Resveratrol attenuates staphylococcal enterotoxin B-activated immune cell metabolism via upregulation of miR-100 and suppression of mTOR signaling pathway.

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of insults, such as bacterial and viral infections, including SARS-CoV-2, leading to high mortality. In the murine model of ARDS induced by Staphylococcal enterotoxin-B (SEB), our previous studies showed that while SEB triggered 100% mortality, treatment with Resveratrol (RES) completely prevented such mortality by attenuating inflammation in the lungs. In the current study, we investigated the metabolic profile of SEB-activated immune cells in the lungs following treatment with RES. RES-treated mice had higher expression of miR-100 in the lung mononuclear cells (MNCs), which targeted mTOR, leading to its decreased expression. Also, Single-cell RNA-seq (scRNA seq) unveiled the decreased expression of mTOR in a variety of immune cells in the lungs. There was also an increase in glycolytic and mitochondrial respiration in the cells from SEB + VEH group in comparison with SEB + RES group. Together these data suggested that RES alters the metabolic reprogramming of SEB-activated immune cells, through suppression of mTOR activation and its down- and upstream effects on energy metabolism. Also, miR-100 could serve as novel potential therapeutic molecule in the amelioration of ARDS.

Targeting Virus-Induced Reprogrammed Cell Metabolism via Glycolytic Inhibitors: An Effective Therapeutic Approach Against SARS-CoV-2.

Reprogrammed cell metabolism has been observed in a wide range of viral infected cells. Viruses do not have their metabolism; they rely on the cellular metabolism of the host to ensure the energy and macromolecules requirement for replication. Like other viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) does not own its metabolism, but viral infected cells adopt aberrant cell metabolism. Infected viral cells, uses the energy and macromolecules to make their own copies, to do so they need to increase the rate of metabolism to ensure the requirement of macromolecules In contrast, the cellular metabolism of noninfected cells is more plastic than infected cells. Therefore, it is essential to examine the virus infection in the context of metabolic alterations of host cells. A novel therapeutic approach is urgently required to treat highly infectious COVID-19 disease and its pathogenesis. Interference of glucose metabolism might be a promising strategy to determine COVID-19 treatment options. Based on the recent research, this mini-review aims to understand the impact of reprogrammed cell metabolism in COVID-19 pathogenesis and explores the potential of targeting metabolic pathways with small molecules as a new strategy for the development of a novel drug to treat COVID-19 disease. This type of research line provides new hope in the development of antiviral drugs by targeting hijacked cell metabolism in case of viral diseases and also in COVID-19.

Precision Nanomedicine Targeting Novel Endothelial Mechano-Sensing Mechanisms and Treating Vascular Complications in vivo

Introduction: Endothelial mechano-transduction mechanisms are instrumental to vascular health and disease. Novel strategies targeting disease-causing mechano-sensitive pathways in dysfunctional endothelial cells could revolutionize future cardiovascular therapeutics. Vascular complications such as atherosclerosis and stenosis preferentially develop at arterial curvatures and bifurcations where endothelial cells are activated by local disturbed blood flow, leading to peripheral artery disease, carotid artery disease and ischemic stroke. Hypothesis: Current vascular therapies mainly target systematic risk factors (e.g. hypercholesterolemia and hypertension) but not the diseased vasculature, distinct molecular/cellular signatures of which can be targeted by innovated precision nanomedicine approaches. Method(s): We first elucidated novel mechano-sensitive molecular mechanisms in endothelium activated by disturbed flow (DF) and then engineered rationally-designed nano-materials with purposed-constructed functionalities to deliver therapeutic nucleotides to DF-activated endothelial cells. Result(s): Our results elucidated previously unrecognized endothelial mechano-sensitive pathways in endothelial activation, with emphasis upon cellular metabolism (DF-induced glycolysis), human genetic variants (DF-induced suppression of PLPP3, a CAD GWAS gene), miRNA, protein stability (DF-induced NOS3 protein degradation via TXNDC5) and mRNA chemical modification/epitranscriptome (DF-induced suppression of m7G). VCAM1-targeting nanoparticles were engineered to deliver therapeutic nucleotides such as mRNA, miRNA inhibitor, or CRISPR/Cas9 constructs specifically to inflamed endothelial cells to intervene aforementioned mechano-sensitive pathways, effectively reducing atherosclerosis and stenosis in mice. Similar approaches were very effective to promote endothelial health and lessen acute respiratory distress syndrome (ARDS) in mice induced by influenza or SARS-CoV-2 viruses. Conclusion(s): These results elucidate novel endothelial mechano-sensing mechanisms and provide a proof of concept of innovative targeted nanomedicine approaches, addressing an unmet medical need in vascular therapies.

