Role of Epigenetic Modulation in Neurodegenerative Diseases: Implications of Phytochemical Interventions.

Epigenetics defines changes in cell function without involving alterations in DNA sequence. Neuroepigenetics bridges neuroscience and epigenetics by regulating gene expression in the nervous system and its impact on brain function. With the increase in research in recent years, it was observed that alterations in the gene expression did not always originate from changes in the genetic sequence, which has led to understanding the role of epigenetics in neurodegenerative diseases (NDDs) including Alzheimer's disease (AD) and Parkinson's disease (PD). Epigenetic alterations contribute to the aberrant expression of genes involved in neuroinflammation, protein aggregation, and neuronal death. Natural phytochemicals have shown promise as potential therapeutic agents against NDDs because of their antioxidant, anti-inflammatory, and neuroprotective effects in cellular and animal models. For instance, resveratrol (grapes), curcumin (turmeric), and epigallocatechin gallate (EGCG; green tea) exhibit neuroprotective effects through their influence on DNA methylation patterns, histone acetylation, and non-coding RNA expression profiles. Phytochemicals also aid in slowing disease progression, preserving neuronal function, and enhancing cognitive and motor abilities. The present review focuses on various epigenetic modifications involved in the pathology of NDDs, including AD and PD, gene expression regulation related to epigenetic alterations, and the role of specific polyphenols in influencing epigenetic modifications in AD and PD.

Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial.

Background: Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations of these agents. The aim of this trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19, which may be particularly relevant to low-resource countries. Methods: We conducted an open-label, randomized, outpatient, controlled trial in Thailand from October 1, 2021, to June 21, 2022, to assess whether early treatment within 48-h of symptoms onset with combinations of fluvoxamine, bromhexine, cyproheptadine, and niclosamide, given to adults with confirmed mild SARS-CoV-2 infection, can prevent 28-day clinical deterioration compared to standard care. Participants were randomly assigned to receive treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care. The primary outcome measured was clinical deterioration within 9, 14, or 28 days using a 6-point ordinal scale. This trial is registered with ClinicalTrials.gov (NCT05087381). Findings: Among 1900 recruited, a total of 995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen. In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5% (21). Additionally, 20.8% (70) of patients in the standard care arm required low-flow oxygen by day 9, and 12.5% (16) needed non-invasive or mechanical ventilation by day 28. All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p < 0.0001). Also, by day 28, the three 2-drug treatments were significantly better than the fluvoxamine arm (p < 0.0001). No deaths occurred in any study group. Compared to standard care, participants treated with the combination agents had significantly decreased viral loads as early as day 3 of treatment (p < 0.0001), decreased levels of serum cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) as early as day 5 of treatment, and interleukin-8 (IL-8) by day 7 of treatment (p < 0.0001) and lower incidence of post-acute sequelae of COVID-19 (PASC) symptoms (p < 0.0001). 23 serious adverse events occurred in the standard care arm, while only 1 serious adverse event was reported in the fluvoxamine arm, and zero serious adverse events occurred in the other arms. Interpretation: Early treatment with these combinations among outpatients diagnosed with COVID-19 was associated with lower likelihood of clinical deterioration, and with significant and rapid reduction in the viral load and serum cytokines, and with lower burden of PASC symptoms. When started very soon after symptom onset, these repurposed drugs have high potential to prevent clinical deterioration and death in vaccinated and unvaccinated COVID-19 patients. Funding: Ped Thai Su Phai (Thai Ducks Fighting Danger) social giver group.

Repurposing fluoxetine to treat lymphocytic leukemia: Apoptosis induction, sigma-1 receptor upregulation, inhibition of IL-2 cytokine production, and autophagy induction.

BACKGROUND: Childhood cancer has a cure rate of as low as 15% in low-income countries, suggesting a need for cheaper treatment options. Fluoxetine is a thoroughly safety-tested drug that may target the sigma-1 receptor (σ1-R). RESEARCH DESIGN AND METHODS: Using the human leukemic cell line, Jurkat, we investigated the effects of fluoxetine on cell survival using XTT and trypan blue staining. Apoptosis was measured using AnnexinV/PI staining and western blot analysis of caspase cleavage. IL-2 secretion of Jurkat cells in response to PHA/PMA was measured using ELISA, and the expression of AKT/pAKT and the σ1-R were measured using western blotting. RESULTS: Fluoxetine-induced apoptosis and G-2 cell cycle arrest. Fluoxetine reduced IL-2 secretion dose-dependently and could be further potentiated by σ1-R antagonist BD1047 (P < 0.05). Fluoxetine inhibited pAKT six hours post-treatment (P < 0.05). The expression of the σ1-R showed a significant increase between 12 to 48 hours in Jurkat cells (P < 0.05). At the same time, there was a substantial increase in autophagy. CONCLUSIONS: Fluoxetine may have the potential for acute leukemia treatment. Co-treatment with a σ1-R antagonist increases fluoxetine-induced apoptosis, possibly targeting AKT phosphorylation and autophagy activation.

