Biology subjects

Gowda, K.

Publications and source records attributed to Gowda, K..

11 recordsLinked to original sources

bioRxiv2026

Delivery of defective interfering RNA antivirals to the lungs using hyperbranched poly(beta-amino ester) nanoparticles

Hyperbranched poly(beta-amino ester) (hPBAE) nanoparticles represent a promising platform for nucleic acid delivery, particularly to the lungs. In this study, we evaluate the potential of hPBAE nanoparticles to deliver defective interfering RNA (diRNA) antivirals targeting betacoronaviruses under a range of formulations and storage conditions. hPBAE-diRNA nanoparticles demonstrated efficient cellular uptake of functional diRNA across diverse cell types, conferred protection against nuclease-mediated degradation, and exhibited low in vitro cytotoxicity. In vivo, these nanoparticles enabled effective delivery of functional diRNA to the lungs of golden hamsters without inducing adverse physiological effects. Collectively, these findings support hPBAE nanoparticles as a safe and effective platform for diRNA delivery for the treatment of respiratory viral infections. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=66 SRC="FIGDIR/small/721911v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@2fc386org.highwire.dtl.DTLVardef@1cda4f9org.highwire.dtl.DTLVardef@9f61borg.highwire.dtl.DTLVardef@1fc8461_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Defective interfering RNA was mixed with hyperbranched poly(beta-amino ester) nanoparticles and delivered to cells in vitro and to golden hamsters in vivo, to measure toxicity and the replication potential of the RNA. C_FIG

microbiology↗

bioRxiv2026

Interkingdom glycine conjugates of indole-3-carboxylates are Ah receptor ligands

Substituted indoles are conserved metabolites across all kingdoms of life and may function as a mediators of inter- and intra-species communication. Indole-3-carboxylates (indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA)) represent abundant tryptophan-derived AHR agonists in human serum, potentially influencing AHR-dependent physiology. LC-MS analysis of mouse serum, urine and cecal/fecal contents reveals that both IAA and IPA undergo host and microbial mediated glycine conjugation to facilitate urinary elimination. Notably, at physiologically detectable human serum concentrations (M), IAA-Glycine retains human AHR activation potential. Comparative in silico docking simulations corroborate IAA-Glycine as a direct ligand for the human AHR. Data suggest, in contrast to xenobiotic ligands, AHR activation by endogenous tryptophan metabolites is greater in humans than in mice. These results underscore the role of microbial and host-derived amino acid conjugation in generating bioactive metabolites. Thus, positioning interkingdom auxin chemistry within human physiology and revealing an unexpected link between plants, microbes, and humans.

biochemistry↗

bioRxiv2025

Novel Pan-ALDH Inhibitor KS100 Effectively Targets ALDH+/CD138- Stem-like Cells to Overcome Relapse in Multiple Myeloma

Multiple myeloma (MM), a clonal plasma cell disorder is the second most frequent hematological malignancy in the United States. This malignancy is characterized by a series of symptoms such as bone lesions, hypercalcemia, renal failure, and anemia. The current clinical drugs in the market are successful in treating multiple myeloma patients into remission but does not address relapse where a more aggressive phenotype of the cancer remains untreatable. We hypothesize that a small subset of multiple myeloma stem-like cells (MMSLCs) that overexpress aldehyde dehydrogenases (ALDH+) is the cause of the relapse. Overexpression of ALDH bolsters drug resistance via detoxification and stemness via the retinoic acid signaling pathway. The phenotype of MMSLCs is not yet known for certainty but there are a few well established markers such CD138 negative (CD138neg) cells that are known to overexpress ALDH. In this study, we target regular MM cells and bortezomib resistant ALDH+/CD138neg MMSLCs with a novel, potent, pan-ALDH inhibitor, KS100. Here we report KS100 effectively lowered ALDH expression in regular and bortezomib resistant ALDH+/CD138neg cells, MM cell viability as well as proteins associated with MMSLCs. Most importantly we showed that KS100 lowered ALDH+ populations in regular, bortezomib resistant and CD138neg cells via ALDEFLUOR assay.

molecular biology↗

bioRxiv2023

A new efficacious Mcl-1 inhibitor maximizes bortezomib and venetoclax responsiveness in resistant multiple myeloma cells

