Biology subjects

Parween, S.

Publications and source records attributed to Parween, S..

10 recordsLinked to original sources

bioRxiv2026

Integrated Skin Sensitization Assessment Using Consensus Modelling and Tiered New Approach Methodology: A SaferSkin Case Study

The transition toward animal-free safety assessment of chemicals has accelerated the development of New Approach Methodologies (NAMs) for predicting skin sensitization. However, individual in silico models and experimental NAM assays frequently produce inconsistent or contradictory results, limiting their reliability when used in isolation. To address this challenge, we present a tiered integrated assessment framework implemented through the open source SaferSkin application, which enables systematic comparison and integration of multiple predictive models and experimental data within a transparent weight-of-evidence workflow. In this case study, a diverse set of 21 reference compounds was evaluated using a battery of in silico approaches, including the OECD QSAR Toolbox, VEGA, CASE Ultra and additional machine-learning models implemented within SaferSkin. The platform enables side-by-side comparison of predictions and integration of experimental data through Bayesian network models, allowing probabilistic updating of predictions as new evidence becomes available. Our results demonstrate that reliance on any single predictive model is insufficient for robust hazard identification due to frequent disagreement between models. In contrast, consensus interpretation across multiple modelling approaches combined with targeted experimental evidence substantially improves predictive confidence. The integrated weight-of-evidence framework showed strong concordance with reference classifications and was further supported by independent validation using the Pred-Skin Bayesian model. Importantly, the tiered workflow enables resolution of ambiguous cases. For example, lower-tier predictions for ethyl (2E,4Z)-deca-dienoate were inconsistent across models, whereas targeted third-tier testing using the SENS-IS assay identified the compound as a strong sensitiser (GHS Category 1A). Overall, this study demonstrates how integrated modelling, Bayesian evidence updating and targeted NAM testing can reduce uncertainty in skin sensitization assessment. The SaferSkin framework provides a transparent and reproducible approach for implementing Next Generation Risk Assessment (NGRA) strategies and supports the development of animal-free regulatory toxicology and Safe-and-Sustainable-by-Design chemical innovation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/711911v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@196a52eorg.highwire.dtl.DTLVardef@13690a6org.highwire.dtl.DTLVardef@1528703org.highwire.dtl.DTLVardef@11e05d2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

pharmacology and toxicology↗

bioRxiv2025

Darwin21 Genome Database: A Curated Whole-Genome Repository of Endophytic Bacteria from Desert Plants

Microbial communities associated with desert plants play a pivotal role in enhancing host survival under extreme environmental stressors, including drought, salinity, and nutrient limitation. The Darwin21 Endophytic Microbial Collection is one of the largest curated repositories of 2,500 cultivable endophytic bacteria isolated from 23 native desert plant species across Saudi Arabia, Jordan, and Pakistan. Representing a broad spectrum of arid microhabitats from inland deserts and mountain wadis to coastal mangroves and date palm oases, the collection supports integrative studies on microbial ecology and plant-microbe interactions in water-limited ecosystems. A central component of this initiative is the Darwin21 Genome Database, which currently hosts whole-genome sequences (WGS) of 534 endophytic bacterial isolates annotated with extensive ecological metadata, assembly statistics, functional traits, and host associations. The database interface provides tools for genome exploration, metadata filtering, and functional gene mining, enabling users to identify taxa and traits of agronomic interest, particularly for applications in sustainable agriculture and sustainable desert revegetation. By combining genomic, ecological, and functional data, the Darwin21 Genome Database serves as a foundational platform for the development of targeted microbial inoculants and fosters data-driven research into desert microbiomes and plant resilience mechanisms. Database URLhttps://www.genomedatabase.org/ O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/672100v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1703432org.highwire.dtl.DTLVardef@172fce7org.highwire.dtl.DTLVardef@39bd1borg.highwire.dtl.DTLVardef@ae3fef_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Oxalotrophic bacteria in desert and drylands: Enzymatic pathways and Carbon sequestration

