Effect of phthalocyanine oral and nasal antiseptic solutions on the infectivity of SARS-CoV-2 in patients with COVID-19: a randomized controlled trial.

Background: In individuals with coronavirus disease (COVID-19), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL) plays an important role in infectivity. Objectives: This study aimed to evaluate the reduction in the VL and infectivity induced by phthalocyanine mouthwash and nasal spray in patients with COVID-19. Methods: Patients with mild COVID-19 were recruited to participate in a triple-blinded randomized controlled trial. Participants were assigned to one of three groups: Group 1, non-active mouthwash and saline nasal spray (SNS); Group 2, phthalocyanine mouthwash and SNS; and Group 3 phthalocyanine mouthwash and phthalocyanine nasal spray. VL was assessed in nasopharyngeal and oropharyngeal swabs collected at the time of clinical diagnosis at baseline as well as 24 and 72 hours after starting the rinsing protocols. Findings: Forty-six participants were included in the analysis: 15, 16, and 15 in Groups 1, 2, and 3, respectively. After 72 hours, the reduction in VL was significantly higher in Group 3 (mean cycle threshold (Ct) decrease: 11.21) than in Group 1 (mean Ct decrease: 5.53). Additionally, only the mean VL in Group 3 was reduced to a non-contagious level after 72 hours. Main conclusions: Use of phthalocyanine mouthwash and nasal spray is effective at reducing SARS-CoV-2 infectivity.

Immunopathogenesis and Immunogenetic Variants in COVID-19.

Coronavirus disease 2019 (COVID-19) continues to spread globally despite the discovery of vaccines. Many people die due to COVID-19 as a result of catastrophic consequences, such as acute respiratory distress syndrome, pulmonary embolism, and disseminated intravascular coagulation caused by a cytokine storm. Immunopathology and immunogenetic research may assist in diagnosing, predicting, and treating severe COVID-19 and the cytokine storm associated with COVID-19. This paper reviews the immunopathogenesis and immunogenetic variants that play a role in COVID-19. Although various immune-related genetic variants have been investigated in relation to severe COVID-19, the NOD-like receptor protein 3 (NLRP3) and interleukin 18 (IL-18) have not been assessed for their potential significance in the clinical outcome. Here, we a) summarize the current understanding of the immunogenetic etiology and pathophysiology of COVID-19 and the associated cytokine storm; and b) construct and analyze protein-protein interaction (PPI) networks (using enrichment and annotation analysis) based on the NLRP3 and IL18 variants and all genes, which were established in severe COVID-19. Our PPI network and enrichment analyses predict a) useful drug targets to prevent the onset of severe COVID-19, including key antiviral pathways such as Toll-Like-Receptor cascades, NOD-like receptor signaling, RIG-induction of interferon (IFN) α/ß, and interleukin (IL)-1, IL-6, IL-12, IL-18, and tumor necrosis factor signaling; and b) SARS-CoV-2 innate immune evasion and the participation of MYD88 and MAVS in the pathophysiology of severe COVID-19. The PPI network genetic variants may be used to predict more severe COVID-19 outcomes, thereby opening the door for targeted preventive treatments.

The role of zinc, copper, manganese and iron in neurodegenerative diseases.

Metals are involved in different pathophysiological mechanisms associated with neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS). The aim of this study was to review the effects of the essential metals zinc (Zn), copper (Cu), manganese (Mn) and iron (Fe) on the central nervous system (CNS), as well as the mechanisms involved in their neurotoxicity. Low levels of Zn as well as high levels of Cu, Mn, and Fe participate in the activation of signaling pathways of the inflammatory, oxidative and nitrosative stress (IO&NS) response, including nuclear factor kappa B and activator protein-1. The imbalance of these metals impairs the structural, regulatory, and catalytic functions of different enzymes, proteins, receptors, and transporters. Neurodegeneration occurs via association of metals with proteins and subsequent induction of aggregate formation creating a vicious cycle by disrupting mitochondrial function, which depletes adenosine triphosphate and induces IO&NS, cell death by apoptotic and/or necrotic mechanisms. In AD, at low levels, Zn suppresses ß-amyloid-induced neurotoxicity by selectively precipitating aggregation intermediates; however, at high levels, the binding of Zn to ß-amyloid may enhance formation of fibrillar ß-amyloid aggregation, leading to neurodegeneration. High levels of Cu, Mn and Fe participate in the formation α-synuclein aggregates in intracellular inclusions, called Lewy Body, that result in synaptic dysfunction and interruption of axonal transport. In PD, there is focal accumulation of Fe in the substantia nigra, while in AD a diffuse accumulation of Fe occurs in various regions, such as cortex and hippocampus, with Fe marginally increased in the senile plaques. Zn deficiency induces an imbalance between T helper (Th)1 and Th2 cell functions and a failure of Th17 down-regulation, contributing to the pathogenesis of MS. In MS, elevated levels of Fe occur in certain brain regions, such as thalamus and striatum, which may be due to inflammatory processes disrupting the blood-brain barrier and attracting Fe-rich macrophages. Delineating the specific mechanisms by which metals alter redox homeostasis is essential to understand the pathophysiology of AD, PD, and MS and may provide possible new targets for their prevention and treatment of the patients affected by these NDDs.