Despite a record number of clinical studies investigating various anti-cancer drugs, the 5-year survival rate for multiple myeloma (MM) patients in the United States is only 55%, and nearly all patients relapse. Poor patient outcomes demonstrate that myeloma cells are "born to survive," which means they can adapt and evolve following treatment. As a result, new therapeutic approaches to combat this survival mechanism and target treatment-resistant malignant cells are required. Mcl-1, an anti-apoptotic protein, is required for the development of MM and resistance to therapy. This study looks at the possibility of KS18, a Mcl-1 inhibitor derived from pyoluteorin, to treat resistant MM. We show that KS18 inhibits Mcl-1 selectively and promotes post-translational modifications, resulting in UPS-dependent Mcl-1 degradation. Our findings show that KS18-induced Mcl-1 degradation results in caspase-dependent apoptosis. Importantly, KS18 triggered apoptosis in MM patient samples and bortezomib-resistant cells, synergizing with venetoclax to boost apoptosis. Furthermore, KS18 inhibits colony formation in bortezomib-resistant cells. KS18 treated NSG mice displayed significant tumor shrinkage without significant toxicity after four weeks of therapy with a single acceptable dose each week, indicating its powerful anti-neoplastic and anti-resistance characteristics. This study strongly implies that KS18 may treat MM and provide new hope to patients who are experiencing recurrence or resistance. Key pointsO_LIGiven that KS18 is a robust Mcl-1 inhibitor that targets Mcl-1 efficiently, it has the potential to be a novel treatment for multiple myeloma. C_LIO_LIKS18 has shown promise in re-sensitizing myeloma cells to chemotherapy as well as in overcoming resistance to bortezomib, venetoclax, and ABT-737. C_LI

pharmacology and toxicology↗

bioRxiv2023

Genomic patterns in the global soil microbiome emerge from microbial interactions

Microbial metabolism sustains life on Earth. Sequencing surveys of communities in hosts, oceans, and soils have revealed ubiquitous patterns linking the microbes present, the genes they possess, and local environmental conditions. One prominent explanation for these patterns is environmental filtering: local conditions select strains with particular traits. However, filtering assumes ecological interactions do not influence patterns, despite the fact that interactions can and do play an important role in structuring communities. Here, we demonstrate the insufficiency of the environmental filtering hypothesis for explaining global patterns in topsoil microbiomes. Using denitrification as a model system, we find that the abundances of two characteristic genotypes trade-off with pH; nar gene abundances increase while nap abundances decrease with declining pH. Contradicting the filtering hypothesis, we show that strains possessing the Nar genotype are enriched in low pH conditions but fail to grow alone. Instead, the dominance of Nar genotypes at low pH arises from an ecological interaction with Nap genotypes that alleviates nitrite toxicity. Our study provides a roadmap for dissecting how global associations between environmental variables and gene abundances arise from environmentally modulated community interactions.

ecology↗

bioRxiv2023

Learning the functional landscape of microbial communities

Microbial consortia exhibit complex functional properties in contexts ranging from soils to bioreactors to human hosts. Understanding how community composition determines emergent function is a major goal of microbial ecology. Here we address this challenge using the concept of community-function landscapes - analogs to fitness landscapes - that capture how changes in community composition alter collective function. Using datasets that represent a broad set of community functions, from production/degradation of specific compounds to biomass generation, we show that statistically-inferred landscapes quantitatively predict community functions from knowledge of strain presence or absence. Crucially, community-function landscapes allow prediction without explicit knowledge of abundance dynamics or interactions between species, and can be accurately trained using measurements from a small subset of all possible community compositions. The success of our approach arises from the fact that empirical community-function landscapes are typically not rugged, meaning that they largely lack high-order epistatic contributions that would be difficult to fit with limited data. Finally, we show this observation is generic across many ecological models, suggesting community-function landscapes can be applied broadly across many contexts. Our results open the door to the rational design of consortia without detailed knowledge of abundance dynamics or interactions.

ecology↗

bioRxiv2023

Complex chemical signals dictate Ah receptor activation through the gut-lung axis

The aryl hydrocarbon receptor (AHR) mediates intestinal barrier homeostasis. Many AHR ligands are also CYP1A1/1B1 substrates, which can result in the rapid clearance within the intestinal tract, limiting AHR activation. This led us to the hypothesis that there are dietary substrates of CYP1A1/1B1 that increase the half-life of potent AHR ligands. We examined the potential of urolithin A (UroA) as a CYP1A1/1B1 substrate to enhance AHR activity in vivo. UroA is a competitive substrate for CYP1A1/1B1 in an in vitro competition assay. A broccoli-containing diet promotes the gastric formation of the potent hydrophobic AHR ligand and CYP1A1/1B1 substrate, 5,11-dihydroindolo[3,2-b]carbazole (ICZ). Dietary exposure to UroA in a broccoli diet led to a coordinated increase in duodenal, cardiac, and pulmonary AHR activity, but no increase in activity in liver. Thus, CYP1A1 dietary competitive substrates can lead to intestinal "escape", likely through the lymphatic system, increasing AHR activation in key barrier tissues.

biochemistry↗

bioRxiv2023

Contribution of circulating host and microbial tryptophan metabolites towards Ah receptor activation

