Background: The recent outbreak of coronavirus disease 2019 (COVID-19) has been rapidly spreading on a global scale and poses a great threat to human health. Acute respiratory distress syndrome, characterized by a rapid onset of generalized inflammation, is the leading cause of mortality in patients with COVID-19. We thus aimed to explore the effect of risk factors on the severity of the disease, focusing on immune-inflammatory parameters, which represent the immune status of patients. Methods: A comprehensive systematic search for relevant studies published up to April 2020 was performed by using the PubMed, Web of Science, EMBASE, and China National Knowledge Internet (CNKI) databases. After extracting all available data of immune-inflammatory indicators, we statistically analyzed the risk factors of severe and non-severe COVID-19 patients with a meta-analysis. Results: A total of 4,911 patients from 29 studies were included in the final meta-analysis. The results demonstrated that severe patients tend to present with increased white blood cell (WBC) and neutrophil counts, neutrophil-lymphocyte ratio (NLR), procalcitonin (PCT), C-reaction protein (CRP), erythrocyte sedimentation rate (ESR), and Interleukin-6 (IL-6) and a decreased number of total lymphocyte and lymphocyte subtypes, such as CD4+ T lymphocyte and CD8+ T lymphocyte, compared to the non-severe patients. In addition, the WBC count>10 × 10 9 /L, lymphocyte count<1 × 10 9 /L, PCT>0.5 ng/mL, and CRP>10 mg/L were risk factors for disease progression in patients with COVID-19 (WBC count>10 × 10 9 /L: OR = 2.92, 95% CI: 1.96-4.35; lymphocyte count<1 × 10 9 /L: OR = 4.97, 95% CI: 3.53-6.99; PCT>0.5 ng/mL: OR = 6.33, 95% CI: 3.97-10.10; CRP>10 mg/L: OR = 3.51, 95% CI: 2.38-5.16). Furthermore, we found that NLR, as a novel marker of systemic inflammatory response, can also help predict clinical severity in patients with COVID-19 (OR = 2.50, 95% CI: 2.04-3.06). Conclusions: Immune-inflammatory parameters, such as WBC, lymphocyte, PCT, CRP, and NLR, could imply the progression of COVID-19. NLR has taken both the levels Feng et al. Immune-Inflammatory Parameters in COVID-19 of neutrophil and lymphocyte into account, indicating a more complete, accurate, and reliable inspection efficiency; surveillance of NLR may help clinicians identify high-risk COVID-19 patients at an early stage.

Endotoxin tolerance (ET) triggered by prior exposure to Toll-like receptor (TLR) ligands provides a mechanism to dampen inflammatory cytokines. Receptor-interacting protein 140 (RIP140) interacts with NF-κB to regulate the expression of proinflammatory cytokine genes. We identify lipopolysaccharide (LPS) stimulation of Syk-mediated tyrosine phosphorylation on RIP140 and RelA interaction with RIP140. These events increase recruitment of SOCS1-Rbx1 (SCF) E3 ligase to tyrosine-phosphorylated RIP140, thereby degrading RIP140 to inactivate inflammatory cytokine genes. Macrophages expressing a non-degradable RIP140 were resistant to the establishment of ET for specific genes. The results reveal RelA as an adaptor for SCF ubiquitin ligase to fine-tune NF-κB target genes by targeting co-activator RIP140, and an unexpected role for RIP140 protein degradation in resolving inflammation and ET.

The increasing global prevalence of obesity and its associated disorders point to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules with mRNA expression profiles similar to that of celastrol, a naturally-occurring compound we previously identified as a leptin sensitizer. By this process we identified another natural compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin A treatment of diet-induced obese mice resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities including hepatic steatosis. Withaferin A marginally affects the body weight of ob/ob and db/db mice, which are both deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism independently from its leptin-sensitizing effect. Our results show that the metabolic abnormalities of diet-induced obesity can be mitigated by sensitizing animals to endogenous leptin, and indicate that withaferin A is a potential leptin sensitizer with additional anti-diabetic actions.

Celastrol, a pentacyclic triterpene is the most potent anti-obesity agent that has been reported to date 1. The mechanism of celastrol's leptin sensitizing and anti-obesity effects has not yet been elucidated. In this study, we identified interleukin 1 receptor 1 (IL1R1) as a mediator of celastrol action by using temporally-resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to celastrol's leptin sensitization, anti-obesity, anti-diabetic and anti-NASH effects. Thus, we conclude that IL1R1 is a gate-keeper for celastrol's metabolic actions. Increased ER stress in the hypothalamus plays a central role in the development of leptin resistance, and thus obesity 2-5. Given these findings, we undertook in silico screens utilizing systems biology approaches to identify new chemical chaperones that would serve as stronger leptin sensitizers. These efforts yielded celastrol, a pentacyclic triterpene as a potentially efficacious chemical chaperone and leptin sensitizer 1. Celastrol reduces the body weight of diet-induced obese (DIO) mice by 45-50% and further ameliorates insulin resistance/type-2 diabetes, nonalcoholic steatohepatitis (NASH), hypercholesterolemia, and liver damage in DIO mice 1. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: