BMPR2 promotes fatty acid oxidation and protects white adipocytes from cell death in mice.

Adipocyte cell death is pathologically involved in both obesity and lipodystrophy. Inflammation and pro-inflammatory cytokines are generally regarded as inducers for adipocyte apoptosis, but whether some innate defects affect their susceptibility to cell death has not been extensively studied. Here, we found bone morphogenetic protein receptor type 2 (BMPR2) knockout adipocytes were prone to cell death, which involved both apoptosis and pyroptosis. BMPR2 deficiency in adipocytes inhibited phosphorylation of perilipin, a lipid-droplet-coating protein, and impaired lipolysis when stimulated by tumor necrosis factor (TNFα), which lead to failure of fatty acid oxidation and oxidative phosphorylation. In addition, impaired lipolysis was associated with mitochondria-mediated apoptosis and pyroptosis as well as elevated inflammation. These results suggest that BMPR2 is important for maintaining the functional integrity of adipocytes and their ability to survive when interacting with inflammatory factors, which may explain why adipocytes among individuals show discrepancy for death responses in inflammatory settings.

cis-Silicon phthalocyanine conformation endows J-aggregated nanosphere with unique near-infrared absorbance and fluorescence enhancement: a tumor sensitive phototheranostic agent with deep tissue penetrating ability.

Organic phototheranostic nanomedicines with an optimized near-infrared (NIR) biological transparent window (700-900 nm) are highly desirable for the diagnosis and treatment of deep-seated tumors in clinic. As excellent organic photosensitizers for photodynamic therapy (PDT) with outstanding photo- and thermo-stability, phthalocyanines (Pcs) have been used as the building blocks of single-component nanomedicines. However, to the best of our knowledge, all the Pc-based single-component self-assemblies reported to date are of an H-aggregate nature. This results in the simultaneous self-quenching of fluorescence emission and photodynamic activity as well as greatly reduced tissue penetration due to blue-shifted absorption. In the present work, intramolecular hydrogen bonding was formed between the two long and flexible axial NH2-terminated diethylene glycol ligands of the amphiphilic SiPc molecule (SiPc-NH2) in solution, leading to the employment of a cis-conformation of this molecule according to the 1H-NMR spectroscopy result, which as a building block then further self-assembled into monodisperse nanospheres (SiPcNano) with a J-aggregation nature on the basis of electronic absorption spectroscopic results. As a result, SiPcNano exhibited significantly enhanced red-shifted absorption in the NIR range of 750-850 nm and fluorescence emission. This in combination with the increased photodynamic effect for SiPcNano triggered by the protonation of amine groups due to the acidic nature of tumors endowed effective synergistic NIR photodynamic and photothermal effects in different cancer cells and thus effective inhibition of tumor growth in A549 tumor-bearing mice on the basis of a series of in vitro and in vivo evaluations. The present result provides a new approach for constructing novel single-component NIR organic nanomedicines for multifunctional cancer therapy.

Stimulation of histamine H4 receptor participates in cold-induced browning of subcutaneous white adipose tissue.

Although many studies have shown that histamine and its signaling regulate energy homeostasis through the central nervous system, their roles in adipose tissues remain poorly understood. Here, we identified that the histamine H4 receptor (HrH4) was highly expressed in adipocytes at a level higher than that of the other three receptors (i.e., HrH1, HrH2, and HrH3). The HrH4 expression in adipocytes responded to cold through thermogenesis and lipolysis, supported by results from both mouse and cell models. When HrH4 expression was knocked down in the subcutaneous white adipose tissue (scWAT), browning and lipolysis effects triggered by cold were ablated, and the oxygen consumption was also lowered both at the normal and cold conditions. Moreover, mice exhibited browned scWAT, accelerated metabolic rates, and tolerance to hypothermia when 4-methylhistamine (4MH), a selective HrH4 agonist, was adjacently injected to the scWAT. Consistent with these findings, 4MH also triggered the browning and lipolytic effects in cultured C3H10T1/2 adipocytes. Mechanically, we demonstrated that p38/MAPK and ERK/MAPK pathways were involved in these processes. In conclusion, our findings have uncovered an effective role of HrH4 in adipose tissue browning.

BMP4 facilitates beige fat biogenesis via regulating adipose tissue macrophages.

