Background and Purpose: Peptides derived from retroviral envelope proteins have been shown to possess a wide range of immunosuppressive and anti-inflammatory activities. We have previously reported identification of such a peptide derived from the envelope protein coded by a human endogenous retrovirus (HERV). In this study we assessed effects of this peptide treatment on inhibition of immune response in the DSS-induced mice model of colitis. Furthermore, we identified that in vitro the peptide inhibits the KCa3.1 potassium channel, a potential target for therapy of immune diseases. Experimental Approach: We characterized an immunosuppressive peptide ENV59, from a specific HERV envelope protein, in vivo effects on inflammation control in acute colitis mice model and in vitro on the production of pro-inflammatory cytokines. Furthermore, we described in vitro ENV59-GP3 effects with respect to potency of inhibition on KCa3.1 channels and calcium influx. Key Results: ENV59-GP3 peptide treatment showed reduction of the disease score in the DSS-induced acute colitis mice model, which was comparable to effects of the KCa3.1 channel blocker NS6180. Analysis of cytokine production from DSS-mice model treated animals revealed equipotent inhibitory effects of the ENV59-GP3 and NS6180 compounds on the production of IL-6, TNF-α, IL-1β. Patch clamp studies show that the peptide ENV59-GP3 is a blocker of the potassium channel KCa3.1. Conclusion and Implications: Env59-GP3 represents KCa3.1 channel inhibitor underlining the implications of using virus derived channel blockers for treatment of autoimmune diseases. There are no drugs with a similar mechanism of action currently on the market.
Background and Purpose: The Covid-19 is a viral infection classified as a pandemic by the World Health Organization. There is not currently therapy against the Sars-cov-2. We aimed to assess the best drug therapy approach for the management of Covid-19. Experimental Approach: We did a systematic review and meta-analysis of randomized controlled trials of drugs used in patients with Covid-19. We performed research in the PubMed and the Medrxiv. The trials were included if the patients were over 12 years old, diagnosed through the rt-PCR test and who assessed as primary outcomes or decreased mortality, or time to clinical improvement, or hospitalization time. Random-effects meta-analysis was used to pool individual studies. Heterogeneity was assessed using I². The review has been registered on PROSPERO, number 179879. Key Results: Nine trials were included for analysis. Remdesivir, mainly early after the onset of symptoms, led to a reduction in mortality (OR, 0·85; 95% CI, 0·05 to 0·98; P=0·045). Although this meta-analysis did not observe a reduction using dexamethasone, the Recovery Trial indicates that it can be an option for a patient that needs oxygen support. Our study did not demonstrate the efficacy of any treatment to minimize the effects of Covid-19 related to large hospital stay or time to clinical improvement. Conclusion and Implications: Remdesivir is the only drug that can change the course of Covid-19, reducing mortality rates. Despite this result, other studies must evaluate the effectiveness of this and other drugs in the management of Covid-19 mainly studies with robust methods.
Marciano Lee1, Elise Anderson1, Ali Farooq1, Mohammed Yasin1, Yazan Alkawaleet1, Frank Annie2Charleston Area Medical Center, Department of Cardiology, 3200 MacCorkle Ave. SE,Charleston, WV 25304CAMC Health Education and Research Institute, 3200 MacCorkle Ave. SE,Charleston, WV 25304Corresponding:Frank Annie MA; MPA; PhDResearch Scientist (Department of Cardiology)CAMC Health Education and Research Institute3200 MacCorkle Ave. SE,Charleston, WV 25304Cell 304 -395 – 3830Phone 304-388-9921Fax: 304-388-9921Email: [email protected]:COVID-19, GEMFIBROZIL, IMMUNE MODULATING TREATMENTAbstract:The current Covid-19 viral infection has been declared a pandemic causing significant global morbidity and mortality predominantly from the manifestation of severe acute respiratory syndrome (SARS). It has been designated as SARS-CoV 2. Epidemiological studies show predilection in patients with associated chronic medical conditions including those with cardiovascular disease. Exaggerated host immune response known as cytokine storm syndrome (CSS) leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is the proposed mechanism for the development of SARS in Covid-19 infection. Gemfibrozil has proven benefits in patients with cardiovascular disease. More importantly, it has established anti-inflammatory, anti-oxidative, and anti-migratory properties. Gemfibrozil has shown survival benefits as immune modulation of ALI/ARDS from viral pathogens. This article reviews the potential of gemfibrozil as adjuntive immue modulating therapy for SARS associated with Covid-19 infected patients who have associated cardiovascular