Mélatonine: une meilleure immunocompromisation contre le C..

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Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis
Suvojit Hazra Life Sciences Volume 257, 15 September 2020, 118096


Highlights
• Identified differentially expressed genes using microarray data of SARS-CoV patients
• Identification of repurposed drugs in COVID-19
• Network analysis of PPI-CPI interactome to find novel targets
• Identification of chloroquine and melatonin as the repurposed drugs targeting MMP9
• Control of MMP9-induced immunoinflammation in COVID-19

Aims
The molecular pathogenesis of COVID-19 is similar to other coronavirus (CoV) infections viz. severe acute respiratory syndrome (SARS) in human. Due to scarcity of the suitable treatment strategy, the present study was undertaken to explore host protein(s) targeted by potent repurposed drug(s) in COVID-19.

Materials and methods
The differentially expressed genes (DEGs) were identified from microarray data repository of SARS-CoV patient blood. The repurposed drugs for COVID-19 were selected from available literature. Using DEGs and drugs, the protein-protein interaction (PPI) and chemo-protein interaction (CPI) networks were constructed and combined to develop an interactome model of PPI-CPI network. The top-ranked sub-network with its hub-bottleneck nodes were evaluated with their functional annotations.

Key findings
A total of 120 DEGs and 65 drugs were identified. The PPI-CPI network (118 nodes and 293 edges) exhibited a top-ranked sub-network (35 nodes and 174 connectivities) with 12 hub-bottleneck nodes having two drugs chloroquine and melatonin in association with 10 proteins corresponding to six upregulated and four downregulated genes. Two drugs interacted directly with the hub-bottleneck node i.e. matrix metallopeptidase 9 (MMP9), a host protein corresponding to its upregulated gene. MMP9 showed functional annotations associated with neutrophil mediated immunoinflammation. Moreover, literature survey revealed that angiotensin converting enzyme 2, a membrane receptor of SARS-CoV-2 virus, might have functional cooperativity with MMP9 and a possible interaction with both drugs.

Significance
The present study reveals that between chloroquine and melatonin, melatonin appears to be more promising repurposed drug against MMP9 for better immunocompromisation in COVID-19.

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Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): a case series
Adjuvant melatonin treatment in COVID19 pneumonia
Rafael Ricafranca Castillo Melatonin Res., 3 (2020), pp. 297-310

Treatment for coronavirus disease 2019 (COVID19) pneumonia remains empirical and the search for therapies that can improve outcomes continues. Melatonin has been shown to have anti-inflammatory, antioxidant, and immune-modulating effects that may address key pathophysiologic mechanisms in the development and progression of acute respiratory distress syndrome (ARDS), which has been implicated as the likely cause of death in COVID19.

We aimed to describe the observable clinical outcomes and tolerability of high-dose melatonin (hdM) given as adjuvant therapy in patients admitted with COVID19 pneumonia. We conducted a retrospective descriptive case series of patients who: 1) were admitted to the Manila Doctors Hospital in Manila, Philippines, between March 5, 2020 and April 4, 2020; 2) presented with history of typical symptoms (fever, cough, sore throat, loss of smell and/or taste, myalgia, fatigue); 3) had admitting impression of atypical pneumonia; 4) had history and chest imaging findings highly suggestive of COVID19 pneumonia, and, 5) were given hdM as adjuvant therapy, in addition to standard and/or empirical therapy. One patient admitted to another hospital, who one of the authors helped co-manage, was included. He was the lone patient given hdM in that hospital during the treatment period. Main outcomes described were: time to clinical improvement, duration of hospital stay from hdM initiation, need for mechanical ventilation (MV) prior to cardiopulmonary resuscitation, and final outcome (death or recovery/discharge).

Of 10 patients given hdM at doses of 36-72mg/day per os (p.o.) in 4 divided doses as adjuvant therapy, 7 were confirmed COVID19 positive (+) by reverse transcription polymerase chain reaction (RT-PCR) and 3 tested negative (-), which was deemed to be false (-) considering the patients’ typical history, symptomatology, chest imaging findings and elevated bio-inflammatory parameters. In all 10 patients given hdM, clinical stabilization and/or improvement was noted within 4-5 days after initiation of hdM. All hdM patients, including 3 with moderately severe ARDS and 1 with mild ARDS, survived; none required MV. The 7 COVID19(+) patients were discharged at an average of 8.6 days after initiation of hdM. The 3 highly probable COVID19 patients on hdM were discharged at an average of 7.3 days after hdM initiation. Average hospital stay of those not given hdM (non-hdM) COVID19(+) patients who were admitted during the same period and recovered was 13 days. To provide perspective, although the groups are not comparable, 12 of the 34 (35.3%) COVID19(+) non-hdM patients admitted during the same period died, 7/34 (20.6%) required MV; while 6 of 15 (40%) non-hdM (-) by RT-PCR but highly probable COVID19 pneumonia patients also died, 4/15 (26.7%) required MV. No significant side-effects were noted with hdM except for sleepiness, which was deemed favorable by all patients, most of whom had anxiety- and symptom-related sleeping problems previously. HdM may have a beneficial role in patients treated for COVID19 pneumonia, in terms of shorter time to clinical improvement, less need for MV, shorter hospital stay, and possibly lower mortality. HdM was well tolerated.

