Therapeutic Potential of Resveratrol in COVID-19-Associated Hemostatic Disorders

Coagulation disorders, endotheliopathy and inflammation are the most common hallmarks in SARS-CoV-2 infection, largely determining COVID-19’s outcome and severity. Dysfunctions of endothelial cells and platelets are tightly linked in contributing to the systemic inflammatory response that appears to be both a cause and a consequence of COVID-19-associated coagulation disorders and thrombotic events. Indeed, elevated levels of circulating inflammatory cytokines are often associated with abnormal coagulation parameters in COVID-19 patients. Although treatments with low molecular weight heparin (LMWH) have shown beneficial effects in decreasing patient mortality with severe COVID-19, additional therapeutic strategies are urgently needed. Utilizing the anti-inflammatory and anti-thrombotic properties of natural compounds may provide alternative therapeutic approaches to prevent or reduce the risk factors associated with pre-existing conditions and comorbidities that can worsen COVID-19 patients’ outcomes. In this regard, resveratrol, a natural compound found in several plants and fruits such as grapes, blueberries and cranberries, may represent a promising coadjuvant for the prevention and treatment of COVID-19. By virtue of its anti-thrombotic and anti-inflammatory properties, resveratrol would be expected to lower COVID-19-associated mortality, which is well known to be increased by thrombosis and inflammation. This review analyzes and discusses resveratrol’s ability to modulate vascular hemostasis at different levels targeting both primary hemostasis (interfering with platelet activation and aggregation) and secondary hemostasis (modulating factors involved in coagulation cascade).     

呼吸机相关性肺炎患者肺部超声评分与NAMPT、Endocan、NLR的关系

本文探讨了呼吸机相关性肺炎患者肺部超声评分(LUS)与外周血烟酰胺磷酸核糖转移酶(NAMPT)、内皮细胞特异性分子-1(Endocan)、中性粒细胞/淋巴细胞值(NLR)的关系。选取呼吸机相关性肺炎患者80例(观察组)和非呼吸机相关性肺炎患者40例(对照组),采用酶联免疫吸附试验检测患者外周血NAMPT、Endocan,自动血细胞分析仪检测NLR。分析结果显示,观察组通气24 h、48 h和72 h时NAMPT、Endocan和NLR均高于对照组(P<0.05),此外,观察组死亡患者NAMPT、Endocan、NLR和LUS及变化值高于存活患者(P<0.05),上述指标联合预测患者死亡的AUC值高于各指标单独预测(P<0.05)。说明呼吸机相关性肺炎患者LUS变化与外周血NAMPT、Endocan、NLR呈正相关,联合预测患者预后有一定的应用价值。     

心电图结合中性粒细胞/淋巴细胞比值对急性前壁心肌梗死患者PCI术后预后的预测价值

本文分析心电图结合中性粒细胞/淋巴细胞比值(NLR)对急性前壁心肌梗死患者PCI术后预后的预测价值.选取行PCI术的急性前壁AMI患者180例,观察其心电图和NLR水平变化,并应用Cox回归分析心电图变化、NLR水平高低与预后的相关性.180例患者不良心血管事件发生率为17.78％;NLR水平＞3人数有113人;存在有...     

Catechins: Therapeutic Perspectives in COVID-19-Associated Acute Kidney Injury

Data obtained from several intensive care units around the world have provided substantial evidence of the strong association between impairment of the renal function and in-hospital deaths of critically ill COVID-19 patients, especially those with comorbidities and requiring renal replacement therapy (RRT). Acute kidney injury (AKI) is a common renal disorder of various etiologies characterized by a sudden and sustained decrease of renal function. Studies have shown that 5–46% of COVID-19 patients develop AKI during hospital stay, and the mortality of those patients may reach up to 100% depending on various factors, such as organ failures and RRT requirement. Catechins are natural products that have multiple pharmacological activities, including anti-coronavirus and reno-protective activities against kidney injury induced by nephrotoxic agents, obstructive nephropathies and AKI accompanying metabolic and cardiovascular disorders. Therefore, in this review, we discuss the anti-SARS-CoV-2 and reno-protective effects of catechins from a mechanistic perspective. We believe that catechins may serve as promising therapeutics in COVID-19-associated AKI due to their well-recognized anti-SARS-CoV-2, and antioxidant and anti-inflammatory properties that mediate their reno-protective activities.     