disease.Introduction:The severe acute respiratory syndrome (SARS) seen in Covid-19 infection share similarities with previous coronavirus epidemics, particularly SARS-CoV 1 and the Middle East Respiratory Syndrome (MERS-CoV). (1) It has been designated SARS-CoV 2. Acute lung injury (ALI) with subsequent development of acute respiratory distress syndrome (ARDS) from robust host hyper-immune response is the proposed pathophysiological mechanism. This so called ”cytokine storm” may be independent of viral load and replication. (2) Thus, the rationale for adding immune modulating strategies on top of antiviral/antimicrobial therapies is warranted to prevent this complication and hopefully improve survival. The development of ALI/ARDS amplifies mortality in Covid-19 infection, more so in patients with associated chronic medical conditions including cardiovascular disease. (3)Gemfibrozil, a drug discovered over 40 years ago, have beneficial effects and safety profile in both primary and secondary prevention of cardiovascular disease. (4) In addition to its lipid lowering ability, it has important immune modulating properties that inhibit pro-inflammatory factors involved in cytokine storms.(5) It is a peroxisome proliferators-activated receptor (PPAR) agonist known to reduce the release of inflammatory cytokines including interleukin-6 (IL-6), tumor necrosing factors (TNF) and interferon-gamma (IFN-g).IL-6 elevation have been reported as an important marker of severity with Covid-19 infection. (3) Together with other markers for inflammation such as CRP, the degree of IL-6 elevation correlates with increased morbidity and mortality.Gemfibrozil has shown survival benefits by attenuating ALI/ARDS development from viral etiologies. (6) Since gemfibrozil is currently indicated for patients with cardiovascular disease, its adjunctive use does not have to be repurposed for SARS associated with Covid-19 infection. Therefore, Gemfibrozil’s potential as an immune modulating strategy to prevent ALI/ARDS cannot be ignored.Immune Modulating Targets for Gemfibrozil in Covid-19 SARS pathogenesis:Gemfibrozil has been shown to attenuate pro-inflammatory effects of disease states through its immune-modulating, anti-inflammatory and anti-migratory properties. (5). It belongs to the fibrate family of drugs used to lower plasma lipds and cholesterol. They are one of several known synthetic lignads acting as agonists to the PPARs. (7) Their action in turn decrease serum levels of TNF, IFN-g and IL-6. (8,9)As an an anti-inflammatory, gemfibrozil reduces superoxide production and expression of nuclear factor kB (NF-kB). (10) Moreover, it inhibits astrocyte production of TNF, IL-1b, IL-6 and nitric oxide (NO) production. (11) Gemfibrozil also promotes the production of anti-inflammatory cytokine IL-4. (12) It reduces the production of C-reactive protein (CRP), TNF-a and IL-6 in peripheral blood mononuclear cells. It inhibits the production of cyclooxygenase-2 (COX-2) and prostaglandins. (13)As an immune-modulating agent, gemfibrozil attenuates pro-inflammatory transcription factor activation. This includes IFN-g regulatory factor 1 (IRF-1)bidning to gamma activation site (GAS), nuclear factor-kB (NF-kB), activator protein 1 (AP-1), and CCAT/enhancer binding protein beta (C/EBPb). (5) It also promotes switching of T helper (Th) cells from the pro-inflammatory Th1 to anti-inflammatory Th2. Production of Th2-specific cytokines is amplified including IL-4, IL-5 and IL-10. (14)As an anti-oxidant, gemfibrozil not only prevents low density lipoprotein (LDL) peroxidation but also acts on other signals of inflammation. Reactive oxygen species (ROS) have emerged as important signaling molecules during inflammatory conditions. Excessive ROS generation results in damage to most cellular components of the living organism. Gemfibrozil is known to inhibit ROS-mediated inflammation. (15) It has free radical scavenging ability as well. Its para-hydroxyl metabolite has been shown to reduce the burden of ROS. (16)As an anti-migratory agent, gemfibrozil affects the expression of cell-surface adhesion molecules icluding intracellular adhesion molecule 1 (ICAM-1), VCAM-1 and selectins inhibiting trans endothelial migration of mononuclear cells and macrophages. (17) It also down-regulates the expression of chemokines including monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1), monokines induced by IFN-g (MIG) and IL-8. The expression of IL-8 induces inflammation, monocyte/macrophage recruitment, angiogenesis and vascular smooth muscle migration. Thus, gemfibrozil can function as an anti-migratory factor by down-regulating the expression of different soluble chemokines and inhibit the expression of different cell surface proteins and selectins.Discussion:Over the years, viral pathogens including Influenzas and Coronaviruses cause ALI/ARDS from excessive release of pro-inflammatory cytokines and chemokines described in