Molecular Mechanisms of Anti-Inflammatory Phytochemicals.

Naturally occurring bioactives, also known as phytochemicals, have been widely recognized and researched owing to their multiple potentialities [...].

Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases.

The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington's disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells' substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic.

The genes road: impact of migration on newborn screening and health amid the COVID-19 pandemic in the Eastern Mediterranean region.

Nearly two-thirds of migrants residing in camps in Europe are women and children. Many of these children, being born on the way without essential newborns screening, are at some point admitted to pediatric wards in asylum countries. With hospitals overwhelmed with COVID-19 cases, taking appropriate care of newborns becomes a considerable burden. In this frame, prevention, in the form of adequate newborn screening, emerges as a better and more feasible strategy than healing.

Management of Coronavirus Disease 2019 Patients With Lung Cancer: Experience From a Thoracic Oncology Center.

BACKGROUND: Cancer patients appear to be at a higher risk of complications from coronavirus disease 2019 (COVID-19). Specific data related to lung cancer (LC) patient management, active treatment, and/or recent diagnosis are still very limited. Here, we aimed to investigate the clinical presentation, baseline features, and clinical outcomes of LC patients with COVID-19. METHODS: A retrospective case study was performed at Centro Hospitalar Universitário de São Joao, a tertiary hospital in the North of Portugal. Data from LC patients diagnosed with COVID-19 were collected during the first 10 months of the COVID-19 pandemic (March 2020-January 2021). RESULTS: Twenty-eight patients with active LC were diagnosed with COVID-19, being adenocarcinoma the most common histological type present (n = 13, 46.4%). Sixteen patients had metastatic stage IV LC (61.5%). Twenty-five patients (89.3%) had relevant comorbidities including hypertension (39.3%) and chronic obstructive pulmonary disease (32.1%). For patients undergoing antineoplastic treatment, the median time from the last chemotherapy administration to COVID-19 diagnosis was of 16 days (interquartile range = 13-41 days). Half of patients were previously on corticosteroid therapy. Twenty patients (71.4%) needed hospitalization, 18 received oxygen therapy (64.3%), 3 (10.7%) of them received high-flow nasal cannula with good tolerability, and 1 (3.6%) needed non-invasive ventilation. Hydroxychloroquine and antibiotics were given to 4 (14.3%) and 12 (42.9%) patients, respectively. Seven patients (25%) died at a median time of 5 days following COVID-19 diagnosis. CONCLUSION: This is one of the first studies reporting the adverse outcomes associated with COVID-19 in LC patients at same time that adds evidence regarding the need to create protocols and guidelines to reduce the infection risk in such patients.

Dairy-Derived and Egg White Proteins in Enhancing Immune System Against COVID-19.

Coronavirus disease (COVID-19) is a global health challenge, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) triggers a plethora of respiratory disturbances and even multiple organs failure that can be fatal. Nutritional intervention is one of the key components toward to a proper management of COVID-19 patients, especially in those requiring medication, and should thus be considered the first-line treatment. Immuno-modulation and -stimulation are currently being explored in COVID-19 management and are gaining interest by food and pharmaceutical industries. Various dietary combinations, bioactive components, nutrients and fortified foods have been reported to modulate inflammation during disease progression. Dietary combinations of dairy-derived products and eggs are gaining an increasing attention given the huge immunomodulatory and anti-inflammatory properties attributed to some of their chemical constituents. Eggs are complex dietary components containing many essential nutrients and bioactive compounds as well as a high-quality proteins. Similarly, yogurts can replenish beneficial bacteria and contains macronutrients capable of stimulating immunity by enhancing cell immunity, reducing oxidative stress, neutralizing inflammation and regulating the intestinal barriers and gut microbiome. Thus, this review highlights the impact of nutritional intervention on COVID-19 management, focusing on the immunomodulatory and inflammatory effects of immune-enhancing nutrients.

