Association between obesity and bacterial vaginosis as assessed by Nugent score

Background Bacterial vaginosis is one of the most common vaginal conditions in the U.S. Recent studies have suggested obese women have an abnormal microbiota reminiscent of BV; however, few studies have investigated the prevalence of bacterial vaginosis in overweight and obese populations. Moreover, despite the increased prevalence of obesity and bacterial vaginosis in black women, it is not known whether racial disparities exist in the relationship between obesity and bacterial vaginosis. Objective The objective of this study was to examine the relationship between body mass index and bacterial vaginosis as determined by Nugent score and to determine the influence of race in this context. Study Design We performed a cross-sectional study using patient data and vaginal smears from 5,918 participants of the Contraceptive CHOICE Project. Gram stained vaginal smears were scored using the Nugent method and categorized as BV-negative (Nugent score 0-3), BV-intermediate (Nugent score 4-6), or BV-positive (Nugent score 7-10). Body mass index was determined using Centers for Disease Control and Prevention guidelines and obese individuals were categorized as Class I, II, or III obese based on NIH and World Health Organization body mass index parameters. Linear regression was used to model mean differences in Nugent scores and Poisson regression with robust error variance was used to model prevalence of bacterial vaginosis. Results In our cohort, 50.7% of participants were black, 41.5% were white, and 5.1% were of Hispanic ethnicity with an average age of 25.3 years old. Overall, 28.1% of participants were bacterial vaginosis-positive. Bacterial vaginosis was prevalent in 21.3% of lean, 30.4% of overweight, and 34.5% of obese women (p<0.001). The distribution of bacterial vaginosis-intermediate individuals was similar across all body mass index categories. Compared to lean women, Nugent scores were highest among overweight and obese Class I women (adjusted mean difference; overweight 0.33 [95% CI 0.14, 0.51] and Class I obese 0.51 [95% CI 0.29, 0.72]). Consistent with this, overweight and obese women had a higher frequency of bacterial vaginosis compared to lean women, even after adjusting for variables including race. Among white women, the prevalence of BV was higher for overweight and Class I and Class II/III obese white women compared to lean white women, a phenomenon not observed among black women, suggesting an effect modification. Conclusion Overweight and obese women have higher Nugent scores and a greater occurrence of bacterial vaginosis compared to lean women. Black women have a greater prevalence of bacterial vaginosis independent of their body mass index compared to white women

Site-1 protease inhibits mitochondrial respiration by controlling the TGF-β target gene Mss51

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P disruption in mouse skeletal muscle reduces Mss51 expression and increases muscle mass and mitochondrial respiration. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing Mss51, suggesting that one way S1P inhibits respiration is by regulating Mss51. These discoveries expand our understanding of TGF-β signaling and S1P function

Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations

Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1-/- hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1-/- mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling

In utero exposure to cigarette smoke and effects across generations:A conference of animals on asthma

Background: The prevalence of asthma and chronic obstructive pulmonary disease (COPD) has risen markedly over the last decades and is reaching epidemic proportions. However, underlying molecular mechanisms are not fully understood, hampering the urgently needed development of approaches to prevent these diseases. It is well established from epidemiological studies that prenatal exposure to cigarette smoke is one of the main risk factors for aberrant lung function development or reduced fetal growth, but also for the development of asthma and possibly COPD later in life. Of note, recent evidence suggests that the disease risk can be transferred across generations, that is, from grandparents to their grandchildren. While initial studies in mouse models on in utero smoke exposure have provided important mechanistic insights, there are still knowledge gaps that need to be filled. Objective: Thus, in this review, we summarize current knowledge on this topic derived from mouse models, while also introducing two other relevant animal models: the fruit fly Drosophila melanogaster and the zebrafish Danio rerio. Methods: This review is based on an intensive review of PubMed-listed transgenerational animal studies from 1902 to 2018 and focuses in detail on selected literature due to space limitations. Results: This review gives a comprehensive overview of mechanistic insights obtained in studies with the three species, while highlighting the remaining knowledge gaps. We will further discuss potential (dis)advantages of all three animal models. Conclusion/Clinical Relevance: Many studies have already addressed transgenerational inheritance of disease risk in mouse, zebrafish or fly models. We here propose a novel strategy for how these three model organisms can be synergistically combined to achieve a more detailed understanding of in utero cigarette smoke-induced transgenerational inheritance of disease risk

