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Obesity is a global health problem and a major risk factor for several metabolic conditions including dyslipidemia, diabetes, insulin resistance and cardiovascular diseases. Obesity develops from chronic imbalance between energy intake and energy expenditure. Stimulation of cellular energy burning process has the potential to dissipate excess calories in the form of heat via the activation of uncoupling protein-1 (UCP1) in white and brown adipose tissues. Recent studies have shown that activation of transforming growth factor-β (TGF-β) signaling pathway significantly contributes to the development of obesity, and blockade or inhibition is reported to protect from obesity by promoting white adipose browning and increasing mitochondrial biogenesis. Identification of novel compounds that activate beige/brown adipose characteristics to burn surplus calories and reduce excess storage of fat are actively sought in the fight against obesity. In this review, we present recent developments in our understanding of key modulators of TGF-β signaling pathways including follistatin (FST) and myostatin (MST) in regulating adipose browning and brown adipose mass and activity. While MST is a key ligand for TGF-β family, FST can bind and regulate biological activity of several TGF-β superfamily members including activins, bone morphogenic proteins (BMP) and inhibins. Here, we review the literature supporting the critical roles for FST, MST and other proteins in modulating TGF-β signaling to influence beige and brown adipose characteristics. We further review the potential therapeutic utility of FST for the treatment of obesity and related metabolic disorders.

Breast cancer results from a complex interplay of genetics and environment that alters immune and inflammatory systems to promote tumorigenesis. Obesity and cigarette smoking are well-known risk factors associated breast cancer development. Nicotine known to decrease inflammatory signals also modulates immune responses that favor breast cancer development. However, the mechanisms by which nicotine and obesity contribute to breast cancer remain poorly understood. In this study, we examined potential mechanisms by which nicotine (NIC) and high-fat diet (HFD) promote growth of HCC70 and HCC1806 xenografts from African American (AA) triple negative (TN) breast cancer cells. Immunodeficient mice fed on HFD and treated with NIC generated larger HCC70 and HCC1806 tumors when compared to NIC or HFD alone. Increased xenograft growth in the presence of NIC and HFD was accompanied by higher levels of tissue-resident macrophage markers and anti-inflammatory cytokines including IL4, IL13, and IL10. We further validated the involvement of these players by in vitro and ex vivo experiments. We found a proinflammatory milieu with increased expression of IL6 and IL12 in xenografts with HFD. In addition, nicotine or nicotine plus HFD increased a subset of mammary cancer stem cells (MCSCs) and key adipose browning markers CD137 and TMEM26. Interestingly, there was upregulation of stress-induced pp38 MAPK and pERK1/2 in xenografts exposed to HFD alone or nicotine plus HFD. Scratch-wound assay showed marked reduction in proliferation/migration of nicotine and palmitate-treated breast cancer cells with mecamylamine (MEC), a nicotine acetylcholine receptor (nAchR) antagonist. Furthermore, xenograft development in immune-deficient mice, fed HFD plus nicotine, was reduced upon cotreatment with MEC and SB 203580, a pp38MAPK inhibitor. Our study demonstrates the presence of nicotine and HFD in facilitating an anti-inflammatory tumor microenvironment that influences breast tumor growth. This study also shows potential efficacy of combination therapy in obese breast cancer patients who smoke.

During semiconductor manufacturing, the high temperature sulfuric acid peroxide mixture (SPM) and airborne molecule contaminants (AMCs) can result in the formation of defects such as Silicon-carbide (Si-C) on the wafer surface. Furthermore, defects adversely affect device performance, yield, and manufacturing productivity. In this work, a novel approach is proposed by introducing an additional nitrogen (N2) gas purge nozzle inside the single wafer chamber to reduce total volatile organic compounds (t-VOC). Additionally, we provide insights into the mechanism underlying defect formation in SPM which has not been previously explained. In SPM process, defects are formed by AMCs and high temperature. So, various AMCs were investigated in this work. Moreover, the correlation of the number of Si-C defect with temperature and duration of chemical flow was also analyzed. The experimental results demonstrated that defects and t-VOC follow the same concentration trend. Our nitrogen purge method effectively diluted the chamber environment, reducing the adhesion energy between contamination particles and the wafer surface. A suitable N2 purging rate inside the single-wafer chamber facilitated the elimination of around 63% of defects from wafer surface. Hence, this approach can be crucial in minimizing the Si-C defects and improving the chamber environment for high-temperature SPM wet-cleaning process. [ABSTRACT FROM AUTHOR]

