Background & Aims:The mechanisms by which the I148M mutant variant of the patatin-like phospholip... more Background & Aims:The mechanisms by which the I148M mutant variant of the patatin-like phospholipase domain-containing 3 (PNPLA3I148M) drives development of nonalcoholic steatohepatitis (NASH) is not known. The aim of this study was to obtain insights on mechanisms underlying PNPLA3I148M induced acceleration of NASH.Approach & Results:Hepatocyte-specific overexpression of empty vector (Luc), human wild-type PNPLA3 (PNPLA3WT), or PNPLA3I148M was achieved using adeno-associated virus (AAV)-8 in DIAMOND mice followed by chow diet or high fat Western diet with ad lib administration of sugar in drinking water (WDSW) for 8 weeks. Under WDSW, PNPLA3I148M overexpression accelerated steatohepatitis with increased steatosis, inflammation ballooning and fibrosis (p< 0.001 vs other groups for all). Silencing PNPLA3I148M after its initial overexpression abrogated these findings. PNPLA3I148M caused 22:6n3 docosahexanoic acid depletion and increased ceramides under WDSW in addition to increasing triglycerides and diglycerides especially enriched with unsaturated fatty acids. It also increased oxidative stress and ER-stress. Increased total ceramides was associated with STAT3 activation with downstream activation of multiple immune-inflammatory pathways at a transcriptomic level by network analyses. Silencing PNPLA3I148M reversed STAT3 activation. Conditioned media from HepG2 cells overexpressing PNPLA3I148M increased procollagen mRNA expression in LX2 cells; this was abrogated by hepatocyte STAT3 inhibition.Conclusions:Under WDSW, PNPLA3I148M overexpression promotes steatosis and NASH by metabolic reprogramming characterized by increased triglycerides and diglycerides, n3 PUFA depletion and increased ceramides with resultant STAT3 phosphorylation and downstream inflammatory pathway activation driving increased stellate cell fibrogenic activity.
AimsTo explore the hepatoprotective role of quercetin and its novel molecular mechanism of action... more AimsTo explore the hepatoprotective role of quercetin and its novel molecular mechanism of action on breast cancer associated hepatic inflammation and fibrosis via Vitamin D receptor (VDR).Main methodsWe used Ehrlich Ascites Carcinoma (mouse mammary carcinoma) model for our in-vivo experiments and human breast cancer cell lines for in-vitro assays. We inoculated 1.5 × 106 Ehrlich ascites carcinoma cells into female Swiss albino mice. Quercetin (50 mg/kg) was administered intraperitoneally for 15 days. Liver enzymes activity was determined using a spectrophotometric assay. The hallmarks of inflammation and fibrosis were determined using Immunohistochemistry. The effect of quercetin on tumor formation was elucidated using human breast cancer cell lines and chick chorioallantoic membrane assay. Docking study was performed to explore the binding mode of quercetin with VDR.Key findingsIn EAC tumor-bearing mice, cell numbers, tumor volume, body weight and liver weight were dramatically in...
ABSTRACTHepatocellular carcinoma (HCC), a highly fatal cancer with a mortality rate proportional ... more ABSTRACTHepatocellular 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 t...
Development of the vascular system in humans is a complex process that involves formation, retent... more Development of the vascular system in humans is a complex process that involves formation, retention, regression, and reconnection of primitive vascular channels, ultimately forming a definite pattern of the venous vascular architecture. Any errors in these processes would lead to anomalous venous structures, which would pose severe diagnostic and therapeutic challenges. Herein, we report a case of left-sided inferior vena cava that was noticed in the posterior abdominal wall of a male cadaver aged about 80 years. Although venous anomalies are common in their occurrence, a left-sided transposition of the inferior vena cava is a rare and significant finding in retroperitoneal surgeries because this can be misdiagnosed as para-aortic lymphadenopathy, a tumor or dilated gonadal vein that may result in iatrogenic damage during surgeries. The unusual location and course of the inferior vena cava and its embryological basis are discussed in this case.
