Effects and mechanism of Morus alba L. (Sangzhi) alkaloids combined with metformin on glucose metabolism in diabetic KKAy mice / 药学学报

To investigate the effects and mechanism of the combination of Morus alba L. (Sangzhi) alkaloids(SZ-A) and metformin (Met) on glucose metabolism in type 2 diabetic mice, KKAy mice were divided into four groups according to the glucose and lipid indexes: control group (control), Morus alba L. (Sangzhi) alkaloids group (SZ-A, 100 mg·kg-1), metformin group (Met, 100 mg·kg-1) and combined administration group (combination, Comb, 100 mg·kg-1 SZ-A + 100 mg·kg-1 Met). All groups were administered by gavage once daily for 7 weeks accompanied with monitoring food intake, water intake, body weight as well as glycemia. Additionally, oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and oral sodium pyruvate tolerance test (OPTT) were performed at week 2, week 5, week 6, respectively. The experiments were approved by the Institutional Animal Care and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (00004332). We determined the weight and lipid content of liver, and then performed the histopathological analysis after sacrificed. Furthermore, Western blot assay was used to detect the protein levels of key molecules of PI3K/PDK1/Akt/GLUT signaling pathway in liver, muscle and adipose tissue. Compared to the SZ-A or Met monotherapy group, SZ-A + Met significantly improved the glucose metabolism disorder, which was showed in reduced food intake, water intake, the level of fasting blood glucose, postprandial blood glucose and glycosylated hemoglobin A1c (HbA1c) of KKAy mice, as well as improved glucose tolerance, enhanced insulin sensitivity and inhibited gluconeogenesis. In addition, SZ-A + Met obviously up-regulated the protein expression levels in PI3K/PDK1/Akt/GLUT signaling pathway in liver, muscle and adipose tissue of KKAy mice. Moreover, the liver lipid accumulation and blood aminotransferase level of KKAy mice in the combined administration group were significantly reduced. Therefore, we concluded that the combination of SZ-A and Met improved glucose metabolism and inhibited the occurrence and development of T2DM via promoting glucose uptake and utilization, suggesting that the combination of SZ-A and Met is a more useful treatment for T2DM.

The effect and mechanism of metformin on peripheral neuropathy in type 1 diabetic rats / 药学学报

Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications occurring in both type 1 and type 2 diabetes mellitus patients, which often results in patients suffering from severe hyperalgesia and allodynia. Up to now, the clinical therapeutic effect of DPN is still unsatisfactory. Metformin is an anti-diabetic drug that has been safely and widely used for the treatment of type 2 diabetes for decades. Studies have shown that metformin can improve pain caused by DPN, but its effects on the nerve conduction velocity and morphology of the sciatic nerve of DPN, and the mechanism for improving DPN are not clear. Therefore, the STZ-induced model of type 1 DPN in SD rats was used to study the effects of metformin on DPN, and to preliminarily explore its mechanism in this study. All animal experiments were carried out with approval of the Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica (Chinese Academy of Medical Sciences and Peking Union Medical College). After the model was established successfully, STZ diabetic rats were randomly divided into a model group and a metformin treatment group, and 10 normal SD rats were selected as the normal control group, and the rats were intragastrically administered for 12 weeks. The results showed that metformin significantly reduced blood glucose, glycosylated hemoglobin, food consumption and water consumption in STZ rats. Metformin markedly increased the motor nerve conduction velocity and mechanical stabbing pain threshold, prolonged the hot plate latency threshold, and improved the pathological morphological abnormalities of the sciatic nerve in STZ rats. In addition, metformin increased the content of glutathione (GSH), enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and reduced the content of malondialdehyde (MDA) in serum and sciatic nerve of STZ diabetic rats, as well as regulating the expression of genes related to oxidative stress in the sciatic nerve. Metformin obviously reduced the levels of pro-inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 in the serum in STZ rats, and inhibited the gene expression of these inflammatory factors in the sciatic nerve. In summary, metformin significantly increased nerve conduction velocity, improved sciatic nerve morphological abnormalities and pain in DPN rats, which may be related to its effect in improving oxidative stress and reducing inflammation.

