Search

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3-7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions., Introduction Innate immune cells, such as monocytes and macrophages, play vital roles in tissue injury and repair. Cell death caused by myocardial ischemia in the infarct region recruits and activates [...]

OBJECTIVE: We performed a systematic review to identify which genetic variants predict response to diabetes medications. RESEARCH DESIGN AND METHODS: We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance. RESULTS: Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication-gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis. CONCLUSIONS: We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition.

Background: ILC2s are capable of generating memory. The mechanism of memory induction and memory-driven effector function (trained immunity) in ILC2s is unknown. Objective: NFkB1 is preferentially expressed at a high level in ILC2s. We examined the role of NFkB1 in memory induction and memory-driven effector function in a mouse model of asthma. Methods: Intranasal administration of Alternaria, flexivent, ELISA, histology, realtime PCR, western blot, flow cytometry and immunofluorescence staining. Results: NFkB1 was essential for the effector phase of memory-driven asthma. NFkB1 was critical for IL33 production, ILC2 generation, and production of type2 cytokines, which resulted in eosinophilic inflammation and other features of asthma. NFkB1 induction of type-2 cytokines in ILC2s was independent of GATA3. NFkB1 was important for allergen induction of ILC3s and FoxP3+ Tregs. NFkB1 did not affect Th2 cells or their cytokine production. In contrast to its protagonistic role in the effector phase, NFkB1 had an antagonistic role in the memory phase. NFkB1 inhibited allergen-induced upregulation of memoryassociated repressor and preparedness genes in ILC2s. NFkB1 upregulated RUNX1. NFkB1 formed a heterodimer with RUNX1 in ILC2s. Conclusions: NFkB1 positively regulated the effector phase but inhibited the induction phase of memory. The foregoing pointed to an interdependent antagonism between the memory induction and the memory effector processes. The NFkB1-RUNX1 heterodimer represented a non-canonical transcriptional activator of type-2 cytokines in ILC2 [ABSTRACT FROM AUTHOR]

The scavenger receptor (SR) super family consists of integral membrane glycoproteins that are involved in recognition of polyanionic structures of either endogenous (e.g., oxidized low-density lipoprotein) or exogenous (e.g., bacterial lipopolysaccharides) origin. SRs are structurally diverse and can be classified into seven different classes (A–G) based on the multidomain structure of the individual members. SRs are present on various types of tissues, such as vascular, adipose, and steroidogenic tissues. In addition to modified lipoprotein uptake, these proteins are also known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens. Different SRs are involved in many physiological and pathological processes; more importantly, the function of SRs is highly implicated in the initiation and progression of atherosclerotic plaque. Targeting the SR gene products that mediate the response to and uptake of modified lipids holds great promise in the prevention of cardiovascular diseases. Inhibition of SR expression using a combined gene therapy and RNA interference strategy also appears to be an option for long-term therapy. The present review focuses on the involvement of SRs in atherosclerosis, thrombosis, and other cardiovascular diseases. Moreover, the role of SRs is not restricted to vascular lesions; it is also implicated in a number of different cellular functions.

Abstract Background Obesity is a health hazard which is closely associated with various complications including insulin resistance, hypertension, dyslipidemia, atherosclerosis, type 2 diabetes and cancer. In spite of numerous preclinical and clinical interventions, the prevalence of obesity and its related disorders are on the rise demanding an urgent need for exploring novel therapeutic agents that can regulate adipogenesis. In the present study, we evaluated whether a dietary supplement ReishiMax (RM), containing triterpenes and polysaccharides extracted from medicinal mushroom Ganoderma lucidum, affects adipocyte differentiation and glucose uptake in 3T3-L1 cells. Methods 3T3-L1 pre-adipocytes were differentiated into adipocytes and treated with RM (0-300 μg/ml). Adipocyte differentiation/lipid uptake was evaluated by oil red O staining and triglyceride and glycerol concentrations were determined. Gene expression was evaluated by semi-quantitative RT-PCR and Western blot analysis. Glucose uptake was determined with [3H]-glucose. Results RM inhibited adipocyte differentiation through the suppresion of expression of adipogenic transcription factors peroxisome proliferator-activated receptor-γ (PPAR-γ), sterol regulatory element binding element protein-1c (SREBP-1c) and CCAAT/enhancer binding protein-α (C/EBP-α). RM also suppressed expression of enzymes and proteins responsible for lipid synthesis, transport and storage: fatty acid synthase (FAS), acyl-CoA synthetase-1 (ACS1), fatty acid binding protein-4 (FABP4), fatty acid transport protein-1 (FATP1) and perilipin. RM induced AMP-activated protein kinase (AMPK) and increased glucose uptake by adipocytes. Conclusion Our study suggests that RM can control adipocyte differentiation and glucose uptake. The health benefits of ReishiMax warrant further clinical studies.

