Rutin

BACKGROUND/OBJECTIVES: Advanced glycation end products (AGEs) and oxidative stress increase with aging and are implicated in Alzheimer's disease (AD). We developed an anti-glycation blend using LC-MS-based screening and assessed its effects on oxidative and glycation-related biomarkers in humans. METHODS: Twelve candidate compounds were screened in a BSA-glucose model using LC-MS peptide mapping to quantify lysine glycation and rank inhibitory activity. The top candidates were combined into a three-compound blend (quercetin, rutin, genistein). In a randomized, double-blind, placebo-controlled 3-month trial, older healthy adults (n = 30) and individuals with AD (n = 30) received anti-AGE blend (n = 15 in older group and n = 15 in AD group) or placebo (n = 15 in older group and n = 15 in AD group). Serum malondialdehyde and urinary Nε-(carboxymethyl)lysine were measured pre-post intervention. Pre/post and between-arm comparisons within each population were performed using REML ANOVA with Tukey post hoc tests. Serum MDA (malondialdehyde) and urinary CML (Nε-(carboxymethyl)lysine) were prespecified biomarker outcomes and are reported here as co-primary biomarker endpoints. No formal a priori sample size calculation was performed; the study size was feasibility-based. RESULTS: LC-MS screening identified genistein, quercetin, and rutin as the most consistent inhibitors of glucose-driven BSA glycation. In older healthy adults, serum MDA decreased after anti-AGE supplementation (p < 0.001) and differed from the placebo (p < 0.01), while no change was observed within the placebo group (ns). In the AD cohort, MDA did not change significantly from baseline within either arm (ns), but post-intervention MDA was lower in anti-AGE than in the placebo (p < 0.05). Urinary CML was unchanged in older healthy adults (ns in both arms), whereas in AD, it decreased after anti-AGE supplementation (p < 0.01) and differed from the placebo (p < 0.05). CONCLUSIONS: A screening-guided anti-glycation blend supplementation was associated with changes in selected biomarkers in humans: MDA decreased across cohorts, while CML decreased selectively in AD. Larger trials with extended biomarker pan

Brazilian native fruits are excellent sources of polyphenols, especially berries, which are rich in anthocyanins. These compounds are associated with improvements in the insulin signaling pathway, reduced glucose absorption, and the inhibition of carbohydrate-digesting enzymes. This study aimed to evaluate the impact of consuming native fruits, including grumixama (GM), Rio Grande cherry (RGc), and uvaia (UV), on the 2-hour postprandial glucose, plasma insulin, and inflammatory responses in healthy individuals. No study has evaluated the effects of these fruits on carbohydrate-digesting enzymes alongside glucose transporters. This was assessed using two methods: (i) post-bread glycemic response and (ii) post-glucose glycemic response. Healthy volunteers participated in a crossover study with control, consuming juices from GM, RGc, UV, or water, followed by white bread or a glucose solution. Capillary glucose, plasma insulin, and pro-inflammatory cytokine levels were measured. Additionally, the inhibitory activities of α-amylase and α-glucosidase by fruit extracts were evaluated in vitro. Molecular docking assessed the affinity of individual anthocyanins and flavonols. Cyanidin 3-glucoside was identified as the predominant flavonoid in GM and RGc, while quercetin 3-galactoside and rutin were the primary flavonols in GM and RGc, respectively. RGc juice significantly reduced 2-hour postprandial glucose levels, and juices rich in anthocyanins delayed the glucose peak to 45 minutes. Only GM juice delayed the insulin peak. Phenolic extracts from GM and RGc inhibited α-amylase and α-glucosidase activities in vitro. In silico analysis showed high-affinity binding of anthocyanins and flavonols found in the GM and RGc extracts to both enzymes. Therefore, GM and RGc may be considered beneficial foods and serve as additional nutritional supplements in managing postprandial hyperglycemia.

BACKGROUND: Metabolic syndrome (MetS) patients have impaired hypothalamic regulatory functions involved in food intake and energy expenditure and suffer from a state of meta-inflammation. Pre-clinical studies demonstrated that ultramicronized palmitoylethanolamide (PEA) acts both on the adipose tissue and the central nervous system, while hydroxytyrosol (HTyr) counteracts several types of dysmetabolism. OBJECTIVES: The aim of our randomized crossover double-blind placebo-controlled pilot study was to evaluate the potential effects of a food supplement (FS) containing a co-micronized formulation of PEA and rutin along with HTyr, combined with a tailored calorie-controlled Mediterranean diet, in patients with MetS. METHODS: Nineteen patients were enrolled and block-randomized to an eight-week MD together with the FS or placebo. After a two-week washout period, the treatments were reversed. Data on laboratory parameters and those detected by capillary sampling, anthropometry, body composition analysis, ultrasound examination, blood pressure monitoring, the 36-Item Short-Form Health Survey questionnaire, handgrip strength test, and physical performance tests were collected at each time point (protocol code R.S. 262.22, registered on 20 December 2022). RESULTS: At the end of the study, patients supplemented with the FS showed a significant reduction in body weight, body mass index, fat mass, and inflammation biomarkers (CRP and ESR), compared to placebo-supplemented patients. In contrast, the fat-free mass, phase angle, and body cell mass were increased in FS compared to placebo patients. CONCLUSIONS: Although preliminary, the results of our clinical study suggest that co-micronized PEA-rutin and HTyr may be of help against adiposopathy in patients with MetS.