Thermogenic beige fat improves metabolism and prevents obesity. Emerging evidence shows that the activation of M2 macrophages stimulates beige adipogenesis, whereas the activation of M1 macrophages, which play a major role in inflammation, impedes beige adipogenesis. Thus, the identification of factors that regulate adipose tissue macrophages (ATMs) will help clarify the mechanism involved in beiging. Here, we found that one of the secreted proteins in adipose tissue, namely, BMP4, alters the ATM profile in subcutaneous adipose tissue by activating M2 and inhibiting M1 macrophages. Mechanistically, the BMP4-stimulated p38/MAPK/STAT6/PI3K-AKT signalling pathway is involved. Meanwhile, BMP4 improved the potency of M2 macrophages to induce beige fat biogenesis. Considering that the overexpression of BMP4 in adipose tissue promotes the beiging of subcutaneous adipose tissue and improves insulin sensitivity, these findings provide evidence that BMP4 acts as an activator of beige fat by targeting immuno-metabolic pathways.

RPS3A positively regulates the mitochondrial function of human periaortic adipose tissue and is associated with coronary artery diseases.

Pericardial adipose tissue, which comprises both epicardial adipose tissue (EAT) and paracardial adipose tissue (PAT), has recently been recognized as a novel factor in the pathophysiology of cardiovascular diseases, especially coronary artery disease (CAD). The goal of this study was to evaluate differences in the brown-like characteristic and proteome among human EAT, PAT, and subcutaneous adipose tissue (SAT) to identify candidate molecules causing CAD. Uncoupling protein 1 (UCP-1) and other brown-related proteins were highly expressed in pericardial adipose tissue but was weakly expressed in SAT from the same non-CAD patient. Moreover, pericardial adipose tissues displayed a higher thermogenesis than SAT. However, brown-related genes were lower in CAD pericardial fat. Remarkably, there were lower levels of metabolic enzymes involved in glycolysis, tricarboxylic acid cycle, and fatty acid metabolism in pericardial adipose tissues of CAD. EAT is an organ adjacent to aortic root without anatomy barriers, which differs from PAT. We found that the expression of ribosomal protein S3A (RPS3A) was decreased in human EAT as well as in mouse perivascular adipose tissue (PVAT). Knockdown of RPS3A significantly inhibited adipocyte differentiation in preadipocytes and impaired the function of mitochondria in mature adipocytes. Moreover, RPS3A knockdown in mouse periaortic adipose tissue impaired browning of PVAT, accelerated vascular inflammation, and atherosclerosis progression. Mechanistically, RPS3A can migrate to the mitochondria to maintain the function of brown adipocytes. These findings provide compelling evidence that RPS3A was a key factor for modulating the brown fat-specific gene UCP-1 and carbon metabolic enzymes in EAT for preventing CAD.

A content analysis of depression-related discourses on Sina Weibo: attribution, efficacy, and information sources.

BACKGROUND: Depression is a mood disorder that may lead to severe outcomes including mental breakdown, self-injury, and suicide. Potential causes of depression include genetic, sociocultural, and individual-level factors. However, public understandings of depression guided by a complex interplay of media and other societal discourses might not be congruent with the scientific knowledge. Misunderstandings of depression can lead to under-treatment and stigmatization of depression. Against this backdrop, this study aims to achieve a holistic understanding of the patterns and dynamics in discourses about depression from various information sources in China by looking at related posts on social media. METHOD: A content analysis was conducted with 902 posts about depression randomly selected within a three-year period (2014 to 2016) on the mainstream social media platform in China, Sina Weibo. Posts were analyzed with a focus on attributions of and solutions to depression, attitudes towards depression, and efficacy indicated by the posts across various information sources. RESULTS: Results suggested that depression was most often attributed to individual-level factors. Across all the sources, individual-level attributions were often adopted by state-owned media whereas health and academic experts and organizations most often mentioned biological causes of depression. Citizen journalists and unofficial social groups tended to make societal-level attributions. Overall, traditional media posts suggested the lowest efficacy in coping with depression and the most severe negative outcomes as compared with other sources. CONCLUSIONS: The dominance of individual-level attributions and solutions regarding depression on Chinese social media on one hand manifests the public's limited understanding of depression and on the other hand, may further constrain adoption of scientific explanations about depression and exacerbate stigmatization towards depressed individuals. Mass media's posts centered on description of severe outcomes of depression without suggestions of solutions' effectiveness, which may induce more anxiety among depressed individuals. Campaigns promoting comprehensive understandings about depression and popular works translating scientific findings on depression to the public are called for.

