Beyond polio: Exploring non-polio enteroviruses, global health preparedness, and the "Disease X" paradigm.

Background and Aims: Disease X represents the possibility that an unidentified infection may spread globally and start a pandemic. This study explored various aspects of emerging non-polio enteroviruses (NPEVs) as a possible source of "Disease X," an enigmatic agent declared by the World Health Organization, and discussed the potential impact of NPEVs on global public health. Methods: In this perspective article, we collected information from publicly available sources such as Google Scholar, PubMed, and Scopus. We used NPEVs, viral diseases, pandemics, and zoonotic diseases as keywords. We extracted information from the most relevant articles. Results: Notable outbreaks caused by NPEVs include enterovirus D68 (EV-D68) and enterovirus A71 (EV-A71), among many others. With a focus on therapeutic and preventative components, alternate modes of therapy, and the development of broad-spectrum antivirals, this analysis looks at the origin, epidemiology, genetic alterations, transmission dynamics, and disease pathophysiology of NPEVs. The information presented in the review indicates the current risk assessment of NPEVs, taking into account the following factors: the need for research and therapeutic interventions, the diversity of clinical manifestations, the impact of genetic variability on virulence, the persistence of emergence despite vaccination efforts, recurrent outbreaks, and the global impact of these viruses. Conclusion: There is a possibility that NPEVs could trigger global pandemics based on their zoonotic origins and urges for complete readiness, continuous research, cooperation, and a comprehensive strategy to combat emerging infectious diseases in a constantly changing global environment. It is peak time to acknowledge how important it is to abide by safety and health laws to prevent these illnesses.

The Neuropathological Impacts of COVID-19: Challenges and Alternative Treatment Options for Alzheimer's Like Brain Changes on Severely SARS-CoV-2 Infected Patients.

Recently, some researchers claimed neuropathological changes lead to Alzheimer's-like brains after severe infection of SARS-CoV-2. Several mechanisms have been postulated on how SARS-CoV-2 neurological damage leads to Alzheimer's disease (AD) development. Neurobiochemical changes during infection may significantly induce Alzheimer's disease in severely COVID-19 infected people. The immune system is also compromised while infected by this novel coronavirus. However, recent studies are insufficient to conclude the relationship between Alzheimer's disease and COVID-19. This review demonstrates the possible pathways of neuropathological changes induced by the SARS-CoV-2 virus in AD patients or leading to AD in COVID-19 patients. Therefore, this study delineates the challenges for COVID-19 infected AD patients and the mechanism of actions of natural compounds and alternative treatments to overcome those. Furthermore, animal studies and a large cohort of COVID-19 survivors who showed neuroinflammation and neurological changes may augment the research to discover the relationship between Alzheimer's disease and COVID-19.

Plausibility of natural immunomodulators in the treatment of COVID-19-A comprehensive analysis and future recommendations.

The COVID-19 pandemic has inflicted millions of deaths worldwide. Despite the availability of several vaccines and some special drugs approved for emergency use to prevent or treat this disease still, there is a huge concern regarding their effectiveness, adverse effects, and most importantly, their efficacy against the new variants. A cascade of immune-inflammatory responses is involved with the pathogenesis and severe complications with COVID-19. People with dysfunctional and compromised immune systems display severe complications, including acute respiratory distress syndrome, sepsis, multiple organ failure etc., when they get infected with the SARS-CoV-2 virus. Plant-derived natural immune-suppressant compounds, such as resveratrol, quercetin, curcumin, berberine, luteolin, etc., have been reported to inhibit pro-inflammatory cytokines and chemokines. Therefore, natural products with immunomodulatory and anti-inflammatory potential could be plausible targets to treat this contagious disease. This review aims to delineate the clinical trials status and outcomes of natural compounds with immunomodulatory potential in COVID-19 patients along with the outcomes of their in-vivo studies. In clinical trials several natural immunomodulators resulted in significant improvement of COVID-19 patients by diminishing COVID-19 symptoms such as fever, cough, sore throat, and breathlessness. Most importantly, they reduced the duration of hospitalization and the need for supplemental oxygen therapy, improved clinical outcomes in patients with COVID-19, especially weakness, and eliminated acute lung injury and acute respiratory distress syndrome. This paper also discusses many potent natural immunomodulators yet to undergo clinical trials. In-vivo studies with natural immunomodulators demonstrated reduction of a wide range of proinflammatory cytokines. Natural immunomodulators that were found effective, safe, and well tolerated in small-scale clinical trials are warranted to undergo large-scale trials to be used as drugs to treat COVID-19 infections. Alongside, compounds yet to test clinically must undergo clinical trials to find their effectiveness and safety in the treatment of COVID-19 patients.

