A hypothesis that Notopterol may be effective in COVID-19 via JAK/STAT and other signaling pathways.

COVID-19 is a rapidly spreading disease, causing a global pandemic. It is circulating in multiple countries and causing a series of respiratory infections. Due to the uncertain safety and efficacy of the vaccines and lack of specific medicines, it's important to investigate new pharmacological procedures and find out new drugs that help us eradicate this pandemic. We suggest the hypothesis that Notopterol (NOT), the main Secondary metabolite of Notopterygium incisum Ting ex H.T (a common Chinese medicinal herb), may have the potential benefits on SARS-CoV2 infection for this reasons: (a) NOT exhibits anti-inflammatory, anticancer, and anti-angiogenic properties, (b) NOT indicates a significant reduction in cytokines and chemokines releasing including TNFa, IL-6, interferon-γ, which may decrease COVID-19 cytokine storm (c) NOT can suppress the expression of genes which leads to inflammation via Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway. It is exactly acting like tocilizumab, (an approved drug against COVID-19) and (d) Notopterygium incisum has antiviral activity against influenza virus, it can reduce the viral-induced oxidative stress. By these explanations, it is hopeful that NOT may be effective in COVID-19 infections which needs further investigations to examine Notopterol as a beneficial agent against the SARS-CoV2 infection.

Therapeutic implications of current Janus kinase inhibitors as anti-COVID agents: A review.

Severe cases of COVID-19 are characterized by hyperinflammation induced by cytokine storm, ARDS leading to multiorgan failure and death. JAK-STAT signaling has been implicated in immunopathogenesis of COVID-19 infection under different stages such as viral entry, escaping innate immunity, replication, and subsequent inflammatory processes. Prompted by this fact and prior utilization as an immunomodulatory agent for several autoimmune, allergic, and inflammatory conditions, Jakinibs have been recognized as validated small molecules targeting the rapid release of proinflammatory cytokines, primarily IL-6, and GM-CSF. Various clinical trials are under investigation to evaluate Jakinibs as potential candidates for treating COVID-19. Till date, there is only one small molecule Jakinib known as baricitinib has received FDA-approval as a standalone immunomodulatory agent in treating critical COVID-19 patients. Though various meta-analyses have confirmed and validated the safety and efficacy of Jakinibs, further studies are required to understand the elaborated pathogenesis of COVID-19, duration of Jakinib treatment, and assess the combination therapeutic strategies. In this review, we highlighted JAK-STAT signalling in the pathogenesis of COVID-19 and clinically approved Jakinibs. Moreover, this review described substantially the promising use of Jakinibs and discussed their limitations in the context of COVID-19 therapy. Hence, this review article provides a concise, yet significant insight into the therapeutic implications of Jakinibs as potential anti-COVID agents which opens up a new horizon in the treatment of COVID-19, effectively.

Cytokine nanosponges suppressing overactive macrophages and dampening systematic cytokine storm for the treatment of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction. Inspired by macrophage membranes harbor the receptors with special high affinity for proinflammation cytokines, lipopolysaccharide (LPS)-stimulated macrophage membrane-coated nanoparticles (LMNP) were developed to show strong sponge ability to both IFN-γ and IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo. Besides, LMNP also efficiently alleviated HLH-related symptoms including cytopenia, hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models. Furthermore, its sponge effect also worked well for five human HLH samples in vitro. Altogether, it's firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation, which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.

Therapeutic and anti-inflammatory effects of baricitinib on mortality, ICU transfer, clinical improvement, and CRS-related laboratory parameters of hospitalized patients with moderate to severe COVID-19 pneumonia: a systematic review and meta-analysis.

BACKGROUND: Due to the high incidence and mortality of the worldwide COVID-19 pandemic, beneficial effects of effective antiviral and anti-inflammatory drugs used in other diseases, especially rheumatic diseases, were observed in the treatment of COVID-19. METHODS: Clinical and laboratory parameters of eight included cohort studies and five Randomized Control Trials between the baricitinib group and the control group were analyzed on the first day of admission and days 7, 14, and 28 during hospitalization. RESULTS: According to the meta-analysis result of eight included cohort studies with 2088 patients, the Pooled Risk Ratios were 0.46 (P < 0.001) for mortality, 6.14 (P < 0.001) for hospital discharge, and the mean differences of 76.78 (P < 0.001) for PaO2/FiO2 ratio was -47.32 (P = 0.02) for CRP, in the baricitinib group vs. control group on the seventh or fourteenth day of the treatment compared to the first day. Based on the meta-analysis of five RCT studies with 11,825 patients, the pooled RR was 0.84 (P = 0.001) for mortality and 1.07 (P = 0.014) for patients' recovery. The mean differences were -0.80 (P < 0.001) for hospitalization days, -0.51(P = 0.33) for time to recovery in the baricitinib group vs. control group. CONCLUSIONS: Baricitinib prescription is strongly recommended in moderate to severe COVID-19.

Porcine epidemic diarrhea virus strain FJzz1 infection induces type I/III IFNs production through RLRs and TLRs-mediated signaling.

