ABSTRACT
BACKGROUND: Various antioxidant substances are added to sperm extenders to protect spermatozoa against oxidative stress and cryodamage. OBJECTIVE: To investigate the effects of the flavonoid diosmin (DIO) and a flavanone glycoside naringin (NAR) on the freezability of ram semen. MATERIALS AND METHODS: In this study, six Merino rams were used during the breeding season. The ejaculates were pooled after collection from the rams. Pooled ejaculates were divided into six groups: control, NAR 1 mM, NAR 2 mM, NAR 4 mM, DIO 2 mM, and DIO 4 mM, and then diluted with a TRIS-based diluent. The pooled semen was equilibrated, placed in 0.25 mL pipettes with 10 × 10 7 sperm cells in each pipette, and frozen in liquid nitrogen vapor. After 24 h, the pipettes were thawed at 37 degree C for 25 s and analyzed in terms of spermatological parameters. RESULTS: The highest plasma membrane integrity ratio was found in the DIO 4 mM group, whereas a statistically significant difference was found between the NAR 1 mM and NAR 2 mM groups (p < 0.05). While the DIO 4 mM group had the highest acrosome integrity rate, a statistically significant difference was found between the other groups (p < 0.05). Mitochondrial activity was the highest in the NAR 4 mM, DIO 4 mM and DIO 2 mM groups (p < 0.05). In the analysis of the sperm membrane lipid profile, it was observed that the DIO group had the highest lipid-phospholipid ratio. In sperm membrane protein profile analysis, it was found that both additives exerted protective effects at different levels. The highest total protein content was seen in the DIO 4 mM and NAR 4 mM groups. 8-hydroxydeoxyguanosine (8-OhDG) positivity was more common in the control group than in the DIO and NAR groups. Cu-Zn superoxide dismutase (SOD) expression was lower in the control group and more intense in all other groups. Positive results were especially observed in the acrosome of the sperm cells. CONCLUSION: The addition of NAR and DIO to the ram semen extender increased the quality of sperm parameters after the freeze-thaw process. Doi.org/10.54680/fr24510110412.
Subject(s)
Cryopreservation , Diosmin , Flavanones , Semen Preservation , Spermatozoa , Male , Animals , Diosmin/pharmacology , Sheep , Semen Preservation/methods , Semen Preservation/veterinary , Flavanones/pharmacology , Cryopreservation/methods , Cryopreservation/veterinary , Spermatozoa/drug effects , Semen/drug effects , Acrosome/drug effects , Antioxidants/pharmacology , Sperm Motility/drug effects , Cryoprotective Agents/pharmacology , Cell Membrane/drug effects , Cell Membrane/metabolism , Oxidative Stress/drug effects , Semen Analysis , Superoxide Dismutase/metabolismABSTRACT
OBJECTIVE: Colorectal cancer, one of the most frequently diagnosed cancers worldwide, has a high mortality rate. Thus, our research aims to examine the preventive effects of diosmin (DIO) alone and in conjunction with the anti-cancer drug irinotecan (camptothecin-11, CPT-11), on 1,2-dimethylhydrazine (DMH)-induced colon cancer (CC) in male Wistar rats. MATERIALS AND METHODS: Fifty adult male Wistar rats were categorized into five groups. Group I (Normal) received saline 0.9 orally % as a vehicle once a week for 14 weeks. Group II (DMH) received DMH (20 mg/kg/week) orally dissolved in 0.9% saline for 14 weeks and 1% carboxymethylcellulose (CMC) every other day for the final 10 weeks. Group III (DMH+DIO) received DMH orally for 14 weeks and DIO (10 mg/kg, suspended in 1% CMC) every other day for the final 10 weeks. Group IV (DMH+CPT-11) received DMH orally for 14 weeks and intraperitoneal injection of CPT-11 (3 mg/kg) twice a week for the final 10 weeks. Group V (DMH+DIO+CPT-11) orally received DMH for 14 weeks and both DIO and CPT-11. RESULTS: All treated groups showed a significant reduction (p<0.05) in their elevated serum malondialdehyde levels and significant amelioration (p<0.05) of their lowered activities of colon glutathione-S-transferase (GST) and glutathione reductase (GR) as well as serum glutathione level (GSH). In addition, simultaneous treatment with DIO and CPT-11 led to a significant decrease (p<0.05) in the elevated serum levels of carcinoembryonic antigen (CEA) in rats administered with DMH, as well as a reduction in the colon expression levels of the inflammatory mediator (NF-κB), cell proliferator protein (Ki-67), and proapoptotic protein (p53). CONCLUSIONS: These findings suggest DIO, CPT-11, and their combination have anticarcinogenic effects against DMH-induced CC by suppressing oxidative stress, simulating the antioxidant defense system, attenuating the inflammatory effects, and reducing cell proliferation.
