Sodium butyrate ameliorated diabetic nephropathy-associated tubulointerstitial inflammation by modulating the tight junctions of renal tubular epithelial cells.

As one of the most significant pathological changes of diabetic nephropathy (DN), tubulointerstitial fibrosis (TIF) had a close relationship with tubulointerstitial inflammation (TI), and the occurrence of TI could have resulted from the disrupted tight junctions (TJs) of renal tubular epithelial cells (RTECs). Studies have demonstrated that sodium butyrate (NaB), a typical short chain fatty acid (SCFA), played an important regulatory role in intestinal TJs and inflammation. In this study, our in vivo and in vitro results showed that accompanied by TI, renal tubular TJs were gradually disrupted in the process of DN-related TIF. In HG and LPS co-cultured HK-2 cells and db/db mice, NaB treatment regained the TJs of RTECs via the sphingosine 1-phosphate receptor-1 (S1PR1)/AMPK signaling pathway, relieving inflammation. Small interfering RNA of S1PR1, S1PR1 antagonist W146 and agonist SEW2871, and AMPK agonist AICAR were all used to further confirm the essential role of the S1PR1/AMPK signaling pathway in NaB's TJ protection in RTECs in vitro. Finally, NaB administration not only improved the renal function and TIF, but also relieved the TI of db/db mice. These findings suggested that the use of NaB might be a potential adjuvant treatment strategy for DN-associated TIF, and this protective effect was linked to the TJ modulation of RTECs via the S1PR1/AMPK signaling pathway, leading to the improvement of TI.

Removal of Expression of Concern: Sodium butyrate ameliorated diabetic nephropathy-associated tubulointerstitial inflammation by modulating tight junction of renal tubular epithelial cells.

Removal of Expression of Concern for 'Sodium butyrate ameliorated diabetic nephropathy-associated tubulointerstitial inflammation by modulating tight junction of renal tubular epithelial cells' by Tingting Yang et al., Food Funct., 2022, Accepted Manuscript, https://doi.org/10.1039/D2FO00940D.

Metformin: A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation.

The occurrence of benign prostate hyperplasia (BPH) was related to disrupted sex steroid hormones, and metformin (Met) had a clinical response to sex steroid hormone-related gynaecological disease. However, whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear. Here, our clinical study showed that along with prostatic epithelial cell (PEC) proliferation, sex steroid hormones were dysregulated in the serum and prostate of BPH patients. As the major contributor to dysregulated sex steroid hormones, elevated dihydrotestosterone (DHT) had a significant positive relationship with the clinical characteristics of BPH patients. Activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor (AR)-mediated Yes-associated protein (YAP1)-TEA domain transcription factor (TEAD4) heterodimers. Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 cells. Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

Downregulation of Sirt3 contributes to ß-cell dedifferentiation via FoxO1 in type 2 diabetic mellitus.

AIMS: FoxO1 is an important factor in the ß-cell differentiation in type 2 diabetes mellitus (T2DM). Sirt3 is found to be involved in FoxO1 function. This study investigated the role of Sirt3 in the ß-cell dedifferentiation and its mechanism. METHODS: Twelve-week-old db/db mice and INS1 cells transfected with Sirt3-specific short hairpin RNA (shSirt3) were used to evaluate the dedifferentiation of ß-cell. Insulin levels were measured by enzyme linked immunosorbent assay. The proteins of Sirt3, T-FoxO1, Ac-FoxO1 and differentiation indexes such as NGN3, OCT4, MAFA were determined by western blot or immunofluorescence staining. The combination of Sirt3 and FoxO1 was determined by the co-immunoprecipitation assay. The transcriptional activity of FoxO1 was detected by dual luciferase reporter assay. RESULTS: Both the in vivo and in vitro results showed that Sirt3 was decreased along with ß-cell dedifferentiation and decreased function of insulin secretion under high glucose conditions. When Sirt3 was knocked down in INS1 cells, increased ß-cell dedifferentiation and lowered insulin secretion were observed. This effect was closely related to the amount loss and the decreased deacetylation of FoxO1, which resulted in a reduction in transcriptional activity. CONCLUSION: Downregulation of Sirt3 contributes to ß-cell dedifferentiation in high glucose via FoxO1. Intervention of Sirt3 may be an effective approach to prevent ß-cell failure in T2DM.

Resveratrol prevents Drp1-mediated mitochondrial fission in the diabetic kidney through the PDE4D/PKA pathway.

