The Synergistic Influence of Polyflavonoids from Citrus aurantifolia on Diabetes Treatment and Their Modulation of the PI3K/AKT/FOXO1 Signaling Pathways: Molecular Docking Analyses and In Vivo Investigations.

This study was aimed at probing the modulatory influence of polyflavonoids extracted from Citrus aurantifolia, lemon peel extract (LPE-polyflavonoids), on attenuating diabetes mellitus (DM) and its complications. HPLC investigations of the LPE exhibited the incidence of five flavonoids, including diosmin, biochanin A, hesperidin, quercetin, and hesperetin. The in silico impact on ligand-phosphatidylinositol 3-kinase (PI3K) interaction was investigated in terms of polyflavonoid class to explore the non-covalent intakes and binding affinity to the known protein active site. The drug likeness properties and pharmacokinetic parameters of the LPE-polyflavonoids were investigated to assess their bioavailability in relation to Myricetin as a control. Remarkably, the molecular docking studies demonstrated a prominent affinity score of all these agents together with PI3K, implying the potency of the extract to orchestrate PI3K, which is the predominant signal for lessening the level of blood glucose. To verify these findings, in vivo studies were conducted, utilizing diabetic male albino rats treated with LPE-polyflavonoids and other groups treated with hesperidin and diosmin as single flavonoids. Our findings demonstrated that the LPE-polyflavonoids significantly ameliorated the levels of glucose, insulin, glycogen, liver function, carbohydrate metabolizing enzymes, G6Pd, and AGEs compared to the diabetic rats and those exposed to hesperidin and diosmin. Furthermore, the LPE-polyflavonoids regulated the TBARS, GSH, CAT, TNF-α, IL-1ß, IL-6, and AFP levels in the pancreatic and hepatic tissues, suggesting their antioxidant and anti-inflammatory properties. In addition, the pancreatic and hepatic GLUT4 and GLUT2 were noticeably increased in addition to the pancreatic p-AKT in the rats administered with the LPE-polyflavonoids compared to the other diabetic rats. Remarkably, the administration of LPE-polyflavonoids upregulated the expression of the pancreatic and hepatic PI3K, AMPK, and FOXO1 genes, emphasizing the efficiency of the LPE in orchestrating all the signaling pathways necessitated to reduce the diabetes mellitus. Notably, the histopathological examinations of the pancreatic and hepatic tissues corroborated the biochemical results. Altogether, our findings accentuated the potential therapeutic role of LPE-polyflavonoids in controlling diabetes mellitus.

The Effect of Diosmin, Escin, and Bromelain on Human Endothelial Cells Derived from the Umbilical Vein and the Varicose Vein-A Preliminary Study.

In this study, we investigated the properties of human varicose vein (VV) endothelial cells (HVVEC) in comparison to the human umbilical vein endothelial cells (HUVEC). The cells were treated with three bioactive compounds with proven beneficial effects in the therapy of patients with VV, diosmin, escin, and bromelain. Two concentrations of tested drugs were used (1, 10 mg/mL), which did not affect the viability of either cell type. Escin led to a slight generation of reactive oxygen species in HUVEC cells. We observed a slight release of superoxide in HVVEC cells upon treatment with diosmin and escin. Diosmin and bromelain showed a tendency to release nitric oxide in HUVEC. Using membrane fluorescent probes, we demonstrated a reduced fluidity of HVVEC, which may lead to their increased adhesion, and, consequently, a much more frequent occurrence of venous thrombosis. For the first time, we show the mechanism of action of drugs used in VV therapy on endothelial cells derived from a VV. Studies with HVVEC have shown that tested drugs may lead to a reduction in the adhesive properties of these cells, and thus to a lower risk of thrombosis.

Diosmin and Bromelain Stimulate Glutathione and Total Thiols Production in Red Blood Cells.