The potential role of neopterin in Covid-19: a new perspective.

Neopterin (NPT) is a member of pteridines group, synthesized by macrophages when stimulated by interferon gamma (INF-γ). NPT is regarded as a macrophage stimulation indicator, marker of cellular immune activation and T helper 1 (Th1) type 1 immune response. Here, we aimed to provide a view point on the NPT features and role in Covid-19. Serum NPT level is regarded as an independent prognostic factor for Covid-19 severity, with levels starting to increase from the 3rd day of SARS-CoV-2 infection, being associated with severe dyspnea, longer hospitalization period and complications. Also, early raise of NPT reflects monocytes/macrophages activation before antibody immune response, despite the NPT level may also remain high in Covid-19 patients or at the end of incubation period before the onset of clinical symptoms. On the other hand, NPT attenuates the activity of macrophage foam cells and is linked to endothelial inflammation through inhibition of adhesion molecules and monocytes migration. However, NPT also exerts anti-inflammatory and antioxidant effects by suppressing NF-κB signaling and NLRP3 inflammasomes. NPT can be viewed as a protective compensatory mechanism to counterpoise hyper-inflammation, oxidative stress, and associated organ damage.

Factors Behind the Higher COVID-19 Risk in Diabetes: A Critical Review.

Diabetes mellitus (DM) and coronavirus disease 2019 (COVID-19) are public health issues worldwide, and their comorbidities trigger the progress to severe disease and even death in such patients. Globally, DM has affected an estimated 9.3% adults, and as of April 18, 2021, the World Health Organization (WHO) has confirmed 141,727,940 COVID-19 confirmed cases. The virus is spread via droplets, aerosols, and direct touch with others. Numerous predictive factors have been linked to COVID-19 severity, including impaired immune response and increased inflammatory response, among others. Angiotensin receptor blockers and angiotensin converting enzyme 2 have also been identified as playing a boosting role in both susceptibility and severity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Specifically, in DM patients, both their control and management during this pandemic is herculean as the restriction periods have markedly hampered the maintenance of means to control glycemia, hypertension, and neuroendocrine and kidney diseases. In addition, as a result of the underlyin cardio-metabolic and immunological disorders, DM patients are at a higher risk of developing the severe form of COVID-19 despite other comorbidities, such as hypertension, also potentially boosting the development of higher COVID-19 severity. However, even in non-DM patients, SARS-CoV-2 may also cause transient hyperglycemia through induction of insulin resistance and/or pancreatic ß-cell injury. Therefore, a strict glucose monitoring of DM patients with COVID-19 is mandatory to prevent life-threatening complications.

Naturally Occurring Bioactives as Antivirals: Emphasis on Coronavirus Infection.

The current coronavirus disease (COVID-19) outbreak is a significant threat to human health and the worldwide economy. Coronaviruses cause a variety of diseases, such as pneumonia-like upper respiratory tract illnesses, gastroenteritis, encephalitis, multiple organ failure involving lungs and kidneys which might cause death. Since the pandemic started there have been more than 107 million COVID-19 infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ∼2.4 million deaths globally. SARS-CoV-2 is easily transmitted from person-to-person and has spread quickly across all continents. With the continued increase in morbidity and mortality caused by COVID-19, and the damage to the global economy, there is an urgent need for effective prevention and treatment strategies. The advent of safe and effective vaccines has been a significant step forward in the battle against COVID-19, however treatment of the symptoms associated with the disease still requires new anti-viral and anti-inflammatory drug therapies. To this end, scientists have been investigating available natural products that may be effective against SARS-CoV-2, with some products showing promise in fighting several viral infections. Since many natural products are dietary components or are prepared as dietary supplements people tend to consider them safer than synthetic drugs. For example, Traditional Chinese Medicines have been effectively utilized to treat SARS-CoV-2 infected patients with promising results. In this review, we summarize the current knowledge of COVID-19 therapies and the therapeutic potential of medicinal plant extracts and natural compounds for the treatment of several viral infections, with special emphasis on SARS-CoV-2 infection. Realistic strategies that can be employed for the effective use of bioactive compounds for anti-SARS-CoV-2 research are also provided.

