Haiyan Min

Association between telomere length and survival in patients with idiopathic pulmonary fibrosis

Short telomere is a crucial risk factor for idiopathic pulmonary fibrosis (IPF). However, little is known about the association between baseline telomere length and survival in IPF. We aimed to determine whether telomere length is associated with survival of IPF.

Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1

The antitumor effect of luteolin, a plant flavonoid, in gastric cancer (GC) cells has not been fully understood. Here we show that luteolin selectively kills STAT3 overactivated GC cells that are often drug resistant. The treatment of luteolin in these GC cells significantly inhibited STAT3 phosphorylation and reduced the expression of STAT3 targeting gene Mcl-1, Survivin and Bcl-xl. Silencing of SHP-1, a protein tyrosine phosphatase, abolished the inhibitory effect of luteolin on STAT3 and cell apoptosis, suggesting that SHP-1 is crucial in luteolin-mediated cellular function. Moreover, this luteolin effect of STAT3 dephosphorylation by SHP-1 involved in HSP-90, which protected STAT3 phosphorylation by forming HSP-90/STAT3 complex. Thus, luteolin inhibited STAT3 activation through disrupting the binding of HSP-90 to STAT3, which promoted its interaction to SHP-1, resulted in the dephosphorylation of STAT3. The GC cell xenograft mouse model confirmed the effectiveness of luteolin induced inhibition of tumor growth in vivo.

Puerarin acts on the skeletal muscle to improve insulin sensitivity in diabetic rats involving μ-opioid receptor

Abstract Puerarin, a major active isoflavone extracted from the root of Pueraria lobate, significantly increases plasma &bgr;‐endorphin and insulin levels and improves impaired insulin signaling in diabetic animals. However, the target tissues and underlying mechanisms in and through which puerarin functions to ameliorating insulin resistance remains largely unclear. In this study, we showed that puerarin enhanced &mgr;‐opioid receptor expression and phosphorylation, and increased insulin‐stimulated glucose transporter 4 translocation to the plasma membrane in the skeletal muscle of diabetic rats, which were recaptured by a direct application of puerarin in the palmitate‐induced insulin‐resistant L6 myotubes. Naloxone, an antagonist of &mgr;‐opioid receptor, blocked these functions of puerarin. No &bgr;‐endorphin was detected either in the muscle of diabetic rats or in the palmitate‐induced insulin‐resistant L6 cells. Furthermore, we presented the evidence to show the interaction between &mgr;‐opioid receptor and insulin receptor substrate 1 in the muscle tissues and cells. These results suggested that puerarin improved insulin sensitivity in the skeletal muscle at least in part by its local effects involving &mgr;‐opioid receptor function.

STAT3 degradation mediated by calcineurin involved in the neurotoxicity of isoflurane.

Isoflurane, a commonly used volatile anesthetic, causes widespread neuronal apoptosis in the developing brain of rodents. Signal transducer and activator of transcription-3 (STAT3) signaling is crucial for cell survival during the neural network establishment period. The aim of this study was to determine whether isoflurane would target STAT3 to deliver its neurotoxicity. Mice at postnatal day 7 and primary cortical neurons cultured for 5 days were treated with isoflurane. Our data showed that isoflurane exposure downregulated the STAT3 survival pathway in the brain of mice and in primary neurons, whereas the mRNA levels of STAT3 remained unchanged after isoflurane exposure. We found that inhibiting the activity of calcineurin, which specifically promotes STAT3 degradation, alleviated isoflurane-induced neural apoptosis. Further studies showed that isoflurane increased calcineurin activity and that the inositol 1,4,5-trisphosphate-sensitive Ca2+ channel was involved in these isoflurane-induced molecular cascades. These findings suggest that isoflurane-induced neurotoxicity may stem from STAT3 degradation, partially through the activation of calcineurin.

Persistent mitoKATP Activation Is Involved in the Isoflurane-induced Cytotoxicity.

Isoflurane exposure induces apoptosis in cultured cells and in the developing brain, while the underlying mechanism remains largely unclarified. This study was designed to determine whether the disruption of mitoKATP-mediated ATP balance was involved in the cytotoxicity of isoflurane. Human neuroglioma cells U251 and 7-day-old mice were treated with isoflurane. A specific mitoKATP antagonist 5-HD was used, and the cellular ATP levels, NAD+/NADH ratios, and mitochondrial transmembrane potential (ΔΨm) were measured. Our data showed that the blockage of mitoKATP by 5-HD mitigated the isoflurane-induced ΔΨm disruption, reactive oxygen species (ROS) accumulation, and apoptosis in U251 cells. Moreover, we found that the toxic effect of isoflurane was not observed in the first 2-h exposure; instead, the cellular ATP levels and NAD+/NADH ratios were markedly increased. The reduction of ATP levels and NAD+/NADH ratios was only detected after this initial phase. This dynamical effect of isoflurane was blocked by 5-HD. In contrast, a ROS scavenger NAC sustained the isoflurane-induced ATP elevation. Similar results were observed in animal studies. And again, 5-HD attenuated isoflurane-induced cognitive disorders in the Intellicage test, a system that assesses place learning behavior in a social environment. Our study uncovered a potential mechanism underlying isoflurane’s toxicity with a therapeutic future.

Protective role of low-dose TGF-β1 in early diabetic nephropathy induced by streptozotocin.