cytokine storm syndromes. They induce much higher transcription and up regulation of TNF genes including TNF related aptoptosis-inducing lignad and TNF-mRNA in human monocyte-derived macrophages. (18) This macrophage activation syndrome (MAS) seen with the current SARS-CoV 2 may be a dysregulated host response to Covid-19 viral induced immunosuppression and lymphopenia leading to unintended ALI/ARDS consequences at the site of infection. (19) The development of ALI/ARDS and the need for ventilator support portends to increased mortality rates. Markers of inflammation including CRP and IL-6 have been used as surrogates for MAS, and their degree of elevation have correlated well with disease severity. (3)Experiments with SARS-CoV indicate that MAS induced cytokine storms result more from amplification of gene related inflammatory signals regardless of viral load. In one model, immune modulation of receptor sites or alteration of recruitment signals resulted in dramatic improvement in host survival with viral load remaining constant. (20) This suggests that immune modulating therapy may have as important a role in addition to antiviral therapy in altering the course of Covid-19 infection. Reports of clinical improvement have been reported with the adjuvant use of IL-6 antagonists including tocilizumab. However, cost and repurposing use of these medications may be limiting factors.Gemfibrozil has been in clinical use for patients with cardiovascular disease and has achieved generic status. In addition, it has vital immune modulating properties against cytokine storms that mitigate the development of ALI/ARDS from both viral and nonviral pathogens. (21). It not only reduces the levels of IL-6, TNF and IFN-g. But it has also been shown to attneuate gene recruiting signals of inflammation utlizing human equivalent dosing. In one animal study, the adjuvant use of gemfibrozil resulted in enhanced host survival that developed ALI/ARDS from viral pathogens. (6) Enhanced survival is seen even after exposure to the virus. This implies that gemfibrozil has the potential to be a treatment rather than a preventive therapy in human disease.Therefore, the potential of gemfibrozil as adjunct immune modulating therapy in conjunction with antiviral treatment for SARS associated with Covid-19 infection in patients with associated cardiovascular disease is emphasized.References:1. Petrosillo N, Vicenconte G, et al. Covid-19, SARS and MERS: are they closely related? JCMI. 20202. Smits S, Lang A, et al. Exacerbated inane host response to SARS-CoV in aged non-human primates. PLos Patholog. 20103. Zhou F, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with Covid-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020. 3954. Rubins HB, Robins SJ, et al. Gemfibrozil for the secondary prevention of coronary aretery disease inmen with low levels of high-density lipoprotein cholesterol. Veterans Affairs high-density lipoprotein cholesterol intervention trial group. N Engl J Med. 1999. 341: 410-4185. Roy A, Pahan K, et al. Gemfibrozil, stretching the arms beyond lipid lowering. Immunopharmacol Immunotoxicol. 2009. 31: 339-3516. Budd A, Alleva L, et al. Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrobial Agents and Chemotherapy. 2007. 2965-29687. Berger J, Moler DE. The mechanisms of action of PPARs. Annu Rev Med. 53: 409-4358. Madej A, Okopien B, et al. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. Int J Clin Pharmacol. 36: 345-3499. Staels B, Koenig W, et al. Activation of human oartic smooth muscle cells is inhibited by PPARa. Nature. 303: 790-79310. Calkin AC, Cooper KA, et al. Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation. Diabetologia. 49: 766-77411. Xu J, Chavis JA, et al. Gemfibrozil reduces release of tumor necrosis factor-alpha in peripheral blood mononuclear cells from healthy subjects and patients with coronary heart disease. Clin Chem Acta. 332: 61-6712. Lovette-Racke AE, Hussain RZ, et al. Peroxisome proliferator-activated receptor-alpha agonists as therapy for autoimmune diesease. J Immunol. 172: 5790-579813. neve BP, Frutchart JC, et al. Role of PPAR in atherosclerosis. Biochem Pharmacol. 2000. 60: 1245-125014. Heyworth PG, Bohl BP, et al. Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its ineteraction with flavocytochrome b558. J Biol Chem. 1994. 269: 30749-3075215. Aviram M, Rosenblat M, et al. Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation. Ahterosclerosis. 1998. 138: 271-28016. Dasgupta S, Roy A, et al. Gemfibrozil ameliorates relapsing-remitting experimental autoimmune encephalomyelitis of peroxisome proliferator-acivated receptor-alpha. Molecular Pharmacol. 2007. 72: 934-94617. Zhou JF, Law HK, et al. Functional tumor necrosis factor-related apoptosis-inducing ligand production by avian flu influenza virus-infected macrophages. J Infect Dis. 193: 945-95318. Xu J, Shi I, et al. Pathological findings of Covid-19 associated with acute respiratory distress syndrome. Lancet. 2020. Epub ahead of print19. McGonagle D, Sharif K, et al. The role of cytokines including interleukin-6 in Covid-19 induced pneumonia and macrophage activation syndrome-like disease. J AutRev. 2020. 10253720. Channappanavar AR, Fehr R, et al. Dysregulated type 1 interferon and inflammatory monocytes-macrophage responses cause lethal pneumonia in SARS-CoV infected mice. Cell Host Microbe. 2016.19: 181-19321. Kim YS, Kim JK, et al. The peroxisome proliferator-activated receptor-alpha agonist gemfibrozil promotes defense against mycobacterium abcessus infections. Cells. 2020. 9: 648
