Biology subjects

Hammer, S. S.

Publications and source records attributed to Hammer, S. S..

4 recordsLinked to original sources

bioRxiv2025

Evaluation of Probiotic Bacteria for the Reduction of Urea, p-Cresol, and Indole Levels

IntroductionEnd-stage kidney disease (ESKD) is associated with the accumulation of uremic toxins such as urea, p-cresol, and indole, which significantly contribute to systemic complications such as inflammation, oxidative stress, and gut dysbiosis. Probiotics have demonstrated potential in modulating gut microbiota and reducing these toxins. We evaluated the in vitro efficacy of multiple probiotic strains of Lactobacillus, Bifidobacterium, Sterptococcus, Bacillus and others in degrading urea, p-cresol, and indole. MethodsThe probiotic strains were initially trained on toxin media prior to their evaluation of their toxin breakdown efficiency. Additionally microbiological methods using selective Christiansons broth/agar and Stuarts broth/agar were applied to assess urea breakdown. Liquid Chromatography-Mass Spectrometry (LC-MS) was utilized to quantify p-cresol and indole degradation. ResultsThe results indicated that all probiotic strains exhibited significant activity in reducing urea, p-cresol, and indole concentrations in the culture media. In urea breakdown we observed an oscillation urea/ammonia ratio at 24 hr intervals, although a complete elimination of the ammonium byproduct was not feasible. Among all tested probiotics, Lactobacillus species showed the highest efficiency in urea breakdown. Furthermore, the toxin removing efficacy of the probiotics was evaluated in a simulated gut environment using the TNO invitro gut model. ConclusionCumulatively, the findings suggest that probiotics could offer a promising strategy for the reduction of uremic toxins and their associated complications in ESKD patients.

microbiology↗

bioRxiv2024

Comparative analysis of Endoxifen, Tamoxifen and Fulvestrant: A Bioinformatics Approach to Uncover Mechanisms of Action in Breast Cancer

Breast cancer remains a significant health challenge, with estrogen receptor positive (ER+) subtypes being particularly prevalent forms of breast cancer. Current anti-estrogen therapies, such as tamoxifen and fulvestrant, have limitations, including partial agonist activity and resistance development, which evidence the need for more potent alternatives. Endoxifen, a metabolite of tamoxifen, has emerged as a promising breast cancer therapeutic candidate due to its superior anti-estrogenic effects and side effect profile. The omics signatures for endoxifen, tamoxifen and fulvestrant, obtained from publicly available datasets, were aggregated and harmonized by means of the PandaOmics platform, a commercially available target-discovery platform using multiple AI engines including generative pretrained transformers. Pathway enrichment analyses provided insight into these agents mechanisms of action (MOA) in breast cancer. The analyses revealed unexpected variances in several key pathways from expected interactions via estrogen-dependent and independent effects. All three drugs downregulated estrogen signaling and cell cycle-related pathways, such as E2F targets, G2-M checkpoints, Myc targets, and mitotic spindle, and stimulated apoptosis. Fulvestrant and tamoxifen activated pro-inflammatory and immune pathways and perturbed epithelial-mesenchymal transition (EMT). Endoxifen perturbed the PI3K/Akt/mTORC1 pathway, pursuant to distinct molecular mechanisms compared to its parent compound, tamoxifen, and fulvestrant. In summary, advanced AI-driven methodologies demonstrate the capacity to analyze multi-omics data in a comparative way to advance the understanding of endocrine therapy mechanisms in breast cancer. This insight into the distinct effects of endoxifen, tamoxifen, and fulvestrant may aid in selecting the most effective therapies for specific indications and in identifying drug-specific biomarkers.

cancer biology↗

bioRxiv2020

Selective LXR agonist, DMHCA, corrects the retina-bone marrow axis in type 2 diabetes

In diabetic dyslipidemia, cholesterol accumulates in the plasma membrane, decreasing fluidity and thereby suppressing the ability of cells to transduce ligand-activated signaling pathways. Liver X receptors (LXRs) are the main cellular mechanism by which intracellular cholesterol is regulated and play important roles in inflammation and disease pathogenesis. N,N-dimethyl-3{beta}-hydroxy-cholenamide (DMHCA), a selective LXR agonist, specifically activates the cholesterol efflux arm of the LXR pathway without stimulating triglyceride synthesis. Thus, DMHCA possesses superior clinical potential as a cholesterol lowering agent than current LXR pan-agonist. In this study, we use a multi-systems approach to understand the effects and molecular mechanisms of DMHCA treatment in type 2 diabetic db/db mice and human -derived circulating angiogenic cells (CACs), which are vascular reparative cells. We find that DMHCA is sufficient to correct the retina-bone marrow (BM) axis in diabetes, thereby restoring retinal structure, function, and cholesterol homeostasis, rejuvenating membrane fluidity in circulating vascular reparative cells, hampering systemic inflammation, and correcting BM dysfunction. Using single-cell RNA-seq on lineage-sca1+cKit+ (LSK) hematopoietic stem cells (HSCs) from untreated and DMHCA-treated diabetic mice, we provide novel insights into hematopoiesis and reveal DMHCAs mechanism of action in correcting diabetic HSCs by reducing myeloidosis and increasing CACs and erythrocyte progenitors. Taken together, these findings demonstrate the broad and pleiotropic effects of DMHCA treatment, which has exciting potential to correct the retina-BM axis in diabetic subjects.

cell biology↗

bioRxiv2019

Pharmacological and fasting-induced activation of SIRT1/LXRα signaling alleviates diabetes-induced retinopathy.

In diabetes, the retina, a tissue with unique metabolic needs, demonstrates dysregulation of the intricate balance between nutrient availability and utilization. This results in cholesterol accumulation, pro-inflammatory and pro-apoptotic changes, and consequently neurovascular damage. Sirtuin 1 (SIRT1), a nutrient sensing deacetylase, is downregulated in the diabetic retina. In this study, the effect of SIRT1 stimulation by fasting or by pharmacological activation using SRT1720, was evaluated on retinal cholesterol metabolism, inflammation and neurovascular damage. SIRT1 activation, in retinal endothelial cells (REC) and neuronal retinal progenitor cells (R28), led to Liver X Receptor alpha (LXR) deacetylation and subsequent increased activity, as measured by increased ATP-binding cassette transporter (ABC) A1 and G1 mRNA expression. In turn, increased cholesterol export resulted in decreased REC cholesterol levels. SIRT1 activation also led to decreased inflammation. SIRT1 activation, in vivo, prevented diabetes-induced inflammation and vascular and neural degeneration. Diabetes-induced visual function impairment, as measured by electroretinogram and optokinetic response, was significantly improved as a result of SIRT1 activation. Taken together, activation of SIRT1 signaling is an effective therapeutic strategy that provides a mechanistic link between the advantageous effects associated with fasting regimes and prevention of diabetic retinopathy (DR).

cell biology↗