Macrophage dynamics in prostate cancer: Molecular to therapeutic insights.

This review provides an in-depth examination of the role that tumor-associated macrophages (TAMs) play in the progression of prostate cancer (PCa), with a particular focus on the factors influencing the polarization of M1 and M2 macrophages and the implications of targeting these cells for cancer progression. The development and prognosis of PCa are significantly influenced by the behavior of macrophages within the tumor microenvironment. M1 macrophages typically exhibit anti-tumor properties by secreting pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), thereby enhancing the immune response. Conversely, M2 macrophages contribute to tumor cell migration and invasion through the production of factors like arginase-1 (Arg1) and interleukin-10 (IL-10). This review not only explores the diverse factors that affect macrophage polarization but also delves into the potential therapeutic strategies targeting macrophage polarization, including the critical roles of non-coding RNA and exosomes in regulating this process. The polarization state of macrophages is highlighted as a key determinant in PCa progression, offering a novel perspective for clinical treatment. Future research should concentrate on gaining a deeper understanding of the molecular mechanisms underlying macrophage polarization and on developing effective targeted therapeutic strategies. The exploration of the potential of combination therapies to improve treatment efficacy is also emphasized. By emphasizing the importance of macrophages as a therapeutic target in PCa, this review aims to provide valuable insights and research directions for clinicians and researchers.

Dietary supplementation with a wild green oat extract (Avena sativa L.) to improve wellness and wellbeing during smoking reduction or cessation: a randomized double-blind controlled study.

Objective: Smoking reduction or cessation are critical public health goals, given the well-documented risks of tobacco use to health. Reducing smoking frequency and cessation entirely are challenging due to nicotine addiction and withdrawal symptoms, which can significantly affect mental wellness and overall wellbeing. Previous research has suggested that certain dietary supplements may support smoking cessation and reduction efforts by mitigating these adverse effects. The objective of this study was to assess the effect of supplementation with 900 mg/day of Neuravena®, a green oat extract (GOE) of Avena sativa L., in enhancing wellness and wellbeing during a smoking reduction or cessation experience. Methods: This was an 8-week randomized, double-blind, placebo-controlled study, ClinicalTrials Identifier: NCT04749017 (https://classic.clinicaltrials.gov/ct2/show/NCT04749017). Participants were assigned to one of the study groups, 72 participants were assigned to GOE and 73 to placebo. The subjects were followed for 8-weeks intervention period as well as an additional 4-week follow-up period. At subsequent visits, they underwent clinical assessments including assessments of quality of life, perceived stress, depression, nicotine dependence, anxiety, cognitive performance, and specific assessments of craving intensity. Results: GOE was associated with greater improvements in elements of the abbreviated World Health Organization Quality of Life (WHOQOL-BREF) questionnaire as compared with placebo. Similar results were obtained from the SF-36 questionnaire and a visual QoL analogue scale (VAS). Perceived stress levels showed greater decline from baseline among the GOE supplemented participants as compared to placebo. Sleep quality parameters improved with GOE supplementation and worsened in the placebo group. At the end of the intervention period, the percentage of successful reducers (defined as >20% reduction in daily cigarettes) was higher in the GOE group as compared to placebo (66.7% vs. 49.3%, p = 0.034). The improvements from baseline in QoL measures in the GOE group persisted at 4 weeks after termination of the intervention. Conclusion: GOE supplementation demonstrated greater improvements in quality of life measures, stress and sleep related parameters during a smoking reduction or cessation experience and the product was shown to be safe and well tolerated.

Kavalactones support motivation to move during intensive training in males preparing for military special operations forces.

