Impact of cytokine storm and systemic inflammation on liver impairment patients infected by SARS-CoV-2:Prospective therapeutic challenges

Coronavirus disease 2019(COVID-19)is a devastating worldwide pandemic infection caused by a severe acute respiratory syndrome namely coronavirus 2(SARS-CoV-2)that is associated with a high spreading and mortality rate.On the date this review was written,SARS-CoV-2 infected about 96 million people and killed about 2 million people.Several arguments disclosed the high mortality of COVID-19 due to acute respiratory distress syndrome or change in the amount of angiotensin-converting enzyme 2(ACE2)receptor expression or cytokine storm strength production.In a similar pattern,hepatic impairment patients co-infected with SARS-CoV-2 exhibited overexpression of ACE2 receptors and cytokine storm overwhelming,which worsens the hepatic impairment and increases the mortality rate.In this review,the impact of SARS-CoV-2 on hepatic impairment conditions we overviewed.Besides,we focused on the recent studies that indicated cytokine storm as well as ACE2 as the main factors for high COVID-19 spreading and mortality while hinting at the potential therapeutic strategies.

Mesenchymal stem/stromal cells as adjuvant therapy in COVID-19- associated acute lung injury and cytokine storm: Importance of cell identification

Theoretically, mesenchymal stem cells (MSCs) are very promising as adjuvanttherapy to alleviate coronavirus disease 2019 (COVID-19)-associated acute lunginjury and cytokine storm. Several published studies, which used MSCs toalleviate COVID-19-associated acute lung injury and cytokine storm, reportedpromising results. However, the evidence came from a case report, case series,and clinical trials with a limited number of participants. Therefore, more studiesare needed to get robust proof of MSC beneficial effects.

Liver dysfunction as a cytokine storm manifestation and prognostic factor for severe COVID-19

patients with or without preexisting liver disorders,posing a significant complication and mortality risk.During coronavirus disease 2019(COVID-19),abnormal liver function is typically observed.However,liver injury may occur because of the treatment as well.Ischemia,cytokine storm,and hypoxia were identified as the three major factors contributing to liver damage during COVID-19.Indeed,raised liver enzymes during hospitalizations may be attributed to medications used,as well as sepsis and shock.As a result,the proportion of hospitalized patients afflicted with COVID-19 and pathological liver biomarkers varies from 14%to 53%.Aminotransferases and bilirubin are found most often elevated.Usually,increased gamma-glutamyltransferase,alkaline phosphatase,and decreased serum albumin levels are demonstrated.Additionally,although there is no specific treatment for COVID-19,many of the drugs used to treat the infection are hepatotoxic.In this mini-review,we focus on how liver dysfunction can be one of the features associated with the COVID-19 cytokine storm.Furthermore,data show that liver injury can be an independent predictor of severe COVID-19,the need for hospitalization,and death.

Network pharmacological study of Qingfei Paidu Decoction intervening on cytokine storm mechanism of COVID-19

Objective:To explore the possible mechanism of Qingfei Paibu Decoction in the treatment of COVID-19 from the perspective of cytokine storm by network pharmacology.Methods: The TCMSP and SymMap databases were used to screen out the active components and targets of Qingfei Paibu Decoction;The GeneCards database was used to screen the predicted targets of COVID-19;Two targets were mapped;The STRING database and Cytoscape3.7.2 software were used to construct the network diagram of active drag-ingredient-target and screen out the core components and targets;The GO enrichment analysis and KEGG pathway enrichment analysis were carried out by OmicShare cloud platform and David respectively.Results:A total of 52 potential targets of Qingfei Paibu Decoction for the treatment of COVID-19 were obtained, among which 17 were core targets related to inflammation, mainly including cytokines such as IL, IFN, TNF and chemokines. And 26 core components were obtained, including quercetin, luteolin, kaempferol, naringenin, and baicalein;The GO enrichment results showed 224 biological processes, 15 molecular functions and 33 cell components related to inflammation;There were 5 inflammatory signaling pathways in KEGG enrichment results, including TNF signaling pathway, Nod-like receptor signaling pathway, Toll-like receptor signaling pathway, MAPK signaling pathway and cytokine receptor interaction. Conclusion: Qingfei Paibu Decoction can inhibit cytokine storms by acting on multiple targets and pathways with multiple components and thus treat COVID-19.