Diosmin and bromelain are bioactive compounds of plant origin with proven beneficial effects on the human cardiovascular system. We found that diosmin and bromelain slightly reduced total carbonyls levels and had no effect on TBARS levels, as well as slightly increased the total non-enzymatic antioxidant capacity in the RBCs at concentrations of 30 and 60 µg/mL. Diosmin and bromelain induced a significant increase in total thiols and glutathione in the RBCs. Examining the rheological properties of RBCs, we found that both compounds slightly reduce the internal viscosity of the RBCs. Using the MSL (maleimide spin label), we revealed that higher concentrations of bromelain led to a significant decrease in the mobility of this spin label attached to cytosolic thiols in the RBCs, as well as attached to hemoglobin at a higher concentration of diosmin, and for both concentrations of bromelain. Both compounds tended to decrease the cell membrane fluidity in the subsurface area, but not in the deeper regions. An increase in the glutathione concentration and the total level of thiol compounds promotes the protection of the RBCs against oxidative stress, suggesting that both compounds have a stabilizing effect on the cell membrane and improve the rheological properties of the RBCs.

Nephroprotective Effect of Diosmin against Cisplatin-Induced Kidney Damage by Modulating IL-1ß, IL-6, TNFα and Renal Oxidative Damage.

Cisplatin (CP) is a platinum compound of the alkylating agent class that is used for the treatment of various types of cancer. However, CP treatments in cancer patients are accountable for nephrotoxicity, as it is a major adverse effect. Hence, this research study was proposed to investigate the nephroprotective effect of diosmin, a flavonoid glycoside of hesperidin derivatives against cisplatin-induced kidney damage. Wistar rats received a single intraperitoneal (i.p) injection of CP (7.5 mg/kg, i.p) to induce nephrotoxicity. The administration of CP significantly (p < 0.001) increased the markers of kidney function test (creatinine, blood urea nitrogen, and uric acid) and demonstrated histopathological changes in the kidney of the CP-treated nephrotoxic group. In addition, the CP-treated nephrotoxic group demonstrated a significant (p < 0.001) increase in lipid peroxidation (LPO) levels and depleted activities of reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT).However, diosmin (100 and 200 mg/kg) treatments significantly reduced the elevated levels of kidney function test parameters and restored structural changes in the kidney (p < 0.001). The administration of diosmin (100 and 200 mg/kg) significantly (p < 0.001) reduced LPO levels, increased GSH content and showed improvements in the activities of GPx, GR, SOD and CAT. The markers of inflammatory cytokines such as IL-1ß, IL-6 and TNFα significantly (p < 0.001) increased in the CP-treated nephrotoxic group, whereas diosmin (100 and 200 mg/kg) treatments significantly (p < 0.001) reduced the elevated levels of these cytokines. The findings of this research demonstrate the nephroprotective effect of diosmin against CP-induced kidney damage. Therefore, we conclude that diosmin may be used as a supplement in the management of nephrotoxicity associated with CP treatments in cancer patients.

The Effect of Hesperidin and Diosmin Individually or in Combination on Metabolic Profile and Neuropathy among Diabetic Patients with Metabolic Syndrome: A Randomized Controlled Trial.

Current evidence supports the association of metabolic syndrome (MetS) with neuropathy. Limited data are available on proper strategies to control metabolic disorders and neuropathy among patients with type2 diabetes mellitus (T2DM). We aimed to determine hesperidin and diosmin efficacy individually and in combination among T2DM patients with neuropathy and meet MetS criteria. In this parallel-group designed trial, 129 T2DM patients with MetS and neuropathy were recruited and randomized to receive their oral hypoglycemics with either hesperidin (1g/day), or diosmin (1g/day), or combination of both or oral hypoglycemics without intervention for 12 weeks. Diabetic neuropathy was evaluated using Michigan Neuropathy Screening Instrument (MNSI) at baseline and after trial. Anthropometric parameters, blood glucose and lipid profile were also assessed before and after the intervention using paired student t-test within groups. The trial is registered at clinicaltrials.gov as NCT05243238. By completion of the trial duration, both hesperidin and diosmin groups showed significant reduction in blood glucose, triglycerides (TGs) and low density lipoprotein (LDL) from baseline (p<0.05). However, the magnitude of improvement in metabolic components significantly increased with hesperidin and diosmin combination. Although MNSI scores improved significantly in both groups, the reduction was more significant with the combination of hesperidin and diosmin. Moreover, the change in MNSI score was significantly correlated with the improvement in metabolic profile components including LDL, TGs and fasting blood glucose. Oral supplementation of hesperidin and diosmin was associated with improvement in metabolic syndrome and diabetic neuropathy and the combination of both was superior in efficacy.

