噻唑烷二酮类药物对骨作用的利弊比较 ——————- PPARγ2与骨的研究进展

最近,有关噻唑烷二酮类药物的使用又出现了争议,美国食品和药品监督局（ＦＤＡ）甚至要求医生少用或不用该药。两年前,文迪亚导致骨折和心血管事件的报道时有出现。因此,这类药物的治疗作用和副作用成为学术界争论的热点。目前研究表明,PPARγ2在调节糖脂代谢,机体抗炎等方面发挥重要的作用。但最近一些大型临床研究结果显示,TZDs使用可增加绝经后糖尿病老年妇女骨折的风险[1][2]。事物总有它的两面性,这是符合唯物主义辩证法规律的。因此,全方位了解噻唑烷二酮类药物作用对于更好地防治糖尿病,防治骨质疏松等疾病具有重要的现实意义。关于过氧化物酶配体增殖物激活受体γ2（PPARγ2）对骨代谢的影响近年来报道结果众说不一。我们结合自己的工作浅谈这类药物的应用前景。     

Aging and enhanced hepatocarcinogenicity by peroxisome proliferator-activated receptor alpha agonists

The hepatocarcinogenic effect of PPARalpha agonists is enhanced by aging. Exposure to these chemicals produces a five- to seven-fold higher yield of grossly visible hepatic tumors in old relative to young animals. This review presents current experimental evidence, which supports a mechanism involving enhanced exposure to oxidative stress, and diminished apoptosis in this age-related difference in sensitivity. In the aged liver, a decrease in hepatic antioxidant activity, coupled with a PPARalpha agonist-induced increase in the activities of various oxidases, may expose these livers to oxidative stress. Additionally, livers of senescent animals appeared more sensitive to the anti-apoptotic effect of PPARalpha agonists. Since apoptosis safeguards cells with damaged DNA from progressing to the point of tumor formation, inhibition of hepatocellular apoptosis by PPARalpha agonists could well lead to the formation of focal lesions in the aged liver. Although PPARalpha-dependent alterations in cell cycle regulatory proteins have been reported, the correlation between hepatocellular DNA replication and liver cancer caused by PPARalpha agonists is a weak one. These findings have implications for human susceptibility to these chemicals.     

Anti-diabetic effects of Centratherum anthelminticum seeds methanolic fraction on pancreatic cells, β-TC6 and its alleviating role in type 2 diabetic rats

Ethnopharmacological relevance

Seeds of Centratherum anthelminticum (Asteraceae) have been popularly used in Ayurvedic medicine to treat diabetes and skin disorders. Folk medicine from Rayalaseema (Andhra Pradesh, India) reported wide spread usage in diabetes.

Aim of the study

To investigate the hypoglycemic properties and mechanism of the methanolic fraction of C. anthelminticum seeds (CAMFs) on mouse β-TC6 pancreatic cell line and streptozotocin (STZ)-induced diabetic rat models.

Materials and Methods

We investigated the crude methanolic fraction of C. anthelminticum seeds (CAMFs) on β-TC6 cell line and confirmed its effects on type 1 and type 2 diabetic rats to understand its mechanism in managing diabetes mellitus. CAMFs were initially tested on β-TC6 cells for cytotoxicity, 2-NBDG glucose uptake, insulin secretion and glucose transporter (GLUT-1, 2 and 4) protein expression. Furthermore, streptozotocin (STZ)-induced type 1 diabetic and STZ-nicotinamide-induced type 2 diabetic rats were intraperitoneally (i.p) injected or administered orally with CAMFs daily for 28 days. The effect of CAMFs on blood glucose and insulin levels was subsequently evaluated.

Results

In cell line studies, CAMFs showed non-cytotoxic effect on β-TC6 cell proliferation compared to untreated control cells at 50 μg/ml. CAMFs increased glucose uptake and insulin secretion dose-dependently by up-regulating GLUT-2 and GLUT-4 expression in these cells. Further in vivo studies on streptozotocin induced diabetic rat models revealed that CAMFs significantly reduced hyperglycemia by augmenting insulin secretion in type 2 diabetic rats. However, CAMFs displayed less significant effects on type 1 diabetic rats.

