Biology subjects

Saxena, U.

Publications and source records attributed to Saxena, U..

At least 19 recordsLinked to original sources

bioRxiv2026

Restoration of Redox Homeostasis and Endogenous Aldehyde Detoxification by UT-018 Following Acute Ethanol Exposure

Alcohol-induced toxicity is driven largely by the accumulation of acetaldehyde and disruption of hepatic redox homeostasis during ethanol metabolism. Oxidation of ethanol by alcohol dehydrogenase (ADH) consumes nicotinamide adenine dinucleotide (NAD) while generating NADH, shifting the intracellular redox state toward a highly reduced environment that impairs mitochondrial function, limits endogenous aldehyde dehydrogenase (ALDH)-mediated acetaldehyde clearance, and promotes oxidative stress and tissue injury. We investigated whether UT-018, a novel metabolic intervention, could support endogenous metabolic resilience during acute ethanol exposure using complementary in vitro and in vivo models. Mechanistic in vitro studies evaluated ADH-dependent NADH generation and NAD add-back experiments, while in vivo investigations assessed serum ALDH-associated activity, circulating acetaldehyde concentrations, and gross gastrointestinal and hepatic morphology following acute ethanol challenge. UT-018 reduced ethanol-associated NADH accumulation in a concentration-dependent manner without evidence of irreversible ADH inhibition. Restoration of NADH generation following supplementation with exogenous NAD demonstrated reversible modulation of ethanol-associated redox biology rather than direct enzymatic inhibition. In vivo, UT-018 enhanced serum ALDH-associated activity, reduced circulating acetaldehyde concentrations by approximately 27 to 33% compared with ethanol-treated controls. Metabolic biomarkers were accompanied by preservation of gross colon and liver morphology following acute ethanol exposure. Collectively, these findings support coordinated biological activity across multiple interconnected stages of alcohol metabolism and support a systems-level mechanism in which restoration of redox homeostasis enhances endogenous aldehyde detoxification, reduces acetaldehyde burden, and preserves tissue integrity. These results identify alcohol metabolism restoration as a promising strategy for enhancing physiological resilience to acute alcohol exposure and provide a rationale for further preclinical and clinical evaluation of UT-018. HighlightsO_LIUT-018 restored ethanol-associated redox homeostasis by reducing excessive NADH accumulation without irreversible inhibition of alcohol dehydrogenase in vitro. C_LIO_LIRestoration of redox balance was associated with enhanced endogenous aldehyde dehydrogenase (ALDH)-associated activity following acute ethanol exposure in vivo. C_LIO_LIUT-018 reduced circulating acetaldehyde concentrations by approximately 30%. C_LIO_LIThe metabolic homeostasis was accompanied by preservation of gross gastrointestinal and hepatic morphology in an acute ethanol challenge model. C_LIO_LIThe collective findings support a systems-level mechanism in which modulation of endogenous alcohol related metabolic pathways enhances physiological resilience to acute alcohol exposure. C_LI

pharmacology and toxicology↗

bioRxiv2026

Fructooligosaccharide Supplementation Improves Glucose Homeostasis in Human-Relevant hyperglycemic Diet-Induced Obese Mice

Fructooligosaccharides (FOS) are prebiotic fibers that influence gut microbiota and host metabolic function. In a diet-induced obesity (DIO) mouse study, FOS supplementation was compared with PBS-treated obese controls. Blood glucose was markedly lower at Day 42 (221.9 {+/-} 7.8 vs 138.3 {+/-} 9.0 mg/dL), and remained lower at Day 56. FOS reduced body-weight gain from 8.4 {+/-} 0.9 g in PBS controls to 2.6 {+/-} 0.2 g, corresponding to an approximate 69.5% reduction in gain over Days 1-70. Cumulative feed consumption was not significantly different between PBS and FOS cages, suggesting that the observed metabolic effects were not explained simply by reduced food intake. These data support our thesis that FOS works as an active metabolic ingredient acting through the gut-liver-metabolic axis. Thus, in the present study, dietary FOS supplementation produced marked improvements in glucose homeostasis in a severe DIO model characterized by diabetic-range hyperglycemia that more closely resembles poorly controlled human type 2 diabetes. HIGHLIGHTSO_LIFructooligosaccharide (FOS) normalized glucose levels in a severe DIO model that mimics poorly controlled human type 2 diabetes. C_LIO_LIDay-42 blood glucose was reduced by [~]37.7% in FOS-treated DIO mice. C_LIO_LIFOS reduced body-weight gain by [~]69.5% versus controls over 70 days. C_LIO_LIMetabolic benefits occurred without a statistically significant reduction in feed intake. C_LIO_LIFindings support a gut-liver-metabolic mechanism rather than simple caloric restriction. C_LIO_LIData position FOS as an active metabolic ingredient with potential utility in diabetes and metabolic health. C_LI

