Search

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a significant global burden of morbidity and mortality, with lung injury being the primary cause of death in affected patients. The pathogenesis of lung injury, however, remains a complex issue. In recent years, the role of the immune system in lung injury has attracted extensive attention worldwide. Despite advancements in our understanding of various lung injury subtypes, significant limitations persist in both prevention and treatment. This review investigates the immunopathogenesis of ALI/ARDS, aiming to elucidate the pathological processes of lung injury mediated by dendritic cells (DCs), natural killer (NK) cells, phagocytes, and neutrophils. Furthermore, the article expounds on the critical contributions of gut microbiota, inflammatory pathways, and cytokine storms in the development of ALI/ARDS. [Display omitted] • Damage to lung tissue caused by immune cell dysfunction. • The ecological stability of intestinal flora is important in protecting lung tissue. • The inflammatory pathway plays a crucial role in regulating and mediating lung injury. • The impact of cytokine storm on lung injury is severe. [ABSTRACT FROM AUTHOR]

Stroke is a prevalent cerebrovascular condition with a global impact, causing significant rates of illness and death. Despite extensive research, the available treatment options for stroke remain restricted. Hence, it is crucial to gain a deeper understanding of the molecular mechanisms associated with the onset and advancement of stroke in order to establish a theoretical foundation for novel preventive and therapeutic approaches. NF-κB, also known as nuclear factor κB, is a transcription factor responsible for controlling the expression of numerous genes and plays a crucial role in diverse physiological processes. NF-κB is triggered and regulates neuroinflammation and other processes after stroke, promoting the generation of cytokine storms and contributing to the advancement of ischemic stroke (IS). Therefore, NF-κB could potentially play a vital role in stroke by regulating diverse pathophysiological processes. This review provides an overview of the functions of NF-κB in stroke and its governing mechanisms. In addition, our attention is directed towards various potential therapies that aim to inhibit the NF-κB signaling pathway in order to offer valuable insights for the advancement of innovative treatment approaches for stroke. [Display omitted] ● NF-κB plays a key role in neuroinflammation following ischemic stroke. ● NF-κB is involved in regulating the pathological mechanisms of ischemic stroke. ● A series of therapies exert neuroprotective effects on ischemic stroke via inhibiting NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]

The use of natural compounds, such as curcumin, to treat infections caused by bacteria, viruses, fungi, parasites, inflammatory diseases, and various types of cancer is an active and dynamic area of research. Curcumin has a long history of use in the food industry, and there is currently a growing interest in its therapeutic applications. Numerous clinical trials have consistently shown that curcumin, a polyphenolic compound, is safe and well-tolerated even at high doses. There is no toxicity limit. However, the clinical efficacy of curcumin has been limited by its constraints. However, scientific evidence indicates that the use of adjuvants and carriers, such as nanoparticles, exosomes, micelles, and liposomes, can help overcome this limitation. The properties, functions, and human benefits of using nanocurcumin are well-supported by scientific research. Recent evidence suggests that nanocurcumin may be a beneficial therapeutic modality due to its potential to decrease gene expression and secretion of specific inflammatory biomarkers involved in the cytokinestorm seen in severe COVID-19, as well as increase lymphocyte counts. Nanocurcumin has demonstrated the ability to improve clinical manifestations and modulate immune response and inflammation in various autoinflammatory diseases. Additionally, its efficacy, affordability, and safety make it a promising replacement for residual cancer cells after tumor removal. However, further studies are necessary to evaluate the safety and efficacy of nanocurcumin as a new therapeutic in clinical trials, including appropriate dosage, frequency, and duration. In Brief • Curcumin has a wide range of pharmacological effects against a variety of pathologies with limitations such as poor aqueous solubility, extensive metabolism and rapid elimination. • Nanoscale techniques have been used to overcome these pharmacokinetic limitations, with encouraging results in both laboratory experiments and in vivo. • The observed decrease in gene expression and secretion of inflammatory biomarkers (implicated in the cytokine storm seen in severe COVID-19 cases), as well as the increase in lymphocyte count, have provided evidence for the therapeutic potential of nanocurcumin. [Display omitted] [ABSTRACT FROM AUTHOR]

An archetypal anti-inflammatory compound against cytokine storm would inhibit it without suppressing the innate immune response. AG5, an anti-inflammatory compound, has been developed as synthetic derivative of andrographolide, which is highly absorbable and presents low toxicity. We found that the mechanism of action of AG5 is through the inhibition of caspase-1. Interestingly, we show with in vitro generated human monocyte derived dendritic cells that AG5 preserves innate immune response. AG5 minimizes inflammatory response in a mouse model of lipopolysaccharide (LPS)-induced lung injury and exhibits in vivo anti-inflammatory efficacy in the SARS-CoV-2-infected mouse model. AG5 opens up a new class of anti-inflammatories, since contrary to NSAIDs, AG5 is able to inhibit the cytokine storm, like dexamethasone, but, unlike corticosteroids, preserves adequately the innate immunity. This is critical at the early stages of any naïve infection, but particularly in SARS-CoV-2 infections. Furthermore, AG5 showed interesting antiviral activity against SARS-CoV-2 in humanized mice. [Display omitted] • AG5, a synthetic derivative of andrographolide, is a novel anti-inflammatory drug • AG5 minimizes inflammatory response by inhibition of caspase-1 route • AG5 inhibits cytokine storm and preserves adequately the innate immunity • AG5 shows antiviral activity against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Hepatocytes, the predominant cellular constituents of the liver, exhibit the highest mitochondrial density within the human body. Remarkably, experimental insights from the latter part of the previous century involving extracellular injection of mitochondrial DNA (mtDNA) elucidated its potential to incite autoimmune disorders. Consequently, in instances of liver injury, the substantial release of mtDNA has the potential to trigger the activation of the innate immune response, thereby inducing sustained pathogenic consequences within the organism. This article provides a comprehensive retrospective analysis of recent literature pertaining to the impact of mtDNA release on various hepatic cell populations, elucidating its role and potential mechanisms in liver injury. The findings underscore the central role of mtDNA in modulating the immune system, primarily through the orchestration of a cytokine storm, further exacerbating the occurrence of liver injury. [ABSTRACT FROM AUTHOR]

