The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1.

Epilepsy, one of the most common neurological disorders, is characterized by spontaneous recurrent seizures. Temporal lobe epilepsy (TLE) is one of the most common medically intractable seizure disorders. Traf2-and NcK-interacting kinase (TNIK) has recently attracted attention as a critical modulation target of many neurological and psychiatric disorders, but its role in epilepsy remains unclear. In this study, we hypothesized the involvement of TNIK in epilepsy and investigated TNIK expression in patients with intractable TLE and in a pilocarpine-induced rat model of epilepsy by western blotting, immunofluorescence, and immunohistochemistry. A pentylenetetrazole (PTZ)-induced epilepsy rat model was used to determine the effect of the TNIK inhibitor NCB-0846 on behavioral manifestations of epilepsy. Coimmunoprecipitation (Co-IP)/mass spectrometry (MS) was used to identify the potential mechanism. Through Co-IP, we detected and confirmed the main potential TNIK interactors. Subcellular fractionation was used to establish the effect of NCB-0846 on the expression of the main interactors in postsynaptic density (PSD) fractions. We found that TNIK was primarily located in neurons and decreased significantly in epilepsy model rats and TLE patients compared with controls. NCB-0846 delayed kindling progression and decreased seizure severity. Co-IP/MS identified 63 candidate TNIK interactors in rat hippocampi, notably CaMKII. Co-IP showed that TNIK might correlate with endogenous GRIA1, SYN2, PSD-95, CaMKIV, GABRG1, and GABRG2. In addition, the significant decrease in GRIA1 in hippocampal total lysate and PSDs after NCB-0846 treatment might help modify the progression of PTZ kindling. Our results suggest that TNIK contributes to epileptic pathology and is a potential antiepileptic drug target.

Disorders of sodium balance and its clinical implications in COVID-19 patients: a multicenter retrospective study.

BACKGROUND: The worldwide spread of SARS-CoV-2 has infected millions of people leading to over 0.3 million mortalities. The disruption of sodium homeostasis, tends to be a common occurrence in patients with COVID-19. METHODS AND RESULTS: A total of 1,254 COVID-19 patients comprising 124 (9.9%) hyponatremic patients (under 135 mmol/L) and 30 (2.4%) hypernatremic patients (over 145 mmol/L) from three hospitals in Hubei, China, were enrolled in the study. The relationships between sodium balance disorders in COVID-19 patients, its clinical features, implications, and the underlying causes were presented. Hyponatremia patients were observed to be elderly, had more comorbidities, with severe pneumonic chest radiographic findings. They were also more likely to have a fever, nausea, higher leukocyte and neutrophils count, and a high sensitivity C-reactive protein (HS-CRP). Compared to normonatremia patients, renal insufficiency was common in both hyponatremia and hypernatremia patients. In addition, hyponatremia patients required extensive treatment with oxygen, antibiotics, and corticosteroids. The only significant differences between the hypernatremia and normonatremia patients were laboratory findings and clinical complications, and patients with hypernatremia were more likely to use traditional Chinese medicine for treatment compared to normonatremia patients. This study indicates that severity of the disease, the length of stay in the hospital of surviving patients, and mortality were higher among COVID-19 patients with sodium balance disorders. CONCLUSION: Sodium balance disorder, particularly hyponatremia, is a common condition among hospitalized patients with COVID-19 in Hubei, China, and it is associated with a higher risk of severe illness and increased in-hospital mortality.

Incorporation of molybdenum disulfide into polyetheretherketone creating biocomposites with improved mechanical, tribological performances and cytocompatibility for artificial joints applications.

To improve mechanical, tribological and biological performances of polyetheretherketone (PEEK) for artificial joints applications, molybdenum disulfide (MoS2, MS) nanosheets were incorporated into PEEK to fabricate MS/PEEK biocomposites (MPC) with MS content of 4 w% (MPC4) and 8 w% (MPC8). The results revealed that the MS nanosheets with the size of about 400 nm and sheet thickness of about 70 nm were distributed into PEEK matrix, and surface roughness as well as hydrophilicity of MPC increased with the MS content increasing. Moreover, the compressive strength and shore hardness of the MPC were accordingly enhanced. Furthermore, the coefficient of friction of the MPC decreased while the wear resistance of the MPC increased with the MS content increasing in both water-sliding and dry-sliding contact. In addition, rat bone marrow derived stromal cells adhered and proliferated on the composites, indicating that the MPC had no adverse influences on cell behaviors, indicating good cytocompatibility. The results demonstrated that incorporation of MS nanosheets into PEEK produced biocomposites with improved mechanical, tribological and biological performances. MPC8 with no cytotoxicity would have a great potential for artificial joints applications.