Efficacy and Safety of Mulberry Twig Alkaloids Tablet for Treatment of Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Multicenter Clinical Study / 中国结合医学杂志

OBJECTIVE@#To assess the efficacy and safety of mulberry twig alkaloids (Sangzhi alkaloids, SZ-A) for treatment of type 2 diabetes in a randomized, double-blind, placebo-controlled multicenter clinical trial.@*METHODS@#A total of 200 patients were randomized to receive SZ-A (n=100) or placebo (n=100) for 16 weeks. The data analysis system for electronic data capture clinical trial central randomization system was used for randomization and dispensing of drugs. The primary outcome was the change in glycosylated hemoglobin (HbA1c) level. The secondary outcome included the proportions of cases with HbA1c <7.0% and HbA1c <6.5%, fasting blood glucose (FBG), postprandial blood glucose (PBG), area under curve for the PBG (AUC0-2h), body weight, and body mass index (BMI). Adverse events (AEs), severe adverse events (SAEs), treatment-related adverse events (TAEs), gastrointestinal disorders (GDs), blood pressure, routine blood tests, and liver and kidney function were monitored.@*RESULTS@#Compared with baseline, the change of HbA1c at week 16 was -0.80% (95% CI: -0.98% to -0.62%) and -0.09% (95% CI: -0.27% to 0.09%) in SZ-A group and placebo group, respectively. The proportion of patients with HbA1c <7% and <6.5% was higher in the SZ-A group than in the placebo group (46.8% vs. 21.6% and 29.9% vs. 10.8%). The observed values and changes in FBG, 1 h-PBG, 2 h-PBG, and AUC0-2h differed significantly between groups (P<0.001), but differences were not significant in body weight and BMI (P>0.05). The incidence rates of AEs, TAEs, and GDs differed significantly between groups (P=0.010, P=0.005, and P=0.006, respectively), whereas the incidence rates of SAEs showed no significant differences between groups (P=1.000).@*CONCLUSION@#SZ-A are effective and safe for treatment of type 2 diabetes. The protocol was registered in http://www.chictr.org.cn/showproj.aspx?proj=60117 (ChiCTR2000038550).

Updated research progress of selective PPARγ modulators / 药学学报

Thiazolidinediones (TZDs) are currently the only recognized insulin sensitizers available for the clinical treatment of type 2 diabetes. Although their advantages are recognized, the profiles of numerous adverse effects hinder the continued use of these drugs. Peroxisome proliferator-activated receptor γ (PPARγ) is known as a receptor for TZDs, and its underlying mechanisms of pharmacological actions and adverse effects have been deeply explored. To maximally preserve the PPARγ-mediated insulin sensitizing effects and reduce the occurrence of related adverse effects, the concept of "selective PPARγ modulators (SPPARMs)" has been proposed and developed, guiding the development of new drugs. In this review, we summarize the recent research progress in the definition of SPPARMs, the candidate classification and the molecular underpinnings, as well as present the discovery of the YR series compounds as an example, and discuss the potential application prospects of SPPARMs.

The Chinese patent medicine, Jin-tang-ning, ameliorates hyperglycemia through improving β cell function in pre-diabetic KKAy mice / 中国天然药物

Jin-tang-ning (JTN), a Chinese patent medicine, mainly comprised of Bombyx moriL., has been proved to show α-glucosidase inhibitory efficacy and clinically effective for the treatment of type 2 diabetes (T2DM). Recently, we have reported that JTN could ameliorate postprandial hyperglycemia and improved β cell function in monosodium glutamate (MSG)-induced obese mice, suggesting that JTN might play a potential role in preventing the conversion of impaired glucose tolerance (IGT) to T2DM. In this study, we evaluated the effect of JTN on the progression of T2DM in the pre-diabetic KKAy mice. During the 10 weeks of treatment, blood biochemical analysis and oral glucose tolerance tests were performed to evaluate glucose and lipid profiles. The β cell function was quantified using hyperglycemic clamp at the end of the study. JTN-treated groups exhibited slowly raised fasting and postprandial blood glucose levels, and also ameliorated lipid profile. JTN improved glucose intolerance after 8 weeks of treatment. Meanwhile, JTN restored glucose-stimulated first-phase of insulin secretion and induced higher maximum insulin levels in the hyperglycemic clamp. Thus, to investigate the underlying mechanisms of JTN in protecting β cell function, the morphologic changes of the pancreatic islets were observed by optical microscope and immunofluorescence of hormones (insulin and glucagon). Pancreatic protein expression levels of key factors involving in insulin secretion-related pathway and ER stress were also detected by Western blot. Pre-diabetic KKAy mice exhibited a compensatory augment in β cell mass and abnormal α cell distribution. Long-term treatment of JTN recovered islet morphology accompanied by reducing α cell area in KKAy mice. JTN upregulated expression levels of glucokinase (GCK), pyruvate carboxylase (PCB) and pancreas duodenum homeobox-1 (PDX-1), while down-regulating C/EBP homologous protein (Chop) expression in pancreas of the hyperglycemic clamp, which indicated the improvement of mitochondrial metabolism and relief of endoplasmic reticulum (ER) stress of β cells after JTN treatment. These results will provide a new insight into exploring a novel strategy of JTN for protecting β cell function and preventing the onset of pre-diabetes to T2DM.