A cytokine storm (CS) is a rapidly occurring, complex, and highly lethal systemic acute inflammatory response induced by pathogens and other factors. Currently, no clinical therapeutic drugs are available with a significant effect and minimal side effects. Given the pathogenesis of CS, natural products have become important resources for bioactive agents in the discovery of anti-CS drugs. This study aimed to provide guidance for preventing and treating CS-related diseases by reviewing the natural products identified to inhibit CS in recent years. A comprehensive literature review was conducted on CS and natural products, utilizing databases such as PubMed and Web of Science. The quality of the studies was evaluated and summarized for further analysis. This study summarized more than 30 types of natural products, including 9 classes of flavonoids, phenols, and terpenoids, among others. In vivo and in vitro experiments demonstrated that these natural products could effectively inhibit CS via nuclear factor kappa-B, mitogen-activated protein kinase, and Mammalian target of rapamycin (mTOR) signaling pathways. Moreover, the enzyme inhibition assays revealed that more than 20 chemical components had the potential to inhibit ACE2, 3CL-protease, and papain-like protease activity. The experimental results were obtained using advanced technologies such as biochips and omics. Various natural compounds in traditional Chinese medicine (TCM) extracts could directly or indirectly inhibit CS occurrence, potentially serving as effective drugs for treating CS-related diseases. This study may guide further exploration of the therapeutic effects and biochemical mechanisms of natural products on CS. [Display omitted] • Initially reviews the potential natural products for the treatment of cytokine storm. • Initially summarizes target proteins for natural products treating cytokine storm. • Initially summarizes the pathways of natural products inhibiting cytokine storm. • Investigates the potential targets- ACE2、3CLpro、PLpro based enzyme inhibition assays. • Initially summarizes technical methods in investigated relevant research experiments. [ABSTRACT FROM AUTHOR]

Cytokine storm (CS) is a major contributor to the fatal outcome of severe infectious diseases, including Covid-19. Treatment with the complement (C) C5 inhibitor eculizumab was beneficial in end-stage Covid-19, however, the mechanism of this effect is unknown. To clarify this, we analyzed the relationship between C activation and production of pro-inflammatory cytokines in a PBMC model. Human PBMC with or without 20 % autologous serum was incubated with C3a, C5a, zymosan or zymosan-pre-activated serum (ZAS) for 24 h with or without eculizumab or the C5a receptor antagonist, DF2593A. C activation (sC5b-9) and 9 inflammatory cytokines were measured by ELISA. In serum-free unstimulated PBMC only IL-8 release could be measured during incubation. Addition of C5a increased IL-8 secretion only, ZAS induced both IL-2 and IL-8, while zymosan led to significant production of all cytokines, most abundantly IL-8. In the presence of serum the above effects were greatly enhanced, and the zymosan-induced rises of IL-1α, IL-1β IFN-γ and IL-2 were significantly attenuated by eculizumab but not by DF2593a. These data highlight the complexity of interrelationships between C activation and cytokine secretion under different experimental conditions. The clinically relevant findings include the abundant formation of the chemokine IL-8, which was stimulated by C5a, and the suppression of numerous inflammatory cytokines by eculizumab, which explains its therapeutic efficacy in severe Covid-19. These data strengthen the clinical relevance of the applied PBMC model for drug screening against CS, enabling the separation of complex innate immune cross-talks. • In serum-free unstimulated human PBMC culture only IL-8 release could be measured. • Serum increased the release of all cytokines measured. • Zymosan increased the release of all cytokines much more in the presence of serum. • Eculizumab suppressed zymosan-induced secretion of IL-1a, IL-1b, IFγ and IL-2. • A differential relationship between C activation and cytokine release was revealed. [ABSTRACT FROM AUTHOR]

Cell therapy is one of the methods that have shown promising results in treating diseases in recent decades. However, the use of different types of cells comes with limitations. The application of immune cells in cell therapy can lead to cytokine storms and inappropriate responses to self-antigens. Also, the use of stem cells has the potential to create tumors. Also, cells may not migrate to the injury site after intravenous injection. Therefore, using exosomes from different cells as therapeutic candidates were proposed. Due to their small size and favorable characteristics, such as biocompatibility and immunocompatibility, the easy storage and isolation, exosomes have attracted much attention. They are used in treating many diseases, including cardiovascular diseases, orthopedic diseases, autoimmune diseases, and cancer. However, the results of various studies have shown that the therapeutic efficiency of exosomes (Exo) can be increased by loading different drugs and microRNAs inside them (encapsulated exosomes). Therefore, analyzing studies investigating encapsulated exosomes' therapeutic ability is critical. In this study, we have examined the studies related to the use of encapsulated exosomes in treating diseases such as cancer and infectious diseases and their use in regenerative medicine. Compared to intact exosomes, the results show that the application of encapsulated exosomes has a higher therapeutic ability. Therefore it is suggested to use this method depending on the treatment type to increase the treatment's efficiency. [Display omitted] • The use of encapsulated exosomes has a higher therapeutic efficiency than intact exosomes. • Different drugs with the purpose of treating various diseases have the possibility of being loaded in exosomes. • The load of chemotherapy drugs can lead to an increase in the apoptosis of tumor cells. • Exosomes encapsulated with microbial antigens can be used as new-generation vaccines. [ABSTRACT FROM AUTHOR]