Selected polyphenolic compounds and their use as a supportive therapy in metabolic syndrome.

Metabolic syndrome is diagnosed mainly in people of economically developed parts of the world and it affects 20-25% of the adult population worldwide. Nowadays, it is also more frequently diagnosed in children and adolescents. In addition to standard treatment that often involves polypharmacotherapy, and thus increases risk of side effects caused by drugdrug interactions, it is appropriate to look for alternative tools to support the treatment of metabolic syndrome components. Natural polyphenolic compounds, usually present in the so-called functional foods, are suitable candidates for that matter, due to the bioactivity and beneficial effects on the human body. Quercetin, troxerutin, diosmin, hesperidin or silybin are among the currently studied and used natural polyphenolic compounds with a positive effect on aspects of the metabolic syndrome. In addition to their antioxidant and anti-inflammatory effects, these compounds have other positive properties that very often outweigh their side effects whilst their usage in the pharmacotherapy.

Evaluation of Diabetes Effects of Selenium Nanoparticles Synthesized from a Mixture of Luteolin and Diosmin on Streptozotocin-Induced Type 2 Diabetes in Mice.

The absence of a treatment efficient in the control of type 2 diabetes mellitus requires more functional products to assist treatment. Luteolin (LU) and diosmin (DIO) have been known as bioactive molecules with potential for the treatment of diabetes. This work aimed to establish the role that a combination of LU and DIO in selenium nanoparticles (SeNPs) played in streptozotocin (STZ)- induced diabetes mice. Green synthesis of Se NPs was performed by mixing luteolin and diosmin with the solution of Na2SeO3 under continuous stirring conditions resulting in the flavonoids conjugated with SeNPs. The existence of flavonoids on the surface of SeNPs was confirmed by UV-Vis spectra, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) images, and DLS graphs via Zetasizer. The average diameter of GA/LU/DIO-SeNPs was 47.84 nm with a PDI of -0.208, a zeta potential value of -17.6, a Se content of 21.5% with an encapsulation efficiency of flavonoids of 86.1%, and can be stabilized by gum Arabic for approximately 175 days without any aggregation and precipitation observed at this time. Furthermore, The C57BL/6 mice were treated with STZ induced-diabetes and were exposed to LU/DIO, SeNPs, and GA/LU/DIO-SeNPs for six weeks. The treatment by nanospheres (GA/LU/DIO-SeNPs) in the mice with diabetes for a period of 6 weeks restored their blood glucose, lipid profile, glycogen, glycosylated hemoglobin, and insulin levels. At the same time, there were significant changes in body weight, food intake, and water intake compared with the STZ- untreated induced diabetic mice. Moreover, the GA/LU/DIO-SeNPs showed good antioxidant activity examined by catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) in liver and kidney and can prevent the damage in the liver evaluated by aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) activities. The nanospheres exhibited a significant anti-diabetic activity with a synergistic effect between the selenium and flavonoids. This investigation provides novel SeNPs nanospheres prepared by a high-efficiency strategy for incorporating luteolin and diosmin to improve the efficiency in type 2 diabetes.