Subject(s)
1,2-Dimethylhydrazine , Colonic Neoplasms , Diosmin , Irinotecan , Rats, Wistar , Animals , Male , Colonic Neoplasms/chemically induced , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Colonic Neoplasms/prevention & control , Colonic Neoplasms/metabolism , Rats , Diosmin/pharmacology , Diosmin/administration & dosage , Irinotecan/pharmacology , Irinotecan/administration & dosage , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Oxidative Stress/drug effectsABSTRACT
BACKGROUND: Pelvic congestion syndrome (PCS) is associated with chronic pelvic pain (CPP). The efficacy of flavonoids for treating PCS symptoms is still a matter of debate, and little has been published. The aim of this study was to assess the efficacy of a mixture of diosmin, troxerutin, and hesperidin in improving symptoms of patients with PCS, observing a direct effect on circulation by specific color Doppler ultrasonography (CDU) evaluations. METHODS: This was a pilot, prospective, independent, cross-over, daily-diary-based trial. Women were evaluated with CDU for 3 times (baseline, 60 days, 120 days). Data about N.=13 women who completed the study were analyzed. RESULTS: During the treatment, we recorded a significant reduction of intermenstrual and menstrual pain intensity (total points) (P<0.05). The satisfaction after treatment was significantly higher than after placebo (P<0.0001). A significant reduction in the diameter of the major ovarian vein (P=0.004 compared to placebo), associated with an increase in peak systolic velocity (P=0.01) and a corresponding significant increase in the Resistivity Index (P<0.0001) were recorded during treatment. CONCLUSIONS: The use of a mixture of diosmin, troxerutin and hesperidin in women with PCS can significantly help to manage typical symptoms of pelvic pain and it is associated with an evident Doppler effect on pelvic microcirculation.
Subject(s)
Cross-Over Studies , Diosmin , Hesperidin , Hydroxyethylrutoside , Pelvic Pain , Ultrasonography, Doppler, Color , Humans , Female , Hydroxyethylrutoside/analogs & derivatives , Hydroxyethylrutoside/therapeutic use , Hydroxyethylrutoside/pharmacology , Diosmin/therapeutic use , Diosmin/pharmacology , Diosmin/administration & dosage , Hesperidin/therapeutic use , Pelvic Pain/drug therapy , Pelvic Pain/diagnostic imaging , Pelvic Pain/etiology , Adult , Prospective Studies , Pilot Projects , Syndrome , Young Adult , Treatment Outcome , Ovary/drug effects , Ovary/diagnostic imaging , Ovary/blood supply , Drug CombinationsABSTRACT
BACKGROUND: Testicular toxicity is a complication of cisplatin therapy and it limits its use. Since cisplatin-induced testicular damage is mediated by inflammation and oxidative stress, evaluation of the protective role of antioxidant and anti-inflammatory molecules such as micronized purified flavonoid fraction (Daflon®) is pertinent. AIM: Therefore, this study investigated the mitigating effect of daflon against cisplatin-induced testicular toxicity. Also, the impact of daflon on Nrf2/HO-1 and TLR4/NF-kB pathways, which are key pathways in cisplatin toxicity, was explored. MATERIALS AND METHODS: After 2 weeks of acclimatization, 20 male albino Wistar rats were allotted at random into 4 equal groups; control, daflon-treated, cisplatin-treated, and cisplatin+daflon-treated. RESULTS: Daflon significantly restored cisplatin-induced reductions in body weight (112.20±9.01 vs. 129.60±5.68, P= 0.0175), body weight gain (-39.80±9.52 vs. -16.80±16.53, P= 0.0154), and testicular weight (1.69±0.08 vs. 1.95±0.13, P= 0.0980) and alterations in testicular histology. In addition, daflon abrogated cisplatin-induced rise in testicular CK (55.53±2.77 vs. 37.40±3.29, P< 0.0001) and LDH (74.52±3.20 vs. 65.89±2.08, P= 0.0009) activities, and lactate content (180.50±4.19 vs. 166.20±2.78, P< 0.0001). Also, daflon alleviated cisplatin-induced suppression of GnRH (5.09±0.60 vs. 10.17±0.51, P< 0.0001), LH (1.33±0.07 vs. 2.77±0.13, P< 0.0001), FSH (0.51±0.10 vs. 1.82±0.09, P< 0.0001), and testosterone (2.39±0.11 vs. 4.70±0.33, P< 0.001) as well as lowered sperm quality. More so, daflon attenuated cisplatin-induced testicular oxidative stress, inflammation, and apoptosis evidenced by daflon-driven suppression of MDA (14.16±0.66 vs. 9.22±0.52, P< 0.0001), TNF-α (79.42±5.66 vs. 54.13±3.56, P< 0.0001), IL-1ß (8.63±0.41 vs. 3.37±0.43, P< 0.0001), IL-6 (6.87±0.48 vs. 3.67±0.32, P< 0.0001), and caspase 3 activity (4.20±0.26 vs. 0.72±0.23, P< 0.0001) and DNA fragmentation (34.60±3.05 vs. 17.20±3.19, P< 0.0001), and upregulation of GSH level (0.07±0.03 vs. 0.36±0.03, P< 0.0001), and GPx (5.96±0.46 vs. 11.88±1.05, P< 0.0001), GST (5.16±0.71 vs. 11.50±0.81, P< 0.0001), SOD (1.29±0.15 vs. 2.81±0.29, P< 0.0001), and catalase activities (6.18±0.69 vs. 10.71±0.74, P< 0.0001). Furthermore, daflon upregulated testicular Nrf2 expression (40.25±2.65 vs. 66.62±4.01, P< 0.0001) and HO-1 (4.18±0.56 vs. 8.79±0.55, P< 0.0001) activity but downregulated TLR4 (11.63±0.89 vs. 7.23±0.43, P< 0.0001) and NF-kB levels (113.20±3.36 vs. 78.22±3.90, P< 0.0001) in cisplatin-treated rats. CONCLUSION: Collectively, the ameliorative effect of daflon on cisplatin-induced testicular toxicity is associated with inhibition of oxidative stress and TLR4/NF-kB-mediated inflammatory pathways and activation of Nrf2/HO-1 signaling.
