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New meta-analyses, RCTs and systematic reviews that we monitor daily in PubMed. Independently indexed, not editorially curated.
Asian journal of surgery · 2024
The gut microbiome is the entirety of microorganisms and their genomes residing in the gut, characterised by diversity, stability, and resilience. Disrupted gut microbiome has been implicated in multiple disease entities. The aim of this paper is to summarise the rapidly evolving contemporary evidence of gut dysbiosis on the development and progression of abdominal aortic aneurysm (AAA), discuss possible mechanisms, and explore potential microbiota-targeted interventions and prognostic markers for AAA. A systematic literature search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, using PubMed, ScienceDirect, Web of Science, Ovid, Embase. Search terms of "microbiome" OR "dysbiosis" OR "microorganism"; AND "aneurysm" OR "dilatation" OR "aorta" were used. Study endpoints included effects of microbiota on AAA formation, effects of specific type of bacteria and its metabolite on AAA formation, and pre- or post-treatment by novel small-molecules/inhibitors. From May to August 2023, a total of twelve animal studies and eight human studies were included. Akkermansia muciniphila, Lactobacillus acidophilus and species from the Bacteroidetes phylum were associated with lower AAA incidence in both animal and human studies, while Proteobacteria phylum, Campylobacter, Fusobacterium and Faecalibacterium prausnitzii were found to be in abundance in the AAA group and were associated with larger aneurysms. The diversity of gut microbiota was inversely correlated with AAA diameter. Three important mechanisms were identified: including trimethylamine N-oxide pathway, butyric acid pathway, and aberrant tryptophan metabolism. With our expanding knowledge of the downstream pathogenic mechanisms of gut dysbiosis, novel therapeutics such as short-chain fatty acids and spermidine, as well as prognostic biomarkers such as TMAO have yielded promising preclinical results. In conclusion, there is strong evidence corroborating the role of gut dysbiosis in the pathogenesis of AAA, wherein its therapeutic and prognostic potential deserves further exploration.
Journal of the American Heart Association · 2024
Polyamines have been reported to be associated with neurological function, but the associations between polyamines and the prognosis of ischemic stroke remain unclear. We aimed to prospectively investigate whether elevated plasma polyamine levels are associated with adverse outcomes in patients with ischemic stroke. Plasma polyamine levels were measured at admission in 3570 patients with acute ischemic stroke, and clinical outcomes were assessed at 3 months after stroke onset. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale score≥3), and secondary outcomes included the individual outcomes of death and major disability. During a 3-month follow-up period, 877 participants (25.1%) experienced the primary outcome. Increased putrescines were associated with a decreased risk of the primary outcome (the highest versus the lowest tertile: odds ratio, 0.72 [95% CI, 0.58-0.91]; P=0.005) and major disability (odds ratio, 0.59 [95% CI, 0.47-0.74]; P<0.001). Conversely, increased spermidines were associated with an increased risk of death (hazard ratio, 1.86 [95% CI, 1.10-3.14]; P=0.020), and increased spermines were associated with an increased risk of the primary outcome (odds ratio, 1.36 [95% CI, 1.08-1.71]; P=0.009) and major disability (odds ratio, 1.27 [95% CI, 1.01-1.59]; P=0.041). Among patients with ischemic stroke, high plasma putrescine levels were associated with a decreased risk of adverse outcomes, whereas high plasma spermidine and spermine levels were associated with an increased risk of adverse outcomes. Further studies are needed to investigate whether targeting these polyamines can improve the prognosis of patients with ischemic stroke. https://clinicaltrials.gov. Identifier: NCT01840072.
