High glucose-induced defective thrombospondin-1 release from astrocytes via TLR9 activation contributes to the synaptic protein loss.

Diabetes, characterized by chronic hyperglycemia, is known to induce synaptic degeneration in the brain, thereby resulting in cognitive dysfunction. Thrombospondin-1(TSP-1), the secreted protein produced by astrocytes, plays a crucial role in promoting synapse formation. Toll-like receptor 9 (TLR9) has been widely known to initiate the innate immune response. We recently reported TLR9 activation in neurons results in tau hyperphosphorylation induced by HG in vitro. Its activation has been also considered to mediate oxidative stress and astrocytic dysfunction under pathological circumstance. However, whether astrocytic TSP-1 alteration plays a role in synaptic protein loss under high glucose condition and whether TLR9 activation is involved in this process have not been reported. In this study, we found that primary mouse astrocytes incubated in high glucose (30mM) induced a significant decreased TSP-1 secretion and increased intracellular contents of TSP-1 without affecting transcription level. Addition of conditioned medium from high glucose (30mM) treated astrocytes to the primary neurons exhibited reduced synaptic proteins expression, which was attenuated by treatment with exogenous rTSP-1. In addition, we demonstrated that TLR9 activation along with reactive oxygen species (ROS) generation in astrocytes was induced by high glucose (30mM). Furthermore, we explored the relationship between TLR9 activation and TSP-1 production. Both TLR9 deficiency and the antioxidant N-acetyl-L-cysteine treatment improved altered intra- and extracellular TSP-1 levels under high glucose condition. Together, our findings suggest that high glucose (30mM) impairs TSP-1 secretion from astrocytes, which depends on astrocytic dysfunction associated with TLR9 activation mediated ROS signaling, ultimately contributing to the synaptic proteins loss.

High glucose-induced complement component 3 up-regulation via RAGE-p38MAPK-NF-κB signalling in astrocytes: In vivo and in vitro studies.

Diabetes is considered as a risk for cognitive decline, which is characterized by neurodegenerative alteration and innate immunity activation. Recently, complement 3 (C3), the critical central component of complement system, has been reported to play a key role in neurodegenerative alterations under pathological condition. Receptor for advanced glycation end products (RAGE) activation is confirmed to mediate several inflammatory cytokines production. However, whether C3 activation participates in the diabetic neuropathology and whether this process is regulated by RAGE activation remains unknown. The present study aimed to investigate the role of C3 in streptozotocin-induced diabetic mice and high glucose-induced primary astrocytes and the underlying modulatory mechanisms. The decreased synaptophysin density and increased C3 deposition at synapses were observed in the diabetic brain compared to the control brain. Furthermore, the elevated C3 was co-localized with GFAP-positive astrocytes in the diabetic brain slice in vivo and high glucose-induced astrocytes culture in vitro. Diabetes/high glucose-induced up-regulation of C3 expression at gene, protein and secretion levels, which were attenuated by pre-treatment with RAGE, p38MAPK and NF-κB inhibitors separately. These results demonstrate that high glucose induces C3 up-regulation via RAGE- p38MAPK-NF-κB signalling in vivo and in vitro, which might be associated with synaptic protein loss.

Serum levels of tumor necrosis factor-related apoptosis-inducing ligand correlate with the severity of pulmonary hypertension.

Pulmonary hypertension (PH) is a rapidly progressive disease that eventually leads to right heart failure and death. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-Rs) play an important role in the survival, migration, and proliferation of vascular smooth muscle cells. However, the association between serum TRAIL levels and PH is unknown. In this study, we assayed the serum soluble TRAIL (sTRAIL) levels in 78 patients with PH and 80 controls. The sTRAIL concentrations were elevated in the PH patients compared with the controls (138.76 ± 6.60 pg/mL vs. 80.14 ± 3.38 pg/mL, p < 0.0001). The presence of sTRAIL levels of >103 pg/mL could discriminate PH patients from healthy individuals, with a sensitivity of 75.6% and specificity of 81.2%. Moreover, elevated sTRAIL concentrations were associated with eventual pathological complications; this is consistent with the finding that sTRAIL levels decreased in patients who responded to treatment. In a hypoxia-induced PH mouse model, sTRAIL levels were significantly higher compared with those in normoxia mice, and clearly decreased when the mice were treated with treprostinil. The sTRAIL levels were positively correlated with right ventricular systolic pressure and the index of right ventricular hypertrophy. In conclusion, serum sTRAIL could be a biomarker for diagnosis and effective therapy for PH patients.

ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression.