Supplementation with prebiotic polyphenol rutin is a potential dietary therapy for type 2 diabetes prevention in adults with obesity, based on previous glycaemic improvement in transgenic mouse models. Gut microbiota are hypothesised to underpin these effects. We investigated the effect of rutin supplementation on pancreatic β-cell function measured as C-peptide/glucose ratio, and 16S rRNA gene-based gut microbiota profiles, in a cohort of individuals with overweight plus normoglycaemia or prediabetes. Eighty-seven participants were enrolled, aged 18-65 years with BMI of 23-35 kg/m2. This was a 12-week double-blind randomised controlled trial (RCT), with 3 treatments comprising (i) placebo control, (ii) 500 mg/day encapsulated rutin, and (iii) 500 mg/day rutin-supplemented yoghurt. A 2-h oral glucose tolerance test (OGTT) was performed at baseline and at the end of the trial, with faecal samples also collected. Compliance with treatment was high (~90%), but rutin in both capsule and dietary format did not alter pancreatic β-cell response to OGTT over 12 weeks. Gut bacterial community composition also did not significantly change, with Firmicutes dominating irrespective of treatment. Fasting plasma glucose negatively correlated with the abundance of the butyrate producer Roseburia inulinivorans, known for its anti-inflammatory capacity. This is the first RCT to investigate postprandial pancreatic β-cell function in response to rutin supplementation.

This study aimed to investigate the effects of rutin flavonoid in type 2 diabetes mellitus (T2DM) patients. In this trial (double-blind, placebo-controlled), 50 T2DM patients (supplement, n = 25 and placebo, n = 25) were randomized and supplemented with 500 mg rutin or placebo per day for 3-months. At the beginning and at the end of the study, metabolic parameters including fasting blood glucose (FBG), insulin, glycosylated hemoglobin (HbA1c), homeostasis model assessment of insulin resistance (HOMO-IR), quantitative insulin sensitivity check index (QUICKI), homeostasis model assessment of β-cell function (HOMA-β), triglyceride (TG), total cholesterol (CHOL), high-density and low-density lipoprotein cholesterol (HDL-c and LDL-c), and atherogenic index of plasma (AIP), inflammatory and oxidative stress markers such as interleukin 6 (IL-6), total antioxidant capacity (TAC), and malondialdehyde (MDA) and brain-derived neurotrophic factor (BDNF) were assessed. The results showed a significant decrease in FBG, insulin, HbA1c, HOMO-IR, LDL-c, TG, VLDL, CHOL, LDL-c.HDL-c ratio, AIP, IL-6, and MDA and a significant increase in HDL-c, QUICKI index, BDNF, and TAC compared with the initial value (p for all <.05). In the adjusted model, the mean changes of FBG, insulin, HbA1c, HOMO-IR, LDL-c, CHOL, LDL.HDL ratio, AIP, MDA, and IL-6 were significantly lower and mean changes of QUICKI index, HDL-c, and TAC were significantly higher in the rutin group compared with the placebo group (adjusted p for all <.05). It seems that rutin may have beneficial effects on improving metabolic parameters, BDNF, and inflammatory and oxidative stress factors in T2DM patients. © 2022 John Wiley & Sons Ltd.

BACKGROUND: Hyperlipidemia is one of the consequences of type 2 diabetes mellitus (T2DM) that puts the patients at the risk of getting cardiovascular disease. Pistacia atlantica subsp. Kurdica is used by local people for the improvement of lipid and glucose indices. This study was carried out to evaluate clinical effects of P. atlantica subsp. Kurdica on hyperlipidemia related to T2DM patients. MATERIALS AND METHODS: In this randomized, triple-blind, and placebo-controlled study, type 2 diabetes patients with hyperlipidemia were randomly allocated to receive either P. atlantica kurdica or placebo capsule for 2 months. 58 Patients were followed up at the beginning and after the end of each month for assessment of lipid profiles, glucose indices, and liver and renal function tests. The herbal capsule was standardized according to volatile and nonvolatile compounds by GC-MS/FID and RP-HPLC-PDA, respectively. The total phenolic and flavonoid contents were also determined with a spectrophotometer. RESULTS: After 1 and 2 months of the intervention period, mean differences of 2HPP, total cholesterol, and LDL-c have been reduced significantly (P < 0.05) between the two groups, but there were not reported any significant statistical changes in FBS, HbA1c, TG, HDL-c, ALT, AST, and Cr. The herbal capsule was standardized according to benzoic acid, ballic acid, rutin, and quercetin standard (6.5, 2.1, 1.4, 0.7 mg, respectively), and also α-pinene as major volatile constituent 28.51%. CONCLUSION: According to results the P. atlantica kurdica is effective in the improvement of lipid profile and glucose indices in line with its local application. CLINICAL TRIAL ID: (IRCT201708109014N178).