Therapeutic Observation of Shipiyin Combined with Diosmin in Treatment of Lymphedema with Spleen Yang Deficiency Syndrome After Modified Radical Mastectomy / 中国实验方剂学杂志

ObjectiveTo investigate the clinical effect of Shipiyin combined with diosmin in the treatment of lymphedema with spleen Yang deficiency syndrome（SYDS）after modified radical mastectomy and the specific effect on the function of the affected limb. MethodEighty-two patients with lymphedema with SYDS after modified radical mastectomy from outpatient and inpatient department of breast department and oncology department of the First Affiliated Hospital of Hunan University of Chinese Medicine were randomly divided into an observation group（41 cases） and a control group（41 cases）. The control group was given diosmin tablets（0.9 g per time， two times per day）on the basis of conventional treatment，and the observation group was given Shipiyin（one dose per day）on the basis of the control group. The course of treatment was 14 days. The clinical symptoms were observed and the limb circumference，traditional Chinese medicine（TCM） syndrome score，functional assessment of cancer therapy-breast cancer（FACT-B） score，disability of arm， shoulder and hand questionnaire（DASH） score，and joint range of motion were measured to analyze the TCM syndrome therapeutic effect and clinical efficacy. ResultAfter 14 days of treatment， the total effective rate of the observation group was 85.37% （35/41） and that of the control group was 63.41% （26/41） in the TCM symptoms， showing a statistically significant difference （Z=-2.212， P<0.05）. In terms of the clinical efficacy， the total effective rate in the observation group was 82.93% （34/41） and that in the control group was 75.61% （31/41）， indicating a statistically significant difference （Z=-2.061， P<0.05）. Compared with the situations before treatment， the scores of clinical symptoms such as the swelling of the upper limb， pain， sense of heaviness， stuffiness， fatigue， fullness， tightness， and skin keratosis and pruritus in the two groups were significantly lowered （P<0.01） after treatment. Compared with the control group， the observation group could better improve the swelling and fullness（P<0.01），as well as the feeling of pain，heaviness，stuffiness，fatigue，tightness，skin keratosis and pruritus （P<0.05）of the upper limbs of patients. The affected limb circumference， TCM syndrome score， and DASH score decreased significantly， while the FACT-B score and upper limb joint range of motion increased significantly in the two groups after treatment （P<0.01）. Compared with the control group， the observation group showed significantly reduced limb circumference at 10 cm proximal to the elbow striae， lowered TCM syndrome score， elevated FACT-B score（P<0.05）， decreased DASH score and improved range of motion of the upper limb joint （P<0.01） after treatment. ConclusionShipiyin combined with diosmin has better clinical efficacy in the treatment of lymphedema with SYDS after modified radical mastectomy than diosmin alone，which can better improve the clinical symptoms，signs，quality of life and limb functional activity of patients. This provides a new clinical program for the treatment of lymphedema after breast cancer surgery with integrated Chinese and western medicine.

Assessment of Platelet Reactivity and Inflammatory Markers in Coronary Artery Bypass Graft Patients Treated with Acetylsalicylic Acid with Flavonoid Supplementation.

The recommended pharmacological therapy for patients with coronary artery disease (CAD) treated by coronary artery bypass grafting (CABG) is acetylsalicylic acid (ASA). To improve the antiplatelet effect, supplementation with flavonoids is also recommended. The aim of this study was to estimate anti-aggregation properties of diosmin, in combination with ASA, pre- and postoperatively and assess the relationship of this therapy with inflammatory processes in CAD patients undergoing CABG. The study patients (n = 26) took diosmin (1000 mg/day); the control patients (n = 27) took a placebo. The therapeutic period for taking diosmin was from at least 30 days before to 30 days after CABG. All patients also took 75 mg/day ASA. Platelet aggregation and IL-6, CRP, and fibrinogen concentrations were determined before and 30 days after surgery. Results showed that diosmin did not enhance the anti-aggregation effect of ASA at any assessment time. However, there was a stronger anti-aggregation effect 30 days after surgery that was diosmin independent and was associated with acute-phase markers in the postoperative period. Increased levels of inflammatory markers in the late phase of the postoperative period may provide an unfavorable prognostic factor in long-term follow-up, which should prompt the use of stronger antiplatelet therapy in patients after CABG.