Clinical oral investigations · 2024
To evaluate the effects of non-surgical mechanical debridement with or without adjunctive application of a gel with spermidine and sodium hyaluronate associated to a sealing gel (i.e. calcium chloride) in the treatment of peri-implant mucositis (PiM). Forty patients with one implant with PiM were randomly allocated in test and control groups. Test implants were treated with non-surgical mechanical debridement and local unique application of spermidine and calcium chloride gel while control implants were treated using non-surgical mechanical debridement alone. The primary outcome was BOP change. FMPS, FMBS and PD were also assessed. For an Implant the presence of a single bleeding spot (1 site/implant without a continuous line or profuse bleeding) was considered as complete disease resolution. After 3 months, a statistically significant improvement of all parameters were recorded in each group (p < 0.05). However, no statistically significant differences were found between test and control procedures (p > 0.05). At 3 months, 85% of test implants and 70% of control implants resulted in disease resolution. Residual implants with PiM in control group displayed a greater number of BOP-positive sites when compared with those of test group (p < 0.05). Whitin the limitations of the present study, results indicate that the clinical parameters improved following non-surgical mechanical debridement regardless the adjunct of spermidine and calcium chloride gel. Nevertheless complete resolution of PiM was not obtained in both experimental groups. Although no statistically significant differences were found between test and control procedures, the adjunctive application of spermidine and calcium chloride gel to non-surgical mechanical debridement may be considered in order to reduce the number of sites with BOP-positive.
Nutrition research (New York, N.Y.) · 2024
This study represents the first investigation into the safety of a novel, high-purity spermidine trihydrochloride supplement (hpSPD) in humans. Spermidine, a natural compound found in various foods, has demonstrated potential health benefits in animal and epidemiological studies. However, evidence from clinical trials and safety evaluations of spermidine supplements is limited because pure spermidine for human administration has not been available. In this randomized, double-blind, within-subject and placebo-controlled trial, 37 healthy men (age 50-70 years; body mass index, 18.5-28 kg/m2) were administered either hpSPD or a placebo. We hypothesized that 7-day and 28-day dosing of 40 mg/day of hpSPD would have minimal effects on safety, although metabolic and polyamine homeostasis has not previously been examined at this dosage level. Consistent with our hypothesis, 40 mg/day hpSPD did not result in any significant changes in clinical, lipids, chemistry, or hematological parameters compared to placebo. Compliance was high, and no study product-related adverse events were reported. Substantial changes in serum and urine polyamine concentrations were not observed following hpSPD supplementation, suggesting effective homeostatic control of full-dose highly purified spermidine supplements with no evidence of adaptation of spermidine metabolism at 40 mg/day. These findings suggest that hpSPD at 40 mg/day for up to 28 days is safe and well-tolerated in healthy older men. The study is consistent with preclinical results and provides important evidence supporting the safety of high-purity spermidine supplementation, enabling further research with single-molecule spermidine to investigate its potential biology for improving human health. This trial was registered at clinicaltrials.gov (NCT05459961).
Mechanisms of ageing and development · 2024
Sarcopenia, the gradual loss of muscle mass, strength, and function with age, poses a significant risk to older adults, making early diagnosis crucial for preventing disability and enhancing quality of life. Biomarkers are vital for the early detection, monitoring progression, and assessing the efficacy of treatments for sarcopenia, offering a detailed evaluation of muscle health. This systematic review examined the clinical potential of circulating biomarkers in sarcopenia by analyzing studies up to May 2024 from PubMed, Scopus, Web of Science. A total of 45 studies involving 641,730 patients were reviewed, revealing notable biomarker differences between sarcopenic and non-sarcopenic individuals. Sarcopenic patients exhibited lower levels of certain microRNAs, hemoglobin, albumin, and anti-inflammatory factors, alongside higher levels of red and white blood cells, pro-inflammatory factors, growth factors, matrix proteins, free thyroxine, cortisol, and adiponectin. Additionally, they had lower levels of irisin, free triiodothyronine, and insulin, with reduced phosphatidylcholines and elevated spermidine. The studies were generally of fair to good quality, but due to heterogeneity, a meta-analysis was not feasible. The review underscores the need for standardized biomarkers and diagnostic criteria and suggests that improving outcomes for sarcopenic patients may involve addressing inflammation, metabolic, and hormonal issues through nutrition, medication, and exercise.