Regulation of cytokine storm by marine traditional Chinese medicine

At present,COVID-19 is outbreaking worldwide,and the severity of the disease is closely related to the intensity of cytokine storm and inflammatory response.Cytokine storm is an excessive immune response to external stimuli,with complex pathogenesis and high mortality.In the New Coronavirus Infected Pneumonia Diagnosis and Treatment Program,a variety of measures are recommended for treatment,such as respiratory support,circulatory support,glucocorticoids and traditional Chinese medicine prescriptions to suppress the cytokine storm in the late clinical stage.At present,the combination of traditional Chinese medicine and Western medicine has achieved good results in clinical practice.Traditional Chinese medicine has contributed greatly to human health and world civilization,and is also a characteristic health resource in China.It has been adhering to the principle of"treating the symptoms at the time and treating the root cause in ordinary time",and has shown obvious efficacy in a variety of immune diseases.Ocean occupies 70%of the earth's surface,which contains abundant resources of traditional Chinese medicine.This paper analyzed the effect of marine algae traditional Chinese medicine on cytokine storm and immune regulation,hoping to provide a supplement to the existing application of traditional Chinese medicine,and provide some references for the development of drugs to inhibit cytokine storm from the sea.

May mesenchymal stem cell transplantation be a solution for COVID-19 induced cytokine storm?

The recently emergent disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),transmitted by droplets and aerosols,was named coronavirus disease 2019(COVID-19)by World Health Organization.Predominantly,the disease progress is asymptomatic or mild,but one-fifth of the patients advance to severe or critical illness.In severe COVID-19 patients,type-2 T helper cells release numerous cytokines;this excessive immune response is named as cytokine storm.The cytokine storm,which is the hallmark of the COVID-19 induced by the disease and aggravates due to lack of proper immune response,similar to SARS and Middle East respiratory syndrome(MERS),and the disease status may progress forward to acute respiratory distress syndrome(ARDS),systemic inflammatory response syndrome,multi-organ dysfunction syndrome,and death.Mesenchymal stromal cell transplantation is up-and-coming in treating many diseases such as HIV,hepatitis B,influenza,coronavirus diseases(SARS,MERS),lung injuries,and ARDS.Upon closer inspection on respiratory diseases,COVID-19,influenza,SARS,and MERS have similarities in patho-genesis,especially cytokine and immune response profiles.These comparable features in terms of the cytokine storm will provide hints for the treatment of COVID-19.

Clinical Manifestations of Cytokine Storm and Immune Response to COVID-19: Literature Review

Spreading COVID-19 disease caused by coronavirus 2 causes tremendous health challenges worldwide. Owing to a high transmission rate, fast-spreading disease, asymptomatic carriers, and high infectivity, we observe a pandemic status that we follow today. Although there are different reports of case fatality rates around the globe, the primary determinant of mortality is age. Symptoms of COVID-19 disease vary from asymptomatic individuals to severe acute respiratory distress syndrome (ARDS) and death. The most common complication of COVID-19 is ARDS. Hyperinflammation due to excessive immune response to coronavirus is the leading cause of severe symptoms seen in the course of COVID-19. The virus enters cells utilizing the S1 subunit through the ACE2 receptor. The innate immune response is the primary immune reaction to virus entry. RNA viruses, including corona-virus, replicate in the cytoplasm, assemble, and then exit by exocytosis. Some suggest that SARS-Cov2 uses cell-cell fusion to infect adjacent cells. Different sensors detect the virus particles in the endosomal compartment and cytoplasm, and infected cells induce an immune response to surrounding cells. As a result, the production of cytokines and chemokines such as interferons (INFs) will be augmented. Since coronavirus uses different means to evade the immune system, it is difficult for immune cells to “sense” them;thus, the coronavirus response is not adequate. It has been showing that even a sufficient level of immunoglobulin response couldn’t neutralize virus replication. Therefore, the innate immune response is unable to eradicate SARS-Cov2, causes overexpression of cytokines and chemokines that cannot eliminate the virus. Diminished INFs secretion and apoptosis of regulatory T cells (Treg) are the leading cause of dysregulated immune response in a cytokine storm. Inflammatory cells attack infected and uninfected cells, causing more inflammation and apoptosis of endothelial and epithelial cells. In the end, organ failure occurs due to immune cells’ overactivity, cell proliferation, hemorrhage, microthrombi, and remodeling of tissue cells. This review discusses the immune response and pathomechanisms of the associated symptoms in COVID-19.