OBJECTIVES: To study the effects of alfacalcidol on serum 25-(OH)D3 level, cellular immune function, and inflammatory factors in children with Henoch-Schönlein purpura (HSP). METHODS: A total of 200 children with HSP were prospectively enrolled from June 2018 to June 2020. According to the random number table method, they were divided into an observation group and a control group (n=100 each). The control group was treated with vitamin C, rutin tablets, dipyridamole, cimetidine, calcium supplements, and glucocorticoids. In addition to the treatment for the control group, the observation group received alfacalcidol capsules (0.25 μg/d) orally before bed for 4 weeks. The two groups were compared in terms of the level of 25-(OH)D3, the percentages of T lymphocyte subsets (CD3+, CD4+, and CD8+) and NK cells, and the levels of inflammatory factors, interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-21 (IL-21), and tumor necrosis factor-α (TNF-α), before treatment and after 4 weeks of treatment. The children were followed up for 6 months to determine the recurrence rate and the incidence of renal damage. RESULTS: After treatment, the observation group showed a significantly higher serum 25-(OH)D3 level, significantly higher percentages of CD3+T cells, CD4+T cells, and NK cells, and significantly lower levels of IL-6, IL-17, IL-21, and TNF-α compared with the control group (P<0.05). After 6 months of follow-up, the recurrence rate and the incidence of renal damage in the observation group were significantly lower than those in the control group (P<0.05). CONCLUSIONS: Alfacalcidol can increase the serum 25-(OH)D3 level, improve cellular immune function, decrease inflammatory factor levels, and reduce recurrence and renal damage in children with HSP. Publisher: 目的: 探讨阿法骨化醇对过敏性紫癜（Henoch-Schönlein purpura，HSP）患儿血清25羟基维生素D3［25-(OH)D3］水平、细胞免疫功能及炎性因子的影响。方法: 前瞻性选取2018年6月至2020年6月诊断为HSP的患儿200例为研究对象，按照随机数字表法分为观察组及对照组各100例。对照组给予维生素C、芦丁片、双嘧达莫、西咪替丁、钙剂、糖皮质激素等治疗，观察组在对照组的基础上加用阿法骨化醇软胶囊0.25 μg/d，睡前口服，疗程4周。于治疗前及治疗4周后检测并比较患儿25-(OH)D3水平、T淋巴细胞亚群指标（CD3+、CD4+、CD8+）、NK细胞百分率和炎性因子指标（IL-6、IL-17、IL-21、肿瘤坏死因子-α）；随访6个月，统计患儿复发率及肾损害发生率。结果: 治疗后，观察组血清25-(OH)D3水平高于对照组（P<0.05）；观察组CD3+、CD4+和NK细胞水平高于

OBJECTIVE: To assess the efficacy of the combination of Tadalafil 5 mg and nutritional supplements composed by Panax ginseng, Moringa Oleifera and Rutin on erectile function in men with mild and moderate vasculogenic ED. METHODS: we prospectively enrolled 86 patients divided into two groups A (45), B (33) in this multicenter randomized, doubleblind, placebo-controlled trial . Drop out was 8 patients (3 patients in group A and 5 in Group B). At screening visit patients underwent clinical examination, blood test (hormonal and metabolic profile) and filled out the IIEF-5 questionnaire and the SEP-2, SEP-3. Patients were randomized by a computergenerated list to receive either Tadalafil 5 mg once daily plus nutritional supplement once daily (group A) or Tadalafil 5 mg plus placebo with the same administration schedule (group B) for 3 months. Blood samples, IIEF-5, SEP-2 and SEP-3 have been collected again after 3 months. cGMP was measured in platelets of 38 patients at baseline and after one months. RESULTS: Mean age was 59.98 ± 6.90 (range 38-69), mean IIEF-5 score at baseline was 13.59 ± 3.90. After three months of treatment, IIEF-5 score significantly improved in both groups compared to baseline (13.18 ± 3.75 vs 20.48 ± 2.24, p < 0.0001; 14.15 ± 4.09 vs 19.06 ± 4.36, p < 0.0001, in group A and group B respectively). Patients treated with Tadalafil plus nutritional supplement showed a significantly higher increase in IIEF-5 score compared to those who received placebo (7.27 ± 2.20 and 4.9 ± 2.79, respectively; p < 0.0001;). No hormonal differences and metabolic effects were found. According cGMP result, nutritional supplements ameliorates and extends the activity of the chronic treatment. CONCLUSIONS: IIEF-5 significant increase in group B, can be ascribed to the nutritional supplement properties and antioxidant effects of moringa oleifera, ginseng and rutin and this can enhance the endothelial NO and cGMP production.

Malpighia glabra L., commonly known as acerola or Barbados cherry, is a non-commercial tropical fruit species in Thailand that is primarily consumed fresh by local communities. Limited scientific data have restricted its potential for future food applications. In this study, we investigated the nutritional composition, phenolic profiles, and in vitro biological activity of M. glabra fruits. Results demonstrated that the ripened fruits (100 g fresh weight) provided low energy (36.9 kcal) with negligible fat content but exceptionally high vitamin C content (838 mg). The ethanolic extract exhibited strong antioxidant activities as examined by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay (250.98 µmol Trolox equivalent (TE) per g dry weight (DW)), ferric ion reducing antioxidant power (FRAP) assay (642.35 µmol TE per g DW), and oxygen radical absorbance capacity (ORAC) assay (443.90 µmol TE per g DW). These activities were attributed to the phenolic composition, of which rutin was the predominant compound, as detected by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The extract also demonstrated in vitro inhibition of α-glucosidase, with a half-maximal inhibitory concentration (IC50) of 4.81 mg mL-1, and β-secretase, with an IC50 value of 5.45 mg mL-1. Synergistic interactions were observed in vitro between the extract and acarbose (an anti-diabetic drug) and the extract and donepezil (an anti-Alzheimer's drug). These findings characterize the nutritional composition and in vitro bioactivities of ripened M. glabra fruits, supporting further investigation into their potential development as functional food ingredients.