SOCS1 Regulates the Immunomodulatory Roles of MSCs on B Cells

Background and Objectives@#The effective use of MSCs for the treatment of some B cell-mediated immune diseases is quite limited. The main reason is that the immunomodulatory effects of mesenchymal stem cells (MSCs) on B cells are unclear, and their underlying mechanisms have not been fully explored. @*Methods@#and Results: By co-culturing B cells with MSCs without (MSC/CTLsh) or with suppressor of cytokine signaling 1 (SOCS1) knockdown (MSC/SOCS1sh), we found that MSCs inhibited B cell proliferation, activation and terminal differentiation. Remarkably, the highest inhibition of B cell proliferation was observed in MSC/SOCS1sh co-culture. Besides, MSC/SOCS1sh reversed the inhibitory effect of MSCs in the last stage of B cell differentiation. However, MSC/SOCS1sh had no effect on inhibiting B cell activation by MSCs. We also showed that IgA+ B cell production was significantly higher in MSC/SOCS1sh than in MSC/CTLsh, although no difference was observed when both MSCs co-cultures were compared to isolated B cells. In addition, MSCs increased PGE2 production after TNF-α/IFN-γ stimulation, with the highest increase observed in MSC/SOCS1sh co-culture. @*Conclusions@#Our results highlighted the role of SOCS1 as an important new mediator in the regulation of B cell function by MSCs. Therefore, these data may help to develop new treatments for B cell-mediated immune diseases.

Surgical treatment of mixed total anomalous pulmonary venous connection / 中国胸心血管外科临床杂志

@#Objective    To analyze the outcomes of surgical repair for mixed total anomalous pulmonary venous connection (TAPVC). Methods    Between 2006 and 2018, a total of 51 patients with mixed TAPVC underwent surgery in our hospital. Patients with such associated anomalies as single ventricle and tetralogy of Fallot were excluded. There were 35 males and 16 females with a median age of 102.0 (59.0, 181.0) days and a median weight of 5.0 (4.1, 6.4) kg. Patients were divided into three categories based on the anatomy: "3+1" pattern (n=38, three pulmonary veins drained at one site, and the other drained at the opposite site); "2+2" pattern (n=9, the pulmonary veins from each lung joined to form a confluence and drained at separate sites); bizarre pattern (n=4, the anatomy could not be classified into the above two patterns). Results    There was no in-hospital death. The median follow-up was 41.0 (18.0, 86.5) months. Postoperative pulmonary venous obstruction occurred in 10 patients. Kaplan-Meier survival curves showed no statistically significant difference in postoperative pulmonary venous obstruction among the three groups (P=0.239). Cox risk regression showed that preoperative pulmonary venous obstruction was significantly associated with postoperative pulmonary venous obstruction (P=0.024). Conclusion    Mixed TAPVC has various anatomic morphologies and requires individualized surgery.