The antihypertensive potential of flavonoids from Chinese Herbal Medicine: A review.

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.

The Growth Suppression Activity of Diosmin and PGV-1 Co-Treatment on 4T1 Breast Cancer Targets Mitotic Regulatory Proteins.

OBJECTIVE: We aim to enhance the effectiveness of curcumin analog PGV-1 through co-treatment with diosmin, a citrus flavonoid, on 4T1 cells and evaluate the molecular targets underlying its effect on the cell cycle. METHODS: Cytotoxic effects were performed by MTT assay against 4T1 cells. The May Grünwald-Giemsa staining was used to observe cell cycle arrest. The senescence was assayed with SA-ß-gal staining. Bioinformatic studies were utilized to discover protein targets of PGV-1 and diosmin on triple-negative breast cancer (TNBC) using SwissTargetPrediction, then exploration of protein targets was performed using the TCGA dataset via the UALCAN website. Kaplan-Meier was performed using GraphPad with data from the TCGA dataset via Oncoln. Using MOE 2010, we conducted the binding affinity between PGV-1 and diosmin to protein targets. RESULTS: PGV-1 and diosmin showed cytotoxic effect with IC50 values of 9 µM and 389 µM, respectively, and the combined cytotoxic assay exhibited a synergistic effect with a combination index (CI) of <1. PGV-arrested 4T1 cells in pro-metaphase and induced mitotic catastrophe, while the combination of diosmin with PGV-1 increased the number of mitotic catastrophes. The SA-ß-gal assay revealed that both compounds were capable of inducing senescence in 4T1 cells. Study bioinformatics and molecular docking showed that PGV-1 and diosmin target cell cycle regulatory proteins in TNBC, namely CDK1, KIF11, and AURKA. Thus, the combination of diosmin and PGV-1 modulating the cell cycle that causes senescence and catastrophic death of 4T1 cancer cells is related to the inhibition of these cell cycle proteins. CONCLUSION: Diosmin enhances the cytotoxic effect of PGV-1 synergistically on 4T1 cancer cells, which correlates to the increasing senescence and mitotic catastrophe. The synergistic effect of the co-treatment is likely to target AURKA, CDK1, and KIF11. The combination of PGV-1 and diosmin performs a potential as a combinatorial anticancer drug for TNBC.

Therapeutic potential of diosmin, a citrus flavonoid against arsenic-induced neurotoxicity via suppression of NOX 4 and its subunits.

OBJECTIVES: Water contaminated with arsenic affected millions of people worldwide and arsenic exposure is related to various neurological disorders. Hence, the current study was planned to investigate the neuroprotective activity of diosmin (DSN) against arsenic induced neurotoxicity as an attempt to identify therapeutic intervention to combat arsenicism. MATERIALS AND METHODS: Sodium arsenite an inducer of neurotoxicity was administered orally (13 mg/kg) and DSN treatment at two selected doses (50 and 100 mg/kg) was done for 21 days. Behavioral and biochemical variations were examined by various parameters. Furthermore, histopathological and immunohistochemistry studies were done with the brain sections. RESULTS: The behavioral studies evidenced that arsenic has suppressed the exploratory behavior and motor coordination in rats and DSN treatment has recovered the behavioral changes to normal. Arsenic administration has also found to induce oxidative stress and DSN co-treatment has ameliorated the oxidative stress markers. Interestingly, depleted levels of neurotransmitters were observed with the arsenic and it was restored back by the DSN treatment. Histopathological alterations like pyknosis of the neuronal cells were identified with arsenic exposure and subsided upon DSN co administration. Immunohistochemical studies have revealed the expression of NOX4 and its gp91phox and P47phox subunits and its suppression by DSN treatment may be the key therapeutic factor of it. CONCLUSIONS: Treatment with DSN showed a beneficial effect in protecting against arsenic-induced neurotoxicity by suppressing the toxicity changes and the antioxidant effect of DSN might be attributed to its ability of suppressing NOX4 and its subunits.

