Retinal vascular density as a potential biomarker of diabetic cerebral small vessel disease.

AIM: The retina and brain share similar anatomical and physiological features. Thus, retinal imaging by optical coherence tomography angiography (OCTA) might be a potential tool for the early diagnosis of diabetic cerebral small vessel disease (CSVD). In this study, we aimed to evaluate retinal vascular density (VD) in diabetic CSVD by OCTA imaging and explore the associations between retinal VD and cerebral magnetic resonance imaging (MRI) markers and cognitive function. METHODS: In total, 131 patients were enrolled, including CSVD (n = 43) and non-CSVD groups (n = 88). The VD and foveal avascular zone of the retinal capillary plexus were measured with OCTA. A brain MRI was performed. RESULTS: MRI imaging showed that in the diabetic CSVD group, white matter hyperintensities (WMHs), particularly deep WMHs (58.82%), are the most common MRI marker, followed by cerebral microbleeds in the subtentorial and cortical areas (34.78%). The CSVD group showed increases in the prevalence of cognitive dysfunction (p = .034) and depression (p = .033) and decreases in visuospatial/executive ability and delayed recall ability. In the CSVD group, VDs of the macular superficial vascular plexus (32.93 ± 7.15% vs. 36.97 ± 6.59%, p = .002), intermediate capillary plexus (20.87 ± 4.30% vs. 23.08 ± 4.30%, p = .005) and deep capillary plexus (23.54 ± 5.00% vs. 26.05 ± 4.20%, p = .003) were lower than those of the non-CSVD group. Multiple linear regression analysis showed that VD of the macular superficial vascular plexus was independently associated with cerebral microbleeds. Meanwhile, VD of the macular intermediate capillary plexus was associated with white matter lacunar infarcts after adjustment. CONCLUSIONS: Diabetic CSVDs are characterized by MRI markers, including deep WMHs and cerebral microbleeds, and showed impaired cognition with decreased visuospatial/executive ability and delayed recall ability. OCTA imaging revealed a significant decrease in retinal microvascular perfusion in diabetic CSVD, which was related to MRI markers and cognitive function. OCTA might be a valuable potential measurement for the early diagnosis of CSVD.

Glycerol-3-phosphate acyltransferases and metabolic syndrome: recent advances and future perspectives.

Triglycerol-3-phosphate acyltransferases (GPATs) are the key enzymes in the first step of the synthesis of triacylglycerol (TAG). In mammals, there are four isoforms of GPATs. GPAT1 and GPAT2 are localised in the outer mitochondrial membrane, while GPAT3 and GPAT4 are localised in the endoplasmic reticulum. Previous research has emphasised that GPAT plays a critical effect on the development of metabolic syndromes, such as liver steatosis, obesity, and insulin resistance. In this review, we will critically evaluate the regulatory effects of GPATs isoforms in metabolic syndrome. In addition, we also discuss perspectives on clinical intervention strategies for the neurometabolic disease.

Immune checkpoint inhibitor-associated pituitary adverse events: an observational, retrospective, disproportionality study.

PURPOSE: The aim of this study was to identify and characterize immune checkpoint inhibitors (ICIs)-associated pituitary adverse events (AEs). METHODS: This is a retrospective disproportionality study based on VigiBase, the World Health Organization (WHO) global database of individual case safety reports (ICSRs), with a study period from January 1, 2011 to March 6, 2019. Information component (IC) and reporting odds ratio (ROR) are measures of disproportionate analysis. IC was used to evaluate the association between ICIs and pituitary AEs, while ROR was used to evaluate the differences in reporting of pituitary AEs between different ICI subgroups. RESULTS: The following ICI-associated pituitary diseases have been increasingly reported: hypophysitis (835 reports; information component 6.74 [95% CI 6.63-6.83]), hypopituitarism (268; 6.12 [95% CI 5.92-6.27]), pituitary enlargement (28; 5.19 [95% CI 4.57-5.63]). The anti-CTLA-4 subgroup had a stronger association with hypophysitis/hypopituitarism than the anti-PD (anti-PD-1 or anti-PD-L1) subgroup (ROR 8.0 [95% CI 6.7-9.6]). Among ICI-associated hypophysitis/hypopituitarism cases, the proportion of male was higher than female (630 [63.9%] vs 356 [36.1%]). Anti-CTLA-4 subgroup and ICI combination (nivolumab plus ipilimumab) subgroup both had a significantly earlier onset time than anti-PD subgroup (67 days [IQR 48-87]; 90 [IQR 34-155]; 140 [IQR 62-218], both p < 0.05). Other endocrinopathies that co-occurred with hypophysitis/hypopituitarism were adrenal insufficiency, thyroid dysfunction, diabetes mellitus and diabetes insipidus. Gastrointestinal disorder was the most common concurrent disease except for endocrinopathies. CONCLUSIONS: ICI-associated pituitary adverse events have significantly increased, and their clinical characteristics should be kept in mind by oncologists and endocrinologists who manage patients treated by immunotherapy.

