Background: Memory-impairment was one of the common characteristics in patients with diabetes mellitus. The release of chronic inflammation mediators and insulin resistance in diabetic brain gave rise to the generation of toxic factor Aβ42 which was the marker of Alzheimer’s disease. In addition, the impairment of memory in diabetes mellitus was also correlated predominantly with uptake/metabolism of glucose in medial prefrontal cortex (mPFC). Previously, anti-inflammation and hypoglycemic effects of berberine (BBr) have been described in peripheral tissues. For better understanding the effects of BBr on cognitive action in diabetics, we investigated the functions of BBr involved in anti-inflammation and ameliorating insulin resistance in prefrontal cortex of diabetic rats.Methods: Intragastric administration of BBr (187.5 mg/Kg/d) was used in diabetic rats. Fear-condition assay was applied for cognitive assessment, and relative protein expressions were detected by western-blot. The glucose uptake in prefrontal cortex of diabetic rats was tested by Positron-Emission Tomography imaging. The levels of inflammation mediators were determined by commercial ELISA kits.Results: The inflammation mediator release and insulin resistance in the mPFC of diabetic rats was inhibited by BBr. The activation of PI3K/Akt/mTOR and MAPK signaling pathway, as well as two novel isoforms PKCη and PKC𝜀 and the translocation of NF-κB in neuron were also down-regulated by BBr; furthermore, the neuron specific glucose transporter GLUT3 was remarkably augmented by 2–3 times when compared with diabetic group; meanwhile, BBr also promoted glucose uptake in the brain. Additionally BBr decreased the expressions of amyloid precursor protein and BACE-1, and the production of oligomeric Aβ42. Finally, it accelerates the reinforcement of the information and ameliorates cognitive impairment.Conclusion: BBr inhibited the activation of inflammation pathway and insulin resistance in the mPFC of diabetic rats. Finally, it improved the lesion of cognition in diabetic rats.

Mammalian HSP90K K and HSP90L L are encoded by two individual genes. On the basis of the upstream sequences of the human hsp90K K gene, GenBank accession number U25822, we have constructed CAT reporter plasmids driven by individual fragments of the hsp90K K gene. We found that (1) the proximal heat shock element complex located at 396/360 enhances hsp90K K promoter expression; (2) heat shock induction depends upon the coexistence of distal heat shock element at 31031/ 31022 and the proximal heat shock element complex of the hsp90K K gene; (3) unlike hsp90L L, downstream sequences of the transcription start site inhibit hsp90K K expression. We conclude that the regulatory mechanisms for the expression of hsp90K K and hsp90L L genes are different.z 1999 Federation of European Biochemical Societies.

Tumor suppressor p53 has been implicated in cell stress response and determines cell fate of either growth arrest or apoptosis. Heat shock proteins (Hsps) expressed under stress usually confer survival protection to the cell or interruption in the apoptotic pathways. Although Hsp90 can physically interact with p53, whether or not the hsp90 gene is influenced downstream of p53 in UV irradiation-induced apoptosis remains unclear. We have found that the level of p53 is elevated with the decline of Hsp90 in UV-irradiated cells and that malfunction of Hsp90, as inhibited by geldanamycin, enhances the p53-involved UV irradiation-induced apoptosis. In addition, the expression of the hsp90␤ gene was reduced in both UV-irradiated and wild type p53-transfected cells. These results suggest a negative correlation between the trans factor p53 and a chaperone gene hsp90␤ in apoptotic cells. Mutation analysis demonstrated that the p53 binding site in the first exon was indispensable for p53 regulation on the hsp90␤ gene. In addition, with p53 bound at the promoter of the hsp90␤ gene, mSin3a and p300 were differentially recruited in UV irradiation-treated or untreated Jurkat cells in vivo. The evidence of p53-repressed hsp90␤ gene expression in UV-irradiated cells shed light on a novel pathway of Hsp90 in the survival control of the stressed cells.