BACKGROUND: Military special operators, elite athletes, and others requiring uninterrupted optimal performance currently lack options for sleep and mood support without performance-inhibiting effects. Kavalactones, derived from the root of the kava plant (Piper methysticum Forst), have been shown to elevate mood and wellbeing by producing a feeling of relaxation without addiction or cognitive impairment. METHODS: In this placebo-controlled, crossover study (NCT05381025), we investigated the effects of 2 weeks of kavalactones use on cortisol (diurnal salivary), sleep (RSQ-W; Restorative Sleep Questionnaire, Weekly), mood (DASS-21; Depression Anxiety Stress Scale-21), and motivation state to expend (Move) or conserve (Rest) energy (CRAVE; Cravings for Rest and Volitional Energy Expenditure, Right Now) in a cohort of 15 healthy, physically fit young males engaged in a rigorous, two-a-day preparation class for special operations forces qualification. RESULTS: Cortisol, sleep, and mood were within normal, healthy parameters in this cohort at baseline. This remained unchanged with kavalactones use with no significant findings of clinical interest. However, a statistically similar, positive slope for within-group Move scores was seen in both groups during kavalactones loading (first group Move slope 2.25, second group Move slope 3.29, p = 0.299). This trend was seen regardless of order and with no apparent effects on the Rest metric (all p ≥ 0.05). Moreover, a significant between-group difference appeared after 1 week of kavalactones use in the first phase (p = 0.044) and persisted through the end of the first loading period (p = 0.022). Following the 10-day washout, this between-groups divergence remained significant (p = 0.038) but was reversed by 1 week after the crossover (p = 0.072), with Move scores once again statistically similar between groups and compared to baseline at study end. Furthermore, the group taking kavalactones first never experienced a significant decrease in Move motivation state (lowest mean score 21.0, highest 28.6, all p ≥ 0.05), while the group receiving kavalactones in the last 2 weeks of the study had Move scores that were statistically lower than baseline (lowest mean score 8.6, highest 25.9, all p ≤ 0.05) at all time points but the last (p = 0.063) after 2 weeks of kavalactones exposure. CONCLUSIONS: We report a novel finding that kavalactones may support performance by maintaining or rescuing the desire to expend energy in the context of significant physical and mental strain in well-conditioned individuals, even in a context of already normal cortisol, sleep, and mood.

Opportunities and challenges in using NIH's Dietary Supplement Label Database for research on non-nutrient ingredients: Use case for ingredients in honeybee products.

Background: Non-nutrient bioactive ingredients of foods such as bee products are often of interest in preclinical and clinical research to explore their possible beneficial effects. The National Institute of Health's Dietary Supplement Label Database (DSLD) contains over 165,000 labels of dietary supplements marketed in the United States of America (US), including declarations on labels for many of these ingredients, including those in honeybee products which have been used in foods and traditional medicines for centuries worldwide and are now also appearing in dietary supplements. Methods: This article presents a use case for honeybee products that describes and tests the utility of the DSLD and other databases available in the US as research tools for identifying and quantifying the prevalence of such ingredients.. It focuses on the limitations to the information on product composition in these databases and describes how to code the ingredients using the LanguaL™ or FoodEx2 description and classification systems and the strengths and limitations of information on honeybee product ingredients, including propolis, bee pollen, royal jelly, beeswax, and bee venom. Results and Conclusions: Codes for the ingredients are provided for identifying their presence in LanguaL™ or FoodEx2 ontologies used in Europe and elsewhere. The prevalence of dietary supplement products containing these ingredients in DSLD and on the US market is low compared to some other products and ingredients. Unfortunately label declarations in DSLD do not provide quantitative information and so the data can be used only to screen for their presence, but cannot be used for quantitative exposure estimates by researchers and regulators .

The relative nature of the standards for proof of safety: a review of FDA's safety standards for various consumer products.

Are all food ingredients, dietary supplement ingredients and even foods, required to meet the same safety standards? Are they all equally safe? If so, then why do the various categories have different expressions describing their safety, such as "reasonable certainty of no harm" for food ingredients and "reasonable expectation of no harm" for dietary supplement ingredients? The basis for these different expressions is that they are not standards of safety, but standards of proof of safety. Just as in criminal vs. civil courts, the threshold for proving guilt or fault is different, so too are there differences between various categories of consumer products regulated by the US Food and Drug Administration. This manuscript describes the threshold requirements for each standard, as well as to the identity of the decision makers on what is safe, their credentials as decision makers and the databases mandated for their use.