Ageratum houstonianum Mill. (Asteraceae) leaves extract (in distilled water and methanol) was evaluated against five phytopathogenic fungi: Alternaria brassicae, Botrytis cinerea, Fusarium oxysporum, Phytophthora capsici and Sclerotium rolfsii at different concentrations (50, 100, 150, 200, and 250 mg/mL). The phytochemical screening depicted the presence of terpenoids, saponins, flavonoids, tannins and alkaloids. The activity test of extracts against fungi was determined by poisoned food technique and linear mycelium growth reduction (LMGR) percentage was calculated. Methanol crude leaf extract had higher antifungal potential than the distilled water extract. Aqueous and methanolic extracts of leaves of A. houstonianum greatly reduced the mycelium growth of tested fungi, which can be used for the disease management. [ABSTRACT FROM AUTHOR]

Objectives: Genes related to endothelial function are responsible for the regulation of vascular functions. Aim: The aim of this study is to investigate whether endothelial gene-associated polymorphism and their plasma levels can be used to predict the risk for venous thromboembolism (VTE). Methods: We studied 133 patients with VTE and 164 healthy controls. Endothelin (EDN) G8002A, EDN T1370G, EDN 3A/4A, eNOSG894T, angiotensin-converting enzyme I/D, vascular endothelial growth factor C936T, and endothelial cell protein C receptor A6936G polymorphism was genotyped by restriction fragment length polymorphism. Plasma levels of endothelin 1 (EDN1), endothelial nitric oxide synthase, and angiotensin-converting enzyme were measured by enzyme-linked immunoassay kit. Results: The genotype and allele frequency between control and patients with VTE were significantly altered only for EDN T1370G polymorphism. The plasma EDN1 concentration was relatively higher in patients with VTE (P = .0017) compared to healthy controls and showed an association with the EDN1 gene polymorphism in male Indian population. Logistic regression model analysis for EDN T1370G indicated a significant association between EDN G allele and occurrence of VTE. Conclusion: The EDN1 gene polymorphism may play a significant role in predicting individual’s susceptibility toward VTE and its clinical progression. [ABSTRACT FROM AUTHOR]

Background: We have recently synthesized novel N-alkylated amino acid-derived hydroxamate, 2-[Benzyl-(2-nitrobenzenesulfonyl)- amino]-N-hydroxy-3-methyl-N-propyl-butyramide (NAHA). Here, we evaluate the anticancer activity of NAHA against highly invasive human breast cancer cells MDA-MB-231 in vitro and in vivo. Methodology/Principal Findings: Cell growth was evaluated by MTT and soft agar assays. Protein expression was determined by DNA microarray and Western blot analysis. Metastatic potential was evaluated by cell adhesion, migration, invasion, capillary morphogenesis, and ELISA assays. The anticancer activity in vivo was evaluated in mouse xenograft model. NAHA inhibited proliferation and colony formation of MDA-MB-231 cells together with the down-regulation of expression of Cdk2 and CDC20 proteins. NAHA inhibited cell adhesion, migration, and invasion through the suppression of secretion of uPA. NAHA suppressed secretion of VEGF from MDA-MB-231 cells and inhibited capillary morphogenesis of human aortic endothelial cells (HAECs). Finally, NAHA at 50 mg/kg was not toxic and decreased tumor volume and tumor weight in vivo. This suppression of tumor growth was associated with the inhibition of mitotic figures and induction of apoptosis, and the reduction of CD31 and VEGF positive cells in tumors. Conclusion: NAHA could be a novel promising compound for the development of new drugs for the therapy of invasive breast cancers. [ABSTRACT FROM AUTHOR]

Poria cocos is a medicinal mushroom that is widely used in traditional Asian medicine. Here, we show that a characterized mixture of triterpenes extracted from P. cocos (PTE) and three purified triterpenes: pachymic acid (PA), dehydropachymic acid (DPA) and polyporenic acid C (PPAC) suppress the proliferation of the human pancreatic cancer cell lines Panc-1, MiaPaca-2, AsPc-1 and BxPc-3. Moreover, the most effective compound, PA, only slightly affects the proliferation of HPDE-6 normal pancreatic duct epithelial cells. The anti-proliferative effects of PTE on BxPc-3 cells are mediated by the cell cycle arrest at G0/G1 phase. DNA microarray analysis demonstrated that PTE significantly downregulates the expression of KRAS and matrix metalloproteinase-7 (MMP-7) in BxPc-3 cells. In addition, PTE and PA suppress the invasive behavior of BxPc-3 cells. The inhibition of invasiveness by PTE and PA was associated with the reduction of MMP-7 at the protein level and the role of MMP-7 further confirmed by the gene silencing of MMP-7 which also suppressed the invasiveness of BxPc-3 cells. In conclusion, triterpenes from P. cocos demonstrate anticancer and anti-invasive effects on human pancreatic cancer cells and can be considered as new therapeutic agents in the treatment of pancreatic cancer.