Resveratrol treatment modulates several antioxidant and anti-inflammatory genes expression and ameliorated oxidative stress mediated fibrosis in the kidneys of high-fat diet-fed rats.

Objective: Resveratrol is a polyphenolic compound that possesses strong antioxidant and anti-inflammatory activities. This study evaluated the effects of resveratrol on oxidative stress, fibrosis and multiple genes regulation in the kidneys of high fat (HF) diet-fed rats. Methods: Wistar rats were fed with HF diet for eight weeks. These rats were also treated with resveratrol for eight weeks. Finally, kidney tissue samples were isolated from all sacrificed rats. The histological changes, creatinine and uric acid levels, oxidative stress parameters such as malondialdehyde (MDA), nitric oxide, and advanced oxidation protein product (AOPP) levels were analyzed. The antioxidant enzymes such as catalase, superoxide dismutase (SOD) activities and reduced glutathione (GSH) levels; gene expression of inflammatory and fibrosis-related genes namely, inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), transforming growth factor beta1 (TGF-ß1), and collagen-1 were assessed. Moreover, gene expression of oxidative stress-related genes such as nuclear factor erythroid 2-related factor 2 (Nrf-2), SOD, catalase, and glutathione reductase, were also assessed. Results: HF diet-fed rats showed increased creatinine and uric acid levels in plasma which were lowered by resveratrol treatment. The study findings also revealed that resveratrol counterbalanced the oxidative stress and prevented the expression of the inflammatory genes; restored the catalase and SOD activities followed by the up-regulation of antioxidant genes expression in the kidneys of HF diet-fed rats. HF diet caused the Nrf-2 down-regulation followed by the decreased expression of HO-1 and HO-2 genes, which was restored by resveratrol treatment. Moreover, the histological assessment showed lipotoxicity and increased fibrosis in the kidneys of HF diet-fed rats. Resveratrol prevented the kidney fibrosis probably by limiting oxidative stress, inflammation, and down-regulating TGF-ß1 mediated signaling pathway. Conclusion: In conclusion, resveratrol treatment showed beneficial effects in preventing oxidative stress and fibrosis in the kidneys of HF diet-fed rats probably by modulating the gene expression of oxidative stress and inflammation related factors and enzymes.

A comprehensive look into the association of vitamin D levels and vitamin D receptor gene polymorphism with obesity in children.

Childhood obesity accounts for several psychosocial and clinical consequences. Psychosocial consequences include lower self-esteem, social isolation, poor academic achievement, peer problems, and depression, whereas clinical consequences are cardiovascular diseases, type 2 diabetes, dyslipidemia, cancer, autoimmune diseases, girls early polycystic ovarian syndrome (PCOS), asthma, bone deformities, etc. A growing number of studies have uncovered the association of childhood obesity and its consequences with vitamin-D (vit-D) deficiency and vitamin-D receptor (VDR) gene polymorphisms such as single nucleotide polymorphisms (SNPs), e.g., TaqI, BsmI, ApaI, FokI, and Cdx2. Considering the impact of vit-D deficiency and VDR gene polymorphisms, identifying associated factors and risk groups linked to lower serum vit-D levels and prevention of obesity-related syndromes in children is of utmost importance. Previously published review articles mainly focused on the association of vit-D deficiency with obesity or other non-communicable diseases in children. The nature of the correlation between vit-D deficiency and VDR gene polymorphisms with obesity in children is yet to be clarified. Therefore, this review attempts to delineate the association of obesity with these two factors by identifying the molecular mechanism of the relationship.