Quercetin promotes antipromastigote effect by increasing the ROS production and anti-amastigote by upregulating Nrf2/HO-1 expression, affecting iron availability.

American cutaneous leishmaniasis is a zoonotic disease caused by protozoans of the genus Leishmania. The treatment of cutaneous leishmaniasis is unsatisfactory, thus, much research effort has been focused on investigating new compounds with lower collateral effects to the patients and derived from low-cost sources, such as natural products. In the present study, we evaluated the in vitro directly effect of the flavonoid quercetin against Leishmania (Viannia) braziliensis. Quercetin inhibited the proliferation of promastigote forms at all tested concentrations, these effect were due to increasing the reactive oxygen species (ROS) production, phosphatidylserine exposure and loss of plasma membrane integrity. Moreover, quercetin reduced the number of parasites in L. braziliensis-infected macrophages, reducing the levels of TNF-α and increasing IL-10 synthesis without modulate nitric oxide (NO) production. In addition, quercetin upregulated Nrf2/HO-1 expression and modulated the labile iron pool in infected macrophages, culminating in a depletion of available iron for L. braziliensis replication.

Insulin resistance, atherogenicity, and iron metabolism in multiple sclerosis with and without depression: Associations with inflammatory and oxidative stress biomarkers and uric acid.

Depression is accompanied by metabolic disorders in iron metabolism, lipoproteins, and insulin resistance. We measured plasma levels of ferritin, iron, lipids, insulin, and glucose and computed the homeostasis model assessment (HOMA2IR) and atherogenic index of plasma (AIP) in MS patients with and without depression and healthy controls. Explanatory variables were serum uric acid, interleukin (IL)-6, lipid hydroperoxides (CL-LOOH), albumin, and C-reactive protein (CRP). Depression was assessed using the Hospital Anxiety and Depression Scale (HADS), neurological disability using the Expanded Disability Status Scale (EDSS), and disease progression using ∆EDSS over five years earlier. HOMA2IR and insulin were predicted by diagnosis (increased in MS), age and body mass index (BMI); AIP by diagnosis, sex, BMI, CRP, and uric acid; triglycerides by diagnosis (higher in MS without depression), age, BMI and uric acid; ferritin by diagnosis (higher in MS), sex, CRP, and albumin; and iron by albumin. The HADS score was significantly predicted by ∆EDSS, gastro-intestinal symptoms, iron (inverse), and age. MS is characterized by significantly increased insulin resistance, which is determined by increased insulin levels; and increased ferritin, a biomarker of inflammation. Depression in MS is not associated with increased insulin resistance and atherogenicity but with lowered iron.

Redox-driven events in the human immunodeficiency virus type 1 (HIV-1) infection and their clinical implications.

Oxidative stress is a condition characterized by the imbalance between the production of reactive species (RS) or free radicals and their neutralization by the antioxidant defenses, leading to the accumulation of RS and their derived metabolites, with changes in the redox status of the cell. These RS can act on biological components and induce the oxidative and nitrosative reactions on lipids, proteins, and DNA. In this context, a wide variety of chronic diseases present oxidative stress as a part of the pathogenesis, including the human immunodeficiency virus type 1 (HIV-1) infection. The relationship between oxidative stress and HIV-1 infection lies in the fact that the RS species are important components of the innate immune response, and their derived metabolites and reactions participate in several events of the adaptative immune response. On the other hand, studies have shown specific roles for oxidative-driven events in both the host immunity and the virus biology. Undoubtedly, the occurrence of oxidative stress in HIV-1-infected patients has been implicated in disease progression, as well as in developing other secondary disorders, such as cardiovascular diseases, insulin resistance, and metabolic syndrome. This review aims to characterize the redox-driven events in the HIV-1 infection and their clinical implications in the disease features.

Beneficial effects of Lactobacillus plantarum on glycemia and homocysteine levels in postmenopausal women with metabolic syndrome.