Subject(s)
Cisplatin , NF-E2-Related Factor 2 , NF-kappa B , Rats, Wistar , Signal Transduction , Testis , Toll-Like Receptor 4 , Animals , Male , Cisplatin/adverse effects , NF-E2-Related Factor 2/metabolism , Testis/drug effects , Testis/metabolism , Testis/pathology , NF-kappa B/metabolism , Signal Transduction/drug effects , Toll-Like Receptor 4/metabolism , Rats , Diosmin/pharmacology , Oxidative Stress/drug effectsABSTRACT
INTRODUCTION: Citri Sarcodactylis Fructus (CSF), a common fruit and traditional Chinese medicine (TCM), has been hindered in its further development and research owing to the lack of comprehensive and specific quality evaluation standards. OBJECTIVE: This study aimed to establish clear TCM quality standards related to the therapeutic mechanisms of CSF and to provide a basis for subsequent research and development. METHODS: Ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry (UPLC-Q-orbitrap HRMS) technology was used to comprehensively identify CSF components and explore their absorbance levels in rat serum. Network pharmacology research methods were employed to investigate the potential mechanisms of action of the identified components in the treatment of major clinical diseases. Subsequently, a combination of HPLC chromatographic fingerprinting for qualitative analysis and multi-index content determination was used to evaluate the detectability of the identified quality markers (Q-markers). RESULTS: Twenty-six prototype components were tentatively characterized in rat serum. Network pharmacology analysis showed six effective components, namely 7-hydroxycoumarin, isoscopoletin, diosmin, hesperidin, 5,7-dimethoxycoumarin, and bergapten, which played important roles in the treatment of chronic gastritis, functional dyspepsia, peptic ulcer, and depression and were preliminarily identified as Q-markers. The results of content determination in 15 batches of CSF indicated significant differences in the content of medicinal materials from different origins. However, compared with the preliminarily determined Q-markers, all six components could be measured and were determined as Q-markers of CSF. CONCLUSION: The chemical Q-markers obtained in this study could be used for effective quality control of CSF.
Subject(s)
Drugs, Chinese Herbal , Network Pharmacology , Animals , Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Network Pharmacology/methods , Rats , Rats, Sprague-Dawley , Fruit/chemistry , Male , Quality Control , Citrus/chemistry , Biomarkers/blood , Medicine, Chinese Traditional , Diosmin/pharmacology , Diosmin/blood , Coumarins/blood , Coumarins/pharmacology , Mass Spectrometry/methods , FlavonoidsABSTRACT
Flavonoids are a class of secondary metabolites widely distributed in plants. Regiospecific modification by methylation and glycosylation determines flavonoid diversity. A rare flavone glycoside, diosmin (luteolin-4'-methoxyl-7-O-glucosyl-rhamnoside), occurs in Chrysanthemum indicum. How Chrysanthemum plants evolve new biosynthetic capacities remains elusive. Here, we assemble a 3.11-Gb high-quality C. indicum genome with a contig N50 value of 4.39 Mb and annotate 50,606 protein-coding genes. One (CiCOMT10) of the tandemly repeated O-methyltransferase genes undergoes neofunctionalization, preferentially transferring the methyl group to the 4'-hydroxyl group of luteolin with ortho-substituents to form diosmetin. In addition, CiUGT11 (UGT88B3) specifically glucosylates 7-OH group of diosmetin. Next, we construct a one-pot cascade biocatalyst system by combining CiCOMT10, CiUGT11, and our previously identified rhamnosyltransferase, effectively producing diosmin with over 80% conversion from luteolin. This study clarifies the role of transferases in flavonoid diversity and provides important gene elements essential for producing rare flavone.
