Thermogenic adipocyte-derived zinc promotes sympathetic innervation in male mice.

Sympathetic neurons activate thermogenic adipocytes through release of catecholamine; however, the regulation of sympathetic innervation by thermogenic adipocytes is unclear. Here, we identify primary zinc ion (Zn) as a thermogenic adipocyte-secreted factor that promotes sympathetic innervation and thermogenesis in brown adipose tissue and subcutaneous white adipose tissue in male mice. Depleting thermogenic adipocytes or antagonizing ß3-adrenergic receptor on adipocytes impairs sympathetic innervation. In obesity, inflammation-induced upregulation of Zn chaperone protein metallothionein-2 decreases Zn secretion from thermogenic adipocytes and leads to decreased energy expenditure. Furthermore, Zn supplementation ameliorates obesity by promoting sympathetic neuron-induced thermogenesis, while sympathetic denervation abrogates this antiobesity effect. Thus, we have identified a positive feedback mechanism for the reciprocal regulation of thermogenic adipocytes and sympathetic neurons. This mechanism is important for adaptive thermogenesis and could serve as a potential target for the treatment of obesity.

CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats.

BACKGROUND AND PURPOSE: C-C motif chemokine ligand 17 (CCL17) presents an important role in immune regulation, which is critical in the pathophysiology of brain injury after subarachnoid haemorrhage (SAH). There is rare evidence to illustrate the function of CCL17 towards SAH. In this study, we try to reveal the therapeutic effects of CCL17 and its underlying mechanism in rat SAH model. METHODS: SAH rat models were assigned to receive recombinant CCL17 (rCCL17) or phosphate buffer saline (PBS). AZD2098 and JR-AB2-011 were applied to investigate the C-C motif chemokine receptor 4 (CCR4)/mammalian target of rapamycin complex 2 (mTORC2) axis in CCL17-mediated neuroprotection. To elucidate the underlying mechanism, the in vitro kinase assay was performed in primary microglia. Microglial-specific Rictor knockdown was administered via intracerebroventricular injection of adenovirus-associated virus. Brain water content, short-term neurobehavioural evaluation, western blot analysis, quantitative RT-PCR and histological staining were performed. RESULTS: The expression of CCL17 was increased and secreted from neurons after oxyhaemoglobin stimulation. Exogenous rCCL17 significantly alleviated neuronal apoptosis, and alleviated short-term neurofunction after SAH in rats. In addition, rCCL17 increased M2-like polarisation of microglia in rats post-SAH and in primary microglia culture. The neuroprotection of rCCL17 was abolished via inhibition of either CCR4 or mTORC2. CONCLUSION: CCL17 activated the CCR4/mTORC2 axis in microglia, which can alleviate SAH-induced neurological deficits by promoting M2-like polarisation of microglia.

Targeting parvalbumin promotes M2 macrophage polarization and energy expenditure in mice.

Exercise benefits M2 macrophage polarization, energy homeostasis and protects against obesity partially through exercise-induced circulating factors. Here, by unbiased quantitative proteomics on serum samples from sedentary and exercised mice, we identify parvalbumin as a circulating factor suppressed by exercise. Parvalbumin functions as a non-competitive CSF1R antagonist to inhibit M2 macrophage activation and energy expenditure in adipose tissue. More importantly, serum concentrations of parvalbumin positively correlate with obesity in mouse and human, while treating mice with a recombinant parvalbumin blocker prevents its interaction with CSF1R and promotes M2 macrophage polarization and ameliorates diet-induced obesity. Thus, although further studies are required to assess the significance of parvalbumin in mediating the effects of exercise, our results implicate parvalbumin as a potential therapeutic strategy against obesity in mice.

The Role of Caspase Family in Acute Brain Injury: The Potential Therapeutic Targets in the Future.

The caspase family is commonly involved in the pathophysiology of acute brain injury (ABI) through complex apoptotic, pyroptotic, and inflammatory pathways. Current translational strategies for caspase modulation in ABI primarily focus on caspase inhibitors. Because there are no caspase-inhibiting drugs approved for clinical use on the market, the development of caspase inhibitors remains an attractive challenge for researchers and clinicians. Therefore, we conducted the present review with the aim of providing a comprehensive introduction of caspases in ABI. In this review, we summarized the available evidence and potential mechanisms regarding the biological function of caspases. We also reviewed the therapeutic effects of caspase inhibitors on ABI and its subsequent complications. However, various important issues remain unclear, prompting further verification of the efficacy and safety regarding clinical application of caspase inhibitors. We believe that our work will be helpful to further understand the critical role of the caspase family and will provide novel therapeutic potential for ABI treatment.