Oxalotrophy refers to the ability of bacteria to utilize oxalate as a carbon and energy source. This is a critical process with significant implications for the global carbon cycle. Oxalate-degrading bacteria play a key role in carbon sequestration through the oxalate-carbonate pathway (OCP), contributing to stable inorganic carbon pools. In this study, we identified and cataloged 20 enzymes associated with various facets of oxalate metabolism to characterize the oxalotrophic potential of bacteria. Within this group, sets of enzymes were grouped into two functional categories in the context of carbon sequestration: a biomineralization toolkit for converting oxalate to inorganic carbon and an assimilation toolkit for incorporating oxalate into metabolic pathways such as amino acid biosynthesis and energy production. Using bioinformatic approaches, we analyzed a collection of 536 bacterial genomes from desert and dryland strains spanning 81 genera to identify oxalotrophs. To validate our findings, we tested several bacterial strains for growth on media supplemented with exogenous oxalate. Notably, while multiple bacterial strains grew on oxalate media, two Pseudomonas species, namely JZ043 and JZ097, failed to grow despite genomic predictions suggesting otherwise. Further investigation of these strains revealed several non-conservative amino acid substitutions in the glyoxylate carboligase enzyme (EC 4.1.1.47), a key player in oxalate metabolism, suggesting a potential link between these mutations and their inability to metabolize oxalate. Our findings highlight the significance of our approach for identifying oxalotrophic bacteria (OxB) and offer valuable insights into the molecular basis of oxalate metabolism. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/637404v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@13d1408org.highwire.dtl.DTLVardef@ee2e5eorg.highwire.dtl.DTLVardef@1265323org.highwire.dtl.DTLVardef@11c56d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration

Photoreceptor death causes blinding inheritable retinal diseases, such as retinitis pigmentosa (RP). As disease progression often outpaces therapeutic advances, finding effective treatments is urgent. This study focuses on developing a targeted approach by evaluating the efficacy of small peptides derived from pigment epithelium-derived factor (PEDF), known to restrict common cell death pathways associated with retinal diseases. Peptides with affinity for the PEDF receptor, PEDF-R, (17-mer and H105A) delivered via eye drops reached the retina, efficiently promoted photoreceptor survival, and improved retinal function in RP mouse models based on both the rd10 mutation and the rhodopsin P23H mutation. Additionally, intravitreal delivery of AAV-H105A vectors delayed photoreceptor degeneration in the latter RP mouse model. Furthermore, peptide H105A specifically prevented photoreceptor death induced by oxidative stress, a contributing factor to RP progression, in human retinal organoids. This promising approach for peptide eye drop delivery holds significant potential as a therapeutic for preventing photoreceptor death in retinal disorders, offering a high safety profile, low invasiveness and multiple delivery options. One Sentence SummaryNeurotrophic PEDF peptides delivered as eye drops preserve photoreceptor viability, morphology, and function in models of human retinal diseases.

neuroscience↗

bioRxiv2024

Skin Sensitisation Case Study: Comparison of Defined Approaches including OECD 497 Guidance

Characterising known and new chemical compounds for skin sensitisation provides a basis for the development of safer products where ingredients are exposed to skin. By including new approaches, such as tiered testing strategies and integrated data analysis, it is possible to develop next generation products adhering to emerging regulations, scientific evidence and animal welfare principles. To ensure data integrity during such assessment the OECD provides characterisation guidelines and Defined Approaches (DAs) to uniform work-flows. In this study we developed and applied the integrated characterisation tool called < > to compare the results of different DAs for eight compounds and included results obtained from current OECD guidance and emerging methods. We tested two compounds with unclear or indeterminate results with the SENS-IS assay to explore the value of the experiment in strengthening the weight of evidence and arriving at a clearer conclusion.

pharmacology and toxicology↗

bioRxiv2024

AMPK-activator ATX-304 reduces oxidative stress and improves MASLD via metabolic switching

AbstractMetabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease worldwide for which there are no approved treatments. Adenosine monophosphate-activated protein kinase (AMPK) is an interesting therapeutical target since it acts as a central regulator of cellular metabolism. Despite efforts to target the AMPK, no direct activators has yet been approved for treatment of this disease. This study investigates the effect of AMPK activator ATX-304 in a preclinical mouse model of progressive fatty liver disease. The data demonstrate that ATX-304 diminishes body fat mass, lowers blood cholesterol levels, mitigates liver steatosis, and ameliorates the development of liver fibrosis. The beneficial effects of ATX-304 treatment are accompanied by a shift in the liver metabolic program, including increased lipid oxidation, reduced lipid synthesis, as well as remodeling of cholesterol and lipid transport. We also observed variations in lipid distribution among liver lobes in response to ATX-304, and a shift in the zonal distribution of lipid droplets upon treatment. Taken together, our data suggest that ATX-304 holds promise as a potential treatment for Metabolically Associated Fatty Liver Disease (MAFLD), including in human patients.

molecular biology↗

bioRxiv2020

Across kingdom biased CYP-mediated metabolism via small-molecule ligands docking on P450 oxidoreductase

Metabolic control is mediated by the dynamic assemblies and function of multiple redox enzymes. A key element in these assemblies, the P450 oxidoreductase (POR), donates electrons and selectively activates numerous (>50 in humans and >300 in plants) cytochromes P450 (CYPs) controlling metabolism of drugs, steroids and xenobiotics in humans and natural product biosynthesis in plants. The mechanisms underlying POR-mediated CYP metabolism remain poorly understood and to date no ligand binding has been described to regulate the specificity of POR. Here, using a combination of computational modeling and functional assays, we identified ligands that dock on POR and bias its specificity towards CYP redox partners. Single molecule FRET studies revealed ligand docking to alter POR conformational sampling, which resulted in biased activation of metabolic cascades in whole cell assays. We propose the model of biased metabolism, a mechanism akin to biased signaling of GPCRs, where ligand docking on POR stabilizes different conformational states that are linked to distinct metabolic outcomes. Biased metabolism may allow designing pathway-specific therapeutics or personalized food suppressing undesired, disease related, metabolic pathways.

biophysics↗

bioRxiv2019

Differential effects of variations in human P450 oxidoreductase on the aromatase activity of CYP19A1 polymorphisms R264C and R264H

Aromatase (CYP19A1) converts androgens into estrogens and is required for female sexual development and growth and development in both sexes. CYP19A1 is a member of cytochrome P450 family of heme-thiolate monooxygenases located in the endoplasmic reticulum and depends on reducing equivalents from the reduced nicotinamide adenine dinucleotide phosphate via the cytochrome P450 oxidoreductase coded by POR. Both the CYP19A1 and POR genes are highly polymorphic, and mutations in both these genes are linked to disorders of steroid biosynthesis. We have previously shown that R264C and R264H mutations in CYP19A1, as well as mutations in POR, result in a reduction of CYP19A1 activity. The R264C is a common polymorphic variant of CYP19A1, with high frequency in Asian and African populations. Polymorphic alleles of POR are found in all populations studied so far and, therefore, may influence activities of CYP19A1 allelic variants. So far, effects of variations in POR on enzymatic activities of allelic variants of CYP19A1 or any other steroid metabolizing cytochrome P450 proteins have not been studied. Here we are reporting the effects of three POR variants on the aromatase activities of two CYP19A1 variants, R264C and R264H. We used bacterially expressed and purified preparations of WT and variant forms of CYP19A1 and POR and constructed liposomes with embedded CYP19A1 and POR proteins and assayed the CYP19A1 activities using radiolabeled androstenedione as a substrate. With the WT-POR as a redox partner, the R264C-CYP19A1 showed only 15% of aromatase activity, but the R264H had 87% of aromatase activity compared to WT-CYP19A1. With P284L-POR as a redox partner, R264C-CYP19A1 lost all activity but retained 6.7% of activity when P284T-POR was used as a redox partner. The R264H-CYP19A1 showed low activities with both the POR-P284L as well as the POR-P284T. When the POR-Y607C was used as a redox partner, the R264C-CYP19A1 retained around 5% of CYP19A1 activity. Remarkably, The R264H-CYP19A1 had more than three-fold higher activity compared to WT-CYP19A1 when the POR-Y607C was used as the redox partner, pointing towards a beneficial effect. The slight increase in activity of R264C-CYP19A1 with the P284T-POR and the three-fold increase in activity of the R264H-CYP19A1 with the Y607C-POR point towards a conformational effect and role of protein-protein interaction governed by the R264C and R264H substitutions in the CYP19A1 as well as P284L, P284T and Y607C variants of POR. These studies demonstrate that the allelic variants of P450 when present with a variant form of POR may show different activities, and combined effects of variations in both the P450 enzymes as well as in the POR should be considered when genetic data are available. Recent trends in the whole-exome and whole-genome sequencing as diagnostic tools will permit combined evaluation of variations in multiple genes that are interdependent and may guide treatment options by adjusting therapeutic interventions based on laboratory analysis.

