Use of Tregs as a cell‐based therapy via CD39 for benign prostate hyperplasia with inflammation

Benign prostatic hyperplasia (BPH) occurs most commonly among older men, often accompanied by chronic tissue inflammation. Although its aetiology remains unclear, autoimmune dysregulation may contribute to BPH. Regulatory T cells (Tregs) prevent autoimmune responses and maintain immune homeostasis. In this study, we aimed to investigate Tregs frequency, phenotype, and function in BPH patients and to evaluate adoptive transfer Tregs for immunotherapy in mice with BPH via CD39. Prostate specimens and peripheral blood from BPH patients were used to investigate Treg subsets, phenotype and Treg‐associated cytokine production. Sorted CD39^+/? Tregs from healthy mice were adoptively transferred into mice before or after testosterone propionate administration. The Tregs percentage in peripheral blood from BPH patients was attenuated, exhibiting low Foxp3 and CD39 expression with low levels of serum IL‐10, IL‐35 and TGF‐β. Immunohistochemistry revealed Foxp3+ cells were significantly diminished in BPH prostate with severe inflammatory. Although the Tregs subset was comprised of more effector/memory Tregs, CD39 was still down‐regulated on effector/memory Tregs in BPH patients. Before or after testosterone propionate administration, no alterations of BPH symptoms were observed due to CD39‐ Tregs in mice, however, CD39⁺Tregs existed more potency than Tregs to regulate prostatic hyperplasia and inhibit inflammation by decreasing IL‐1β and PSA secretion, and increasing IL‐10 and TGF‐β secretion. Furthermore, adoptive transfer with functional Tregs not only improved prostate hyperplasia but also regulated muscle cell proliferation in bladder. Adoptive transfer with Tregs may provide a novel method for the prevention and treatment of BPH clinically.     

Activation of NFKB-JMJD3 signaling promotes bladder fibrosis via boosting bladder smooth muscle cell proliferation and collagen accumulation

Chronic cystitis is characterized by the hyperplasia and fibrosis of the bladder wall as well as attenuated compliance of the bladder. To further unravel its underlying molecular mechanism, the role of NFκB-JMJD3 signaling pathway in cystitis induced bladder fibrosis was investigated. Jmjd3 and Col1/3 expression was detected in a cystitis mouse model that was developed by intraperitoneal injection of cyclophosphamide (CYP). Human bladder smooth muscle cells (hBSMCs) were stimulated in vitro with lipopolysaccharide (LPS), and the cell proliferation and collagen accumulation were detected using EdU, CCK8, flow cytometry, qPCR, western blotting and immunofluorescence assays. Furthermore, the effects of NFκB and JMJD3 on cell proliferation and collagen accumulation were investigated using its selective antagonists, JSH23 and GSK-J4, respectively. CYP induced cystitis significantly increased Jmjd3, Col1 and Col3 expression in the bladder muscle cells. Furthermore, LPS stimulation markedly activated NFκB signaling and elevated JMJD3 expression in hBSMCs, and the activation of NFκB-JMJD3 signaling significantly promoted cell proliferation and collagen accumulation by upregulating CCND1 and COL1/3 expression, respectively. Our study reveals the critical role of NFκB-JMJD3 signaling in cystitis induced bladder reconstruction by regulating hBSMC proliferation and extracellular matrix (ECM) deposition, and these findings provide an avenue for effective treatment of patients with cystitis.     

Host genetics and diet,but not immunoglobulin A expression,converge to shape compositional features of the gut microbiome in an advanced intercross population of mice

Background

Individuality in the species composition of the vertebrate gut microbiota is driven by a combination of host and environmental factors that have largely been studied independently. We studied the convergence of these factors in a G₁₀ mouse population generated from a cross between two strains to search for quantitative trait loci (QTLs) that affect gut microbiota composition or ileal Immunoglobulin A (IgA) expression in mice fed normal or high-fat diets.

Results

We found 42 microbiota-specific QTLs in 27 different genomic regions that affect the relative abundances of 39 taxa, including four QTL that were shared between this G₁₀ population and the population previously studied at G₄. Several of the G₁₀ QTLs show apparent pleiotropy. Eight of these QTLs, including four at the same site on chromosome 9, show significant interaction with diet, implying that diet can modify the effects of some host loci on gut microbiome composition. Utilization patterns of IghV variable regions among IgA-specific mRNAs from ileal tissue are affected by 54 significant QTLs, most of which map to a segment of chromosome 12 spanning the Igh locus. Despite the effect of genetic variation on IghV utilization, we are unable to detect overlapping microbiota and IgA QTLs and there is no significant correlation between IgA variable pattern utilization and the abundance of any of the taxa from the fecal microbiota.

