COVID-19: Pathogenesis,cytokine storm and therapeutic potential of interferons

The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into an unprecedented global pandemic. Clinical investigations in patients with COVID-19 has shown a strong upregulation of cytokine and interferon production in SARS-CoV2- induced pneumonia, with an associated cytokine storm syndrome. Thus, the identification of existing approved therapies with proven safety profiles to treat hyperinflammation is a critical unmet need in order to reduce COVI-19 associated mortality. To date, no specific therapeutic drugs or vaccines are available to treat COVID-19 patients. This review evaluates several options that have been proposed to control SARS-CoV2 hyperinflammation and cytokine storm, eincluding antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).     

Cardiovascular disease in patients with COVID-19:evidence from cardiovascular pathology to treatment

The coronavirus disease-2019(COVID-19)caused by the novel coronavirus severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has rapidly developed into a gl...     

NK细胞免疫治疗防治COVID-19应用潜力的研究进展

新型冠状病毒肺炎(corona virus disease 2019, COVID-19)作为一种新发型急性呼吸道传染病,目前已对全球公共卫生安全构成严重威胁。严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)感染导致COVID-19重症患者淋巴细胞减少、淋巴细胞功能障碍并引起不可控的炎症反应。由于自然杀伤细胞(natural killer cell, NK细胞)在抗病毒和免疫调节中具有重要作用,以NK细胞为基础的免疫治疗可能是有效抗击COVID-19的治疗策略之一。现就已发表的SARS-CoV-2临床研究报告,整理介绍了该病毒的基本特征及COVID-19患者的主要免疫病理学状态,阐述NK细胞在抗病毒领域的潜在作用机制与研究进展,并对NK细胞防治COVID-19的免疫治疗策略及所面临的问题与挑战作一综述。     

Novel approaches for COVID-19 diagnosis and treatment: a nonsystematic review

Since COVID-19 pandemic has been continuously rising and spreading, several original contributions and review articles on COVID-19 started to appear in the literature. The review articles are mainly focus on the current status of the pandemic along with current status of the corona diagnosis and treatment process. Due to some disadvantages of the currently used methods, the improvement on the novel promising diagnosis and treatment methods of corona virus is very important issue. In this review, after briefly discussing the status of current diagnosis and treatment methods, we present to the scientific community, novel promising methods in the diagnosis and treatment of COVID-19. As with other novel approaches, first, the diagnosis potential of mass spectroscopy and optical spectroscopic methods such as UV/visible, infrared, and Raman spectroscopy coupled with chemometrics will be discussed for the corona virus infected samples based on the relevant literature. In vibrational spectroscopy studies, due to complexity of the data, multivariate analysis methods are also applied to data. The application of multivariate analysis tools that can be used to extract useful information from the data for diagnostic and characterisation purposes is also included in this review. The reviewed methods include hierarchical cluster analysis, principal component analysis, linear and quadratic discriminant analysis, support vector machine algorithm, and one form of neural networks namely deep learning method. Second, novel treatment methods such as photodynamic therapy and the use of nanoparticles in the in-corona virus therapy will be discussed. Finally, the advantages of novel promising diagnosis and treatment methods in COVID-19, over standard methods will be discussed. One of the main aims of this paper is to encourage the scientific community to explore the potential of this novel tools for their use in corona virus characterization, diagnosis, and treatment.     

Cyanobacteria: potential candidates for drug discovery

Cyanobacteria are a rich source of vast array of bioactive molecules including toxins with wide pharmaceutical importance. They show varied bioactivities like antitumor, antiviral, antibacterial, antifungal, antimalarial, antimycotics, antiproliferative, cytotoxicity, immunosuppressive agents and multi-drug resistance reversers. A number of techniques are now developed and standardized for the extraction, isolation, detection and purification of cyanobacterial bioactive molecules. Some of the compounds are showing interesting results and have successfully reached to phase II and phase III of clinical trials. These compounds also serve as lead compounds for the development of synthetic analogues with improved bioactivity. Cyanobacterial bioactive molecules hold a bright and promising future in scientific research and great opportunity for drug discovery. This review mainly focuses on anticancerous, antiviral and antibacterial compounds from cyanobacteria; their clinical status; extraction and detection techniques.     