A Potent Leukocyte Transmigration Blocker: GT-73 Showed a Protective Effect against LPS-Induced ARDS in Mice

We recently developed a molecule (GT-73) that blocked leukocyte transendothelial migration from blood to the peripheral tissues, supposedly by affecting the platelet endothelial cell adhesion molecule (PECAM-1) function. GT-73 was tested in an LPS-induced acute respiratory distress syndrome (ARDS) mouse model. The rationale for this is based on the finding that the mortality of COVID-19 patients is partly caused by ARDS induced by a massive migration of leukocytes to the lungs. In addition, the role of tert-butyl and methyl ester moieties in the biological effect of GT-73 was investigated. A human leukocyte, transendothelial migration assay was applied to validate the blocking effect of GT-73 derivatives. Finally, a mouse model of LPS-induced ARDS was used to evaluate the histological and biochemical effects of GT-73. The obtained results showed that GT-73 has a unique structure that is responsible for its biological activity; two of its chemical moieties (tert-butyl and a methyl ester) are critical for this effect. GT-73 is a prodrug, and its lipophilic tail covalently binds to PECAM-1 via Lys536. GT-73 significantly decreased the number of infiltrating leukocytes in the lungs and reduced the inflammation level. Finally, GT-73 reduced the levels of IL-1β, IL-6, and MCP-1 in bronchoalveolar lavage fluid (BALF). In summary, we concluded that GT-73, a blocker of white blood cell transendothelial migration, has a favorable profile as a drug candidate for the treatment of ARDS in COVID-19 patients.     

Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca²⁺-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.     

Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms

Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman’s disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19.Subject terms: Sepsis, Interleukins     

Type I and III interferon responses in SARS-CoV-2 infection

Coronavirus disease 2019 (COVID-19), the current pandemic disease, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Type I and III interferons (IFNs) are innate cytokines that are important in the first-line defense against viruses. Similar to many other viruses, SARS-CoV-2 has evolved mechanisms for evading the antiviral effects of type I and III IFNs at multiple levels, including the induction of IFN expression and cellular responses to IFNs. In this review, we describe the innate sensing mechanisms of SARS-CoV-2 and the mechanisms used by SARS-CoV-2 to evade type I and III IFN responses. We also discuss contradictory reports regarding impaired and robust type I IFN responses in patients with severe COVID-19. Finally, we discuss how delayed but exaggerated type I IFN responses can exacerbate inflammation and contribute to the severe progression of COVID-19.Subject terms: Infectious diseases, Infection     

Systemic LPS administration induces brain inflammation but not dopaminergic neuronal death in the substantia nigra

It has been suggested that brain inflammation is important in aggravation of brain damage and/or that inflammation causes neurodegenerative diseases including Parkinson's disease (PD). Recently, systemic inflammation has also emerged as a risk factor for PD. In the present study, we evaluated how systemic inflammation induced by intravenous (iv) lipopolysaccharides (LPS) injection affected brain inflammation and neuronal damage in the rat. Interestingly, almost all brain inflammatory responses, including morphological activation of microglia, neutrophil infiltration, and mRNA/protein expression of inflammatory mediators, appeared within 4-8 h, and subsided within 1-3 days, in the substantia nigra (SN), where dopaminergic neurons are located. More importantly, however, dopaminergic neuronal loss was not detectable for up to 8 d after iv LPS injection. Together, these results indicate that acute induction of systemic inflammation causes brain inflammation, but this is not sufficiently toxic to induce neuronal injury.     