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial on the Effect of a Dietary Supplement Containing Dry Artichoke and Bergamot Extracts on Metabolic and Vascular Risk Factors in Individuals with Suboptimal Cholesterol Levels.

The aim of this study was to assess whether dietary supplementation with a nutraceutical blend comprising extracts of bergamot and artichoke-both standardized in their characteristic polyphenolic fractions-could positively affect serum lipid concentration and insulin sensitivity, high-sensitivity C-reactive protein (hs-CRP), and indexes of non-alcoholic fatty liver disease (NAFLD) in 90 healthy individuals with suboptimal cholesterol levels. Participants were randomly allocated to treatment with a pill of either active treatment or placebo. After 6 weeks, the active-treated group experienced significant improvements in levels of triglycerides (TG), apolipoprotein B-100 (Apo B-100), and apolipoprotein AI (Apo AI) versus baseline. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (Non-HDL-C), and hs-CRP also significantly decreased in the active-treated group compared to both baseline and placebo. At the 12-week follow-up, individuals allocated to the combined nutraceutical experienced a significant improvement in TC, LDL-C, Non-HDL-C, TG, Apo B-100, Apo AI, glucose, alanine transaminase (ALT), gamma-glutamyl transferase (gGT), hs-CRP, several indexes of NAFLD, and brachial pulse volume (PV) in comparison with baseline. Improvements in TC, LDL-C, Non-HDL-C, TG, fatty liver index (FLI), hs-CRP, and endothelial reactivity were also detected compared to placebo (p < 0.05 for all). Overall, these findings support the use of the tested dietary supplement containing dry extracts of bergamot and artichoke as a safe and effective approach for the prevention and management of a broad spectrum of cardiometabolic disorders.

Nutraceuticals for Diabetic Retinopathy: Recent Advances and Novel Delivery Systems.

Diabetic retinopathy (DR) is a major vision-threatening disease among the working-age population worldwide. Present therapeutic strategies such as intravitreal injection of anti-VEGF and laser photocoagulation mainly target proliferative DR. However, there is a need for early effective management in patients with early stage of DR before its progression into the more severe sight-threatening proliferative stage. Nutraceuticals, natural functional foods with few side effects, have been proposed to be beneficial in patients with DR. Over the decades, many studies, either in vitro or in vivo, have demonstrated the advantages of a number of nutraceuticals in DR with their antioxidative, anti-inflammatory, neuroprotective, or vasoprotective effects. However, only a few clinical trials have been conducted, and their outcomes varied. The low bioavailability and instability of many nutraceuticals have indeed hindered their utilization in clinical use. In this context, nanoparticle carriers have been developed to deliver nutraceuticals and to improve their bioavailability. Despite its preclinical nature, research of interventive nutraceuticals for DR may yield promising information in their clinical applications.

Use of Dietary Supplements and Influencing Factors in Children.

INTRODUCTION: In recent years, the use of dietary supplements has increased in all age groups. Parents may also use these supplements for their children for different reasons. This study aims to determine the use of dietary supplements by children, the factors affecting this use, and the attitudes of parents about these products. METHODS: A total of 1038 children aged 2-18 years without any chronic disease who presented to the pediatric outpatient clinics of Ege University Children's Hospital were included in this study. Parents (n = 1000) who agreed to participate in the study were interviewed face-to-face, and a comprehensive questionnaire including questions about children's use of dietary supplements, sociodemographic characteristics, and parents' attitudes towards dietary supplements was administered. Analyses were performed with SPSS 25.0. RESULTS: The mean age of the children included in our study was 8.6 ± 4.8 years, and 51% (n = 510) were male. It was found that 32.5% of the children used nutritional supplements, and vitamin-mineral preparations (23.2%) were the most frequently used. Omega-3 (19.3%) and immune support products (9.4%) were the second and third most frequently used supplements, respectively. A significant relationship was found between the use of dietary supplements and the child's age, body weight, body mass index, parents' educational level, being health worker, and economic status (p < 0.05). It was found that most of the families thought that vitamin-mineral and omega-3 products were beneficial for growth and development and that they received information from doctors most frequently before taking these products. However, it was found that families followed the media as the second most frequent source of information for these products. CONCLUSIONS: Approximately one-third of the children in our study use dietary supplements. It is very important to raise awareness among families about the use of these products when necessary and with the recommendation of a physician. To prevent families from using dietary supplements that are not necessary for their children, especially due to misinformation in the media, pediatricians should provide correct information to parents about these products at every clinic visit. A concerted effort is needed from policy makers, media organizations, and health care providers to guide the safe use of DS. The results obtained from this study will shed light on future randomized controlled prospective studies.