GC-MS-employed phytochemical characterization, synergistic antioxidant, and cytotoxic potential of Triphala methanol extract at non-equivalent ratios of its constituents.

Triphala is a famous triherbal drug, comprising three herb fruits, including Terminalia chebula (Haritaki), Terminalia bellirica (Bibhitaki), and Phyllanthus emblica (Amalaki). It is enriched with vitamin C, polyphenols, flavonoids, sterols, saponins, etc., and is well-documented for its potent antioxidant, anticancer, chemoprotective, antimicrobial, and anti-inflammatory effects. This research was conducted to evaluate the synergistic antioxidative and cytotoxic potential of mixtures of the individual constituents of Triphala at their nonequivalent ratios along with the chemical characterization of individual constituents of Triphala to identify and quantify individual compounds. The antioxidative potential was measured using total antioxidant capacity (TAC), DPPH free radical scavenging assay, and total phenolic content (TPC) tests. The cytotoxic potential was assessed on brain cancer cells (N4X4) using MTT assay, and phytochemical characterization was performed by GS-MS analysis. Nonequivalent ratios of Triphala constituents exhibited significantly higher synergistic antioxidant and cytotoxic potential than the equivalent ratios of them. Moreover, the nonequivalent ratio where the quantity of Amalaki was doubled than the other two constituents showed the highest synergistic antioxidant and cytotoxic effect. GC-MS analysis of individual constituents of Triphala identified and quantified the presence of a wide array of compounds, and fatty acid, fatty acid ester, triterpene, and aminoglycoside remained the predominant class of compounds. Thus, it can be inferred that the observed bioactivities can be attributed to the phytocompounds characterized and extracts at the nonequivalent ratio of Triphala constituents where Amalaki is doubled can be more effective in treating oxidative degenerative diseases and glioblastoma.

Therapeutic potential of dopamine agonists in the treatment of type 2 diabetes mellitus.

Diabetes is a global health concern that has affected almost 415 million people globally. Bromocriptine is a dopamine D2 agonist, which is a Food and Drug Administration (FDA)-approved drug to treat type 2 diabetes mellitus (T2DM) patients. However, it is considered that a novel treatment therapy is required which can be used in the treatment of diabetes with or without other antidiabetic agents. Dopamine agonists are usually used in neurological disorders like Parkinson's disease (PD), restless leg syndrome, and hyperprolactinemia. However, dopamine agonists including bromocriptine and cabergoline are also effective in reducing the glycemic level in T2DM patients. Bromocriptine was formerly used for the treatment of PD, hyperprolactinemia, and restless leg syndrome, but now it is used for improving glycemic levels as well as reducing free fatty acids and triglycerides. In addition, cabergoline has been found to be effective in glycemic control, but this drug is yet to be approved by the FDA due to its limitations and lack of study. Findings of the clinical trials of bromocriptine have suggested that it reduces almost 0.4-0.8% glycated hemoglobin and cardiovascular risk by 40% in insulin-resistant patients. Moreover, the safe use of bromocriptine in obese T2DM patients makes it a more attractive option as it causes weight loss. Indeed, bromocriptine is a novel therapy for T2DM patients, as its mechanism of action is unique in T2DM patients with minimal adverse effects. This review summarizes the potential of dopamine agonists in the treatment of T2DM.

Therapeutic Potential of Polyphenols in the Management of Diabetic Neuropathy.

