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1.
Vaccines (Basel) ; 10(7)2022 Jul 08.
Article in English | MEDLINE | ID: covidwho-1928698

ABSTRACT

Type 1 diabetes (T1D), which is caused by the autoimmune destruction of insulin-secreting pancreatic beta cells, represents a high-risk category requiring COVID-19 vaccine prioritization. Although COVID-19 vaccination can lead to transient hyperglycemia (vaccination-induced hyperglycemia; ViHG), its influence on the course of the clinical remission phase of T1D (a.k.a. "honeymoon phase") is currently unknown. Recently, there has been an increasing concern that COVID-19 vaccination may trigger autoimmune phenomena. We describe the case of a 24-year-old young Italian man with T1D who received two doses of the BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine during a prolonged honeymoon phase. He experienced a transient impairment in glucose control (as evidenced by continuous glucose monitoring) that was not associated with substantial changes in stimulated C-peptide levels and islet autoantibody titers. Nonetheless, large prospective studies are needed to confirm the safety and the immunometabolic impact of the BNT162b2 vaccine in T1D patients during the honeymoon phase. Thus far, T1D patients who are going to receive COVID-19 vaccination should be warned about the possible occurrence of transient ViHG and should undergo strict postvaccination surveillance.

2.
Stem Cells Transl Med ; 11(7): 688-703, 2022 Jul 20.
Article in English | MEDLINE | ID: covidwho-1873996

ABSTRACT

MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I  2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I  2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Aged , COVID-19/therapy , Cell- and Tissue-Based Therapy , Female , Humans , Male , Respiratory Distress Syndrome/therapy
3.
Int J Mol Sci ; 23(6)2022 Mar 13.
Article in English | MEDLINE | ID: covidwho-1760647

ABSTRACT

Parkinson's disease (PD) is second-most common disabling neurological disorder worldwide, and unfortunately, there is not yet a definitive way to prevent it. Polyphenols have been widely shown protective efficacy against various PD symptoms. However, data on their effect on physio-pathological mechanisms underlying this disease are still lacking. In the present work, we evaluated the activity of a mixture of polyphenols and micronutrients, named A5+, in the murine neuroblastoma cell line N1E115 treated with 6-Hydroxydopamine (6-OHDA), an established neurotoxic stimulus used to induce an in vitro PD model. We demonstrate that a pretreatment of these cells with A5+ causes significant reduction of inflammation, resulting in a decrease in pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α, and CXCL1), a reduction in ROS production and activation of extracellular signal-regulated kinases (ERK)1/2, and a decrease in apoptotic mechanisms with the related increase in cell viability. Intriguingly, A5+ treatment promoted cellular differentiation into dopaminergic neurons, as evident by the enhancement in the expression of tyrosine hydroxylase, a well-established dopaminergic neuronal marker. Overall, these results demonstrate the synergic and innovative efficacy of A5+ mixture against PD cellular pathological processes, although further studies are needed to clarify the mechanisms underlying its beneficial effect.


Subject(s)
Parkinson Disease , Animals , Disease Models, Animal , Dopaminergic Neurons/metabolism , Mice , Micronutrients/metabolism , Micronutrients/pharmacology , Micronutrients/therapeutic use , Oxidopamine/pharmacology , Parkinson Disease/drug therapy , Parkinson Disease/etiology , Parkinson Disease/metabolism , Polyphenols/metabolism , Polyphenols/pharmacology , Polyphenols/therapeutic use
4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314876

ABSTRACT

Background: Acute Respiratory Distress Syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal Stem Cells (MSC) are potent immunomodulatory cells. The aim of this study was to determine safety and explore efficacy of Umbilical Cord (UC)-MSC infusions in COVID-19 ARDS.Methods: A double-blind, phase 1/2a, randomized, controlled trial was performed in subjects with ARDS secondary to COVID-19, at a single institution in Miami, Florida, USA. Randomization and stratification by ARDS severity was used to foster balance among groups. Participants received two intravenous infusions of 100x106 UC-MSC, or vehicle, at day 0 and 3. The primary endpoint was safety, defined by occurrence of pre-specified infusion associated adverse events, along with adverse events during 28 day follow-up. All subjects were analyzed under an intention to treat design. Exploratory efficacy endpoints included survival at 28 days and time to recovery.Findings: 24 subjects (12 per group) were recruited between April 25 and July 21 2020. At 28 days post last infusion, patient survival was 91% and 42% in the UC-MSC and Control groups, respectively (p=0.015). No serious adverse events (SAEs) were observed related to UC-MSC infusions. There was no observed difference in number of subjects experiencing infusion-associated adverse events. Treatment unrelated SAEs were reported in 2 and 8 patients in the UC-MSC and Control groups, respectively (p=0.04). UC-MSC treatment was associated with increased SAE-free survival (p=0.008) and decreased time to recovery (p=0.03) compared to controls.Interpretation: UC-MSC infusions in COVID-19 subjects with ARDS were safe and associated with fewer SAEs, compared to control. Further, exploratory efficacy analyses provide preliminary evidence of reduction in mortality and time to recovery. Notwithstanding sample size limitations of this trial, the observed findings strongly support further investigation in a larger trial designed to estimate and test for efficacy.Trial Registration: (ClinicalTrials.gov NCT04355728).Funding Statement: The trial was funded by the Barilla Group and Family, The Cure Alliance, the Fondazione Silvio Tronchetti Provera, the Simkins Family Foundation, the North America’s Building Trades Unions, and the Diabetes Research Institute Foundation. This publication was supported by the Clinical Translational Research Site Grants Number UL1TR000460 and UL1TR002736 from the National Center for Advancing Translational Sciences (NCATS).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: Ethics Committee Approval by the regulatory and institutional review boards were obtained by the Western Institutional Review Board (WIRB) and UM Human Subject Research Office/Institutional Review Board, in accordance with local institutional requirements.

