Search

The dysfunction and decreased number of islet β cells are central to the main pathogenesis of diabetes. Improving islet β cell function and increasing the number of β cells are effective approaches to treat diabetes and constitute the main direction of diabetes drug development. The role of Chinese medicine in the treatment of diabetes began to be recognized. In recent years, Chinese medicine monomers have been found to increase insulin synthesis and secretion, reduce β cell-apoptosis, and protect the function of β cells. The results of in vivo animal experiments and in vitro studies on insulinoma cells also suggested TCMs could promote the proliferation of pancreatic islet β cells and induce other cells differentiation or transdifferentiation to islet β cells. Thereby, they may play a role in the treatment of diabetes. In this paper, we will review islet β cell protection with TCMs and the related mechanisms found in recent studies. An in-depth explanation of the role of TCM in islet β cell protection can provide a theoretical basis and research ideas for the development of TCM-based diabetes treatment drugs. [ABSTRACT FROM AUTHOR]

Background:A large proportion of patients with chronic hepatitis B (CHB) in China do not respond to entecavir (ETV) treatment. It remains unclear whether the Killer immunoglobulin-like receptor (KIR) genotypes and haplotypes were associated with the advantage of seroconversion in phepatitis B e-Antigen (HBeAg) positive CHB patients treated with ETV. Methods: Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to analyze KIR genes in a Chinese Han population of 198 ETV-treated HBeAg-positive CHB patients and 200 healthy controls. Of the 198 patients, 59 were complete response group (CRG) and 139 were null or partial response group (NPRG) to the treatment with ETV. Results: The frequencies of KIR genotype M, and haplotype 8 were significantly higher(P = 0.017, OR = 2.497，95%CI = 5.39–1.16 and P = 0.034, OR = 1.905，95%CI = 3.48–1.04, respectively), while the frequencies of genotype AH and haplotype 5 were significantly lower (P = 0.039, OR = 0.504, 95%CI = 0.97–0.26 and P = 0.031, OR = 0.601, 95%CI = 0.96–0.38, respectively) in HBeAg-positive CHB patient group than those in healthy group. Of note, the frequencies of KIR genotype AF and haplotype 1 were significantly higher (P = 0.022, OR = 2.860, 95%CI = 7.24–1.13 and P = 0.001, OR = 3.261, 95%CI = 6.47–1.64, respectively), while the frequencies of genotype AH and haplotype 5 were significantly lower (P = 0.038, OR = 0.338, 95%CI = 0.98–0.12 and P = 0.004, OR = 0.354, 95%CI = 0.73–0.17, respectively) in NPRG than those in CRG. Conclusions: The patients with KIR genotype AF and haplotype 1 might be negative, while genotype AH and haplotype 5 might be of advantage to the therapy with ETV, which are useful for improving novel personalized precise therapy strategy in HBeAg-positive CHB patients. [ABSTRACT FROM AUTHOR]

The mechanisms facilitating hypertension in diabetes still remain to be elucidated. Nonalcoholic fatty liver disease (NAFLD), which is a higher risk factor for insulin resistance, shares many predisposing factors with diabetes. However, little work has been performed on the pathogenesis of hypertension in type 2 diabetes (T2DM) with NAFLD. The aim of this study is to investigate the prevalence of hypertension in different glycemic statuses and to analyze relationships between NAFLD, metabolic risks, and hypertension within a large community-based population after informed written consent. A total of 9473 subjects aged over 45 years, including 1648 patients with T2DM, were enrolled in this cross-sectional study. Clinical and biochemical parameters of all participants were determined. The results suggested that the patients with prediabetes or T2DM were with higher risks to have hypertension. T2DM with NAFLD had significantly higher levels of blood pressure, triglyceride, uric acid, and HOMA-IR than those without NAFLD. Data analyses suggested that hypertriglyceridemia [OR = 1.773 (1.396, 2.251)], NAFLD [OR = 2.344 (1.736, 3.165)], hyperuricemia [OR = 1.474 (1.079, 2.012)], and insulin resistance [OR = 1.948 (1.540, 2.465)] were associated with the higher prevalence of hypertension independent of other metabolic risk factors in type 2 diabetes. Further studies are needed to focus on these associations. [ABSTRACT FROM AUTHOR]