Background: Metabolic activity is the basic life activity of organisms and the fundamental for maintaining body functions. With the improvement of living standards, the incidence of metabolic disorder is also increasing. At present, most of the clinical treatment strategies and meta-analysis for metabolic disorder uncover that combined medicines with berberine ameliorate several metabolic disorders. However, evidence to disclose the therapeutic effect of berberine treatment alone and the possible factors affecting the efficacy is limited. Therefore, we have formulated strict inclusion criteria and selected more reliable data for meta-analysis through more refined screening strategies to provide evidence and guidance for clinical decision-making and understand the effect of berberine treatment alone and the factors affecting its efficacy.Methods and results: Using meta-analysis of “Cochrane Handbook for Systematic Reviews of Interventions” as guidelines, we searched PubMed, GeenMedical, Cochrane library, and china national knowledge infrastructure (CNKI) for trials reporting clinical treatment data of berberine. Another 417 trials were included through other sources to increase confidence in results. Among the 1,660 related documents retrieved from the four databases, 18 eligible documents were selected for analysis. Given the differences in trial design and measurement units, we used the standardized mean difference (SMD) method to eliminate the differences and then summarize the data for analysis. The main factors are triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), homeostasis model assessment-insulin resistance (HOMA-IR), and fasting plasma glucose (FPG). Random-effect model analysis was performed: TG (SMD: 0.94; 95%CI: 0.49,1.38; p = 0.00), TC (SMD: 1.06; 95%CI: 0.64, 1.48; p = 0.00), LDL (SMD: 1.77; 95%CI: 1.11,2.44; p = 0.00), HDL (SMD: −1.59; 95%CI: −2.32, −0.85; p = 0.00), HOMA-IR (SMD: 1.25; 95%CI: 0.25,2.24; p = 0.01), and FPG (SMD: 0.65; 95%CI: 0.28,1.03; p = 0.00). This study aimed to conduct a systematic review and meta-analysis of the literature to evaluate the therapeutic effect of berberine singly on metabolic diseases.Conclusion: Berberine can improve obesity and hyperlipidemia by reducing TG, TC, and LDL and increasing HDL; reduce insulin resistance to improve type Ⅱ diabetes; and prevent diabetic encephalopathy.

The human HSP90 gene family contains introns. There are two typical heat shock elements (HSE) in the first intron of human hsp90p gene. As detected by chloramphenicol acetyl transferase (CAT) reporter activity assays, the HSEcontaining intron is essential in maintaining high constitutive expression and is critical for heat shock inducibility of the human hsp90P gene. Cellular heat shock factor 1 (HSF 1) shows much higher binding affinity toward the intronic HSEs in comparison to an atypical HSE in the 5' flanking sequence. Novel initiation sites found in the first intron probably also contribute to constitutive and heat-inducible expression of the Iisp9()p gene in Jurkat cells.

Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3β signaling pathway.

Myogenin and its upstream regulator MyoD are known to be required for myogenic cell differentiation. Although both of them can be expressed in rhabdomyosarcoma-derived RD cells, the cells are unable to undergo full-scale terminal myogenic differentiation. 12-O-Tetradecanoylphorbol-13-acetate (TPA) has been found to be functional in the induction of RD cell differentiation, whereas its mechanism is not fully understood. By using quantitative real-time-based chromatin immunoprecipitation and real-time reverse transcription-PCR-based promoter activity assays, we examined the activation mechanism of the myogenin gene during TPA-induced differentiation of the RD cells. We have shown that a histone acetyltransferase PCAF and ATPase subunit BRG1 of the SWI/SNF chromatin remodeling complex are sequentially recruited to the promoter of the myogenin gene. Both PCAF and BRG1 are also involved in the activation of the myogenin gene. In addition, we have found that the p38 mitogen-activated protein kinase is required for BRG1 recruitment in TPA-mediated myogenin induction. We propose that there are two distinct activation steps for the induction of myogenin in TPA-induced early differentiation of RD cells: 1) an early step that requires PCAF activity to acetylate core histones and MyoD to initiate myogenin gene expression, and 2) a later step that requires p38-dependent activity of the SWI/SNF remodeling complex to provide an open conformation for the induction of myogenin. Our studies reveal an essential role for epigenetic regulation in TPA-induced differentiation of RD cells and provide potential drug targets for future treatment of the rhabdomyosarcoma.

Neurogenin1 is an important bHLH protein that plays crucial role in neurogenesis. We first show that the expression of ngn1 increases drastically in RA induced neuronal differentiation. During which, a three successive stages of the epigenetic changes surrounding the ngn1 gene are found correlated with a repression to activation of the gene in P19 cells. Recruiting of a repressive histone code H3K27me3 on the ngn1 gene is the dominant change in first repression stage, which is followed by the binding of the active codes of H3K9ac, H3K14ac, and the H3K4me3 in the second and third stages of RA treatment. Additionally, BRM but not BRG1 is specifically recruited to ngn1 gene at the third stage and is positively involved in the RA induced ngn1 expression. We propose that histone modifiers and chromatin remodelers are pivotal in the activation of the ngn1 gene in RA induced differentiation of P19 cells.