ETHNOPHARMACOLOGICAL RELEVANCE: The Danshen (root of Salvia miltiorrhiza Bge.) and Shanzha (fruit of Crataegus pinnatifida Bge. var. major N.E.Br.) (SD) herb combination is a commonly used traditional Chinese medicine with potential for treating cardiovascular diseases. This study aimed to evaluate the anti-MASLD efficacy of SD and the potential mechanism of synergistic treatment of MASLD with its active ingredients. MATERIALS AND METHODS: The chemical composition of SD was elucidated using high-resolution mass spectrometry. A mouse model of MASLD was developed to assess therapeutic efficacy of SD. An integrated method, combining network pharmacology and multi-omics, was utilized to explore the anti-MASLD effects and mechanisms of SD. Additionally, molecular docking, Western blotting (WB), and other methodologies were employed to investigate the synergistic intervention mechanisms of SD's active ingredients in MASLD. RESULTS: SD can substantially mitigate liver lipid accumulation and inflammation in MASLD mice. We identified 92 components in SD, of which 55 were recognized as potential active ingredients. Notably, four chemical constituents-rutin, quercetin, salvianolic acid B, and hyperoside-have been identified as the active compounds responsible for the anti-MASLD effects of SD. Rutin, hyperoside and salvianolic acid B interacts with the Plin-5, facilitating the recruitment of lipid droplets to the mitochondria. Subsequently, salvianolic acid B, rutin and hyperoside activates PPARα, thereby promoting the oxidation of fatty acids. Concurrently, rutin, hyperoside and quercetin modulates Plin-2 to mitigate excessive fatty acid oxidation, thereby reducing the risk of oxidative stress. CONCLUSIONS: Our research preliminarily confirms the anti-MASLD effects and the mechanism of synergistic intervention by SD's active ingredients, providing valuable evidence to support the use of TCM formulae for treating MASLD.

Plants of the genus Terminalia have been widely used in traditional medicine for the treatment of multiple ailments, including infectious diseases. Previously, our group performed metabolomic analyses using liquid chromatography-mass spectrometry of various Terminalia spp. and highlighted several phytochemicals (particularly flavonoids) that may contribute to the antibacterial activities of those species. Herein, we screen 15 flavonoids found in Terminalia spp. against antibiotic-resistant and antibiotic-sensitive strains of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. Orientin, hispidulin, vitexin, rutin, fisetin, and isoorientin inhibited the growth of both methicillin- and β-lactam-resistant pathogens, producing MIC values ranging from 250 to 62.5 µg/mL. Orientin and isoorientin were the most effective at restricting the growth of methicillin-resistant and β-lactamase pathogens, with MIC values of 125 µg/mL against E. coli and extended-spectrum β-lactamase E. coli and 62.5 µg/mL against S. aureus. In combination with selected conventional antibiotics, some flavonoids potentiated the antimicrobial activity of selected conventional antibiotics. A total of 4 synergistic, 4 additive, and 22 non-interactive interactions were identified. The toxicity of the flavonoids was examined using Artemia franciscana nauplii lethality assays. With the exception of fisetin, genistein, and gossypetin, the flavonoids were non-toxic. Orientin and isoorientin were assessed for their potential to inhibit efflux pumps and demonstrated notable efflux pump inhibitory activity at four different concentrations: 125.0, 62.5, 31.25, and 15.26 µg/mL. The results obtained suggest that these flavonoids could serve as a valuable tool in combating antibiotic resistance. IMPORTANCE: Bacteria are becoming resistant to many types of antibiotics. This study has identified plant phytochemicals known as flavonoids, which were found to be capable of inhibiting the growth of numerous bacterial pathogens. Evidence is shown which reveals that the compounds are capable of blocking bacterial efflux pumps, which demonstrate that the flavonoids may be valuable compounds in the design