Does Dietary Supplement Use Increase Micronutrient Intake Adequacy in Healthy Adults with Habitual Omnivorous, Vegetarian, Vegan, and Low-Carbohydrate High-Fat Diets?

Diets omitting whole food groups pose a risk for micronutrient insufficiencies, but there are no data as to whether those are suitably attenuated with dietary supplements (DS). Micronutrient intakes with food and DSs were analyzed in 130 healthy adults: 32 vegans, 37 vegetarians, 24 following low-carbohydrate high-fat diet (LCHF), and 37 omnivores. A total of 63% used DS (84% of vegans, 75% of LCHF, 54% of vegetarians, and 46% of omnivores); however, a DS did not always tackle dietary insufficiencies. Vitamin B12 was often supplemented in vegans in doses substantially higher than recommended, but it was supplemented less often in vegetarians, despite the low prevalence of sufficient intake. Only 43% of participants supplemented vitamin D in wintertime, 23% of them with an insufficient dose. Supplementation of potassium, calcium, and iodine was rare, despite low intake adequacy with food alone in all groups. Some micronutrients were supplemented unnecessarily, such as vitamin K, riboflavin, biotin, and iron. Multimicronutrient DSs were used often; they increased intake adequacy of group B vitamins but failed to sufficiently supplement vitamin D, potassium, calcium, and iodine. Although DS use increased micronutrient intake sufficiency when used properly, the knowledge on micronutrient inadequacy in all dietary patterns should be increased and the public should be educated on the proper use of DSs. Multimicronutrient DSs should be reformulated to tackle the insufficiencies.

Mixture of Rhodiola rosea and Nelumbo nucifera Extracts Ameliorates Sleep Quality of Adults with Sleep Disturbance.

Chronic sleep disturbance affects daily functioning, leading to decreased concentration, fatigue, and higher healthcare costs. Traditional insomnia medications are often associated with adverse side effects. This study investigated the efficacy of a novel compound derived from Rhodiola rosea and Nelumbo nucifera extracts (named RNE) in improving sleep quality with fewer side effects. The study included individuals between the ages of 20 and 65 with subthreshold insomnia and evaluated the effects of RNE on sleep, fatigue, and quality of life. Participants took 750 mg of RNE daily at bed-time for two weeks. The study used the Insomnia Severity Index (ISI), the Pittsburgh Sleep Quality Index (PSQI), a sleep diary, the Fatigue Severity Scale (FSS), and the Short Form 36 Health Survey (SF-36) for assessments. Of the 20 participants, 13 completed the study and showed significant improvements in sleep quality. The results showed improvements in ISI and PSQI scores, a 57% reduction in wake-time after sleep onset, and improved sleep efficiency. Although FSS scores remained unchanged, significant improvements were seen in SF-36 physical and mental health scores. The results suggest that RNE is an effective, low-risk option for sleep disturbance, significantly improving sleep quality and overall wellbeing without significant side effects.

Effects of a Dietary Supplement Composed of Baicalin, Bromelain and Escin for Venous Chronic Insufficiency Treatment: Insights from a Retrospective Observational Study.