Diabetic neuropathy (DN) is a common and serious diabetes-associated complication that primarily takes place because of neuronal dysfunction in patients with diabetes. Use of current therapeutic agents in DN treatment is quite challenging because of their severe adverse effects. Therefore, there is an increased need of identifying new safe and effective therapeutic agents. DN complications are associated with poor glycemic control and metabolic imbalances, primarily oxidative stress (OS) and inflammation. Various mediators and signaling pathways such as glutamate pathway, activation of channels, trophic factors, inflammation, OS, advanced glycation end products, and polyol pathway have a significant contribution to the progression and pathogenesis of DN. It has been indicated that polyphenols have the potential to affect DN pathogenesis and could be used as potential alternative therapy. Several polyphenols including kolaviron, resveratrol, naringenin, quercetin, kaempferol, and curcumin have been administered in patients with DN. Furthermore, chlorogenic acid can provide protection against glutamate neurotoxicity via its hydrolysate, caffeoyl acid group, and caffeic acid through regulating the entry of calcium into neurons. Epigallocatechin-3-gallate treatment can protect motor neurons by regulating the glutamate level. It has been demonstrated that these polyphenols can be promising in combating DN-associated damaging pathways. In this article, we have summarized DN-associated metabolic pathways and clinical manifestations. Finally, we have also focused on the roles of polyphenols in the treatment of DN.

A Comprehensive Analysis into the Therapeutic Application of Natural Products as SIRT6 Modulators in Alzheimer's Disease, Aging, Cancer, Inflammation, and Diabetes.

Natural products have long been used as drugs to treat a wide array of human diseases. The lead compounds discovered from natural sources are used as novel templates for developing more potent and safer drugs. Natural products produce biological activity by binding with biological macromolecules, since natural products complement the protein-binding sites and natural product-protein interactions are already optimized in nature. Sirtuin 6 (SIRT6) is an NAD+ dependent histone deacetylase enzyme and a unique Sirtuin family member. It plays a crucial role in different molecular pathways linked to DNA repair, tumorigenesis, glycolysis, gluconeogenesis, neurodegeneration, cardiac hypertrophic responses, etc. Thus, it has emerged as an exciting target of several diseases such as cancer, neurodegenerative diseases, aging, diabetes, metabolic disorder, and heart disease. Recent studies have shown that natural compounds can act as modulators of SIRT6. In the current review, a list of natural products, their sources, and their mechanisms of SIRT6 activity modulation has been compiled. The potential application of these naturally occurring SIRT6 modulators in the amelioration of major human diseases such as Alzheimer's disease, aging, diabetes, inflammation, and cancer has also been delineated. Natural products such as isoquercetin, luteolin, and cyanidin act as SIRT6 activators, whereas vitexin, catechin, scutellarin, fucoidan, etc. work as SIRT6 inhibitors. It is noteworthy to mention that quercetin acts as both SIRT6 activator and inhibitor depending on its concentration used. Although none of them were found as highly selective and potent modulators of SIRT6, they could serve as the starting point for developing selective and highly potent scaffolds for SIRT6.

A Review of the Recent Advances Made with SIRT6 and its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets.

Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide⁺ (NAD⁺) dependent enzyme and stress response protein that has sparked the curiosity of many researchers in different branches of the biomedical sciences. A unique member of the known Sirtuin family, SIRT6 has several different functions in multiple different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses, and more. Only in recent times, however, did the potential usefulness of SIRT6 come to light as we learned more about its biochemical activity, regulation, biological roles, and structure Frye (2000). Even until very recently, SIRT6 was known more for chromatin signaling but, being a nascent topic of study, more information has been ascertained and its potential involvement in major human diseases including diabetes, cancer, neurodegenerative diseases, and heart disease. It is pivotal to explore the mechanistic workings of SIRT6 since future research may hold the key to engendering strategies involving SIRT6 that may have significant implications for human health and expand upon possible treatment options. In this review, we are primarily concerned with exploring the latest advances in understanding SIRT6 and how it can alter the course of several life-threatening diseases such as processes related to aging, cancer, neurodegenerative diseases, heart disease, and diabetes (SIRT6 has also shown to be involved in liver disease, inflammation, and bone-related issues) and any recent promising pharmacological investigations or potential therapeutics that are of interest.

A new cytotoxic diterpenoid glycoside from the leaves of Blumea lacera and its effects on apoptosis and cell cycle.