pharmacology and toxicology↗

bioRxiv2026

UT-018 Protects Collagen Extracellular Matrix Through Substrate-Directed Stabilization and Collagenase Modulation

Pathological collagen degradation is a central feature of impaired wound healing, dermal aging, periodontal breakdown, intestinal barrier injury and connective tissue degeneration. Current strategies often focus on direct inhibition of matrix metalloproteinases or collagenases; however, complete blockade of collagen remodeling may interfere with normal repair. UT-018, a bioactive formulation that acts as a tissue-protective and regenerative agent, was evaluated as a collagenous extracellular matrix modulator. Across in vitro kinetic assays, endpoint signal analysis, integrated area-under-curve (AUC) analysis and substrate preincubation studies, UT-018 produced concentration-dependent preservation of collagen against collagenase challenge. Importantly, collagen protection persisted after substrate preincubation with UT-018, with approximately 33%, 60% and 65% protection at 5, 10 and 25 mM UT-018 concentrations, respectively. Exploratory kinetic transformations did not support a simple competitive collagenase inhibitor model. Instead, the collective pattern supports a substrate-directed mechanism involving collagen shielding, reduced cleavage susceptibility and indirect modulation of collagenase activity. These findings position UT-018 as a potential first-in-class collagen resilience modulator for wound healing, gastrointestinal barrier protection, oral care, dermal preservation and regenerative medicine applications. Highlights- UT-018 preserves collagen content in in vitro collagenase challenge assays. - The Protection is UT-018 concentration-dependent across kinetic, endpoint and AUC readouts. - Preincubation of substrate with UT-018 retains protection after collagenase challenge. - The data support matrix-directed stabilization by UT-018 rather than classical active-site collagenase inhibition.

pharmacology and toxicology↗

bioRxiv2026

UT-018 Accelerates Wound Repair and Hair Follicle Regeneration in Murine Models

UT-018, a stem cell chemoattractant formulation, demonstrated significant regenerative activity across independent murine wound-healing and hair-regeneration studies. Topical treatment accelerated wound closure, enhanced granulation tissue formation, improved collagen organization, increased fibroblast proliferation, and enhanced dermal vascularization. Separate hair-growth studies demonstrated increased follicular density, deeper follicular penetration, enhanced dermal vascularization, and induction of anagen-phase transition by UT-018. Mechanistic studies demonstrated strong intracellular cAMP generation and activation-associated {beta}-catenin phosphorylation consistent with GPCR-mediated regenerative signaling.

pharmacology and toxicology↗

bioRxiv2026

An Indian Diet Relevant Rat Screening Model for Hypertriglyceridemia Associated Fatty Liver

Hypertriglyceridemia is a dominant and early metabolic abnormality underlying fatty liver disease in Indian populations, often preceding obesity, insulin resistance, or inflammatory liver injury. Many diet-induced rodent models of hepatic steatosis rely on extreme obesogenic or fructose-rich diets that poorly reflect real-world Indian dietary patterns. Here, we describe a diet-induced rat screening model designed to reflect typical Indian cereal-rich, visible-fat dietary exposure and to preferentially induce triglyceride-centric hepatic lipid accumulation. The model reproducibly induces hepatic triglyceride deposition with preserved liver architecture and minimal inflammatory features, aligning with early-stage fatty liver observed clinically in Indian patients. This work does not propose a novel disease model nor evaluate therapeutic efficacy, but establishes a translationally relevant screening tool for prioritizing lipid-modulating interventions in hypertriglyceridemia-associated fatty liver. We show that the high-fat diet increased serum triglycerides [~]1.8 -fold versus chow (normalized index 1.0 vs 1.8), with organ weights remaining within [~]0.95-1.00 of reference (normalized indices), supporting screening tolerability. Secondary changes in liver morphology and histopathology were indicative of fatty liver.