Chronic venous insufficiency (CVI) represents a risk factor for cardiovascular events. The first-line treatment includes the use of compression stockings and lifestyle changes. Natural products, such as flavonoids, could be used to improve the effects of compression therapy due to their anti-inflammatory and anti-oxidant properties. This study aims to evaluate the effects of a dietary supplement containing baicalin, bromeline and escin in CVI patients. A retrospective cohort study was performed by using the medical records of CVI affected outpatients. Patients treated with the dietary supplement were defined as "users". A modified Venous Clinical Severity Score (VCSS) was calculated, including pain, inflammation, vessels induration and skin pigmentation. All clinical variables were evaluated at baseline (T0), after 30 (T1) and 90(T2) days in "users" and "non-users". Out of 62 patients, 30 (48.4%) were "users". No difference was observed between groups at baseline. A lower VCSS value was recorded in "users" than that observed in "non-users" at T2 (7.0 (4.0-9.0) vs. 9.0 (5.0-10.0); p = 0.025). Vessels' induration and pain significantly reduced in 53.3% and 43.3% of "users" and in 18.8% and 9.4% of "non-users". Only "users" (33.3%) showed a reduction of the inflammatory signs as well as a decrease in malleolar circumference, from 29.0 (26.5-30.0) to 27.5 (26.0-28.5) (p < 000.1). A reduction of C-reactive Protein levels was found in "users" compared to "non-users" at T2 (1.0 (0.9-1.2) vs. 1.3 (1.0-1.5); p = 0.006). These findings suggest that implementation of a dietary supplement could improve the clinical outcomes of CVI patients.

The dietary supplements effect on metabolic markers in non-pharmacologically managed gestational diabetes mellitus patients: a systematic review and meta-analysis and meta-regression of randomized controlled trials.

Background: Although several randomized clinical trials have tested the effect of prenatal dietary supplements on plasma glucose and lipid levels in non-pharmacologically managed gestational diabetes mellitus patients (GDM), a rigorous meta-analytic compendium lacks in the context. Therefore, this study aims to address this evidence gap. Method: Eligible trials retrieved from searches in the PubMed, Embase, and Scopus databases were appraised using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). The weighted mean differences (WMD) between dietary supplements and placebo were estimated using random-effect meta-analysis models for plasma glycemic and lipid markers. Meta-regression analysis ensued for effect modifier identification. The statistical significance estimation happened at p < 0.05 (95% confidence interval). Results: This review included 19 trials (mostly Iranian and of low risk of bias primarily) of > 8000 GDM patients. Meta-analysis showed favorable effects of dietary supplementation on fasting plasma glucose (WMD: -5.42 mg/dL, p < 0.001), homeostasis model assessment indexes- insulin resistance (HOMA-IR; WMD: -1.02, p < 0.001), quantitative insulin sensitivity check index (WMD: 0.01, p < 0.001), total cholesterol (TC; WMD: -7.70 mg/dL, p = 0.006), triglycerides (WMD: -10.23 mg/dL, p = 0.0083), TC/high-density lipoprotein (WMD: -0.31 mg/dL, p < 0.001), low-density lipoprotein (WMD: -5.79 mg/dL; p < 0.001) and very-low-density lipoprotein (WMD: -5.67 mg/dL, p < 0.001) levels. However, the HOMA- ß-cell function didn't increase (WMD: -17.91, p < 0.001). Baseline maternal age (ß = 0.28, p = 0.014) and GDM diagnostic criteria (ß = 0.90, p = 0.012) were effect moderators of HOMA-IR and body mass index (BMI) (ß = 6.07, p = 0.022) and supplement type (solo versus combined) (ß = 14.99, p = 0.006) were effect moderators of triglyceride levels. Conclusion: Altogether, antenatal dietary supplements achieved control over plasma glycemic and lipid profiles in non-pharmacologically treated GDM patients. Maternal age and GDM diagnostic criteria moderated HOMA-IR levels. BMI and supplement-type moderated triglyceride levels. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01369-0.

Oleuropein has hypophagic effects in broiler chicks.