RELATIONSHIP BETWEEN THE ENVIRONMENTAL ENDOCRINE DISRUPTOR BISPHENOL A AND DYSLIPIDEMIA: A FIVE-YEAR PROSPECTIVE STUDY.

Objective: To investigate whether serum bisphenol A (BPA) concentration is related to the occurrence of dyslipidemia. Methods: A total of 574 adults were enrolled at baseline and followed up for 5 years. Concentrations of serum BPA, triglycerides (TGs), low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured. Dyslipidemia was defined as the existence of one or more of the following conditions: high-LDL-cholesterolemia (LDL ≥140 mg/dL), hypertriglyceridemia (TGs ≥150 mg/dL), or low-HDL-cholesterolemia (HDL <40 mg/dL). Participants were stratified into tertiles according to low, median, and high baseline serum BPA levels. Multivariable linear and logistic regression models were used. Data from baseline and follow-up were used for cross-sectional and longitudinal analyses, respectively. Results: In the cross-sectional analysis, compared to subjects in the low BPA tertile, those in the high BPA tertile showed a higher level of LDL cholesterol (108.1 ± 24.4 mg/dL versus 119.5 ± 26.9 mg/dL; P<.05) and a lower level of HDL cholesterol (46.2 ± 11.7 mg/dL versus 39.5 ± 7.5 mg/dL; P<.05). In multivariable linear regression models, Z-transformed BPA was positively associated with LDL cholesterol (ß= 0.13, P = .002) and negatively associated with HDL cholesterol (ß= -0.28; P<.001). After cross-sectionally adjusting for confounders, subjects in higher BPA exposure was associated with a higher prevalence of low-HDL-cholesterolemia. Longitudinally, in subjects without low-HDL-cholesterolemia at baseline, each SD increment in baseline BPA was associated with a higher incidence of low-HDL-cholesterolemia after adjustment for confounders (odds ratio [95% confidence interval; CI] 2.76, 95% CI 1.21, 6.29). Conclusion: Cross-sectionally, higher BPA exposure is associated with a higher prevalence of low-HDL-cholesterolemia. Longitudinally, baseline BPA is an independent predictor of the 5-year incidence of low-HDL-cholesterolemia. Abbreviations: BMI = body mass index; BPA = bisphenol A; CI = confidence interval; CVD = cardiovascular disease; EIMDS = environment, inflammation and metabolic diseases study; HDL = high density lipoprotein; LDL = low density lipoprotein; OR = odds ratio; PPAR = peroxisome proliferator-activated receptor; SBP = systolic blood pressure; TG = triglyceride; Z-BPA = Z-transformed bisphenol A.

Lack of association between EGF +61A>G polymorphism and melanoma susceptibility in Caucasians: a HuGE review and meta-analysis.

Emerging evidence showed that the common polymorphism (+61A>G, rs4444903) in the promoter region of epidermal growth factor (EGF) gene might be associated with melanoma susceptibility in humans. But individually published results are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis is to derive a more precise estimation of the association between EGF +61A>G polymorphism and melanoma risk. The PubMed, Embase, Web of Science and CBM databases were searched for all articles published up to July 1st, 2012. Seven case-control studies were included with a total of 2367 melanoma cases and 4184 healthy controls. Meta-analysis results showed that there was no significant relationship between EGF +61A>G polymorphism and the risk of melanoma (G vs A: odds ratio [OR]=1.08, 95% confidence interval [CI]: 0.91-1.28, P=0.386; GG+AG vs AA: OR=1.05, 95%CI: 0.88-1.26, P=0.580; GG vs AA+AG: OR=1.10, 95%CI: 0.81-1.49, P=0.552; GG vs AA: OR=1.06, 95%CI: 0.80-1.41, P=0.700; GG vs AG: OR=1.12, 95%CI: 0.81-1.56, P=0.494). Further subgroup analyses based on source of controls, country, detection samples, genotype methods, and Breslow thickness of tumor, we also found no significant association between EGF +61A>G polymorphism and melanoma risk. In conclusion, this meta-analysis indicates that EGF +61A>G polymorphism might not be a primary determinant in melanoma development and progression; EGF gene might be expected to interact with other genes in different signaling pathways to initiate and promote the carcinogenic process.