No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination

The impact of Coronavirus Disease 2019 (COVID-19) mRNA vaccination on pregnancy and fertility has become a major topic of public interest. We investigated 2 of the most widely propagated claims to determine (1) whether COVID-19 mRNA vaccination of mice during early pregnancy is associated with an increased incidence of birth defects or growth abnormalities; and (2) whether COVID-19 mRNA-vaccinated human volunteers exhibit elevated levels of antibodies to the human placental protein syncytin-1. Using a mouse model, we found that intramuscular COVID-19 mRNA vaccination during early pregnancy at gestational age E7.5 did not lead to differences in fetal size by crown-rump length or weight at term, nor did we observe any gross birth defects. In contrast, injection of the TLR3 agonist and double-stranded RNA mimic polyinosinic-polycytidylic acid, or poly(I:C), impacted growth in utero leading to reduced fetal size. No overt maternal illness following either vaccination or poly(I:C) exposure was observed. We also found that term fetuses from these murine pregnancies vaccinated prior to the formation of the definitive placenta exhibit high circulating levels of anti-spike and anti-receptor-binding domain (anti-RBD) antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) consistent with maternal antibody status, indicating transplacental transfer in the later stages of pregnancy after early immunization. Finally, we did not detect increased levels of circulating anti-syncytin-1 antibodies in a cohort of COVID-19 vaccinated adults compared to unvaccinated adults by ELISA. Our findings contradict popular claims associating COVID-19 mRNA vaccination with infertility and adverse neonatal outcomes.

The impact of COVID-19 mRNA vaccination on pregnancy and fertility has become a major topic of public interest. This study shows that after inoculation of pregnant mice with COVID mRNA vaccines, no birth defects or growth restrictions were found, and no induction of anti-syncytin-1 antibodies was detected in a longitudinal human cohort compared to unvaccinated volunteers.     

Synthesis of new praziquantel analogues: potential candidates for the treatment of schistosomiasis

An efficient synthesis of antischistosomal drug praziquantel and analogues was achieved and the synthetic route designed was to afford structurally diverse analogues for better structure-activity relationship understanding. Total of nineteen PZQ analogues with structural variations at amide, piperazine and aromatic moieties have been synthesized and fully characterized. Among all the new analogues tested for antischistosomal activity, one dimethoxy tetrahydroisoquinoline analogue and two tetrahydro-β-carboline analogues exhibited moderate activity against adult Schistosoma mansoni. Tetrahydro-β-carboline analogues showed moderate activity whereas the presence of p-trifluoromethylbenzoyl and p-toluenesulphonyl moieties resulted in complete suppression of antischistosomal activity.     

Paclitaxel C-10 carbamates: potential candidates for the treatment of neurodegenerative tauopathies

A series of paclitaxel C-10 carbamates was synthesized and evaluated in a bi-directional permeability assay in comparison with paclitaxel and the blood-brain barrier-permeable C-10 ester derivative, TX-67. A number of the carbamates were found not to be substrates for Pgp. Moreover, when tested for Pgp-inhibitory potential, representative compounds proved to be devoid of Pgp interactions. Side-by-side comparison between TX-67 and the corresponding C-10 carbamate, CNDR-3, revealed a significantly longer half-life for CNDR-3 in both mouse and human plasma, suggesting that this class of derivatives is appropriate for further in vivo evaluation.     

氯雷他定的生物信息学分析及其对COVID-19的潜在治疗意义

为探讨氯雷他定对新型冠状病毒肺炎的潜在治疗作用.从基因表达谱数据库(Gene expression omnibus,GEO)获取氯雷他定数据,分别进行差异分析、基因本体学(GO)富集分析、京都基因与基因组百科全书(KEGG)富集分析、蛋白质相互作用(Protein-protein interaction,PPI)网络分...     