COVID-19 in Relation to Hyperglycemia and Diabetes Mellitus.

Coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), may lead to extrapulmonary manifestations like diabetes mellitus (DM) and hyperglycemia, both predicting a poor prognosis and an increased risk of death. SARS-CoV-2 infects the pancreas through angiotensin-converting enzyme 2 (ACE2), where it is highly expressed compared to other organs, leading to pancreatic damage with subsequent impairment of insulin secretion and development of hyperglycemia even in non-DM patients. Thus, this review aims to provide an overview of the potential link between COVID-19 and hyperglycemia as a risk factor for DM development in relation to DM pharmacotherapy. For that, a systematic search was done in the database of MEDLINE through Scopus, Web of Science, PubMed, Embase, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), and Wanfang Data. Data obtained underline that SARS-CoV-2 infection in DM patients is more severe and associated with poor clinical outcomes due to preexistence of comorbidities and inflammation disorders. SARS-CoV-2 infection impairs glucose homeostasis and metabolism in DM and non-DM patients due to cytokine storm (CS) development, downregulation of ACE2, and direct injury of pancreatic ß-cells. Therefore, the potent anti-inflammatory effect of diabetic pharmacotherapies such as metformin, pioglitazone, sodium-glucose co-transporter-2 inhibitors (SGLT2Is), and dipeptidyl peptidase-4 (DPP4) inhibitors may mitigate COVID-19 severity. In addition, some antidiabetic agents and also insulin may reduce SARS-CoV-2 infectivity and severity through the modulation of the ACE2 receptor expression. The findings presented here illustrate that insulin therapy might seem as more appropriate than other anti-DM pharmacotherapies in the management of COVID-19 patients with DM due to low risk of uncontrolled hyperglycemia and diabetic ketoacidosis (DKA). From these findings, we could not give the final conclusion about the efficacy of diabetic pharmacotherapy in COVID-19; thus, clinical trial and prospective studies are warranted to confirm this finding and concern.

Boldness Personality Traits Are Associated With Reduced Risk Perceptions and Adoption of Protective Behaviors During the First COVID-19 Outbreak.

The containment measures imposed during the first COVID-19 outbreak required economic, social, and behavioral changes to minimize the spread of the coronavirus. Some studies have focused on how personality predicts distinct patterns of adherence to protective measures with psychopathic and antisocial traits predicting reduced engagement in such measures. In this study we extended previous findings by analyzing how boldness, meanness, and disinhibition psychopathic traits relate with both risk perceptions and protective behaviors during the first COVID-19 outbreak. A sample of 194 individuals (24% male) engaged in the survey, were assessed for psychopathic traits with the Triarchic Psychopathy Measure, and completed a COVID-19 survey targeting risk perceptions (spread, risk of becoming infected, state anxiety toward the COVID-19, and perceived risk of specific behaviors) and frequency of protective behaviors (e.g., not engaging in social distancing). Overall results show that boldness predicts reduced estimate of COVID-19 spread, reduced perceived risk of becoming infected, reduced state anxiety toward COVID-19, and reduced frequency of protective behaviors. Exploratory mediation models suggest that risk perceptions are not significant mediators of the association between psychopathic traits and reduced engagement in protective behaviors. Our results unveil that psychopathic traits affect risk perceptions and the propensity to engage in protective measures, emphasizing the need to accommodate these personality features in the public health strategy to control the COVID-19 spread.

Natural Products Modulating Angiotensin Converting Enzyme 2 (ACE2) as Potential COVID-19 Therapies.