HSV-2 is a common human pathogen worldwide that causes genital herpes. Due to the lack of an effective HSV-2 vaccine in the foreseeable future, there is an urgent need to develop effective, safe and affordable anti-HSV-2 agents. Our previous studies confirmed that a small-molecule compound, Q308, effectively inhibits the reactivation of latent HIV and might be developed as an anti-HIV-1 agent. Patients infected with HSV-2 are generally more susceptible to HIV-1 infection than normal humans. In this study, we found that Q308 treatment had strong inhibitory activity against both HSV-2 and acyclovir-resistant HSV-2 strains in vitro and reduced the viral titers in tissue. And this treatment effectively ameliorated the cytokine storm and pathohistological changes caused by HSV-2 infection in HSV-2-infected mice. Unlike nucleoside analogs such as acyclovir, Q308 inhibited post-viral entry events by attenuating the synthesis of viral proteins. Furthermore, Q308 treatment blocked HSV-2-induced PI3K/AKT phosphorylation due to its inhibition on viral infection and replication. Overall, Q308 treatment exhibits potent anti-HSV-2 activity by inhibiting viral replication both in vitro and in vivo. Q308 is a promising lead compound for the development of new anti-HSV-2/HIV-1 therapies, particularly against acyclovir-resistant HSV-2 strains. [Display omitted] • A potential anti-HIV-1 compound, Q308, inhibited HSV-2 infection and replication. • Q308 inhibited post-viral entry by blocking the synthesis of viral proteins. • Q308 treatment affected HSV-2-induced PI3K/AKT phosphorylation. • Q308 is a lead compound for the development of a new anti-HSV-2/HIV-1 agent. [ABSTRACT FROM AUTHOR]

The healthy immune system eliminates pathogens and maintains tissue homeostasis through extraordinarily complex networks with feedback systems while avoiding potentially massive tissue destruction. Many parameters influence humoral and cellular vaccine responses, including intrinsic and extrinsic, environmental, and behavioral, nutritional, perinatal and administrative parameters. The relative contributions of persisting antibodies and immune memory as well as the determinants of immune memory induction, to protect against specific diseases are the main parameters of long-term vaccine efficacy. Natural and vaccine-induced immunity and monoclonal antibody immunotherapeutic, may be evaded by SARS-CoV-2 variants. Besides the complications of the production of COVID-19 vaccinations, there is no effective single treatment against COVID-19. However, administration of a combined treatment at different stages of COVID-19 infection may offer some cure assistance. Combination treatment of antiviral drugs and immunomodulatory drugs may reduce inflammation in critical COVID-19 patients with cytokine release syndrome. Molnupiravir, remdesivir and paxlovid are the approved antiviral agents that may reduce the recovery time. In addition, immunomodulatory drugs such as lactoferrin and monoclonal antibodies are used to control inflammatory responses in their respective auto-immune conditions. Therefore, the widespread occurrence of highly transmissible variants like Delta and Omicron indicates that there is still a lot of work to be done in designing efficient vaccines and medicines for COVID-19. In this review, we briefly discussed the immunological response against SARS-CoV-2 and the vaccines approved by the World Health Organization (WHO) for COVID-19, their mechanisms, and side effects. Moreover, we mentioned various treatment trials and strategies for COVID-19. [Display omitted] • Available vaccines and treatments in COVID-19 management of, including their effect against SARS-CoV-2 variants of concern. • Some vaccines against SARS-CoV-2 are under emergency approval, and the mRNA vaccine shows the most effective technique. • Paxlovid, molnupiravir, and remdesivir are the currently effective antiviral agents against Omicron subvariants of SARS-CoV-2. • Bebtelovimab is the only monoclonal antibody that is active against all Omicron subvariants. • Some supportive treatments against SARS-CoV-2 such as lactoferrin show immunomodulatory and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a lethal clinical entity that has become an emergency event with the outbreak of COVID-19. However, to date, there are no well-proven pharmacotherapies except dexamethasone. This study is aimed to evaluate IRAK4 inhibitors as a potential treatment for ARDS-cytokine release syndrome (CRS). We applied two IRAK4 inhibitors, BAY-1834845 and PF-06650833 to an inhaled lipopolysaccharide (LPS)-induced ARDS mouse model with control of high dose dexamethasone (10 mg/kg). Unexpectedly, although both compounds had excellent IC 50 on IRAK4 kinase activity, only BAY-1834845 but not PF-06650833 or high dose dexamethasone could significantly prevent lung injury according to a blinded pathology scoring. Further, only BAY-1834845 and BAY-1834845 combined with dexamethasone could effectively improve the injury score of pre-existed ARDS. Compared with PF-06650833 and high dose dexamethasone, BAY-1834845 remarkably decreased inflammatory cells infiltrating lung tissue and neutrophil count in BALF. BAY-1834845, DEX, and the combination of the two agents could decrease BALF total T cells, monocyte, and macrophages. In further cell type enrichment analysis based on lung tissue RNA-seq, both BAY-1834845 and dexamethasone decreased signatures of inflammatory cells and effector lymphocytes. Interestingly, unlike the dexamethasone group, BAY-1834845 largely preserved the signatures of naïve lymphocytes and stromal cells such as endothelial cells, chondrocytes, and smooth muscle cells. Differential gene enrichment suggested that BAY-1834845 downregulated genes more efficiently than dexamethasone, especially TNF, IL-17, interferon, and Toll-like receptor signaling. • IRAK4 inhibition is a potentially feasible treatment for ARDS. • BAY-1834845 shows unexpectedly discrepant efficacy in vivo with PF-06650833. • BAY-1834845 inhibits natural immunity signaling stronger than dexamethasone. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a viral disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a member of the Coronaviridae family. On March 11, 2020 the World Health Organization (WHO) has named the newly emerged rapidly-spreading epidemic as a pandemic. Besides the risk-reduction measures such as physical and social distancing and vaccination, a wide range of treatment modalities have been developed; aiming to fight the disease. The immune system is known as a double-edged sword in COVID-19 pathogenesis, with respect to its role in eliminating the pathogen and in inducing complications such as cytokine storm syndrome. Hence, immune-based therapeutic approaches have become an interesting field of COVID-19 research, including corticosteroids, intravenous immunoglobulins (IVIG), interferon therapy, and more COVID-19-specific approaches such as anti-SARS-CoV-2-monoclonal antibodies. Herein, we did a comprehensive review on immune-based therapeutic approaches for COVID-19. Not applicable. [Display omitted] • Since the emergence of the virus, COVID-19 has caused morbidities and mortalities worldwide. • The immune system plays a dual role, eliminating pathogens and inducing poorly regulated responses. • Immune-based therapeutic approaches affect both roles and help to resolve disease complications. • These approaches are a promising candidate in controlling poorly regulated responses especially in severely ill patients. • Examples of such modalities include corticosteroids, IVIG, interferons, and monoclonal antibodies. [ABSTRACT FROM AUTHOR]

COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation. Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine analysis using Luminex kit was performed. BromAc® displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo. BromAc® showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control. BromAc® acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250 µg. These results indicate robust mucolytic and anti-inflammatory effect of BromAc® ex vivo in tracheal aspirates from critically ill COVID-19 patients, indicating its potential to be further assessed as pharmacological treatment for COVID-19. • BromAc is a strong mucolytic for COVID-19 sputum ex vivo. • Select chemokines and cytokines were downregulated following BromAc exposure. • Mucolytic and anti-inflammatory effects of BromAc were dose-dependent. • Further assessment of BromAc in COVID-19 clinical trials is warranted. [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) is a multi-tasking cytokine that represents high activity in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and cancer. High concentration of this pleiotropic cytokine accounts for hyperinflammation and cytokine storm, and is related to multi-organ failure in patients with SARS-CoV-2 induced disease. IL-6 promotes lymphopenia and increases C-reactive protein (CRP) in such cases. However, blockade of IL-6 is not a full-proof of complete response. Hypoxia, hypoxemia, aberrant angiogenesis and chronic inflammation are inter-related events occurring as a response to the SARS-CoV-2 stimulatory effect on high IL-6 activity. Taking both pro- and anti-inflammatory activities will make complex targeting IL-6 in patient with SARS-CoV-2 induced disease. The aim of this review was to discuss about interactions occurring within the body of patients with SARS-CoV-2 induced disease who are representing high IL-6 levels, and to determine whether IL-6 inhibition therapy is effective for such patients or not. We also address the interactions and targeted therapies in cancer patients who also have SARS-CoV-2 induced disease. • IL-6 is a hallmark of inflammatory feature in severe/critical SARS-CoV-2 induced disease. • CRP level is a predictor of response to IL-6 inhibitor therapy. • The efficacy of tocilizumab is moderate in severe SARS-CoV-2 induced disease. • SARS-CoV-2-induced IL-6 seemingly strengthens cancer aggression. • IL-6 inhibitors can go with ICI in cancer (not in SARS-CoV-2 induced disease). [ABSTRACT FROM AUTHOR]

One of the hallmarks of COVID-19 is the cytokine storm that provokes primarily pneumonia followed by systemic inflammation. Emerging evidence has identified a potential link between elevated interleukin-17A (IL-17A) levels and disease severity and progression. Considering that per se, IL-17A can activate several inflammatory pathways, it is plausible to hypothesize an involvement of this cytokine in COVID-19 clinical outcomes. Thus, IL-17A could represent a marker of disease progression and/or a target to develop therapeutic strategies. This hypothesis paper aims to propose this "unique" cytokine as a silent amplifier of the COVID-19 immune response and (potentially) related therapy. [Display omitted] • One of the hallmarks of COVID-19 is the cytokine storm that provokes systemic inflammation. • Elevated levels of interleukin-17A (IL-17A) are associated to disease severity and progression. • We propose IL-17A as a silent amplifier of the COVID-19 immune response and (potentially) related therapy. [ABSTRACT FROM AUTHOR]

It has become evident that the actions of pro-inflammatory cytokines and/or the development of a cytokine storm are responsible for the occurrence of severe COVID-19 during SARS-CoV-2 infection. Although immunomodulatory mechanisms vary among viruses, the activation of multiple TLRs that occurs primarily through the recruitment of adapter proteins such as MyD88 and TRIF contributes to the induction of a cytokine storm. Based on this, controlling the robust production of pro-inflammatory cytokines by macrophages may be applicable as a cellular approach to investigate potential cytokine-targeted therapies against COVID-19. In the current study, we utilized TLR2/MyD88 and TLR3/TRIF co-activated macrophages and evaluated the anti-cytokine storm effect of the traditional Chinese medicine (TCM) formula Babaodan (BBD). An RNA-seq-based transcriptomic approach was used to determine the molecular mode of action. Additionally, we evaluated the anti-inflammatory activity of BBD in vivo using a mouse model of post-viral bacterial infection-induced pneumonia and seven severely ill COVID-19 patients. Our study reveals the protective role of BBD against excessive immune responses in macrophages, where the underlying mechanisms involve the inhibition of the NF-κB and MAPK signaling pathways. In vivo, BBD significantly inhibited the release of IL-6, thus resulting in increased survival rates in mice. Based on limited data, we demonstrated that severely ill COVID-19 patients benefited from BBD treatment due to a reduction in the overproduction of IL-6. In conclusion, our study indicated that BBD controls excessive immune responses and may thus represent a cytokine-targeted agent that could be considered to treating COVID-19. [Display omitted] • Cytokine-targeted therapeutic strategies to reduce lung inflammatory injury have been proposed for the treatment of patients with severe COVID-19. • TCM within the "heat-clearing and detoxifying (qingre jiedu)" category have been demonstrated to exert strong anti-inflammatory activities. • Baobadan (BBD) exerts pronounced anti-inflammatory effects on TLR1/2 and TLR3 dual activated macrophages that are associated with NF-κB and MAPKs. • BBD protects mice from excessive cytokine production and inflammatory lung injury. • Based on limited data, BBD appears to reduce the overproduction of IL-6 in severely ill COVID-19 patients. [ABSTRACT FROM AUTHOR]

