Jinhan He

Irisin Is Regulated by CAR in Liver and Is a Mediator of Hepatic Glucose and Lipid Metabolism

Irisin, a hormone proteolytically processed from fibronectin type III domain-containing protein 5 (FNDC5), has been reported to induce the browning of sc adipocytes by increasing the level of uncoupling protein 1. In this study, we showed that activation of the nuclear receptor constitutive androstane receptor induced FNDC5 mRNA expression in the liver and increased the circulating level of irisin in mice. FNDC5/irisin is a direct transcriptional target of constitutive androstane receptor. Hepatic-released irisin functioned as a paracrine/autocrine factor that inhibited lipogenesis and gluconeogenesis via the Adenosine 5-monophosphate (AMP)-activated protein kinase pathway. Adenovirus-overexpressed irisin improved hepatic steatosis and insulin resistance in genetic-induced obese mice. Irisin transgenic mice were also protected against high-fat diet-induced obesity and insulin resistance. In conclusion, our results reveal a novel pathway in regulating FNDC5/irisin expression and identify a physiological role for this hepatic hormone in glucose and lipid homeostasis.

Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet–Induced Obesity and Insulin Resistance by Inhibiting Lipolysis

Sirt6 is an NAD+-dependent deacetylase that is involved in the control of energy metabolism. However, the tissue-specific function of Sirt6 in the adipose tissue remains unknown. In this study, we showed that fat-specific Sirt6 knockout (FKO) sensitized mice to high-fat diet–induced obesity, which was attributed to adipocyte hypertrophy rather than adipocyte hyperplasia. The adipocyte hypertrophy in FKO mice likely resulted from compromised lipolytic activity as an outcome of decreased expression of adipose triglyceride lipase (ATGL), a key lipolytic enzyme. The suppression of ATGL in FKO mice was accounted for by the increased phosphorylation and acetylation of FoxO1, which compromises the transcriptional activity of this positive regulator of ATGL. Fat-specific Sirt6 KO also increased inflammation in the adipose tissue, which may have contributed to insulin resistance in high-fat diet–fed FKO mice. We also observed that in obese patients, the expression of Sirt6 expression is reduced, which is associated with a reduction of ATGL expression. Our results suggest Sirt6 as an attractive therapeutic target for treating obesity and obesity-related metabolic disorders.

Patients Aged 80 Years or Older are Encountered More Potentially Inappropriate Medication Use.

Background:Polypharmacy and potentially inappropriate medications (PIMs) are prominent prescribing issues in elderly patients. This study was to investigate the different prevalence of PIM use in elderly inpatients between 65–79 years of age and 80 years or older, who were discharged from Geriatric Department in West China Hospital. Methods:A large-scale cohort of 1796 inpatients aged 65 years or over was recruited. Respectively, 618 patients were 65–79 years and 1178 patients were 80 years or older. Updated 2012 Beers Criteria by the American Geriatric Society was applied to assess the use of PIM among the investigated samples. Results:A review of the prescribed medications identified 686 patients aged 80 years or older consumed at least one PIM giving a rate of 58.2%. Conversely, 268 (43.4%) patients aged 65–79 years consumed at least one PIM (&khgr;2 = 40.18, P < 0.001). Patients aged 80 years or older had higher hospitalization expenses, length of stay, co-morbidities, medical prescription, and mortality than patients aged 65–79 years (all with P < 0.001). Patients aged 80 years or older were prescribed with more benzodiazepines, drugs with strong anticholinergic properties, megestrol, antipsychotics, theophylline, and aspirin. In multiple regression analysis, PIM use was significantly associated with female gender, age, number of diagnostic disease, and number of prescribed medication. Conclusions:The finding from this study revealed that inpatients aged 80 years or older encountered more PIM use than those aged 65–79 years. Anticholinergic properties, megestrol, antipsychotics, theophylline, and aspirin are medications that often prescribed to inpatients aged 80 years or older. Doctors should carefully choose drugs for the elderly, especially the elderly aged 80 years or older.

Increased dosage of cyclosporine induces myopathy with increased seru creatine kinase in an elderly patient on chronic statin therapy

The concomitant administration of atorvastatin and cyclosporine has been shown to increase the serum concentration of 3‐hydroxy‐3‐methylglutaryl coenzyme A, which may be associated with the elevation of creatine kinase and an increased risk of myopathy. Our objective is to report on a case of statin‐induced myopathy associated with concomitant use of cyclosporine and other contributing factors.