Oleuropein, a phenolic compound derived from olives, has known glucoregulatory effects in mammalian models but effects in birds are unknown. We investigated effects of dietary supplementation and exogenous administration of oleuropein on broiler chick feed intake and glucose homeostasis during the first 7 days post-hatch. One hundred and forty-eight day-of-hatch broiler chicks were randomly allocated to one of four dietary treatments with varying oleuropein concentrations (0, 250, 500, or 1,000 mg/kg). Body weight and breast muscle and liver weights were recorded on day 7. In the next experiment, chicks received intraperitoneal (IP) injections of oleuropein at doses of 0 (vehicle), 50, 100, or 200 mg/kg on day 4 post-hatch, with feed intake and blood glucose levels measured thereafter. Lastly, chicks fed a control diet were fasted and administered intracerebroventricular (ICV) injections of oleuropein at doses of 0, 50, 100, or 200 µg, after which feed intake was recorded. Results indicated that IP and ICV injections led to decreased feed intake, primarily at 60 min post-injection, with effects diminishing by 90 min in the IP study. Blood glucose levels decreased 1-h post-IP injection at higher oleuropein doses. These findings suggest that oleuropein acts as a mild appetite suppressant and influences energy metabolism in broiler chickens.

Pharmacognostical characterization, GC-MS profiling, and elemental analysis of Curcuma caesia Roxb. rhizomes for public health.

OBJECTIVES: The study provides a thorough examination of the rhizomes of Curcuma caesia Roxb., which is a medicinal substance sometimes referred to as black turmeric and has not been well studied. METHODS: The study examines the pharmacognostical characteristics, GC-MS profiling, and elemental analysis of the substance to determine its potential for use in medicine. The presence of heavy metal contamination in herbal products is a significant issue, which necessitates the use of Atomic Absorption Spectrophotometry to quantitatively analyze eight elements. RESULTS: The investigation validates the existence of crucial trace elements while guaranteeing that the levels of heavy metals are within the toxicity limits set by the World Health Organization. This indicates that the rhizome is safe for medicinal purposes. The selection of a solvent has a substantial impact on the efficiency of extraction. Acetone has the highest extraction yield, followed by ethanol and ethyl acetate. The GC-MS analysis uncovers a wide range of phytochemicals, such as alkaloids, flavonoids, phenols, tannins, steroids, and proteins. Additionally, particular solvents exclusively detect specific molecules. Epicurzerenone and zederone are chemicals that show promise for use in reducing inflammation and fighting cancer. CONCLUSIONS: On the basis of results it can be concluded that rhizome's quality based on acceptable physicochemical characteristics and provides a strong basis for future pharmacological research. The research has potential for the development of novel organic drugs, utilizing the abundant phytochemical composition of C. caesia Roxb. rhizomes.

Network Pharmacology Analysis of the Potential Pharmacological Mechanism of a Sleep Cocktail.

Insomnia, also known as sleeplessness, is a sleep disorder due to which people have trouble sleeping, followed by daytime sleepiness, low energy, irritability, and a depressed mood. It may result in an increased risk of accidents of all kinds as well as problems focusing and learning. Dietary supplements have become popular products for alleviating insomnia, while the lenient requirements for pre-market research result in unintelligible mechanisms of different combinations of dietary supplements. In this study, we aim to systematically identify the molecular mechanisms of a sleep cocktail's pharmacological effects based on findings from network pharmacology and molecular docking. A total of 249 targets of the sleep cocktail for the treatment of insomnia were identified and enrichment analysis revealed multiple pathways involved in the nervous system and inflammation. Protein-protein interaction (PPI) network analysis and molecular complex detection (MCODE) analysis yielded 10 hub genes, including AKT1, ADORA1, BCL2, CREB1, IL6, JUN, RELA, STAT3, TNF, and TP53. Results from weighted correlation network analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of insomnia-related transcriptome data from peripheral blood mononuclear cells (PBMCs) showed that a sleep cocktail may also ease insomnia via regulating the inflammatory response. Molecular docking results reveal good affinity of Sleep Cocktail to 9 selected key targets. It is noteworthy that the crucial target HSP90AA1 binds to melatonin most stably, which was further validated by MD simulation.