Hyperinflammatory response caused by infections such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) increases organ failure, intensive care unit admission, and mortality. Cytokine storm in patients with Coronavirus Disease 2019 (COVID-19) drives this pattern of poor clinical outcomes and is dependent upon the activity of the transcription factor complex nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and its downstream target gene interleukin 6 (IL6) which interacts with IL6 receptor (IL6R) and the IL6 signal transduction protein (IL6ST or gp130) to regulate intracellular inflammatory pathways. In this study, we compare transcriptomic signatures from a variety of drug-treated or genetically suppressed (i.e. knockdown) cell lines in order to identify a mechanism by which antidepressants such as fluoxetine demonstrate non-serotonergic, anti-inflammatory effects. Our results demonstrate a critical role for IL6ST and NF-kappaB Subunit 1 (NFKB1) in fluoxetine's ability to act as a potential therapy for hyperinflammatory states such as asthma, sepsis, and COVID-19. [Display omitted] • Fluoxetine treatment elicits genetic changes which parallel those caused by IL6ST or NFKB1 knockdown. • Fluoxetine's anti-inflammatory mechanism of action may depend upon NF-kappaB/IL6ST signaling. • The anti-inflammatory effects of fluoxetine are likely independent of its monoaminergic mechanism. • The anti-inflammatory effects of fluoxetine may prevent cytokine storm associated with COVID-19. [ABSTRACT FROM AUTHOR]

The solubility and Immunogenicity of protein significantly impacted the production efficiency and medical application of Nbs. The soluble and humanized framework was rationally designed through bioinformatics analysis. The phagemids carrying genetic diversity of Nb were electro-transformed into TG1 cells for library construction and isolated the binding TNF-α function of Nb. Protein products of TNF-α specific Nb were prepared with E.coli expression system and its bioactivity was verified by cytotoxicity assay. [Display omitted] • Nanobodies are the variable domains of camelid heavy chain antibodies (VHH). • A new method was built to design humanized framework with high solubility using bioinformatics tools. • The constructed library was of high quality and used to screen anti-TNF-a Nanobodies. • NT-3 showed a good expression in supernatant and significant inhibitory effect for L929 cells apoptosis mediated by TNF-α. Tumor necrosis factor (TNF-α) is an important clinically tested cytokine that could induce autoimmune diseases and inflammation. Therefore, the anti-TNF-α therapy strategy was developed and used therapeutically in various diseases, especially in the cytokine storm associated chimeric antigen receptor (CAR) T-cell therapy and antiviral therapy. Compare with other anti-TNF-α inhibitors, anti-TNF-α Nb (nanobody) has many unique advantages. Herein, we reported a novel humanized scaffold for library construction, which could be soluble and expressed in Escherichia coli (E.coli), and the efficiency capacity could reach as high as 2.01 × 109. Meanwhile, an anti-TNF-α Nb was selected for further study after 4 rounds of screening, NT-3, as the optimal Nb could effectively inhibit TNF-mediated cytotoxicity. The IC50 of NT-3 was determined as 0.804 μM, and its apoptosis inhibition rate was 62.47 % in L929 cells. Furthermore, the molecular docking results showed that complementarity-determining regions (CDRs) of NT-3 could connect to TNF for blocking function through strong hydrogen bonds and salt bridges. In general, our study not only provided a good Nb screening platform in vitro without animal immunization, but also generated a series of novel humanized anti-TNF-α Nb candidates with potential applications. [ABSTRACT FROM AUTHOR]

• GI symptoms are common in patients with COVID-19, which may be related to abundant ACE2 expression in the intestinal epithelium. • Changes in ACE2 expression may affect functions of B0AT1 in AA absorption, thus contributing to the GI symptoms in COVID-19 patients. • Immune irregularities associated with IBD share cellular components with immune responses in COVID-19. • Immune modulating treatment for IBD may have overlapping effect on outcome of COVID-19 in IBD patients. Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, has led to the ongoing global pandemic. Although most patients experience no or only mild symptoms, some patients can develop severe illness, such as progressive pneumonia, acute respiratory distress syndrome, secondary hemophagocytic lymphohistiocytosis and multiple organ failure caused by cytokine release syndrome. A majority of COVID-19 patients also develop gastrointestinal symptoms. These can present special challenges to the management of patients with inflammatory bowel disease (IBD) due to potential interactions between the immune response related to SARS-CoV-2 infection and dysregulated immunity associated with IBD. In this context, the pathogenesis of COVID-19 is reviewed in order to address these questions regarding immune interactions between COVID-19 and IBD. [ABSTRACT FROM AUTHOR]

• MYR has extensive antitumor effects and its mechanisms are distinct. • Other biological activities have been reported, as anti-inflammatory, cardio-cerebrovascular protection, etc. • The potential effects of MYR targeting SARS-CoV-2 M Pro or human ACE2, and future research prospects. Myricetin(MYR) is a flavonoid compound widely found in many natural plants including bayberry. So far, MYR has been proven to have multiple biological functions and it is a natural compound with promising research and development prospects. This review comprehensively retrieved and collected the latest pharmacological abstracts on MYR, and discussed the potential molecular mechanisms of its effects. The results of our review indicated that MYR has a therapeutic effect on many diseases, including tumors of different types, inflammatory diseases, atherosclerosis, thrombosis, cerebral ischemia, diabetes, Alzheimer's disease and pathogenic microbial infections. Furthermore, it regulates the expression of Hippo, MAPK, GSK-3β, PI3K/AKT/mTOR, STAT3, TLR, IκB/NF-κB, Nrf2/HO-1, ACE, eNOS / NO, AChE and BrdU/NeuN. MYR also enhances the immunomodulatory functions, suppresses cytokine storms, improves cardiac dysfunction, possesses an antiviral potential, can be used as an adjuvant treatment against cancer, cardiovascular injury and nervous system diseases, and it may be a potential drug against COVID-19 and other viral infections. Generally, this article provides a theoretical basis for the clinical application of MYR and a reference for its further use. [ABSTRACT FROM AUTHOR]