A new diterpenoid glycoside, 6E,10E,14Z-(3S)-17-hydroxygeranyllinalool-17-O-ß-d-glucopyranosyl-(1 → 2)-[α-l-rhamnopyranosyl-(1 → 6)]-ß-d-glucopyranoside (1) together with the known diterpenoid glycoside (2) and two known flavonoid glycosides (3, 4) were isolated from the methanol extract of Blumea lacera leaves. The structures were determined by the interpretation of their spectroscopic data and comparison with the literature. All compounds were isolated for the first time from B. lacera and evaluated for their cytotoxic activity. Only the new compound (1) showed strong cytotoxic activity with the lowest IC50 value (8.3 µM) being displayed against MCF-7 breast cancer cells. In apoptosis and cell cycle analysis, 1 revealed strong apoptotic activity against MCF-7 cells (45.5% AV+/PI-) after 24 h, but showed no arresting of any of the cell cycle phases in MCF-7.

A New Cytotoxic Steroidal Glycoalkaloid from the Methanol Extract of Blumea lacera Leaves.

PURPOSE: Blumea lacera (B. lacera) (Asteraceae) is a well-known Bangladeshi medicinal plant. This study aimed to identify and characterize constituents associated with the significant cytotoxic activity of this plant that we reported previously. Here, we describe the isolation and characterization of a new steroidal glycoalkaloid (SGA) 1, the evaluation of its cytotoxic activity, apoptotic potential, and effect on cell cycle in comparison to analogous steroidal glycoalkaloids (SGAs). METHODS: SGA 1 was isolated using C18 SPE and HPLC, and subsequently structurally characterized using 1D and 2D NMR, MS and other spectroscopic methods, along with a comparative inspection of the literature. Cytotoxic activity of 1 and seven SGA analogues and steroidal alkaloids (SAs), (ß-solamarine, α-solanine, ß-solamargine, α-solasonine, khasianine, solasodine, tomatidine HCl) were evaluated for their cytotoxicity against two healthy (NIH3T3 and VERO) and four human cancer (AGS, HT-29, MCF-7 and MDA-MB-231) cell lines using the MTT assay. Cytotoxic SGAs were further evaluated for apoptosis-inducing potential and cell cycle arresting ability against breast cancer cells (MCF-7) using the FITC Annexin V and propidium iodide (PI) assay. RESULTS: Bioactivity guided fractionation of the methanol extract of B. lacera led to isolation of compound 1: (25R)-3ß-{O-ß-D-glucopyranosyl-(1 → 4)-O-α-L-rhamnopyranosyl-(1 → 4)-[O-α-L-rhamnopyranosyl-(1 → 2)]-α-L-rhamnopyranosyl}-22αN-spirosol-5-ene. SGA 1 was the most cytotoxic compound against a number of human cancer cell lines with an IC50 of 2.62 µM against MCF-7 cells. It displayed the highest apoptotic potential (32% AV+/PI-) on MCF-7 cells compared to other cytotoxic SGA analogues and a slight, but significant cell cycle arresting effect. CONCLUSIONS: A new SGA 1 was isolated from B. lacera and its cytotoxic activity, as well as that of other SAGs, was evaluated. SAR investigations on SGA 1, in relation to SGA analogues, show that the number and nature of sugar moieties along with the linkages of the sugar to the aglycone are crucial for cytotoxic and apoptotic activity. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

HPLC-Analysis of Polyphenolic Compounds in Gardenia jasminoides and Determination of Antioxidant Activity by Using Free Radical Scavenging Assays.

PURPOSE: Gardenia jasminoides is a traditional medicinal plant rich in anti-inflammatory flavonoids and phenolic compounds and used for the treatment of inflammatory diseases and pain. In this present study, antioxidant potential of Gardenia jasminoides leaves extract was evaluated by using various antioxidant assays. METHODS: Various antioxidant assays such as 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, reducing power and total antioxidant capacity expressed as equivalent to ascorbic acid were employed. Moreover, phenolic compounds were detected by high-performance liquid chromatography (HPLC) coupled with diode-array detection. RESULTS: The methanol extract showed significant free radical scavenging activities in DPPH radical scavenging antioxidant assays compared to the reference antioxidant ascorbic acid. Total antioxidant activity was increased in a dose dependent manner. The extract also showed strong reducing power. The total phenolic content was determined as 190.97 mg/g of gallic acid equivalent. HPLC coupled with diode-array detection was used to identify and quantify the phenolic compounds in the extracts. Gallic acid, (+)-catechin, rutin hydrate and quercetin have been identified in the plant extracts. Among the phenolic compounds, catechin and rutin hydrate are present predominantly in the extract. The accuracy and precision of the presented method were corroborated by low intra- and inter-day variations in quantitative results in leaves extract. CONCLUSION: These results suggest that phenolic compounds and flavonoids might contribute to high antioxidant activities of Gardenia jasminoides leaves.