OBJECTIVE To determine whether low-dose TGF-β1 and/or IL-6-receptorα monoclonal antibody (anti-IL-6Rα) can be used to delay renal damage and preserve renal function by rebalancing regulatory T (Treg)/Th17 cells during the course of early diabetic nephropathy (DN) induced by streptozotocin (STZ). METHODS Diabetes was induced in C57BL/6 mice by multiple STZ injection. Low-dose TGF-β1 (0.1 μg/mouse/week) and/or anti-IL-6Rα (10 μg/mouse/week) were administered 6 dozes after STZ injection. After 40 days of diabetes onset, metabolic indices, renal structure, activated Akt and Stat3, Treg/Th17 balance, markers and inflammatory cytokines, and oxidative stress in glomeruli were assessed. RESULTS Low-dose TGF-β1, instead of causing renal damage, decreased blood glucose, ameliorated kidney hypertrophy, attenuated oxidative stress, maintained activated Stat3, and induced Treg/Th17 balance in early DN. Interestingly, low-dose TGF-β1+anti-IL-6Rα or anti-IL-6Rα alone did not attenuate DN. CONCLUSIONS This study provides convincing experimental evidence of the protective effects of low-dose TGF-β1 in improving metabolic disorder and slowing renal damage in early DN.

Effect of puerarin in promoting fatty acid oxidation by increasing mitochondrial oxidative capacity and biogenesis in skeletal muscle in diabetic rats

BackgroundType 2 diabetes is characterized by dyslipidemia and the accumulation of lipids in non-adipose tissue, including skeletal muscle. Puerarin, which is a natural isoflavonoid isolated from the root of the plant Pueraria lobata, has been shown to have antidiabetic activity. However, the lipid-reducing effect of puerarin, in particular in skeletal muscle, has not yet been addressed.MethodsWe examined the effect of puerarin on mitochondrial function and the oxidation of fatty acids in the skeletal muscle of high-fat diet/streptozotocin-induced diabetic rats.ResultsPuerarin effectively alleviated dyslipidemia and decreased the accumulation of intramyocellular lipids by upregulating the expression of a range of genes involved in mitochondrial biogenesis, oxidative phosphorylation, the detoxification of reactive oxygen species, and the oxidation of fatty acids in the muscle of diabetic rats. Also, the effect of puerarin on mitochondrial biogenesis might partially involve the function of the μ-opioid receptor. In addition, puerarin decreased the trafficking of fatty acid translocase/CD36 to the plasma membrane to reduce the uptake of fatty acids by myocytes. In vitro studies confirmed that puerarin acted directly on muscle cells to promote the oxidation of fatty acids in insulin-resistant myotubes treated with palmitate.ConclusionsPuerarin improved the performance of mitochondria in muscle and promoted the oxidation of fatty acids, which thus prevented the accumulation of intramyocellular lipids in diabetic rats. Our findings will be beneficial both for elucidating the mechanism of the antidiabetic activity of puerarin and for promoting the therapeutic potential of puerarin in the treatment of diabetes.

Combinatorial Treatment of Bone Marrow Transplantation and Regulatory T Cells Improves Glycemia in Streptozotocin-diabetic Mice.

Autologous hematopoietic stem cell transplantation (HSCT) has limited benefits in patients with a long-duration of diabetes. To test whether a T regulatory cells (Tregs) and syngeneic bone marrow transplantation (syn-BMT) co-transplantation regimen will be effective, BMT±Tregs infusion was performed in streptozotocin-diabetic mice with a long-duaration of diabetes. Diabetic status, pancreata morphometry and Tregs/Th17 balancing were tested on day 100 after transplantation. While hyperglycemia relapsed in mice receiving BMT monotherapy about 6 weeks after transplantation, combined therapy with BMT+Tregs improved hyperglycemia and C-peptides, preserved islet cell mass within 100 days after BMT. Although both groups BMT and BMT+Tregs induced Tregs/Th17 rebalancing, combined treatment of BMT+Tregs synergistically elevated TGF-β1 and FoxP3 expression compared with BMT monotherapy. The sustained rebalance of Tregs/Th17 may be one possible explanation for the longer benefits of the combined treatment of BMT+Tregs over BMT monotherapy to mice with a long-duaration of diabetes. This observation of the therapeutic potential of BMCs+Tregs treatment may have important implications for clinical therapy for patients with a long-duration of diabetes.

S1PR1 predicts patient survival and promotes chemotherapy drug resistance in gastric cancer cells through STAT3 constitutive activation

Background S1PR1-STAT3 inter-regulatory loop was initially suggested to be oncogenic in several cancer cells. However, the clinical relevance of this mechanism in tumor progression, disease prognosis and drug response was not established. Methods The correlations between S1PR1 transcription, overall survival and chemotherapy response of GC patients were tested using a large clinical database. The relevance of S1PR1 expression and STAT3 activation in both tumor tissues and cancer cell lines was also tested. The effect of S1PR1 high expression achieved by persistent STAT3 activation on tumor cell drug resistance was investigated in vitro and in vivo. Findings An enhanced S1PR1 expression was highly related with a reduced overall survival time and a worse response to chemotherapy drug and closer correlation to STAT3 in gastric cancer patients. The issue chip analysis showed that the expressions of S1PR1 and STAT3 activation were increased in higher graded gastric cancer (GC) tissues. Cellular studies supported the notion that the high S1PR1 expression was responsible for drug resistance in GC cells through a molecular pattern derived by constitutive activation of STAT3. The disruption of S1PR1-STAT3 signaling significantly re-sensitized drug resistance in GC cells in vitro and in vivo. Interpretation S1PR1-STAT3 signaling may participate drug resistance in GC, thus could serve as a drug target to increase the efficacy of GC treatment. Fund This work was supported by the National Natural Science Foundation of China (No. 81570775, 81471095), the grant from the research projects in traditional Chinese medicine industry of China (No. 201507004-2).