Biology subjects

Velenosi, T. J.

Publications and source records attributed to Velenosi, T. J..

4 recordsLinked to original sources

bioRxiv2025

GABA-GABA_A Receptor Signaling Orchestrates Invasion and Metastasis in Triple Negative Breast Cancer

Cancer is a leading cause of death globally, with the majority of cancer-related deaths resulting from cancer metastasis -the process by which cancer cells disseminate to distant sites. To metastasize, cancer cells acquire traits in support of diverse cellular processes that enable dissemination, survival, and colonization. Tumor cell dissemination requires invasion at local and distant sites and this process can be influenced by intrinsic and extrinsic factors. Here, we investigate the role of the neurotransmitter gamma-aminobutyric acid (GABA) in triple-negative breast cancer (TNBC) invasion and metastasis. TNBC cells increased invasion in response to GABA and this was found to be mediated through the GABAA receptor family. TNBC cell lines were found to be responsive to exogenous GABA and also produced endogenous GABA. Pharmacological inhibition of GABAA receptors reduced TNBC invasion and cancer cell dissemination and resulted in inhibition of GSK3 activity. TNBC cell lines were found to express the GABRE subunit and loss of GABRE impaired GABA-mediated invasion and tumor cell dissemination. These findings support a role for GABA signaling through GABAA receptors in mediating TNBC progression.

cancer biology↗

bioRxiv2022

Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer

Triple-negative breast cancer (TNBC) patients receive chemotherapy treatment, including doxorubicin, due to the lack of targeted therapies. Drug resistance is a major cause of treatment failure in TNBC and therefore, there is a need to identify biomarkers that determine effective drug response. Here, a pharmacometabolomics study was performed using TNBC patient-derived xenograft models to detect urinary metabolic biomarkers of doxorubicin effectiveness. Diacetylspermine was identified as a urine metabolite that robustly changed in response to effective doxorubicin treatment, which persisted after the final dose. Diacetylspermine was directly traced back to the tumor and correlated with tumor volume. Ex vivo tumor slices revealed that doxorubicin directly increases diacetylspermine production by increasing tumor spermidine/spermine N1-acetyltransferase 1 expression and activity, which was corroborated by elevated polyamine flux. In breast cancer patients, tumor diacetylspermine was elevated compared to matched non-cancerous tissue and increased in HER2+ and TNBC compared to ER+ subtypes. In addition, 12-hour urine diacetylspermine was associated with breast cancer tumor volume and poor tumor grade. This study describes a pharmacometabolomics strategy for identifying cancer metabolic biomarkers that indicate drug response. Our findings characterize urine diacetylspermine as a non-invasive biomarker of doxorubicin effectiveness in TNBC.

cancer biology↗

bioRxiv2019

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Fasting paradigms elicit a wide-range of health benefits including suppressing inflammation. Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising new therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARA directly upregulates the long non-coding RNA gene Gm15441 through binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLRP3 inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1 beta (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to metabolic and inflammatory stimuli. These findings provide evidence for a novel mechanism by which PPARA attenuates hepatic inflammasome activation in response to metabolic stress through lncRNA Gm15441 induction.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC=\"FIGDIR/small/675785v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (23K):\norg.highwire.dtl.DTLVardef@1db1d5dorg.highwire.dtl.DTLVardef@64c8b2org.highwire.dtl.DTLVardef@b4402borg.highwire.dtl.DTLVardef@1e0fbba_HPS_FORMAT_FIGEXP M_FIG Graphical abstract\n\nC_FIG

molecular biology↗

bioRxiv2019

The Impact of Uremia and Intestinal Dysbiosis on Hepatic Drug Metabolism in a Rat Model of Progressive Chronic Kidney Disease

Nonrenal clearance pathways such as drug metabolism are decreased in chronic kidney disease (CKD). Although the mechanism remains elusive, uremic toxin retention and an altered gut microbiota are suspected to influence cytochrome P450s (CYPs) contributing to the unpredictable pharmacokinetics in patients with CKD. We characterized dysbiosis and uremia in CKD to elucidate associations between CYP expression and CKD progression. Rats fed control or CKD-inducing adenine diet were subsequently studied at five time points over 42 days. CYP expression and activity were compared to alterations in the 1) plasma and liver metabolome and 2) gut bacterial microbiota. CYP3A2 and CYP2C11 were downregulated in CKD by [≥]76% (p<0.001) concurrently with or slightly prior to CKD onset as defined by serum creatinine. Metabolite profiles were altered prior to changes in the gut microbiota, and gut-derived uremic toxins including indoxyl sulfate, phenyl sulfate and 4-ethylphenyl sulfate correlated with CYP3A2 or CYP2C11 expression. Bacterial genera Turicibacter and Parabacteroides were identified as being characteristic of CKD. In conclusion, CYP3A2 and CYP2C11 are downregulated before dysbiosis and correlate with select uremic toxins.

pharmacology and toxicology↗