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that plays an integral role in homeostatic maintenance by regulating cellular functions such as cellular differentiation, metabolism, barrier function, and immune response. An important but poorly understood class of AHR activators are compounds derived from host and bacterial metabolism of tryptophan. The commensal bacteria of the gut microbiome are major producers of tryptophan metabolites known to activate the AHR, while the host also produces AHR activators through tryptophan metabolism. We used targeted mass spectrometry-based metabolite profiling to determine the presence and metabolic source of these metabolites in the sera of conventional mice, germ-free mice, and humans. Surprisingly, sera concentrations of many tryptophan metabolites are comparable between germ-free and conventional mice. Therefore, many major AHR-activating tryptophan metabolites in mouse sera are produced by the host, despite their presence in feces and mouse cecal contents. AHR activation is rarely studied in the context of a mixture at relevant concentrations, as we present here. The AHR activation potentials of individual and pooled metabolites were explored using cell-based assays, while ligand binding competition assays and ligand docking simulations were used to assess the detected metabolites as AHR agonists. The physiological and biomedical relevance of the identified metabolites was investigated in the context of cell-based models for cancer and rheumatoid arthritis. We present data here that reframe AHR biology to include the presence of ubiquitous tryptophan metabolites, improving our understanding of homeostatic AHR activity and models of AHR-linked diseases.

biochemistry↗

bioRxiv2022

Development of a Novel Bruton's Tyrosine Kinase Inhibitor that exerts Anti-Cancer Activities Potentiates Response of Chemotherapeutic Agents In Multiple Myeloma Stem Cell-Like Cells

Despite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Brutons tyrosine kinase (BTK) in MM stem cell-like cells is correlated with drug resistance and poor prognosis. We have developed a novel small BTK inhibitor, KS151, which is unique compared to other BTK inhibitors. Unlike ibrutinib, and the other BTK inhibitors such as acalabrutinib, orelabrutinib, and zanubrutinib that covalently bind to the C481 residue in the BTK kinase domain, KS151 can inhibit BTK activities without binding to C481. This feature of KS151 is important because C481 becomes mutated in many patients and causes drug resistance. We demonstrated that KS151 inhibits in vitro BTK kinase activities and is more potent than ibrutinib. Furthermore, by performing a semi-quantitative, sandwich-based array for 71-tyrosine kinase phosphorylation, we found that KS151 specifically inhibits BTK. Our western blotting data showed that KS151 inhibits BTK signaling pathways and is effective against bortezomib-resistant cells as well as MM stem cell-like cells. Moreover, KS151 potentiates the apoptotic response of bortezomib, lenalidomide, and panobinostat in both MM and stem cell-like cells. Interestingly, KS151 inhibits stemness markers and is efficient in inhibiting Nanog and Gli1 stemness markers even when MM cells were co-cultured with bone marrow stromal cells (BMSCs). Overall, our results show that we have developed a novel BTK inhibitor effective against the stem cell-like population, and potentiates the response of chemotherapeutic agents.

molecular biology↗

bioRxiv2020

A sparse mapping of structure to function in microbial communities

The metabolic function of microbial communities has played a defining role in the evolution and persistence of life on Earth, driving redox reactions that form the basis of global biogeochemical cycles. Community metabolism emerges from a hierarchy of processes including gene expression, ecological interactions, and environmental factors. In wild communities, gene content is correlated with environmental context, but predicting metabolic dynamics from genomic structure remains elusive. Here we show, for the process of denitrification, that community metabolism is predictable from the genes each member of the community possesses. Machine learning reveals a sparse and generalizable mapping from gene content to metabolite dynamics across a genomically-diverse library of bacteria. A consumer-resource model correctly predicts community metabolism from single-strain phenotypes. Our results demonstrate that the conserved impacts of metabolic genes can predict community function, enabling the prediction of metabolite dynamics from metagenomes, designing denitrifying communities, and discovering how genome evolution impacts metabolism.

ecology↗

bioRxiv2019

Evolution of generalists by phenotypic plasticity

Adapting organisms face a tension between specializing their phenotypes for certain ecological tasks or developing generalist strategies which permit persistence in multiple environmental conditions. Understanding when and how generalists or specialists evolve is therefore an important question in evolutionary dynamics. Here we study the evolution of bacterial range expansions by selecting Escherichia coli for faster migration through porous media containing one of four different sugars supporting growth and chemotaxis. We find that selection in any one sugar drives the evolution of faster migration in all sugars relative to the ancestral strain. Measurements of growth and motility of all evolved lineages in all nutrient conditions reveal that the ubiquitous evolution of fast migration arises via phenotypic plasticity. Phenotypic plasticity permits evolved strains to exploit distinct phenotypic strategies to achieve fast migration in each environment irrespective of the environment in which they were evolved. Our work suggests that plasticity plays an important role in the evolution of generalist phenotypes.

evolutionary biology↗