Cytotoxic activity screening of Bangladeshi medicinal plant extracts.

The cytotoxic activity of 23 crude methanol extracts from 19 Bangladeshi medicinal plants was investigated against healthy mouse fibroblasts (NIH3T3), healthy monkey kidney (VERO) and four human cancer cell lines (gastric, AGS; colon, HT-29; and breast, MCF-7 and MDA-MB-231) using MTT assay. High cytotoxicity across all cell lines tested was exhibited by Aegiceras corniculatum (fruit) and Hymenodictyon excelsum (bark) extracts (IC50 values ranging from 0.0005 to 0.9980 and 0.08 to 0.44 mg/mL, respectively). Fourteen extracts from 11 plant species, namely Clitoria ternatea (flower and leaf), Dillenia indica (leaf), Diospyros peregrina (leaf), Dipterocarpus turbinatus (bark and leaf), Ecbolium viride (leaf), Glinus oppositifolius (whole plant), Gnaphalium luteoalbum (leaf), Jasminum sambac (leaf), Lannea coromandelica (bark and leaf), Mussaenda glabrata (leaf) and Saraca asoca (leaf), were also significantly cytotoxic (IC50 < 1.0 mg/mL) against at least one of the cancer cell lines tested. More selectively, Avicennia alba (leaf), C. ternatea (flower and leaf), Caesalpinia pulcherrima (leaf), E. viride (leaf) and G. oppositifolius (whole plant) showed cytotoxicity only against both of the breast cancer cell lines (MCF-7 and MDA-MB-231). In contrast, C. ternatea (flower and leaf) exhibited high cytotoxic activity against MDA-MB-231 (IC50 values of 0.11 and 0.49 mg/mL, respectively), whereas E. viride and G. oppositifolius whole plant extracts exhibited high activity against MCF-7 cells (IC50 values of 0.06 and 0.15 mg/mL, respectively). The cytotoxic activity test results for 9 of the plant species correlate with their traditional use as anticancer agents, thus making them interesting sources for further drug development.

Antidiarrhoeal property of the hydroethanolic extract of the flowering tops of Anthocephalus cadamba / Propriedade antidiarréica do extrato hidroetanólico dos topos floridos de Anthocephalus cadamba

A propriedade antidiarréica do extrato hidroetanólico dos topos floridos de Anthocephalus cadamba foi avaliada em animais experimentais. O extrato hidroetanólico seco (250-500 mg/kg massa corpórea, v.o.) exibiu uma diminuição dose-dependente do número total de excrementos na diarréia induzida por óleo de castor em camundongos. O extrato também causou uma redução significativa (p < 0.01) e dose-dependente do acúmulo de fluidos intestinais e do trânsito gastrointestinal de 64,59 por cento e 71,19 por cento nas doses de 250 e 500 mg/kg. As taxas de redução foram de 37,85 por cento e 74,91 por cento, respectivamente, com o grupo controle e da droga padrão.

The antidiarrhoeal property of the hydroethanolic extract of the flowering tops of Anthocephalus cadamba was assessed on experimental animals. The dry hydroethanolic extract (250-500 mg/kg body mass, p.o.) exhibited a dose-dependent decrease in the total number of faecal droppings in castor oil-induced diarrhoea in mice. The extract also produced a significant (p < 0.01) and dose-dependent reduction in intestinal fluids accumulation and in the gastrointestinal transit from 64.59 percent and 71.19 percent at doses of 250 and 500 mg/kg. The reduction rates were 37.85 percent and 74.91 percent, respectively, with the control and standard drug group.