This is the first report describing the benefits of hdM in patients being treated for COVID19 pneumonia. Being a commonly available and inexpensive sleep-aid supplement worldwide, melatonin may play a role as adjuvant therapy in the global war against COVID19.

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Estimated doses of melatonin for treating deadly virus infections: focus on COVID-19
Melatonin dose and viral infection
Dun-Xian Tan

Increased evidence implies that melatonin may be a promising molecule for combating COVID-19 due to its potent antioxidative, anti-inflammatory and immunoregulatory capacities. A frequently asked question concerns the suitable dosage of melatonin for deadly virus infections including COVID-19 patients. The golden standards for a suitable dosage of medicine are safety and effectiveness. By reviewing the pharmacokinetics as well as animal studies and clinical trials of melatonin in the deadly viral infections and sepsis, we estimate that a dose of 8 mg/kg/day of melatonin is suitable for COVID-19 patients, especially for the severe cases.

To maintain an elevated melatonin serum level lasting longer and smoother, this daily dose can be divided into 5 sub-doses with the initial dose of doubling over the other sub-doses. The recommended dose is in the ranges used to treat septic patients clinically and is devoid of any adverse effect; thus, it is safe.

This dose is calculated from an effective dose which significantly reduces the mortality of virus-infected mice and is, therefore, assumed to be effective for COVID-19 severe patients. In our opinion, a dose or a medicine which can only improve the symptoms of mild or moderately severe patients of COVID-19 lack biological significance since virus infection is a self-limited disease and most of the patients with mild or moderate symptoms will recover by themselves whether treated or not. A meaningful treatment is to target the severe patients and significantly reduce the resulting mortality. The suggested melatonin dose is, thus, mainly recommended for the severe COVID-19 patients. The possibility of using suppositories for the delivery of highly dosed melatonin is also addressed, since long-term experience with this treatment is available for another disease.

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Traduction de l'étude

Estimation des doses de mélatonine pour le traitement des infections virales mortelles: focus sur COVID-19
Dose de mélatonine et infection virale
Dun-Xian Tan

De plus en plus de preuves suggèrent que la mélatonine peut être une molécule prometteuse pour lutter contre le COVID-19 en raison de ses puissantes capacités antioxydantes, anti-inflammatoires et immunorégulatrices. Une question fréquemment posée concerne le dosage approprié de mélatonine pour les infections virales mortelles, y compris les patients COVID-19. Les normes d'or pour un dosage approprié de médicament sont la sécurité et l'efficacité. En passant en revue la pharmacocinétique ainsi que les études animales et les essais cliniques de la mélatonine dans les infections virales mortelles et la septicémie, nous estimons qu'une dose de 8 mg / kg / jour de mélatonine convient aux patients COVID-19, en particulier pour les cas graves.

Pour maintenir un taux sérique de mélatonine élevé pendant plus longtemps et plus régulièrement, cette dose quotidienne peut être divisée en 5 sous-doses, la dose initiale étant doublée par rapport aux autres sous-doses. La dose recommandée se situe dans les plages utilisées pour traiter cliniquement les patients septiques et est exempte de tout effet indésirable; ainsi, il est sûr.

Cette dose est calculée à partir d'une dose efficace qui réduit considérablement la mortalité des souris infectées par le virus et est, par conséquent, supposée efficace pour les patients sévères au COVID-19. À notre avis, une dose ou un médicament qui ne peut qu'améliorer les symptômes des patients légers ou modérément sévères du COVID-19 n'a pas de signification biologique car l'infection virale est une maladie auto-limitée et la plupart des patients présentant des symptômes légers ou modérés se rétablissent en eux-mêmes traités ou non. Un traitement significatif consiste à cibler les patients sévères et à réduire considérablement la mortalité qui en résulte. La dose de mélatonine suggérée est donc principalement recommandée pour les patients atteints de COVID-19 sévère. La possibilité d'utiliser des suppositoires pour l'administration de mélatonine hautement dosée est également envisagée, car une expérience à long terme avec ce traitement est disponible pour une autre maladie.

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Can Melatonin Be a Potential "Silver Bullet" in Treating COVID-19 Patients?
Daniel P Cardinali Diseases . 2020 Nov 26;8(4):44.

