Biology subjects

Kumar, D. P.

Publications and source records attributed to Kumar, D. P..

3 recordsLinked to original sources

bioRxiv2023

Curcumin Ameliorates AATF-mediated Liver Damage and Inflammation to Cancer in NASH-HCC

In tandem with the expanding obesity pandemic, the prevalence of metabolic dysfunction associated steatohepatitis (MASH, formerly known as NASH)-driven hepatocellular carcinoma (HCC) is predicted to rise globally, creating a significant need for therapeutic interventions. We previously identified the upregulation of apoptosis antagonizing transcription factor (AATF), which is implicated in facilitating the progression from MASH to HCC. The objective of this study was to examine whether the intervention of curcumin could alleviate AATF-mediated MASH, inhibit tumor growth, and elucidate the underlying mechanism. A preclinical murine model mimicking human MASH-HCC was employed, subjecting mice to either a chow diet normal water (CDNW) or western diet sugar water (WDSW) along with very low dose of carbon tetrachloride (CCl4-0.2 l/g, weekly). Mice receiving curcumin (CUR) alongside WDSW/CCl4 exhibited significant improvements, including reduced liver enzymes, dyslipidemia, steatosis, inflammation, and hepatocellular ballooning. Curcumin treatment also suppressed hepatic expression of inflammatory, fibrogenic, and oncogenic markers. Of note, there was a significant reduction in the expression of AATF upon curcumin treatment in WDSW/CCl4 mice and human HCC cells. In contrast, curcumin upregulated Kruppel-like factor 4 (KLF4) in MASH liver and HCC cells, which is known to downregulate sp1 (specificity protein-1) expression. Thus, curcumin treatment effectively inhibited the progression of MASH to HCC by downregulating the expression of AATF via the KLF4-Sp1 signaling pathway. These preclinical findings establish a novel molecular connection between curcumin and AATF in reducing hepatocarcinogenesis, and provide a strong rationale for the development of curcumin as a viable treatment for MASH-HCC in humans.

cancer biology↗

bioRxiv2022

AATF Inhibition Exerts Antiangiogenic Effects AgainstHuman Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC), a highly fatal cancer with a mortality rate proportional to its incidence, continues to pose a global health care challenge. Angiogenesis is a key factor in the growth and metastasis of hepatic tumors and thus a potential therapeutic target in HCC. We previously showed that the apoptosis antagonizing transcription factor (AATF) affects tumor growth and metastasis in a mouse xenograft model. However, the regulatory role of AATF in tumor angiogenesis and its underlying mechanisms in HCC remain unknown. In the current study, we identified high levels of AATF in human HCC tissues compared to adjacent normal liver tissues, and the expression was found to be correlated with the stages and tumor grades of HCC. Inhibition of AATF in human HCC cells showed high levels of pigment epithelium-derived factor (PEDF) compared to controls as a resultant of reduced matric metalloproteinases activity. Conditioned media from AATF knockdown (KD) cells inhibited the proliferation, migration, and invasion of human umbilical vein endothelial cells as well as the vascularization of the chick chorioallantoic membrane. Furthermore, the VEGF-mediated downstream signaling pathway responsible for endothelial cell survival and vascular permeability, cell proliferation, and migration favoring angiogenesis was suppressed by AATF inhibition. Of note, PEDF inhibition by its respective antibody profoundly reversed the anti-angiogenic effect of AATF KD. In conclusion, our study demonstrates that inhibition of AATF suppresses angiogenesis in HCC via PEDF. Thus, a therapeutic strategy based on the inhibition of AATF to disrupt tumor angiogenesis may be a promising approach for HCC treatment.

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↗