Mesenchymal stromal cell delivery as a potential therapeutic strategy against COVID-19: Promising evidence from in vitro results

BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic, which was initiated in December 2019. COVID-19 is characterized by a low mortality rate (< 6%); however, this percentage is higher in elderly people and patients with underlying disorders. COVID-19 is characterized by mild to severe outcomes. Currently, several therapeutic strategies are evaluated, such as the use of anti-viral drugs, prophylactic treatment, monoclonal antibodies, and vaccination. Advanced cellular therapies are also investigated, thus representing an additional therapeutic tool for clinicians. Mesenchymal stromal cells (MSCs), which are known for their immunoregulatory properties, may halt the induced cytokine release syndrome mediated by SARS-CoV-2, and can be considered as a potential stem cell therapy.AIMTo evaluate the immunoregulatory properties of MSCs, upon stimulation with COVID-19 patient serum. METHODSMSCs derived from the human Wharton’s Jelly (WJ) tissue and bone marrow (BM) were isolated, cryopreserved, expanded, and defined according to the criteria outlined by the International Society for Cellular Therapies. Then, WJ and BM-MSCs were stimulated with a culture medium containing 15% COVID-19 patient serum, 1% penicillin-streptomycin, and 1% L-glutamine for 48 h. The quantification of interleukin (IL)-1 receptor a (Ra), IL-6, IL-10, IL-13, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF)-a, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and indoleamine-2,3-dioxygenase (IDO) was performed using commercial ELISA kits. The expression of HLA-G1, G5, and G7 was evaluated in unstimulated and stimulated WJ and BM-MSCs. Finally, the interactions between MSCs and patients’ macrophages were established using co-culture experiments.RESULTSThawed WJ and BM-MSCs exhibited a spindle-shaped morphology, successfully differentiated to “osteocytes”, “adipocytes”, and “chondrocytes”, and in flow cytometric analysis were characterized by positivity for CD73, CD90, and CD105 (> 95%) and negativity for CD34, CD45, and HLA-DR (< 2%). Moreover, stimulated WJ and BM-MSCs were characterized by increased cytoplasmic granulation, in comparison to unstimulated cells. The HLA-G isoforms (G1, G5, and G7) were successfully expressed by the unstimulated and stimulated WJ-MSCs. On the other hand, only weak expression of HLA-G1 was identified in BM-MSCs. Stimulated MSCs secreted high levels of IL-1Ra, IL-6, IL-10, IL-13, TGF-β1, FGF, VEGF, PDGF, and IDO in comparison to unstimulated cells (P < 0.05) after 12 and 24 h. Finally, macrophages derived from COVID-19 patients successfully adapted the M2 phenotype after co-culturing with stimulated WJ and BM-MSCs.CONCLUSIONWJ and BM-MSCs successfully produced high levels of immunoregulatory agents, which may efficiently modulate the over-activated immune responses of critically ill COVID-19 patients.     

Structure-guided antibody cocktail for prevention and treatment of COVID-19

Development of effective therapeutics for mitigating the COVID-19 pandemic is a pressing global need. Neutralizing antibodies are known to be effective antivirals, as they can be rapidly deployed to prevent disease progression and can accelerate patient recovery without the need for fully developed host immunity. Here, we report the generation and characterization of a series of chimeric antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Some of these antibodies exhibit exceptionally potent neutralization activities in vitro and in vivo, and the most potent of our antibodies target three distinct non-overlapping epitopes within the RBD. Cryo-electron microscopy analyses of two highly potent antibodies in complex with the SARS-CoV-2 spike protein suggested they may be particularly useful when combined in a cocktail therapy. The efficacy of this antibody cocktail was confirmed in SARS-CoV-2-infected mouse and hamster models as prophylactic and post-infection treatments. With the emergence of more contagious variants of SARS-CoV-2, cocktail antibody therapies hold great promise to control disease and prevent drug resistance.     