The 2019 coronavirus disease (COVID-19) is a potentially fatal multisystemic infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Currently, viable therapeutic options that are cost effective, safe and readily available are desired, but lacking. Nevertheless, the pandemic is noticeably of lesser burden in African and Asian regions, where the use of traditional herbs predominates, with such relationship warranting a closer look at ethnomedicine. From a molecular viewpoint, the interaction of SARS-CoV-2 with angiotensin converting enzyme 2 (ACE2) is the crucial first phase of COVID-19 pathogenesis. Here, we review plants with medicinal properties which may be implicated in mitigation of viral invasion either via direct or indirect modulation of ACE2 activity to ameliorate COVID-19. Selected ethnomedicinal plants containing bioactive compounds which may prevent and mitigate the fusion and entry of the SARS-CoV-2 by modulating ACE2-associated up and downstream events are highlighted. Through further experimentation, these plants could be supported for ethnobotanical use and the phytomedicinal ligands could be potentially developed into single or combined preventive therapeutics for COVID-19. This will benefit researchers actively looking for solutions from plant bioresources and help lessen the burden of COVID-19 across the globe.

Role of leukotriene pathway and montelukast in pulmonary and extrapulmonary manifestations of Covid-19: The enigmatic entity.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the responsible agent for the coronavirus disease 2019 (Covid-19), has its entry point through interaction with angiotensin converting enzyme 2 (ACE2) receptors, highly expressed in lung type II alveolar cells and other tissues, like heart, pancreas, brain, and vascular endothelium. This review aimed to elucidate the potential role of leukotrienes (LTs) in the pathogenesis and clinical presentation of SARS-CoV-2 infection, and to reveal the critical role of LT pathway receptor antagonists and inhibitors in Covid-19 management. A literature search was done in PubMed, Scopus, Web of Science and Google Scholar databases to find the potential role of montelukast and other LT inhibitors in the management of pulmonary and extra-pulmonary manifestations triggered by SARS-CoV-2. Data obtained so far underline that pulmonary and extra-pulmonary manifestations in Covid-19 are attributed to a direct effect of SARS-CoV-2 in expressed ACE2 receptors or indirectly through NF-κB dependent induction of a cytokine storm. Montelukast can ameliorate extra-pulmonary manifestations in Covid-19 either directly through blocking of Cys-LTRs in different organs or indirectly through inhibition of the NF-κB signaling pathway.

Pleiotropic Effects of Tetracyclines in the Management of COVID-19: Emerging Perspectives.

Coronavirus disease 2019 (COVID-19) is a global infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Approximately 15% of severe cases require an intensive care unit (ICU) admission and mechanical ventilation due to development of acute respiratory distress syndrome (ARDS). Tetracyclines (TCs) are a group of bacteriostatic antibiotics, like tetracycline, minocycline, and doxycycline, effective against aerobic and anaerobic bacteria as well as Gram-positive and Gram-negative bacteria. Based on available evidences, TCs may be effective against coronaviruses and thus useful to treat COVID-19. Thus, this review aims to provide a brief overview on the uses of TCs for COVID-19 management. SARS-CoV-2 and other coronaviruses depend mainly on the matrix metalloproteinases (MMPs) for their proliferation, cell adhesion, and infiltration. The anti-inflammatory mechanisms of TCs are linked to different pathways. Briefly, TCs inhibit mitochondrial cytochrome c and caspase pathway with improvement of lymphopenia in early COVID-19. Specifically, minocycline is effective in reducing COVID-19-related complications, through attenuation of cytokine storm as apparent by reduction of interleukin (IL)-6, IL-1, and tumor necrosis factor (TNF)-α. Different clinical trials recommend the replacement of azithromycin by minocycline in the management of COVID-19 patients at high risk due to two main reasons: 1) minocycline does not prolong the QT interval and even inhibits ischemia-induced arrhythmia; 2) minocycline displays synergistic effect with chloroquine against SARS-CoV-2. Taken together, the data presented here show that TCs, mainly doxycycline or minocycline, may be potential partners in COVID-19 management, derived pneumonia, and related complications, such as acute lung injury (ALI) and ARDS.