The Genetic Signatures of Noncoding RNAs

The majority of the genome in animals and plants is transcribed in a developmentally regulated manner to produce large numbers of non–protein-coding RNAs (ncRNAs), whose incidence increases with developmental complexity. There is growing evidence that these transcripts are functional, particularly in the regulation of epigenetic processes, leading to the suggestion that they compose a hitherto hidden layer of genomic programming in humans and other complex organisms. However, to date, very few have been identified in genetic screens. Here I show that this is explicable by an historic emphasis, both phenotypically and technically, on mutations in protein-coding sequences, and by presumptions about the nature of regulatory mutations. Most variations in regulatory sequences produce relatively subtle phenotypic changes, in contrast to mutations in protein-coding sequences that frequently cause catastrophic component failure. Until recently, most mapping projects have focused on protein-coding sequences, and the limited number of identified regulatory mutations have been interpreted as affecting conventional cis-acting promoter and enhancer elements, although these regions are often themselves transcribed. Moreover, ncRNA-directed regulatory circuits underpin most, if not all, complex genetic phenomena in eukaryotes, including RNA interference-related processes such as transcriptional and post-transcriptional gene silencing, position effect variegation, hybrid dysgenesis, chromosome dosage compensation, parental imprinting and allelic exclusion, paramutation, and possibly transvection and transinduction. The next frontier is the identification and functional characterization of the myriad sequence variations that influence quantitative traits, disease susceptibility, and other complex characteristics, which are being shown by genome-wide association studies to lie mostly in noncoding, presumably regulatory, regions. There is every possibility that many of these variations will alter the interactions between regulatory RNAs and their targets, a prospect that should be borne in mind in future functional analyses

The Non-Coding RNA gadd7 is a Feed-Forward Regulator of Oxidative Stress

In obesity and diabetes, an imbalance in fatty acid uptake and fatty acid utilization leads to excess accumulation of lipid in non-adipose tissues. This lipid overload is associated with cellular dysfunction and cell death contributing to organ and tissue failure, a phenomenon termed lipotoxicity. While lipotoxicity is implicated in several complications of obesity and type 2 diabetes, the molecular mechanisms involved in lipotoxic stress are not fully understood. Here we describe the non-coding RNA (ncRNA) gadd7 as a key regulator involved in the response to metabolic stress. To elucidate the molecular mechanisms of lipid-mediated cell death, we generated and characterized a mutant Chinese hamster ovary (CHO) cell line that is resistant to fatty acid-induced cell death. In this mutant, random insertion of a retroviral promoter trap has disrupted the gene for the ncRNA gadd7. Here we report that gadd7 is induced by lipid overload in a reactive oxygen species (ROS)-dependent fashion and is necessary for both lipid- and general oxidative stress-mediated cell death. In vitro depletion of gadd7 by mutagenesis or short hairpin RNA knockdown in CHO cells significantly reduces lipid and non-lipidinduced ROS. Furthermore, depletion of gadd7 delays and diminishes ROSinduced endoplasmic reticulum stress. Gadd7 has only been identified in the hamster species. The lack of disease models in the hamster makes investigating the pathophysiological significance of gadd7 difficult. Therefore, we extended our studies of gadd7 into the murine species, for which there exist several models of metabolic stress. We identified and characterized mouse gadd7 orthologs in murine fibroblasts and show that, like gadd7, the mouse orthologs participate in a feed-forward loop with ROS in response to lipid-induced oxidative stress. We investigated the pathophysiological role of gadd7 and show that expression is induced during cerebral ischemia and liver injury, pathophysiologic processes in which oxidative stress is a known contributor. Our data are the first to describe a ncRNA involved in the feed-forward regulation of oxidative stress. Further study into the pathophysiological significance of gadd7 will provide valuable insight into the propagation of oxidative stress in disease and may enable the development of novel therapeutic approaches

Effects of S1P Mutation on ER Stress and Cholesterol Synthesis Markers in Human Epithelial Cells

Site-1 Protease (S1P) is a Golgi-resident enzyme required for activation and subsequent nuclear localization of several major transcription factors. A 24-year-old female patient with a de novo single point mutation in S1P presented with a complex phenotype that includes gut hypomotility and abnormal optic nerves. Exomic sequencing revealed a heterozygous amino acid substitution of S1P. Previous research has shown that S1P plays an integral role in the activation of ATF6 and SREBP2, key transcription factors involved in the ER stress response and cholesterol biosynthetic pathway, respectively. The goal of this study was to characterize the mutant S1P protein by assessing protein activity and localization. Over-expression of mutant S1P in a lipid and cholesterol auxotrophic S1P-null cell line rescued the dependence on exogenous lipids and sterols similar to null cells expressing wild-type S1P. Furthermore, induction of ER stress with tunicamycin showed a heightened expression of ATF6 target genes in mutant S1P patient fibroblasts relative to control patient cells. A similar elevated response in SREBP2 target genes was also observed when the SREBP2 pathway was stimulated in the mutant fibroblasts. In addition, EndoH sensitivity assays showed that localization of mutant S1P to the Golgi was not impaired. This initial characterization demonstrated that the de novo mutation produces a gain-of function phenotype and that the mutation does not disrupt proper localization of the protein. This is the first known case of S1P mutation in humans and it is unknown how many harbor similar mutations of the S1P protein, critical for sterol homeostasis. Abstract updated November 7, 201