The therapeutic potential of melatonin as a chronobiotic cytoprotective agent to counteract the consequences of COVID-19 infections has been advocated. Because of its wide-ranging effects as an antioxidant, anti-inflammatory, and immunomodulatory compound, melatonin could be unique in impairing the consequences of SARS-CoV-2 infection. Moreover, indirect evidence points out to a possible antiviral action of melatonin by interfering with SARS-CoV-2/angiotensin-converting enzyme 2 association.

Melatonin is also an effective chronobiotic agent to reverse the circadian disruption of social isolation and to control delirium in severely affected patients. As a cytoprotector, melatonin serves to combat several comorbidities such as diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases, which aggravate COVID-19 disease. In view of evidence on the occurrence of neurological sequels in COVID-19-infected patients, another putative application of melatonin emerges based on its neuroprotective properties. Since melatonin is an effective means to control cognitive decay in minimal cognitive impairment, its therapeutic significance for the neurological sequels of SARS-CoV-2 infection should be considered. Finally, yet importantly, exogenous melatonin can be an adjuvant capable of augmenting the efficacy of anti-SARS-CoV-2 vaccines.

We discuss in this review the experimental evidence suggesting that melatonin is a potential "silver bullet" in the COVID 19 pandemic.

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Traduction de l'étude

La mélatonine peut-elle être une «balle d'argent» potentielle dans le traitement des patients COVID-19?
Maladies de Daniel P. Cardinali. 26 novembre 2020; 8 (4): 44.

Le potentiel thérapeutique de la mélatonine en tant qu'agent cytoprotecteur chronobiotique pour contrer les conséquences des infections au COVID-19 a été préconisé. En raison de ses effets étendus en tant que composé antioxydant, anti-inflammatoire et immunomodulateur, la mélatonine pourrait être unique pour altérer les conséquences de l'infection par le SRAS-CoV-2. De plus, des preuves indirectes indiquent une possible action antivirale de la mélatonine en interférant avec l'association SARS-CoV-2 / enzyme de conversion 2 de l'angiotensine.

La mélatonine est également un agent chronobiotique efficace pour inverser la perturbation circadienne de l'isolement social et pour contrôler le délire chez les patients gravement atteints. En tant que cytoprotecteur, la mélatonine sert à lutter contre plusieurs comorbidités telles que le diabète, le syndrome métabolique et les maladies cardiovasculaires ischémiques et non ischémiques, qui aggravent la maladie COVID-19. Au vu des preuves sur l'apparition de séquelles neurologiques chez les patients infectés par COVID-19, une autre application putative de la mélatonine émerge sur la base de ses propriétés neuroprotectrices. Étant donné que la mélatonine est un moyen efficace de contrôler la dégradation cognitive en cas de troubles cognitifs minimes, son importance thérapeutique pour les séquelles neurologiques de l'infection par le SRAS-CoV-2 doit être prise en compte. Enfin, mais surtout, la mélatonine exogène peut être un adjuvant capable d'augmenter l'efficacité des vaccins anti-SRAS-CoV-2.

Nous discutons dans cette revue des preuves expérimentales suggérant que la mélatonine est une «solution miracle» potentielle dans la pandémie COVID 19.

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Melatonin multifaceted pharmacological actions on melatonin receptors converging to abrogate COVID‐19
Jessica L. Reynolds Journal of Pineal Research 23 March 2021

Data indicate that controlling inflammatory responses to COVID‐19 may be as important as antiviral therapies or could be an important adjunctive approach. Melatonin possesses anti‐inflammation, antioxidation, and immune‐enhancing features directly and/or indirectly through its own receptor signaling and is therefore well suited to reduce the severity of COVID‐19. Studies have proposed that melatonin regulates COVID‐19–associated proteins directly through regulation of molecules such as calmodulin (CALM) 1 and CALM 2, calreticulin (CalR), or myeloperoxidase (MPO) and/or indirectly through actions on GPCR (eg, MTNR1A, MTNR1B) and nuclear (eg, RORα, RORβ) melatonin receptor signaling. However, the exact mechanism(s) and doses by which melatonin reduces the severity of COVID‐19 is still open for debate, warranting the need for further testing of melatonin in placebo‐controlled randomized clinical trials for COVID‐19.