SARS-CoV-2-the Unforeseen Peril of David Winning Against Goliath:the Immune Giant Collapsing Under Its Own Rampaging Cytokine Storm

We examined SARS-CoV-2(Covid-19)available treatments and prophylactic methods that included interventions associated with inhibiting the“type II transmembrane serine protease”(TMPRSS2)to limit the fusion between the Covid-19 Spike proteins and ACE2 receptors,or newly developed therapeutics like Remdesivir that interferes with the viral RNA replication.We explored the dilemma of ACE2 receptors that have a protective function against high blood pressure associated disorders,yet,they serve as the viral points of entry,elevating the probability of infection.Human tissues’analysis reveals a higher ACE2 expression in adipose tissue,placing obesity-related conditions in the eye of the pandemic storm.It primarily exposes males due to the surge of ACE2 receptors in the testes along with other tissues.Males manifest a relatively higher positive ACE2 correlations with certain immune cells in the lungs,thyroid,adrenals,liver and colon,while females evidence higher ACE2 correlations with immune cells in the heart.The remaining tissues’ACE2/immunity expressions are equivalent in both sexes,indicating that despite its preference for males,the threat of Covid-19 can easily target females.Recent reports indicate that Covid-19 is empowered by hindering the critical process of viral recognition during the adaptive immune response leading to the“cytokine storm”,the aggravated immune response that indiscriminately perseveres,rampaging the host’s vital organs.Sedentary lifestyle,age-related hormonal imbalance,and adiposity induced inflammation predispose the body to the immune collapse following Covid-19 invasion,spotlighting the detrimental aftermath of metabolic dysfunction,and excess food consumption provoked by elevated cortisol and dysregulated appetite hormones.ACE 2 expression is suppressed in the skeletal muscle,rendering fitness and weight management an effective Covid-19 preventive intervention,along with social distancing,hygiene,and facial coverings.Physical activity,or exercise alternative methods have recently demonstrated statistically significant reductions of the inflammatory marker C-Reactive Protein(CRP),triglycerides,visceral fat,cortisol and the orexigenic hormone ghrelin,juxtaposed by optimal increases of IGF-1,skeletal muscle mass,Free T3,HDL,and the anorexic hormone leptin.

^(137)Cs γ射线辐照对手工分血小板制品细胞因子灭活的研究

目的探讨137Cs γ射线辐照对手工分血小板制品中细胞因子的灭活作用,明确手工分血小板制品辐照处理技术的可行性。方法手工分离血小板后,用25Gy的137Cs γ射线照射,于照射后0、1、3、5d检测血小板制品中IL-β、IL-6、IL-8和TNF-α等细胞因子含量的变化;并分别于贮存的第0、5天分别进行pH值测定和血小板计数。结果对照组和照射组的细胞因子含量均随保存时间延长而显著增加,但对照组中细胞因子含量增加更为明显;而在同一保存时间对照组中细胞因子含量高于照射组(P<0.05);保存过程中,辐照组血小板计数及pH值与对照组差异无统计学意义(P>0.05)。结论137Cs γ射线辐照可以显著降低手工分血小板制品中细胞因子的水平。

InfoWorks CS在北京香山地区应用研究

以北京市西郊香山地区为研究区域,基于地势变化、下垫面和雨水管道等资料,建立了InfoWorks CS二维数学模型,用2012年7月21日特大暴雨进行了验证,模拟计算了不同重现期(50年、100年)暴雨情景下香山路洪水过程、过流水深,探讨了InfoWorks CS在基本无管网山区的适用性,为InfoWorks CS的应用开拓了更广阔的空间。

糖尿病患者合并新型冠状病毒感染的研究进展

糖尿病患者不仅是新型冠状病毒(新冠)的易感人群,并且在感染新冠后容易出现免疫失衡、过度炎症反应、多脏器功能损伤等并发症,导致病情更为复杂,危重症的概率显著升高,应引起临床医师重视。本文通过回顾国内外相关文献,总结了新冠导致糖代谢异常的机制,以及糖尿病患者感染新冠的临床特点和血糖管理的原则,以提高对此类患者的临床认知和治疗成功率。

