Flavonoids as Potential Therapeutics Against Neurodegenerative Disorders: Unlocking the Prospects.

Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca2+ stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant.

Flavonoids and Alzheimer's disease: reviewing the evidence for neuroprotective potential.

Neurodegeneration, which manifests as several chronic and incurable diseases, is an age-related condition that affects the central nervous system (CNS) and poses a significant threat to the public's health for the elderly. Recent decades have experienced an alarming increase in the incidence of neurodegenerative disorders (NDDs), a severe public health issue due to the ongoing development of people living in modern civilizations. Alzheimer's disease (AD) is a leading trigger of age-related dementia. Currently, there are no efficient therapeutics to delay, stop, or reverse the disease's course development. Several studies found that dietary bioactive phytochemicals, primarily flavonoids, influence the pathophysiological processes underlying AD. Flavonoids work well as a supplement to manufactured therapies for NDDs. Flavonoids are effective in complementing synthetic approaches to treat NDDs. They are biologically active phytochemicals with promising pharmacological activities, for instance, antiviral, anti-allergic, antiplatelet, anti-inflammatory, antitumor, anti-apoptotic, and antioxidant effects. The production of nitric oxide (NO), tumor necrosis factor (TNF-α), and oxidative stress (OS) are downregulated by flavonoids, which slow the course of AD. Hence, this research turned from preclinical evidence to feasible clinical applications to develop newer therapeutics, focusing on the therapeutic potential of flavonoids against AD.

Apoptosis and Phagocytosis as Antiviral Mechanisms.

Viruses are infectious entities that make use of the replication machinery of their hosts to produce more progenies, causing disease and sometimes death. To counter viral infection, metazoan hosts are equipped with various defense mechanisms, from the rapid-evoking innate immune responses to the most advanced adaptive immune responses. Previous research demonstrated that cells in fruit flies and mice infected with Drosophila C virus and influenza, respectively, undergo apoptosis, which triggers the engulfment of apoptotic virus-infected cells by phagocytes. This process involves the recognition of eat-me signals on the surface of virus-infected cells by receptors of specialized phagocytes, such as macrophages and neutrophils in mice and hemocytes in fruit flies, to facilitate the phagocytic elimination of virus-infected cells. Inhibition of phagocytosis led to severe pathologies and death in both species, indicating that apoptosis-dependent phagocytosis of virus-infected cells is a conserved antiviral mechanism in multicellular organisms. Indeed, our understanding of the mechanisms underlying apoptosis-dependent phagocytosis of virus-infected cells has shed a new perspective on how hosts defend themselves against viral infection. This chapter explores the mechanisms of this process and its potential for developing new treatments for viral diseases.

Mechanistic insights into anti-inflammatory and immunosuppressive effects of plant secondary metabolites and their therapeutic potential for rheumatoid arthritis.

The anti-inflammatory and immunosuppressive activities of plant secondary metabolites are due to their diverse mechanisms of action against multifarious molecular targets such as modulation of the complex immune system associated with rheumatoid arthritis (RA). This review discussed and critically analyzed the potent anti-inflammatory and immunosuppressive effects of several phytochemicals and their underlying mechanisms in association with RA in experimental studies, including preliminary clinical studies of some of them. A wide range of phytochemicals including phenols, flavonoids, chalcones, xanthones, terpenoids, alkaloids, and glycosides have shown significant immunosuppressive and anti-inflammatory activities in experimental RA models and a few have undergone clinical trials for their efficacy and safety in reducing RA symptoms and improve patient outcomes. These phytochemicals have potential as safer alternatives to the existing drugs in the management of RA, which possess a wide range of serious side effects. Sufficient preclinical studies on safety and efficacy of these phytochemicals must be performed prior to proper clinical studies. Further studies are needed to address the barriers that have so far limited their human use before the therapeutic potential of these plant-based chemicals as anti-arthritic agents in the treatment of RA is fully realized.

Cytokine profiles in dengue fever and dengue hemorrhagic fever: A study from Indonesia.