An abundance of data indicate there are sex differences in endogenous opioid peptides and opioid receptors, leading to functional differences in sensitivity to opioid-mediated behaviors between males and females. Many of these sex differences are mediated by the effects of gonadal hormones on the endogenous opioid system. Whereas much research has examined the role of ovarian hormones on opioid-mediated endpoints, comparatively less research has examined the role of androgens. This review describes what is currently known regarding the influence of androgens on opioid-mediated endpoints and how androgens may contribute to sex differences in opioid-mediated effects. The review also addresses the clinical implications of androgenic modulation of opioid-mediated behaviors and suggests future lines of research for preclinical and clinical investigators, We conclude that further investigation into androgenic modulation of opioid-mediated effects may lead to new options for addressing conditions such as chronic pain and substance use disorders.
Background and Purpose: Coronavirus disease (COVID-19) has resulted in high mortality worldwide. However, information regarding cardiac markers for precise risk-stratification is limited. We aimed to discover a sensitive and reliable early-warning biomarker for optimizing management and improving COVID-19 patients’ prognosis. Experiments Approach: This retrospectively single-center case series was conducted between February 4 and April 10, 2020. 3,046 consecutive COVID-19 patients who were receiving treatment at Wuhan Huoshenshan Hospital in China were included. Serum levels of cardiac markers and coronary artery disease (CAD) diagnosis were collected after admission. Single-cell RNA-sequencing was performed to analyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor expression. Key Results: Median patient age was 60 years; 1,461 (49.5%) were female, and 1,515 (51.3%) were in a severe/critical condition. Compared to mild/moderate patients, severe/critical patients showed significantly higher levels of cardiac markers within the first week after admission. Among severe/critical COVID-19 patients, those with abnormal serum levels of brain natriuretic peptide had a significantly higher mortality than patients with normal levels. Severe/critical COVID-19 patients with pre-existing CAD (165/1,515) had more cases of abnormal brain natriuretic peptide levels than those without CAD. Enhanced SARS-CoV-2 receptor expression was observed in patients with CAD. Regression analysis revealed patients with elevated brain natriuretic peptide were at a higher risk of death. Conclusion and Implications: Brain natriuretic peptide is an effective biomarker for early risk assessment in COVID-19 patients with or without pre-existing CAD. Monitoring BNP status will improve the risk-stratification management and prognosis of patients within one week after admission.
Metabolic stress and associated mitochondrial dysfunction are implicated in retinal degeneration irrespective of the underlying cause. We identified seven unique chemicals from a screen of the Chembridge DiverSET and tested their protection against calcium ionophore and IBMX-induced loss of mitochondrial capacity, as measured by viability and respirometry, in mouse retinal photoreceptor-derived 661W cells. Six of the agents (CB1, 2, 6, 10 11, 12) were protective. Cheminformatic analyses identified a unique pharmacophore with 6 physico-chemical features based on two of the compounds (CB11 and CB12). The protective efficacy of CB11 was further shown by a decrease in the loss of rod photoreceptor cells in retinal explants from two retinitis pigmentosa rodent models, the rd1 mouse and the S334ter-line-3 rat exposed to CB11 in the media. Using eye drops, CB11 biodistribution was confirmed in the retina of the pig eye. The same eye drops decreased photoreceptor cell loss in Balb/c mouse exposed to constant light, a model of age-related macular degeneration. Our studies have identified new chemicals that protect from mitochondrial damage and leads to improved mitochondrial function. Using ex vivo and in vivo models, CB11 decreased the loss of photoreceptor cells in murine models of retinal degeneration and may be effective in the treatment of a wide variety of retinal dystrophies.