Nutrition research (New York, N.Y.) · 2024
This pilot dose-escalation study evaluated the absorption and metabolism of a novel fasting mimetic formulation containing spermidine, nicotinamide, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) taken as oral supplements in young adults. Five healthy men consumed a standardized breakfast, followed by control (wheat flour) or low, medium, or high doses of supplements containing spermidine, nicotinamide, PEA, and OEA 2 hours later. Blood was drawn at 0, 1, 2, and 4 hours after the supplement (2, 3, 4, and 6 hours postprandial). Plasma concentrations of spermidine, 1-methylnicotinamide, PEA and OEA were quantified by liquid chromatography-mass spectrometry. The secretion of tumor necrosis factor alpha and production of reactive oxygen species by stimulated macrophages incubated with plasma, and cholesterol efflux capacity of plasma were analyzed. Plasma 1-methylnicotinamide, PEA, and OEA concentrations increased after supplement intake (P < .05). Spermidine concentrations decreased in the control arm (P < .05) but not the supplement arms. Net incremental area under the curve for tumor necrosis factor alpha and reactive oxygen species in stimulated macrophages decreased when incubated with plasma following supplement intake (P < .05). Intake of the combined supplements showed they were bioavailable and increased in plasma in a dose-dependent manner and provide preliminary data showing enhanced plasma anti-inflammatory and antioxidant functions. This trial was registered at clinicaltrials.gov (NCT05017428).
Journal of the American Heart Association · 2025
Polyamines have been suggested to play pivotal roles in ischemic stroke and neurodegenerative disorders, but the associations of plasma polyamines with poststroke cognitive impairment (PSCI) remain unclear. We aimed to prospectively investigate the associations of plasma putrescine, spermidine, and spermine with PSCI among patients with ischemic stroke in a multicenter cohort study. We measured plasma polyamine levels at baseline among 619 patients with ischemic stroke from a preplanned ancillary study of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). We used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke, and PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. According to the Mini-Mental State Examination score, plasma polyamines were positively associated with PSCI. The adjusted odds ratios of PSCI for the highest versus lowest quartile of putrescine, spermidine, and spermine were 1.81 (95% CI, 1.09-3.00), 1.81 (95% CI, 1.09-3.01), and 1.92 (95% CI, 1.15-3.20), respectively. In addition, plasma putrescine (net reclassification improvement, 32.08%; P<0.001; integrated discrimination improvement, 1.62%; P=0.002), spermidine (net reclassification improvement, 25.29%; P=0.002; integrated discrimination improvement, 1.22%; P=0.006), and spermine (net reclassification improvement, 16.54%; P=0.045; integrated discrimination improvement, 1.36%; P=0.004) could significantly improve the risk reclassification of PSCI beyond established risk factors. There were similar significant relationships when PSCI was defined by Montreal Cognitive Assessment score. Higher plasma polyamine levels were associated with increased risk of PSCI among patients with ischemic stroke. Our findings suggest that plasma polyamines should be implicated in the pathophysiologic processes of PSCI and may be the potential intervention targets for PSCI. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.
Alternative therapies in health and medicine · 2025
Although epidemiological and preclinical research suggests that the polyamine spermidine improves the efficiency of autophagy, human clinical research demonstrating a specific dose of any source of spermidine capable of increasing biomarkers of autophagy is lacking. The study aimed to examine the effects of spermidine from Miricell™ rice germ extract (Nutraland USA) on biomarkers/indices of autophagy, neuroprotection, and cardiometabolic health, as well as safety and adverse events. This 56-day study was conducted as a single-blinded, interventional, parallel-group, pilot trial. Vitals, diet records, and protocol compliance were recorded at weeks 0 and 8. Blood draws for cardiometabolic markers and adverse event monitoring took place at screening and weeks 0 and 8. Conducted at a clinical research laboratory in Ohio. Twelve (N=12) healthy men and women (age: 54.5 ± 7.9 years). Random assignment to 1.5 mg or 3.3 mg of spermidine daily from Miricell™ rice germ extract (Nutraland USA). Biomarkers of autophagy [Beclin-1 and Unc-51-like kinase 1(ULK1)], and biomarkers/indices of neuroprotection, including brain-derived neurotrophic factor (BDNF), homocysteine, and cardiometabolic health (high sensitivity C-reactive protein (hs-CRP), lipid panel). Compared to baseline, only the 3.3 mg dose of spermidine from Miricell® increased Beclin-1 by 7.3%, ULK-1 by 13.4%, and BDNF by 12.1%. Compared to baseline, the same dose resulted in a 20.8% decrease in hs-CRP, a 20.1% decrease in VLDL, and a 26.9% decrease in triglycerides. Secondary outcomes, including clinical chemistry panel, CBC, vital signs, and adverse events, reflect a good safety profile for the use of 3.3 mg/day of spermidine from Miricell®. This pilot study found that 3.3 mg/day of spermidine from Miricell® rice germ extract tends to improve biomarkers of autophagy, neuroprotection, and cardiometabolic health. Appropriate follow-up studies are warranted to confirm these findings. spermidine, autophagy, beclin-1, ULK1, rice germ extract, neuroprotection, BDNF, homocysteine, cardiometabolic, CRP, C-reactive protein, VLDL, triglycerides, aging.