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CLINICAL TRIALS USING MELATONIN FOR THE TREATMENT OF COVID‐19

Currently, there are 9 clinical trial studies reported in Clinicaltrials.gov database (see https://www.clinicaltrials.gov/ for current studies), proposing melatonin (8) or a melatonin agonist (1) for COVID‐19 treatment in mild‐to‐moderate (4), or severe hospitalized (4), or as a prophylactic indication (1). With the exception of our two randomized, double‐blind, placebo‐controlled studies using melatonin in COVID‐19 outpatients at the University at Buffalo, all the clinical trials listed above are testing combination drug therapy (eg, estrogen, vitamin C, pentoxifylline). It is therefore imperative to design well‐controlled and powered clinical trials to test the hypothesis that melatonin is safe and efficacious to treat COVID‐19. In fact, our study, currently enrolling, assesses the safety and efficacy of melatonin (9, 30, and 90 mg/day in 3 divided doses) in mitigating the COVID‐19. Melatonin, if proven effective in this double‐blind randomized study, could be tested in children and the elderly, as well as under‐represented minorities that are disproportionately affected by COVID‐19, and provide an inexpensive therapy with minimal side effects.

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Traduction de l'étude

ESSAIS CLINIQUES UTILISANT LA MÉLATONINE POUR LE TRAITEMENT DU COVID ‐ 19

Actuellement, il y a 9 études d'essais cliniques rapportées dans la base de données Clinicaltrials.gov (voir https://www.clinicaltrials.gov/ pour les études en cours), proposant de la mélatonine (8) ou un agoniste de la mélatonine (1) pour le traitement COVID-19 -À-modérée (4), ou sévèrement hospitalisée (4), ou en tant qu'indication prophylactique (1). À l'exception de nos deux études randomisées, en double aveugle et contrôlées par placebo utilisant de la mélatonine chez des patients ambulatoires COVID-19 à l'Université de Buffalo, tous les essais cliniques énumérés ci-dessus testent une polythérapie (p. Ex., Œstrogène, vitamine C, pentoxifylline). . Il est donc impératif de concevoir des essais cliniques bien contrôlés et puissants pour tester l'hypothèse selon laquelle la mélatonine est sûre et efficace pour traiter le COVID-19. En fait, notre étude, actuellement en cours de recrutement, évalue l'innocuité et l'efficacité de la mélatonine (9, 30 et 90 mg / jour en 3 doses fractionnées) pour atténuer le COVID-19. La mélatonine, si son efficacité est avérée dans cette étude randomisée en double aveugle, pourrait être testée chez les enfants et les personnes âgées, ainsi que chez les minorités sous-représentées qui sont affectées de manière disproportionnée par le COVID-19, et fournir une thérapie peu coûteuse avec des effets secondaires minimes.

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Role of NLRP3 inflammasome in COVID-19 and periodontitis: Possible protective effect of melatonin
Ahmet Özer Medical Hypotheses Volume 151, June 2021, 110588


Daily new information emerges regarding the COVID-19, infection of SARS-CoV-2, which is considered a global pandemic. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) are required to complete the viral invasion pathway and are present in the oral mucosa, gingiva and periodontal pocket. Thus, increasing the likelihood of periodontitis and gingivitis caused by COVID-19. The cytokine storm during COVID-19 similarly arises during periodontal inflammation.

Studies have reported that NOD-Like Receptor family pyrin domain-containing 3 (NLRP3) inflammasome is significant in the cytokine storm. Recently, the course of the COVID-19 has been related to the melatonin levels in both COVID-19 and periodontal diseases. It is known that melatonin prevents the activation of NLRP3 inflammasome. In light of these findings, we think that melatonin treatment during COVID-19 or periodontal diseases may prevent the damage seen in periodontal tissues by preventing the activation of NLRP3 inflammasome.

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Traduction de l'étude

Rôle de l'inflammasome NLRP3 dans le COVID-19 et la parodontite: effet protecteur possible de la mélatonine
Ahmet Özer Medical Hypotheses Volume 151, juin 2021, 110588


De nouvelles informations émergent quotidiennement concernant le COVID-19, une infection par le SRAS-CoV-2, considérée comme une pandémie mondiale. L'enzyme de conversion de l'angiotensine 2 (ACE2) et la protéase transmembranaire sérine 2 (TMPRSS2) sont nécessaires pour compléter la voie d'invasion virale et sont présentes dans la muqueuse buccale, la gencive et la poche parodontale. Ainsi, augmentant la probabilité de parodontite et de gingivite causées par COVID-19. La tempête de cytokines pendant le COVID-19 se produit de la même manière pendant l'inflammation parodontale.

Des études ont rapporté que l'inflammasome de la famille des récepteurs de type NOD contenant le domaine pyrine 3 (NLRP3) est important dans la tempête des cytokines. Récemment, l'évolution du COVID-19 a été liée aux niveaux de mélatonine dans le COVID-19 et les maladies parodontales. On sait que la mélatonine empêche l'activation de l'inflammasome NLRP3. À la lumière de ces résultats, nous pensons que le traitement à la mélatonine pendant le COVID-19 ou les maladies parodontales peut prévenir les dommages observés dans les tissus parodontaux en empêchant l'activation de l'inflammasome NLRP3.