化湿败毒方干预COVID-19细胞因子风暴的网络药理学研究

目的 通过网络药理学从免疫微环境、细胞因子角度探讨化湿败毒方治疗新型冠状病毒肺炎(COVID-19)的机制。方法 利用数据库筛选化湿败毒方作用靶点、COVID-19病理靶点;对交集靶点基因进行富集分析;采用基因集富集分析(GSEA)分析基因涉及的具体信号通路。结果 得到47个化湿败毒方治疗COVID-19的潜在靶点;基因本体(GO)富集分析涉及通路为对脂多糖的反应、膜筏、细胞因子活性等。京都基因与基因组百科全书(KEGG)富集涉及通路为白细胞介素-17(IL-17)信号通路、辅助性T细胞17(Th17)分化等信号通路。结论 化湿败毒方可以通过调节细胞因子活性、IL-17等通路达到调节免疫浸润微环境的作用,从而抑制细胞因子风暴,达到治疗COVID-19的作用。

Current remarks and future directions on the interactions between metabolic dysfunction-associated fatty liver disease and COVID-19

During the outbreak of the coronavirus disease 2019(COVID-19)pandemic,particular interest rose regarding the interaction between metabolic dysfunctionassociated fatty liver disease(MAFLD)and the COVID-19 infection.Several studies highlighted the fact that individuals with MAFLD had higher probability of severe acute respiratory syndrome coronavirus 2 infection and more severe adverse clinical outcomes.One of the proposed mechanisms is the inflammatory response pathway,especially the one involving cytokines,such as interleukin 6,which appeared particularly elevated in those patients and was deemed responsible for additional insult to the already damaged liver.This should increase our vigilance in terms of early detection,close follow up and early treatment for individuals with MAFLD and COVID-19 infection.In the direction of early diagnosis,biomarkers such as cytokeratin-18 and scoring systems such as Fibrosis-4 index score are proposed.COVID-19 is a newly described entity,expected to be of concern for the years to come,and MAFLD is a condition with an ever-increasing impact.Delineating the interaction between these two entities should be brought into the focus of research.Reducing morbidity and mortality of patients with COVID-19 and MAFLD should be the ultimate objective,and the optimal way to achieve this is by designing evidence-based prevention and treatment policies.

Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19

Coronavirus disease 2019(COVID-19)is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).SARS-CoV-2 infection typically presents with fever and respiratory symptoms,which can progress to severe respiratory distress syndrome and multiple organ failure.In severe cases,these complications may even lead to death.One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response.Therefore,suppressing the overactive immune response may be an effective strategy for treating COVID-19.Mesenchymal stem cells(MSCs)and their derived exosomes(MSCs-Exo)have potent homing abilities,immunomodulatory functions,regenerative repair,and antifibrotic effects,promising an effective tool in treating COVID-19.In this paper,we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19.We also summarize relevant recent clinical trials,including the source of cells,the dosage and the efficacy,and the clinical value and problems in this field,providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.

急性重症感染后炎症细胞因子风暴下心肌状态及超声心动图心脏检测的价值

目的探讨急性重症感染后炎症细胞因子风暴下的心肌状态及超声心动图心脏检测的价值。方法选取2020年1月—2023年2月在海南西部中心医院就诊的急性重症感染患者110例,其中,合并细胞因子风暴患者45例(观察组),无细胞因子风暴患者65例(对照组)。比较两组患者的临床资料、心肌损伤标志物、心电图、超声心动图参数等差异。结果观察组患者年龄高于对照组(P<0.05);观察组乳酸脱氢酶、肌酸激酶、肌酸激酶同工酶、肌钙蛋白T、肌钙蛋白I和N-末端B型脑钠肽原高于对照组(P<0.05);观察组白细胞计数和中性粒细胞计数高于对照组(P<0.05),而血小板计数和红细胞计数低于对照组(P<0.05);观察组心房颤动、室性期前收缩、房性期前收缩和异常Q波占比高于对照组(P<0.05);观察组左心室舒张末期内径、左心室收缩末期内径、左心室舒张末期容积、左心室收缩末期容积、E峰、三尖瓣反流压差和肺动脉收缩压高于对照组(P<0.05),而左室射血分数和A峰低于对照组(P<0.05)。结论急性重症感染后炎症细胞因子风暴下患者心肌损伤明显,超声心动图可直观检测心脏情况。