COVID-19 is a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early reported symptoms include fever, cough, and respiratory symptoms. There were few reports of digestive symptoms. However, with COVID-19 spreading worldwide, symptoms such as vomiting, diarrhoea, and abdominal pain have gained increasing attention. Research has found that angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, is strongly expressed in the gastrointestinal tract and liver. Whether theoretically or clinically, many studies have suggested a close connection between COVID-19 and the digestive system. In this review, we summarize the digestive symptoms reported in existing research, discuss the impact of SARS-CoV-2 on the gastrointestinal tract and liver, and determine the possible mechanisms and aetiology, such as cytokine storm. In-depth exploration of the relationship between COVID-19 and the digestive system is urgently needed. [ABSTRACT FROM AUTHOR]

Mode of action of kefir supplementary dietary against viral infection. • Kefir and kefir derivatives can suppress viral activity by modulating immune-system responses and/or causing disruption of viral adhesion. • The antiviral mechanisms of kefir involve enhancement of macrophage production and boosting the activity of proinflammatory cytokines. • Kefir dietaries have anti-inflammatory activity by inhibiting the activity of proinflammatory cytokines such as IL-1β, TNF-α and IL-6. • Using kefir (and its byproducts) as an inhibitor of expression of proinflammatory cytokines in COVID-19 patients could be a viable policy. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a recently discovered coronavirus termed 'severe acute respiratory syndrome coronavirus 2′ (SARS-CoV-2). Several scholars have tested antiviral drugs and compounds to overcome COVID-19. 'Kefir' is a fermented milk drink similar to a thin yogurt that is made from kefir grains. Kefir and its probiotic contents can modulate the immune system to suppress infections from viruses (e.g., Zika, hepatitis C, influenza, rotaviruses). The antiviral mechanisms of kefir involve enhancement of macrophage production, increasing phagocytosis, boosting production of cluster of differentiation-positive (CD4+), CD8+, immunoglobulin (Ig)G+ and IgA+ B cells, T cells, neutrophils, as well as cytokines (e.g., interleukin (IL)-2, IL-12, interferon gamma-γ). Kefir can act as an anti-inflammatory agent by reducing expression of IL-6, IL-1, TNF-α, and interferon-γ. Hence, kefir might be a significant inhibitor of the 'cytokine storm' that contributes to COVID-19. Here, we review several studies with a particular emphasis on the effect of kefir consumption and their microbial composition against viral infection, as well as discussing the further development of kefir as a protective supplementary dietary against SARS-CoV-2 infection via modulating the immune response. [ABSTRACT FROM AUTHOR]

Cytokines, the main players in the cytokine storm, can act as immunomodulators regulating inflammatory responses. S. baicalensis active components (SBACs) can act directly on immune cells such as lymphocytes, macrophages, mast cells, dendritic cells, monocytes, and neutrophils, and inhibit the production of inflammatory cytokines and alleviate inflammatory damage to organ tissues. "→", promotion; " ", inhibition. • Infection-associated cytokine storms can readily lead to organ failure or death. • The bioactive substances of S. baicalensis act directly on multiple immune cells. • The bioactive substances inhibit the production of diverse inflammatory cytokines. • The immunomodulatory mechanisms include multiple inflammatory signaling pathways. • S. baicalensis active components are potential drugs for cytokine storm treatment. Scutellaria baicalensis Georgi., a plant used in traditional Chinese medicine, has multiple biological activities, including anti-inflammatory, antiviral, antitumor, antioxidant, and antibacterial effects, and can be used to treat respiratory tract infections, pneumonia, colitis, hepatitis, and allergic diseases. The main active substances of S. baicalensis , baicalein, baicalin, wogonin, wogonoside, and oroxylin A, can act directly on immune cells such as lymphocytes, macrophages, mast cells, dendritic cells, monocytes, and neutrophils, and inhibit the production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and other inflammatory mediators such as nitric oxide, prostaglandins, leukotrienes, and reactive oxygen species. The molecular mechanisms underlying the immunomodulatory and anti-inflammatory effects of the active compounds of S. baicalensis include downregulation of toll-like receptors, activation of the Nrf2 and PPAR signaling pathways, and inhibition of the nuclear thioredoxin system and inflammation-associated pathways such as those of MAPK, Akt, NFκB, and JAK-STAT. Given that in addition to the downregulation of cytokine production, the active constituents of S. baicalensis also have antiviral and antibacterial effects, they may be more promising candidate therapeutics for the prevention of infection-related cytokine storms than are drugs having only antimicrobial or anti-inflammatory activities. [ABSTRACT FROM AUTHOR]