pharmacology and toxicology↗

bioRxiv2026

NexaSweet Attenuates DSS-Induced Colitis and Preserves Colon Architecture in BALB/c Mice

We evaluated NexaSweet(R), a nutraceutical comprising fructooligosaccharides (FOS) combined with UT18 (a composition of selected amino acids and organic acid), in a dextran sulfate sodium (DSS)-induced colitis model in male BALB/c mice. Compared with DSS controls, NexaSweet improved bodyweight preservation ([~]13.4% relative improvement), reduced Disease Activity Index (DAI) by[~] 57.9%, increased colon length by[~] 32.1%, and reduced composite colon histopathology severity by[~] 53.1%, without adverse safety signals. These data support NexaSweet as a regenerationoriented, foodgrade intervention for mucosal repair. . Based on these data and by comparing with steroid therapy reported in literature, NexaSweet could be a favorable disease modifying ( not just symptomatic relief) therapeutic for gut diseases and wellness.

pharmacology and toxicology↗

bioRxiv2025

UT-018, A Stem-Cell Chemoattractant Nutraceutical for intestinal Healing in DSS-Induced Colitis

We show here that UT-018, a proprietary nutraceutical designed to act as a stem-cell chemoattractant, protects against DSS-induced colitis in mice. UT-018 composed of amino acids and organic acid, promotes epithelial repair and mucosal regeneration by enhancing endogenous stem-cell migration and modulating inflammation. Treatment resulted in rapid recovery of body weight, reduced disease activity, and histological preservation of colonic mucosa. The effect was comparable to direct stem-cell delivery models reported elsewhere, achieved here through a safe, orally available formulation. UT-018 thus represents a new class of regenerative nutraceuticals that link metabolic signaling to mucosal healing.

pharmacology and toxicology↗

bioRxiv2024

Human like severe hypertriglyceridemia in a high fat fed chicken model

Cardiovascular disease (CVD) is the biggest cause of mortality globally. Controlling the risk factors for CVD such as blood cholesterol and triglycerides is the hallmark of primary prevention of CVD. There are several drugs to control cholesterol that are available but not many approaches to reducing triglycerides safely are available. High blood triglycerides or hypertriglyceridemia in humans is classified as moderate (200-400 mg/dl plasma levels) severe (400-800 mg/dl) and very severe (>800 mg/dl). There are not many appropriate in vivo models to study human like severe hypertriglyceridemia. We show here that high fat fed chickens rapidly and in a sustained manner respond by demonstrating triglyceride levels reminiscent of severe hypertriglyceridemia in humans. Such a model could be useful in better understanding this human disease as well as serve to test new therapies.

pharmacology and toxicology↗

bioRxiv2023

Robust acidic pH and digestive enzyme stability of anti-SarsCov2 IgY antibodies: Implications for treatment of viral transmission thru gastrointestinal, ocular, nasal and skin tissues

There are many paths for the transmission of SarsCov2 virus. The main routes are nasal and oral and the droplets carrying the virus can also be transmitted thru ocular and skin tissues. The gastrointestinal (small intestine), nasal, ocular and skin tissues all present an acidic pH milieu and therefore any treatment with antibodies thru these routes has to have the antibodies remain active at acid pH as well as be resistant to typical protease digestion. To this end we profiled our anti-SarasCov2 receptor binding domain IgY antibodies for retention of activity at acidic and basic pHs and trypsin digestion. We find that the IgY are strongly resistant to denaturation at acid pH as well as not digested by trypsin. Our data strongly support the use of these IgY in treatment of viral transmission thru the GI, nasal, ocular and skin all tissues where the pH is acidic. We also provide an enabling platform to rapidly asses the suitability of any antibody or protein therapeutic for use at acidic pH.

pharmacology and toxicology↗

bioRxiv2023

Metformin an anti-diabetic drug, possess ACE-2 receptor-SARS- Cov-2 RBD binding antagonist activity, anti-inflammatory and cytokine inhibitory properties suitable for treatment of COVID-19