Anticancer and Anti-inflammatory Effect of Diosmin against Dalton Ascitic Lymphoma Induced Leukemia.

Cancer is the world's biggest health problem and cancer-induced mortality happened all over the planet after the heart disease. The present study was to scrutinize the anti-leukemia effect of diosmin against Dalton Ascitic Lymphoma (DAL) induced leukemia in mice. DAL cell was used for induction the solid tumor. Body weight, life spans, tumor volume and mean survival time was estimated. Antioxidant, biochemical and pro-inflammatory cytokines were estimated. Diosmin showed the cell viability effect at dose dependent manner against the both cell lines. DAL induced solid tumor mice showed the decreased body weight, mean survival days, non viable cell count and increased the tumor volume, viable cell count and diosmin significantly (p < 0.001) reverse the effect of DAL. Diosmin significantly (p < 0.001) altered the hematological, differential leukocytes, antioxidant, biochemical, pro-inflammatory cytokines at dose dependently. Collectively, we can say that diosmin might alter the DAL induced abnormality via antioxidant and anti-inflammatory effects.

Diosmin restores the skin barrier by targeting the aryl hydrocarbon receptor in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory chronic skin disease that is characterized by the dysfunction or lack of skin barrier proteins. Recent studies have proposed that the pharmacological upregulation of skin barrier proteins is an effective treatment for AD. Aryl hydrocarbon receptor (AhR) is a transcription factor that positively regulates the expression of skin barrier proteins upon its activation. PURPOSE: This study aimed to identify AhR agonists from phytochemicals and investigate its effect on skin barrier restoration as well as its mechanisms of action in AD. STUDY DESIGN: A publicly available assay database and HaCaT cells stably transduced with a luciferase gene driven by an AhR-target gene promoter (CYP1A1) were used to screen for the activity of AhR agonists from phytochemicals. Normal human epidermal keratinocytes (NHEKs) and a human skin equivalent (HSE) model were used to investigate the effect of AhR agonists on skin restoration and its underlying mechanisms. METHODS: A Gaussia luciferase assaywas performed to screen for AhR agonist activity. Western blotting, qRT-PCR analysis, immunofluorescence, drug affinity responsive target stability assay, and siRNA-mediated AhR knockdown were performed in NHEKs. Hematoxylin and eosin staining was performed to measure epidermal thickness in the HSE model. RESULTS: Diosmin, a potential AhR agonist derived from natural products, upregulated the expression of skin barrier proteins (filaggrin and loricrin) and their upstream regulator (OVOL1) in NHEKs. Diosmin treatment also increased epidermal thickness in the HSE model. In addition, incubating NHEKs with diosmin restored the expression of skin barrier proteins and mRNAs that were suppressed by Th2 cytokines and inhibited STAT3 phosphorylation that was induced by Th2 cytokines. Diosmin also upregulated the expression of NQO1, a negative regulator of STAT3. Immunofluorescence results showed that diosmin stimulated AhR nuclear translocation, and the drug affinity responsive target stability assay revealed that this phytochemical directly bound to AhR. Furthermore, AhR knockdown abolished diosmin-induced filaggrin and loricrin expression. CONCLUSION: These results suggest that diosmin is a potential treatment for AD that targets AhR.

Antioxidant activity and polyphenol composition of sugarcane molasses extract.

