Biology subjects

Suresh, D.

Publications and source records attributed to Suresh, D..

6 recordsLinked to original sources

bioRxiv2026

A Moonlighting Function of Kinetochore Complex Proteins in Golgi Assembly of Neural Stem Cells

Kinetochores play an essential role in mitosis, and human kinetochore variants are associated with microcephaly. However, their functions in quiescent/interphase cells are unknown. Here, we demonstrate that Drosophila kinetochore proteins promote the reactivation of quiescent NSCs and their regeneration upon injury by organizing Golgi-dependent acentrosomal microtubules. Drosophila kinetochore proteins localize to the Golgi vicinity in quiescent NSCs and are required for proper localization of Golgi proteins, including the Golgi-resident small GTPase Arf1 known to regulate quiescent NSC reactivation and regeneration. Moreover, Drosophila kinetochore proteins physically associate with Arf1 and function upstream of it during reactivation. Remarkably, human kinetochore protein SPC25 localizes to Golgi in interphase NSCs and HEK293T cells. Furthermore, human kinetochores have a conserved function in promoting Golgi organization and, in turn, microtubule dynamics, in interphase cells. Together, our findings reveal a conserved moonlighting role for kinetochores in Golgi assembly in quiescent Drosophila NSCs and human interphase cells.

neuroscience↗

bioRxiv2026

A TSST 1 structural motif disrupts endothelial programs required for vascular regeneration.

Staphylococcus aureus causes profound vascular damage during infection, where it inflicts vascular injury across organs and generates lesions that fail to heal. Superantigens are major virulence factors in S. aureus infections, yet their direct effects on vascular repair remain unclear. We provide evidence that TSST-1 disrupts endothelial regeneration through coordinated mechanisms. TSST-1 interferes with collective directed migration, impairing endothelial cell directional persistence and preventing re-endothelialization in vitro. These defects stem from cytoskeletal disorganization, characterized by stress fiber accumulation and loss of lamellipodia, and broad suppression of motility-associated secreted factors. In an ex vivo aortic ring assay, TSST-1 suppresses angiogenic sprouting and generates dysmorphic vascular networks. Proteomic profiling reveals a shift toward matrix rigidity, adhesion stabilization, and overall suppression of angiogenesis. These activities map to a conserved dodecapeptide motif. Hence, TSST-1 suppression of vascular repair may convert sites of tissue injury into persistently non-healing niches suited for S. aureus persistence.

cell biology↗

bioRxiv2024

Silencing of Hepatic AATF Ameliorates Metabolic Dysfunction Associated Steatohepatitis by Promoting Fatty Acid β-Oxidation in Experimental models

Background & aimsMetabolic dysfunction-associated steatohepatitis (MASH) is a multifactorial disease driven by complex molecular mechanisms. Identifying key regulators is critical for developing targeted therapies. Here, we demonstrate the impact of the loss of apoptosis antagonizing transcription factor (AATF) on hepatic lipid metabolism and MASH progression. MethodsA preclinical mouse model recapitulating human MASH was established by feeding C57Bl/6 mice either a chow diet (CD) or a western diet with sugar water (WD). Hepatic AATF silencing was achieved by tail vein injection of siAATF delivered by adeno-associated virus 8 (AAV8) with the liver-specific thyroxine-binding globulin (TBG) promoter. In addition to histological, biochemical, and molecular biology evaluations, the mechanistic insights were derived from whole transcriptomics and untargeted metabolomics analyses. ResultsAAV8-mediated specific knockdown of AATF in hepatocytes significantly reduced body weight, liver weight, and insulin resistance in mice fed with western diet (WD). However, no such effects were observed in mice fed with a chow diet (CD). Further analyses showed reduced liver injury, steatosis, and steatohepatitis in WDsiAATF mice. Transcriptomic analysis demonstrated that loss of AATF alleviated cellular stress, inflammation, and fibrosis in WD-fed mice. Moreover, AATF silencing led to alterations in lipid metabolism, notably by decreasing hepatic lipogenesis in the WD mice. Interestingly, untargeted metabolomics revealed an increase in the biosynthesis of glycerophospholipids and beta-oxidation of fatty acids in WDsiAATF mice. ConclusionOur findings reveal a previously unrecognized role of AATF as a central regulator of hepatic lipid metabolism in MASH, acting through the AKT-mTORC1 signaling pathway, and establish its inhibition as a promising therapeutic strategy for metabolic liver disease.

molecular biology↗

bioRxiv2024

Green Jackfruit Flour Prevents Metabolic Dysfunction-Associated Steatohepatitis and Progression to Hepatocellular Carcinoma via the AMPK and MAPK Signaling Pathways