Cancers are known to have multifactorial etiology. Certain bacteria and viruses are proven carcin... more Cancers are known to have multifactorial etiology. Certain bacteria and viruses are proven carcinogens. Lately, there has been in-depth research investigating carcinogenic capabilities of some bacteria. Reports indicate that chronic inflammation and harmful bacterial metabolites to be strong promoters of neoplasticity. Helicobacter pylori-induced gastric adenocarcinoma is the best illustration of the chronic inflammation paradigm of oncogenesis. Chronic inflammation, which produces excessive reactive oxygen species (ROS) is hypothesized to cause cancerous cell proliferation. Other possible bacteria-dependent mechanisms and virulence factors have also been suspected of playing a vital role in the bacteria-induced-cancer(s). Numerous attempts have been made to explore and establish the possible relationship between the two. With the growing concerns on anti-microbial resistance and over-dependence of mankind on antibiotics to treat bacterial infections, it must be deemed critical to u...
The liver is one of the vital organs in human beings. It is responsible for several functions suc... more The liver is one of the vital organs in human beings. It is responsible for several functions such as energy homeostasis, detoxification, regulating blood sugar levels, protein synthesis, bile acid secretion, cholesterol production and glycogen storage. Hepatocellular Carcinoma (HCC) alternately referred to as malignant hepatoma accounts to ~75% of all liver cancers and its resistance to therapeutics at progressed stages makes it lethal. Some of the main causes of HCC include HBV, HCV, aflatoxin, chronic alcoholism, excess nutrition, liver cirrhosis, iron over load, Wilson's disease, and type 2 diabetes. It is essential to detect the underlying causes of HCC at the cellular and molecular levels to develop drugs and find a potential cure for the disease. Several ongoing studies on HCC cell lines help to understand the gene expressions, multiple signaling pathways and differential drug responses to HCC. This review article provides insights to the possible molecular pathways invol...
Background & Aims:The mechanisms by which the I148M mutant variant of the patatin-like phospholip... more Background & Aims:The mechanisms by which the I148M mutant variant of the patatin-like phospholipase domain-containing 3 (PNPLA3I148M) drives development of nonalcoholic steatohepatitis (NASH) is not known. The aim of this study was to obtain insights on mechanisms underlying PNPLA3I148M induced acceleration of NASH.Approach & Results:Hepatocyte-specific overexpression of empty vector (Luc), human wild-type PNPLA3 (PNPLA3WT), or PNPLA3I148M was achieved using adeno-associated virus (AAV)-8 in DIAMOND mice followed by chow diet or high fat Western diet with ad lib administration of sugar in drinking water (WDSW) for 8 weeks. Under WDSW, PNPLA3I148M overexpression accelerated steatohepatitis with increased steatosis, inflammation ballooning and fibrosis (p< 0.001 vs other groups for all). Silencing PNPLA3I148M after its initial overexpression abrogated these findings. PNPLA3I148M caused 22:6n3 docosahexanoic acid depletion and increased ceramides under WDSW in addition to increasing triglycerides and diglycerides especially enriched with unsaturated fatty acids. It also increased oxidative stress and ER-stress. Increased total ceramides was associated with STAT3 activation with downstream activation of multiple immune-inflammatory pathways at a transcriptomic level by network analyses. Silencing PNPLA3I148M reversed STAT3 activation. Conditioned media from HepG2 cells overexpressing PNPLA3I148M increased procollagen mRNA expression in LX2 cells; this was abrogated by hepatocyte STAT3 inhibition.Conclusions:Under WDSW, PNPLA3I148M overexpression promotes steatosis and NASH by metabolic reprogramming characterized by increased triglycerides and diglycerides, n3 PUFA depletion and increased ceramides with resultant STAT3 phosphorylation and downstream inflammatory pathway activation driving increased stellate cell fibrogenic activity.