Interferons (IFNs) including type I/III IFNs are the major components of the host innate immune response against porcine epidemic diarrhea virus (PEDV) infection, and several viral proteins have been identified to antagonize type I/III IFNs productions through diverse strategies. However, the modulation of PEDV infection upon the activation of the host's innate immune response has not been fully characterized. In this study, we observed that various IFN-stimulated genes (ISGs) were upregulated significantly in a time- and dose-dependent manner in LLC-PK1 cells infected with the PEDV G2 strain FJzz1. The transcriptions of IRF9 and STAT1 were increased markedly in the late stage of FJzz1 infection and the promotion of the phosphorylation and nuclear translocation of STAT1, implicating the activation of the JAK-STAT signaling pathway during FJzz1 infection. In addition, abundant type I/III IFNs were produced after FJzz1 infection. However, type I/III IFNs and ISGs decreased greatly in FJzz1-infected LLC-PK1 cells following the silencing of the RIG-I-like receptors (RLRs), including RIG-I and MDA5, and the Toll-like receptors (TLRs) adaptors, MyD88 and TRIF. Altogether, FJzz1 infection induces the production of type-I/III IFNs in LLC-PK1 cells, in which RLRs and TLRs signaling pathways are involved, followed by the activation of the JAK-STAT signaling cascade, triggering the production of numerous ISGs to exert antiviral effects of innate immunity.

Janus kinase inhibitors in dermatology: Part II. A comprehensive review.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) intracellular signaling pathway is implicated in the pathogenesis of a number of inflammatory dermatoses. Clinical trials and other studies have demonstrated the efficacy of JAK inhibitors in the treatment of a variety of dermatologic conditions. Here we review JAK inhibitors currently under investigation for the treatment of alopecia areata, vitiligo, sarcoidosis, necrobiosis lipoidica, granuloma annulare, and systemic lupus erythematosus with a special emphasis on safety and the implications of JAK inhibitors during the novel coronavirus 2019 pandemic.

SARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway.

SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we generated a panel of phenotypically diverse, SARS-CoV-2-infectible human cell lines representing different body organs and performed longitudinal survey of cellular proteins and pathways broadly affected by the virus. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cells and primary-like cardiomyocytes, and found that SARS-CoV-2 targeted the proximal pathway components, including Janus kinase 1 (JAK1), tyrosine kinase 2 (Tyk2), and the interferon receptor subunit 1 (IFNAR1), resulting in cellular desensitization to type I IFN. Detailed mechanistic investigation of IFNAR1 showed that the protein underwent ubiquitination upon SARS-CoV-2 infection. Furthermore, chemical inhibition of JAK kinases enhanced infection of stem cell-derived cultures, indicating that the virus benefits from inhibiting the JAK-STAT pathway. These findings suggest that the suppression of interferon signaling is a mechanism widely used by the virus to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19. IMPORTANCE SARS-CoV-2 can infect various organs in the human body, but the molecular interface between the virus and these organs remains unexplored. In this study, we generated a panel of highly infectible human cell lines originating from various body organs and employed these cells to identify cellular processes commonly or distinctly disrupted by SARS-CoV-2 in different cell types. One among the universally impaired processes was interferon signaling. Systematic analysis of this pathway in diverse culture systems showed that SARS-CoV-2 targets the proximal JAK-STAT pathway components, destabilizes the type I interferon receptor though ubiquitination, and consequently renders the infected cells resistant to type I interferon. These findings illuminate how SARS-CoV-2 can continue to propagate in different tissues even in the presence of a disseminated innate immune response.

Measurement of Cellular Immune Response to Viral Infection and Vaccination.

Combined cellular and humoral host immune response determine the clinical course of a viral infection and effectiveness of vaccination, but currently the cellular immune response cannot be measured on simple blood samples. As functional activity of immune cells is determined by coordinated activity of signaling pathways, we developed mRNA-based JAK-STAT signaling pathway activity assays to quantitatively measure the cellular immune response on Affymetrix expression microarray data of various types of blood samples from virally infected patients (influenza, RSV, dengue, yellow fever, rotavirus) or vaccinated individuals, and to determine vaccine immunogenicity. JAK-STAT1/2 pathway activity was increased in blood samples of patients with viral, but not bacterial, infection and was higher in influenza compared to RSV-infected patients, reflecting known differences in immunogenicity. High JAK-STAT3 pathway activity was associated with more severe RSV infection. In contrast to inactivated influenza virus vaccine, live yellow fever vaccine did induce JAK-STAT1/2 pathway activity in blood samples, indicating superior immunogenicity. Normal (healthy) JAK-STAT1/2 pathway activity was established, enabling assay interpretation without the need for a reference sample. The JAK-STAT pathway assays enable measurement of cellular immune response for prognosis, therapy stratification, vaccine development, and clinical testing.

Screening of JAK-STAT modulators from the antiviral plants of Indian traditional system of medicine with the potential to inhibit 2019 novel coronavirus using network pharmacology.