A20-binding inhibitor of NF-κB activation (ABIN1) is a polyubiquitin-binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin-binding site (Abin1Q478H/Q478H ) is generated. These mice develop MDS-like diseases characterized by anemia, thrombocytopenia, and megakaryocyte dysplasia. Extramedullary hematopoiesis and bone marrow failure are also observed in Abin1Q478H/Q478H mice. Although Abin1Q478H/Q478H cells are sensitive to RIPK1 kinase-RIPK3-MLKL-dependent necroptosis, only anemia and splenomegaly are alleviated by RIPK3 deficiency but not by MLKL deficiency or the RIPK1 kinase-dead mutation. This indicates that the necroptosis-independent function of RIPK3 is critical for anemia development in Abin1Q478H/Q478H mice. Notably, Abin1Q478H/Q478H mice exhibit higher levels of type I interferon (IFN-I) expression in bone marrow cells compared towild-type mice. Consistently, blocking type I IFN signaling through the co-deletion of Ifnar1 greatly ameliorated anemia, thrombocytopenia, and splenomegaly in Abin1Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression.

A Convergent fabrication of silk fibroin nanoparticles on quercetin loaded metal-organic frameworks for promising nanocarrier of myocardial infraction.

The biomacromolecule silk fibroin (SF) may be constructed to promote biomimetic nucleation and nanostructures of inorganic nanomaterials, offering it a promising candidate for use in various biomimetic applications. We combined SF-NPs and ZIF-8-NPs to fabricate new drug vehicles that effectively release the drug. SF nanoparticles (SF-NPs) were assembled into quercetin (QCT), a myocardial drug added to fabricate QSF-NPs. By acting as a template for the ZIF-8 nucleation onto the surface, the QSF-NPs fabricated core-shell-structured nanocomposites (named QSF@Z-NCs) with ZIF-8 as the core-shell and the QSF-NPs. The biocompatibility analysis using the MTT assay revealed that the developed QCT, SF-NPs, and QSF@Z-NCs are not harmful to cardiac myoblast (H9C2) cells. The in vivo model demonstrated that H9C2 cells encouraged cardiomyocyte fibre regeneration in myocardial infarction rats. We fabricated a brand-new technique using H9C2 cells and QSF@Z-NCs that might encourage the healing processes in myocardial ischemia cells. This study's results demonstrate that it successfully treats myocardial injury.

Two new species and a new record of eriophyoid mites (Acari: Eriophyodea) from Guangxi, China.

Two new species of eriophyoid mites are described and illustrated from Guangxi, China: Acaphylla quercus sp. nov. collected on Quercus glauca Thunb. (Fagaceae), Rhyncaphytoptus miliusius sp. nov. collected on Miliusa sinensis Finet Gagnep. (Annonaceae). We further report Cecidodectes euzonus Nalepa, 1917, collected on Trema tomentosa (Roxb.) H.Hara (Cannabaceae), for the first time from China. All the species are vagrants on lower leaf surface causing no apparent damage to their host plants.

Ubiquitin-binding domain in ABIN1 is critical for regulating cell death and inflammation during development.

ABIN1 is a polyubiquitin-binding protein known to regulate NF-κB activation and cell death signaling. Mutations in Abin1 can cause severe immune diseases in human, such as psoriasis, systemic lupus erythematosus, and systemic sclerosis. Here, we generated mice that disrupted the ubiquitin-binding domain of ABIN1 (Abin1UBD/UBD) died during later embryogenesis owing to TNFR1-mediated cell death, similar to Abin1-/- mice. Abin1UBD/UBD cells were rendered sensitive to TNF-α-induced apoptosis and necroptosis as the inhibition of ABIN1UBD and A20 recruitment to the TNF-RSC complex leads to attenuated RIPK1 deubiquitination. Accordingly, the embryonic lethality of Abin1UBD/UBD mice was rescued via crossing with RIPK1 kinase-dead mice (Ripk1K45A/K45A) or the co-deletion of Ripk3 and one allele of Fadd, but not by the loss of Ripk3 or Mlkl alone. Unexpectedly, Abin1UBD/UBD mice with the co-deletion of Ripk3 and both Fadd alleles died at E14.5. This death was caused by spontaneous RIPK1 ubiquitination-dependent multiple inflammatory cytokines over production and could be rescued by the co-deletion of Ripk1 or Tnfr1 combined with Ifnar. Collectively, these data demonstrate the importance of the ABIN1 UBD domain, which mediates the ABIN1-A20 axis, at limiting RIPK1 activation-dependent cell death during embryonic development. Furthermore, our findings reveal a previously unappreciated ubiquitin pathway that regulates RIPK1 ubiquitination by FADD/Casp8 to suppress spontaneous IKKε/TBK1 activation.

Two new Diptacus and one new Trimeroptes species (Acari: Diptilomiopidae) from China.