Anti-diabetic effects of the fraction of alkaloids from Ramulus Mori, an innovative Sangzhi alkaloids as an α-glucosidase inhibitor / 药学学报

Sangzhi alkaloids (SZ-A) are derived from traditional Chinese medicine Ramulus Mori, serving well as an innovative antidiabetic drug, due to α-glucosidase inhibition. To evaluate the potency of glucosidase inhibitory effect of SZ-A, the enzyme-based screening platforms, including sucrase, maltase and amylase were established, and IC50 was calculated. The effects of SZ-A on postprandial blood glucose at a single dose, oral sucrose, starch and glucose loading were determined in normal ICR mice and alloxan-induced hyperglycemic mice. To confirm the anti-diabetic effects of SZ-A on glucose and lipid metabolism after long-term administration, the postprandial and fasting blood glucose, serum insulin, urinary glucose levels, glycosylated serum proteins and blood lipid levels were determined in high-fat fed C57 obese mice (pre-diabetic HFC57 mice) and diabetic rats induced by streptozotocin (STZ). The Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College approved all of the protocols for this research. We found that SZ-A exhibited a significant inhibitory effect on the sucrase and maltase. SZ-A showed no effect on amylase. In normal ICR mice and alloxan-induced hyperglycemic mice, SZ-A at a single dose significantly delayed and reduced the peak of blood glucose after sucrose or starch loading, but showed no effect on the increase of blood glucose after glucose loading. In STZ diabetic rats, SZ-A significantly reduced the postprandial or fasting blood glucose levels, glycosylated serum proteins and urinary glucose. SZ-A also reduced serum triglyceride (TG) and cholesterol (TC) levels after 3 weeks of treatment. SZ-A ameliorated the postprandial blood glucose or the fasting blood glucose elevation, and reduced the incidence of hyperglycemia in HFC57 mice. SZ-A decreased the basal insulin level, improved insulin sensitivity, and ameliorated glucose intolerance in pre-diabetic HFC57 mice. Our results indicated that SZ-A had a novel inhibitory activity on α-glucosidase, especially on disaccharidases. SZ-A at a single dose significantly reduced the peak of blood glucose elevation and delayed the increase of blood glucose in normal and diabetic mice after disaccharide and polysaccharide loading. Long-term SZ-A treatment improved glucose and lipid metabolic profiles by delaying carbohydrate absorption from the intestine and reduced the postprandial blood glucose levels in both pre-diabetic and diabetic animal models. Therefore, SZ-A application may display a beneficial role in preventing the development and complications of diabetes.

A piglet model of pulmonary vein stenosis / 中国胸心血管外科临床杂志

@#Objective    Pulmonary vein banding was used to establish a piglet model of pulmonary vein stenosis. We investigated the pathomorphological alterations of pulmonary veins in the model and compared it with the vascular tissue of recurrent stenosis after total anomalous pulmonary venous connection (TAPVC). Methods    Ten pigs of 6 weeks old were selected and randomly divided into 2 groups: 5 in a sham operation group and 5 in a pulmonary vein banding group. The operation had two stages, in which thoracotomies through intercostal space were done respectively on both sides. Biocompatible materials were applied around the pulmonary veins in the experimental group. The same method was used in the sham group. But the pulmonary veins were not banded. Six weeks after the operation, the pulmonary veins of the animals were harvested for hematoxylin-eosin staining and immunofluorescence staining to observe the pathological alterations of pulmonary veins. The proliferative tissues of patients with recurrent stenosis after TAPVC repair were collected and observed by hematoxylin-eosin staining and immunofluorescence staining. Results    Both the sham operation group and the pulmonary vein banding group survived. But the pulmonary vein banding group had obvious clinical manifestations of pulmonary venous stenosis. Compared with the sham group, the pulmonary vein banding group showed intimal hyperplasia, decreased expression of endothelial marker and increased expression of mesenchymal markers, and co-expression of endothelial and mesenchymal markers in intimal cells. Human pathology also showed intimal hyperplasia and co-expression of endothelial and mesenchymal markers in intimal cells. Conclusion    The surgical pulmonary vein stenosis in piglets shows intimal hyperplasia and myofibroblasts, which was consistent with clinical pathology.

