Dietary Supplementation with 20-Hydroxyecdysone Ameliorates Hepatic Steatosis and Reduces White Adipose Tissue Mass in Ovariectomized Rats Fed a High-Fat, High-Fructose Diet.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is defined as hepatic steatosis in combination with overweight, diabetes, or other metabolic risk factors. MAFLD affects a significant number of the global population and imposes substantial clinical and economic burdens. With no approved pharmacotherapy, current treatment options are limited to diet and exercise.

Molecular determinants of peri-apical targeting of inositol 1,4,5-trisphosphate receptor type 3 in cholangiocytes.

Fluid and bicarbonate secretion is a principal function of cholangiocytes, and impaired secretion results in cholestasis. Cholangiocyte secretion depends on peri-apical expression of the type 3 inositol trisphosphate receptor (ITPR3), and loss of this intracellular Ca release channel is a final common event in most cholangiopathies. Here we investigated the mechanism by which ITPR3 localizes to the apical region to regulate secretion.

Morphological alteration of the pancreatic islet in ovariectomized rats fed a high-fat high-fructose diet.

Diabetes and its complications are major causes of mortality worldwide. Type 2 diabetes coexists with insulin resistance and β-cell dysfunction, which are aggravated by overconsumption and estrogen-deprived conditions. However, the morphology of pancreatic islets in a combined condition of excessive caloric intake and estrogen deficiency has never been described.

Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis.

Background & Objectives: Alcoholic hepatitis (AH) is a common but life-threatening disease with limited treatment options. It is thought to result from hepatocellular damage, but the presence of cholestasis worsens prognosis, so we examined whether bile ducts participate in the pathogenesis of this disease.

Design: Cholangiocytes derived from human bile ducts were co-cultured with neutrophils from patients with AH or controls.

Inhibition of Adipogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by a Phytoestrogen Diarylheptanoid from .

We investigated the effect of a phytoestrogen, (3)-1,7-diphenyl-(4,6)-4,6-heptadien-3-ol (DPHD), from Roxb. (Zingiberaceae family) on the adipogenic differentiation of mesenchymal progenitors, human bone marrow-derived mesenchymal stem cells (hBMSCs). DPHD inhibited adipocyte differentiation of hBMSCs by suppressing the expression of genes involved in adipogenesis.

20-Hydroxyecdysone ameliorates metabolic and cardiovascular dysfunction in high-fat-high-fructose-fed ovariectomized rats.

Background: Ecdysteroids are polyhydroxylated steroids present in invertebrates and plants. 20-Hydroxyecdysone (20E) is the most common and the main biologically active compound of ecdysteroids. Previous studies have demonstrated anabolic and metabolic effects of 20E in mammals.

Type 3 Inositol 1,4,5-Trisphosphate Receptor Is Increased and Enhances Malignant Properties in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the second most common malignancy arising in the liver. It carries a poor prognosis, in part because its pathogenesis is not well understood. The type 3 inositol 1,4,5-trisphosphate receptor (ITPR3) is the principal intracellular calcium ion (Ca ) release channel in cholangiocytes, and its increased expression has been related to the pathogenesis of malignancies in other types of tissues, so we investigated its role in CCA.

Estrogen and voluntary exercise attenuate cardiometabolic syndrome and hepatic steatosis in ovariectomized rats fed a high-fat high-fructose diet.

The prevalence of cardiometabolic syndrome (CMS) is increased in women after menopause. While hormone replacement therapy has been prescribed to relieve several components of CMS in postmenopausal women, some aspects of cardiometabolic dysfunction cannot be completely restored. The present study examined the effectiveness of estrogen replacement alone and in combination with exercise by voluntary wheel running (VWR) for alleviating the risks of CMS, insulin-mediated skeletal muscle glucose transport, and hepatic fat accumulation in ovariectomized Sprague-Dawley rats fed a high-fat high-fructose diet (OHFFD).

Dysregulated microRNA expression profiles in cholangiocarcinoma cell-derived exosomes.

Aim: Cholangiocarcinoma (CCA) is a malignant tumor of bile duct epithelial cells. The prognosis of CCA is poor due to lack of effective therapeutic targets and detection at an advanced stage. Exosomes are secreted nano-sized vesicles and contribute to the malignancy of several cancers via transferring their miRNAs between cells.

Effects of Endotoxin on Type 3 Inositol 1,4,5-Trisphosphate Receptor in Human Cholangiocytes.

Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis (AH), often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide (LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion.

Curcuma comosa reduces visceral adipose tissue and improves dyslipidemia in ovariectomized rats.

Ethnopharmacological Relevance: Curcuma comosa Roxb. (C. comosa) or Wan chak motluk Zingiberaceae family, is widely used in Thai traditional medicine for treatment of gynecological problems as well as relief of postmenopausal symptoms.

Nonalcoholic fatty liver disease impairs expression of the type II inositol 1,4,5-trisphosphate receptor.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide. It may result in several types of liver problems, including impaired liver regeneration (LR), but the mechanism for this is unknown. Because LR depends on calcium signaling, we examined the effects of NAFLD on expression of the type II inositol 1,4,5-trisphosphate receptor (ITPR2), the principle calcium release channel in hepatocytes.

Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver.

The role of gender in the progression of fatty liver due to chronic high-fat high-fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were fed either a control diet or HFFD for 12 wk.

Type 2 inositol trisphosphate receptor gene expression in hepatocytes is regulated by cyclic AMP.

The type 2 inositol 1,4,5-trisphosphate receptor (IP3R2) is the principal intracellular Ca release channel in hepatocytes, and so is important for bile secretion and other functions. IP3R2 activity is regulated in part by post-translational modifications but little is known about transcriptional regulation of its expression. We found that both IP3R2 mRNA and protein levels in liver were increased during fasting.