Conclusions

CAMFs demonstrated anti-diabetic potential on β-TC6 cells and type 2 diabetic rat model, plausibly through enhancing glucose uptake and insulin secretion.     

脓毒症研究新进展

脓毒症正逐渐成为全世界严峻的医学问题,脓毒症的发病率与病死率逐年上升,然而脓毒症的临床治疗并未取得理想的效果,可能归咎于其复杂的病理生理过程和尚未完全揭示的发病机制。近年来研究发现,氧化还原反应失衡、过氧化物酶增生物激活受体的功能下降、补体的激活与释放、神经调节紊乱、免疫麻痹等参与了脓毒症的发病机制,有助于我们对脓毒症的进一步认识。至此,本文将对这些新机制加以综述。     

Managing diabetes and liver disease association

There is strong association between liver diseases and diabetes (DM) which is higher than expected by a chance association of two very common disorders. It can be classified into three categories: Liver disease related to diabetes, hepatogenous diabetes (HD), and liver disease occurring coincidentally with DM. The criteria for the diagnosis of diabetes associating liver disease are the same for primary diabetes. Two hours post glucose load is a better screening test for HD. HbA1c may not be suitable for diagnosis or monitoring of diabetes associating advanced liver disease. Apart from the increased cardiovascular risk in patients with type 2 DM (T2 DM) and NAFLD, the cardiovascular and retinopathy risk is low in HD. Patients with metabolic derangement should be screened for NAFLD which in turn may predict T2 DM development. Similarly, patients with established T2 DM should also be screened for NAFLD which further contributes to diabetes worsening.Diabetes is a significant risk factor for progression of the chronic liver disease. It is associated with poor patient survival.Treatment of diabetes associating liver disease appears beneficial. Metformin, if tolerated and not contraindicated, is recommended as a first-line therapy for patients with diabetes and chronic liver disease (CLD). If the hepatic disease is severe, insulin secretagogues should be avoided because of the increased risk of hypoglycaemia. Pioglitazone may be useful in patients with fatty liver disease. DPP-4 inhibitors showed effectiveness and safety for the treatment of T2 DM in CLD patients up to those with child B stage. GLP-1 receptor agonists and SGLT-2 inhibitors exhibit positive effects on weight and are associated with minimal risk of hypoglycaemia. Insulin must be used with caution, as hypoglycaemia may be a problem. Insulin analogues are preferred in the context of hypoglycaemiaStatins can be used to treat dyslipidaemia in NAFLD, also the use of angiotensin II receptor antagonist for hypertension is safe and beneficialGiven the clear association between diabetes mellitus and hepatocellular carcinoma, the strict control of glycaemia with insulin sensitizers can be essential in its prevention.The addition of DM to the currently used scores (Child-Pugh and MELD scores) may enhance the sensitivity and the specificity for prediction of morbidity and mortality rates in cirrhotic patients.In the new era of directly acting antiviral agents (DAAs) for HCV treatment, it is recommended to follow up lipid profile and blood sugar levels following SVR in order to adjust doses of medications used in diabetic (SVR is associated with reduction in insulin requirements) and dyslipidaemic patients (rebound increase in the lipid profile after clearing the virus may increase risk of cardiovascular disease (CVD)). The issues of post liver transplant diabetes and relation between DM and chronic HBV are highlighted.This narrative review and Consensus-based practice guidance (under revision and criticism) are based on a formal review and analysis of the recently published world literature on the topic (Medline search up to September 2017); and the experience of the authors and independent reviewers.     

PPARs与皮肤病的关系研究进展

过氧化物酶体增殖物激活受体（PPARs）在过氧化物酶体增殖、脂肪生成、B氧化增加和细胞周期的调节等方面起着重要作用，它在皮肤生理及病理方面的作用逐渐受到重视。PPARct影响皮肤的成熟、分化和增殖，皮肤外伤后，PPARβ／δ一直保持表达直到创口愈合。PPARs对皮脂形成、皮肤肿瘤发展有不同的影响，在银屑病和色素性皮肤病中也起一定的作用。这些发现可为治疗皮肤病提供新途径。