Subject(s)
Chrysanthemum , Diosmin , Flavones , Methyltransferases/genetics , Luteolin , Glucosyltransferases/genetics , Chrysanthemum/genetics , Genomics , FlavonoidsABSTRACT
BACKGROUND: Renal fibrosis is considered an irreversible pathological process and the ultimate common pathway for the development of all types of chronic kidney diseases and renal failure. Diosmin is a natural flavonoid glycoside that has antioxidant, anti-inflammatory, and antifibrotic activities. However, whether Diosmin protects kidneys by inhibiting renal fibrosis is unknown. We aimed to investigate the role of Diosmin in renal interstitial fibrosis and to explore the underlying mechanisms. METHODS: The UUO mouse model was established and gavaged with Diosmin (50 mg/kg·d and 100 mg/kg·d) for 14 days. HE staining, Masson staining, immunohistochemistry, western blotting and PCR were used to assess renal tissue injury and fibrosis. Elisa kits were used to detect the expression levels of IL-1ß, IL-6, and TNF-α and the activity of SIRT3 in renal tissues. In addition, enrichment maps of RNA sequencing analyzed changes in signaling pathways. In vitro, human renal tubular epithelial cells (HK-2) were stimulated with TGF-ß1 and then treated with diosmin (75 µM). The protein and mRNA expression levels of SIRT3 were detected in the cells. In addition, 3-TYP (selective inhibitor of SIRT3) and SIRT3 small interfering RNA (siRNA) were used to reduce SIRT3 levels in HK-2. RESULTS: Diosmin attenuated UUO-induced renal fibrosis and TGF-ß1-induced HK-2 fibrosis. In addition, Diosmin reduced IL-1ß, IL-6, and TNF-α levels in kidney tissues and supernatants of HK-2 medium. Interestingly, Diosmin administration increased the enzymatic activity of SIRT3 in UUO kidneys. In addition, Diosmin significantly increased mRNA and protein expression of SIRT3 in vitro and in vivo. Inhibition of SIRT3 expression using 3-TYP or SIRT3 siRNA abolished the anti-inflammatory effects of diosmin in HK-2 cells. Enrichment map analysis by RNA sequencing indicates that the nuclear factor-kappa B (NF-κB) signaling pathway was inhibited in the Diosmin intervention group. Furthermore, we found that TGF-ß1 increased the nuclear expression of nuclear NF-κB p65 but had little significant effect on the total intracellular expression of NF-κB p65. Additionally, Diosmin reduced TGF-ß1-caused NF-κB p65 nuclear translocation. Knockdown of SIRT3 expression by SIRT3 siRNA increased the nuclear expression of NF-κB p65 and abolished the inhibition effect of Diosmin in NF-κB p65 expression. CONCLUSIONS: Diosmin reduces renal inflammation and fibrosis, which is contributed by inhibiting nuclear translocation of NF-κB P65 through activating SIRT3.
Subject(s)
Diosmin , Kidney Diseases , Sirtuin 3 , Humans , Animals , Mice , NF-kappa B , Diosmin/pharmacology , Transforming Growth Factor beta1 , Interleukin-6 , Tumor Necrosis Factor-alpha , Kidney Diseases/drug therapy , Inflammation/drug therapy , Anti-Inflammatory Agents/pharmacology , Fibrosis , RNA, Messenger , RNA, Small InterferingABSTRACT
The substantial nutritional content and diversified biological activity of plant-based nutraceuticals are due to polyphenolic chemicals. These chemicals are important and well-studied plant secondary metabolites. Their protein interactions are extensively studied. This relationship is crucial for the logical development of functional food and for enhancing the availability and usefulness of polyphenols. This study highlights the influence of protein types and polyphenols on the interaction, where the chemical bindings predominantly consist of hydrophobic interactions and hydrogen bonds. The interaction between polyphenolic compounds (PCs) and digestive enzymes concerning their inhibitory activity has not been fully studied. Therefore, we have examined the interaction of four digestive enzymes (α-amylase, pepsin, trypsin, and α-chymotrypsin) with four PCs (curcumin, diosmin, morin, and 2',3',4'-trihydroxychalcone) through in silico and in vitro approaches. In vitro plate assays, enzyme kinetics, spectroscopic assays, molecular docking, and simulations were performed. We observed all these PCs have significant docking scores and preferable interaction with the active site of the digestive enzymes, resulting in the reduction of enzyme activity. The enzyme-substrate binding mechanism was determined using the Lineweaver Burk plot, indicating that the inhibition occurred competitively. Among four PCs diosmin and morin has the highest interaction energy over digestive enzymes with IC50 value of 1.13 ± 0.0047 and 1.086 ± 0.0131 µM. Kinetic studies show that selected PCs inhibited pepsin, trypsin, and chymotrypsin competitively and inhibited amylase in a non-competitive manner, especially by 2',3',4'-trihydroxychalcone. This study offers insights into the mechanisms by which the selected PCs inhibit the enzymes and has the potential to enhance the application of curcumin, diosmin, morin, and 2',3',4'-trihydroxychalcone as natural inhibitors of digestive enzymes.