To explore the role of PDE4D in diabetic nephropathy (DN) and investigate whether resveratrol protects against DN via inhibiting PDE4D. Diabetic db/db mouse and glomerular mesangial cell line (GMCs) were used to investigate the role of PDE4D and the protective effect of resveratrol on renal fibrosis under high glucose (HG) environment. Resveratrol alleviated the progress of DN via inhibiting mitochondrial fragmentation and restoring the expression of PDE4D, PKA, phosphorylated Drp1-Ser637 and Drp1 in kidney of db/db mice. In HG-exposed GMCs, resveratrol treatment decreased the expression of PDE4D, increased PKA level, and inhibited Drp1-mediated mitochondrial fission. In contrast, PDE4D over-expression blunted the inhibitory effects of resveratrol on Drp1 expression and mitochondrial fission. Moreover, PKA inhibitor H89 blunted the effects of resveratrol on phosphorylated Drp1-Ser637 expression and mitochondrial fission in HG-treated GMCs. Inhibition of mitochondrial fission with Drp1 inhibitor Mdivi-1 alleviated mitochondrial dysfunction in GMCs under HG. These findings indicate PDE4D plays an important role in the process of DN. Resveratrol attenuates the development of DN by preventing mitochondrial fission through inhibiting PDE4D, which regulates the expression of phosphorylated Drp1-Ser637 directly.

TRAF6 promotes chemoresistance to paclitaxel of triple negative breast cancer via regulating PKM2-mediated glycolysis.

Ample evidence reveals that glycolysis is crucial to tumor progression; however, the underlying mechanism of its drug resistance is still worth being further explored. TRAF6, an E3 ubiquitin ligase, is well recognized to overexpress in various types of cancer, which predicts a poor prognosis. In our study, we discovered that TRAF6 was expressed more significantly in the case of triple-negative breast cancer (TNBC) than in other of breast cancers, promoting chemoresistance to paclitaxel; that inhibited TRAF6 expression in the chemoresistant TNBC (TNBC-CR) cells enhanced the sensitivity by decreasing glucose uptake and lactate production; that TRAF6 regulated glycolysis and facilitated chemoresistance via binding directly to PKM2; and that overexpressing PKM2 in the TNBC-CR cells with TRAF6 knocked down regained significantly TRAF6-dependent drug resistance and glycolysis. Additionally, we verified that TRAF6 could facilitate PKM2-mediated glycolysis and chemoresistance in animal models and clinical tumor tissues. Thus, we identified the novel function of TRAF6 to promote glycolysis and drug resistance in TNBC with the regulation of PKM2, which could provide a potential molecular target for TNBC treatment.

Resveratrol ameliorates diabetic encephalopathy through PDE4D/PKA/Drp1 signaling.

Diabetic encephalopathy (DE) is a central nervous complication of diabetes mellitus which is characterized by cognitive impairment and neurochemical abnormalities. However, no effective approaches are available to prevent its progression and development. PDE4D serves many functions in the pathogenesis of neurodegenerative diseases involving PKA signaling. This study illustrated the role of PDE4D in DE and investigated whether resveratrol protected against DE via inhibiting PDE4D. db/db male mice and hippocampus cell line (HT22) were used to investigate the role of PDE4D and the protective effect of resveratrol on cognitive function under high glucose (HG). PDE4D overexpression or knockdown lentivirus and PKA specific inhibitor H89 were used to further identify the indispensable role of PDE4D/PKA signaling pathway in resveratrol's amelioration effect of neurotoxicity. Resveratrol attenuated cognitive impairment in db/db mice, reduced PDE4D protein, restored the impaired mitochondrial function in db/db mice. The in vitro study also confirmed the neuroprotective effect of resveratrol on neurotoxicity. PDE4D overexpression resulted in cell injury and downregulation of cAMP, PKA and pDrp1(Ser637) under normal condition. In contrast, PDE4D knockdown improved cell injury and elevated cAMP, PKA and pDrp1(Ser637) levels caused in HG-cultured HT22 cells. PDE4D over-expression blunted the improvement effects of resveratrol on PKA, pDrp1(Ser637) and mitochondrial function. Moreover, PKA inhibitor H89 blunted the inhibitory effects of resveratrol on pDrp1(Ser637) and mitochondrial function in HG-treated HT22. These data indicated that resveratrol may improve cognitive impairment in db/db mice by modulating mitochondrial function through the PDE4D dependent pathway.