The antioxidant activity of sugarcane molasses ethanol extract (ME) and its fraction (ME-RBF) was evaluated using ABTS, ORAC 6.0 and CAA assays and ME-RBF demonstrated 26-fold, 12-fold and 2-fold higher values, respectively than ME. Likewise, total polyphenol and flavonoid concentration in ME-RBF are more than 10-fold higher than ME, that suggested antioxidant activity is correlated with polyphenol composition. Quantitative analysis of 13 polyphenols (chlorogenic acid, caffeic acid, sinapic acid, syringic acid, vanillin, homoorientin, orientin, vitexin, swertisin, diosmin, apigenin, tricin and diosmetin) was carried out by LCMS. MS/MS analysis allowed the tentative identification of seven apigenin-C-glycosides, three methoxyluteolin-C-glycosides and three tricin-O-glycosides some of which have not been reported in sugarcane before to the best of our knowledge. The results demonstrated that sugarcane molasses can be used as potential source of polyphenols that can be beneficial to health.

The effect of diosmin against liver damage caused by cadmium in rats.

A total of 40, male Wistar Albino, 2-3-months-old rats were used and divided into four groups. Control group received the vehicle alone, diosmin group received 100 mg/kg.bw diosmin, the cadmium group received 200 ppm cadmium, cadmium plus diosmin group received 200 ppm cadmium, and 100 mg/kg.bw diosmin for 30 days. Some biochemical parameters (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase) and oxidative stress parameters (malondialdehyde [MDA], nitric oxide [NO], superoxide dismutase [SOD], catalase [CAT], gluthatione peroxidase [GSH-Px], and glutathione [GSH]) were analyzed in the samples. Histo-pathological findings were evaluated in the liver. The body weights and liver weights of the animals were measured. The MDA and NO levels and biochemical enzyme activities examined were increased, whereas SOD, CAT, and GSH-Px activities and GSH levels decreased in cadmium-exposed group. There were also negative changes in body weight, liver weight, and liver tissue histo-phathology. Positive improvements were observed in all these parameters evaluated of the group co-administered cadmium and diosmin. PRACTICAL APPLICATIONS: Cadmium is one of the common environmental pollutants. Diosmin is a type of flavonoid found mainly in citrus fruits. It can also be produced from hesperidine. This compound is used for medical purposes and also has strong antioxidant properties. One of the toxic effects mechanisms of cadmium is oxidative stress and causes liver damage with different pathways. This compound can be used as a supporting agent in addition to the main treatment options against liver damage in case of exposure to possible cadmium. This flavonoid can also be taken with food for prophylactic purposes.

The chondroprotective effect of diosmin on human articular chondrocytes under oxidative stress.

Excessive oxidative stress, which can amplify inflammatory responses, is involved in the pathologic progression of knee osteoarthritis. Diosmin is known to possess a variety of biological functions such as antiinflammatory and antioxidant activities. We therefore demonstrated the chondroprotective potentials of diosmin on human articular chondrocytes under oxidative stress. The cytotoxicity of diosmin (5, 10, 50, and 100 µM) to chondrocytes was first evaluated. Subsequently, the cells were treated with diosmin (5 and 10 µM) after hydrogen peroxide (H2 O2 ) exposure. We found that the cytotoxicity of diosmin occurred in a dose-dependent manner (10, 50, and 100 µM), and low-dose diosmin (5 µM) slightly impaired cell viability. Diosmin supplementations (5 and 10 µM) did not show beneficial effects on mitochondrial activity, cytotoxicity, proliferation, and survival and the cell senescence was ameliorated in H2 O2 -exposed chondrocytes. On the other hand, diosmin down-regulated the mRNA levels of iNOS, COX-2, IL-1ß, COL1A1, MMP-3, and MMP-9; up-regulated TIMP-1 and SOX9; and improved COL2A1 in chondrocytes under oxidative stresses. Furthermore, diosmin also regulated glutathione reductase and glutathione peroxidase of H2 O2 -exposed chondrocytes. In conclusion, diosmin displayed a remarkable antiinflammatory effect compared with the antioxidant capacity on human chondrocytes. Diosmin can maintain the homeostasis of extracellular matrix of articular cartilage.

