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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.

The aim of this study was to identify and characterize immune checkpoint inhibitors (ICIs)-associated pituitary adverse events (AEs). 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. 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

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.

Background and Objectives: Research suggested that diabetic peripheral neuropathy (DPN) was related to plasma fibrinogen (Fib) concentration, while there was no research on the correlation with fibrinogen function. In this study, two indexes reflecting the function of plasma fibrinogen, k value and angle α, were used to analyze its correlation with DPN, and to explore the possibility of using them as biological indicators for diagnosing DPN.Subjects and methods: This study is a prospective observational clinical study. About 561 T2DM patients were enrolled and divided into the diabetes with symptomatic neuropathy group (161 cases), the diabetes with asymptomatic neuropathy group (132 cases) and the diabetes with no neuropathy group (268 cases). Meanwhile, 160 healthy unrelated subjects were recruited as control group. The levels of k value and angle α were detected.Results: The Fib levels increased slightly in diabetic subjects with neuropathy compared with those without. The angle α levels increased slightly in diabetic with asymptomatic neuropathy subjects compared with diabetes with no neuropathy subjects, and the levels increased greatly in diabetic subjects with symptomatic neuropathy compared with those without. The k value levels declined slightly in diabetic with asymptomatic neuropathy subjects compared with diabetes with no neuropathy subjects, and the levels declined greatly in diabetic subjects with symptomatic neuropathy compared with those without. The association of k value and angle α with diabetic neuropathy was independent of the hyperglycemic state (HbA1c, duration) and other potential confounders affecting k value and angle α levels (e.g., age, Fib, vitamin B12 and renal status) (odds ratio 0.080 [0.051–0.124], P= 0.001; odds ratio 1.131 [1.063–1.204], P= 0.001). In addition, k value and angle α levels were closely correlated to the stages of neuropathy (r= -0.686, P = 0.000; r= 0.314, P = 0.000). Meanwhile, the optimal cutoff point for k value levels to distinguish patients with diabetic neuropathy from those without was 1.8min, with a sensitivity of 73.7% and a specificity of 83.2% (AUC= 0.873). The optimal cutoff point for angle α levels was 60deg, with a sensitivity of 41.0% and a specificity of 95.6% (AUC= 0.669).Conclusions: The levels of k value and angle α are closely associated with peripheral neuropathy in patients with diabetes. The levels of k value and angle α may be helpful for early diagnosis of diabetic peripheral neuropathy.

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.

With the improvement of people's living standards, gastrointestinal adverse reactions caused by various adverse factors have attracted more and more people's attention. A recent study has indicated that coronavirus disease 2019 (COVID-19) could also invade the gastrointestinal tract, leading to gastrointestinal adverse reactions (Song et al., 2020). In recent years, immunotherapy has provided certain effects for some patients with advanced malignant tumors. A microencapsulation of immunoglobulin Y (IgY) was reported to provide an effective way to preserve IgY and improve its performance in the gastrointestinal tract (Zhang J et al., 2020). Immune checkpoint inhibitors (ICIs) can significantly improve the survival of some advanced malignant tumors, especially metastatic malignant melanoma and lung cancer (Afzal et al., 2018; Madden and Kasler, 2019). They include anti-cytotoxic T lymphocyte-associated antigen-4 (anti-CTLA-4) antibodies (ipilimumab and tremelimumab), anti-programmed cell death protein 1 (anti-PD-1) antibodies (nivolumab and pembrolizumab), and anti-programmed death-ligand 1 (anti-PD-L1) antibodies (atezolizumab, avelumab, and durvalumab) (Baxi et al., 2018). Previous studies have shown that ICI combination therapy, such as nivolumab plus ipilimumab, has particular efficacy in lung cancer, renal cell carcinoma, and malignant melanoma (Wolchok et al., 2017; Derosa et al., 2018; Doroshow et al., 2019). However, ICIs may also lead to many immune-related adverse events (irAEs), even causing severe complications in certain cases. The most well-established toxicities from ICI therapy are gastrointestinal irAEs, including enteritis, enterocolitis, microscopic colitis, and gastritis, which have attracted public attention in recent years; reports of such events associated with ICI therapy also have increased (Tandon et al., 2018; de Malet et al., 2019). These gastrointestinal irAEs may generally respond well to corticosteroids and infliximab (Haanen et al., 2017). Although most of these irAEs are low-grade, a lack of detection and timely treatment may incur severe or fatal complications.

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.

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.

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.

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.

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.

ObjectiveAn increase in the expression of autoantigens and their presenting molecules human leukocyte antigen (HLA) class I has been demonstrated to be responsible for autoimmune diseases. Thyroid transcription factor-1 (TTF-1 or NKX2-1) synchronously upregulates both HLA class I and thyroid-specific autoantigen, which may be involved in the pathological process of autoimmune thyroiditis. In this study, the expressions and potential role of TTF-1 and HLA class I in Hashimoto's disease (HT) were examined.PatientsIn this study, 22 resection specimens clinically and histopathologically confirmed to have Hashimoto's disease and 30 normal thyroid specimens from adjacent tissues of thyroid adenoma were used.MeasurementWestern blot, real-time PCR, and immunohistochemistry were performed to assay TTF-1 and HLA class I in the thyrocytes of Hashimoto's disease as well as in the normal thyroid from adjacent tissues of thyroid adenoma.ResultsThe TTF-1 and HLA class I in Hashimoto's disease were significantly higher than those in the controls.ConclusionUpregulation of TTF-1 and HLA class I in Hashimoto's disease provide a clinical evidence for possible triggering of autoimmune reaction.

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.

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.

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.

In this paper, we give several properties related to highly connected graph. Based on these properties, we give a redefinition of highly connected subgraph which results in an algorithm for determining whether a given graph is highly connected in linear time. Then we present a computationally efficient algorithm, called MOHCS, for mining overlapping highly connected subgraphs. We experimentally evaluate the performance of MOHCS using a variety of real and synthetic data sets. Our results show that MOHCS is effective in finding overlapping highly connected subgraphs both in computer- generated graph and yeast protein network.