Terminalia catappa L. (Family: Combretaceae) is used globally to treat various diseases, including bacterial infections. Whilst the antibacterial activity of T. catappa has previously been tested against antibiotic-sensitive bacterial strains, the antimicrobial activity against methicillin and β-lactam-resistant pathogens has been relatively ignored. The antibacterial activity of T. catappa extracts, both alone and combined with selected clinical antibiotics, was evaluated in this study. The inhibition of bacterial growth by the extracts was determined using agar diffusion and broth micro-dilution assays. Combinations of the extracts and several clinical antibiotics were also examined and the ∑FICs were calculated to determine the interaction class. Synergistic combinations were further evaluated by isobologram analysis. The T. catappa leaf extracts were screened for toxicity using Artemia franciscana lethality bioassays (ALA). Orbitrap liquid chromatography-mass spectrometry (LC-MS) profiling analysis was undertaken to identify flavonoid components of the extracts, putatively. The T. catappa methanolic extract inhibited all the tested bacterial strains. It displayed especially good inhibitory activity against E. coli (MIC = 130 µg/mL). Combining the T. catappa extracts with some conventional antibiotics potentiated the inhibitory activity of the combinations compared to the activity of individual components. LC-MS profiling analysis identified multiple flavonoid components, including rutin, quercitin, orientin, the tannin component, and ellagic acid in the extracts. All extracts were non-toxic against Artemia nauplii. The phytochemical constituents present in the T. catappa leaf extracts warrant future investigation as potential antibacterial agents. Synergistic Phenolic Compounds in Medicinal Plant Extracts: Enhanced Furin Protease Inhibition via Solvent-Specific Extraction from Lamiaceae and Asteraceae Families. Üzer FB(1), Helvacı N(1), Elmastaş M(1). Author information: (1)Department of Phytotherapy, University of Health Sciences, Selimiye Complex, Selimiye Neighborhood, Atolyeler Street No: 4, Uskudar, 34668 Istanbul, Turkey. This study aimed to evalua

13. Molecules. 2025 Aug 22;30(17):3450. doi: 10.3390/molecules30173450. Synergistic Phenolic Compounds in Medicinal Plant Extracts: Enhanced Furin Protease Inhibition via Solvent-Specific Extraction from Lamiaceae and Asteraceae Families. Üzer FB(1), Helvacı N(1), Elmastaş M(1). Author informat

In this study, phytochemical characterization of Anethum graveolens extract, in-vitro, in-vivo and in-silico biological activities and synergistic and antagonistic effects of main components were investigated. Advanced analytical techniques such as LC-MS/MS and GC-MS were integrated with in-vitro, in-vivo and in-silico methodologies to provide valuable information on the therapeutic potential of the plant and its synergistic and antagonistic interactions, which are crucial for developing effective plant-based therapeutic agents. LC-MS/MS analysis revealed the presence of protecatechuic aldehyde, sesamol, caffeic acid, vannilin, p-coumaric acid, rutin and quercetin among the standards tested. Among the essential oils, γ-terpinene, limonene, γ-cadinene, dillapiole were detected in major proportions. The radical scavenging activity of A. graveolens extract was investigated by DPPH and superoxide anion scavenging tests. DPPH scavenging activity was observed in the range of 15.9-80.8% and superoxide anion scavenging activity in the range of 11.5-69.9%. The extract exhibited a broad spectrum activity against all tested microorganism species and the antimicrobial activity ranking among microorganisms was gram-positive > gram-negative > fungus. A. graveolens extract exhibited an inhibition zone of 15.2 ± 0.4 against E. coli and the main components tested individually exhibited a lower activity. And also MIC and MBC values ​​obtained with four main components were higher compared to the extract.This indicates that the extract exhibits a stronger antimicrobial activity due to the cumulative and synergistic effects of the active ingredients in the content. The most prominent synergistic effect was found in anti-genotoxic activity. While the most common fragment rate among the chromosomal aberrations induced by NaN3 decreased by 73.3% with the 20 mg/L extract application, the fragment ratio decreased by 37.3%, 35.3%, 31.5% and 28.07% with the caffeic acid, rutin, dillapiole and terpinen applications, respectively. These results suggest that the ingredients have a strong synergistic effect. In molecular docking studies the major components of A. graveolens were found to inte

The genus Terminalia has a long history of use in traditional medicine to treat various diseases, including bacterial infections. We previously reported a metabolomic analysis using liquid chromatography-mass spectrometry of selected Australian Terminalia spp. and highlighted numerous flavonoids that may contribute to the antimicrobial activities of those plants. This study examines the antibacterial activities of fifteen flavonoids found in Terminalia spp. against a range of gastrointestinal pathogens using broth dilution assays. Flavonoids were also combined with six different classes of conventional antibiotics to investigate interactions. The efflux pump inhibitory activity of the flavonoid was evaluated using ethidium bromide accumulation and efflux assays. Toxicities were assessed via human dermal fibroblast cell line assays. Fisetin, hispidulin, isoorientin, orientin, rutin, and vitexin showed noteworthy growth inhibitory activity (MIC values 62.5-250 µg/mL). Isoorientin and orientin were most potent against Bacillus cereus and Alcaligenes faecalis, displaying MIC values of 62.5 µg/mL against both bacteria. All flavonoids except genistein, isorhamnetin, kaempferol, luteolin, taxifolin, and vitexin were nontoxic in human dermal fibroblast (HDF) cell proliferation assays. When individual flavonoids were combined with selected antibiotics, some potentiated the activity of these antibiotics. Two synergistic, eighteen additive and thirty-one non-interactive interactions were observed. The synergistic interactions were all observed in combination with orientin. Notably, orientin exhibited efflux pump inhibitory effects at concentrations from 15.26 µg/mL to 125 µg/mL. The findings reported herein indicate that the selected flavonoids have the potential for addressing bacterial antibiotic resistance and highlight the need for further study.