Conclusions

We conclude that host genetics and diet can converge to shape the gut microbiota, but host genetic effects are not manifested through differences in IgA production.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-014-0552-6) contains supplementary material, which is available to authorized users.     

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences.     

长江经济带旅游-经济-生态系统脆弱性时空演变及趋势预测

基于2004—2018年的面板数据,借助脆弱性研究方法、冷热点分析法、空间变差模型和灰色预测模型探索长江经济带旅游-经济-生态系统的时空演变特征及趋势预测。研究表明:(1)2004—2018年长江经济带总体脆弱性指数在波动中上涨,各省市脆弱性指数洼地集中于东部地区且呈平稳发展态势;峰值集中于西部地区但下降趋势显著;总体可持续发展水平呈现"东部>中部>西部"的空间分布格局,但西部地区可持续发展水平可能将在未来超越中部地区。(2)长江经济带脆弱性指数集聚性在扩张,冷热点时空分布变化显著,冷点区域减少,热点区域增多,印证了总体区域的脆弱性数值在不断提升。(3)长江经济带脆弱性指数空间分异特征呈阶段性变化,"东散西集"的分异特征逐渐被打破,总体指数呈均衡化发展态势。(4)通过预测计算2019—2023年长江经济带各区域脆弱性指数,发现2019—2023年的脆弱性指数基本形成了对2014—2018年的全包围态势,长江经济带三系统脆弱性指数较高的发展隐患逐步成为现实问题。     

Increased energy expenditure, dietary fat wasting, and resistance to diet-induced obesity in mice lacking renin

An overactive renin-angiotensin system is associated with obesity and the metabolic syndrome. However, the mechanisms behind it are unclear. Cleaving angiotensinogen to angiotensin I by renin is a rate-limiting step of angiotensin II production, but renin is suggested to have angiotensin-independent effects. We generated mice lacking renin (Ren1c) using embryonic stem cells from C57BL/6 mice, a strain prone to diet-induced obesity. Ren1c^−/− mice are lean, insulin sensitive, and resistant to diet-induced obesity without changes in food intake and physical activity. The lean phenotype is likely due to a higher metabolic rate and gastrointestinal loss of dietary fat. Most of the metabolic changes in Ren1c^−/− mice were reversed by angiotensin II administration. These results support a role for angiotensin II in the pathogenesis of diet-induced obesity and insulin resistance.     

SnO2 as Advanced Anode of Alkali‐Ion Batteries: Inhibiting Sn Coarsening by Crafting Robust Physical Barriers,Void Boundaries,and Heterophase Interfaces for Superior Electrochemical Reaction Reversibility

Superior reaction reversibility of electrode materials is urgently pursued for improving the energy density and lifespan of batteries. Tin dioxide (SnO₂) is a promising anode material for alkali‐ion batteries, having a high theoretical lithium storage capacity of 1494 mAh g^? based on the reactions of SnO₂ + 4Li⁺ + 4e^? ? Sn + 2Li₂O and Sn + 4.4Li⁺ + 4.4e^? ? Li_4.4Sn. The coarsening of Sn nanoparticles into large particles induced reaction reversibility degradation has been demonstrated as the essential failure mechanism of SnO₂ electrodes. Here, three key strategies for inhibiting Sn coarsening to enhance the reaction reversibility of SnO₂ are presented. First, encapsulating SnO₂ nanoparticles in physical barriers of carbonaceous materials, conductive polymers or inorganic materials can robustly prevent Sn coarsening among the wrapped SnO₂ nanoparticles. Second, constructing hierarchical, porous or hollow structured SnO₂ particles with stable void boundaries can hinder Sn coarsening between the void‐divided SnO₂ subunits. Third, fabricating SnO₂‐based heterogeneous composites consisting of metals, metal oxides or metal sulfides can introduce abundant heterophase interfaces in cycled electrodes that impede Sn coarsening among the isolated SnO₂ crystalline domains. Finally, a perspective on the future prospect of the structural/compositional designs of SnO₂ as anode of alkali‐ion batteries is highlighted.