Retinoblastoma (RB) is the most frequent primary intraocular cancer. It has been demonstrated by previous studies that retinoblastoma is initiated primarily by the inactivation of the retinoblastoma Rb1 gene in retinal cells. However, additional genetic alterations than Rb1 mutation could play important roles in the process of transforming benign retinal cells into retinoblastoma tumor cells. In this study, we identified that microRNA miR-433 is one of such genetic factors. We found that the expression levels of miR-433 were downregulated in RB tissues. We also determined that miR-433 negatively regulated RB cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis of RB cells. We used bioinformatics method to predict and confirmed that Notch1 and PAX6 were miR-433 target genes in RB cells. Importantly, we demonstrated that restoration of Notch1 and PAX6 expression partially rescued the inhibition of cell proliferation and metastasis induced by miR-433 overexpression, suggesting that miR-433 regulates RB cell proliferation and metastasis through suppressing the expression of Notch1 and PAX6. [ABSTRACT FROM AUTHOR]

Synthesis of the 2-deoxy trisaccharide glycal of antitumor antibiotics landomycins A and E has been described. The synthesis involves an anomeric O-alkylation for the synthesis of 2-deoxy β -linked disaccharide, a tert -butyldimethylsilyl triflate-catalyzed α-selective L-rhodinosylation, and a lithium 4,4′-di- tert -butylbiphenyl-mediated reductive debenzylation and concomitant reductive lithiation-elimination for the production of the 2-deoxy trisaccharide glycal. [ABSTRACT FROM AUTHOR]

Objective. To investigate the association of thyroid function and diabetic nephropathy (DN) in euthyroid patients with type 2 diabetes. Methods. A total of 421 patients were included in this cross-sectional study. The following parameters were assessed: anthropometric measurements, fast plasma glucose, serum creatinine, lipid profile, HbA1c, free triiodothyronine (FT3), free thyroxine, thyroid-stimulating hormone levels, and urinary albumin-to-creatinine ratio (UACR). Patients with UACR of ≥30 mg/g were defined as those suffering from DN. Results. Of the 421 patients, 203 (48.2%) suffered from DN, and no difference was found between males and females. The patients with DN yielded significantly lower FT3 levels than those without DN (P<0.01). The prevalence of DN showed a significantly decreasing trend across the three tertiles based on FT3 levels (59.6%, 46.4%, and 38.6%, P<0.01). After adjustment for gender and age, FT3 levels were found to correlate positively with estimated glomerular filtration rate (P=0.03) and negatively with UACR (P<0.01). Multiple linear regression analysis showed that FT3 level was independently associated with UACR (β=-0.18, t=-3.70, and P<0.01). Conclusion. Serum FT3 levels are inversely associated with DN in euthyroid patients with type 2 diabetes, independent of traditional risk factors. [ABSTRACT FROM AUTHOR]

Li X, Liu M, Cai Z, Wang G, Li X. Regulation of glycogen synthase kinase-3 during bipolar mania treatment. Bipolar Disord 2010: 12: 741-752. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Bipolar disorder is a debilitating psychiatric illness presenting with recurrent mania and depression. The pathophysiology of bipolar disorder is poorly understood, and molecular targets in the treatment of bipolar disorder remain to be identified. Preclinical studies have suggested that glycogen synthase kinase-3 (GSK3) is a potential therapeutic target in bipolar disorder, but evidence of abnormal GSK3 in human bipolar disorder and its response to treatment is still lacking. This study was conducted in acutely ill type I bipolar disorder subjects who were hospitalized for a manic episode. The protein level and the inhibitory serine phosphorylation of GSK3 in peripheral blood mononuclear cells of bipolar manic and healthy control subjects were compared, and the response of GSK3 to antimanic treatment was evaluated. The levels of GSK3α and GSK3β in this group of bipolar manic subjects were higher than healthy controls. Symptom improvement during an eight-week antimanic treatment with lithium, valproate, and atypical antipsychotics was accompanied by a significant increase in the inhibitory serine phosphorylation of GSK3, but not the total level of GSK3, whereas concomitant electroconvulsive therapy treatment during a manic episode appeared to dampen the response of GSK3 to pharmacological treatment. Results of this study suggest that GSK3 can be modified during the treatment of bipolar mania. This finding in human bipolar disorder is in agreement with preclinical data suggesting that inhibition of GSK3 by increasing serine phosphorylation is a response of GSK3 to psychotropics used in bipolar disorder, supporting the notion that GSK3 is a promising molecular target in the pharmacological treatment of bipolar disorder. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3β (GSK3β). The mood stabilizer lithium inhibits GSK3β in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3β in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects. Methods: The PBMCs were obtained from 23 healthy control subjects, 9 bipolar subjects currently treated with lithium, and 13 lithium-free bipolar subjects. Immunoblot analyses were used to measure the inhibited, serine9-phosphorylated GSK3β. Results: The level of phospho-Ser9-GSK3β in PBMCs was regulated by agents that modified kinases and phosphatases acting on GSK3β and was increased by in vitro lithium treatment. More important, phospho-Ser9-GSK3β levels were eightfold higher in PBMCs from lithium-treated bipolar than healthy control subjects. Conclusions: Signaling pathways regulating serine9-phosphorylation of GSK3β can be studied in human PBMCs. Both in vitro and in vivo therapeutic lithium treatment is associated with a large increase in phospho-Ser9-GSK3β in PBMCs. Therefore, the inhibitory serine9-phosphorylation of GSK3β in human PBMCs may provide a biochemical marker to evaluate the association between GSK3β inhibition and therapeutic responses to lithium treatment. [Copyright &y& Elsevier]