Two new Diptacus species and one new Trimeroptes species (Acari: Eriophyoidea: Diptilomiopidae) are described and illustrated from China: Diptacus suichangensis sp. nov. on Aralia chinensis L. (Araliaceae) and Diptacus pyracanthae sp. nov. on Pyracanthafortuneana (Maxim.) Li (Rosaceae), and Trimeroptes longlinensis sp. nov. on Carpinus sp. (Betulaceae). These new species were found to be vagrant on the lower surface of their associated plants leaves, albeit with no apparent damage observed.

The impact of shift work on glycemic characteristics assessed by CGM and its association with metabolic indices in non-diabetic subjects.

AIM: To explore the glycemic characteristics of non-diabetic shift workers and associations with metabolic indices. METHODS: In this cross-sectional study, 450 non-diabetic males, including 238 shift workers, aged 23-58 years, were recruited after a screening oral glucose tolerance test. Blood samples and anthropometric data were collected. Hundred and fifty of them finished a continuous glucose monitoring for 3-7 days. RESULTS: Compared to daytime workers, shift workers presented with larger WHR (p < 0.001), higher HOMA-IR (p < 0.001), higher hs-CRP level (p < 0.001) and worse lipid profiles. In glycemic characteristics, shift workers with normal glucose regulation had a similar mean blood glucose (MBG), daytime MBG, percentage of time of hyperglycemia, hypoglycemia, euglycemia, and fluctuation parameters, including standard deviation of blood glucose (SDBG), mean amplitude of glycemic excursions (MAGE) and mean of daily differences (p > 0.05, respectively), while they had a higher nighttime MBG (p = 0.026) and blood glucose (BG) at 3 a.m. (p = 0.015). For subjects with impaired glucose regulation, both groups had no difference in any clinical characteristics or glycemic parameters (p > 0.05, respectively). Further regression analysis revealed the association between MBG/SDBG/MAGE/nighttime MBG/BG at 3 a.m. and age/WHR/hs-CRP/TC. CONCLUSION: For non-diabetic shift workers, the glycemic characteristic was the elevated nighttime glycemia, presented as higher nighttime MBG and BG at 3 a.m. And both metrics were closely associated with central obesity. Elevated nighttime glycemia was an early signal of glucose metabolism disorder in shift workers.

Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance.

Diabetes mellitus (DM) can increase the risk of Alzheimer's disease (AD) in patients. However, no effective approaches are available to prevent its progression and development. Recently, autophagy dysfunction was identified to be involved in the pathogenesis of neurodegenerative diseases. This study was designed to investigate the effect of metformin on hyperphosphorylated tau proteins in diabetic encephalopathy (DE) by regulating autophagy clearance. db/db mice were randomly divided into four groups, db/+ mice were used as control group. Twelve-week old male db/db mice received consecutive intraperitoneal injection of 200 mg/kg/d metformin or (and) 10 mg/kg/d chloroquine for eight weeks. Morris water maze (MWM) tests were performed to test cognitive functions before the mice were euthanized. Metformin attenuated cognitive impairment in db/db mice, reduced hyperphosphorylated tau proteins, restored the impaired autophagy in diabetic mice, all of which were reversed by inhibiting of autophagy activity. In high glucose-cultured HT22 cells, metformin increased autophagy in a dose-dependent manner. Besides, metformin enhanced autophagy activity in an AMPK dependent manner. These data show that metformin may reduce tauopathy and improve cognitive impairment in db/db mice by modulating autophagy through the AMPK dependent pathway. These findings highlight metformin as a new therapeutic strategy for the treatment of DE.

Protective Effects of Sulforaphane on Cognitive Impairments and AD-like Lesions in Diabetic Mice are Associated with the Upregulation of Nrf2 Transcription Activity.

Type 2 diabetes mellitus (T2DM)-associated oxidative stress contributes to cognitive deficiencies and Alzheimer's disease (AD). Sulforaphane (SFN) is a pharmacological activator of Nrf2 that provokes Nrf2-mediated intracellular defenses, including antioxidant and anti-inflammatory responses, under oxidative stress (OS) conditions. This study investigated the effects of SFN on DM-related cognitive decline and its potential mechanisms. Morris water maze (MWM) tests showed that SFN (1 mg/kg i.p. for 28 days) mitigated the cognitive decline of db/db mice, a transgenic mouse model of T2DM. Accordingly, immunoblotting and immunohistochemistry analyses showed that SFN decreased the levels of amyloid-ß (Aß) oligomers and Aß 1-42 plaques as well as phospho-tau at Ser396 and Thr231 in the DM mouse hippocampus. This protective effect of SFN might be due to the activation of Nrf2-regulated antioxidant defense deficiencies in the DM mice, as SFN increased the Nrf2 nuclear accumulation and the downstream expression of the antioxidases HO-1 and NQO1 and reduced the levels of the reactive oxygen/nitrogen species (ROS/RNS) in DM mouse brains. Our results confirm that SFN has potential as a therapeutic agent to protect T2DM patients from cognitive deficiencies and AD-like pathological lesions related to the upregulation of Nrf2-regulated antioxidant defenses.