Profiling and comparison of the metabolites of diosmetin and diosmin in rat urine, plasma and feces using UHPLC-LTQ-Orbitrap MSn.

Diosmin (diosmetin-7-O-rutinoside) and its aglycone diosmetin, natural bioflavonoids distributing in a variety of citrus fruits and Chinese herbal medicines, possessed positive effects against hepatic, renal, lung, gastric, cerebral and cardiac injury. However, the in vivo metabolic profiles of diosmin and diosmetin in urine, plasma and feces still remain ambiguous. In this study, metabolites of diosmin and diosmetin were identified using an UHPLC-LTQ-Orbitrap MSn strategy coupled with multiple metabolite templates, extracted ion chromatograms (EICs) and diagnostic product ions (DPIs). As a result, 46 diosmetin metabolites and 64 diosmin metabolites were respectively identified in rat biological samples. Methylation, demethylation, hydroxylation, glycosylation, glucuronidation, diglucuronidation and sulfation were common metabolic pathways of diosmetin and diosmin, while demethoxylation, decarbonylation, dihydroxylation and dehydroxylation were particular metabolic pathways of diosmin comparing with that of diosmetin. Diosmetin was not detected in all the biological samples, suggesting that it was quickly transformed into other metabolites in vivo. Diosmin and diosmetin-7-O-glucoside identified in urine and feces as well as their subsequent metabolites accounted for a substantial part of all the diosmin metabolic products. Metabolic profiles of diosmetin and diosmin indicated that they were primarily excreted through the urine route possibly originating from the dominant role of their phase II metabolism in vivo. Our results have provided a better understanding of the similarities and differences in pharmacodynamics and pharmacokinetics of diosmetin and diosmin in the future.

[Diosmin in the treatment of venous disease: pharmacokinetics and pharmacodynamics (in Russian only)]. / Diosmin v lechenii venoznoi patologii: osnovy farmakokinetiki i farmakodinamiki.

The issues of absorption, bacterial intestinal metabolism and hepatic metabolism of diosmin are described. The main metabolites of the drug and the ways of their elimination are indicated. The article describes the main therapeutic targets and mechanisms of influence on the course of disease including effect on the venous wall tone and permeability, lymphatic drainage, inflammation and oxidative stress.

Effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy on management of breast cancer-related lymphedema.

PURPOSE: To assess the effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy (CDT) on the management of patients with a breast cancer-related lymphedema (BCRL). METHODS: Fifty outpatients (average age of 56.2 ± 2.7 years, range 28-71) with a BCRL were enrolled for this study. Patients were randomly assigned (1:1 ratio) to receive either CDT consisting of skin care, manual lymphatic drainage, remedial exercises, and elastic compression garment (control group, n = 25) or CDT plus Linfadren® (study group, n = 25). Patients were evaluated before and after treatment and 3 months after the end of treatment. Primary outcomes were reduction of upper limb excess volume (EV) and percentage reduction of excess volume (%REV). Secondary outcomes were improvement in Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire, and patient's perception of treatment effectiveness (PPTE). RESULTS: Addition of Linfadren® to CDT yielded an additional reduction of primary outcomes both after treatment (EV, - 521 ml vs. - 256 ml, P < 0.0001; %REV, - 66.4% vs. - 34%, P = 0.02) and at 3-month follow-up (EV, - 59 ml vs. + 24 ml, P < 0.0001; %REV, - 73.6% vs. - 31.4%, P = 0.004). Moreover, statistically significant differences were found between the two groups for the secondary outcomes after treatment (QuickDASH, P = 0.006; PPTE, P = 0.03) and at 3-month follow-up (QuickDASH, P = 0.006; PPTE, P = 0.02). No patient showed adverse events. CONCLUSIONS: Linfadren® in addition to CDT was a safe and effective therapy for reducing BCRL and was better than CDT alone.