Inflammation markers in point-of-care testing (POCT)

Inflammation is a central issue in medicine. Inflammatory processes may be local or systemic, acute or chronic, and they may be benign or fatal. In bacterial or viral infections fast and reliable diagnosis is essential for appropriate treatment, e.g. antimicrobial therapy. The time to diagnosis is critical because uncontrolled infections may lead to sepsis with a mortality rate close to 50%. Beside clinical signs, laboratory markers are important in detecting, differentiating, and monitoring inflammation, particularly acute infections. Currently several inflammation markers including leukocyte count and leukocyte differentiation, C-reactive protein (CRP), procalcitonin (PCT), and interleukins (IL) 6 and 8, is available, and potential future serum markers are under development. In this article the clinical use of these markers in routine laboratory and in point-of-care testing is described and the diagnostic value of the four groups of laboratory marker is compared. Current data show that leukocyte count or, better, neutrophil count, CRP, and PCT are well suited to support of rapid diagnosis of inflammation and infections in children and adults whereas measurement of IL-6 and 8 are preferable for detection of sepsis in neonates.     

Coronavirus Infection-Associated Cell Death Signaling and Potential Therapeutic Targets

COVID-19 is the name of the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that occurred in 2019. The virus–host-specific interactions, molecular targets on host cell deaths, and the involved signaling are crucial issues, which become potential targets for treatment. Spike protein, angiotensin-converting enzyme 2 (ACE2), cathepsin L-cysteine peptidase, transmembrane protease serine 2 (TMPRSS2), nonstructural protein 1 (Nsp1), open reading frame 7a (ORF7a), viral main protease (3C-like protease (3CLpro) or Mpro), RNA dependent RNA polymerase (RdRp) (Nsp12), non-structural protein 13 (Nsp13) helicase, and papain-like proteinase (PLpro) are molecules associated with SARS-CoV infection and propagation. SARS-CoV-2 can induce host cell death via five kinds of regulated cell death, i.e., apoptosis, necroptosis, pyroptosis, autophagy, and PANoptosis. The mechanisms of these cell deaths are well established and can be disrupted by synthetic small molecules or natural products. There are a variety of compounds proven to play roles in the cell death inhibition, such as pan-caspase inhibitor (z-VAD-fmk) for apoptosis, necrostatin-1 for necroptosis, MCC950, a potent and specific inhibitor of the NLRP3 inflammasome in pyroptosis, and chloroquine/hydroxychloroquine, which can mitigate the corresponding cell death pathways. However, NF-κB signaling is another critical anti-apoptotic or survival route mediated by SARS-CoV-2. Such signaling promotes viral survival, proliferation, and inflammation by inducing the expression of apoptosis inhibitors such as Bcl-2 and XIAP, as well as cytokines, e.g., TNF. As a result, tiny natural compounds functioning as proteasome inhibitors such as celastrol and curcumin can be used to modify NF-κB signaling, providing a responsible method for treating SARS-CoV-2-infected patients. The natural constituents that aid in inhibiting viral infection, progression, and amplification of coronaviruses are also emphasized, which are in the groups of alkaloids, flavonoids, terpenoids, diarylheptanoids, and anthraquinones. Natural constituents derived from medicinal herbs have anti-inflammatory and antiviral properties, as well as inhibitory effects, on the viral life cycle, including viral entry, replication, assembly, and release of COVID-19 virions. The phytochemicals contain a high potential for COVID-19 treatment. As a result, SARS-CoV-2-infected cell death processes and signaling might be of high efficacy for therapeutic targeting effects and yielding encouraging outcomes.     