CBX4 deletion promotes tumorigenesis under KrasG12D background by inducing genomic instability.

Chromobox protein homolog 4 (CBX4) is a component of the Polycomb group (PcG) multiprotein Polycomb repressive complexes 1 (PRC1), which is participated in several processes including growth, senescence, immunity, and tissue repair. CBX4 has been shown to have diverse, even opposite functions in different types of tissue and malignancy in previous studies. In this study, we found that CBX4 deletion promoted lung adenocarcinoma (LUAD) proliferation and progression in KrasG12D mutated background. In vitro, over 50% Cbx4L/L, KrasG12D mouse embryonic fibroblasts (MEFs) underwent apoptosis in the initial period after Adeno-Cre virus treatment, while a small portion of survival cells got increased proliferation and transformation abilities, which we called selected Cbx4-/-, KrasG12D cells. Karyotype analysis and RNA-seq data revealed chromosome instability and genome changes in selected Cbx4-/-, KrasG12D cells compared with KrasG12D cells. Further study showed that P15, P16 and other apoptosis-related genes were upregulated in the primary Cbx4-/-, KrasG12D cells due to chromosome instability, which led to the large population of cell apoptosis. In addition, multiple pathways including Hippo pathway and basal cell cancer-related signatures were altered in selected Cbx4-/-, KrasG12D cells, ultimately leading to cancer. We also found that low expression of CBX4 in LUAD was associated with poorer prognosis under Kras mutation background from the human clinical data. To sum up, CBX4 deletion causes genomic instability to induce tumorigenesis under KrasG12D background. Our study demonstrates that CBX4 plays an emerging role in tumorigenesis, which is of great importance in guiding the clinical treatment of lung adenocarcinoma.

Correction to: YY1 inactivated transcription co-regulator PGC-1α to promote mitochondrial dysfunction of early diabetic nephropathy-associated tubulointerstitial fibrosis.

The development of diabetic nephropathy (DN) could be promoted by the occurrence of tubulointerstitial fibrosis (TIF), which has a close relationship with mitochondrial dysfunction of renal tubular epithelial cells (RTECs). As a key regulator of metabolic homeostasis, Yin Yang 1 (YY1) plays an important role not only in regulating the fibrosis process but also in maintaining the mitochondrial function of pancreatic ß-cells. However, it was not clear whether YY1 participated in maintaining mitochondrial function of RTECs in early DN-associated TIF. In this study, we dynamically detected mitochondrial functions and protein expression of YY1 in db/db mice and high glucose (HG)-cultured HK-2 cells. Our results showed that comparing with the occurrence of TIF, the emergence of mitochondrial dysfunction of RTECs was an earlier even, besides the up-regulated and nuclear translocated YY1. Correlation analysis showed YY1 expressions were negatively associated with PGC-1α in vitro and in vivo. Further mechanism research demonstrated the formation of mTOR-YY1 heterodimer induced by HG up-regulated YY1, the nuclear translocation of which inactivated PGC-1α by binding to the PGC-1α promoter. Overexpression of YY1 induced mitochondrial dysfunctions in normal glucose-cultured HK-2 cells and 8-weeks-old db/m mice. While, dysfunctional mitochondria induced by HG could be improved by knockdown of YY1. Finally, downregulation of YY1 could retard the progression of TIF by preventing mitochondrial functions, resulting in the improvement of epithelial-mesenchymal transition (EMT) in early DN. These findings suggested that YY1 was a novel regulator of mitochondrial function of RTECs and contributed to the occurrence of early DN-associated TIF.

Targeting mTOR/YY1 signaling pathway by quercetin through CYP7A1-mediated cholesterol-to-bile acids conversion alleviated type 2 diabetes mellitus induced hepatic lipid accumulation.