Hepatotoxicity of usnic acid and underlying mechanisms.

Since usnic acid was first isolated in 1844 as a prominent secondary lichen metabolite, it has been used for various purposes worldwide. Usnic acid has been claimed to possess numerous therapeutic properties, including antimicrobial, anti-inflammatory, antiviral, anti-proliferative, and antipyretic activities. Approximately two decades ago, crude extracts of usnic acid or pure usnic acid were marketed in the United States as dietary supplements for aiding in weight loss as a "fat-burner" and gained popularity in the bodybuilding community; however, hepatotoxicity was documented for some usnic acid containing products. The US Food and Drug Administration (FDA) received numerous reports of liver toxicity associated with the use of dietary supplements containing usnic acid, leading the FDA to issue a warning letter in 2001 on a product, LipoKinetix. The FDA also sent a recommendation letter to the manufacturer of LipoKinetix, resulting in the withdrawal of LipoKinetix from the market. These events triggered investigations into the hepatotoxicity of usnic acid and its mechanisms. In 2008, we published a review article titled "Usnic Acid and Usnea Barbata Toxicity". This review is an updated version of our previous review article and incorporates additional data published since 2008. The purpose of this review is to provide a comprehensive summary of the understanding of the liver toxicity associated with usnic acid, with a particular focus on the current understanding of the putative mechanisms of usnic acid-related hepatotoxicity.

Clinical Evaluation of Effectiveness and Safety of Combined Use of Dietary Supplements Amberen® and Smart B® in Women with Climacteric Syndrome in Perimenopause.

INTRODUCTION: Perimenopause is a time of transition in a woman's life that links her reproductive years to the cessation of ovulation, or menopause. For many women, this time is characterized by a variety of physiological and lifestyle changes, including increasing irregularity in menstrual bleeding, frequency and severity of vasomotor symptoms, etc. Therapies evaluated specifically for the perimenopausal women are very limited. This study aimed to evaluate the effectiveness and safety of Amberen® (a succinate-based non-hormonal supplement) combined with a Smart B® (vitamin B) complex in women with typical (without complications) mild to moderate climacteric syndrome during perimenopause. METHODS: Women up to 50 years of age, in perimenopause, with vasomotor and psychosomatic symptoms of the climacteric syndrome were enrolled for the study. The trial was randomized, double-blinded, placebo-controlled, comparative, and prospective. RESULTS: A total of 106 participants were enrolled in the trial and, per protocol, 105 completed the trial. We observed statistically significant improvements in most of the Greene Climacteric Scale symptoms, State-Trait Anxiety Inventory (STAI), Hospital Anxiety and Depression Scale (HADS), and Well-being, Activity, and Mood (WAM) scores. The intervention was well tolerated with few adverse effects reported to be mild and transient. CONCLUSION: The use of this dietary supplement is safe and eliminates or improves vasomotor and psychosomatic symptoms of climacteric symptoms in perimenopausal women: it improves sleep and cognitive abilities, lowers depression and anxiety, improves mood and well-being, and positively affects quality of life. GOV IDENTIFIER: NCT03897738.

Physicochemistry, Nutritional, and Therapeutic Potential of Ficus carica - A Promising Nutraceutical.