Treatment of bipolar disorders has progressed significantly in the last decade due to advances in basic and clinical research. Much of this progress has centered on the development of a new generation of mood stabilizers–anticonvulsants. Valproic acid (VPA) and carbamazepine (CBZ) have clear mood stabilizing properties, while lamotrigine (LTG), topiramate (TPM), and gabapentin (GBP) have been investigated to varying degrees. We provide an overview of mechanisms of these potentially mood-stabilizing anticonvulsants, review their commonalities and dissociations to the gold standard non-anticonvulsant mood stabilizer lithium. Regulations of the glutamate excitatory neurotransmission and/or gamma aminobutyric acid (GABA) inhibitory neurotransmission are mostly studied mechanisms of anticonvulsants. The divergent effects of these agents indicate that this mode of action represents initial effect of anticonvulsants in regulating mood. Similar to lithium, intracellular mechanisms of anticonvulsants, primarily VPA and CBZ, include regulation of several protein kinase signaling pathways, leading to regulation of gene expression. Common genes that can be regulated by mood stabilizers are more likely to be the final normalizing components in bipolar disorders. Several anticonvulsants, such as VPA, LTG, and TPM, show neuronal protective function, a commonality with recently identified neuroprotective function of lithium, although the meaning of neuroprotection in bipolar disorders remains to be identified. Understanding the mechanisms of anticonvulsant mood stabilizers, integrated with clinical observations, may ultimately provide important new insights into the pathophysiology and treatment of bipolar disorders. [Copyright &y& Elsevier]

Endometritis is the inflammation of the endometrium that is associated with lower conception rates, increased intervals from calving to first service, and more culls for failure to conceive, which leads to serious economic losses in the dairy industry. Leonurine, a natural active compound of Leonurus cardiaca , has been proved to possess various biological activities. However, there is still no study about its anti-inflammatory effects on LPS-induced endometritis. The present study aimed to demonstrate the underlying mechanism responsible for the anti-inflammatory effects of leonurine on LPS induced endometritis in mice and in bovine endometrial epithelial cells (bEECs). The results of pathological section displayed that leonurine alleviated LPS induced uterine injury. qRT-PCR and ELISA experiments suggested that leonurine inhibited the expression levels of TNF-α and IL-1β in uterus tissues and bEECs. Molecular studies showed that TLR4 expression and nuclear factor (NF)-κB activation were both inhibited by leonurine treatment. These results suggested that the therapeutic effects of leonurine on LPS-induced endometritis in mice and bEECs may act by inhibiting the expression of TLR4 and its downstream mediated NF-κB pathway. Accordingly, leonurine may serve as an effective drug in preventing and treating LPS induced endometritis. [ABSTRACT FROM AUTHOR]

Anemone flaccida Fr. Shmidt (Ranunculaceae), known as ‘Di Wu’ in China, is a perennial herb which has long been used to treat arthritis. The rhizome of A. flaccida contains pharmacologically active components i.e. oleanane-type triterpenoid saponins. Oleanolic acid is natural triterpenoid in plants with diverse biological activities. The biosynthesis of oleanolic acid involves cyclization of 2,3-oxidosqualene to the oleanane-type triterpenoid skeleton, followed by a series of oxidation reactions catalyzed by cytochrome P450 monooxygenase (CYP450). Previously, we identified four possible cytochrome P450 genes belonging to CYP716A subfamily from the transcriptome of A. flaccida . In this study, we identified one of those genes “CYP716A254” encoding a cytochrome P450 monooxygenase from A. flaccida that catalyzes the conversion of the β-amyrin into oleanolic acid. The heterologous expression of CYP716A254 in yeast resulted in oxidation of β-amyrin at the C-18 position to oleanolic acid production. These results provide an important basis for further studies of oleanane-type triterpenoid saponins synthesis in A. flaccida. [ABSTRACT FROM AUTHOR]

Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure–activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain. [ABSTRACT FROM AUTHOR]