Science advances · 2025
Chronic kidney disease (CKD) is a life-threatening condition, and constipation is a progressive risk factor. We evaluated changes in uremic toxins, renal function, and the safety of lubiprostone, a selective chloride channel activator, in patients with CKD. In this phase 2, randomized, double-blind, placebo-controlled trial across nine centers in Japan, 150 patients with stage IIIb-IV CKD received lubiprostone (8 or 16 micrograms) or placebo for 24 weeks. The primary end point was change in indoxyl sulfate levels. Secondary end points included other uremic toxins and renal function markers. Lubiprostone did not alter uremic toxin levels but improved or preserved estimated glomerular filtration rate and its slope in the 16-microgram group. Mild-to-moderate gastrointestinal events occurred in the placebo and 16-microgram groups. Multiomics analysis revealed that lubiprostone modulated the gut microbial agmatine pathway and increased spermidine levels, thereby improving renal mitochondrial function. Lubiprostone is a previously unknown and safe therapeutic option to mitigate renal decline in CKD.
Frontiers in nephrology · 2025
Filtration slit proteins are important for maintaining the integrity of the glomerular filtration barrier. Genetic mutations and environmental factors can disrupt their structure and functions, leading to proteinuria and kidney diseases. This scoping review aims to synthesize the available information on the genetic and environmental factors that affect the slit proteins to enhance our understanding of the (patho)physiology of glomerular filtration. Online databases such as Wiley and PubMed were used. Relevant studies were selected focusing on genetic variations, environmental influences, and their impact on filtration slit proteins. Data extraction and synthesis were conducted to highlight key themes and knowledge gaps. We summarized at least 20 proteins and their genes, including nephrin, podocin, phospholipase C Epsilon 1 (PLCE1), CD2-Associated Protein (CD2AP), ITGA 3, synaptopodin, myosin 1E (MYO1E), flotillin-2 (Flot2), podocalyxin, FAT1, Apo Hemoglobin-Haptoglobin (Apo Hb-Hp), spermidine, P-Cadherin, ephrin B1, Zo- 1 (Zona Occluden), MAGI 1&2 (MAGUK inverted), Par- complex, IP-10 (interferon-inducible protein), neurexin 1, and liver type fatty acid binding protein. We also reported at least 8 environmental factors, including oxidative stress, inflammation, heavy metals, air-bone pollutants, high-fat diets, vitamins and micronutrient deficiency, mechanical stretch, and nephrotoxic agents. This review highlights various filtration slit proteins and the mechanisms of their alterations by genetic and environmental factors. It contributes to efforts toward personalized therapeutic strategies for disorders of glomerular filtration.
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis · 2019
Recombinant tissue plasminogen activator (rt-PA) can be utilized to treat ischemic stroke with safety and effectiveness but limited by a narrow therapeutic window. In the present clinical trial among patients with stroke, we sought to evaluate the potential of fisetin to extend the therapeutic window of rt-PA treatment. Patients with stroke were divided based on their onset-to-treatment time (OTT) and then randomly assigned to receive the rt-PA treatment combined with fisetin or placebo. Primary outcome was evaluated using the National Institutes of Health Stroke scale (NIHSS), and secondary outcome was assessed by serum levels of matrix metalloproteinase (MMP) 2, MMP 9, and C-reactive protein (CRP). Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT strata, as revealed by lower NIHSS scores. The beneficial effect of fisetin was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum, as evidenced by strong linear correlations between serum levels of such markers with the NIHSS scores in all enrolled patients. Fisetin may possess the potential to supplement traditional rt-PA treatments among patients with stroke, particularly for those with delayed OTT, and thereby extend the otherwise narrow therapeutic window and improve the treatment outcomes.