5.
Biomedicines ; 9(11)2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1523868

ABSTRACT

Polyphenols have been widely studied for their antiviral effect against respiratory virus infections. Among these, resveratrol (RV) has been demonstrated to inhibit influenza virus replication and more recently, it has been tested together with pterostilbene against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present work, we evaluated the antiviral activity of polydatin, an RV precursor, and a mixture of polyphenols and other micronutrients, named A5+, against influenza virus and SARS-CoV-2 infections. To this end, we infected Vero E6 cells and analyzed the replication of both respiratory viruses in terms of viral proteins synthesis and viral titration. We demonstrated that A5+ showed a higher efficacy in inhibiting both influenza virus and SARS-CoV-2 infections compared to polydatin treatment alone. Indeed, post infection treatment significantly decreased viral proteins expression and viral release, probably by interfering with any step of virus replicative cycle. Intriguingly, A5+ treatment strongly reduced IL-6 cytokine production in influenza virus-infected cells, suggesting its potential anti-inflammatory properties during the infection. Overall, these results demonstrate the synergic and innovative antiviral efficacy of A5+ mixture, although further studies are needed to clarify the mechanisms underlying its inhibitory effect.

6.
Cell Death Dis ; 12(8): 773, 2021 08 05.
Article in English | MEDLINE | ID: covidwho-1345547

ABSTRACT

The pathophysiology of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and especially of its complications is still not fully understood. In fact, a very high number of patients with COVID-19 die because of thromboembolic causes. A role of plasminogen, as precursor of fibrinolysis, has been hypothesized. In this study, we aimed to investigate the association between plasminogen levels and COVID-19-related outcomes in a population of 55 infected Caucasian patients (mean age: 69.8 ± 14.3, 41.8% female). Low levels of plasminogen were significantly associated with inflammatory markers (CRP, PCT, and IL-6), markers of coagulation (D-dimer, INR, and APTT), and markers of organ dysfunctions (high fasting blood glucose and decrease in the glomerular filtration rate). A multidimensional analysis model, including the correlation of the expression of coagulation with inflammatory parameters, indicated that plasminogen tended to cluster together with IL-6, hence suggesting a common pathway of activation during disease's complication. Moreover, low levels of plasminogen strongly correlated with mortality in COVID-19 patients even after multiple adjustments for presence of confounding. These data suggest that plasminogen may play a pivotal role in controlling the complex mechanisms beyond the COVID-19 complications, and may be useful both as biomarker for prognosis and for therapeutic target against this extremely aggressive infection.


Subject(s)
COVID-19/blood , COVID-19/mortality , Plasminogen/analysis , Aged , Aged, 80 and over , Biomarkers/blood , Blood Coagulation , COVID-19/diagnosis , Down-Regulation , Female , Humans , Inflammation Mediators/blood , Male , Middle Aged , Prognosis , Risk Assessment , Risk Factors , Time Factors
7.
Int J Mol Sci ; 22(6)2021 Mar 19.
Article in English | MEDLINE | ID: covidwho-1148303

ABSTRACT

COVID-19 is without any doubt the worst pandemic we have faced since the H1N1 virus outbreak. Even if vaccination against SARS-CoV-2 infection is becoming increasingly available, a more feasible approach for COVID-19 prevention and therapy is still needed. Evidence of a pathological link between metabolic diseases and severe forms of COVID-19 has stimulated critical reflection and new considerations. In particular, an abnormal immune response observed in certain patients with SARS-CoV-2 infection suggested possible common predisposing risk factors with autoimmune diseases such as Type 1 Diabetes (T1D). Correct supplementation with dietary factors may be key to preventing and counteracting both the underlying metabolic impairment and the complications of COVID-19. A set of agents may inhibit the cytokine storm and hypercoagulability that characterize severe COVID-19 infection: vitamin D3, omega-3 polyunsaturated fatty acids, polyphenols like pterostilbene, polydatin and honokiol, which can activate anti-inflammatory and antioxidant sirtuins pathways, quercetin, vitamin C, zinc, melatonin, lactoferrin and glutathione. These agents could be highly beneficial for subjects who have altered immune responses. In this review, we discuss the antiviral and metabolic effects of these dietary factors and propose their combination for potential applications in the prevention and treatment of COVID-19. Rigorous studies will be fundamental for validating preventive and therapeutic protocols that could be of assistance to mitigate disease progression following SARS-CoV-2 infection.