Subject(s)
Curcumin , Diosmin , Molecular Docking Simulation , Pepsin A/metabolism , Trypsin/metabolism , Curcumin/pharmacology , Kinetics , Polyphenols/pharmacology , Flavonoids/pharmacology , Flavonoids/chemistry , alpha-Amylases/metabolism , alpha-Glucosidases/metabolismABSTRACT
Diosmin is a flavone glycoside with a confirmed therapeutic effectiveness on the chronic venous disorders. In this paper, the classical mouse depression model induced by LPS was established to explore the effect of Diosmin on depression. Firstly, we found that Diosmin could inhibit the inflammation and neuronal damage in the prefrontal cortex (PFC) of mice, and thus alleviating the LPS-induced depressive-like behaviors. Specifically, Diosmin treatment significantly suppressed the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß), reduced the activation of microglia, and inhibited the expression of NLRP3 inflammasome and its downstream effector caspase-1 in both PFC of mice and BV2 microglial cells exposed to LPS. Then, we demonstrated that pretreatment with Diosmin dramatically suppressed the LPS-induced oxidative stress in the PFC of mice, manifested in the decrease of reactive oxygen species and malondialdehyde while increase of catalase activity. Consistently, Diosmin also alleviated the oxidative stress in BV2 cells exposed to LPS. Finally, we confirmed that Diosmin effectively suppressed the activation of NF-κB signaling pathway in the PFC of LPS-treated mice. Further in vitro experiments also verified that Diosmin could prevent the p65 transposition to nucleus in LPS-treated BV2 cells, suggesting that the antidepressant effects of Diosmin are partially mediated by blocking of NF-κB signaling. Taken together, this study proposes the potential antidepressant effect of Diosmin, which provides useful support to the development of new therapies for depression.
Subject(s)
Diosmin , NF-kappa B , Humans , NF-kappa B/metabolism , Depression/chemically induced , Depression/drug therapy , Diosmin/pharmacology , Diosmin/metabolism , Lipopolysaccharides/pharmacology , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Prefrontal Cortex/metabolism , Antidepressive Agents/therapeutic use , Oxidative Stress , Microglia/metabolismABSTRACT
BACKGROUND: Many patients experience lower-extremity swelling following total knee arthroplasty (TKA), which impedes recovery. Diosmin is a semisynthetic flavonoid that is often utilized to treat swelling and pain caused by chronic venous insufficiency. We aimed to evaluate the efficacy and safety of diosmin in reducing lower-extremity swelling and pain as well as in improving functional outcomes following TKA. METHODS: This study was designed as a randomized, controlled multicenter trial and conducted in 13 university-affiliated tertiary hospitals. A total of 330 patients undergoing TKA were randomized to either receive or not receive diosmin postoperatively. The diosmin group received 0.9 g of diosmin twice per day for 14 consecutive days starting on the day after surgery, whereas the control group received neither diosmin nor a placebo postoperatively. The primary outcome was lower-extremity swelling 1, 2, 3, and 14 days postoperatively. The secondary outcomes were postoperative pain assessed with use of a visual analogue scale, Hospital for Special Surgery score, range of knee motion, levels of the inflammatory biomarkers C-reactive protein and interleukin-6, and complications. RESULTS: At all postoperative time points, diosmin was associated with significantly less swelling of the calf, thigh, and upper pole of the patella as well as with significantly lower pain scores during motion. However, no significant differences in postoperative pain scores at rest, Hospital for Special Surgery scores, range of motion, levels of inflammatory biomarkers, or complication rates were found between the diosmin and control groups. CONCLUSIONS: The use of diosmin after TKA reduced lower-extremity swelling and pain during motion and was not associated with an increased incidence of short-term complications involving the outcomes studied. However, further studies are needed to continue exploring the efficacy and safety of diosmin use in TKA. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.
Subject(s)
Arthroplasty, Replacement, Knee , Diosmin , Humans , Arthroplasty, Replacement, Knee/adverse effects , Diosmin/therapeutic use , Pain, Postoperative/drug therapy , Pain, Postoperative/prevention & control , Pain, Postoperative/etiology , Thigh , Biomarkers , Treatment OutcomeABSTRACT
Arsenic compounds, which are used in different industries like pesticide manufacturing, cause severe toxic effects in almost all organs, including the kidneys. Since the primary route of exposure to arsenic is through drinking water, and millions of people worldwide are exposed to unsafe levels of arsenic that can pose a threat to their health, this research was performed to investigate the nephroprotective effects of Diosmin (Dios), a flavonoid found in citrus fruits, against nephrotoxicity induced by sodium arsenite (SA). To induce nephrotoxicity, SA (10 mg/kg, oral gavage) was administered to mice for 30 days. Dios (25, 50, and 100 mg/kg, oral gavage) was given to mice for 30 days prior to SA administration. After the study was completed, animals were euthanized and blood and kidney samples were taken for biochemical and histopathological assessments. Results showed that SA-treated mice significantly increased the blood urea nitrogen and creatinine levels in the serum. This increase was associated with significant kidney tissue damage in SA-treated mice, which was confirmed by histopathological studies. Furthermore, SA enhanced the amounts of renal thiobarbituric acid reactive substances and decreased total thiol reserves, as well as the activity of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase. Also, in the SA-exposed group, an increase in the levels of kidney inflammatory biomarkers, including nitric oxide and tumor necrosis factor-alpha was observed. The western blot analysis indicated an elevation in the protein expression of kidney injury molecule-1 and nuclear factor-kappa B in SA-treated mice. However, pretreatment with Dios ameliorated the SA-related renal damage in mice. Our findings suggest that Dios can protect the kidneys against the nephrotoxic effects of SA by its antioxidant and anti-inflammatory characteristics.