Phytomelatonin: a potential phytotherapeutic intervention on COVID-19-exposed individuals

Phytomelatonin is a pleiotropic molecule that originated in higher plants with many diverse actions and is primarily an antioxidant. The recent identification and advancement of phytomelatonin unraveled the potential of this modulatory molecule being considered a new plant hormone, suggesting its relevance in treating respiratory infections, including COVID-19. Besides, this molecule is also involved in multiple hormonal, physiological, and biological processes at different levels of cell organization and has been marked for its ability to cross the blood-brain barrier and prominent antioxidant effects, reducing mitochondrial electron leakage, up-regulating antioxidant enzymes, acting as a free radical scavenger, and interfering with pro-inflammatory signaling pathways as seen in mood swings, body temperature, sleep, cancer, cardiac rhythms, and immunological regulation modulators. However, due to its diversity, availability, affordability, convenience, and high safety profile, phytomelatonin has also been suggested as a natural adjuvant. This review discussed the origin, content in various plant species, processes of extraction, and detection and therapeutic potentials of phytomelatonin in treating COVID-19-exposed individuals.     

Protease-activated receptor 1 as a potential therapeutic target for COVID-19

Acute respiratory disease caused by a novel coronavirus (SARS-CoV-2) has spread all over the world, since its discovery in 2019, Wuhan, China. This disease is called COVID-19 and already killed over 1 million people worldwide. The clinical symptoms include fever, dry cough, dyspnea, headache, dizziness, generalized weakness, vomiting, and diarrhea. Unfortunately, so far, there is no validated vaccine, and its management consists mainly of supportive care. Venous thrombosis and pulmonary embolism are highly prevalent in patients suffering from severe COVID-19. In fact, a prothrombotic state seems to be present in most fatal cases of the disease. SARS-CoV-2 leads to the production of proinflammatory cytokines, causing immune-mediated tissue damage, disruption of the endothelial barrier, and uncontrolled thrombogenesis. Thrombin is the key regulator of coagulation and fibrin formation. In severe COVID-19, a dysfunctional of physiological anticoagulant mechanisms leads to a progressive increase of thrombin activity, which is associated with acute respiratory distress syndrome development and a poor prognosis. Protease-activated receptor type 1 (PAR1) is the main thrombin receptor and may represent an essential link between coagulation and inflammation in the pathophysiology of COVID-19. In this review, we discuss the potential role of PAR1 inhibition and regulation in COVID-19 treatment.     

mRNA vaccines for COVID-19: what,why and how

The Coronavirus disease-19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2), has impacted human lives in the most profound ways with millions of infections and deaths. Scientists and pharmaceutical companies have been in race to produce vaccines against SARS-CoV-2. Vaccine generation usually demands years of developing and testing for efficacy and safety. However, it only took less than one year to generate two mRNA vaccines from their development to deployment. The rapid production time, cost-effectiveness, versatility in vaccine design, and clinically proven ability to induce cellular and humoral immune response have crowned mRNA vaccines with spotlights as most promising vaccine candidates in the fight against the pandemic. In this review, we discuss the general principles of mRNA vaccine design and working mechanisms of the vaccines, and provide an up-to-date summary of pre-clinical and clinical trials on seven anti-COVID-19 mRNA candidate vaccines, with the focus on the two mRNA vaccines already licensed for vaccination. In addition, we highlight the key strategies in designing mRNA vaccines to maximize the expression of immunogens and avoid intrinsic innate immune response. We also provide some perspective for future vaccine development against COVID-19 and other pathogens.     

Capivasertib restricts SARS-CoV-2 cellular entry: a potential clinical application for COVID-19

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to more than 150 million infections and about 3.1 million deaths up to date. Currently, drugs screened are urgently aiming to block the infection of SARS-CoV-2. Here, we explored the interaction networks of kinase and COVID-19 crosstalk, and identified phosphoinositide 3-kinase (PI3K)/AKT pathway as the most important kinase signal pathway involving COVID-19. Further, we found a PI3K/AKT signal pathway inhibitor capivasertib restricted the entry of SARS-CoV-2 into cells under non-cytotoxic concentrations. Lastly, the signal axis PI3K/AKT/FYVE finger-containing phosphoinositide kinase (PIKfyve)/PtdIns(3,5)P2 was revealed to play a key role during the cellular entry of viruses including SARS-CoV-2, possibly providing potential antiviral targets. Altogether, our study suggests that the PI3K/AKT kinase inhibitor drugs may be a promising anti-SARS-CoV-2 strategy for clinical application, especially for managing cancer patients with COVID-19 in the pandemic era.