Metformin is a widely used and is a safe anti-diabetic drug. It has also been shown to have anti-inflammatory and anti-viral activities in humans and animal models. Specifically we explored its activity in SARS-CoV-2 initiated COVID19 disease. Here we show that metformin 1. blocks the binding of SARS-CoV-2 spike protein receptor binding domain RBD to human ACE2 receptor 2. We also show that it has anti-inflammatory effects and reduces cytokine secretion as well as blocks the recruitment of monocytes to endothelial cells 3. Finally we show its activity in a hamster in vivo model of SARS-CoV-2 infection as a nasal formulation. Based on the safety and the therapeutic properties relevant to COVID-19 it is feasible to propose a nasal spray of metformin that can be used in treatment of this disease. A nasal spray would deliver the drug to the target organ lung and spare other organs which get exposed upon oral dosing.

pharmacology and toxicology↗

bioRxiv2023

Targeted neutralizing IgY antibodies against SGLT1 glucose transporter reduce glucose uptake and improve glycemic profile in vivo

Despite the use of several drugs available to treat type 2 diabetes, many patients are unable to reach their target fasting plasma glucose and HbA1c levels. SGLT1 is the major intestinal transport transmembrane protein which functions in uptake of dietary glucose. If we antagonise the binding of dietary glucose to this transport protein, it is expected that blood glucose lowering will follow. We designed specific inhibitory avian antibodies (IgY) against the extracellular glucose binding domain of SGLT1 and tested their potential in glucose lowering. We demonstrate here the antibodies block uptake of glucose and improve the glycemic profile in vivo and represent a novel approach to inhibiting dietary glucose absorption as treatment for diabetes.

pharmacology and toxicology↗

bioRxiv2023

An Anti-diabetic Nutraceutical enhances muscle cell glucose uptake of cardiometabolic drugs

Type 2 diabetes is currently treated by multiple drugs that are often combined to achieve maximum blood glucose lowering in patients. Yet more than 50% of patients are unable to attain target glucose levels. There is clear need for agents which can be added to current drugs to help patients achieve their target blood glucose levels safely. To this end we tested an anti-diabetic nutraceutical for its ability to enhance glucose uptake in muscle cells in combination with currently used cardiometabolic drugs. We show here that the nutraceutical is able to effectively improve glucose uptake of multiple drugs suggesting that it may help in enhancement of glucose lowering by the drugs in patients and achieve optimal glucose levels.

pharmacology and toxicology↗

bioRxiv2022

Suppression of insulin stimulated muscle glucose uptake by non-caloric sweetener sucralose and its reversal by an antidiabetic nutraceutical supplement

Non caloric sweeteners (NCS) have been used for decades now as sugar substitutes in foods and beverages. The market for such products has grown immensely over time. There are human studies which report their negative effects on glucose metabolism with various results of disturbances in glucose metabolism, weight gain etc. No studies to the best of our knowledge have directly addressed the impact of the NCS on muscle glucose uptake. Muscle tissue can account for over 70 percent of whole-body glucose uptake. Therefore, we examined directly the effect of NCS on muscle cell glucose uptake. We find that aspartame moderately increased insulin stimulated glucose uptake by muscle cells in vitro. But sucralose, saccharin and stevia suppressed insulin stimulated glucose uptake. Sucralose is one of the most often used sweetener in foods and beverages globally it is important to understand its effects on glucose metabolism. Therefore, we explored the mechanism of its inhibition of glucose uptake by using an anti-diabetic nutraceutical which is known to target insulin mediated glucose uptake and metabolism pathways. We show here that the nutraceutical is able to relieve the suppression by sucrose in muscle uptake by a novel mechanism of action. We propose that such nutraceuticals may be useful to combine with sucralose containing products to offset negative effects of the NCS on glucose metabolism.

pharmacology and toxicology↗

bioRxiv2022

Pharmacogenetic allele variant frequencies: An analysis of the VAs Million Veteran Program (MVP) as a representation of the diversity in US population.

We present allele frequencies of pharmacogenomics relevant variants across multiple ancestry in a sample representative of the US population. We analyzed 658,582 individuals with genotype data and extracted pharmacogenomics relevant single nucleotide variant (SNV) alleles, human leukocyte antigens (HLA) 4-digit alleles and an important copy number variant (CNV), the full deletion/duplication of CYP2D6. We compiled distinct allele frequency tables for European, African American, Hispanic, and Asian ancestry individuals. In addition, we compiled allele frequencies based on local ancestry reconstruction in the African-American (2-way deconvolution) and Hispanic (3-way deconvolution) cohorts.

genomics↗

bioRxiv2022

Nutraceutical supplement targeting multiple molecular steps synergistically enhances muscle glucose uptake and improves in vivo oral glucose disposal