Effects of andrographolide on intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats.

Cholestasis is a cardinal manifestation of liver diseases but effective therapeutic approaches are limited. Therefore, alternative therapy for treating and preventing cholestatic liver diseases is necessary. Andrographolide, a promising anticancer drug derived from the medicinal plant Andrographis paniculata, has diverse pharmacological properties and multi-spectrum therapeutic applications.

Nuclear Factor, Erythroid 2-Like 2 Regulates Expression of Type 3 Inositol 1,4,5-Trisphosphate Receptor and Calcium Signaling in Cholangiocytes.

Background & Aims: Most cholestatic disorders are caused by defects in cholangiocytes. The type 3 isoform of the inositol 1,4,5-trisphosphate receptor (ITPR3) is the most abundant intracellular calcium release channel in cholangiocytes. ITPR3 is required for bicarbonate secretion by bile ducts, and its expression is reduced in intrahepatic bile ducts of patients with cholestatic disorders.

Induction of apoptosis in cholangiocarcinoma by an andrographolide analogue is mediated through topoisomerase II alpha inhibition.

Cholangiocarcinoma (CCA), the common primary malignant tumor of bile duct epithelial cells, is unresponsive to most chemotherapeutic drugs. Diagnosis with CCA has a poor prognosis, and therefore urgently requires effective therapeutic agents. In the present study we investigated anti-cancer effects of andrographolide analogue 3A.

Bone sparing effect of a novel phytoestrogen diarylheptanoid from Curcuma comosa Roxb. in ovariectomized rats.

Phytoestrogens have been implicated in the prevention of bone loss in postmenopausal osteoporosis. Recently, an active phytoestrogen from Curcuma comosa Roxb, diarylheptanoid (DPHD), (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol, was found to strongly promote human osteoblast function in vitro. In the present study, we demonstrated the protective effect of DPHD on ovariectomy-induced bone loss (OVX) in adult female Sprague-Dawley rats with 17β-estradiol (E2, 10 µg/kg Bw) as a positive control.

Deleterious effect of oltipraz on extrahepatic cholestasis in bile duct-ligated mice.

Background & Aims: Oltipraz (4-methyl-5(pyrazinyl-2)-1-2-dithiole-3-thione), a promising cancer preventive agent, has an antioxidative activity and ability to enhance glutathione biosynthesis, phase II detoxification enzymes and multidrug resistance-associated protein-mediated efflux transporters. Oltipraz can protect against hepatotoxicity caused by carbon tetrachloride, acetaminophen and alpha-naphthylisothiocyanate. Whether oltipraz has hepato-protective effects on obstructive cholestasis is unknown.

Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine.

The transcription factor nuclear factor-E2-related factor 2 (Nrf2) is a key regulator for induction of hepatic detoxification and antioxidant mechanisms, as well as for certain hepatobiliary transporters. To examine the role of Nrf2 in bile acid homeostasis and cholestasis, we assessed the determinants of bile secretion and bile acid synthesis and transport before and after bile duct ligation (BDL) in Nrf2(-/-) mice. Our findings indicate reduced rates of biliary bile acid and GSH excretion, higher levels of intrahepatic bile acids, and decreased expression of regulators of bile acid synthesis, Cyp7a1 and Cyp8b1, in Nrf2(-/-) compared with wild-type control mice.

A protective effect of Curcuma comosa Roxb. on bone loss in estrogen deficient mice.

Ethnopharmacological Relevance: Curcuma comosa Roxb. or Wan chak motluk is an indigenous medicinal herb and has traditionally been used among postmenopausal women for relief of unpleasant menopausal symptoms.

Aim Of The Study: Estrogen deficiency is a causative factor in the development of osteoporosis in menopausal women.

Aryl hydrocarbon receptor and NF-E2-related factor 2 are key regulators of human MRP4 expression.

Multidrug resistance protein 4 (MRP4; ABCC4) is an ATP binding cassette transporter that facilitates the excretion of bile salt conjugates and other conjugated steroids in hepatocytes and renal proximal tubule epithelium. MRP4/Mrp4 undergoes adaptive upregulation in response to oxidative and cholestatic liver injury in human and animal models of cholestasis. However, the molecular mechanism of this regulation remains to be determined.

Protection of centrilobular necrosis by Curcuma comosa Roxb. in carbon tetrachloride-induced mice liver injury.

Aim Of The Study: To investigate the protective effect and possible mechanism of Curcuma comosa hexane extract on CCl(4)-induced liver injury in adult male mice.

Materials And Methods: Hepatotoxicity was induced by an intraperitoneal injection of CCl(4) and was evaluated after 24 h from the elevations of plasma alanine transaminase (ALT) and aspartate transaminase (AST) activities, and histological analysis of liver injuries. Hexane extract of Curcuma comosa was given at different time points from 1 to 72 h, prior to CCl(4) administration and the protection from liver injury was assessed.

Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression.

Unlabelled: The bile salt export pump (BSEP) is the major determinant of bile salt-dependent bile secretion, and its deficiency leads to cholestatic liver injury. BSEP/Bsep gene expression is regulated by the nuclear farnesoid X receptor. However, BSEP expression, though reduced, is retained in the livers of Fxr(-/-) mice, indicating that additional transcriptional factors may regulate its expression.

Identification of transport pathways for citric acid cycle intermediates in the human colon carcinoma cell line, Caco-2.

Citric acid cycle intermediates are absorbed from the gastrointestinal tract through carrier-mediated mechanisms, although the transport pathways have not been clearly identified. This study examines the transport of citric acid cycle intermediates in the Caco-2 human colon carcinoma cell line, often used as a model of small intestine. Inulin was used as an extracellular volume marker instead of mannitol since the apparent volume measured with mannitol changed with time.