Mitochondrial Oxidative Phosphorylation Complex Regulates NLRP3 Inflammasome Activation and Predicts Patient Survival in Nasopharyngeal Carcinoma

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Highlights

• •Flow cytometry analysis is used to isolate ASC speck⁽⁺⁾ NPC cells.
• •Proteome analysis of ASC speck⁽⁺⁾ NPC cells reveals enriched mitochondrial OxPhos proteins.
• •OxPhos proteins mediate NLRP3 inflammasome activation through mtROS.
• •OxPhos proteins, NDUFB8 and ATP5B are correlated with NPC local recurrence.

     

The transient and constitutive inflammatory signaling in tumorigenesis

Comment on: Rokavec M, et al. Mol Cell 2012; 45:777-89.     

Probing binding mechanism of interleukin-6 and olokizumab: in silico design of potential lead antibodies for autoimmune and inflammatory diseases

Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen–antibody (Ag???Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag???Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases.     

Upregulation of miR-183 represses neuropathic pain through inhibiton of MAP3K4 in CCI rat models

Many studies have verified that microRNAs contribute a lot to neuropathic pain progression. Furthermore, nerve-related inflammatory cytokines play vital roles in neuropathic pain progression. miR-183 has been identified to have a common relationship with multiple pathological diseases. However, the potential effects of miR-183 in the process of neuropathic pain remain undetermined. Therefore, we performed the current study with the purpose of finding the functions of miR-183 in neuropathic pain progression using a chronic sciatic nerve injury (CCI) rat model. We demonstrated that miR-183 expression levels were evidently reduced in CCI rats in contrast with the control group. Overexpression of miR-183 produced significant relief of mechanical hyperalgesia, as well as thermal hyperalgesia in CCI rats. Furthermore, neuropathic pain-correlated inflammatory cytokine expression levels containing interleukin-6 (IL-6) and interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2) were obviously inhibited by upregulation of miR-183. Meanwhile, dual-luciferase reporter assays showed MAP3K4 was a direct downstream gene of miR-183. The expression levels of MAP3K4 were modulated by the increased miR-183 negatively, which lead to the downregulation of IL-6, IL-1β, and COX-2, and then reduced neuropathic pain progression, respectively. Overall, our study pointed out that miR-183 was a part of the negative regulator which could relieve neuropathic pain by targeting MAP3K4. Thus it may provide a new clinical treatment for neuropathic pain patients clinical therapy.     

Oncogene expression in mammary epithelial cells.

Mouse strains which develop tumors at a high incidence with characteristics very similar to human cancers have been derived over the last 8 years. The tumors are caused by defined genetic alterations in the mouse genome. Three areas of research have contributed to the derivation of these mouse strains: (1) Molecular analysis of human tumors has shown that distinct oncogenes and tumor suppressor genes are consistently involved in a high percentage of primary tumors. (2) Regulatory enhancer-promoter sequences have been identified which direct gene expression to specific target cells, preferentially mammary epithelial cells. (3) The introduction of recombinant DNA molecules into fertilized mouse eggs by microinjection and integration of the injected DNA into the genome of injected cells has given rise to mutant mouse strains with unique and defined genetic alterations. Studies with different promoter-oncogene combinations introduced into transgenic mouse strains have led to the following general conclusions: (1) Oncogenes expressed in mammary gland cells predispose transgenic mice to mammary tumors. (2) The oncogenic potential of individual oncogenes in mammary epithelial cells differs. (3) Oncogene expression initially often causes a preneoplastic state affecting growth and differentiation parameters of cells. (4) The expression of different oncogenes synergizes to reduce tumor latency. Synergism can also be observed with physiological growth signals like estrogen or growth hormone. The oncogenes with a role in mammary carcinomas which have been investigated in transgenic mice will be described here. The phenotypic consequences of oncogene expression and the implications for the multistep carcinogenesis model will be discussed.     

Caerulein and secretin induced pancreatic growth: a possible control by endogenous pancreatic somatostatin

Pancreatic hypertrophy and hyperplasia following chronic joint (CA + SE), or separate, caerulein (CA: 1 microgram . kg-1) and secretin (SE: 75 micrograms . kg-1) administration were studied in parallel with pancreatic somatostatin (SRIF) contents following 2, 4, 7 and 10 days of treatment. Parameters indicative of pancreatic growth (tissue weight, DNA and protein contents, cellular protein concentrations) increased significantly after 2 days of CA or CA + SE and reached a plateau between days 4 and 10. SE merely induced a mild hypertrophy after 4 days. Endogenous pancreatic SRIF contents varied upon treatment, differently so with each peptide regimen. Indeed, CA and CA + SE treatments decreased total SRIF contents after 2 days with no effect thereafter. SE also decreased the latter after 2 days while significant increases were observed after 7 and 10 days. The inverse relationship seemingly existing between SRIF contents and the amplitude of hormonally-induced pancreatic growth supports the hypothesis that endogenous pancreatic SRIF, operating as an 'antigrowth' factor, may participate in the exogenous CA, SE and CA + SE stimulated pancreatic growth phenomena.     