MiR-146a-5p Contributes to Microglial Polarization Transitions Associated With AGEs.

M1/M2 polarization transitions of microglial phenotypes determine the states of neuroinflammation, which is critical in the pathophysiology of diabetic encephalopathy. This study aims to investigate the effects of advanced glycation end products (AGEs) on the microglial polarization state, the role of miR-146a-5p in the regulation of microglial polarization, and the underlying signaling pathways. BV-2 cells were incubated with N-ε-carboxymethyl lysine (CML), one kind of Advanced Glycation End Products (AGEs), to induce polarization. CD11b and iNOS and CD206 and Arg-1 were used to evaluate M1 and M2 microglia, respectively. The mRNA and protein expression levels of miR-146a-5p, transcription factor NF-κB, and inflammasome NLRP3 were measured. High and low expression of miR-146a-5p in the BV-2 cell line was generated by lentivirus transfection technology. RAGE, TLR-4, and NF-κB antagonists were applied to evaluate the underlying signaling pathways. Compared with the control group, CML upregulated the M1 phenotype and downregulated the M2 phenotype. These effects were reversed by overexpression of miR-146a. Furthermore, the expression of inflammasome NLRP3 and NF-κB was upregulated in the CML group and was reduced after miR-146a overexpression. And then overexpression of miR-146a effects was reversed by inhibition miR-146a expression. An NF-κB antagonist (PDTC), a RAGE antagonist (FPS-ZMI), and a TLR-4 antagonist (TLI-095) all reversed the polarization state induced by CML. In summary, CML induced polarization transitions to M1 phenotype and promoted inflammasome NLRP3 expression in BV-2 cells. The RAGE or TLR-4/miR-146a/NLRP3/NF-кB pathway might participate in the regulation of CML-induced BV-2 polarization.

AI algorithms for accurate prediction of osteoporotic fractures in patients with diabetes: an up-to-date review.

Osteoporotic fractures impose a substantial burden on patients with diabetes due to their unique characteristics in bone metabolism, limiting the efficacy of conventional fracture prediction tools. Artificial intelligence (AI) algorithms have shown great promise in predicting osteoporotic fractures. This review aims to evaluate the application of traditional fracture prediction tools (FRAX, QFracture, and Garvan FRC) in patients with diabetes and osteoporosis, review AI-based fracture prediction achievements, and assess the potential efficiency of AI algorithms in this population. This comprehensive literature search was conducted in Pubmed and Web of Science. We found that conventional prediction tools exhibit limited accuracy in predicting fractures in patients with diabetes and osteoporosis due to their distinct bone metabolism characteristics. Conversely, AI algorithms show remarkable potential in enhancing predictive precision and improving patient outcomes. However, the utilization of AI algorithms for predicting osteoporotic fractures in diabetic patients is still in its nascent phase, further research is required to validate their efficacy and assess the potential advantages of their application in clinical practice.

Fibrinogen function indexes are potential biomarkers of diabetic peripheral neuropathy.