Wheat Germ Spermidine and Clove Eugenol in Combination Stimulate Autophagy In Vitro Showing Potential in Supporting the Immune System against Viral Infections

Impaired autophagy, responsible for increased inflammation, constitutes a risk factor for the more severe COVID-19 outcomes. Spermidine (SPD) is a known autophagy modulator and supplementation for COVID-19 risk groups (including the elderly) is recommended. However, information on the modulatory effects of eugenol (EUG) is scarce. Therefore, the effects of SPD and EUG, both singularly and in combination, on autophagy were investigated using different cell lines (HBEpiC, SHSY5Y, HUVEC, Caco-2, L929 and U937). SPD (0.3 mM), EUG (0.2 mM) and 0.3 mM SPD + 0.2 mM EUG, significantly increased autophagy using the hallmark measure of LC3-II protein accumulation in the cell lines without cytotoxic effects. Using Caco-2 cells as a model, several crucial autophagy proteins were upregulated at all stages of autophagic flux in response to the treatments. This effect was verified by the activation/differentiation and migration of U937 monocytes in a three-dimensional reconstituted intestinal model (Caco-2, L929 and U937 cells). Comparable benefits of SPD, EUG and SPD + EUG in inducing autophagy were shown by the protection of Caco-2 and L929 cells against lipopolysaccharide-induced inflammation. SPD + EUG is an innovative dual therapy capable of stimulating autophagy and reducing inflammation in vitro and could show promise for COVID-19 risk groups.     

Evaluation of a potential prognostic parameter for the inflammatory status in COVID-19 patients: The inflammatory protein ratio

C-reactive protein (CRP), fibrinogen, and d -dimer are determined in the human plasma of 2745 hospitalized patients with and without coronavirus disease 2019 (COVID-19) by automated-latex enhanced immunoassay and immuno-turbidimetric assay. SARS-COV-2 RNA qualitative test, real time polymerase chain reaction (RT-PCR) based, is performed in nasopharyngeal swabs to confirm those with SARS-COV-2 positivity. Furthermore, serum proteins are separated and quantified in all the patients by serum protein electrophoresis (SPE). A new SPE parameter, inflammatory protein ratio (IPR), is elaborated for the first time by a mathematical equation that considers the albumin, α1-globulin, and α2-globulin. IPR normal reference range (10.7%–28.3%) is calculated considering the normal reference range of albumin, α1-globulin, and α2-globulin obtained for controls. Analysis of variance (ANOVA), Pearson's, Kruskal–Wallis, and Spearman's tests application show that IPR significantly correlates with direct proportionality with d -dimer, CRP, and fibrinogen. Significant (p < 0.001) increase of these parameters, IPR included, is detected in COVID-19 patients only. Our results show that IPR is more specific for monitoring inflammatory status thanks to its correlation with the only three serum proteins involved in inflammation: albumin, α1-globulin, and α2-globulin. Furthermore, IPR can simplify the interpretation of SPE results about inflammatory status, being of unique value compared to the six-serum protein classes separately presented in the typical SPE clinical reports.     

Bioavailability Enhancement of Cepharanthine via Pulmonary Administration in Rats and Its Therapeutic Potential for Pulmonary Fibrosis Associated with COVID-19 Infection

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-β1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection.     

Natural Polyphenols as Immunomodulators to Rescue Immune Response Homeostasis: Quercetin as a Research Model against Severe COVID-19

The COVID-19 pandemic is caused by SARS-CoV-2 and is leading to the worst health crisis of this century. It emerged in China during late 2019 and rapidly spread all over the world, producing a broad spectrum of clinical disease severity, ranging from asymptomatic infection to death (4.3 million victims so far). Consequently, the scientific research is devoted to investigating the mechanisms of COVID-19 pathogenesis to both identify specific therapeutic drugs and develop vaccines. Although immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, new understanding has emerged about the innate and adaptive immune responses elicited in SARS-CoV-2 infection, which are mainly focused on the dysregulated inflammatory response in severe COVID-19. Polyphenols are naturally occurring products with immunomodulatory activity, playing a relevant role in reducing inflammation and preventing the onset of serious chronic diseases. Mainly based on data collected before the appearance of SARS-CoV-2, polyphenols have been recently suggested as promising agents to fight COVID-19, and some clinical trials have already been approved with polyphenols to treat COVID-19. The aim of this review is to analyze and discuss the in vitro and in vivo research on the immunomodulatory activity of quercetin as a research model of polyphenols, focusing on research that addresses issues related to the dysregulated immune response in severe COVID-19. From this analysis, it emerges that although encouraging data are present, they are still insufficient to recommend polyphenols as potential immunomodulatory agents against COVID-19.     