Dynamics of host immune responses to SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the most recent global health threat,is spreading throughout the world with worrisome speed,and the current wave of coronavirus disease 2019(COVID-19)seems to have no mercy.While this mysterious virus challenges our ability to control viral infections,our opportunities to control the COVID-19 pandemic are gradually fading.Currently,pandemic management relies on preventive interventions.Although prevention is a good strategy to mitigate SARS-CoV-2 transmission,it still cannot be considered an absolute solution to eliminate this pandemic.Currently,developing a potent immunity against this viral infection seems to be the most promising strategy to drive down this ongoing global tragedy.However,with the emergence of new challenges in the context of immune responses to COVID-19,the road to control this devastating pandemic seems bumpier;thus,it is pivotal to characterize the dynamics of host immune responses to COVID-19,in order to develop efficient prophylactic and therapeutic tools.This begs the question of whether the effector mechanisms of the immune system are indeed potent or a possible contributing factor to developing more severe and lethal forms of COVID-19.In this review,the possible role of the immunopathologic phenomena including antibody-dependent enhancement,cytokine storm,and original antigenic sin in severity and mortality of COVID-19 will be discussed.

金属蛋白酶在新型冠状病毒肺炎致病机制中的研究进展

自新型冠状病毒肺炎在全球蔓延以来,世界各国纷纷对其展开研究。随着研究的不断深入,金属蛋白酶(metalloproteinase)在其发病机制中的作用逐渐受到重视。文章综述了目前国内外关于金属蛋白酶在新型冠状病毒肺炎发病过程中的作用研究,旨在为临床治疗提供新的思路与靶点。

COVID-19 and liver injury: An ongoing challenge

The new coronavirus severe acute respiratory syndrome coronavirus 2(SARSCoV-2)was identified in December 2019,in Wuhan,China.The virus was rapidly spread worldwide,causing coronavirus disease 2019(COVID-19)pandemic.Although COVID-19 is presented,usually,with typical respiratory symptoms(i.e.,dyspnea,cough)and fever,extrapulmonary manifestations are also encountered.Liver injury is a common feature in patients with COVID-19 and ranges from mild and temporary elevation of liver enzymes to severe liver injury and,even,acute liver failure.The pathogenesis of liver damage is not clearly defined;multiple mechanisms contribute to liver disorder,including direct cytopathic viral effect,cytokine storm and immune-mediated hepatitis,hypoxic injury,and druginduced liver toxicity.Patients with underlying chronic liver disease(i.e.,cirrhosis,non-alcoholic fatty liver disease,alcohol-related liver disease,hepatocellular carcinoma,etc.)may have greater risk to develop both severe COVID-19 and further liver deterioration,and,as a consequence,certain issues should be considered during disease management.The aim of this review is to present the prevalence,clinical manifestation and pathophysiological mechanisms of liver injury in patients with SARS-CoV-2 infection.Moreover,we overview the association between chronic liver disease and SARS-CoV-2 infection and we briefly discuss the management of liver injury during COVID-19.

新冠病毒嗜神经性致神经系统损伤及功能紊乱

临床研究发现,2019年新型冠状病毒肺炎可引起神经系统损伤及功能紊乱,这表明严重急性呼吸系统综合征冠状病毒在某些情况下具有嗜神经性,可侵入中枢神经系统并引发症状。细胞因子风暴可损伤血管且加剧急、慢性神经炎症反应。本文主要针对严重急性呼吸系统综合征冠状病毒嗜神经性探讨其致病机制及2019年新型冠状病毒与相关神经系统疾病之间的关系,为未来寻找有效的预防和治疗方法及改善患者神经系统预后提供新思路。

Insight into the liver dysfunction in COVID-19 patients: Molecular mechanisms and possible therapeutic strategies

As of June 2022,more than 530 million people worldwide have become ill with coronavirus disease 2019(COVID-19).Although COVID-19 is most commonly associated with respiratory distress(severe acute respiratory syndrome),metaanalysis have indicated that liver dysfunction also occurs in patients with severe symptoms.Current studies revealed distinctive patterning in the receptors on the hepatic cells that helps in viral invasion through the expression of angiotensinconverting enzyme receptors.It has also been reported that in some patients with COVID-19,therapeutic strategies,including repurposed drugs(mitifovir,lopinavir/ritonavir,tocilizumab,etc.)triggered liver injury and cholestatic toxicity.Several proven indicators support cytokine storm-induced hepatic damage.Because there are 1.5 billion patients with chronic liver disease worldwide,it becomes imperative to critically evaluate the molecular mechanisms concerning hepatotropism of COVID-19 and identify new potential therapeutics.This review also designated a comprehensive outlook of comorbidities and the impact of lifestyle and genetics in managing patients with COVID-19.