Recent studies have demonstrated that cytokine dysregulation has a critical role in the pathogenesis of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The aim of this study was to investigate the association between tumor necrosis factor (TNF- α), interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 17 (IL-17) with infection status, and severity of dengue. A prospective cross-sectional study was conducted at three hospitals in Gianyar regency and Denpasar municipality, Bali, Indonesia, from June to December 2022. Sixty-four dengue infected patients were involved. Patients' serum was tested for dengue infection using NS1 antigen rapid test, dengue virus immunoglobulin M (IgM) and immunoglobulin G (IgG) test, and reverse transcription polymerase chain reaction (RT-PCR). Cytokine levels (TNF-α, IL-6, IL-10, and IL-17) were measured using enzyme-linked immunosorbent assay (ELISA). Infection status was determined by combining serological and RT-PCR results, categorizing patients into primary and secondary infections. The present study found that DF patients had lower TNF-α, IL-6, and IL-17 but higher IL-10 levels compared to DHF patients (p<0.001). Elevated TNF-α, IL-6, and IL-17 levels were higher in secondary infection, while IL-10 level was higher in primary infection (p<0.001). In conclusion, cytokines play a crucial role in the interplay between cytokine dysregulation and dengue infection dynamics.

Effects of tobacco smoke on the expression of virulence genes in Escherichia coli.

It is widely acknowledged that smoking exacerbates the severity of infectious diseases. A presumed mechanism involves the damage inflicted by tobacco smoke on the organs of host organisms. In this study, an alternative hypothesis was explored: smoking enhances the virulence of bacteria. This possibility was investigated using Escherichia coli as the model bacteria and Drosophila as the host organism. Our inquiry focused on the potential gene expression changes in E. coli subsequent to exposure to tobacco smoke extracts. Analysis of the transcription promoter activity of genes encoding proteins within the E. coli two-component system, a regulatory machinery governing gene expression, revealed the suppression of thirteen out of 23 promoters in response to tobacco smoke extracts. Subsequently, Drosophila was infected with E. coli exposed to tobacco smoke extracts or left untreated. Interestingly, there were no significant differences observed in the survival periods of Drosophila following infection with E. coli, whether treated or untreated with tobacco smoke extracts. Contrary to the initial hypothesis, the findings suggest that while tobacco smoke extracts alter gene expression in E. coli, these changes do not appear to impact bacterial virulence. Although this study has illuminated the influence of tobacco smoke extracts on the gene expression of E. coli, further analyses are necessary to elucidate the implications of these changes. Nevertheless, the results imply that smoking affects not only host organisms but may also exert influence on invading bacteria.

Curcumin-mediated alleviation of dextran-induced leaky gut in Drosophila melanogaster.

Aging is commonly characterized by a decline in the physiological functioning of the body organs, with one hallmark being the impairment of intestinal function, leading to increased intestinal permeability known as leaky gut. The aim of this study was to investigate the potential of curcumin to prevent the development of leaky gut in Drosophila melanogaster utilizing the smurf fly method. In this study, flies aged 3-5 days underwent a 10-day dextran sulfate sodium (DSS) treatment to induce intestinal permeability, followed by a smurf assay using brilliant blue dye and locomotor testing the next day. Flies displaying the smurf phenotype were divided into four groups: untreated control and curcumin-treated (10 µM, 50 µM, and 250 µM). After 21 days of treatment, flies were reassessed for the smurf phenotype and underwent locomotor testing. On day 23, flies were subjected to RT-qPCR analysis. By inducing increased intestinal permeability through the administration of DSS, a higher proportion of flies exhibiting the smurf phenotype and a reduced survival rate in the DSS-treated group were observed. Such phenotypes were reversed, decreased number of flies displaying the smurf phenotype and improved fly survival, upon the incorporation of curcumin in the fly food at concentrations of 10, 50, and 250 µM. Subsequent molecular analysis revealed upregulated expression of sod1, cat, and pepck genes, while no significant changes were observed in the expression of sod2, indy, and srl genes following treatment with curcumin at high concentration. Overall, our findings provide insight into the potential effect of curcumin to alleviate the phenotypical features associated with DSS-induced leaky gut, possibly via the selective regulation of aging-related genes.

Correction: Chakraborty et al. Bromelain a Potential Bioactive Compound: A Comprehensive Overview from a Pharmacological Perspective. Life 2021, 11, 317.

The authors were not aware of errors made in one small subsection (Section 6.17. Antidiarrheal Effect, including the data in the table of effects) of this paper [...].

Evaluating the Impact of Vitamin D3 on NF-κB and JAK/STAT Signaling Pathways in Drosophila melanogaster.