BACKGROUND AND PURPOSE Chicken colibacillosis, caused by avian Escherichia coli (APEC), results in huge economic losses to the poultry industry. Baicalin exerts protective effects during the development of colibacillosis. In this study, we mainly explored the mechanism of this protective effects with regard to gut microbiota. EXPERIMENTAL APPROACH The chicken colibacillosis model was established by intratracheal instillation of APEC. The gut microbiota-depleted chicken model was established with broad-spectrum antibiotics. Viscera index measurement and Haematoxylin and eosin stain were applied to assess histological changes of tissues. ELISA were used to measure the cytokines and Quantitative-PCR were used to evaluate the gene expression. The gut microbiota and its metabolite were detected by 16srDNA and ultrahigh-performance liquid chromatography (LC-MS). KEY RESULTS Depletion of gut microbiota exacerbated the tissue damage and weakened the protective effects of baicalin during APEC-induced chicken colibacillosis while pretreatment of baicalin reduced these changes and inflammatory response induced by APEC. Moreover, APEC infection led to dysbiosis of gut microbiota and its metabolites. However, the pretreatment of baicalin remodeled the gut microbiota featured with increased abundance of Intestinimonas and its associated with beneficial metabolites. CONCLUSIONS Gut microbiota played a protective role in the prevention of chicken colibacillosis and the pharmacological action of baicalin. The altered specific gut bacterial and/or metabolites may be served as indicators to predict the occurrence and prognosis of chicken colibacillosis. Our findings may provide a paradigm for the mechanistic studies of compounds and aid the exploration of the mechanisms and pathways underlying the function of herbal medicines.
Endocrine disrupting effects have become a major issue in the field of environmental toxicology. Due to the testicular toxicity reported for acrylamide and confirmed in our study, and the double jeopardy with its well-documented carcinogenicity following leaching out from overcooked starchy foods, the current study was extended to address the possible protective effects of two nutraceuticals. The present study was designed to assess the possible reproductive toxicity of acrylamide in adult male Swiss albino rats. Also, the work was extended to investigate the potential protective effects of two nutraceuticals namely; thymoquinone (TQ) and capsaicin against acrylamide-induced reproductive toxicity. Sixty male albino rats were allotted into six groups. Group 1: Rats received free tap water and served as control group. Group 2: Rats received acrylamide in a daily dose and served as the model. Group 3: Rats were administered TQ twice weekly. Group 4: Rats were administered capsaicin once daily. Group 5: Rats challenged with acrylamide were administered TQ twice weekly. Group 6: Rats challenged with acrylamide were administered capsaicin once daily. A murine model of acrylamide testicular toxicity was reproduced and was characterized biochemically, morphologically and histologically. Acrylamide increased oxidative stress, expression of testicular NF-κB/p65, in addition down regulated the expression of occludin that may further account for its testicular toxicity. Both nutraceuticals; TQ and capsaicin have proven more or less efficacy in ameliorating all the toxic insults exerted by acrylamide in the current reproductive toxicity model. Key words: Testicular failure; Thymoquinone; Capsaicin; Acrylamide; NF-ΚB/P65; Occludin
Background and Purpose: Currently there are no licensed vaccines and limited antivirals for the treatment of COVID-19. Heparin (delivered systemically) is currently being used to treat anticoagulant anomalies in COVID-19 patients. In addition, in the UK, nebulised unfractionated heparin (UFH) is currently being trialled in COVID-19 patients as a potential treatment. A systematic comparison of the potential antiviral effect of various heparin preparations on live wild-type SARS-CoV-2, in vitro, is thus urgently needed. Experimental Approach: A range of heparin preparations both UFH (n=4) and low molecular weight heparins (LMWH) (n=3) of porcine or bovine origin were screened for antiviral activity against live SARS-CoV-2 (Victoria/01/2020) using a plaque reduction neutralisation assay and Vero E6 cells. ND50 values for each heparin were calculated using a mid-point probit analysis. Key Results: UFH had potent antiviral effects, with ND50 values of 12.5 and 23 μg/ml for two porcine mucosal UFH tested. Bovine mucosal UFH had similar antiviral effects although it was ~50% less active (ND50, 50-75 μg/ml). In contrast, LMWHs such as Clexane and Fragmin were markedly less active by ~100-fold (ND50 values of 2.6-6.8 mg/ml). Conclusions and Implications: This comparison of a panel of clinically relevant heparins, including the UFH preparation under trial in the UK, demonstrated that distinct products exhibit different degrees of antiviral activity against live SARS-CoV-2. Porcine mucosal UFH has the strongest antiviral activity followed by bovine mucosal UFH, whereas LMWHs had the lowest amount of antiviral activity (by 100-fold). Overall the data strongly support further clinical investigation of UFH as a potential treatment for patients with COVID-19.