BACKGROUND AND OBJECTIVES: Research suggests that diabetic peripheral neuropathy (DPN) is related to plasma fibrinogen (Fib) concentrations, although its correlation with Fib function has not been reported. Here, the k value and angle α, reflecting the plasma Fib function, were used to analyse its correlation with DPN, and their potential as biological indicators for diagnosing DPN was explored. SUBJECTS AND METHODS: This prospective observational clinical study enrolled 561 type 2 diabetes mellitus (T2DM) patients, who were divided into the diabetes with symptomatic neuropathy (161 cases), diabetes with asymptomatic neuropathy (132 cases) and diabetes with no neuropathy (268 cases) groups. Meanwhile, 160 healthy unrelated subjects were recruited as controls. RESULTS: Fib levels increased slightly in diabetic subjects with neuropathy compared with those without. The angle α levels increased slightly in subjects with asymptomatic DPN compared with those with no neuropathy and increased greatly in subjects with symptomatic DPN compared with those without. The k value levels slightly decreased in subjects with asymptomatic DPN compared with those with no neuropathy and greatly decreased in subjects with symptomatic DPN compared with those without. The association of the k value and angle α with diabetic neuropathy was independent of the hyperglycaemic state and other potential confounders (odds ratio 0.080 [0.051-0.124], P < 0.001; odds ratio 1.131 [1.063-1.204], P < 0.001). The k value and angle α levels were closely correlated with neuropathy stage (r = - 0.686, P < 0.000; r = 0.314, P < 0.001). The optimal cut-off point for k value levels to distinguish patients with diabetic neuropathy from those without was 1.8 min, with a sensitivity of 73.7% and a specificity of 83.2% (AUC = 0.873). The optimal cut-off point for angle α levels was 60°, with a sensitivity of 41.0% and a specificity of 95.6% (AUC = 0.669). CONCLUSIONS: The k value and angle α are closely associated with DPN. The levels of the k value and angle α may be helpful in the early diagnosis of DPN.

Optical coherence tomography of the retina combined with color Doppler ultrasound of the tibial nerve in the diagnosis of diabetic peripheral neuropathy.

Objective: To investigate the value of the retinal nerve fiber layer (RNFL) thickness in the optic disc and the cross-sectional area (CSA) of lower limb nerves in the diagnosis of diabetic peripheral neuropathy (DPN) separately and in combination. Methods: A total of 140 patients with type 2 diabetes were enrolled, including 51 patients with DPN (DPN group) and 89 patients without DPN (NDPN group). Clinical data and biochemical parameters were collected. Electromyography/evoked potential instrument was performed for nerve conduction study. Optical coherence tomography was performed to measure the RNFL thickness of the optic disc. Color Doppler ultrasound was performed to measure CSA of lower limb nerves. Results: The RNFL thickness was lower and the CSA of the tibial nerve (TN) in the DPN group was larger than that in the NDPN group. The album/urine creatinine ratio, diabetic retinopathy, and CSA of TN at 3 cm were positively correlated with DPN. The RNFL thickness in the superior quadrant of the optic disc was negatively correlated with DPN. For RNFL thickness to diagnose DPN, the area under the curve (AUC) of the superior quadrant was the largest, which was 0.723 (95% confidence interval [CI]: 0.645-0.805), and the best cutoff value was 127.5 µm (70.5% sensitivity, 72.1% specificity). For CSA of TN to diagnose DPN, the AUC of the distance of 5 cm was the largest, which was 0.660 (95% CI: 0.575-0.739), and the best cutoff value was 13.50 mm2 (82.0% sensitivity, 41.6% specificity). For the combined index, the AUC was greater than that of the above two indicators, which was 0.755 (95% CI: 0.664-0.846), and the best cutoff value was 0.376 (64.3% sensitivity, 83.0% specificity). Conclusions: Patients with DPN have a reduction of the RNFL thickness and an increase in the CSA of TN, and these two changes are related to DPN. The RNFL thickness of the optic disc and the CSA of TN can be used as diagnostic indicators of DPN, and the combination of the two indicators has a higher diagnostic value.

Inhibition of thyroid-restricted genes by follicular thyroglobulin involves iodinated degree.

Follicular thyroglobulin (TG) reflects the storage of both iodine and thyroid hormone. This is because it is a macromolecular precursor of thyroid hormone and organic iodinated compound in follicular lumen. Thus, it may have an important feedback role in thyroid function. In this study, monolayer cells were cultured and follicles were reconstituted with primary pig thyroid cells in vitro. Reconstituted follicles were treated with iodine and methimazole (MMI), a drug that blocks iodine organification and reduces the degree of TG iodination in follicular lumen. The high degree of iodinated TG in follicular lumen was observed to inhibit thyroid-restricted gene expression. To confirm this finding, monolayer thyroid cells were treated with a different degree of TG iodination at the same concentration. These iodinated TG were extracted from reconstituted follicles of different groups. In this manner, this study provides firsthand evidence suggesting that follicular TG inhibits the expressions of thyroid-restricted genes NIS, TPO, TG, and TSHr.