Molecules (Basel, Switzerland) · 2020
Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer's disease (AD) is closely associated with aging and is defined by increasing memory loss and severe dementia. Currently, there are no therapy options available that halt AD progression. This work investigates three hallmarks of the disease (autophagy, neuroinflammation, and senescence) and systematically analyzes if there is a beneficial effect from three substances derived from food sources, the so called "nutraceuticals" epigallocatechin gallate, fisetin, and spermidine, on these hallmarks. The results imply a positive outlook for the reviewed substances to qualify as a novel treatment option for AD. A combination of nutraceutical substances and other preventive measures could have significant clinical impact in a multi-layered therapy approach to counter AD.
International journal of environmental research and public health · 2021
A chronic multi-symptom illness of unknown etiology, Gulf War Illness (GWI) affects 175,000 to 250,000 veterans of the Gulf War. Because inflammation has suspected involvement in the pathophysiology of GWI, botanical treatments that target inflammation may be beneficial in reducing symptoms. No FDA-approved treatments currently exist for GWI, and rapid prioritization of agents for future efficacy testing is important. This study is part of a larger project that screened nine different botanical compounds with purported anti-inflammatory properties for potential treatment of GWI. We tested three botanicals (resveratrol [Polygonum cuspidatum], luteolin, and fisetin [Rhus succedanea]) on symptom severity of GWI in this placebo-controlled, pseudo-randomized clinical trial. Twenty-one male veterans with GWI completed the study protocol, which consisted of 1 month (30 days ± 3) of baseline symptom reports, 1 month of placebo, 1 month of lower-dose botanical, and 1 month of higher-dose botanical. Participants completed up to 3 different botanicals, repeating the placebo, lower-dose, and higher-dose cycle for each botanical assigned. Linear mixed models were used for analyses. Resveratrol reduced GWI symptom severity significantly more than placebo at both the lower (p = 0.035) and higher (p = 0.004) dosages. Luteolin did not decrease symptom severity more than placebo at either the lower (p = 0.718) or higher dosages (p = 0.492). Similarly, fisetin did not reduce symptom severity at either the lower (p = 0.504) or higher (p = 0.616) dosages. Preliminary findings from this screening study suggest that resveratrol may be beneficial in reducing symptoms of GWI and should be prioritized for future testing. Larger trials are required to determine efficacy, response rates, durability of effects, safety, and optimal dosage. This trial was registered on ClinicalTrials.gov (NCT02909686) on 13 September 2016.
Nutrients · 2021
Flavonols are ones of the most common phytochemicals found in diets rich in fruit and vegetables. Research suggests that molecular functions of flavonoids may bring a number of health benefits to people, including the following: decrease inflammation, change disease activity, and alleviate resistance to antibiotics as well as chemotherapeutics. Their antiproliferative, antioxidant, anti-inflammatory, and antineoplastic activity has been proved. They may act as antioxidants, while preventing DNA damage by scavenging reactive oxygen radicals, reinforcing DNA repair, disrupting chemical damages by induction of phase II enzymes, and modifying signal transduction pathways. One of such research areas is a potential effect of flavonoids on the risk of developing cancer. The aim of our paper is to present a systematic review of antineoplastic activity of flavonols in general. Special attention was paid to selected flavonols: fisetin, kaempferol, and quercetin in preclinical and in vitro studies. Study results prove antiproliferative and proapoptotic properties of flavonols with regard to head and neck cancer. However, few study papers evaluate specific activities during various processes associated with cancer progression. Moreover, an attempt was made to collect the majority of substantive studies on bioactive potential of the selected flavonols, especially with regard to modulation of a range of signal transduction pathways that participate in cancer development.
Pharmacological research · 2021
With the coming of the era of the aging population, hypertension has become a global health burden to be dealt with. Although there are multiple drugs and procedures to control the symptoms of hypertension, the management of it is still a long-term process, and the side effects of conventional drugs pose a burden on patients. Flavonoids, common compounds found in fruits and vegetables as secondary metabolites, are active components in Chinese Herbal Medicine. The flavonoids are proved to have cardiovascular benefits based on a plethora of animal experiments over the last decade. Thus, the flavonoids or flavonoid-rich plant extracts endowed with anti-hypertension activities and probable mechanisms were reviewed. It has been found that flavonoids may affect blood pressure in various ways. Moreover, despite the substantial evidence of the potential for flavonoids in the control of hypertension, it is not sufficient to support the clinical application of flavonoids as an adjuvant or core drug. So the synergistic effects of flavonoids with other drugs, pharmacokinetic studies, clinical trials and the safety of flavonoids are also incorporated in the discussion. It is believed that more breakthrough studies are needed. Overall, this review may shed some new light on the explicit recognition of the mechanisms of anti-hypertension actions of flavonoids, pointing out the limitations of relevant research at the current stage and the aspects that should be strengthened in future researches.