Subject(s)
Arsenic , Diosmin , Humans , Rats , Mice , Animals , Antioxidants/pharmacology , Diosmin/pharmacology , Diosmin/metabolism , Arsenic/pharmacology , Arsenic/toxicity , Rats, Wistar , Oxidative Stress , Kidney , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/prevention & control , Glutathione/metabolismABSTRACT
Our previous study with artificial intelligence (AI)-assisted screening found that diosmin, a natural flavonoid extracted from citrus, may affect myoblast proliferation and differentiation. At present, few studies have been conducted regarding the biological function of diosmin in muscle cells. Here, using molecular biological techniques, we found that diosmin elevated the proliferation ability of C2C12 myoblasts via activating the Akt/FOXO1 pathway to promote FOXO1 nuclear export, thus repressing p27 protein expression, increasing CDK2, CDK4, and cyclin D1 and cyclin E1 protein expression and accelerating cell cycle transformation, which contributed to myogenesis. Moreover, diosmin suppressed differentiation of C2C12 myoblasts by delaying the terminal exit of the cell cycle in early differentiated myoblasts and inhibiting autophagic flux in mature myotubes. Furthermore, diosmin promoted myogenesis by activating the Akt/FOXO1 pathway to facilitate myoblast proliferation, which had a positive biological effect on the repair of muscle injury. This study revealed the effect and mechanism of diosmin on skeletal muscle cells and simultaneously provided a new candidate drug for the treatment of myopathy.
Subject(s)
Diosmin , Proto-Oncogene Proteins c-akt , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Diosmin/metabolism , Diosmin/pharmacology , Artificial Intelligence , Cell Proliferation , Myoblasts , Cell Differentiation , Muscle DevelopmentABSTRACT
INTRODUCTION: Chronic venous disease (CVD) can lead to considerable morbidity and impact health-related quality of life (HRQoL). The aim of this review was twofold: (i) to provide a deeper understanding of how CVD affects HRQoL (physical, psychological and social functioning), and (ii) to review the impact of evidence-based veno-active drugs (VADs) on HRQoL. EVIDENCE ACQUISITION: For the effect of CVD on HRQoL, information was gathered during an Expert Consensus Meeting, during which data were presented from both the patient and physician perspective assessed with validated quality-of-life measures. For the impact of VADs on HRQoL, a systematic literature review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases were searched for real world evidence or randomized-controlled trials (RCT) vs. placebo, reporting data on the influence of VADs on HRQoL in patients with CVD. EVIDENCE SYNTHESIS: CVD can negatively affect daily life in a number of areas related to pain, physical function and social activities. The impact of CVD on HRQoL begins early in the disease and for patients the emotional burden of the disease is as high as the physical burden. In contrast, physicians tend to overestimate the physical impact. The database search yielded 184 unique records, of which 19 studies reporting on VADs and HRQoL in patients with CVD met the inclusion criteria (13 observational and 6 RCTs). Micronized purified flavonoid fraction (MPFF) was the most represented agent, associated with 12/19 studies (2 RCTs and 10 observational). Of the 6 RCTs, only MPFF, aminaphthone and low-dose diosmin provided statistically significant evidence for improvement on HRQoL compared with placebo; for the other VADs improvements in HRQoL were not statistically different from placebo. MPFF was also associated with improvements in HRQoL in the observational studies, across all CEAP clinical classes, as monotherapy or in combination with other conservative therapy, and for all aspects of HRQoL: physical, psychological, and social. Real-world data for the other VADs were scarce. Ruscus extract, sulodexide and a semi-synthetic diosmin were each represented by a single observational study and these limited data were associated with statistically significant improvements compared with baseline in overall and subdomain scores across the range of CEAP clinical classes. CONCLUSIONS: CVD can impair patients' HRQoL significantly at all stages of the disease. MPFF has the greatest evidence base of clinical use in both RCT and real-world observational studies for effectiveness on HRQoL and is recognized by international guidelines. The complete video presentation of the work is available online at www.minervamedica.it (Supplementary Digital Material 1: Supplementary Video 1, 5 min, 194 MB).