Background:Follistatin (Fst) promotes brown adipocyte characteristics in adipose tissues. Methods:Abdominal fat volume (CT scan), glucose clearance (GTT test), and metabolomics analysis (mass spectrometry) of adipose tissues from Fst transgenic (Fst-Tg) and wild type (WT) control mice were analyzed. Oxygen consumption (Seahorse Analyzer) and lipidomics (gas chromatography) was analyzed in 3T3-L1 cells. Results:Fst-Tg mice show significant decrease in abdominal fat content, increased glucose clearance, improved plasma lipid profiles and significant changes in several conventional metabolites compared to the WT mice. Furthermore, overexpression of Fst in 3T3-L1 cells resulted in up regulation of key brown/beige markers and changes in lipidomics profiles. Conclusion:Fst modulates key factors involved in promoting metabolic syndrome and could be used for therapeutic intervention.

BackgroundBreast cancer is a complex heterogeneous disease where many distinct subtypes are found. Younger African American (AA) women often present themselves with aggressive form of breast cancer with unique biology which is very difficult to treat. Better understanding the biology of AA breast tumors could lead to development of effective treatment strategies. Our previous studies indicate that AA but not Caucasian (CA) triple negative (TN) breast cancer cells were sensitive to nitrosative stress-induced cell death. In this study, we elucidate possible mechanisms that contribute to nitric oxide (NO)-induced apoptosis in AA TN breast cancer cells.MethodsBreast cancer cells were treated with various concentrations of long-acting NO donor, DETA-NONOate and cell viability was determined by trypan blue exclusion assay. Apoptosis was determined by TUNEL and caspase 3 activity as well as changes in mitochondrial membrane potential. Caspase 3 and Bax cleavage, levels of Cu/Zn superoxide dismutase (SOD) and Mn SOD was assessed by immunoblot analysis. Inhibition of Bax cleavage by Calpain inhibitor, and levels of reactive oxygen species (ROS) as well as SOD activity was measured in NO-induced apoptosis. In vitro and in vivo effect of NO treatment on mammary cancer stem cells (MCSCs) was assessed.Results and discussionNO induced mitocondria-mediated apoptosis in all AA but not in CA TN breast cancer cells. We found significant TUNEL-positive cells, cleavage of Bax and caspase-3 activation as well as depolarization mitochondrial membrane potential only in AA TN breast cancer cells exposed to NO. Inhibition of Bax cleavage and quenching of ROS partially inhibited NO-induced apoptosis in AA TN cells. Increase in ROS coincided with reduction in SOD activity in AA TN breast cancer cells. Furthermore, NO treatment of AA TN breast cancer cells dramatically reduced aldehyde dehydrogenase1 (ALDH1) expressing MCSCs and xenograft formation but not in breast cancer cells from CA origin.ConclusionsEthnic differences in breast tumors dictate a need for tailoring treatment options more suited to the unique biology of the disease.

Leishmania donovani are intracellular, human blood parasites that cause visceral leishmaniasis or kala-azar. Cell-penetrating peptides (CPPs) have been shown to modulate intracellular processes and cargo delivery, whereas host defense peptides (HDPs) promote proliferation of both naïve and antigen activated CD4+ T-cells. We report newly designed tripeptides that were able to trigger proinflammatory cytokine (IL-12 and IFN-γ) secretion by CD4+CD44+ T-cells in response to Leishmania donovani infection. These peptides can be used to induce antigen specific TH1 responses to combat obstacles of cytotoxicity and drug resistance associated with current anti-leishmanial drugs. Furthermore, these peptides can also be used as adjuvants to develop an effective immunoprophylactic approach for immunity restoration against visceral leishmaniasis. [ABSTRACT FROM AUTHOR]