Trials · 2021
Fermented Rhus verniciflua Stokes extract (FRVE) reported an anti-hepatic lipidemic property mediated by the upregulation of AMP-activated protein kinase (AMPK) in cell and animal models. However, it remains unclear whether there is an effect of FRVE on liver disease-related parameters and serum lipid levels in humans. We investigated the effects of FRVE intake for 12 weeks on liver disease-related parameters and serum lipid profiles in Korean adults. A randomized, double-blind, placebo-controlled study was conducted among 79 subjects. An aqueous extract of fermented Rhus verniciflua Stokes that was filtered and fermented was prepared. For 12 weeks, the test group (n = 39) consumed two capsules of FRVE (main components: fustin 129 mg and fisetin 59 mg) once daily. The control group (n = 40) consumed two placebo pills (main component: lactose 627.0 mg) once daily. A 1:1 randomization of control and test was performed using computer-generated randomization. Both before and after FRVE intake, anthropometric parameters, liver function-related parameters, and clinical laboratory parameters were measured. The effects between the test and control groups were compared using the Mann-Whitney U test and independent t-test, and the difference between baseline and follow-up values was compared using Wilcoxon rank-sum test and paired t-test. There was no significant difference when comparing the change values of liver disease-related parameters and serum lipid profiles in between groups. In our study, we did not confirm the significance in liver function parameters and serum lipid profiles. The study protocol was registered in the Clinical Research Information Service (CRIS: https://cris.nih.go.kr/cris/index.jsp ) under number KCT0005687. Registered on 2 December 2020.
Nutrients · 2021
Prostate and bladder cancer represent the two most frequently diagnosed genito-urinary malignancies. Diet has been implicated in both prostate and bladder cancer. Given their prolonged latency and high prevalence rates, both prostate and bladder cancer represent attractive candidates for dietary preventive measures, including the use of nutritional supplements. Flavonols, a class of flavonoids, are commonly found in fruit and vegetables and are known for their protective effect against diabetes and cardiovascular diseases. Furthermore, a higher dietary intake of flavonols was associated with a lower risk of both bladder and prostate cancer in epidemiological studies. In this systematic review, we gathered all available evidence supporting the anti-cancer potential of selected flavonols (kaempferol, fisetin and myricetin) against bladder and prostate cancer. A total of 21, 15 and 7 pre-clinical articles on bladder or prostate cancer reporting on kaempferol, fisetin and myricetin, respectively, were found, while more limited evidence was available from animal models and epidemiological studies or clinical trials. In conclusion, the available evidence supports the potential use of these flavonols in prostate and bladder cancer, with a low expected toxicity, thus providing the rationale for clinical trials that explore dosing, settings for clinical use as well as their use in combination with other pharmacological and non-pharmacological interventions.