Loss of 5‐lipoxygenase activity protects mice against paracetamol‐induced liver toxicity

Paracetamol (acetaminophen) is the most widely used over‐the‐counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5‐Lipoxygenase (5‐LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5‐LO could protect mice against paracetamol‐induced hepatic toxicity.

5‐Lipoxygenase ablation protects mice against acetaminophen‐induced liver toxicity

Paracetamol (acetaminophen) is the most widely used over‐the‐counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5‐Lipoxygenase (5‐LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5‐LO could protect mice against paracetamol‐induced hepatic toxicity.

Activation of Constitutive Androstane Receptor Prevents Cholesterol Gallstone Formation

Cholesterol gallstone disease (CGD) is one of the most common gastrointestinal diseases. Lithogenic hepatic bile secretion precedes the formation of cholesterol gallstones. Constitutive androstane receptor (CAR), a member of nuclear family, plays an important role in cholesterol and bile acid metabolism. To examine whether activation of CAR can prevent cholesterol gallstone formation, we treated C57BL6/J mice maintained on a lithogenic diet with CAR agonist 1,4-bis-[2-(3, 5-dichlorpyridyloxy)] benzene and performed bile duct cannulation to study the dynamics of biliary lipids. We report that activation of CAR decreases the biliary cholesterol concentration and prevents CGD formation. The lower biliary cholesterol level was largely attributed to suppressed Abcg5 and Abcg8 expression in CAR-activated mice. CAR activation also promoted cholesterol conversion into bile acids by increasing the expression of Cyp7a1, a rate-limiting enzyme in bile acid biosynthesis. Activation of CAR enhanced bile acid re-absorption via increasing the expression of bile acid transporters Asbt and Ostβ in the ileum. The hepatic steatosis was also improved in the liver of CAR-activated mice. Furthermore, activation of CAR protected the mice against the liver X receptor α-sensitized CGD through suppressing the expression of Abcg5/8. Collectively, CAR plays an important role in maintaining the homeostasis of cholesterol, bile acids, and triglycerides levels, and it might be a promising therapeutic target for preventing or treating CGD.

Design and Validation of PEG-Derivatized Vitamin E Copolymer for Drug Delivery into Breast Cancer

This study examined the ability of amphiphilic poly(ethylene glycol) (PEG) derivatives to assemble into micelles for drug delivery. Linear PEG chains were modified on one end with hydrophobic vitamin E succinate (VES), and PEG and VES were mixed in different molar ratios to make amphiphiles, which were characterized in terms of critical micelle concentration (CMC), drug loading capacity (DLC), serum stability, tumor spheroid penetration and tumor targeting in vitro and in vivo. The amphiphile PEG5K-VES6 (PAMV6), which has a wheat-like structure, showed a CMC of 3.03 × 10(-6) M, good serum stability, and tumor accumulation. The model drug, pirarubicin (THP), could be efficiently loaded into PAMV6 micelles at a DLC of 24.81%. PAMV6/THP micelles were more effective than THP solution at inducing cell apoptosis and G2/M arrest in 4T1 cells. THP-loaded PAMV6 micelles also inhibited tumor growth much more than free THP in a syngeneic mouse model of breast cancer. PAMV6-based micellar systems show promise as nanocarriers for improved anticancer chemotherapy.

Update meta-analysis of the CYP2E1 RsaI/PstI and DraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: evidence from 26 studies

Several studies have investigated the association of the CYP2E1 RsaI/PstI and/or DraI polymorphisms with susceptibility to antituberculosis drug‐induced hepatotoxicity (ATDH), but the results have been inconsistent. Therefore, we performed a large meta‐analysis to determine a more precise estimation of this relationship.

Potentially inappropriate medications in Chinese older adults: The beers criteria compared with the screening tool of older persons’ prescriptions criteria: Potentially inappropriate medications in China elderly

The present study aimed to assess the prevalence of potentially inappropriate medications (PIM) use in West China Hospital residents aged ≥65 years, using two sets of criteria – the Beers and Screening Tool of Older Persons’ Prescriptions (STOPP) criteria – and to compare the Beers and STOPP criteria, and to determine the better criteria for assessing PIM of older adults in China.