This study delved into the consequences of prolonged administration of vitamin D3 on innate immune systems, particularly NF-κB and JAK/STAT, in Drosophila melanogaster. The outcomes indicated that vitamin D3 treatment exhibited a notable capacity to improve the survival of adult flies with compromised immune functions, a condition induced by the loss of PGRP-LB, particularly when the flies were exposed to heat-killed Escherichia coli. The PGRP-LBΔ mutant line that was treated with heat-killed E. coli experienced reduced survival. Treatment of heat-killed E. coli-treated PGRP-LBΔ with vitamin D3 resulted in improved survival, and this phenotypic feature might be due to the downregulation of gene expression in the NF-κB and JAK/STAT pathways. However, a higher concentration of vitamin D3 was associated with decreased survival, potentially linked to intricate immunological responses. The research also underscored the influence of vitamin D3 on the expression of antioxidant genes, sod1 and sod2, indicating an augmented resistance to oxidative stress. Further, this study revealed the effect of vitamin D3 on the reproductive status of the autoinflammatory model, showing an increase in pupae and adult flies with a treatment of 10 mM vitamin D3, suggesting the potential benefits of vitamin D3 on the reproductive profile. Overall, this study provides preliminary insights into the complex interactions between vitamin D3, immune pathways, oxidative responses in the cell, and reproduction in Drosophila.

Phytoconstituents of Citrus limon (Lemon) as Potential Inhibitors Against Multi Targets of SARS-CoV-2 by Use of Molecular Modelling and In†Vitro Determination Approaches.

In the present work, phytoconstituents from Citrus limon are computationally tested against SARS-CoV-2 target protein such as Mpro - (5R82.pdb), Spike - (6YZ5.pdb) &RdRp - (7BTF.pdb) for COVID-19. Docking was done by glide model, QikProp was performed by in silico ADMET screening & Prime MM-GB/SA modules were used to define binding energy. When compared with approved COVID-19 drugs such as Remdesivir, Ritonavir, Lopinavir, and Hydroxychloroquine, plant-based constituents such as Quercetin, Rutoside, Naringin, Eriocitrin, and Hesperidin. bind with significant G-scores to the active SARS-CoV-2 place. The constituents Rutoside and Eriocitrin were studied in each MD simulation in 100 ns against 3 proteins 5R82.pdb, 6YZ5.pdb and 7BTF.pdb.We performed an assay with significant natural compounds from contacts and in silico results (Rutin, Eriocitrin, Naringin, Hesperidin) using 3CL protease assay kit (B.11529 Omicron variant). This kit contained 3CL inhibitor GC376 as Control. The IC50 value of the test compound was found to be Rutin -17.50 µM, Eriocitrin-37.91 µM, Naringin-39.58 µM, Hesperidine-140.20 µM, the standard inhibitory concentration of GC376 was 38.64 µM. The phytoconstituents showed important interactions with SARS-CoV-2 targets, and potential modifications could be beneficial for future development.

Polyphenols as Therapeutics in Respiratory Diseases: Moving from Preclinical Evidence to Potential Clinical Applications.

Respiratory diseases are the most common and severe health complication and a leading cause of death worldwide. Despite breakthroughs in diagnosis and treatment, few safe and effective therapeutics have been reported. Phytochemicals are gaining popularity due to their beneficial effects and low toxicity. Polyphenols are secondary metabolites with high molecular weights found at high levels in natural food sources such as fruits, vegetables, grains, and citrus seeds. Over recent decades, polyphenols and their beneficial effects on human health have been the subject of intense research, with notable successes in preventing major chronic non-communicable diseases. Many respiratory syndromes can be treated effectively with polyphenolic supplements, including acute lung damage, pulmonary fibrosis, asthma, pulmonary hypertension, and lung cancer. This review summarizes the role of polyphenols in respiratory conditions with sufficient experimental data, highlights polyphenols with beneficial effects for each, and identifies those with therapeutic potential and their underlying mechanisms. Moreover, clinical studies and future research opportunities in this area are discussed.

Phenotypical and molecular assessments on the pharmacological effects of curcumin in Drosophila melanogaster.