Numerical simulation of a self-powered Fontan based on venturi effect / 中国胸心血管外科临床杂志

@#Objective    To investigate the effects of a self-powered conduit in different patients’ models who underwent extracardiac Fontan procedure. Methods    Four children who underwent extracardiac Fontan procedure in Shanghai Children's Medical Center from 2011 to 2017 year were selected. Venae cavae and pulmonary arteries were reconstructed using Mimics 19.0®. In silico, a venturi conduit was introduced to the anastomosis of venae cavae and pulmonary artery. Then computational fluid dynamics simulation was performed using patients’ clinical data. Results    When inferior venae cavae were directly to or to the left of superior venae cavae, the venturi conduit could assist the return of venous blood and reduce the pressures of venae cavae about 0.5 mm Hg. And the pressure differences between venae cavae and pulmonary arteries were about –0.7 mm Hg, which suggested that the conduit could generate right ventricle-like effect. Conclusion    The venturi conduit can reduce the pressure of venae cavae, increase pulmonary circulation flow and improve Fontan hemodynamics.

Advances in the pharmacological function of FBPase and development of FBPase inhibitors / 药学学报

Fructose 1, 6-bisphosptase (FBPase), a second rate-limiting enzyme in gluconeogenesis, has an important role in the control of gluconeogenesis, which involves in energy metabolism and glucose homeostasis. Inhibitors of FBPase exhibit an anti-diabetic activity. Some of FBPase inhibitors have entered the stage of clinical trials, which indicates that FBPase is a promising therapeutic target for the discovery and development of hypoglycemic drugs. In addition, recent studies have shown that FBPase can be used to treat other diseases such as the initiation and development of tumors in several cancer types. Here, we provide a review of the biological characteristics of FBPase and contributions of FBPase on gluconeogenesis and insulin secretion, the research and development of FBPase inhibitors and the regulatory role of FBPase in other diseases.

Anti-diabetes effects and mechanisms of a Chinese herbal medicine preparation JQ-R in diabetic KKAy mice and in vitro / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effects and mechanisms by which JQ-R regulated the glucose metabolism and improves insulin sensitivity in diabetic KKAy mice and insulin-resistant L6 myotubes. JQ-R is a mixture of refined extracts from Coptis chinensis, Astragalus membranaceus and Lonicera japonica, three major herbs of JinQi-JiangTang tablet. METHODS Diabetic KKAy mice were adminis-tered JQ-R (100 mg·kg-1or 200 mg·kg-1BW) for 10 weeks. Levels of fasting plasma glucose, lipids, insulin and hemoglobin A1c were monitored.Systemic insulin sensitivity was quantified using the eugly-cemic clamp.The effect of JQ-R on the expressions of the enzymes involved in insulin signaling,oxidative stress and inflammation(Akt,NFκB,IΚBα, JNK, Erk, p38 MAPK) were measured in L6 insulin-resis-tant myotubes. RESULTS JQ-R showed beneficial effects on glucose homeostasis and insulin sensi-tivity in diabetic KKAy mice after 10 weeks treatment. JQ-R also ameliorated the plasma lipid profiles. Moreover,JQ-R can directly reverse the decreased activity of SOD and increased MDA levels as well as activity of iNOS in insulin resistant L6 cell induced with palmitic acid(PA).The expressions of phos-phorylation of NF-κB p65,IκBα,JNK1/2 and Erk1/2 were also decreased after JQ-R treatment.It was also shown that the insulin-stimulated glucose uptake increased significantly after JQ-R treatment,with upregulated expression of phosphorylation of Akt. CONCLUSION JQ-R ameliorated the glucose and lipid metabolism and insulin sensitivity in diabetic KKAy mice. In vitro treatment with JQ-R directly enhanced insulin stimulated glucose uptake in insulin resistant myotubes with improved insulin signal-ling and inflammatory response and oxidative stress state.

Comparison of Inducing Pluripotent Stem Cells to Differentiate into Motor Neuron Precursor in Two Kinds of System / 中国康复理论与实践

Objective To induce human-induced pluripotent stem cells(iPSCs)to differentiate into spinal motor neuron precursor (MNP)and compare the induction efficiency in systems of feeder and feeder-free. Methods iPSCs cultured on mouse feeder cells or in feeder-free condition were induced into neuroepithelial progenitors (NEP) on the sixth day and MNP on the twelveth day.Their morphology was observed under inverted micro-scope,and the markers of iPSCs,NEP,MNP were detected with immunofluorescence.NEP-related genes SOX1 and HOXA3,MNP-related genes OLIG2 and PAX6,and pluripotency genes SOX2 and OCT4 were detected with real-time quantitative polymerase chain reaction. Results iPSCs expressed pluripotency markers,while NEP and MNP expressed high levels of neural related markers and low levels of pluripotency markers in two systems. The expression of the genes SOX1, HOXA3, OLIG2 and OCT4 was higher in the feeder system,and there was no significant difference in the expression of genes SOX2 and PA X 6. Conclusion iPSCs can differentiate into MNP in culture systems of feeder and feeder-free,and the induction efficiency is higher in the feeder system.