Subject(s)
Autoimmune Diseases/diet therapy , COVID-19/diet therapy , Diet , Metabolic Diseases/diet therapy , Autoimmune Diseases/complications , COVID-19/complications , Cytokine Release Syndrome/diet therapy , Cytokine Release Syndrome/etiology , Disease Progression , Humans , Metabolic Diseases/complications , Thrombophilia/diet therapy , Thrombophilia/etiology
8.
Expert Rev Anti Infect Ther ; 19(1): 5-16, 2021 01.
Article in English | MEDLINE | ID: covidwho-1066153

ABSTRACT

INTRODUCTION: Over the last few months, coronavirus disease 2019 (COVID-19) pandemic caused by the novel coronavirus SARS-CoV-2 has posed a serious threat to public health on a global scale. Given the current lack of an effective vaccine, several drugs have been repurposed for treatment and prophylaxis of COVID-19 in an attempt to find an effective cure. AREAS COVERED: The antimalarial drug hydroxychloroquine (HCQ) initially garnered widespread attention following the publication of preliminary results showing that this drug exerts an anti-SARS-CoV-2 activity in vitro. EXPERT OPINION: To date, clinical evidence suggests lack of benefit from HCQ use for the treatment of hospitalized patients with COVID-19. In such patients, HCQ also appears to be associated with an increased risk of QT interval prolongation and potentially lethal ventricular arrhythmias. Therefore, FDA has recently revoked the Emergency Use Authorization (EUA) for emergency use of HCQ and chloroquine to treat COVID-19. Conversely, whether HCQ use may represent an effective prophylactic strategy against COVID-19 is a separate question that still remains to be answered. In addition, relevant aspects regarding the potential risks and benefits of HCQ need to be clarified, in pursuit of a rational use of this drug in the COVID-19 pandemic era.


Subject(s)
COVID-19/prevention & control , Hydroxychloroquine/therapeutic use , SARS-CoV-2 , COVID-19/drug therapy , COVID-19/epidemiology , Chloroquine/pharmacology , Chloroquine/therapeutic use , Drug Repositioning , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacology
9.
Stem Cells Transl Med ; 10(5): 660-673, 2021 05.
Article in English | MEDLINE | ID: covidwho-1008163

ABSTRACT

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE-free survival (P = .008), and time to recovery (P = .03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/therapy , Mesenchymal Stem Cell Transplantation/methods , Cytokines/blood , Double-Blind Method , Female , Humans , Male , Mesenchymal Stem Cell Transplantation/adverse effects , Mesenchymal Stem Cells , Middle Aged , SARS-CoV-2/drug effects , Severity of Illness Index , Treatment Outcome , Umbilical Cord/cytology
10.
J Diabetes ; 12(9): 659-667, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-245563

ABSTRACT

The antimalarial drug hydroxychloroquine (HCQ) has long been used as a disease-modifying antirheumatic drug for the treatment of several inflammatory rheumatic diseases. Over the last three decades, various studies have shown that HCQ also plays a role in the regulation of glucose homeostasis. Although the mechanisms of action underlying the glucose-lowering properties of HCQ are still not entirely clear, evidence suggests that this drug may exert multifaceted effects on glucose regulation, including improvement of insulin sensitivity, increase of insulin secretion, reduction of hepatic insulin clearance, and reduction of systemic inflammation. Preliminary studies have shown the safety and efficacy of HCQ (at a dose ranging from 400 to 600 mg/day) in patients with type 2 diabetes over a short-term period. In 2014, HCQ has been approved in India as an add-on hypoglycemic agent for patients with uncontrolled type 2 diabetes. However, large randomized controlled trials are needed to establish the safety and efficacy profile of HCQ in patients with type 2 diabetes over a long-term period. With regard to the COVID-19 pandemic, several medications (including HCQ) have been used as off-label drugs because of the lack of proven effective therapies. However, emerging evidence shows limited benefit from HCQ use in COVID-19 in general. The aim of this manuscript is to comprehensively summarize the current knowledge on the antihyperglycemic properties of HCQ and to critically evaluate the potential risks and benefits related to HCQ use in patients with diabetes, even in light of the current pandemic scenario.


Subject(s)
Coronavirus Infections , Diabetes Complications/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Pandemics , Pneumonia, Viral , Antiviral Agents , COVID-19 , Coronavirus Infections/drug therapy , Humans
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