Genetic association and interaction between the IRF5 and TYK2 genes and systemic lupus erythematosus in the Han Chinese population.

OBJECTIVES: The purpose of this case-control study was to investigate whether polymorphisms and gene-gene interactions of the two type I interferon (IFN) genes (IRF5 and TYK2) are the susceptible factors of systemic Lupus erythematosus (SLE) in the Han Chinese population. METHODS: The four variants [rs2004640, rs2070197, rs10954213 and exon6 insertion/deletion (in/de)] of IRF5 gene and five single-nucleotide polymorphisms (SNPs) (rs280500, rs280519, rs2304256, rs8108236, rs12720270) of TYK2 gene were examined in a cohort of 642 SLE patients and 642 healthy controls. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by direct sequencing in 10 % sample randomly. RESULTS: Rs2070197 was not polymorphic in this study, and was excluded in further analysis. Significant association was found for loci on IRF5 (rs2004640: p = 0.0003, p corr = 0.0012) and TYK2 (rs280500: p = 8.83 × 10(-6), p corr = 4.41 × 10(-5); rs2304256: p = 3.71 × 10(-6), p corr = 1.85 × 10(-5); rs8108236: p = 0.0004, p corr = 0.002), but not for other SNPs. Significant association was also observed for genotypes of IRF5 (rs2004640, p = 0.0009, p corr = 0.0036) and TYK2 SNPs (rs280500: p = 5.21 × 10(-5), p corr = 2.61 × 10(-4); rs2304256: p = 7.72 × 10(-6), p corr = 3.86 × 10(-5); rs8108236: p = 0.002, p corr = 0.01). Nevertheless, two haplotypes based on the 3 variants [exon6(in/de), rs10954213, rs2004640] of IRF5 (DAG and IAT) could define protective or susceptibility haplotype in SLE. Similarly, three haplotypes containing 5 SNPs (rs280500, rs280519, rs2304256, rs8108236, rs12720270) of TYK2 (GATAT, AGGAT and GAGGT) may also be associated with SLE in Han Chinese. Additionally, the gene-gene interaction analysis was conducted on the IRF5 and TYK2 SNPs. And a three-way interaction between TYK2 rs280500, rs2304256 and IRF5 rs10954213 and SLE was found (p < 0.0001). CONCLUSIONS: Genetic associations and gene-gene interactions of IRF5 and TYK2 were significantly detected in Han Chinese with SLE. Our results had important implications for future research on the role of type I IFN function in SLE susceptibility.

The recessive model of MRP2 G1249A polymorphism decrease the risk of drug-resistant in Asian Epilepsy: a systematic review and meta-analysis.

ABCC2 gene polymorphisms have been shown to be associated with drug-resistant epilepsy. However, the published results were controversial. To comprehensively re-evaluate the association between ABCC2 gene polymorphisms and drug-resistant epilepsy in Asian, we carried out this meta-analysis, which included eight related studies. Studies were selected using PUBMED, Web of science, the Cochrane database of system reviews and Embase. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. Studies with 1302 drug-resistant cases and 1563 drug-sensitive controls were included. No significant association was detected by combined analyses for C-24T, G-1774delG, C3972T and G2934A. However, significant association was found in recessive model for G1249A polymorphism (GG vs. GA+AA: OR=0.72, 95%CI=0.53-0.96, P=0.03), indicating the recessive model of G1249A in MRP2/ABCC2 might decrease the risk of drug resistance in Asian epilepsy.

A novel method for the determination of the degree of deacetylation of chitosan by coulometric titration.

A novel method to determine the degree of deacetylation of chitosan is described. In this method, the coulometric titrant OH- is generated by the electrolysis of water. The OH- reacted with the residual hydrochloric acid in chitosan solution and the degree of deacetylation was obtained by Faraday's law. The optimized experimental parameters in this study were 1.0 mol/L KCl as supporting electrolyte, 15.00 mA as the intensity of constant current, composite glass electrode as indicating electrode couples, double platinum generated electrode-platinum wire auxiliary electrode as working electrode pairs, pH 3.80 as the titration end-point. The degree of deacetylation in the four samples, which varied from 70 to 95% were measured. The results were similar to those from 1H NMR and the standard deviations were lower than 0.5%. With merit of simplicity, convenience, quickness, high accuracy and precision, automatic detection of titration end-point and low-cost, the proposed method will be very useful in the industrial production.