Submaximal,aerobic exercise training exacerbates the cardiomyopathy of postweanling Cu-depleted rats

To determine the dual effect of exercise training and copper depletion on myocardial function and ultrastructure, postweanling rats were either trained or sedentary while fed copper-adequate or copper-deficient diets for 8 wk. Rats developed characteristic myocardial subcellular degeneration and increased cardiac mitochondrial volume density when copper depleted, despite lack of overt cardiac hypertrophy, hypertension, or anemia. Training combined with copper depletion induced mild left ventricular hypertrophy. Basal laminae appeared fractionated in areas at capillary-myocyte interface, with focal pericapillary and interstitial collagen accumulation, where-as overt fibrosis was absent or minimal. Electrocardiograms revealed increased QRS wave and QT duration and notching of QRS complex with copper depletion, consistent with intraventricular conductance disturbances. The oxidative capacity of soleus muscle increased with training in copper-adequate rats, but was reduced with progressive copper depletion. These data suggest that copper depletion and training are synergistic in effecting focal accumulation of collagen, with deleterious effect on exercise capacity.     

Selenium in combination with a tomato lipid extract as a therapy for benign prostatic hyperplasia and its alterations in rats with induced BPH

Benign prostatic hyperplasia (BPH) is the most common adenoma in old men. Tomatoes are a rich source of bioactive compounds that, as well as selenium (Se), possess antioxidant and antiproliferative activity. The aim was to evaluate the therapeutic effect of Se in combination with a tomato extract in aged rats with BPH. Aged male Wistar rats were divided in the following groups (n = 10 rats/group): Control (C), BPH, BPH + Finasteride (BPH + F), BPH + Tomato Lipidic Extract (BPH + E), BPH + Selenium (BPH + S) and BPH plus E plus S (BPH + E + S). After 4 weeks of treatment, prostate weight, diuresis, antioxidants enzymes, prooxidants and inflammatory markers, growth factors and androgens were determined. BPH + E + S reduced prostate weight by 59.29% and inhibited growth by 99.35% compared to BPH + F which only decreased weight and inhibited growth by 15.31% and 57.54%, respectively. Prooxidant markers were higher with BPH + F (49.4% higher vs. BPH), but BPH + E + S decreased these markers (94.27% vs. BPH) and increased antioxidant activity. Finally, diuresis was higher with the BPH + E + S combination and markers of inflammation and growth factors were significantly lower with respect to BPH + F. Our findings provide a beneficial and protective therapeutic option of E + S directed against androgens, oxidative stress and inflammation that regulates cell proliferation in the prostate gland.     

肠道菌群在脊髓损伤后胃肠道炎症反应中的研究进展

脊髓损伤(spinal cord injury, SCI)目前尚无有效的治疗手段。脊髓损伤后,患者常伴有严重的胃肠功能障碍,严重影响患者的生活质量。研究发现,脊髓损伤后肠道菌群的紊乱和脊髓损伤后的胃肠道功能障碍密切相关。因此,本文围绕脊髓损伤后肠道菌群的变化,探讨肠道菌群在迷走神经、下丘脑-垂体-肾上腺和肠道菌群代谢物3个途径中发挥的作用,及与胃肠道炎症反应相关的研究进展。     

屎肠球菌对斑节对虾肠道代谢组学及炎性因子的影响

【背景】屎肠球菌(Enterococcus faecium)作为乳酸菌属的潜在益生菌,因其具有良好的生物学特性在动物养殖中应用广泛,但是屎肠球菌对肠道代谢组学的研究很少。【目的】以斑节对虾为试验动物,初步探究屎肠球菌R8对肠道代谢组学及炎性因子的影响,为屎肠球菌作为益生菌在对虾养殖中的应用提供理论基础。【方法】将400条斑节对虾随机分配,设计饲料中屎肠球菌添加量分别为107、108、109 CFU/g的3个试验组,不添加屎肠球菌为对照组进行试验,养殖周期为28 d。养殖周期结束后测定斑节对虾免疫球蛋白M (immunoglobulin M,IgM)、对虾酚氧化酶(phenoloxidase,PO)、白介素6 (interleukin 6,IL-6)、补体片段3a (complement fragment 3a,C3a)的活性含量并运用LC-MS代谢组学研究肠道内源代谢物的变化,分析差异代谢物和相关的代谢通路。【结果】添加屎肠球菌对斑节对虾炎性因子有积极的影响,增加了斑节对虾体内免疫球蛋白IgM、对虾酚氧化酶、补体片段3a的含量,降低了其体内IL-6的含量,对肠道差异代谢物的分析发现,对...