Subject(s)
Diosmin , Vascular Diseases , Humans , Diosmin/therapeutic use , Vascular Diseases/drug therapy , Veins , Pain/drug therapy , Flavonoids , Quality of Life , Chronic Disease , Observational Studies as TopicABSTRACT
Chronic venous disease (CVD) is a condition characterized by functional disturbances in the microcirculation of the superficial and deep veins, affecting up to 30% of the global population. Diosmin, a phlebotropic drug, is commonly used in the treatment of CVD, and its beneficial effects have been described in numerous clinical studies. However, the precise molecular mechanism underlying the activity of diosmin is not yet fully understood. Therefore, the objective of our study was to investigate whether diosmin has an impact on oxygen management, as cardiovascular diseases are often associated with hypoxia. In our study, patients were administered a daily dosage of 2 × 600 mg of diosmin for 3 months, and we evaluated several factors associated with oxygen management, angiogenesis, and inflammation using biochemical assays. Our findings indicate that diosmin reduced the levels of fibroblast growth factors (FGF) and vascular endothelial growth factor (VEGF-C), while increasing endostatin and angiostatin levels, suggesting a potential influence on angiogenesis regulation. Furthermore, diosmin exhibited anti-inflammatory properties by suppressing the levels of tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1ß), and interleukin 6 (IL-6), while promoting the production of interleukin 12 (IL-12). Additionally, diosmin significantly decreased the levels of hypoxia-inducible factor (HIF), anion gap (AG), and lactate, indicating its potential influence on the hypoxia-inducible factor pathway. These findings suggest that diosmin may play a crucial role in modulating oxygen management and inflammation in the context of chronic venous disease.
Subject(s)
Cardiovascular Diseases , Diosmin , Humans , Diosmin/pharmacology , Diosmin/therapeutic use , Vascular Endothelial Growth Factor A , Interleukin-12 , Fibroblast Growth Factors , Hypoxia , Inflammation , Interleukin-6 , Lactic Acid , Homeostasis , OxygenABSTRACT
Kelussia odoratissima Mozaff. is a species of Apiaceae endemic to the Zagros Mountains in Iran. In the present investigation, for the first time, the polyphenolic compounds and flavonoids of its leaves were determined by liquid chromatography-mass spectrometry (LC-MS). As a result, p-coumaric acid, ferulic acid, caffeic acid, chlorogenic acid, acetyl phloroglucinol, vanillic acid, m-coumaric acid, and 4-methylsiringol were determined as the main phenolic compounds, while 3-hydroxyflavone, flavone, quercetin, rutin, neohesperidin, polydatin, and diosmin were the main flavonoid components, of which chlorogenic acid (303.08 µL/gDW), neohesperidin (38.37 µL/gDw), and diosmin (28.62 µL/gDW) were the most abundant. Solid-phase microextraction (SPME) was also used to determine the chemical compounds. Based on SPME, (Z)-undec-6-en-2-one (17.48%) and (Z)-butylidenephthalide (4.348%) were the major components. Based on GC-MS analyses, (Z)-ligustilide was the main compound; however, some new compounds were also determined, including 3-ethylisobenzofuran-1 (3H)-one, (E)-ligugustilide, and E-n-butylidene phthalide. Also, for the first time, we have identified EOs ethyl and isobutyl phthalides on the basis of the obtained EI-MS spectra. Finally, the fragmentation of phthalides is also discussed in this research.
Subject(s)
Apiaceae , Diosmin , Gas Chromatography-Mass Spectrometry , Chromatography, Liquid , Solid Phase Microextraction , Tandem Mass Spectrometry , Plant Leaves , FlavonoidsABSTRACT
The bioactive flavonoid diosmin (DSN) has a variety of biological activities, excellent therapeutic activity, however, it has a number of biopharmaceutical problems that limit its advantages. The present study aims to develop chitosan-based nanogels (NGs) as drug-delivery platforms for DSN and characterize them using physicochemical methods. DSN-loaded NGs were prepared using the ionic gelation method and particle size (PS), poly-dispersity index (PDI), zeta potential (ZP), loading efficiency (LE) and loading capacity (LC) of 113.07±12.62nm, 0.266±0.08, 22.32± 0.56 mV, 81.56±2.65% and 10.25±1.43% were obtained, respectively. Transmission electron microscopy analysis of DSN-loaded NGs also revealed that the PS ranged from 100 to 200nm, which is comparable to the outcomes of the dynamic light scattering technique. The NGs swelled in pH 6.8 and pH 7.4 buffers and was easily eroded at pH 1.2 and pH 4.5. DSN was released from NGs in acidic buffers by a Fickian process and this release was followed by both swelling and erosion. According to stability experiments, the PS, ZP and PDI at 25oC and 40oC did not significantly change after 90 days. In conclusion, the NGs system proved very effective at delivering DSN orally.