• CS triggered by excessive inflammatory response drives the pathogenesis of COVID-19. • ASX inhibits TNFα, IL1β, IL6 via regulation of NF-kB & JAK/STAT; prevents CS & ALI/ARDS. • ASX suppresses plasma CRP, iNOS, COX2, PGE2 & ICAM-1; prevents oxidative damages. • ASX inhibits NLRP3, HIF1α, activates Nrf2, Sirtuin pathways; exerts antioxidant effect. • ASX enhances immune responses, NK cell activity, T- & B- cell population. Host excessive inflammatory immune response to SARS-CoV-2 infection is thought to underpin the pathogenesis of COVID-19 associated severe pneumonitis and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Once an immunological complication like cytokine storm occurs, anti-viral based monotherapy alone is not enough. Additional anti-inflammatory treatment is recommended. It must be noted that anti-inflammatory drugs such as JAK inhibitors, IL-6 inhibitors, TNF-α inhibitors, colchicine, etc., have been either suggested or are under trials for managing cytokine storm in COVID-19 infections. Natural astaxanthin (ASX) has a clinically proven safety profile and has antioxidant, anti-inflammatory, and immunomodulatory properties. There is evidence from preclinical studies that supports its preventive actions against ALI/ARDS. Moreover, ASX has a potent PPARs activity. Therefore, it is plausible to speculate that ASX could be considered as a potential adjunctive supplement. Here, we summarize the mounting evidence where ASX is shown to exert protective effect by regulating the expression of pro-inflammatory factors IL-1β, IL-6, IL-8 and TNF-α. We present reports where ASX is shown to prevent against oxidative damage and attenuate exacerbation of the inflammatory responses by regulating signaling pathways like NF-ĸB, NLRP3 and JAK/STAT. These evidences provide a rationale for considering natural astaxanthin as a therapeutic agent against inflammatory cytokine storm and associated risks in COVID-19 infection and this suggestion requires further validation with clinical studies. [ABSTRACT FROM AUTHOR]

• Effect of sex hormones on COVID-19 outcome bias in males and females. • Effect of immunological factors on COVID-19 outcome bias in males and females. • Angiotensin-converting enzyme-2 (ACE2) system and COVID-19 outcome in males and females. • Correlation between smoking and COVID-19 incidence in males and females. • Possible therapeutic options for COVID-19. The severe form of COVID-19 has significant sex disparities, with high fatalities commonly reported among males than females. The incidence of COVID-19 has also been higher in males compared with their female counterparts. This trend could be attributed to a better responsive and robust immune system in females. Cytokine storm is one of the pathophysiological features of severe COVID-19, and it occurs as a result of over-activation of immune cells leading to severe inflammation and tissue damage. Nevertheless, it is well modulated in females compared to their male counterparts. Severe inflammation in males is reported to facilitate progression of mild to severe COVID-19. The sex hormones, estrogens and androgens which exist in varying functional levels respectively in females and males are cited as the underlying cause for the differential immune response to COVID-19. Evidence abounds that estrogen modulate the immune system to protect females from severe inflammation and for that matter severe COVID-19. On the contrary, androgen has been implicated in over-activation of immune cells, cytokine storm and the attendant severe inflammation, which perhaps predispose males to severe COVID-19. In this review efforts are made to expand understanding and explain the possible roles of the immune system, the sex hormones and the angiotensin-converting enzyme (ACE) systems in male bias to severe COVID-19. Also, this review explores possible therapeutic avenues including androgen deprivation therapy (ADT), estrogen-based therapy, and ACE inhibitors for consideration in the fight against COVID-19. [ABSTRACT FROM AUTHOR]

The role of interleukin 6 inhibitors in therapy of severe COVID-19 Nassonov E, Samsonov M. RM, Resident macrophages; INF, interferons; NK, natural killers; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor, TNFα, tumor necrosis factor alpha; IP-10, interferon (IFN)γ-induced protein 10; MIP1α, macrophage inflammatory protein; CCL2, CCL7, CXCL9, CXCL10, chemokines. • Hyperimmune activation plays key role in severe COVID-19. • IL-6 increase associated with poor prognosis and progression. • IL-6 inhibition may improve patient's conditions. • Treat to target strategy may be applied in COVID-19. Cytokine storm syndrome (CSS) is a severe complication of inflammatory immune diseases or treatment of malignancies; it may also appear during the progression of COVID-19. CSS is caused by dysregulation of the synthesis of cytokines, including pro-inflammatory, regulatory, and anti-inflammatory cytokines and chemokines, leading to pathologic activation of innate and adaptive (Th1 and Th17 mediated) immunity. Interleukin-6 (IL-6) plays an important role in the pathogenesis of CSS. The significant role of IL-6 in pathogenesis of COVID-19 was confirmed in a range of studies, which showed that the plasma concentration of IL-6 was increased in patients with severe COVID-19. Currently, IL-6 inhibitor therapeutics are not yet approved for the treatment of COVID-19; however, these medicines, including tocilizumab (TCZ) are used off-label for the treatment of patients with severe COVID-19, including life-threatening conditions. The role of IL-6 in the pathogenesis of CSS during COVID-19 is important however, a number of related issues are not yet clear. These issues include the indications for treatment with IL-6 inhibitors, as well as the estimation of risk associated with the disease, outcomes, treatment options, and adverse drug reactions. The development of personalized immunomodulatory therapy, with respect to the role of cytokines in pathogenesis, requires the studies that aimed to find other relevant therapeutic targets for the treatment of CSS in patients with COVID-19. These therapeutic targets include inhibition of IL-1, IL-6, TNFα, GM-CSF, IFNγ, IL-17, IL-18, and also activation of the complement system. The challenge of CSS in patients with COVID-19 is identifying the correct scientific targets and developing clinical trials aimed to evaluate the pathogenesis and treat immune-mediated inflammatory diseases (IMIDs). Hopefully, the significant efforts of scientists and physicians across the globe will improve the prognosis in COVID-19 patients and provide useful information on IMIDs required to support the struggle for treating potential viral outbreaks, and treatment of well-known IMIDs. [ABSTRACT FROM AUTHOR]