Plant Polyphenols for Aging Health: Implication from Their Autophagy Modulating Properties in Age-Associated Diseases.

Polyphenols are a family of naturally occurring organic compounds, majorly present in fruits, vegetables, and cereals, characterised by multiple phenol units, including flavonoids, tannic acid, and ellagitannin. Some well-known polyphenols include resveratrol, quercetin, curcumin, epigallocatechin gallate, catechin, hesperetin, cyanidin, procyanidin, caffeic acid, and genistein. They can modulate different pathways inside the host, thereby inducing various health benefits. Autophagy is a conserved process that maintains cellular homeostasis by clearing the damaged cellular components and balancing cellular survival and overall health. Polyphenols could maintain autophagic equilibrium, thereby providing various health benefits in mediating neuroprotection and exhibiting anticancer and antidiabetic properties. They could limit brain damage by dismantling misfolded proteins and dysfunctional mitochondria, thereby activating autophagy and eliciting neuroprotection. An anticarcinogenic mechanism is stimulated by modulating canonical and non-canonical signalling pathways. Polyphenols could also decrease insulin resistance and inhibit loss of pancreatic islet ß-cell mass and function from inducing antidiabetic activity. Polyphenols are usually included in the diet and may not cause significant side effects that could be effectively used to prevent and treat major diseases and ailments.

Role of Herbal Teas in Regulating Cellular Homeostasis and Autophagy and Their Implications in Regulating Overall Health.

Tea is one of the most popular and widely consumed beverages worldwide, and possesses numerous potential health benefits. Herbal teas are well-known to contain an abundance of polyphenol antioxidants and other ingredients, thereby implicating protection and treatment against various ailments, and maintaining overall health in humans, although their mechanisms of action have not yet been fully identified. Autophagy is a conserved mechanism present in organisms that maintains basal cellular homeostasis and is essential in mediating the pathogenesis of several diseases, including cancer, type II diabetes, obesity, and Alzheimer's disease. The increasing prevalence of these diseases, which could be attributed to the imbalance in the level of autophagy, presents a considerable challenge in the healthcare industry. Natural medicine stands as an effective, safe, and economical alternative in balancing autophagy and maintaining homeostasis. Tea is a part of the diet for many people, and it could mediate autophagy as well. Here, we aim to provide an updated overview of popular herbal teas' health-promoting and disease healing properties and in-depth information on their relation to autophagy and its related signaling molecules. The present review sheds more light on the significance of herbal teas in regulating autophagy, thereby improving overall health.

Rhinacanthus nasutus "Tea" Infusions and the Medicinal Benefits of the Constituent Phytochemicals.

Rhinacanthus nasutus (L.) Kurz (Acanthaceae) (Rn) is an herbaceous shrub native to Thailand and much of South and Southeast Asia. It has several synonyms and local or common names. The root of Rn is used in Thai traditional medicine to treat snake bites, and the roots and/or leaves can be made into a balm and applied to the skin for the treatment of skin infections such as ringworm, or they may be brewed to form an infusion for the treatment of inflammatory disorders. Rn leaves are available to the public for purchase in the form of "tea bags" as a natural herbal remedy for a long list of disorders, including diabetes, skin diseases (antifungal, ringworm, eczema, scurf, herpes), gastritis, raised blood pressure, improved blood circulation, early-stage tuberculosis antitumor activity, and as an antipyretic. There have been many studies investigating the roles of Rn or compounds isolated from the herb regarding diseases such as Alzheimer's and other neurodegenerative diseases, cancer, diabetes and infection with bacteria, fungi or viruses. There have, however, been no clinical trials to confirm the efficacy of Rn in the treatment of any of these disorders, and the safety of these teas over long periods of consumption has never been tested. This review assesses the recent research into the role of Rn and its constituent compounds in a range of diseases.

Neuroprotective Properties of Green Tea (Camellia sinensis) in Parkinson's Disease: A Review.

Neurodegenerative disease is a collective term given for the clinical condition, which results in progressive degeneration of neurons and the loss of functions associated with the affected brain region. Apart from the increase in age, neurodegenerative diseases are also partly affected by diet and lifestyle practices. Parkinson's disease (PD) is a slow onset neurodegenerative disorder and the second most common neurodegenerative disease, which affects the motor system. Although there is no prescribed treatment method to prevent and cure PD, clinical procedures help manage the disease symptoms. Green tea polyphenols are known for several health benefits, including antioxidant, anti-inflammatory, and neuroprotective activity. The current manuscript summarizes the possible mechanisms of neuroprotective potential of green tea with a special focus on PD. Studies have suggested that the consumption of green tea protects against free-radicals, inflammation, and neuro-damages. Several in vivo studies aid in understanding the overall mechanism of green tea. However, the same dose may not be sufficient in humans to elicit similar effects due to complex physiological, social, and cultural development. Future research focused on more clinical trials could identify an optimum dose that could impart maximum health benefits to impart neuroprotection in PD.