OBJECTIVE: Metabolic syndrome (MetS) in postmenopausal women is an important risk factor for cardiovascular morbidity, especially stroke and coronary heart disease and mortality. Preventing and treating MetS would be useful in preventing disability and promoting normal aging. Previous human studies have found some beneficial effects of Lactobacillus species on some isolated parameters of MetS. Nevertheless, we are not aware, to date, of any study which has verified the influence of probiotics in patients with MetS. Therefore, the aim of the present study was to evaluate the influence of fermented milk with L. plantarum in the classical parameters related to MetS, as well as in other parameters related to cardiovascular risk in postmenopausal women. METHODS: Twenty-four individuals were paired by age, ethnicity, and body mass index in two groups: Non-fermented milk (NFM = 12) 80 mL/d and fermented milk (FM = 12) 80 mL/d. Anthropometric and blood pressure measurements, biochemical, inflammatory, and immunologic biomarkers were measured. RESULTS: Total cholesterol and γ-glutamyltranspeptidase had a significant reduction both in NFM (P = 0.043 and P = 0.036, respectively) and FM groups (P = 0.010 and P = 0.018, respectively) after 90 d, whereas low-density lipoprotein cholesterol showed a significant reduction in NFM group (P = 0.002) and trend in the FM group (P = 0.092). Glucose and homocysteine levels showed a significant reduction in the FM group compared with the NFM group (P = 0.037 and P = 0.019, respectively). In relation to inflammatory biomarkers, there was a significant decrease in interleukin-6 both in NFM (P = 0.032) and in FM (P = 0.001) groups. CONCLUSION: FM with L. plantarum showed more favorable results than NFM in relation to cardiovascular risk factors in postmenopausal women with MetS.

Cytokine profile in relapsing­remitting multiple sclerosis patients and the association between progression and activity of the disease.

Multiple sclerosis (MS) is a progressive immune­ mediated disease caused by demyelination of the central nervous system. Cytokines and their receptors have an important role in the evolution of MS lesions, and pro­ and anti­inflammatory cytokine levels have been found to correlate with changes in MS disease activity. The aims of the present study were to evaluate the pro­inflammatory [tumor necrosis factor (TNF)­α and interleukin (IL) ­1ß, ­6 and ­12], T helper (Th) 1 [interferon (IFN)­Î³], Th17 (IL­17) and Th2 (IL­4 and ­10) cytokine serum levels in relapsing­remitting (RR)­MS patients and to evaluate the association between the cytokine profile and the progression and activity of the disease. Serum cytokine levels were assessed using enzyme linked­immunosorbent assays in 169 RR­MS patients in the remission clinical phase and 132 healthy individuals who were age­, gender­, ethnicity­ and body mass index­matched. Disability and activity of the disease were evaluated using the Expanded Disability Status Scale and magnetic resonance imaging with gadolinium, respectively. IFN­Î³ and IL­6, ­12 and ­4 levels were higher in RR­MS patients compared to controls (P=0.0009, 0.0114, 0.0297 and 0.0004, respectively). IL­1 levels were higher in controls compared with RR­MS patients. IL­4 levels were higher in RR­MS patients with mild disability compared to those with moderate and severe disability (P=0.0375). TNF­α and IL­10 levels were higher in RR­MS patients with inactive disease compared with those with active disease. IL­17 levels showed a trend towards being higher in RR­MS patients with inactive disease compared to those with active disease (P=0.0631). Low TNF­α and high IFN­Î³ levels were independently associated with RR­MS (P=0.0078 and 0.0056, respectively) and also with the activity of the disease (P=0.0348 and 0.0133, respectively). Results indicated that RR­MS patients, even in the remission clinical phase, exhibit a complex system of inflammatory and anti­inflammatory cytokines that may interact to modulate the progression and activity of the disease.

Genistein abrogates pre-hemolytic and oxidative stress damage induced by 2,2'-Azobis (Amidinopropane).

The pre-hemolytic mechanism induced by free radicals initiated from water-soluble 2,2'-azobis (2-amidinopropane) hydrochloride (AAPH) and its reversal by genistein was investigated in human erythrocytes. The time course of K+ efflux compared to the occurrence of hemolysis suggests that AAPH-induced hemolysis occurs indirectly via pore formation and band 3 oxidation as expected. However, genistein inhibited hemolysis, LDH release and membrane protein oxidation but not K+ efflux. This indicated that erythrocyte protein oxidation possibly in the hydrophobic core plays a significant role in the membrane pre-hemolytic damage. Chemiluminescence (CL) analysis carried out in non-lysed erythrocytes treated with AAPH showed a dramatic increase in CL indicating both reduced levels of antioxidants and increased membrane lipid peroxide. The V0 value was also increased up to 6 times, denoting a high degree of membrane peroxidation very early in erythrocyte membrane damage. The whole process was inhibited by genistein in a dose-dependent manner. These results indicate that the genistein inhibited both hemolysis and pre-hemolytic damage and also hindered membrane lipid peroxide formation and protein oxidation. In addition, it is suggested that pre-hemolytic damage is mediated mainly by the oxidation of both phospholipid and protein located in the deeper hydrophobic region of the membrane.