Management of SARS-CoV-2 Infection: Key Focus in Macrolides Efficacy for COVID-19.

Macrolides (e.g., erythromycin, fidaxomicin, clarithromycin, and azithromycin) are a class of bacteriostatic antibiotics commonly employed in medicine against various gram-positive and atypical bacterial species mostly related to respiratory tract infections, besides they possess anti-inflammatory and immunomodulatory effects. Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2). It was first detected in Wuhan, Hubei, China, in December 2019 and resulted in a continuing pandemic. Macrolides have been extensively researched as broad adjunctive therapy for COVID-19 due to its immunostimulant abilities. Among such class of drugs, azithromycin is described as azalide and is well-known for its ability to decrease the production of pro-inflammatory cytokines, including matrix metalloproteinases, tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8. In fact, a report recently published highlighted the effectiveness of combining azithromycin and hydroxychloroquine for COVID-19 treatment. Indeed, it has been underlined that azithromycin quickly prevents SARS-CoV-2 infection by raising the levels of both interferons and interferon-stimulated proteins at the same time which reduces the virus replication and release. In this sense, the current review aims to evaluate the applications of macrolides for the treatment of COVID-19.

The Looming Effects of Estrogen in Covid-19: A Rocky Rollout.

In the face of the Covid-19 pandemic, an intensive number of studies have been performed to understand in a deeper way the mechanisms behind better or worse clinical outcomes. Epidemiologically, men subjects are more prone to severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infections than women, with a similar scenario being also stated to the previous coronavirus diseases, namely, SARS-CoV in 2003 and Middle East Respiratory Syndrome coronavirus diseases (MERS-CoV) in 2012. In addition, and despite that aging is regarded as an independent risk factor for the severe form of the disease, even so, women protection is evident. In this way, it has been expected that sex hormones are the main determinant factors in gender differences, with the immunomodulatory effects of estrogen in different viral infections, chiefly in Covid-19, attracting more attention as it might explain the case-fatality rate and predisposition of men for Covid-19 severity. Here, we aim to provide a mini-review and an overview on the protective effects of estrogen in Covid-19. Different search strategies were performed including Scopus, Web of Science, Medline, Pubmed, and Google Scholar database to find relative studies. Findings of the present study illustrated that women have a powerful immunomodulating effect against Covid-19 through the effect of estrogen. This study illustrates that estrogens have noteworthy anti-inflammatory and immuno-modulatory effects in Covid-19. Also, estrogen hormone reduces SARS-CoV-2 infectivity through modulation of pro-inflammatory signaling pathways. This study highlighted the potential protective effect of estrogen against Covid-19 and recommended for future clinical trial and prospective studies to elucidate and confirm this protective effect.

Interlink between pollution and COVID-19 in India: compelling view and key attributes.

Pollution and pollution-related consequences have a historic reputation, being even considered as chief causative agents behind several tragedies linked to a huge impact on health and environment. Nonetheless, the unforeseen viral outburst has surprisingly led to the recovery of the atmospheric immaculacy, besides to the serious destruction. Thus, here some important aspects related to the impact of pollution on the viral epidemic and vice versa were attempted to be critically discussed.

COVID-19 and Risk of Acute Ischemic Stroke and Acute Lung Injury in Patients With Type II Diabetes Mellitus: The Anti-inflammatory Role of Metformin.