Pre diabetes and type 2 diabetes are increasingly becoming rampant world wide. While there are medications to control blood glucose in type 2 diabetics, currently there are no interventions prescribed for pre diabetes. Alternate strategies to control blood glucose are needed either to act alone in pre diabetes or as supplement to the existing drugs for type 2 diabetes. We report here the targeting of critical molecular steps in muscle glucose uptake and metabolism to result in glucose lowering using a combination of safe vitamins. Our in vitro and in vivo data support the potential for using such vitamin combination for glucose control in pre diabetes and as a supplement in type 2 diabetics.

pharmacology and toxicology↗

bioRxiv2022

An Integrated 3D bioprinted disease in a dish lung cancer model to simultaneously study drug efficacy, toxicity and metabolism

Discovery and development of new drugs is a long, expensive and high risk proposition. Millions of dollars spent and decade plus years of time taken to discover a new drug have haunted pharma industry for many years. In part, the reliance on animal models to make go or no go decisions for selecting drugs for human trials has been a problem because animal biology does not capture human disease in entirety. In recognition of this, the last decade has seen the emergence of more human like tools being developed in the hope of better prediction of human outcomes. Towards that end we have developed a 3D bioprinted disease in a dish lung cancer model which uses human cells and includes ability to measure drug efficacy, toxicity and metabolism simultaneously. For drug profiling studies in our disease in a dish model we 3D bioprinted intestinal cells, layered below which were liver cells and finally underneath were target lung cancer cells. The idea was to simulate the path taken by an oral drug which encounters the gut, followed by liver and target organs. We demonstrate here that a 3D bioprinted disease model composed of human derived cells is able to concurrently measure in vitro drug efficacy, toxicity and metabolism. Such humanized models will help make early go or no go decisions on the potential of a drug to enter human trials.

pharmacology and toxicology↗

bioRxiv2022

A 3-Dimensional bioprinted human gut-liver axis model for studying Alcoholic Liver Disease

Gut-liver axis is the interaction between the gut, its microbiome and the liver. The crosstalk and interaction between these organs plays an important role in their individual health and disease. Alcoholic liver disease (ALD) is a case in point where dysfunction of intestine actively promotes liver damage by alcohol. A flashpoint in ALD is the breach of intestinal integrity caused by gut bacteria Enterococcus faecalis (E.Faecalis). More specifically, Cytolysin, a toxin secreted by this bacteria may have a central role in the genesis of ALD. 3-D bioprinted human simulations of the gut-liver axis may help better understand the genesis of ALD. Here we developed a 3 dimensional bioprinted in vitro model composed of human origin intestinal and liver cells to explore the role of Cytolysin and ethanol in intestinal and liver damage. We find that neither Cytolysin or ethanol are sufficient for cell damage but a combination of the two act in concert to cause maximum breach in intestinal integrity. Secondly we find that enhanced transport of macromolecules thru the intestinal layer is not caused by overt cell toxicity but occurs through potentially paracellular/transcellular pathways. Our model will be used to test repurposed and new drugs/ biologics for treatment of ALD as well as other intestinal inflammatory diseases.

pharmacology and toxicology↗

bioRxiv2022

Differential Activity of Repurposed Drugs as Receptor Binding Domain Antagonists for Omicron and Native Strains of SarsCov2

Omicron strain is the latest variant of concern of SarsCov2 virus. The mutations in this strain in the S protein Receptor Binding domain (RBD) enable it to be more transmissible as well as escape neutralizing activity by antibodies in response to vaccine. Thus, Omicron specific strategies are need to counter infection by this strain. We investigated a collection of approved drugs shown to antagonize the binding of native strain RBD to human ACE2, for their ability to antagonize binding to Omicron strain RBD. While most of the drugs the drugs that antagonize binding to native RBD are also active for Omicron RBD but some were inactive, namely drugs that contain iodine are completely inactive against Omicron RBD. Our data strongly indicate that presence of a single iodine molecule in the drug renders it inactive against Omicron strain. Thus, there is molecular specificity of drugs for antagonizing Omicron strain RBD versus native strain RBD of this virus. Such information will pave way for specific drugs for Omicron. A pragmatic message from our data is that the often-used iodine containing mouth wash and rises may be ineffective in antagonizing receptor binding of Omicron strain.

pharmacology and toxicology↗