Subject(s)
Chitosan , Diosmin , Nanoparticles , Nanogels , Chitosan/chemistry , Diosmin/chemistry , Drug Carriers/chemistry , Particle Size , Nanoparticles/chemistryABSTRACT
Diosmin is used to relieve chronic venous disease (CVD) symptoms. This study aimed to investigate the anti-inflammatory and antioxidant effects of diosmetin-3-O-ß-d-glucuronide, the major metabolite of diosmin, using human skin explants. The explants were exposed to substance P (inflammation model) or UVB irradiation (oxidative model) and to five diosmetin-3-O-ß-d-glucuronide concentrations. Inflammation was evaluated through interleukin-8 (IL-8) secretion measurements and capillary dilation observation, and oxidation was evaluated by measuring the hydrogen peroxide levels and observing cyclobutane pyrimidine dimers (CPDs). In substance-P-exposed explants, diosmetin-3-O-ß-d-glucuronide induced a significant decrease in IL-8 secretions, with a maximal effect at 2700 pg/mL (-49.6%), and it reduced the proportion of dilated capillaries and the mean luminal cross-sectional area (p < 0.0001 at all tested concentrations), indicating a vasoconstrictive effect. In UVB-irradiated fragments, diosmetin-3-O-ß-d-glucuronide induced a significant decrease in hydrogen peroxide production and in the number of CPD-positive cells, reaching a maximal effect at the concentration of 2700 pg/mL (-48.6% and -52.0%, respectively). Diosmetin-3-O-ß-d-glucuronide induced anti-inflammatory and antioxidant responses, with the maximal effect being reached at 2700 pg/mL and corresponding to the peak plasma concentration estimated after the oral intake of 600 mg of diosmin, the daily dose usually recommended for the treatment of CVD. These ex vivo findings suggest a protective role of diosmetin-3-O-ß-d-glucuronide against inflammatory and oxidative stress affecting the vascular system in CVD pathophysiology.
Subject(s)
Cardiovascular Diseases , Diosmin , Humans , Antioxidants/pharmacology , Glucuronides/pharmacology , Diosmin/pharmacology , Hydrogen Peroxide , Interleukin-8 , Anti-Inflammatory Agents/pharmacology , InflammationABSTRACT
BACKGROUND: Interstitial fibrosis is involved in the progression of various chronic kidney diseases and renal failure. Diosmin is a naturally occurring flavonoid glycoside that has antioxidant, anti-inflammatory, and antifibrotic activities. However, whether diosmin protects kidneys by inhibiting renal fibrosis is unknown. METHODS: The molecular formula of diosmin was obtained, targets related to diosmin and renal fibrosis were screened, and interactions among overlapping genes were analyzed. Overlapping genes were used for gene function and KEGG pathway enrichment analysis. TGF-ß1 was used to induce fibrosis in HK-2 cells, and diosmin treatment was administered. The expression levels of relevant mRNA were then detected. RESULTS: Network analysis identified 295 potential target genes for diosmin, 6828 for renal fibrosis, and 150 hub genes. Protein-protein interaction network results showed that CASP3, SRC, ANXA5, MMP9, HSP90AA1, IGF1, RHOA, ESR1, EGFR, and CDC42 were identified as key therapeutic targets. GO analysis revealed that these key targets may be involved in the negative regulation of apoptosis and protein phosphorylation. KEGG indicated that pathways in cancer, MAPK signaling pathway, Ras signaling pathway, PI3K-Akt signaling pathway, and HIF-1 signaling pathway were key pathways for renal fibrosis treatment. Molecular docking results showed that CASP3, ANXA5, MMP9, and HSP90AA1 stably bind to diosmin. Diosmin treatment inhibited the protein and mRNA levels of CASP3, MMP9, ANXA5, and HSP90AA1. Network pharmacology analysis and experimental results suggest that diosmin ameliorates renal fibrosis by decreasing the expression of CASP3, ANXA5, MMP9, and HSP90AA1. CONCLUSIONS: Diosmin has a potential multi-component, multi-target, and multi-pathway molecular mechanism of action in the treatment of renal fibrosis. CASP3, MMP9, ANXA5, and HSP90AA1 might be the most important direct targets of diosmin.
Subject(s)
Diosmin , Kidney Diseases , Humans , Molecular Docking Simulation , Matrix Metalloproteinase 9 , Caspase 3 , Diosmin/pharmacology , Network Pharmacology , Phosphatidylinositol 3-Kinases , FibrosisABSTRACT
Diosmin (DSN) is found mainly in citrus fruits, and has potent antioxidant effects. This study aimed to evaluate pharmacokinetics of diosmetin-7-glucoside-γ-cyclodextrin (DIOSG-CD) inclusion complex. The area under the curve values from AUC0-24 of DIOSG-CD, prepared by reacting DSN and naringinase with γ-CD, were approximately 800-fold higher than those of DSN following their administration in Sprague-Dawley rats.