Lipid profile alteration in sars coronavirus 2 (SARS-CoV-2) affected patients and its association with inflammatory markers

Introduction Coronavirus disease 2019 (COVID-19) caused by the SARS coronavirus 2 has challenged the global healthcare system since 2019. Lipids are integral component of this enveloped virus that play an essential role in in its life cycle starting from fusion of viral membrane to host cell, viral replication and exocytosis. It also disrupts metabolic profile due to the release of pro-inflammatory cytokines leading to systemic inflammation reaction. Aim and Objective Therefore, it was aimed to find association between human host serum lipid levels and its association with inflammatory markers. Materials and Methods It was a retrospective study conducted from June 2020 to December 2020, included 500 COVID-19 admitted patients tested positive by Oral/Nasopharyngeal swab by Real time PCR. Total Cholesterol, Triglycerides (TG), Low Density Lipoprotein (LDL-C), High Density lipoprotein (HDL), Ferritin, Procalcitonin (PCT), High sensitive C Reactive protein (hsCRP) estimated in Vitros XT 7600 Autoanalyzer and Interleukin-6(IL-6) by ELISA. Results A significant increase in Serum Triglycerides(185mg/dL) and decrease in HDLC(30mg/dL) was observed with no remarkable finding in other lipid parameters. A statistically significant (p<0.05)positive correlation was observed between TG and inflammatory markers such as hsCRP, PCT, Ferritin, IL-6. Likewise, a negative correlation was detected between HDL-C and hsCRP, PCT, Ferritin, IL-6. Conclusion Lipid profile and host cell metabolism is altered in COVID 19 patients either by cellular infection or by systemic inflammation. Hence it is important to study lipid profile alterations in synergism with inflammatory markers. It may act as guiding step in management and prognosis of this disease.

Mucormycosis (The black fungus) associated with COVID-19 patients- epidemiology, pathogenesis, diagnosis and treatment regimes

Mucormycosis is an opportunistic fungal infection caused by a member of the order Mucorales. It is an angio-invasive fungal infection because of its propensity to invade blood vessel walls, resulting in catastrophic tissue ischemia (restriction in blood supply to tissues, causing a shortage of oxygen that is needed for cellular metabolism), infarct (tissue death that is necrosis) due to inadequate blood supply to the affected area. Mucorales fungi are distributed worldwide and found in soil and decaying organic substrates. The most common microbiologically confirmed infecting members of the order Mucorales are Rhizopus, Mucor, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia, Saksenaea and Rhizomucor pusillus. The incidence of mucormycosis has increased significantly in patients with diabetes which is the commonest underlying risk factor globally. Recently, COVID-19 caused by SARS CoV-2 has further worsened the incidence of this disease. Diagnosis of mucormycosis remains challenging. The clinical approach to diagnosis has a low sensitivity and specificity;however, it helps raise suspicion and prompt the initiation of laboratory testing. Histopathology, direct examination, and culture remain essential tools, although the molecular methods are improving. The review highlights the current status on epidemiology, pathogenesis diagnosis and treatment regime available for mucormycosis.

Optimization of a modeling platform to predict oncogenes from genome-scale metabolic networks of non-small-cell lung cancers.

Cancer cell dysregulations result in the abnormal regulation of cellular metabolic pathways. By simulating this metabolic reprogramming using constraint-based modeling approaches, oncogenes can be predicted, and this knowledge can be used in prognosis and treatment. We introduced a trilevel optimization problem describing metabolic reprogramming for inferring oncogenes. First, this study used RNA-Seq expression data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) samples and their healthy counterparts to reconstruct tissue-specific genome-scale metabolic models and subsequently build the flux distribution pattern that provided a measure for the oncogene inference optimization problem for determining tumorigenesis. The platform detected 45 genes for LUAD and 84 genes for LUSC that lead to tumorigenesis. A high level of differentially expressed genes was not an essential factor for determining tumorigenesis. The platform indicated that pyruvate kinase (PKM), a well-known oncogene with a low level of differential gene expression in LUAD and LUSC, had the highest fitness among the predicted oncogenes based on computation. By contrast, pyruvate kinase L/R (PKLR), an isozyme of PKM, had a high level of differential gene expression in both cancers. Phosphatidylserine synthase 1 (PTDSS1), an oncogene in LUAD, was inferred to have a low level of differential gene expression, and overexpression could significantly reduce survival probability. According to the factor analysis, PTDSS1 characteristics were close to those of the template, but they were unobvious in LUSC. Angiotensin-converting enzyme 2 (ACE2) has recently garnered widespread interest as the SARS-CoV-2 virus receptor. Moreover, we determined that ACE2 is an oncogene of LUSC but not of LUAD. The platform developed in this study can identify oncogenes with low levels of differential expression and be used to identify potential therapeutic targets for cancer treatment.

Flavonoids against the Warburg phenotype-concepts of predictive, preventive and personalised medicine to cut the Gordian knot of cancer cell metabolism.

The Warburg effect is characterised by increased glucose uptake and lactate secretion in cancer cells resulting from metabolic transformation in tumour tissue. The corresponding molecular pathways switch from oxidative phosphorylation to aerobic glycolysis, due to changes in glucose degradation mechanisms known as the 'Warburg reprogramming' of cancer cells. Key glycolytic enzymes, glucose transporters and transcription factors involved in the Warburg transformation are frequently dysregulated during carcinogenesis considered as promising diagnostic and prognostic markers as well as treatment targets. Flavonoids are molecules with pleiotropic activities. The metabolism-regulating anticancer effects of flavonoids are broadly demonstrated in preclinical studies. Flavonoids modulate key pathways involved in the Warburg phenotype including but not limited to PKM2, HK2, GLUT1 and HIF-1. The corresponding molecular mechanisms and clinical relevance of 'anti-Warburg' effects of flavonoids are discussed in this review article. The most prominent examples are provided for the potential application of targeted 'anti-Warburg' measures in cancer management. Individualised profiling and patient stratification are presented as powerful tools for implementing targeted 'anti-Warburg' measures in the context of predictive, preventive and personalised medicine.