Reactive oxygen species-mediated unfolded protein response pathways in preimplantation embryos

Excessive production of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress-mediated responses are critical to embryonic development in the challenging in vitro environment. ROS production increases during early embryonic development with the increase in protein requirements for cell survival and growth. The ER is a multifunctional cellular organelle responsible for protein folding, modification, and cellular homeostasis. ER stress is activated by a variety of factors including ROS. Such stress leads to activation of the adaptive unfolded protein response (UPR), which restores homeostasis. However, chronic stress can exceed the toleration level of the ER, resulting in cellular apoptosis. In this review, we briefly describe the generation and impact of ROS in preimplantation embryo development, the ROS-mediated activation mechanism of the UPR via the ER, and the subsequent activation of signaling pathways following ER stress in preimplantation embryos.

The beneficial effect of metformin on beta-cell function of type 2 diabetes mice and its possible mechanisms / 药学学报

To investigate the effects of metformin on pancreatic β-cell function and its possible mechanism, high fat diet-induced type 2 diabetic C57BL/6J mice were divided into two groups according to fasting blood glucose (FBG), glucose decreasing rate at 40 min of insulin tolerance test, triglycerides (TG), cholesterol (CHO) and body weight (BW). The C57 mice were gavaged with water or metformin for 58 days. β-Cell function was evaluated by oral glucose tolerance test and hyperglycemic clamp. Genes and proteins related to pancreas proliferation, lipid metabolism and endoplasmic reticulum stress were investigated. Compared with the model group, metformin group exhibited a reduction in the body weight (PPPPPPdx-1, Pβ (Lxr-β, PPPP<0.05) were also down-regulated. These results suggest that metformin could improve the insulin secretion function of type 2 diabetic C57BL/6J mice. The mechanism of the action may rely on its improvement of pancreas cell proliferation, lipid metabolism and amelioration of endoplasmic reticulum stress.

PPARγ non-agonist ligand:the structure optimization based on PPARγ partial agonist / 药学学报

Recent studies indicate that insulin-sensitizing activity of TZDs occurs through the inhibition of PPARγ Ser273 phosphorylation mediated by cyclin-dependent kinase 5(Cdk5), which is resulted from the binding activity for PPARγ. While, the side effects of TZDs may be related to the agonistic potency for PPARγ. In this article, 15 target compounds were designed and synthesized based on the structure of PPAR γ partial agonist INT131, with the aim of maintaining the insulin-sensitizing activity and reducing the side effects of INT131. The structures of these compounds were confirmed by 1H NMR and ESI-MS, and their binding activities and agonistic potencies for PPARγ were measured. The binding activity of compound 15 is 88.47% of rosiglitazone, which is similar to INT131 (98.55%), but the agonistic potency of compound 15 is 1.41% of rosiglitazone, obviously lower than INT131 (15.18%).

Dynamic associations of mitochondria-endoplasmic reticulum in maintenance of pancreatic beta cell homeostasis / 药学学报

The appropriate regulation of intracellular bioenergy and nutrient metabolism is a basic requirement for proper function and survival of pancreatic beta cells, where mitochondria-endoplasmic reticulum (ER)-associations play crucial roles. Mitochondria are changed dynamically according to intracellular energy and nutrients, which provides material foundation for energy homeostasis; while ER regulates metabolic enzymes and protein synthesis in different pathways. This review sheds light upon the development of mitochondria-ER associations and its role in the regulation of insulin secretion in pancreatic beta cell. The impact on beta cell viability is discussed. Interruption of calcium and redox oxidative species results in reduction of glucose-stimulated insulin secretion, while intracellular calcium levels could be partial altered by depleting calcium from the ER. Given the tight link between ER and mitochondria, the association are crucial to the homeostasis and are an indicator of overall beta cell status, with a potential as a novel drug target for treatment of type 2 diabetes mellitus.