Background and Purpose. Since the onset of COVID-19 many clinical trials of drugs and/or vaccines are continuing and new ones are introduce daily. Yet the international research process failed to develop a preventative vaccine or potent therapeutic drugs for relieving the severity of the disease. Therefore, at present the best recommendation to people to slow the spread of the disease is; please stay at home and maintain social distancing! Experimental approach. Many aspects of pharmacotherapeutic mechanism of action of some previously approved drugs with anti-inflammatory effects, such as colchicine, in various disorders is not fully understood. Therefore, many potential therapeutic uses for these drugs and its analogues can be imagined. In this hypothesis article, an attempt has been made to evaluate some potential therapeutic effects of colchicine that may be benefit against COVID-19. Key Results. Prophylactic therapy with colchicine regulates the innate inflammatory response by blocking intracellular signaling pathways. This can inhibit respiratory alveolar destruction following COVID-19 pneumonia, which is the main cause of ARDS and death in these patients. Conclusion and Implications Since the macrophage and granulocytes are the main pro-inflammatory mediators in the lung, it seems application of therapeutic doses of colchicine, before the onset of respiratory problems, will protect the lung against severe damages and respiratory failure in COVID-19 patients. Obviously, many clinical trials are required to prove the validity of this claim.
Until recently, ibuprofen has been avoided in all COVID-19 protocols world-wide. The author has been trying since March, 2020 to publish a paper that disputes this unfortunate incident and he finally managed since May 2020 to publish two manuscripts that not only prove non-steroidal anti-inflammatory drugs not harmful for COVID-19, rather they were shown to possess a potential to cure the disease based on a unique new theory suggested to explain COVID-19 pathogenesis and he suggested NSAIDs to be added to unique protocol he suggested using nitazoxanide/azithromycin to manage early cases of COVID-19. In this manuscript, considered the fourth related to the subject, the author represents the first clinical results of using NSAIDs/Nitazoxanide/Azithromycin protocol, used partly or fully, that includes relatively cheap FDA approved drugs used in seventeen Egyptian patients, whether confirmed or suspected, including children, adults and two pregnant ladies whom have been mostly symptoms-free in five days. The manuscripts also presents a road-map to illustrate how to deal efficiently with early cases of COVID-19 according to the author’s clinical experience.
Background and Purpose: SARS-coV-2 pandemic continues to cause an unprecedented global destabilization. There is an urgent need to develop vaccines or identify molecules to treat severe cases and repurposing of drugs is the best approach at this hour. Thalidomide, despite having an infamous history has been successfully repurposed and tested for various disease conditions including inflammatory diseases and tumor. Few reports emphasize the use of thalidomide with a SARS-coV-2 pneumonia patient being successfully treated with thalidomide. Experimental Approach: A meta-analysis comparing the transcriptomes of SARS-coV-2 infected tissues with thalidomide and lenalidomide-induced transcriptomic changes in transformed lung, endothelial and hematopoietic models was performed. Key Results: Thalidomide and lenalidomide exhibited pleiotropic effects affecting a range of biological processes including inflammation, immune response, angiogenesis, MAPK signaling, NOD-like receptor signaling, TLR signaling, leukocyte differentiation and innate immunity, the processes which are aberrantly regulated in severe COVID-19 patients. In addition, we show the similarities between the expression profiles of SARS-coV-2 infected lung and systemic lupus erythematous. Conclusion and Implications: The present study recommends thalidomide analogs as a “better fit” to treat severe cases of novel viral infections, healing the damaged network by compensating the impairment caused by the Coronavirus disease-2019 (COVID-19).