Rutin is a widely known plant secondary metabolite that exhibits multiple physiological functions. The present study focused on screening for synergistic antibacterial combinations containing rutin, and further explored the mechanisms behind this synergy. In vitro antibacterial test results of rutin showed that the ranges of minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) are 0.125-1 and 0.125-2 mg/mL, respectively. However, rutin and amikacin have a significant synergistic effect, with a fractional inhibitory concentration index (FICI) range of 0.1875-0.5. The time bactericidal curve proved that the combination of rutin and amikacin inhibited bacterial growth within 8 h. Scanning electron microscopy (SEM) revealed that a low-dose combination treatment could disrupt the cell membrane of Escherichia coli (E. coli). A comprehensive analysis using alkaline phosphatase (AKP), K+, and a protein leakage assay revealed that co-treatment destroyed the cell membrane of E. coli, resulting in the significant leakage of AKP, intracellular K+, and proteins. Moreover, confocal laser scanning microscopy (CLSM) and red-green cell ratio analysis indicated severe damage to the E. coli cell membrane following the co-treatment of rutin and amikacin. This study indicates the remarkable potential of strategically selecting antibacterial agents with maximum synergistic effect, which could significantly control antibiotic resistance.

The wide dissemination of multidrug-resistant (MDR) Gram-negative bacteria poses a significant global health and security concern. As developing new antibiotics is generally costly, fastidious, and time-consuming, there is an urgent need for alternative therapeutic strategies to address the gap in antibiotic discovery void. This study aimed to investigate the activity of colistin (CS) in combination with a natural product, rutin (RT), to combat against Salmonella Typhimurium (S. Tm) in vitro and in vivo. The results showed that a combination with RT enabled the potentiation of CS efficacy. Further mechanistic analysis indicated that RT disrupted iron homeostasis to inactivate the PmrA/PmrB system, thereafter reducing the bacterial membrane modifications for enhancing CS binding. Besides enhancing bactericidal activity of CS, RT was also observed to mitigate the CS-induced nephrotoxicity, by which the dosing limitation of CS was overcome for better pathogen clearance. The animal trial eventually confirmed the in vivo synergistic interaction of RT with CS to treat the bacterial infection. To sum up, the present study uncovered the potential of RT as a viable adjuvant of CS to eradicate the infection and protect the hosts, which might serve as a promising alternative to combat infections caused by MDR Gram-negative bacteria.

OBJECTIVE: This study investigated the combination of Bauhinia holophylla (Bong.) Steud. leaf extracts with conventional antifungal agents, highlighting the extracts' potential as adjuvants in treating oral candidiasis. DESIGN: Ethanolic and aqueous extracts of B. holophylla leaves were analyzed using ultra-high-performance liquid chromatography with a diode array detector (UHPLC-DAD) to assess their chemical composition. Their Minimum Inhibitory Concentration (MIC) against standard strains of Candida albicans and isolates from oral mucosa was determined. Additionally, the potential synergistic effects with chlorhexidine gluconate, nystatin, and fluconazole were investigated, along with their impact on inhibiting and disrupting biofilm formation, germ tube formation of C. albicans, and cytotoxicity in human erythrocytes. RESULTS: Protocatechuic acid, epicatechin, and rutin were identified in both extracts. They exhibited fungistatic activity with a median minimum inhibitory concentration (MIC50) of 15.62 µg/mL for the ethanolic extract (EEB) and 62.50 µg/mL for the aqueous extract (AEB) against C. albicans. In growth kinetics, both extracts reduced the viable cell count of C. albicans by 2 logs after 24 h compared to the positive control. The extracts reduced germ tube formation by 81.6 % for EEB and 86.3 % for AEB. The synergistic combination with fluconazole and nystatin resulted in a 50 % reduction in the concentration required to inhibit C. albicans growth. No hemolytic activity was detected in human erythrocytes at the tested concentrations. CONCLUSION: Both ethanolic and aqueous extracts show promising potential as adjuvants in managing oral candidiasis. Notably, the aqueous extract is advantageous due to its non-toxic solvent, cost-effectiveness, and ease of preparation.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease driven by persistent inflammation and oxidative stress. Ilex paraguariensis (yerba mate) contains bioactive compounds-particularly chlorogenic acids, quercetin, and rutin-with documented antioxidant and anti-inflammatory properties. Objectives: To systematically review the mechanistic and clinical evidence on Ilex paraguariensis and its main constituents in RA-relevant inflammatory, oxidative, and bone metabolic pathways. Methods: Following PRISMA 2020, PubMed/MEDLINE, LILACS, and SciELO were searched up to September 2025. Eligible studies included yerba mate preparations (last 10 years) or isolated compounds (last 5 years) assessing RA-relevant clinical, inflammatory, oxidative, or bone metabolic outcomes. Non-original studies were excluded. Owing to heterogeneity, findings were narratively synthesized, and risk of bias was evaluated using RoB 2, ROBINS-I, OHAT, and SYRCLE. Results: Twenty-three studies met inclusion criteria: 11 human (clinical or observational), 7 human-based in vitro, and 5 animal studies. Interventions with yerba mate infusions or standardized extracts suggest reductions in inflammatory markers (e.g., C-reactive protein, interleukin-6) and indicate improvements in glutathione-related oxidative balance. Evidence from isolated compounds, particularly quercetin and rutin, suggests comparable anti-inflammatory and antioxidant effects. Preclinical studies appear to indicate modulation of inflammatory and redox pathways relevant to RA. Conclusions: Yerba mate and its constituents show preliminary indications of anti-inflammatory and antioxidant effects with potential relevance to RA pathophysiology. However, in the absence of clinical trials in RA patients, conclusions remain tentative, constrained by small sample sizes, methodological heterogeneity, species differences, and internal validity concerns. Future research should include rigorously designed randomized trials and mechanistic studies using advanced human-relevant platforms, such as organoids and organ-on-chip systems.

