Smad3 deficiency improves islet-based therapy for diabetes and diabetic kidney injury by promoting ß cell proliferation via the E2F3-dependent mechanism.

Rationale: Poor ß cell proliferation is one of the detrimental factors hindering islet cell replacement therapy for patients with diabetes. Smad3 is an important transcriptional factor of TGF-ß signaling and has been shown to promote diabetes by inhibiting ß cell proliferation. Therefore, we hypothesize that Smad3-deficient islets may be a novel cell replacement therapy for diabetes. Methods: We examined this hypothesis in streptozocin-induced type-1 diabetic mice and type-2 diabetic db/db mice by transplanting Smad3 knockout (KO) and wild type (WT) islets under the renal capsule, respectively. The effects of Smad3KO versus WT islet replacement therapy on diabetes and diabetic kidney injury were examined. In addition, RNA-seq was applied to identify the downstream target gene underlying Smad3-regulated ß cell proliferation in Smad3KO-db/db versus Smad3WT-db/db mouse islets. Results: Compared to Smad3WT islet therapy, treatment with Smad3KO islets produced a much better therapeutic effect on both type-1 and type-2 diabetes by significantly lowering serum levels of blood glucose and HbA1c and protected against diabetic kidney injuries by preventing an increase in serum creatinine and the development of proteinuria, mesangial matrix expansion, and fibrosis. These were associated with a significant increase in grafted ß cell proliferation and blood insulin levels, resulting in improved glucose intolerance. Mechanistically, RNA-seq revealed that compared with Smad3WT-db/db mouse islets, deletion of Smad3 from db/db mouse islets markedly upregulated E2F3, a pivotal regulator of cell cycle G1/S entry. Further studies found that Smad3 could bind to the promoter of E2F3, and thus inhibit ß cell proliferation via an E2F3-dependent mechanism as silencing E2F3 abrogated the proliferative effect on Smad3KO ß cells. Conclusion: Smad3-deficient islet replacement therapy can significantly improve both type-1 and type-2 diabetes and protect against diabetic kidney injury, which is mediated by a novel mechanism of E2F3-dependent ß cell proliferation.

Curcumin attenuates Nrf2 signaling defect, oxidative stress in muscle and glucose intolerance in high fat diet-fed mice.

AIM: To investigate the signaling mechanism of anti-oxidative action by curcumin and its impact on glucose disposal. METHODS: Male C57BL/6J mice were fed with either a normal diet (n = 10) or a high fat diet (HFD) (n = 20) to induce obesity and insulin resistance. After 16 wk, 10 HFD-fed mice were further treated with daily curcumin oral gavage at the dose of 50 mg/kg body weight (BW) (HFD + curcumin group). After 15 d of the curcumin supplementation, an intraperitoneal glucose tolerance test was performed. Fasting blood samples were also collected for insulin and glucose measurements. Insulin-sensitive tissues, including muscle, adipose tissue and the liver, were isolated for the assessments of malondialdehyde (MDA), reactive oxygen species (ROS) and nuclear factor erythroid-2-related factor-2 (Nrf2) signaling. RESULTS: We show here that in a HFD mouse model, short-term curcumin gavage attenuated glucose intolerance without affecting HFD-induced BW gain. Curcumin also attenuated HFD-induced elevations of MDA and ROS in the skeletal muscle, particularly in its mitochondrial fraction, but it had no such an effect in either adipose tissue or the liver of HFD-fed mice. Correspondingly, in skeletal muscle, the levels of total or nuclear content of Nrf2, as well as its downstream target, heme oxygenase-1, were reduced by HFD-feeding. Curcumin intervention dramatically reversed these defects in Nrf2 signaling. Further analysis of the relationship of oxidative stress with glucose level by a regression analysis showed a positive and significant correlation between the area under the curve of a glucose tolerance test with MDA levels either in muscle or muscular mitochondria. CONCLUSION: These findings suggest that the short-term treatment of curcumin in HFD-fed mice effectively ameliorates muscular oxidative stress by activating Nrf2 function that is a novel mechanism for its effect in improving glucose intolerance.

[Phosphorus forms of the suspended particulate matter in the Yellow River downstream during water and sediment regulation 2008].

Suspended particulate matter samples were collected from Lijin Station on the Yellow River during the 2008 water and sediment regulation. Using water elutriation method, samples were physically separated according to grain size, and phosphorus forms were detected by the improved SEDEX technology. Results show that authigenic apatite phosphorus and organic phosphorus are the dominant forms of the particulate phosphorus. During water and sediment regulation, concentrations of total particulate phosphorus, loosely adsorbed phosphorus, organic phosphorus and refractory phosphorus are lower than those in other time of the year, while the concentration of detrital fluorapatite phosphorus is higher than that in other time. Grain size is the primary variable in the determination of the content of various particulate phosphorus forms. In fine particles, loosely adsorbed phosphorus, organic phosphorus and refractory phosphorus concentrations are high, while detrital fluorapatite phosphorus concentration is high in coarse particles. About 28.3% of the total particulate phosphorus is in the form of bio-available phosphorus, of which organic phosphorus is the major component. During the water and sediment regulation, the fluxes of sediment, particulate phosphorus and particulate bio-available phosphorus are 6.63 x 10(7) t, 3.42 x 10(4) t, and 8.30 x 10(3) t, which are 83.2%, 78.6%, and 80.2% each of the total fluxes in 2008.

[POC content in size-fractioned TSS and transportation character in the Yellow River].

Relationship between grain size of total suspended solids (TSS) and particulate organic carbon (POC) content is the base of studying POC transportation and flux in river. Based on sedimentation classification, POC in size-fractioned TSS of The Yellow River was studied by multiple linear regression. The results indicate that: with the median diameter increasing, POC is decreased in a logarithm tendency, the maximum is 0.56% lower than the other rivers; POC is different in the same size-fractioned TSS between characteristic sample stations: the estuary > Huayuankou > Lanshou > Tongguan > Lijin, for example POC is 0.661%, 0.627%, 0.550%, 0.505%, 0.493% in TSS of which the grain size is < 8 microm; the proportion of POC in size-fractioned TSS has little distinction, POC is decreased remarkably with the increasing of the grain size of TSS, and more than 80% of POC is concentrated in the particles < 16 microm while over 95% of POC is concentrated in particles of size < 32 microm. So the transportation of POC is consistent, the main control of transportation of POC is attributed to the grain size of TSS.