In an era where synthetic supplements have raised concerns regarding their effects on human health, Ficus carica has emerged as a natural alternative rich in polyphenolic compounds with potent therapeutic properties. Various studies on F. carica focusing on the analysis and validation of its pharmacological and nutritional properties are emerging. This paper summarizes present data and information on the phytochemical, nutritional values, therapeutic potential, as well as the toxicity profile of F. carica. An extensive search was conducted from various databases, including PubMed, ScienceDirect, Scopus, and Google Scholar. A total of 126 studies and articles related to F. carica that were published between 1999 and 2023 were included in this review. Remarkably, F. carica exhibits a diverse array of advantageous effects, including, but not limited to, antioxidant, anti-neurodegenerative, antimicrobial, antiviral, anti-inflammatory, anti-arthritic, antiepileptic, anticonvulsant, anti-hyperlipidemic, anti-angiogenic, antidiabetic, anti-cancer, and antimutagenic properties. Among the highlights include that antioxidants from F. carica were demonstrated to inhibit cholinesterase, potentially protecting neurons in Alzheimer's disease and other neurodegenerative conditions. The antimicrobial activities of F. carica were attributed to its high flavonoids and terpenoids content, while its virucidal action through the inhibition of DNA and RNA replication was postulated due to its triterpenes content. Inflammatory and arthritic conditions may also benefit from its anti-inflammatory and anti-arthritic properties through the modulation of various signalling proteins. Studies have also shown that F. carica extracts were generally safe and exhibit low toxicity profile, although more research in this aspect is required, specifically its effects on the skin. In conclusion, this study highlights the potential of F. carica as a valuable natural therapeutic agent and dietary supplement. However, continued exploration on F. carica's safety and efficacy is still required prior to embarking on clinical trials, as its role in personalized nutrition and medication will open a new paradigm to improve health outcomes.

Oxidative DNA damage contributes to usnic acid-induced toxicity in human induced pluripotent stem cell-derived hepatocytes.

Dietary supplements containing usnic acid have been increasingly marketed for weight loss over the past decades, even though incidences of severe hepatotoxicity and acute liver failure due to their overuse have been reported. To date, the toxic mechanism of usnic acid-induced liver injury at the molecular level still remains to be fully elucidated. Here, we conducted a transcriptomic study on usnic acid using a novel in vitro hepatotoxicity model employing human induced pluripotent stem cell (iPSC)-derived hepatocytes. Treatment with 20 µM usnic acid for 24 h caused 4272 differentially expressed genes (DEGs) in the cells. Ingenuity Pathway Analysis (IPA) based on the DEGs and gene set enrichment analysis (GSEA) using the whole transcriptome expression data concordantly revealed several signaling pathways and biological processes that, when taken together, suggest that usnic acid caused oxidative stress and DNA damage in the cells, which further led to cell cycle arrest and eventually resulted in cell death through apoptosis. These transcriptomic findings were subsequently corroborated by a variety of cellular assays, including reactive oxygen species (ROS) generation and glutathione (GSH) depletion, DNA damage (pH2AX detection and 8-hydroxy-2'-deoxyguanosine [8-OH-dg] assay), cell cycle analysis, and caspase 3/7 activity. Collectively, the results of the current study accord with previous in vivo and in vitro findings, provide further evidence that oxidative stress-caused DNA damage contributes to usnic acid-induced hepatotoxicity, shed new light on molecular mechanisms of usnic acid-induced hepatotoxicity, and demonstrate the usefulness of iPSC-derived hepatocytes as an in vitro model for hepatotoxicity testing and prediction.

Fisetin from Dietary Supplement to a Drug Candidate: An Assessment of Potential

Fisetin is a bioactive compound found in numerous fruits and vegetables, including strawberries, apples, grapes, persimmon, cucumber, onion, etc. The compound is also wellknown for its neurotrophic, anti-inflammatory, anti-carcinogenic, anti-diabetic, and other healthpromoting properties. Although there is increasing agreement that it has therapeutic properties, but its poor water solubility, high lipophilicity, and lower oral bioavailability make it difficult to use clinically. Extensive research has attempted to overcome these restrictions by developing novel and superior delivery systems. Considering the diverse potential, this review is the first to summarise the available data on Fisetin to collate the information related to analytical methods, pharmacological action, their mechanisms, regulatory aspects, and toxicity profile. It also covers the marketed products, related clinical trials, and patent updates of the moiety. In addition, an endeavor has been attempted to discuss and assess the various drug delivery systems employed to increase the biological attributes of Fisetin. The presented manuscript is the first to present a compendium of up-to-date literature on all of the domains considered necessary for this type of natural molecule to carve down its path from being a mere dietary supplement to a promising therapeutic drug candidate. The manuscript is expected to benefit the researchers working on natural and bioactive compounds, industrial scientists, and the general population interested in Fesitin.