As a complex of enzymes α-l-rhamnosidase and β-d-glucosidase, naringinase catalyzes the deglycosylation of flavonoids. According to the PRISMA method, a systematic literature review was conducted analyzing peer-reviewed scientific articles from the Scopus and Web of Science databases. Recent reviews on naringinase have focused on its sources, production, and general applications, whereas the present study highlights its specific applications, its role in the deglycosylation of flavonoids, and the resulting improvement in their bioavailability. This review focuses on advances in modifying the glycosidic parts of various flavonoids using naringinase by selectively disconnecting the rhamnose or glucose moiety. Removing rhamnose from the flavonoid molecule but leaving the glucose allows more water-soluble compounds to be present and increases bioavailability. A necessary condition for such selective deglycosylation is removing or inhibiting beta-glucosidase, the second enzyme in the native naringinase molecule. The use of naringinase for preparing functional beverages with increased antioxidant activity and for preparing steviol sweeteners is also presented. Naringinase enables the desired sensory properties to be obtained, primarily the taste and aroma of food products, and can be used in combination with other enzymes, e.g., pectinase and tannase.

BACKGROUND: Liver disorders pose a considerable global health challenge, accompanied by rising mortality rates. Current therapeutic strategies, though effective, often face limitations due to adverse effects and therapeutic resistance, prompting the exploration of alternative treatments, particularly safer natural compounds. Rutin, a widely available bioflavonoid, has emerged as a promising candidate owing to its varied pharmacological properties. METHODS: We conducted a comprehensive search on PubMed and Web of Science using the following keywords: 'rutin', 'liver diseases', 'hepatoprotection', 'clinical observations', 'mechanisms, pharmacology' and various combinations of these terms. RESULTS: This review systematically examines rutin's therapeutic potential in hepatic disorders, focusing on its molecular mechanisms, particularly its effects on inflammatory pathways, oxidative stress and hepatocellular protection. CONCLUSION: We analyse existing evidence supporting rutin's hepatoprotective efficacy, identify its cellular and molecular targets and evaluate its potential applications in various liver diseases. Our systematic analysis provides theoretical support for developing rutin-based therapies in hepatic disease management and identifies future research directions and clinical applications. © 2025 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.

BACKGROUND: Post-thrombotic syndrome (PTS) has been highly prevalent; over 50% of the patients develop PTS after lower extremity acute deep vein thrombosis. Venoactive compounds (VACs) have been recommended for decades for patients with chronic venous insufficiency, including PTS. The objective of our study was to perform a systematic review to determine the quality of evidence on the utility of VACs for both prevention and treatment of PTS. METHODS: A systematic review was conducted to search the literature between January 1, 1980, and July 14, 2023, for venoactive drugs or medications, deep vein thrombosis, and PTS using PubMed, MEDLINE, life science journals, and the Cochrane Library. Only randomized controlled trials (RCTs) published in English were included in this review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the revised Cochrane risk-of-bias tool for RCTs were used. RESULTS: Ninety-four references were identified; 11 RCTs fulfilled the inclusion criteria. VACs administered were diosmin, hidrosmin/rutosides, micronized purified flavonoid fraction (MPFF), and sulodexide. The studies included a highly variable proportion of patients with PTS (8.6%-100%). Some older studies omitted details of the methodology. Two studies suggested benefit of diosmin and MPFF as adjunctive treatment to rivaroxaban in the prevention of PTS and showed low or unclear risk of bias. Evaluation of RCTs for the treatment of post-thrombotic chronic venous insufficiency found low or unclear risk of bias in 81.6% to 85.7%. All studies suggested that VACs were beneficial for PTS treatment; they improved venous symptoms, decreased edema, and helped heal venous ulcers. CONCLUSIONS: This systematic review found that VACs had at least moderate quality of evidence in improving venous symptoms, decreasing edema, and accelerating venous ulcer healing. Two pilot RCTs of higher quality suggested the usefulness of diosmin and MPFF as adjunctive treatment to rivaroxaban therapy to reduce the incidence of PTS and improve deep vein recanalization. Because most RCTs were published over two decades ago, and several lacked the required precision i