Surface Modification of 316L Stainless Steel by Grafting Methoxy Poly(ethylene glycol) to Improve the Biocompatibility

Percutaneous coronary intervention(PCI) has become an important method for the treatment of the patients with coronary heart disease; however, problems, such as vascular endothelial inflammation, late thrombosis, and stent restenosis still exist as a result of poor biocompatibility of the materials. To enhance the biocompatibility, methoxy poly(ethylene glycol)(mPEG) was immobilized on the surface of AISI 316 grade stainless steel(SS)(AISI: American Iron and Steel Institute). First, silanized mPEG was synthesized by the direct coupling of mPEG with 3-isocyanatopropyltriethoxysilane(IPTS) via urethane bonds, and the silanized mPEG was then grafted on the surface of SS that was hydroxylated with piranha solution. The results obtained from contact angle goniometry, X-ray photoelectron spectroscopy(XPS), and atomic force microscopy(AFM) confirm that the mPEG modified steel contained more C and Si and less Fe and Cr on its surface, exhibiting a morphological change and decrease in the contact angle. The biocompatibility of the mPEG modified SS was evaluated with fibrinogen adsorption, platelet activation and adhesion, and human umbilical vein endothelial cell(HUVEC) adhesion. Fibrinogen adsorption, platelet activation, and adhesion were clearly suppressed on the surface-modified steel. In addition, human umbilical vein endothelial cell(HUVEC) could adhere and proliferate on the surface of the mPEG-modified SS. This study indicates that the modification of 316L SS with mPEG could enhance the biocompatibility and provide a primary experimental foundation for the development of next-generation coronary stent materials for clinical application.     

Anti-inflammatory or anti-SARS-CoV-2 ingredients in Huashi Baidu Decoction and their corresponding targets: Target screening and molecular docking study

Coronavirus disease 2019 (COVID-19) is a rapidly emerging infectious disease caused by SARS-CoV-2. Inflammatory factors may play essential roles in COVID-19 progression. Huashi Baidu Decoction (HSBD) is a traditional Chinese medicine (TCM) formula that can expel cold, dispel dampness, and reduce inflammation. HSBD has been widely used for the treatment of COVID-19. However, the active ingredients and potential targets for HSBD to exert anti-inflammatory or anti-SARS-CoV-2 effects remain unclear. In this paper, the active ingredients with anti-inflammatory or anti-viral effects in HSBD and their potential targets were screened using the Discovery Studio 2020 software. By overlapping the targets of HSBD and COVID-19, 8 common targets (FYN, SFTPD, P53, RBP4, IL1RN, TTR, SRPK1, and AKT1) were identified. We determined 2 key targets (P53 and AKT1) by network pharmacology. The main active ingredients in HSBD were evaluated using the key targets as receptor proteins for molecular docking. The results suggested that the best active ingredients Kaempferol2 and Kaempferol3 have the potential as supplements for the treatment of COVID-19.     

Plant Polysaccharides Modulate Immune Function via the Gut Microbiome and May Have Potential in COVID-19 Therapy

Plant polysaccharides can increase the number and variety of beneficial bacteria in the gut and produce a variety of active substances, including short-chain fatty acids (SCFAs). Gut microbes and their specific metabolites have the effects of promoting anti-inflammatory activity, enhancing the intestinal barrier, and activating and regulating immune cells, which are beneficial for improving immunity. A strong immune system reduces inflammation caused by external viruses and other pathogens. Coronavirus disease 2019 (COVID-19) is still spreading globally, and patients with COVID-19 often have intestinal disease and weakened immune systems. This article mainly evaluates how polysaccharides in plants can improve the immune system barrier by improving the intestinal microecological balance, which may have potential in the prevention and treatment of COVID-19.