BACKGROUND: Hepatic lipid accumulation was a major promoter for the further development of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2DM). mTOR/YY1 signaling pathway regulated many metabolic processes in different organs, and played an important role in hepatic lipid metabolism. Thus, targeting mTOR/YY1 signaling pathway might be a novel therapeutic strategy of T2DM-associated NALFD. PURPOSE: To investigate the effects and the mechanism of quercetin against T2DM-associated NAFLD. STUDY DESIGN AND METHODS: The combine abilities of 24 flavonoid compounds with mTOR were detected by computer virtual screening (VS) and molecular modeling. mTOR/YY1 signaling pathway was examined in the liver of db/db mice, and high glucose (HG) and free fatty acid (FFA) co-cultured HepG2 cells. YY1 overexpression lentivirus vector and mTOR specific inhibitor rapamycin were used to further identify the indispensable role of mTOR/YY1 signaling pathway in quercetin's amelioration effect of hepatic lipid accumulation in vitro. Clinical studies, luciferase assay and chromatin immunoprecipitation (ChIP) assay were all carried out to investigate the potential mechanisms by which quercetin exerted its amelioration effect of hepatic lipid accumulation. RESULTS: Quercetin had the strongest ability to combine with mTOR and could competitively occupy its binding pocked. Along with the alleviated hepatic injury by quercetin, mTOR/YY1 signaling pathway was down-regulated in vivo and in vitro. However, the alleviation effect of quercetin against hepatic lipid accumulation was inhibited by YY1 overexpression in vitro. Mechanistically, the down-regulated nuclear YY1 induced by quercetin directly bound to CYP7A1 promoter and activated its transcription, resulting in the restoration of cholesterol homeostasis via the conversion of cholesterol-to-bile acids (BAs). CONCLUSION: The hepatoprotective effect of quercetin on T2DM-associated NAFLD was linked to the restoration of cholesterol homeostasis by the conversion of cholesterol-to-BAs via down-regulating mTOR/YY1 signaling pathway, leading to the increased CYP7A1 activity.

Analyses of Transcriptomics upon IL-1ß-Stimulated Mouse Chondrocytes and the Protective Effect of Catalpol through the NOD2/NF-κB/MAPK Signaling Pathway.

The overall objective of this study was to investigate the mechanism of inflammation on chondrocyte injury and the protective effect of catalpol on chondrocytes in an inflammatory environment. Chondrocytes were isolated and cultured from the knee joints of three-day-old newborn mice. Alcian Blue staining and the immunocytochemistry staining of type II collagen were used to identify the purity of chondrocytes. Primary chondrocytes were stimulated by IL-1ß (10 ng/mL) and subjected to transcriptome analysis. Differentially expressed genes (DEGs) were further analyzed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. In this experimental study, we performed the viability assay to determine the effects of different concentrations of catalpol on the cell viability of chondrocytes. Chondrocytes were seeded in six-well plates and exposed to 10 µM catalpol 2 h prior to treatment with IL-1ß (10 ng/mL). Quantitative real-time (qPCR) and Western blotting were performed to evaluate the RNA and protein expression, respectively. Based on the results of transcriptomics analysis, we found the NOD2 signaling pathway, the NF-kappa B signaling pathway, and the MAPK signaling pathway showed significant changes in chondrocyte damage caused by inflammation. Catalpol (10 µM and 100 µM) could significantly reduce NO, IL-6, IL-1ß, and TNF-α in supernatant of chondrocytes. Catalpol significantly inhibited the mRNA expression of IL-1, IL-6, and IL-12 in chondrocytes induced by IL-1ß. Catalpol markedly inhibited MMP3, MMP13 mRNA, and protein levels. Catalpol could significantly reduce TNF-α mRNA levels in inflammatory chondrocytes. Inflammation causes significant increases in mRNA levels and protein levels of NOD2, mRNA levels, and protein levels were markedly suppressed by catalpol. In addition, catalpol could significantly increase IKBα protein levels and significantly lower intranuclear P65 levels. Catalpol significantly lowered the phosphorylation protein levels of ERK, p38, and JNK. Our transcriptomic analysis demonstrated that the activation of NOD2 and its downstream pathways, NF-κB and MAPK, is an important cause of the inflammatory injury to chondrocytes induced by IL-1ß. Catalpol inhibited the activation of the NOD2 signaling pathway, which reduced the phosphorylation of ERK, p38, and JNK, inhibited the degradation of IκBα, inhibited p65 translocation into the nucleus, reduced the release of inflammatory cytokines, and attenuated the inflammatory damage to chondrocytes.

Inhibition of S100A8/A9 ameliorates renal interstitial fibrosis in diabetic nephropathy.

