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High glucose (HG)-induced mammalian target of rapamycin (mTOR) overactivation acts as a signaling hub for the formation of tau hyperphosphorylation, which contributes to the development of diabetes-associated cognitive deficit. How HG induces the sustained activation of mTOR in neurons is not clearly understood. ErbB4, a member of the receptor tyrosine kinase family, plays critical roles in development and function of neural circuitry, relevant to behavioral deficits. Here, we showed HG-induced ErbB4 overexpression in differentiated SH-SY5Y cells and primary hippocampal neurons and hippocampal pyramidal neurons of streptozotocin-induced diabetic rats. Inhibition of ErbB4 signaling prevented the HG-induced activation of mTOR/S6K signaling to suppress tau hyperphosphorylation. In contrast, ErbB4 overexpression increased the activation of mTOR/S6K signaling, resulting in tau hyperphosphorylation similar to HG treatment. We also demonstrated that HG upregulated the expression of ErbB4 at a mTOR-dependent posttranscriptional level. Together, our results provide the first evidence for the presence of a positive feedback loop for the sustained activation of mTOR involving overexpressed ErbB4, leading to the formation of tau hyperphosphorylation under HG condition. Therefore, ErbB4 is a potential therapeutic target for diabetes-associated neurodegeneration.

The microstructure evolution and mechanical reliability of Cu/Au–Sn/Cu sandwich joints during transient liquid phase (TLP) bonding were investigated in this study. The results show that the Au–Sn solder reacted with the Cu substrate to form Au and Au6.6Cu9.6Sn3.8. During the TLP bonding process, (Au, Cu)5Sn was formed first, following which new α(Au) and Au6.6Cu9.6Sn3.8 phases appeared, to finally form a combination of α’(Au), α(Au), and Au6.6Cu9.6Sn3.8 phases when the Au–Sn solder is exhausted. The volume contraction associated with the consumption of the Au–Sn solder results in pore formation and subsequent shear strength deterioration in the Cu/Au–Sn/Cu joint. The presence of the Au6.6Cu9.6Sn3.8 phase also slightly reduced the shear strength of the joint. However, the overall shear strength of the TLP-bonded joint consisting of α’(Au)/α(Au)/Au6.6Cu9.6Sn3.8 phases without pores was approximately 50 MPa. The TLP-bonded joints possess excellent mechanical reliability, with shear strength of 28 MPa even at 350 °C, a temperature that is 70 °C higher than the melting point of the Au–Sn solder. Moreover, the shear strength of the TLP-bonded joint remains stable at 50 MPa even after exposure to high temperatures such as 250 or 350 °C, for 400 h, and only slightly decreased after 400 thermal cycles.

The abnormally hyperphosphorylated tau is thought to be implicated in diabetes-associated cognitive deficits. The role of mammalian target of rapamycin (mTOR) / S6 kinase (S6K) signalling in the formation of tau hyperphosphorylation has been previously studied. Caveolin-1 (Cav-1), the essential structure protein of caveolae, promotes neuronal survival and growth, and inhibits glucose metabolism. In this study, we aimed to investigate the role of Cav-1 in the formation of tau hyperphosphorylation under chronic hyperglycemic condition (HGC). Diabetic rats were induced by streptozotocin (STZ). Primary hippocampal neurons with or without molecular intervention such as the transient over-expression or knock-down were subjected to HGC. The obtained experimental samples were analyzed by real time quantitative RT-PCR, Western blot, immunofluorescence or immunohistochemisty. We found: 1) that a chronic HGC directly decreases Cav-1 expression, increases tau phosphorylation and activates mTOR/S6K signalling in the brain neurons of diabetic rats, 2) that overexpression of Cav-1 attenuates tau hyperphosphorylation induced by chronic HGC in primary hippocampal neurons, whereas down-regulation of Cav-1 using Cav-1 siRNA dramatically worsens tau hyperphosphorylation via mTOR/S6K signalling pathway, and 3) that the down-regulation of Cav-1 induced by HGC is independent of mTOR signalling. Our results suggest that tau hyperphosphorylation and the sustained over-activated mTOR signalling under hyperglycemia may be due to the suppression of Cav-1. Therefore, Cav-1 is a potential therapeutic target for diabetes-induced cognitive dysfunction.

Chronic low-grade inflammation and dysfunction of metabolism has been reported to be involved in obesity. Regulatory T cell (Treg) and helper T cell 17 (Th17) are involved in chronic inflammatory diseases. Impaired balance of Treg/Th17 is one of the major factors contributing to inflammatory status in obesity.Overweight/obese patients (n = 80) were recruited and classified into three subgroups: normal glucose tolerance group (NGT, n = 32), impaired glucose regulation group (IGR, n = 19) and type two diabetes mellitus group (T2DM, n = 29). Healthy individuals were paired as normal control group (NC, n = 37). We used flow cytometry to test the frequencies of circulating Treg and Th17 cells of all subjects. Serum IL-6, IL-10, TNF-α, IL-17A levels were detected by cytometric bead array and clinical information was extracted from medical records.In group IGR and T2DM, we revealed a severe decrease in peripheral ratio of Treg/Th17 compared with NC, but no significant difference was seen in group NGT. The serum level of IL-6 in group NGT and T2DM was higher than healthy subjects. The FPG and HbA1c levels were negatively correlated with the ratio of Treg/Th17 in overweight/obese patients. ROC curve analysis revealed that peripheral Treg/Th17 ratio1.255 was a risk factor for prediabetes and diabetes in overweight/obese patients.Peripheral Treg/Th17 imbalance exists in overweight/obese patients with IGR or T2DM and peripheral Treg/Th17 imbalance might be a risk factor for prediabetes and diabetes in overweight/obese patients.

The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.

Small fiber neuropathy (SFN) is a common complication in diabetes, and is characterized by decreased intraepidermal nerve fiber density (IENFD). Semaphorin 3A (Sema3A), which is produced by keratinocytes, has a chemorepulsive effect on intraepidermal nerve fibers. mTOR signaling can mediate local protein synthesis that is critical for growth of axons and dendrites. Therefore, this study aimed to investigate whether Sema3A is up-regulated in diabetic keratinocytes via the mTOR-mediated p70 S6K and 4E-BP1 signaling pathways, and furthermore whether it is involved in the pathogenesis of diabetic SFN. IENFD, expression of Sema3A, and mTOR signaling, were evaluated in the skin of diabetic patients with SFN as well as control subjects. Sema3A and mTOR signaling were also assessed in HaCaT cells which had been treated with high glucose (HG) or recombinant Sema3A (rSema3A) in the presence or absence of rapamycin. Small fiber dysfunction was evaluated by examining IENFD and using behavioral tests in control and streptozotocin-induced diabetic rats treated with or without rapamycin. We found that higher Sema3A expression and over-activation of mTOR signaling, was accompanied by reduced IENFD in the skin of diabetic patients compared with control subjects. The expression of Sema3A, and mTOR signaling were up-regulated in HaCaT cells incubated with HG or rSema3A, and this could be attenuated by rapamycin. Hyperalgesia, reduced IENFD, and up-regulated Sema3A and mTOR signaling were also detected in diabetic rats. These effects were ameliorated by rapamycin treatment. Our data indicate that HG up-regulates Sema3A expression by activating mTOR signaling in diabetic keratinocytes. This pathway may therefore play a critical role in diabetic SFN.