• Candesartan downregulates expression of many glutamate upregulated genes in cultured neurons. • Glutamate upregulated genes in neurons positively correlate with COVID-19 upregulated genes. • Candesartan gene downregulation negatively correlates with COVID-19 upregulated genes. • Candesartan downregulates genes involved in the COVID-19 cytokine storm. Angiotensin receptor blockers (ARBs) reducing inflammation and protecting lung and brain function, could be of therapeutic efficacy in COVID-19 patients. Using GSEA, we compared our previous transcriptome analysis of neurons injured by glutamate and treated with the ARB Candesartan (GSE67036) with transcriptional signatures from SARS-CoV-2 infected primary human bronchial epithelial cells (NHBE) and lung postmortem (GSE147507), PBMC and BALF samples (CRA002390) from COVID-19 patients. Hundreds of genes upregulated in SARS-CoV-2/COVID-19 transcriptomes were similarly upregulated by glutamate and normalized by Candesartan. Gene Ontology analysis revealed expression profiles with greatest significance and enrichment, including proinflammatory cytokine and chemokine activity, the NF-kappa B complex, alterations in innate and adaptive immunity, with many genes participating in the COVID-19 cytokine storm. There are similar injury mechanisms in SARS-CoV-2 infection and neuronal injury, equally reduced by ARB treatment. This supports the hypothesis of a therapeutic role for ARBs, ameliorating the COVID-19 cytokine storm. [ABSTRACT FROM AUTHOR]

• Propolis, made by bees from bioactive plant resins, has antiviral activity. • Propolis potentially can interfere with host cell invasion by SARS-CoV-2. • Propolis blocks proinflammatory PAK1, a kinase highly expressed in COVID19 patients. • Standardized propolis has consistent properties for lab and clinical research. • Propolis is a safe widely consumed functional food with medicinal properties. Propolis, a resinous material produced by honey bees from plant exudates, has long been used in traditional herbal medicine and is widely consumed as a health aid and immune system booster. The COVID-19 pandemic has renewed interest in propolis products worldwide; fortunately, various aspects of the SARS-CoV-2 infection mechanism are potential targets for propolis compounds. SARS-CoV-2 entry into host cells is characterized by viral spike protein interaction with cellular angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2. This mechanism involves PAK1 overexpression, which is a kinase that mediates coronavirus-induced lung inflammation, fibrosis, and immune system suppression. Propolis components have inhibitory effects on the ACE2, TMPRSS2 and PAK1 signaling pathways; in addition, antiviral activity has been proven in vitro and in vivo. In pre-clinical studies, propolis promoted immunoregulation of pro-inflammatory cytokines, including reduction in IL-6, IL-1 beta and TNF-α. This immunoregulation involves monocytes and macrophages, as well as Jak2/STAT3, NF-kB, and inflammasome pathways, reducing the risk of cytokine storm syndrome, a major mortality factor in advanced COVID-19 disease. Propolis has also shown promise as an aid in the treatment of various of the comorbidities that are particularly dangerous in COVID-19 patients, including respiratory diseases, hypertension, diabetes, and cancer. Standardized propolis products with consistent bioactive properties are now available. Given the current emergency caused by the COVID-19 pandemic and limited therapeutic options, propolis is presented as a promising and relevant therapeutic option that is safe, easy to administrate orally and is readily available as a natural supplement and functional food. [ABSTRACT FROM AUTHOR]

• Entecavir and imipenem alleviated LPS-induced cytokine storm syndrome. • Entecavir and imipenem mitigated LPS-induced acute lung injury. • Entecavir and imipenem inhibited LPS-stimulated TNF-α and IL-10 in hPBMC. • Entecavir and imipenem attenuated LPS-activated NF-κB. Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-α using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and imipenem efficiently suppressed the release of inflammatory cytokines by partly intervention of NF-κB activity. The acute lung injury was also alleviated and the survival time was prolonged in mice. In addition, entecavir and imipenem inhibited the release of TNF-α and IL-10 in human peripheral blood mononuclear cells (hPBMCs). Collectively, we proposed that entecavir and imipenem might be candidates for the treatment of CSS. [ABSTRACT FROM AUTHOR]

• Corona Virus Disease 19 (COVID 19) is caused by novel corona virus (nCoV) & leads to respiratory failure in susceptible individuals. • Many drugs have been repurposed and are potentially used either prophylactically or therapeutically throughout the world. • SOLIDARITY trial by WHO promotes clinical trial with respect to four potentially useful repurposed medications. • The drugs mentioned in SOLIDARITY trial are mainly antivirals except for hydroxychloroquine which is an anti-malarial drug. • Convalescent plasma therapy is an evolving therapy based on the principle of passive immunity. • Cytokine storm are believed to lead to deterioration in patients and drugs against the same are also in research. Novel Corona-virus Disease 2019 (nCOVID 19) is caused by a novel virulent corona virus and leads to potentially fatal virulent pneumonia and severe respiratory distress syndrome. It was initially declared as public health emergency if international concern by WHO followed by Pandemic on 12th March 2020. As of 10th April 2020, more than 1.5 million people are affected globally with around 95,000 deaths. Vaccines for this deadly virus are currently under development and many drugs used for other indications have been repurposed and investigated for prophylaxis and treatment of COVID 19. As per SOLIDARITY trial by WHO, some of the most promising candidates include chloroquine phosphate and hydroxychloroquine which are anti-malarial medications, Remdesivir, Lopinavir-Ritonavir combination with or without interferon which are anti-HIV drugs and convalescent plasma therapy. The current evidence of efficacy and ongoing research has been elaborated in the article. Besides, there has been evidence regarding inflammatory pathogenesis of this virus leading to cytokine storm in susceptible individuals. Thus, anti-proinflammatory cytokine drugs like Anakinra and Tocilizumab are undergoing multiple trials and some results are encouraging. Similarly, use of anti-inflammatory cytokines like IL-37 and IL-38 is hypothesised to be useful and is under research. The situation is still evolving and hence there is yet no definitive therapy but to conclude the use of repurposed medications can be a boon till a definitive therapy and vaccines are developed. [ABSTRACT FROM AUTHOR]