Chemical constituents of the roots of Macleaya microcarpa and activation efficacy of benzophenanthridine alkaloids for the transcription of xbp1 gene / 药学学报

Ongoing study on the chemical constituents of the roots of Macleaya microcarpa led to the isolation of eight compounds of derivatives of triterpenes and organic acids in addition to some previously identified benzophenanthridines. The eight compounds were identified by spectroscopic methods as well as comparison with literature values as 1-oxo-2, 22 (30)-hopandien-29-oic acid (1), 3-oxo-12-oleanen-30-oic acid (2), 3α-hydroxy-12-oleanen-30-oic acid (3), 3β-hydroxy-12-oleanen-30-oic acid (4), ferulic acid (5), ferulic acid 4-O-β-D-glucoside (6), 3-O-feruloylquinic acid (7), and methyl 3-O-feruloylquinate (8). Of which, 1 is a new triterpenoid of hopanes and 2-8 are isolated from M microcarpa for the first time. In order to discover natural active compounds as potential agents of anti-ulcerative colitis (UC), an in vitro drug high-throughput screening model targeted x-box-binding protein 1 (xbp1) was employed to evaluate the activity of the major chemical constituents of M microcarpa. The result confirmed that two dihydrobenzophenanthridines, dihydrosanguinarine (9) and dihydrochelerythrine (10), showed a certain activity on activating the transcription of xbpl, a transcription factor (TF) associated with the occurrence, development, and potential treatment of UC, with their relative activating ratios being 1.76 and 1.77 times, respectively, as compared with control group.

Farnesoid X receptor regulates glucose and lipid metabolisms / 药学学报

As a member of nuclear receptor superfamily, farnesoid X receptor (FXR) has been shown to regulate numerous metabolic pathways, which include playing an important role in bile acid metabolism, maintaining lipid and glucose homeostasis when FXR is activated. With the prevalence of the glucose and lipids disorder, FXR attracts increasing attention. It may be a potential target for the treatment of type 2 diabetes mellitus and lipid disorders.

Effects of Estrogen on Insulin Sensitivity and Adipokines in Mice / 中国医学科学院学报

<p><b>OBJECTIVE</b>To study the potential mechanisms via which estrogen exerts its effects on the insulin sensitivity in mice.</p><p><b>METHODS</b>Totally 36 female C57BL/6J mice aged 6 weeks were randomly divided into six groups:normal diet (NOR) group, normal diet with ovariectomy (NOR+OVX) group, normal diet with ovariectomy and estrogen replacement (NOR+OVX+E2) group,high-fat diet (HF) group, high-fat diet with ovariectomy (HF+OVX) group, and high-fat diet with ovariectomy and estrogen replacement (HF+OVX+E2) group. There were six mice in each group. After the ovariectomy based on the grouping, the mice were given normal diet or high-fat diet for 20 weeks. The intervention groups were given estrogen (5 μg/d,subcutaneous injection) for 20 days. Then,the body weight,visceral fat weight,oral glucose tolerance and insulin sensitivity (by euglycemic hyperinsulinemic clamp test), and serum leptin, adiponectin,and resistin levels were compared among these six groups.</p><p><b>RESULTS</b>Compared with HF group, the HF+OVX group had significantly higher body weight and visceral fat weight and lower glucose tolerance, which were significantly improved after estrogen replacement therapy (all P<0.05). However, these indicators showed no significant differences among groups with normal diets (all P>0.05). The insulin sensitivity of ovariectomized mice was significantly decreased in both high-fat and normal diet groups and was also improved significantly after estrogen replacement (P<0.05). The serum leptin was increased and adiponectin was decreased significantly in ovariectomized mice, and the improvements of these two adipokines were also statistically significant after estrogen therapy (P<0.05): however,the serum resistin level was not significantly different among these 6 groups (P>0.05).</p><p><b>CONCLUSIONS</b>Estrogen replacement therapy can improve insulin resistance by lowering body weight. In addition, it can exert its effect directly on adipose tissue,improve the levels of adipokines,reduce the amount of visceral fat, and improve insulin sensitivity in mice.</p>