The majority of the bioactives under investigation were predicted to target TNF receptor-associated factor 5 in the Janus kinase/signal transducers and activators of the transcription pathway. Similarly, druglikeness prediction identified vitexilactone to possess the highest druglikeness score, i.e., 0.88. Furthermore, proteins targeted in the Janus kinase/signal transducers and activators of transcription pathway were also predicted to regulate multiple pathways, i.e., ErbB, AGE-RAGE, NF-kappa B, Measles, insulin, mTOR, chemokine, Ras, and pathways associated with infectious and non-infectious pathogenesis, where the immune system is compromised. Similarly, the docking study identified sesaminol 2-O-ß-D-gentiobioside to possess the highest binding affinity with 3CLpro, PLpro, and spike proteins. Furthermore, phylogeny comparison identified the common protein domains with other stains of microbes like murine hepatitis virus strain A59, avian infectious bronchitis virus, and porcine epidemic diarrhea virus CV777.

Activation of the SARS-CoV-2 Receptor Ace2 through JAK/STAT-Dependent Enhancers during Pregnancy.

ACE2 binds the coronavirus SARS-CoV-2 and facilitates its cellular entry. Interferons activate ACE2 expression in pneumocytes, suggesting a critical role of cytokines in SARS-CoV-2 target cells. Viral RNA was detected in breast milk in at least seven studies, raising the possibility that ACE2 is expressed in mammary tissue during lactation. Here, we show that Ace2 expression in mouse mammary tissue is induced during pregnancy and lactation, which coincides with the activation of intronic enhancers. These enhancers are occupied by the prolactin-activated transcription factor STAT5 and additional regulatory factors, including RNA polymerase II. Deletion of Stat5a results in decommissioning of the enhancers and an 83% reduction of Ace2 mRNA. We also demonstrate that Ace2 expression increases during lactation in lung, but not in kidney and intestine. JAK/STAT components are present in a range of SARS-CoV-2 target cells, opening the possibility that cytokines contribute to the viral load and extrapulmonary pathophysiology.

Activation of the SARS-CoV-2 Receptor Ace2 by Cytokines Through Pan JAK-STAT Enhancers.

ACE2, in concert with the protease TMPRSS2, binds the novel coronavirus SARS-CoV-2 and facilitates its cellular entry. The ACE2 gene is expressed in SARS-CoV-2 target cells, including Type II Pneumocytes (Ziegler, 2020), and is activated by interferons. Viral RNA was also detected in breast milk (Wu et al., 2020), raising the possibility that ACE2 expression is under the control of cytokines through the JAK-STAT pathway. Here we show that Ace2 expression in mammary tissue is induced during pregnancy and lactation, which coincides with the establishment of a candidate enhancer. The prolactin-activated transcription factor STAT5 binds to tandem sites that coincide with activating histone enhancer marks and additional transcription components. The presence of pan JAK-STAT components in mammary alveolar cells and in Type II Pneumocytes combined with the autoregulation of both STAT1 and STAT5 suggests a prominent role of cytokine signaling pathways in cells targeted by SARS-CoV-2. Funding: This work was supported by the Intramural Research Program (IRP) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)and utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov) Declaration of Interest: The authors declare not competing interests.

The potential of JAK/STAT pathway inhibition by ruxolitinib in the treatment of COVID-19.

Ruxolitinib is the first approved JAK1 and JAK2 inhibitor, and is known to interfere with the JAK / STAT signaling pathway, one of the critical cellular signaling pathways involved in the inflammatory response. This review presents an overview of SARS-CoV-2 and the COVID-19 pandemic, and then focuses on the potential efficacy of ruxolitinib in this infection. The potential targets of ruxolitinib were determined by using genetic alterations that have been reported in COVID-19 patients. The potential effectiveness of ruxolitinib is suggested by evaluating the interactions of these potential targets with ruxolitinib or JAK/STAT pathway.

JAK Inhibition as a New Treatment Strategy for Patients with COVID-19.

After the advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the outbreak of coronavirus disease 2019 (COVID-19) commenced across the world. Understanding the Immunopathogenesis of COVID-19 is essential for interrupting viral infectivity and preventing aberrant immune responses before a vaccine can be developed. In this review, we provide the latest insights into the roles of angiotensin-converting enzyme II (ACE2) and Ang II receptor-1 (AT1-R) in this disease. Novel therapeutic strategies, including recombinant ACE2, ACE inhibitors, AT1-R blockers, and Ang 1-7 peptides, may prevent or reduce viruses-induced pulmonary, cardiac, and renal injuries. However, more studies are needed to clarify the efficacy of these therapeutics. Furthermore, considering the common role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in AT1-R expressed on peripheral tissues and cytokine receptors on the surface of immune cells, potential targeting of this pathway using JAK inhibitors (JAKinibs) is suggested as a promising approach in patients with COVID-19 who are admitted to hospitals. In addition to antiviral therapy, potential ACE2- and AT1-R-inhibiting strategies, and other supportive care, we suggest other potential JAKinibs and novel anti-inflammatory combination therapies that affect the JAK-STAT pathway in patients with COVID-19. Since the combination of MTX and baricitinib leads to outstanding clinical outcomes, the addition of baricitinib to MTX might be a potential strategy.