AimsTo explore the hepatoprotective role of quercetin and its novel molecular mechanism of action... more AimsTo explore the hepatoprotective role of quercetin and its novel molecular mechanism of action on breast cancer associated hepatic inflammation and fibrosis via Vitamin D receptor (VDR).Main methodsWe used Ehrlich Ascites Carcinoma (mouse mammary carcinoma) model for our in-vivo experiments and human breast cancer cell lines for in-vitro assays. We inoculated 1.5 × 106 Ehrlich ascites carcinoma cells into female Swiss albino mice. Quercetin (50 mg/kg) was administered intraperitoneally for 15 days. Liver enzymes activity was determined using a spectrophotometric assay. The hallmarks of inflammation and fibrosis were determined using Immunohistochemistry. The effect of quercetin on tumor formation was elucidated using human breast cancer cell lines and chick chorioallantoic membrane assay. Docking study was performed to explore the binding mode of quercetin with VDR.Key findingsIn EAC tumor-bearing mice, cell numbers, tumor volume, body weight and liver weight were dramatically in...
ABSTRACTHepatocellular carcinoma (HCC), a highly fatal cancer with a mortality rate proportional ... more ABSTRACTHepatocellular 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 t...
Development of the vascular system in humans is a complex process that involves formation, retent... more Development of the vascular system in humans is a complex process that involves formation, retention, regression, and reconnection of primitive vascular channels, ultimately forming a definite pattern of the venous vascular architecture. Any errors in these processes would lead to anomalous venous structures, which would pose severe diagnostic and therapeutic challenges. Herein, we report a case of left-sided inferior vena cava that was noticed in the posterior abdominal wall of a male cadaver aged about 80 years. Although venous anomalies are common in their occurrence, a left-sided transposition of the inferior vena cava is a rare and significant finding in retroperitoneal surgeries because this can be misdiagnosed as para-aortic lymphadenopathy, a tumor or dilated gonadal vein that may result in iatrogenic damage during surgeries. The unusual location and course of the inferior vena cava and its embryological basis are discussed in this case.
Cancers are known to have multifactorial etiology. Certain bacteria and viruses are proven carcin... more Cancers are known to have multifactorial etiology. Certain bacteria and viruses are proven carcinogens. Lately, there has been in-depth research investigating carcinogenic capabilities of some bacteria. Reports indicate that chronic inflammation and harmful bacterial metabolites to be strong promoters of neoplasticity. Helicobacter pylori-induced gastric adenocarcinoma is the best illustration of the chronic inflammation paradigm of oncogenesis. Chronic inflammation, which produces excessive reactive oxygen species (ROS) is hypothesized to cause cancerous cell proliferation. Other possible bacteria-dependent mechanisms and virulence factors have also been suspected of playing a vital role in the bacteria-induced-cancer(s). Numerous attempts have been made to explore and establish the possible relationship between the two. With the growing concerns on anti-microbial resistance and over-dependence of mankind on antibiotics to treat bacterial infections, it must be deemed critical to u...
The liver is one of the vital organs in human beings. It is responsible for several functions suc... more The liver is one of the vital organs in human beings. It is responsible for several functions such as energy homeostasis, detoxification, regulating blood sugar levels, protein synthesis, bile acid secretion, cholesterol production and glycogen storage. Hepatocellular Carcinoma (HCC) alternately referred to as malignant hepatoma accounts to ~75% of all liver cancers and its resistance to therapeutics at progressed stages makes it lethal. Some of the main causes of HCC include HBV, HCV, aflatoxin, chronic alcoholism, excess nutrition, liver cirrhosis, iron over load, Wilson's disease, and type 2 diabetes. It is essential to detect the underlying causes of HCC at the cellular and molecular levels to develop drugs and find a potential cure for the disease. Several ongoing studies on HCC cell lines help to understand the gene expressions, multiple signaling pathways and differential drug responses to HCC. This review article provides insights to the possible molecular pathways invol...
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Papers by Prasanna K. Santhekadur