Curcumin, a dietary polyphenol derived from turmeric's rhizome, exhibits a range of pharmacological activities, such as antioxidant, analgesic, antipyretic, and anti-inflammatory effects. It has been investigated for its therapeutic potential in chronic obstructive pulmonary disease (COPD) due to its ability to inhibit nuclear factor kappa B (NF-κB), modulate oxidative stress, impact cell viability, and regulate gene expression. However, most studies have been limited to in vitro conditions. To address this gap, we conducted in vivo experiments using the fruit fly Drosophila melanogaster to explore the antioxidant activities and biological significance of curcumin. Several parameters were assessed using different assays, including curcumin toxicity assay, fly survival, locomotor response to curcumin treatment (with or without cigarette smoke), trypan blue staining, larval crawling assays, and gene expression analysis. Our data revealed no significant differences in toxicity and locomotor tests across various curcumin concentrations. D. melanogaster tolerated curcumin at concentrations of 0.5 µM, 5 µM, 50 µM, and 500 µM, suggesting its safety without negatively impacting locomotor. Furthermore, curcumin at 5 µM extended the lifespan of D. melanogaster exposed to cigarette smoke, while reversing the negative effects of smoke exposure on gut cell viability and larval locomotor activity. In conclusion, curcumin administration appeared safe for D. melanogaster, with potential benefits for longevity and locomotory function. These findings support the idea that curcumin possesses in vivo antioxidant properties and may serve as a promising pharmacological agent. However, further study is needed to explore its potential applications in human health and disease management, particularly in the context of COPD.

Acute severe hepatitis of unknown etiology in children: A mini-review.

The emergence of acute, severe non hepA-E hepatitis of unknown etiology (ASHUE) has attracted global concern owing to the very young age of the patients and its unknown etiology. Although this condition has been linked to several possible causes, including viral infection, drugs and/or toxin exposure, the exact cause remains unknown; this makes treatment recommendation very difficult. In this review, we summarize recent updates on the clinical manifestations, complemented with laboratory results, case numbers with the global distribution and other epidemiological characteristics, and the possible etiologies. We also provide the proposed actions that could be undertaken to control and prevent further spread of this hepatitis. Since many etiological and pathological aspects of the acute non hepA-E hepatitis remain unclear, further research is needed to minimize the severe impact of this disease.

Global acceptance and hesitancy of COVID-19 vaccination: A narrative review.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major global health threat to human civilization and has disrupted many aspects of the community around the globe. Vaccination is one of the prominent measures to control the COVID-19 pandemic. More than 120 vaccines have entered human clinical trials and at least 8 vaccines have been fully approved. However, the success of the COVID-19 vaccination programs depends on how the community accepts the vaccines. Despite COVID-19 vaccination having been initiated for a while now, more than 50% of the global population have not been vaccinated. In some low- and middle-income countries (LMICs), the vaccine coverage is less than 20%. Since the decision to accept the new vaccine is complex, understanding the factors underpinning vaccine acceptance is critical. This review aimed to summarize the COVID-19 vaccine acceptance rate around the globe as well as its associated determinants. Information from this study might be important to formulate effective strategies to increase the COVID-19 vaccine coverage, and to be able to achieve herd immunity.

Persistence of long COVID symptoms in COVID-19 survivors worldwide and its potential pathogenesis - A systematic review and meta-analysis.

The study sought to determine the prevalence of persistent long COVID symptoms such as anxiety, depression, dizziness, chest pain, sleep difficulty, palpitations, weight loss, and hair loss among coronavirus disease 2019 (COVID-19) survivors worldwide and to discuss the potential pathogeneses. Potential studies were searched in three databases (PubMed, Scopus, and Web of Science) as of January 30, 2021. Data on study characteristics, patient characteristics during the follow-up, the number of patients with persistent long COVID symptoms and total COVID-19 survivors were collected according to PRISMA guidelines. To assess the quality of studies, the Newcastle-Ottawa scale was used. The estimated prevalence of each long COVID symptom and the association between COVID-19 severity and the occurrence of prolonged symptoms was assessed, if appropriate. The global prevalence of prolonged anxiety was 15.76% (95%CI: 6.36%, 25.15%). Chest pain persisted in 10.36% (239/3,224) of COVID-19 patients (95%CI: 4.92%, 15.80%). Prolonged depression was found in 24 of 548 COVID-19 survivors with an estimated prevalence of 4.32% (95%CI: 2.62%, 6.03%) and dizziness was presented in 4.83% (118/2,219, 95%CI: 1.50%, 8.16%) after recovery. Hair loss was complained by 527 of 2,251 recovered patients (cumulative prevalence of 24.76%, 95%CI: 19.60%, 29.91%), while weight loss was identified in 37 cases among 452 COVID-19 survivors (8.19%, 95%CI: 5.66%, 10.71%). Prolonged palpitation was experienced by 19.38% (211/1,926) survivors with 95%CI: 2.40%, 41.16%. Sleep difficulty was found in 541 of 2,622 COVID-19 survivors (17.87%, 95%CI: 7.55%, 28.20%). The association between COVID-19 severity and the occurrence of persistent long COVID symptoms was not analyzed due to the lack of data. In conclusion, persistent psychological symptoms are frequently reported among COVID-19 survivors. Follow-up studies with a longer duration and larger population are warranted to assess the extent of prolonged symptoms and the quality of life of COVID-19 survivors. Despite various potential pathogeneses that have been hypothesized, a definitive mechanism is yet to be addressed. PROSPERO registration: CRD42021247172.

