both high and low ERR group bulls among Holstein Friesian were 08 and in Hallikarthe common variants were 51. Prominent genesviz. UCP2, PANK2, GPD2, PTPRG, LARP7, EZH1, DENND1B and TDRD9 with a role in determining the semen quality were observed to be carriers of the genetic variant.

genomics↗

bioRxiv2019

Parsers, Data Structures and Algorithms for Macromolecular Analysis Toolkit (MAT): Design and Implementation

The structural information of biological macromolecules are stored in .pdb, .mm-cif and lately mmtf files and thus it requires accurate and efficient biological tools for various utilities. Here, we describe Macromolecular Analysis Toolkit (MAT) that parses .pdb, .mmcif and .mmtf files; and builds data structures from the input. This original program is written in C++ programming language to ensure efficiency and consistency to organize structural information in an integral way. The novelty of the program lies in the addition of new structure-based biological algorithms and applications. This package also stands out from other similar libraries by being 1) faster and 2) accurate. We also provide detailed comparison of available parsers on the whole PDB database. The parser of MAT is designed in such a way that it allows quick extraction and organized loading of the core data structure. The same data structure is extended to accommodate information from the .mmcif and .mmtf file parsers. Tokenization of the data allows the extraction of information from disordered text, making it compatible for accurate identification of the entities present in the .pdb file. Additionally, we add a new approach of performance optimization by creating a few derived data structures, namely kD-Tree, Octree and graphs, for certain applications that need spatial coordinate calculations. MAT provides advanced data structure which is time efficient and is designed to avail reusability and consistency in a systematic framework. MAT parser can be accessed online through bitbucket at https://bitbucket.org/gazalk/pdb_parser/.

bioinformatics↗