Neuropeptide Y and Metabolism Syndrome: An Update on Perspectives of Clinical Therapeutic Intervention Strategies.

Through the past decade of research, the pathogenic mechanisms underlying metabolic syndrome have been suggested to involve not only the peripheral tissues, but also central metabolic regulation imbalances. The hypothalamus, and the arcuate nucleus in particular, is the control center for metabolic homeostasis and energy balance. Neuropeptide Y neurons are particularly abundantly expressed in the arcuate of the hypothalamus, where the blood-brain barrier is weak, such as to critically integrate peripheral metabolic signals with the brain center. Herein, focusing on metabolic syndrome, this manuscript aims to provide an overview of the regulatory effects of Neuropeptide Y on metabolic syndrome and discuss clinical intervention strategy perspectives for neurometabolic disease.

Hippocampal Glycerol-3-Phosphate Acyltransferases 4 and BDNF in the Progress of Obesity-Induced Depression.

Background: Obesity has been reported to lead to increased incidence of depression. Glycerol-3-phosphate acyltransferases 4 (GPAT4) is involved in triacylglycerol synthesis and plays an important role in the occurrence of obesity. GPAT4 is the only one of GPAT family expressed in the brain. The aim of this study is to investigate if central GPAT4 is associated with obesity-related depression and its underlying mechanism. Results: A high-fat diet resulted in increased body weight and blood lipid. HFD induced depression like behavior in the force swimming test, tail suspension test and sucrose preference test. HFD significantly up-regulated the expression of GPAT4 in hippocampus, IL-1ß, IL-6, TNF-α and NF-κB, accompanied with down-regulation of BDNF expression in hippocampus and ventromedical hypothalamus, which was attributed to AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB). Conclusion: Our findings suggest that hippocampal GPAT4 may participate in HFD induced depression through AMPK/CREB/BDNF pathway, which provides insights into a clinical target for obesity-associated depression intervention.

Analysis of the Impact of Medical Features and Risk Prediction of Acute Kidney Injury for Critical Patients Using Temporal Electronic Health Record Data With Attention-Based Neural Network.

Acute kidney injury (AKI) is one of the most severe consequences of kidney injury, and it will also cause or aggravate the complications by the fast decline of kidney excretory function. Accurate AKI prediction, including the AKI case, AKI stage, and AKI onset time interval, can provide adequate support for effective interventions. Besides, discovering how the medical features affect the AKI result may also provide supporting information for disease treatment. An attention-based temporal neural network approach was employed in this study for AKI prediction and for the analysis of the impact of medical features from temporal electronic health record (EHR) data of patients before AKI diagnosis. We used the publicly available dataset provided by the Medical Information Mart for Intensive Care (MIMIC) for model training, validation, and testing, and then the model was applied in clinical practice. The improvement of AKI case prediction is around 5% AUC (area under the receiver operating characteristic curve), and the AUC value of AKI stage prediction on AKI stage 3 is over 82%. We also analyzed the data by two steps: the associations between the medical features and the AKI case (positive or inverse) and the extent of the impact of medical features on AKI prediction result. It shows that features, such as lactate, glucose, creatinine, blood urea nitrogen (BUN), prothrombin time (PT), and partial thromboplastin time (PTT), are positively associated with the AKI case, while there are inverse associations between the AKI case and features such as platelet, hemoglobin, hematocrit, urine, and international normalized ratio (INR). The laboratory test features such as urine, glucose, creatinine, sodium, and blood urea nitrogen and the medication features such as nonsteroidal anti-inflammatory drugs, agents acting on the renin-angiotensin system, and lipid-lowering medication were detected to have higher weights than other features in the proposed model, which may imply that these features have a great impact on the AKI case.

Immunoregulation of autocrine prolactin: suppressing the expression of costimulatory molecules and cytokines in T lymphocytes by prolactin receptor knockdown.