The effect of exercise, resveratrol or their combination on Sarcopenia in aged rats via regulation of AMPK/Sirt1 pathway.

Sarcopenia is an age-related syndrome characterized by progressive loss of muscle mass and function. Exercise is an important strategy to prolong life and increase muscle mass, and resveratrol has been shown a variety beneficial effects on skeletal muscle. In the present study, we investigated the potential efficacy of using short-term exercise (six weeks), resveratrol (150mg/kg/day), or combined exercise+resveratrol (150mg/kg/day) on gastrocnemius muscle mass, grip strength, cross-sectional area and microscopic morphology in aged rats, and explored the potential mechanism at the apoptosis level. Six months old SD rats were used as young control group and 24months old SD rats were adopted as aged group. After six weeks intervention, the data provide evidence that exercise, resveratrol or their combination significantly increase the relative grip strength and muscle mass in aged rats (P<0.05). Electron microscopy discovered a significant increase in sarcomere length, I-band and H-zone in aged rats (P<0.05), and exercise, resveratrol or their combination significantly reduced the increasement (P<0.05). Moreover, light microscopy revealed a significant increase on Feret's diameter and cross-sectional area (CSA) in aged rats (P<0.05), but exercise and resveratrol did not show significant effects on them (P>0.05). Furthermore, exercise, resveratrol or their combination significantly increased the expression of p-AMPK and SIRT1, decreased the expression of acetyl P53 and Bax/Bcl-2 ratio in aged rats (P<0.05). These findings show that aged rats show significant changes in gastrocnemius muscle morphology and ultrastructure, and the protective effects of exercise, resveratrol and their combination are probably associated with anti-apoptotic signaling pathways through activation of AMPK/Sirt1.

Lipid profiling reveals different therapeutic effects of metformin and glipizide in patients with type 2 diabetes and coronary artery disease.

OBJECTIVE: We recently demonstrated a beneficial effect of metformin compared with glipizide in type 2 diabetic patients regarding cardiovascular outcomes for 3-year treatment in the SPREAD-DIMCAD study. However, the potential mechanism for the clinical effects remains unclear. Here, we performed a comprehensive lipidomics study to evaluate the different lipid metabolites in serum samples obtained from participants in this study. RESEARCH DESIGN AND METHODS: Liquid chromatography-quadrupole time of flight-mass spectrometry was used to evaluate the different lipid metabolites in serum samples obtained from the participants (21 patients in glipizide group and 23 patients in metformin group) before and after each year of treatment (at 0 [baseline], 1, 2, and 3 years of study drug administration). RESULTS: A total of 118 serum lipid molecular species was identified and quantified. During treatment, metformin induced a substantially greater change in serum lipid species compared with glipizide, especially at the 2- and 3-year time points (with 2, 11, and 12 lipid species being significantly different between the groups after each year of treatment [1, 2, or 3 years], P < 0.05). Among the significantly changed lipid species, three lipid metabolites were linked to long-term composite cardiovascular events (adjusted P < 0.05). After treatment, triacylglycerols (TAGs) of a relatively higher carbon number showed a clearly increased trend in metformin group compared with the glipizide group, whereas the changes in TAGs with different double bonds were minimal. CONCLUSIONS: Our findings revealed the differential therapeutic effects of metformin and glipizide on comprehensive lipidomics, which were comparable with their different long-term effects on cardiovascular outcomes.

Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease.

OBJECTIVE: The two major classes of antidiabetic drugs, sulfonylureas and metformin, may differentially affect macrovascular complications and mortality in diabetic patients. We compared the long-term effects of glipizide and metformin on the major cardiovascular events in type 2 diabetic patients who had a history of coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 304 type 2 diabetic patients with CAD, mean age = 63.3 years (range, 36-80 years), were enrolled. Participants were randomly assigned to receive either glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years. The primary end points were times to the composite of recurrent cardiovascular events, including death from a cardiovascular cause, death from any cause, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization. RESULTS: At the end of study drug administration, both groups achieved a significant decrease in the level of glycated hemoglobin (7.1% in the glipizide group and 7.0% in the metformin group). At a median follow-up of 5.0 years, 91 participants had developed 103 primary end points. Intention-to-treat analysis showed an adjusted hazard ratio (HR) of 0.54 (95% CI 0.30-0.90; P = 0.026) for the composites of cardiovascular events among the patients that received metformin, compared with glipizide. The secondary end points and adverse events were not significantly different between the two groups. CONCLUSIONS: Treatment with metformin for 3 years substantially reduced major cardiovascular events in a median follow-up of 5.0 years compared with glipizide. Our results indicated a potential benefit of metformin therapy on cardiovascular outcomes in high-risk patients.