Flavonoids in fruits, vegetables, and plant-based drinks have potential neuroprotective properties, with clinical research focusing on their role in reducing oxidative stress, controlling inflammation, and preventing apoptosis. Some flavonoids, such as quercetin, kaempferol, fisetin, apigenin, luteolin, chrysin, baicalein, catechin, epigallocatechin gallate, naringenin, naringin, hesperetin, genistein, rutin, silymarin, and daidzein, have been presented to help heal damage to the central nervous system by affecting key signaling pathways including PI3K/Akt and NF-κB. This review systematically analyzed articles on flavonoids, neuroprotection, and brain and spinal cord injury from primary medical databases like Scopus, PubMed, and Web of Science. Flavonoids enhance antioxidant defenses, reduce pro-inflammatory cytokine production, and aid cell survival and repair by focusing on specific molecular pathways. Clinical trials are also exploring the application of preclinical results to therapeutic approaches for patients with spinal cord injury and traumatic brain injury. Flavonoids can enhance injury healing, reduce lesion size, and enhance synaptic plasticity and neurogenesis. The full potential of flavonoids lies in their bioavailability, dose, and administration methods, but there are still challenges to overcome. This review explores flavonoid-induced neuroprotection, its clinical implications, future research opportunities, and molecular mechanisms, highlighting the potential for innovative CNS injury therapies and improved patient health outcomes. © 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

BACKGROUND: Natural products, with incredible chemical diversity, have been widely studied for their antitumor potential. Quercetin (QU) and quercetin glycoside (rutin), both polyphenolic flavonoids, stick out amongst the natural products, through various studies. Rutin (RU) and its aglycone (QU) have various biological properties that include antioxidant, anti-inflammatory, and anticarcinogenic activities. However, several side effects have restricted the efficacy of these polyphenolic flavonoids, which makes it necessary to use new strategies involving low and pharmacological doses of QU and RU, either alone or in combination with other anticancer drugs. PURPOSE: The aim of this study is to present a comprehensive and critical evaluation of the anticancer ability of different nano-formulations of RU and QU for improved treatment of various malignancies. METHODS: Studies were recognized via systematic searches of ScienceDirect, PubMed, and Scopus databases. Eligibility checks were conducted based upon predefined selection criteria. Ninety articles were included in this study. RESULTS: There was conclusive evidence for the association between anticancer activity and treatment with RU or QU. Furthermore, studies indicated that nano-formulations of RU and QU have greater anticancer activities in comparison to either agent alone, which leads to increased efficiency for treating cancer. CONCLUSION: The results of this systematic review demonstrate the anticancer activities of nano-formulations of RU and QU and their molecular mechanisms through preclinical studies. This paper also attempts to contribute to further research by addressing the current limitations/challenges and proposing additional studies to realize the full potential of RU- and QU-based formulations for cancer treatment.

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.

BACKGROUND: Type 2 diabetes (adult onset diabetes) is the most common type of diabetes, accounting for around 90% of all diabetes cases with insulin resistance and insulin secretion defect. The key goal of anti-diabetic therapy is to increase the development of insulin, immunity and/or decrease the amount of blood glucose. While many synthetic compounds have been produced as antidiabetic agents, due to their side effects and limited effectiveness, their usefulness has been hindered. METHODS: This systematic review investigated the bioactive compounds reported to possess activities against type 2 diabetes. Three (3) databases, PubMed, ScienceDirect and Google Scholar were searched for research articles published between January 2010 and October 2020. A total of 6464 articles were identified out of which 84 articles were identified to be elligible for the study. RESULT AND DISCUSSION: From the data extracted, it was found that quercetin, Kaempferol, Rosmarinic acid, Cyanidin, Rutin, Catechin, Luteolin and Ellagic acid were the most cited bioactive compounds which all falls within the class of polyphenolic compounds. The major sources of these bioactive compounds includes citrus fruits, grapes, onions, berries, cherries, broccoli, honey, apples, green tea, Ginkgo biloba, St. John's wort, green beans, cucumber, spinach, tea, Rosmarinus officinalis, Aloe vera, Moringa oleifera, tomatoes, potatoes, oregano, lemon balm, thyme, peppermint, Ocimum basilicum, red cabbage, pears, olive oil and walnut.

BACKGROUND: Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs in the lower limbs. It might result in considerable discomfort, with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is the second update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, French maritime pine bark extract, grape seed extract and aminaftone) in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I2). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analy

The consumption of plant-based food is important for health promotion, especially concerning the prevention and management of chronic diseases. Flavonoids are the main bioactive compounds in citrus fruits, with multiple beneficial effects, especially antidiabetic effects. We systematically review the potential antidiabetic action and molecular mechanisms of citrus flavonoids based on in vitro and in vivo studies. A search of the PubMed, EMBASE, Scopus, and Web of Science Core Collection databases for articles published since 2010 was carried out using the keywords citrus, flavonoid, and diabetes. All articles identified were analyzed, and data were extracted using a standardized form. The search identified 38 articles, which reported that 19 citrus flavonoids, including 8-prenylnaringenin, cosmosiin, didymin, diosmin, hesperetin, hesperidin, isosiennsetin, naringenin, naringin, neohesperidin, nobiletin, poncirin, quercetin, rhoifolin, rutin, sineesytin, sudachitin, tangeretin, and xanthohumol, have antidiabetic potential. These flavonoids regulated biomarkers of glycemic control, lipid profiles, renal function, hepatic enzymes, and antioxidant enzymes, and modulated signaling pathways related to glucose uptake and insulin sensitivity that are involved in the pathogenesis of diabetes and its related complications. Citrus flavonoids, therefore, are promising antidiabetic candidates, while their antidiabetic effects remain to be verified in forthcoming human studies.