Ample evidence indicates that prolactin (PRL) secreted from the pituitary gland plays an important role in a variety of human immune responses. However, the immunoregulation of autocrine PRL in T lymphocytes is not fully understood. To evaluate the role of autocrine PRL in T lymphocyte activation, PRL receptor (PRLR) in Jurkat cells was silenced by lentivirus-mediated stable expression of PRLR shRNAi. Knockdown of PRLR resulted in a considerable reduction of phytohemagglutinin (PHA)-induced T cell proliferation. Moreover, the synthesis and secretion of CD137, CD154, IL-2 and IL-4 were significantly decreased, while the production of CD28, IFN-gamma and IL-10 was not affected in PHA-primed PRLR-deficient cells. These results demonstrate the importance of autocrine regulation of the PRL signaling in T lymphocyte growth and activation, and support a mechanism by which autocrine PRL participates in the immunoregulation through selectively influencing the expression of certain critical costimulatory molecules and cytokines.

Immune checkpoint inhibitor-associated thyroid dysfunction: a disproportionality analysis using the WHO Adverse Drug Reaction Database, VigiBase.

OBJECTIVE: Our study aimed to identify and characterize thyroid dysfunctions associated with immune checkpoint inhibitors (ICIs). DESIGN: Data were obtained from VigiBase, between January 1, 2011 to March 6, 2019. METHODS: All thyroid drug-adverse events are classified by group queries according to the Medical Dictionary for Regulatory Activities. Information component (IC) and reporting odds ratio (ROR) were considered as measures of disproportionality for the assessment of association between ICIs and thyroid dysfunctions. We used IC to identify meaningful drug-adverse events while using ROR to compare differences in the reporting of drug-adverse events caused by different ICI subgroups. Positive IC values are deemed significant. RESULTS: Compared with the full database, the following ICI-associated thyroid dysfunctions were over-reported: hypothyroidism (1125 reports for ICIs vs 12495 for all drugs; Information Component 4.28 (95% CI: 4.18-4.35)), hyperthyroidism (926 vs 7538; 4.66 (95% CI: 4.55-4.74)), thyroiditis (294 vs 1237; 5.40 (95% CI: 5.21-5.54)), thyrotoxic crisis (11 vs 288; 3.55 (95% CI: 2.61-4.20)). Hypothyroidism was over-reported for patients treated with ICI combination therapy versus those treated with ICI monotherapy (ROR 1.3 (95% CI: 1.1-1.7)), and the same was observed for hyperthyroidism (ROR: 1.9 (95% CI: 1.5-2.4)), thyroiditis (ROR: 3.3 (95% CI: 2.3-4.8)), thyrotoxic crisis (ROR: 11.5 (95% CI: 2.4-53.8)). All 11 thyrotoxic crisis cases were malignant melanoma patients, of which seven occurred under ICI combination therapy. CONCLUSIONS: Thyroid dysfunction may occur after ICI therapies, and severe thyrotoxic crisis may even occur. Raising awareness of ICI-associated thyroid dysfunction can improve the detection and treatment of these diseases.

Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase.

PURPOSE: Our study aimed to map endocrine toxicity spectrum of immune checkpoint inhibitors (ICIs). METHODS: We obtained data from VigiBase, between January 1, 2011 and March 6, 2019. All endocrine adverse drug reactions (ADRs) were classified by group queries according to the Medical Dictionary for Regulatory Activities. Disproportionality analysis was performed with information component (IC) and reporting odds ratio (ROR). We used IC to identify meaningful endocrinopathies associated with ICIs and ROR to compare differences between ICI subgroups of ADRs. IC025 (lower end of the 95% confidence interval of IC) is considered significant if larger than 0. RESULTS: In all, 6089 reports for endocrinopathies associated with ICIs were involved, with a male to female ratio of 1.5:1. The disproportionality analysis indicated significance of not only common endocrinopathies: thyroid dysfunction, hypophysitis/hypopituitarism, adrenal insufficiency, T1DM, fulminant T1DM (IC025: 4.12-6.62), but also rare endocrinopathies: hypoparathyroidism, diabetes insipidus, hypogonadism (IC025: 1.56-2.04). Increased risk of ADR reporting emerged in anti-CTLA-4 (e.g., hypophysitis/hypopituitarism, adrenal insufficiency) or in anti-PD-1/PD-L1 (e.g., thyroid dysfunction, T1DM, fulminant T1DM). In general, combination therapy (anti-CTLA-4 plus anti-PD-1/PD-L1) had a stronger association with endocrinopathies than monotherapy (ROR: 2.8, 95% CI: 2.5-3.1). Onset time of common endocrinopathies differed between different ICI therapies, typically within 12 weeks in anti-CTLA-4 monotherapy but diffusely ranging from 0 to 48 weeks in anti-PD-1 monotherapy. CONCLUSIONS: Our study shows rising reporting frequencies of endocrinopathies caused by ICIs, especially aggravated in combination therapy. Clinicians should be early aware of latent endocrine toxicity and different onset time of endocrinopathies when implementing ICI therapies.