The novel coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a serious threat to global public health. Respiratory failure followed by cardiovascular complications with wide-spread endothelial dysfunction and inflammation is rapidly emerging as a key threat in COVID-19. ACE-2 receptors are the cell-entry gate for SARS-CoV-2. Valproic Acid (VPA) is a proposed potential drug to treat COVID-19 but its mechanism of action is not well understood. We demonstrate that VPA-treatment significantly reduced ACE-2 expression in endothelial cells. VPA-treatment significantly reduced the expression of inflammatory cytokines IL-6 along with the endothelial activation marker ICAM-1. We provide evidence and discuss the plausible mechanism in detail for VPA use to prevent and treat COVID-19 in a personalized manner. Our study is expected to entice the scientific and clinical society to investigate VPA as a potential therapeutic option against COVID-19.
SARS-CoV-2 has claimed more than 300,000 lives while infecting 4 million individuals worldwide. There are no specific treatments for COVID-19. Symptoms vary from very mild/asymptomatic to severe, including admission to ICU. Strong sex-bias in COVID-19 have been noted with males showing more than double the odds of requiring ICU admission and higher mortality. Reproductive steroids, including estrogens, progesterone and its physiologically-active metabolite, allopregnanolone exert anti-inflammatory actions and influence the immune system. Intriguingly, pregnant women with COVID-19 appear to experience milder symptoms. In some pregnant women escalated symptoms severity is observed immediately postpartum in coincidence with the rapid hormonal drop associated with parturition. This finding suggests that reproductive steroids’ anti-inflammatory effects and their role in reshaping competence of immune cells may protect during pregnancy. The hypothesis that estradiol, progesterone may provide a treatment against COVID-19 in men and in postmenopausal women is discussed.
The global pandemic from Sars-cov-2 has down caused thousands of deaths worldwide, triggering a health crisis in the various countries involved, with few precedents in history. To date there are no vaccines for prophylaxis, and there are no antivirals directed against the virus. Among the therapeutic options that have shown effectiveness is passive immunization with immune plasma from convalescent patients cured of the infection. Plasma collected from patients cured of Sars-cov-2 infection is rich in antibodies that neutralized the pathogen. Plasma therapy has already demonstrated its efficacy in other epidemics, such as Sars-Cov and MERS. To date, there are limited data for its use in sars-Cov-2 infection, both for prophylaxis and treatment, but the few existing data bode well for the scientific world. Many questions are still unresolved, when to administer it? At what dosage? When is it most appropriate to take the plasma from the cured patient? Are there different answers depending on gender and age? Certainly in view of the high number of patients infected and cured by Sars-Cov-2, there could be a high amount of plasma from donor patients. In this article we want to give an overview on a current and important topic in the perspective of the battle against the new Sars-Cov-2, analysing the therapeutic successes in past epidemics, the clinical data currently available, the future prospect and an expert opinion.
Background and Purpose. Drug resistance is a major problem in cancer treatment with traditional or targeted therapeutics. Gemcitabine, a traditional chemotherapeutics, is approved for several human cancers and the first line treatment for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, gemcitabine resistance is frequently observed and a major problem in successful treatments of these cancers and the mechanism of gemcitabine resistance remains largely unknown. In this study, we aim to seek new and understand the molecule mechanisms of gemcitabine resistance in PDAC. Experimental Approach. Using whole genome Reduced Representation Bisulfite Sequencing analysis, we investigated a gemcitabine resistant PDAC cell line M3K compared with its parental MiaPaCa-2 cells and the resistance revertant cell line Rev followed by detailed analyses of PDGFD in gemcitabine resistance using MTT survival assay, bisulfite sequencing, Western blot, siRNA knockdown and over-expression. Key Results. We found that 65 genes had reversible methylation changes in their promoters in gemcitabine resistant PDAC cells. One of these genes, PDGFD, was further studied in detail for the reversible methylation change in its promoter and shown to reversibly up-regulate in expression, contribute to gemcitabine resistance in vitro and in vivo via activating STAT3 signaling in both autocrine and paracrine manners. Its expression also positively associates with poor outcome of PDAC patients. Conclusion and Implications. Reversible epigenetic regulation may play an important role in gemcitabine resistance and targeting PDGFD signaling may alleviate gemcitabine resistance for PDAC treatment.