Establishment of a nomogram with EMP3 for predicting clinical outcomes in patients with glioma: A bi-center study.

AIM: To demonstrate the clinical value of epithelial membrane protein 3 (EMP3) with bioinformatic analysis and clinical data, and then to establish a practical nomogram predictive model with bicenter validation. METHODS: The data from CGGA and TCGA database were used to analyze the expression of EMP3 and its correlation with clinical prognosis. Then, we analyzed EMP3 expression in samples from 179 glioma patients from 2013 to 2017. Univariate and multivariate cox regression were used to predict the prognosis with multiple factors. Finally, a nomogram to predict poor outcomes was formulated. The accuracy and discrimination of nomograms were determined with ROC curve and calibration curve in training and validation cohorts. RESULTS: EMP3 was significantly higher in higher-grade glioma and predicted poor prognosis. In multivariate analysis, high expression of EMP3 (HR = 2.842, 95% CI 1.984-4.071), WHO grade (HR = 1.991, 95% CI 1.235-3.212), and IDH1 mutant (HR = 0.503, 95% CI 0.344-0.737) were included. The nomogram was constructed based on the above features, which represented great predictive value in clinical outcomes. CONCLUSION: This study demonstrated EMP3 as a novel predictor for clinical progression and clinical outcomes in glioma. Moreover, the nomogram with EMP3 expression represented a practical approach to provide individualized risk assessment for glioma patients.

Prognostic and predictive value of FCER1G in glioma outcomes and response to immunotherapy.

PURPOSE: Glioma is the most prevalent malignant form of brain tumors, with a dismal prognosis. Currently, cancer immunotherapy has emerged as a revolutionary treatment for patients with advanced highly aggressive therapy-resistant tumors. However, there is no effective biomarker to reflect the response to immunotherapy in glioma patient so far. So we aim to assess the clinical predictive value of FCER1G in patients with glioma. METHODS: The expression level and correlation between clinical prognosis and FER1G levels were analyzed with the data from CGGA, TCGA, and GEO database. Univariate and multivariate cox regression model was built to predict the prognosis of glioma patients with multiple factors. Then the correlation between FCER1G with immune cell infiltration and activation was analyzed. At last, we predict the immunotherapeutic response in both high and low FCER1G expression subgroups. RESULTS: FCER1G was significantly higher in glioma with greater malignancy and predicted poor prognosis. In multivariate analysis, the hazard ratio of FCER1G expression (Low versus High) was 0.66 and 95 % CI is 0.54 to 0.79 (P < 0.001), whereas age (HR = 1.26, 95 % CI 1.04-1.52), grade (HR = 2.75, 95 % CI 2.06-3.68), tumor recurrence (HR = 2.17, 95 % CI 1.81-2.62), IDH mutant (HR = 2.46, 95 % CI 1.97-3.01) and chemotherapeutic status (HR = 1.4, 95 % CI 1.20-1.80) are also included. Furthermore, we illustrated that gene FCER1G stratified glioma cases into high and low FCER1G expression subgroups that demonstrated with distinct clinical outcomes and T cell activation. At last, we demonstrated that high FCER1G levels presented great immunotherapeutic response in glioma patients. CONCLUSIONS: This study demonstrated FCER1G as a novel predictor for clinical diagnosis, prognosis, and response to immunotherapy in glioma patient. Assess expression of FCER1G is a promising method to discover patients that may benefit from immunotherapy.

HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation.

Disregulation of fatty acid oxidation, one of the major mechanisms for maintaining hepatic lipid homeostasis under fasting conditions, leads to hepatic steatosis. Although obesity and type 2 diabetes-induced endoplasmic reticulum (ER) stress contribute to hepatic steatosis, it is largely unknown how ER stress regulates fatty acid oxidation. Here we show that fasting glucagon stimulates the dephosphorylation and nuclear translocation of histone deacetylase 5 (HDAC5), where it interacts with PPARα and promotes transcriptional activity of PPARα. As a result, overexpression of HDAC5 but not PPARα binding-deficient HDAC5 in liver improves lipid homeostasis, whereas RNAi-mediated knockdown of HDAC5 deteriorates hepatic steatosis. ER stress inhibits fatty acid oxidation gene expression via calcium/calmodulin-dependent protein kinase II-mediated phosphorylation of HDAC5. Most important, hepatic overexpression of a phosphorylation-deficient mutant HDAC5 2SA promotes hepatic fatty acid oxidation gene expression and protects against hepatic steatosis in mice fed a high-fat diet. We have identified HDAC5 as a novel mediator of hepatic fatty acid oxidation by fasting and ER stress signals, and strategies to promote HDAC5 dephosphorylation could serve as new tools for the treatment of obesity-associated hepatic steatosis.