Diagnostic value of optic disc retinal nerve fiber layer thickness for diabetic peripheral neuropathy.

OBJECTIVE: To investigate the value of optic disc retinal nerve fiber layer (RNFL) thickness in the diagnosis of diabetic peripheral neuropathy (DPN). METHODS: Ninety patients with type 2 diabetes, including 60 patients without DPN (NDPN group) and 30 patients with DPN (DPN group), and 30 healthy participants (normal group) were enrolled. Optical coherence tomography (OCT) was used to measure the four quadrants and the overall average RNFL thickness of the optic disc. The receiver operator characteristic curve was drawn and the area under the curve (AUC) was calculated to evaluate the diagnostic value of RNFL thickness in the optic disc area for DPN. RESULTS: The RNFL thickness of the DPN group was thinner than those of the normal and NDPN groups in the overall average ((101.07± 12.40) µm vs. (111.07±6.99) µm and (109.25±6.90) µm), superior quadrant ((123.00±19.04) µm vs. (138.93±14.16) µm and (134.47±14.34) µm), and inferior quadrant ((129.37±17.50) µm vs. (143.60±12.22) µm and (144.48±14.10) µm), and the differences were statistically significant. The diagnostic efficiencies of the overall average, superior quadrant, and inferior quadrant RNFL thicknesses, and a combined index of superior and inferior quadrant RNFL thicknesses were similar, and the AUCs were 0.739 (95% confidence interval (CI) 0.635-0.826), 0.683 (95% CI 0.576-0.778), 0.755 (95% CI 0.652-0.840), and 0.773 (95% CI 0.672-0.854), respectively. The diagnostic sensitivity of RNFL thickness in the superior quadrant reached 93.33%. CONCLUSIONS: The thickness of the RNFL in the optic disc can be used as a diagnostic method for DPN.

High Expression of Complement Components in the Kidneys of Type 2 Diabetic Rats With Diabetic Nephropathy.

Background: Diabetic nephropathy (DN) is the leading cause of end-stage failure of the kidneys; however, its pathogenesis remains unknown. This study assessed the expression of complement components in the kidneys of rats with type 2 DN to investigate their role in DN. Methods: A rat model of type 2 DN was induced by a high-fat diet combined with low-dose streptozotocin. Blood glucose, fasting insulin levels, insulin resistance index, and 24-h urinary albumin excretion (UAE) were measured. Renal tissue morphological features were observed. The mesangial index and arteriosclerosis index were calculated. Immunohistochemistry and western blot were used to measure the expression of complement components in the kidneys. Results: The kidney weight: body weight (mg/g) ratio in the DN group was significantly greater than those in the control and diabetes mellitus (DM) groups. The arteriosclerosis index, mesangial index, and tube area percentage in the DN group were significantly higher than those in the control and DM groups, but these parameters did not significantly differ between the control and DM groups. The expression of the complement components C1q, mannose-binding lectin (MBL), mannan-binding lectin-associated serine protease (MASP)-2, B factor, C3, and C5b-9 in the DN group was significantly higher than that in the control and DM groups but did not significantly differ between the control and DM groups. Most of the complement components were mainly expressed at the renal tubular site. Correlation analysis showed that 24-h UAE were positively correlated with C1q, MBL, MASP-2, B factor, and C5b-9 expression. MI was positively correlated with MBL, B factor, C3, and C5b-9 expression. AI was positively correlated with C1q, MBL, MASP-2, and B factor expression. Conclusion: Complement components including C1q, MBL, MASP-2, B factor, C3, and C5b-9, were highly expressed in the kidneys of type 2 diabetic rats with DN. Most of the complement components were mainly expressed in the renal tubules. High expression of complement components was found to be associated with the progress of DN. Our study suggests that complement system activation is a progressive factor in type 2 diabetic nephropathy. Inhibition of pathological complement activation may be a promising therapeutic strategy for DN.

Overexpression of miR-146a Might Regulate Polarization Transitions of BV-2 Cells Induced by High Glucose and Glucose Fluctuations.