Phytomedicine : international journal of phytotherapy and phytopharmacology · 2022
The primary therapeutic strategy in managing ischemic heart diseases is to restore the perfusion of the myocardial ischemic area by surgical methods that often result in an unavoidable injury called ischemia-reperfusion injury (IR). Fisetin is an effective flavonoid with antioxidant and anti-inflammatory properties, proven to be cardioprotective against IR injury in both in-vitro and invivo models, apart from its promising health benefits against cancer, diabetes, and neurodegenerative ailments. The potential of fisetin in attenuating myocardial IR is inconclusive as the effectiveness of fisetin needs more understanding in terms of its possible target sites and underlying different mechanisms. Considering the surge in recent scientific interests in fisetin as a pharmacological agent, this review not only updates the existing preclinical and clinical studies with fisetin and its underlying mechanisms but also summarizes its possible targets during IR protection. We performed a literature survey using search engines Pubmed, PMC, Science direct, Google, and research gate published across the years 2006-2021. The relevant studies were extracted from the databases with the combinations of the following keywords and summarized: myocardial ischemia-reperfusion injury, natural products, flavonoid, fisetin, PI3K, JAK-STAT, Nrf2, PKC, JNK, autophagy. Fisetin is reported to be effective in attenuating IR injury by delaying the clotting time, preserving the mitochondrial function, reducing oxidative stress, and inhibiting GSK 3β. But it failed to protect diseased cardiomyocytes challenged to IR. As discussed in the current review, fisetin not only acts as a conventional antioxidant and anti-inflammatory agent to exert its biological effect but may also exert modulatory action on the cellular metabolism and adaptation via direct action on various signalling pathways that comprise PI3K, JAK-STAT, Nrf2, PKC, JNK, and autophagy. Moreover, the dosage of fisetin and co-morbidities like diabetes and obesity are found to be detrimental factors for cardioprotection. For further evaluation and smooth clinical translation of the fisetin molecule in IR treatment, researchers should pay close attention to the potential of fisetin to possibly alter the key cardioprotective pathways and dosage, as the efficacy of fisetin is tissue and cell type-specific and varies with different doses.
Pharmacological research · 2022
As the worldwide population progresses in age, there is an increasing need for effective treatments for age-associated musculoskeletal conditions such as osteoporosis and osteoarthritis (OA). Fisetin, a natural flavonoid, has garnered attention as a promising pharmaceutical option for treating or delaying the progression of osteoporosis and OA. However, there is no systematic review of the effects of fisetin on bone and cartilage. The aim of this review is to report the latest evidence on the effects of fisetin on bone and cartilage, with a focus on clinical significance. The PubMed, Embase, and Cochrane Library databases were searched up to December 9th 2021 to evaluate the effects of fisetin on bone and cartilage in in vitro studies and in vivo preclinical animal studies. The risk of bias, quality, study design, sample characteristics, dose and duration of fisetin treatment, and outcomes of the 13 eligible studies were analyzed in this systematic review. Qualitative evaluation was conducted for each study due to differences in animal species, cell type, created disease model, dose and duration of fisetin treatment, and time between intervention and assessment among the eligible studies. The beneficial effects of fisetin on osteoporosis have been demonstrated in in vitro and in vivo preclinical studies across animal species. Similarly, the beneficial effects of fisetin on OA have been demonstrated in in vivo preclinical animal studies, but the reports on OA are still limited. Fisetin, a natural supplement can be use in orthobiologics treatment, as adjuvant to orthopaedic surgery, to improve clinical outcome.
Journal of nutritional science · 2022
Fisetin, a polyphenol found in several fruits and vegetables, has shown potential health benefits in many pre-clinical studies for neuroprotection, cardioprotection, chemoprevention, diabetes, inflammation and oxidative stress. However, the clinical effectiveness of fisetin may be limited by its poor bioavailability when ingested. Using a novel green technology of Hybrid-FENUMAT™, a food-grade fisetin formulation (FF-20) was developed through encapsulation of fisetin micelles into fenugreek galactomannan (FG) hydrogel scaffold to improve its physical characteristics and bioavailability. This is the first human pharmacokinetic study of fisetin following a single-dose, comparative, double-blinded, cross-over protocol, supplementing with FF-20 and unformulated fisetin (UF). Fifteen healthy volunteers were given a single dose of 1000 mg UF or 1000 mg FF-20 (delivering 192 mg fisetin) with a 10-d washout period between each dose. Blood samples were taken at 0⋅5, 1, 2, 3, 5, 8 and 12 h after both days of supplementation to quantify fisetin and geraldol, an active metabolite. The plasma concentration of fisetin when individuals consumed FF-20 was 26⋅9-fold greater than UF as determined by the area under the curve over 12 h [AUC0–12 h (FF-20) = 341⋅4 v. AUC0–12 h (UF) = 12⋅67]. The maximum plasma concentration (Cmax) was also more than twenty-three times higher when supplemented with FF-20 (238⋅2 ng/ml) compared to UF (9⋅97 ng/ml). The encapsulation also reduced the amount of conversion of fisetin to geraldol. No adverse events were reported during the study. Therefore, the encapsulation of fisetin into FG dietary fibre hydrogel scaffold could improve its delivery and bioavailability in human subjects. [Figure: see text]