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Metabolic syndrome, today affecting more than 20% of the US population, is a group of 5 conditions that often coexist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here, we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial cells throughout the organism and that lipid droplet accumulation in endothelium suppresses endothelial nitric oxide synthase (eNOS), reduces NO production, elevates blood pressure, and accelerates atherosclerosis. Mechanistically, the accumulation of lipid droplets destabilizes eNOS mRNA and activates an endothelial inflammatory signaling cascade that suppresses eNOS and NO production. Pharmacological prevention of lipid droplet formation reverses the suppression of NO production in cell culture and in vivo and blunts blood pressure elevation in response to a high-fat diet. These results highlight lipid droplets as a critical and unappreciated component of endothelial cell biology, explain how lipids increase blood pressure acutely, and provide a mechanistic account for the epidemiological link between obesity and elevated blood pressure., Introduction Numerous epidemiological studies demonstrate a strong connection between obesity and elevated blood pressure (BP) (1). Lipid loading in humans by i.v. infusion of lipids or by oral fat intake [...]

The COVID-19 pandemic caused by the SARS-CoV-2 virus has swept the globe with devastating societal consequences and has placed tremendous stress on health care systems. Although severe respiratory disease is [...]

Technological advances in rapid data acquisition have transformed medical biology into a data mining field, where new data sets are routinely dissected and analyzed by statistical models of ever- increasing complexity. Many hypotheses can be generated and tested within a single large data set, and even small effects can be statistically discriminated from a sea of noise. On the other hand, the development of therapeutic interventions moves at a much slower pace. They are determined from carefully randomized and well-controlled experiments with explicitly stated outcomes as the principal mechanism by which a single hypothesis is tested. In this paradigm, only a small fraction of interventions can be tested, and an even smaller fraction are ultimately deemed therapeutically successful. In this Review, we propose strategies to leverage large- cohort data to inform the selection of targets and the design of randomized trials of novel therapeutics. Ultimately, the incorporation of big data and experimental medicine approaches should aim to reduce the failure rate of clinical trials as well as expedite and lower the cost of drug development., Introduction We are experiencing unprecedented growth in the amount of biological and medical information collected from human populations. Large prospective cohorts, such as the UK Biobank (1), the All of [...]

High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparticles, and ApoM, a chaperone for the bioactive lipid sphingosine 1-phosphate (S1P). A1M forms HDL-like particles, binds to S1P, and is signaling competent. Molecular dynamics simulations showed that the S1P-bound ApoM moiety in A1M efficiently activated EC surface receptors. Treatment of human umbilical vein ECs with A1M-S1P stimulated barrier function either alone or cooperatively with other barrier-enhancing molecules, including the stable prostacyclin analog iloprost, and suppressed cytokine-induced inflammation. A1M-S1P injection into mice during sterile inflammation suppressed neutrophil influx and inflammatory mediator secretion. Moreover, systemic A1M administration led to a sustained increase in circulating HDL-bound S1P and suppressed inflammation in a murine model of LPS-induced endotoxemia. We propose that A1M administration may enhance vascular endothelial barrier function, suppress cytokine storm, and promote resilience of the vascular endothelium. Editor's summary: Endothelial cell function is enhanced by bioactive lipids such as prostacyclin and sphingosine 1-phosphate (S1P) when bound to its chaperone apolipoprotein M (ApoM). Lin et al. generated a fusion protein called A1M to promote both S1P and prostacyclin signaling. A1M consisted of ApoM and ApoA1, a structural component of high-density lipoprotein (HDL) that stabilizes prostacyclin. When bound to S1P or a prostacyclin analog, A1M suppressed inflammation and increased the barrier function of cultured endothelial cells. In mouse models of acute or systemic inflammation, S1P-loaded A1M suppressed neutrophil infiltration, increases in circulating proinflammatory factors, and cytokine storm. The ApoA1 moiety of A1M therefore provides additional benefits over previously engineered S1P chaperones. —Wei Wong [ABSTRACT FROM AUTHOR]

Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. While T cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell-inflamed tumor microenvironment are not fully understood. We used an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment (TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified ephrin-A receptor 2 (EPHA2) as a candidate tumor-intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that prostaglandin endoperoxide synthase 2 (PTGS2), the gene encoding cyclooxygenase- 2, lies downstream of EPHA2 signaling through TGF-[beta] and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2/PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2/TGF-[beta]/PTGS2 pathway inhibitors with antitumor immunotherapy and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma., Introduction Immunotherapies, including immune checkpoint blockade (ICB), have led to significant improvement of clinical care for cancer patients (1-4). Patients with melanoma, lung adenocarcinoma, or kidney cancer have a 20%-40% [...]

Inhibitors of microsomal prostaglandin E synthase 1 (mPGES-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin [E.sub.2] ([PGE.sub.2]), but increasing the biosynthesis of prostacyclin ([PGI.sub.2]). In low-density lipoprotein receptor-deficient ([Ldlr.sup.-/-]) mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of [PGE.sub.2] accounts for its antiatherogenic effect. However, the effect of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. Here, we show that mPges-1 depletion significantly increased the BP response to salt loading in male [Ldlr.sup.-/-] mice, whereas, despite the direct vasodilator properties of [PGI.sub.2], deletion of the I prostanoid receptor (Ipr) suppressed this response. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male [mPges-1.sup.-/-] mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high-salt diet (HSD). This is attributable to the protective effect of estrogen in [Ldlr.sup.-/-] mice and in [Ipr.sup.-/-][Ldlr.sup.-/- ] mice. Thus, estrogen compensates for a deficiency in [PGI.sub.2] to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In male mice, by contrast, the augmented formation of atrial natriuretic peptide (ANP) plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hence, men with hyperlipidemia on a HSD might be at risk of a hypertensive response to mPGES-1 inhibitors., Introduction Both the adverse cardiovascular events associated with nonsteroidal antiinflammatory drugs (NSAIDs) and the opioid crisis have prompted interest in developing new analgesics (1-4). Several clinical trials have shown that [...]

A letter published in Nature Communications raises concerns about the methodology and conclusions of a study by Gomez et al. on specialized pro-resolving mediators (SPM) in biological samples. The authors argue that the study did not adhere to standard criteria for determining the presence and quantification of lipids, leading to flawed results. They specifically criticize the use of a non-standard approach for determining the limit of detection and the poor quality of the mass spectrometry data. The letter suggests that further evaluation is needed to assess the presence of SPM in biological samples and their role in inflammation resolution. [Extracted from the article]

Since the COVID-19 pandemic swept across the globe, researchers have been trying to understand its origin, life cycle, and pathogenesis. There is a striking variability in the phenotypic response to infection with SARS-CoV-2 that may reflect differences in host genetics and/or immune response. It is known that the human epigenome is influenced by ethnicity, age, lifestyle, and environmental factors, including previous viral infections. This Review examines the influence of viruses on the host epigenome. We describe general lessons and methodologies that can be used to understand how the virus evades the host immune response. We consider how variation in the epigenome may contribute to heterogeneity in the response to SARS-CoV-2 and may identify a precision medicine approach to treatment., Introduction There are millions of nucleotide interactions within a cell, and their alteration by single-nucleotide polymorphisms (SNPs) can result in changes to pathways implicated in disease, such as the response [...]

The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT‐like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer‐associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor‐1 (PAI‐1). Consequently, decreased levels of PAI‐1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF‐β into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF‐β signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy. [ABSTRACT FROM AUTHOR]