Microglia are critical in neuroinflammation. M1/M2 polarization transitions of microglial phenotypes determine the states of neuroinflammation and are regulated by multiple pathways, including miRNAs and other epigenetic regulations. This study investigated the polarization transitions of microglia induced by high glucose and glucose fluctuations, and the role of miR-146a in regulating M1/M2 polarization transitions of microglia. BV-2 cells were cultured with 25 mmol/L glucose, 75 mmol/L glucose, and 25 mmol/L-75 mmol/L glucose fluctuation for 48 h. BV-2 cells overexpressing miR-146a were generated using a lentiviral vector. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure mRNA expression of miR-146a, CD11b, iNOS, Arg-1, IRAK1, TRAF6, and NF-κB. Immunofluorescence was used to measure CD11b expression. Western blot was used to measure protein expression of CD11b, iNOS, and Arg-1. Compared with those in the 25 mmol/L glucose control group, expression of CD11b, iNOS, TNF-α, and IL-6 in the 75 mmol/L glucose or glucose fluctuation groups of cultured BV-2 cells were significantly increased, while Arg-1 and IL-10 was significantly decreased. These effects were reversed by overexpression of miR-146a. Furthermore, expression of IRAK1, TRAF6, and NF-κB was significantly increased in the high glucose and glucose fluctuation groups; this was reduced after miR-146a overexpression. In sum, high glucose and glucose fluctuations induced polarization transitions from M1 to M2 phenotype in BV-2 cells. Overexpression of miR-146a might protect BV-2 cells from high glucose and glucose fluctuation associated with M1/M2 polarization transitions by downregulating the expression of IRAK1, TRAF6, and NF-κB.

Endogenous Secretory Receptor for Advanced Glycation End Products Protects Endothelial Cells from AGEs Induced Apoptosis.

Endogenous secretory receptor for advanced glycation end products (esRAGE) binds extracellular RAGE ligands and blocks RAGE activation on the cell surface, protecting endothelial cell function. However, the underlying mechanism remains unclear. Endothelial cells overexpressing the esRAGE gene were generated using a lentiviral vector. Then, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to assess esRAGE mRNA and protein levels, respectively. Hoechst-PI double staining was used to assess apoptosis. Western blot and qRT-PCR were used to assess the expression levels of apoptosis-related factors and the proinflammatory cytokine NF-кB. Compared with the control group, AGEs significantly induced endothelial cell apoptosis, which was significantly reduced by esRAGE overexpression. Incubation with AGEs upregulated the proapoptotic factor Bax and downregulated the antiapoptotic factor Bcl-2. Overexpression of esRAGE reduced Bax expression induced by AGEs and increased Bcl-2 levels. Furthermore, AGEs increased the expression levels of proinflammatory cytokine NF-кB, which were reduced after esRAGE overexpression. esRAGE protects endothelial cells from AGEs associated apoptosis, by downregulating proapoptotic (Bax) and inflammatory (NF-кB) factors and upregulating the antiapoptotic factor Bcl-2.

Intracellular iodinated compounds affect sodium iodide symporter expression through TSH-mediated signaling pathways.

The mechanisms by which thyroid stimulating hormone (TSH) regulates the expression and activity of sodium iodide symporter (NIS) through cAMP-PKA have been partially elucidated by many studies. However, the effects of the TSH-mediated PLC-IP3 signaling pathway on the expression of NIS and how intracellular iodinated compounds interfere with these signaling pathways are poorly understood. In this study, we investigated the effects of the TSH-mediated cAMP-PKA and PLC-IP3 pathways on the expression of NIS in the presence of various intracellular iodinated compounds. The intracellular iodinated compounds were formed by treating cells with different concentrations of iodine with or without methimazole (MMI), an inhibitor of iodine organification, in a pig monolayer thyrocyte in vitro. A high concentration of iodine increased NIS expression at the mRNA and protein levels; however, this phenomenon was not observed in the presence of MMI. Both the cAMP-PKA and PLC-IP3 signaling pathways inhibited the expression of NIS at low iodine concentrations; however, in thyrocytes treated with high concentrations of iodine, the effect of cAMP-PKA on the expression of NIS changed from inhibition to promotion, while the PLC-IP3 pathway continued to inhibit NIS expression. These findings indicate that intracellular iodinated compounds affect NIS expression through the TSH-mediated cAMP-PKA and PLC-IP3 pathways.