biochemistry↗

bioRxiv2019

Loss of multiple enzyme activities due to the human genetic variation P284T in NADPH cytochrome P450 oxidoreductase

Cytochromes P450 located in the endoplasmic reticulum require NADPH cytochrome P450 oxidoreductase (POR) for their catalytic activities. Mutations in POR cause multiple disorders in humans related to the biosynthesis of steroid hormones and also affect drug-metabolizing cytochrome P450 activities. Here we are reporting the effects of a POR genetic variant P284T which is located in the hinge region of POR that is necessary for the flexibility of domain movements. Human wild-type and P284T mutant of POR, as well as cytochrome P450 proteins, were expressed in bacteria, purified and then reconstituted in liposomes for enzyme kinetic assays. Quality of POR proteins was checked by cytochrome c, ferricyanide and tetrazolium dye reduction assay and measurements flavin content. We found that for the P284T variant of POR the cytochrome c reduction activity was reduced to 47% of the WT and MTT reduction was reduced to only 15% of the WT. No impact on ferricyanide reduction activity was observed, but a severe loss of CYP19A1 (aromatase) activity was observed (9% of WT). In the assays of drug metabolizing cytochrome P450 enzymes, the P284T variant of POR showed 26% activity for CYP2C9, 44% activity for CYP2C19, 23% activity for CYP3A4 and 44% activity in CYP3A5 assays compared to the WT POR. These results indicate a severe effect on several cytochrome P450 activities due to the P284T variation in POR which suggests a negative impact on both the steroid as well as drug metabolism in the individuals carrying this variation.

pharmacology and toxicology↗

bioRxiv2019

Variability in Human Drug Metabolizing Cytochrome P450 CYP2C9, CYP2C19 and CYP3A5 Activities Caused by Genetic Variations in Cytochrome P450 Oxidoreductase

A broad spectrum of human diseases are caused by mutations in the NADPH cytochrome P450 oxidoreductase (POR). Cytochrome P450 proteins perform several reactions, including the metabolism of steroids, drugs, and other xenobiotics. In 2004 the first human patients with defects in POR were reported, and over 250 variations in POR are known. Information about the effects of POR variants on drug metabolizing enzymes is limited and has not received much attention. By analyzing the POR sequences from genomics databases, we identified potentially disease-causing variations and characterized these by in vitro functional studies using recombinant proteins. Proteins were expressed in bacteria and purified for activity assays. Activities of cytochrome P450 enzymes were tested in vitro using liposomes prepared with lipids into which P450 and P450 reductase proteins were embedded. Here we are reporting the effect of POR variants on drug metabolizing enzymes CYP2C9, CYP2C19, and CYP3A5 which are responsible for the metabolism of many drugs. POR Variants A115V, T142A, A281T, P284L, A287P, and Y607C inhibited activities of all P450 proteins tested. Interestingly, the POR variant Q153R showed a reduction of 20-50% activities with CYP2C9 and CYP2C19 but had a 400% increased activity with CYP3A5. The A287P is most common POR mutation found in patients of European origin, and significantly inhibited drug metabolism activities which has important consequences for monitoring and treatment of patients. In vitro, functional assays using recombinant proteins provide a useful model for establishing the metabolic effect of genetic mutations. Our results indicate that detailed knowledge about POR variants is necessary for correct diagnosis and treatment options for persons with POR deficiency and the role of changes in drug metabolism and toxicology due to variations in POR needs to be addressed.

pharmacology and toxicology↗