Metabolic dysfunction-associated steatotic liver disease (MASLD), encompassing metabolic-dysfunction associated steatotic liver (MAFL) and steatohepatitis (MASH), which further progresses to hepatocellular carcinoma (HCC), is a serious public health concern. Given the paucity of approved therapeutic strategies for this lifestyle disorder, dietary interventions may prove effective. We evaluated how green jackfruit flour (JF) prevents MASH and progression to HCC and its underlying mechanisms. The study utilized two murine models that mimicked human MASLD disease: (i) a diet-induced MASH model; (ii) a MASH-HCC model induced by diet and a very low dose of CCl4. C57Bl/6 mice were fed with chow (CD) or western diet (WD) with normal (NW) or sugar water (SW) for 12 weeks, then randomized to receive either 5 kcal% green jackfruit flour (JF) or an equal volume of placebo flour (PB). The biochemical, histological, and molecular analyses were assessed. JF significantly reduced body weight, liver injury, insulin resistance, and alleviated obesity, steatosis, inflammation, fibrosis, and tumor development in WDSW or WDSW/CCl4 mice compared to placebo groups. Furthermore, JF activated AMPK (AMP-activated protein kinase) and inhibited MAPK (mitogen-activated protein kinase) signaling pathways in MASH and MASH-HCC experimental models, respectively. This was supported by sodium propionate treatment, the primary short-chain fatty acid entering the liver from JFs soluble fiber microbial fermentation, which also regulated AMPK and MAPK signaling in cellular models of MASH and HCC, respectively. Hence, our findings present strong evidence of JFs therapeutic potential in the prevention of MASH and MASH-HCC, warranting further investigation of JFs efficacy as a dietary intervention in clinical trials.

cancer biology↗

bioRxiv2023

Targeted inhibition of BET proteins in HPV-16 associated head and neck squamous cell carcinoma reveals heterogeneous transcription response

Integrated human papillomavirus (HPV-16) associated head and neck squamous cell carcinoma (HNSCC) tumors have worse survival outcomes compared to episomal HPV-16 HNSCC tumors. Therefore, there is a need to differentiate treatment for HPV-16 integrated HNSCC from other viral forms. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. However, the mechanism of BET protein-mediated transcription of viral-cellular genes in the integrated viral-HNSCC genomes needs to be better understood. We show that BET inhibition downregulates E6 significantly independent of the viral transcription factor, E2, and there was overall heterogeneity in the downregulation of viral transcription in response to the effects of BET inhibition across HPV-associated cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4 and mirrored downregulation of viral E6 and E7 expression. Strikingly, there was heterogeneity in the reactivation of p53 levels despite E6 downregulation, while E7 downregulation did not alter Rb levels significantly. We identified that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A expression. Overall, our studies show that BET inhibition provokes a G1-cell cycle arrest with apoptotic activity and suggests that BET inhibition regulates both viral and cellular gene expression in HPV-associated HNSCC.

cancer biology↗

bioRxiv2022

Tecomella undulata Improves Insulin Sensitivity by Attenuating Inflammation and Oxidative Stress in Experimental NASH

Background and AimThe pathophysiology of NASH is complex owing to its diverse pathological drivers, and until recently, there were no approved drugs for this disease. Tecomella undulata is a popular herbal medicine used to treat hepatosplenomegaly, hepatitis, and obesity. However, the potential role of Tecomella undulata in NASH has not yet been scientifically investigated. Experimental ProcedureMice fed with chow diet and normal water (CDNW) or western diet and sugar water (WDSW) for 12 weeks were randomized to receive vehicle control, Saroglitazar, or Tecomella undulata for an additional 12 weeks. Insulin resistance, lipid profiles, histological analysis, and liver enzymes were assessed. The oxidative stress, ER and inflammatory markers were determined by quantitative RT-PCR (qRT-PCR) and western blot analysis. Results and ConclusionThe administration of Tecomella undulata via oral gavage lowered body weight, insulin resistance, alanine transaminase (ALT), aspartate transaminase (AST), triglycerides, and total cholesterol in WDSW mice but had no effect on CDNW mice. Tecomella undulata improved steatosis, lobular inflammation, and hepatocyte ballooning and resolved NASH in WDSW mice. Furthermore, Tecomella undulata also alleviated the WDSW-induced ER stress and oxidative stress, enhanced antioxidant status, and thus reduced inflammation in the treated mice. Of note, these effects were on par with Saroglitazar, the approved drug used to treat human NASH and positive control used in the study. Thus, our findings indicate the potential of Tecomella undulata to ameliorate WDSW-induced steatohepatitis, and these preclinical data provide a strong rationale for assessing Tecomella undulata for the treatment of NASH in humans.

physiology↗