Background: Coronavirus disease 19 (COVID-19) is regarded as an independent risk factor for acute ischemic stroke (AIS) due to the induction of endothelial dysfunction, coagulopathy, cytokine storm, and plaque instability. Method: In this retrospective cohort study, a total of 42 COVID-19 patients with type 2 diabetes mellitus (T2DM) who presented with AIS within 1 week of displaying COVID-19 symptoms were recruited. According to the current anti-DM pharmacotherapy, patients were divided into two groups: a Metformin group of T2DM patients with COVID-19 and AIS on metformin therapy (850 mg, 3 times daily (n = 22), and a Non-metformin group of T2DM patients with COVID-19 and AIS under another anti-DM pharmacotherapy like glibenclamide and pioglitazone (n = 20). Anthropometric, biochemical, and radiological data were evaluated. Results: Ferritin serum level was lower in metformin-treated patients compared to non-metformin treated patients (365.93 ± 17.41 vs. 475.92 ± 22.78 ng/mL, p = 0.0001). CRP, LDH, and D-dimer serum levels were also lowered in metformin-treated patients compared to non-metformin treated patients (p = 0.0001). In addition, lung CT scan scores of COVID-19 patients was 30.62 ± 10.64 for metformin and 36.31 ± 5.03 for non-metformin treated patients. Conclusion: Metformin therapy in T2DM patients was linked to a lower risk of AIS during COVID-19. Further studies are needed to observe the link between AIS in COVID-19 diabetic patients and metformin therapy.

Sequential doxycycline and colchicine combination therapy in Covid-19: The salutary effects.

Coronavirus virus disease 2019 (COVID-19) is a viral infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), actually considered as a global pandemic. The entry-point for SARS-CoV-2 is angiotensin converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 (DPP4), which are highly expressed in the lung. Among other complications, COVID-19leads to fatal pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) due to development of cytokine storm (CS). The pathogenesis of SARS-CoV-2 infection depends on the viral load and human innate/adaptive immune response that are required for viral elimination in the first phase of COVID-19. However, an exaggerated immune response in the second phase of COVID-19 results in immune overreaction and CS-induced ALI and ARDS. Thus, in view of these considerations, we report here a series of five patients with COVID-19 pneumonia who developed ALI. In addition to the supportive therapy, the patients received doxycycline in the first week and doxycycline plus colchicine in the second week. Following sequential therapy with doxycycline and/or colchicine in patients with COVID-19 pneumonia, the patients had reduction of disease severity and symptoms with better clinical and radiological outcomes. However, it is tough to confirm the link between this therapeutic combination and recovery from COVID-19 pneumonia, as it is a small case-series report. Nevertheless, this study gives a rational for large-scale prospective studies to evaluate the dual sequential effect of doxycycline and colchicine on the COVID-19 severity. This case-series illustrated that use of colchicine: doxycycline combination is linked with marked improvements in the clinical, laboratory and radiological outcomes in patients with COVID-19 pneumonia. However, we cannot sketch any definitive conclusion from our observation, despite we hypothesize that this combination therapeutic regimen may attenuate and treat COVID-19. Further, namely prospective, randomized, and controlled clinical studies are recommended in this regard.

Case Report: Hyperbilirubinemia in Gilbert Syndrome Attenuates Covid-19-Induced Metabolic Disturbances.

Gilbert syndrome (GS) is a liver disorder characterized by non-hemolytic unconjugated hyperbilirubinemia. On the other hand, Coronavirus disease 2019 (Covid-19) is a recent viral infectious disease presented as clusters of pneumonia, triggered by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Little is known on the association between SARS-CoV-2 and GS, despite different studies have recently stated a link between hyperbilirubinemia and SARS-CoV-2 severity. In this case-report study we described a 47-year-old man, a known case of GS since the age of 4, presented to the emergency department with fever (39.8°C), dry cough, dyspnea, headache, myalgia, sweating and jaundice diagnosed with Covid-19-induced pneumonia. Interestingly, GS patient exhibited a rapid clinical recovery and short hospital stay compared to other SARS-CoV-2 positive patient, seeming that hyperbilirubinemia may exert a protective effect of against Covid-19 induced-cardiometabolic disturbances. Data obtained here underlines that the higher resistance against Covid-19 evidenced by the GS patient seems to be due to the antioxidant, anti-inflammatory, and antiviral effects of unconjugated bilirubin.