BACKGROUND: Renal interstitial fibrosis (RIF) is one of the main features of diabetic nephropathy (DN), but the molecular mechanisms mediating RIF in DN has yet been fully understood. S100A8 and S100A9 are the proteins associated with immune and inflammation response. Here we reported the expression of S100A8 and S100A9 were significantly increased on tubular epithelial cells in diabetic kidneys through a proteomic analysis. METHODS: We detected the expression of S100A8/A9 in diabetic kidneys by using immunoblotting, real-time PCR and immunostaining. RNA silencing and overexpression were performed by using S100A8/A9 expression/knockdown lentivirus to investigate the connection between S100A8/A9 and epithelial to mesenchymal transition (EMT) process. We also identify the expression of TLR4/NFκB pathway-related molecules in the case mentioned above. Afterwards a CO-IP assay was used to verify that compound AB38b ameliorates the EMT by interfering S100A8/A9 expression. RESULTS: The expression of S100A8 and S100A9 were significantly increased on tubular epithelial cells in diabetic kidneys. S100A8/A9 knocking-down alleviate and over-expression promote the renal interstitial fibrosis of diabetic mice. Mechanically, high levels of S100A8/A9 expression in tubular epithelial cells during diabetic condition activated the TLR4/NF-κB signal pathway which promoted the EMT process and finally led to RIF progression. S100A8/A9 knockdown ameliorated RIF of diabetic mice. Further experiments revealed that compound AB38b inhibited the EMT progression of tubular epithelial cells induced by S100A8/A9 through interfering the expressions of S100A8/A9. CONCLUSIONS: Our study suggest that abnormal expression of S100A8/A9 in the disease condition promotes EMT process and RIF through TLR4/NF-κB signal pathway. Using small molecular inhibitor AB38b to inhibit the abnormal expressions of S100A8/A9 might be a novel therapeutic strategy in treating DN.

FADD phosphorylation contributes to development of renal fibrosis by accelerating epithelial-mesenchymal transition.

FADD, a classical apoptotic signaling adaptor, has recently been reported to exhibit a series of non-apoptotic functions. Here, we report that FADD may play a critical role in the development of renal fibrosis. Neutrophil infiltration in the renal interstitial part, glomerular mesangial cell proliferation, and base-membrane thickening were observed in FADD-D mice by H&E, PAS, and PASM staining. Immunofluorescence analysis revealed that macrophage infiltration was significantly enhanced in FADD-D mice. Renal fibrosis might be induced by IgA nephritis in FADD-D mice as evidenced by increased Ki67 and type IV collagen. Additionally, the levels of α-SMA, Fibronectin, and Vimentin were also found to be elevated. Mechanism study indicated that the TLR4/myD88/NF-κB signaling pathway was activated in FADD-D mice. Moreover, FADD phosphorylation activated the mTOR and TGF-ß/Smad pathway and accelerated the process of epithelial mesenchymal transition. Further studies indicated that the TGF-ß1 pathway was also activated and the process of EMT was accelerated in both FADD-disrupted HEK293 cells and FADD-deficient MES cells. Thus, we concluded that FADD phosphorylation could lead to IgA nephritis and eventually result in renal fibrosis. Taken together, our study provides evidence, for the first time, that FADD, especially in its phosphorylated form, has an effect on the development of renal fibrosis.Abbreviations: FADD: FAS-associated protein with death domain; DED: death effector domain; DD: death domain; CKD: chronic kidney disease; ECM: extracellular matrix; ESRD: end-stage renal disease; RRT: renal replacement therapy; H&E: hematoxylin and eosin; PASM: periodic acid silver methenamine.

The genetic side of diabetic kidney disease: a review.

BACKGROUND: Diabetic kidney disease (DKD) is one of the most common complications of diabetes, with approximately 30-40% of patients with type 1 diabetes mellitus and 20% of patients with type 2 diabetes mellitus eventually developing DKD. If DKD is not controlled in the early clinical stage and proteinuria develops, the disease will progress to end-stage renal disease. The pathogenesis of DKD remains largely unknown and is multifactorial, likely due to interactions between genetic and environmental factors. Familial clustering also supports a critical role of hereditary factors in DKD. The development of gene detection technology has promoted the exploration of DKD susceptibility genes in different cohorts of patients with diabetes. Identifying susceptibility genes can provide insights into the pathogenesis of DKD, as well as a basis for its clinical diagnosis and therapy. RESULTS: Numerous candidate gene loci have been found to be associated with DKD, many of which play critical regulatory roles in the pathogenesis of this disease, including genes involved in glycol-metabolism, lipid metabolism, the renin-angiotensin-aldosterone system, inflammation and oxidative stress. In this review, we summarize the functions of several susceptibility genes involved in the development of DKD. CONCLUSION: Based on our findings, we recommend that studying susceptibility gene polymorphisms can lead to a better understanding of the pathogenesis of DKD and could help prevent this disease or improve its outcomes.