Original Article: Decline of notified dengue infections in Indonesia in 2017: Discussion of the possible determinants.

This study was conducted to quantify the trend in dengue notifications in the country in 2017 and to explore the possible determinants. Annual nation-wide dengue notification data were obtained from the National Disease Surveillance of Ministry of Health of Indonesia. Annual incidence rate (IR) and case fatality rate (CFR) in 2017 and the previous years were quantified and compared. Correlations between annual larva free index (LFI), implementation coverage of integrated vector management (IVM), El Niño Southern Oscillation (Niño3.4), Dipole Mode Index (DMI), Zika virus seropositivity and the percent change in IR and CFR of dengue were examined. The change of dengue IR and CFRs were mapped. In 2017, dengue IR was declined by 71% (22.55 per 100,000 population) compared to 2016 (77.96 per 100,000 population) while the CFR was slightly reduced from 0.79% to 0.75%. Reduction in IR and CFR occurred in 94.1% and 70.1% out of 34 provinces, respectively. The trend of dengue IR seems to be influenced by Niño3.4 but there is no clear evidence that Niño3.4 is the main reason for dengue reduction in 2017. It is difficult to elucidate that the reduction of dengue in 2017 was associated with previous Zika outbreaks. In conclusion, there was a significant reduction on dengue notifications in Indonesia in 2017. Further investigation is needed to look at the role of climate on the decline of dengue IR at finer temporal scale. In addition, study on the role of cross-protective immunity generated by Zika infection on dengue incidence is also warranted.

Global prevalence of persistent neuromuscular symptoms and the possible pathomechanisms in COVID-19 recovered individuals: A systematic review and meta-analysis.

This study was conducted to determine the prevalence of prolonged neuromuscular symptoms, including fatigue, anosmia, headache, myalgia, and joint pain in COVID-19 survivors hospitalized with mild, moderate, or severe infections worldwide. The search was conducted up to January 30th, 2021 using three databases (PubMed, Scopus, and Web of Science) to identify potentially eligible studies. Data on study characteristics, follow-up characteristics, and severity of COVID-19 during hospitalization were collected in accordance with PRISMA guidelines. The Newcastle-Ottawa scale was used to assess the quality of relevant articles. The estimated prevalence of specific prolonged neuromuscular symptoms and the association between COVID-19 severity and occurrence of prolonged neuromuscular symptoms was analyzed wherever appropriate. Database search yielded 4,050 articles and 22 articles were included for meta-analysis. The estimated prevalence of prolonged fatigue was recorded in 21.2% (95%CI: 11.9%- 34.8%) of 3,730 COVID-19 survivors. Persistent anosmia was recorded in 239 of 2,600 COVID-19 survivors (9.7%, 95%CI: 6.1%-15.2%). In 84 out of 2,412 COVID-19 survivors (8.9%, 95%CI: 3.2%-22.6%), prolonged headache was observed. A total of 53 out of 1,125 COVID-19 patients (5.6%, 95%CI: 2.1%-14.2%) complained of persistent myalgia even after being discharged from the hospital. The prevalence of prolonged joint pain was in 15.4% (95%CI: 8.2%-27.2%) of subjects. Due to data scarcity on COVID-19 severity and prolonged neuromuscular symptoms, association analysis could not be conducted. Widespread concern regarding long-term impacts of COVID-19 was raised after several studies reported prolonged symptoms in COVID-19 survivors. Numerous theories have been proposed to address this concern; however, as the research on this pandemic is still ongoing, no explanation is definitive yet. Therefore, follow-up studies in COVID-19 survivors after recovery from COVID-19 are warranted to determine the pathogenesis of prolonged symptoms. PROSPERO registration: CRD42021242332.