Hesperidin Exerts Anxiolytic-like Effects in Rats with Streptozotocin- Induced Diabetes via PKA/CREB Signaling.

BACKGROUND: The mechanisms underlying synaptic injury and anxiety-like behavioral changes caused by diabetes and the strategies to reverse these changes are not well understood. OBJECTIVES: This study examined the neuroprotective effects of hesperidin on anxiety-like behaviors in diabetic rats and investigated the underlying mechanisms from the perspective of the PKA/CREB pathway. METHODS: Rats with streptozotocin-induced diabetes were treated orally with hesperidin (50 and 150 mg/kg) for 10 weeks. The elevated plus maze (EPM), hole board test (HBT), and marbleburying test (MBT) were used to assess anxiety-like behaviors. We further examined the effects of hesperidin on the PKA/CREB pathway in vivo and in vitro. RESULTS: The results show that supplementation with hesperidin exerted anxiolytic effects on the diabetic rats, as evidenced by increased percentages of open arm entries and time spent in the open arms in the EPM; decreased numbers of hole visits in the HBT; decreased numbers of marbles buried; and increased expression of PKA, CREB, BDNF, and synaptic proteins in the amygdala and hippocampus of diabetic rats. Hesperidin was found to reverse the imbalance in the PKA/CREB/BDNF pathway. In vitro, we found that the PKA inhibitor H89 reversed the protective effects of hesperidin against cell injury and reversed the HG-induced expression of PKA, pCREB/CREB, and BDNF. CONCLUSION: Our results demonstrated that hesperidin could ameliorate the anxiety-like behaviors of diabetic rats and that activating the PKA/CREB/BDNF pathway contributed to the beneficial effects. This study may provide important insights into the mechanisms underlying anxiety-like behaviors in diabetes and identify new therapeutic targets for clinical treatment.

YY1 inactivated transcription co-regulator PGC-1α to promote mitochondrial dysfunction of early diabetic nephropathy-associated tubulointerstitial fibrosis.

The development of diabetic nephropathy (DN) could be promoted by the occurrence of tubulointerstitial fibrosis (TIF), which had a closely relationship with mitochondrial dysfunction of renal tubular epithelial cells (RTECs). As a key regulator of metabolic homeostasis, Yin Yang 1 (YY1) played an important role not only in regulating fibrosis process, but also in maintaining mitochondrial function of pancreatic ß cells. However, it was not clear whether YY1 participated in maintaining mitochondrial function of RTECs in early DN-associated TIF. In this study, we dynamically detected mitochondrial functions and protein expression of YY1 in db/db mice and high glucose (HG)-cultured HK-2 cells. Our results showed that comparing with the occurrence of TIF, the emergence of mitochondrial dysfunction of RTECs was an earlier even, besides the up-regulated and nuclear translocated YY1. Correlation analysis showed YY1 expressions were negatively associated with PGC-1α in vitro and in vivo. Further mechanism research demonstrated the formation of mTOR-YY1 heterodimer induced by HG upregulated YY1, the nuclear translocation of which inactivated PGC-1α by binding to the PGC-1α promoter. Overexpression of YY1 induced mitochondrial dysfunctions in normal glucose cultured HK-2 cells and 8-week-old db/m mice. While, dysfunctional mitochondria induced by HG could be improved by knockdown of YY1. Finally, downregulation of YY1 could retard the progression of TIF by preventing mitochondrial functions, resulting in the improvement of epithelial-mesenchymal transition (EMT) in early DN. These findings suggested that YY1 was a novel regulator of mitochondrial function of RTECs and contributed to the occurrence of early DN-associated TIF .

Dual-function photonic spin Hall effect sensor for high-precision refractive index sensing and graphene layer detection.

In this paper, a photonic spin Hall effect (PSHE) sensor for high-precision refractive index (RI) detection and graphene layer number detection is proposed. Numerical analysis is performed by the transfer matrix method. The graphene material is introduced into the layered topology to stimulate the generation of PSHE phenomenon, and both H polarization and V polarization displacements occur simultaneously. The effects of parameters such as chemical potential, relaxation time, and external temperature on the PSHE shift are also discussed. The displacement of H polarization can be used for RI detection, and the measurement range (MR), sensitivity (S), figure of merit (FOM), and detection limit (DL) are 1.1-1.5, 127.85 degrees/RIU, 2412, and 2.08×10-5, respectively. The superior sensing performance provides a theoretical possibility for the detection of solids, liquids, and gases. The shift characteristic of V polarization is appropriate for detecting the number of layers in graphene, with a MR and S of 1-9 layers and 4.54 degrees/layer. The impacts of dielectric loss on sensor performance are also considered. We hope that the proposed PSHE multifunctional sensor can improve a theoretical idea for novel sensor design.

Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus.

Background: Exenatide is a GLP-1R agonist that often exhibits considerable interindividual variability in therapeutic efficacy. However, there is no evidence about the impact of genetic variants in the PPARD on the therapeutic efficacy of exenatide. This research was aimed to explore the influence of PPARD gene polymorphism on the therapeutic effect of exenatide, and to identify the potential mechanism futher. Methods: A total of 300 patients with T2DM and 200 control subjects were enrolled to identify PPARD rs2016520 and rs3777744 genotypes. A prospective clinical study was used to collect clinical indicators and peripheral blood of T2DM patients treated with exenatide monotherapy for 6 months. The SNaPshot method was used to identify PPARD rs2016520 and rs3777744 genotypes, and then we performed correlation analysis between PPARD gene variants and the efficacy of exenatide, and conducted multiple linear regression analysis of factors affecting the therapeutic effect of exenatide. HepG2 cells were incubated with exenatide in the absence or presence of a PPARδ agonist or the siPPARδ plasmid, after which the levels of GLP-1R and the ratio of glucose uptake were determined. Results: After 6 months exenatide monotherapy, we observed that homeostasis model assessment for insulin resistance (HOMA-IR) levels of the subjects with at least one C allele of the PPARD rs2016520 were significantly lower than those with the TT genotype, which suggested that the PPARD rs2016520 TT genotype conferred the poor exenatide response through a reduction of insulin resistance, as measured by HOMA-IR. The carriers of G alleles at rs3777744 exhibited higher levels of in waist to hip ratio (WHR), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) and HOMA-IR compared to individuals with the AA genotype following 6 months of exenatide treatment, potentially accounting for the lower failure rate of exenatide therapy among the AA homozygotes. In an insulin resistant HepG2 cell model, the PPARδ agonists enhanced exenatide efficacy on insulin resistance, with the expression of GLP-1R being up-regulated markedly. Conclusion: These data suggest that the PPARD rs2016520 and rs3777744 polymorphisms are associated with exenatide monotherapy efficacy, due to the pivotal role of PPARδ in regulating insulin resistance through affecting the expression of GLP-1R. This study was registered in the Chinese Clinical Trial Register (No. ChiCTR-CCC13003536).

Decreased Sirt3 contributes to cyclic production of reactive oxygen species and islet ß-cell apoptosis in high glucose conditions.

BACKGROUND: Reactive oxygen species (ROS) plays a vital role in the apoptosis of islet ß-cells in type 2 diabetes mellitus (T2DM). Sirt3 (Sirtuin 3, a deacetylase) and FoxO1 (a transcription factor) might be involved in ROS production. This study was to investigate mechanism of ROS production and ß-cell apoptosis in T2DM. METHODS: Oxidative stress and apoptosis in islets of db/db mice and high glucose cultured ß-cells were observed by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay and western blotting. Then, H2O2 was used to ascertain the effect of ROS on the expression of Sirt3. Meanwhile, FoxO1, antioxidant enzymes - catalase (CAT) and manganese superoxide dismutase (MnSOD) and ß-cell apoptosis were also determined by western blotting. Finally, Sirt3 was knocked down to evaluate the effect on oxidative stress and apoptosis of ß-cells. RESULTS: Under high glucose environment, enhanced ROS made a decrease of Sirt3 expression, which increased acetylation of FoxO1, thus reduced the expression of its target proteins -MnSOD and CAT, and further significantly increased ROS levels. Increased ROS finally led to the apoptosis of ß-cells. CONCLUSION: Down-regulation of Sirt3 plays an important role in the cyclic production of ROS and ß-cell apoptosis. Targeting Sirt3 may be favorable for the treatment of T2DM.

Erratum: Cx43 deficiency confers EMT-mediated tamoxifen resistance to breast cancer via c-Src/PI3K/Akt pathway: Erratum.

[This corrects the article DOI: 10.7150/ijbs.55453.].