RESUMEN

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.

Asunto(s)

Criopreservación , Diosmina , Flavanonas , Preservación de Semen , Espermatozoides , Masculino , Animales , Diosmina/farmacología , Ovinos , Preservación de Semen/métodos , Preservación de Semen/veterinaria , Flavanonas/farmacología , Criopreservación/métodos , Criopreservación/veterinaria , Espermatozoides/efectos de los fármacos , Semen/efectos de los fármacos , Acrosoma/efectos de los fármacos , Antioxidantes/farmacología , Motilidad Espermática/efectos de los fármacos , Crioprotectores/farmacología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Estrés Oxidativo/efectos de los fármacos , Análisis de Semen , Superóxido Dismutasa/metabolismo

RESUMEN

Even while accelerated cardiomyocyte apoptosis is one of the primary causes of cardiac damage, the underlying mechanism is still mostly unknown. In addition to examining potential protective effects of bisoprolol and diosmin against CoCl2-induced cardiac injury, the goal of this study was to identify potential mechanisms regulating the hypoxic cardiac damage caused by cobalt chloride (CoCl2). For a period of 21 days except Cocl2 14 days from the first day of the experiment, rats were split into the following groups: Normal control group, rats received vehicle only (2 ml/kg/day, p.o.), (Cocl2, 150 mg/kg/day, p.o.), bisoprolol (25 mg/kg/day, p.o.); diosmin (100 mg/kg/day, p.o.) and bisoprolol + diosmin + Cocl2 groups. At the end of the experimental period, serum was taken for estimation of cardiac function, lipid profile, and pro/anti-inflammatory cytokines. Moreover, tissue samples were collected for evaluation of oxidative stress, endothelial dysfunction, α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Diosmin and bisoprolol, either alone or in combination, enhance heart function by reducing abnormalities in the electrocardiogram and the hypotension brought on by CoCl2. Additionally, they significantly ameliorate endothelial dysfunction by downregulating the cardiac expressions of α-SMA, PKC-α, MiR-143-3P, MAPK, ERK5, MCP-1, CXCR4, Orai-1, and STIM-1. Bisoprolol and diosmin produced modulatory activity against inflammatory state, redox balance, and atherogenic index concurrently. Together, diosmin and bisoprolol, either alone or in combination, significantly reduced all the cardiac alterations brought on by CoCl2. The capacity to obstruct hypoxia-induced α-SMA, PKC-α, MiR-143-3P/MAPK/MCP-1, MiR-143-3P/ERK5/CXCR4, Orai-1/STIM-1 signaling activation, as well as their anti-inflammatory, antioxidant, and anti-apoptotic properties, may be responsible for these cardio-protective results.

Asunto(s)

Bisoprolol , Cardiotoxicidad , Cobalto , Diosmina , MicroARNs , Proteína ORAI1 , Receptores CXCR4 , Transducción de Señal , Animales , Cobalto/toxicidad , Masculino , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Cardiotoxicidad/tratamiento farmacológico , Ratas , Bisoprolol/farmacología , Bisoprolol/uso terapéutico , Transducción de Señal/efectos de los fármacos , MicroARNs/metabolismo , MicroARNs/genética , Diosmina/farmacología , Diosmina/uso terapéutico , Proteína ORAI1/metabolismo , Proteína ORAI1/genética , Ratas Wistar , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Quimiocina CCL2

RESUMEN

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.

Asunto(s)

1,2-Dimetilhidrazina , Neoplasias del Colon , Diosmina , Irinotecán , Ratas Wistar , Animales , Masculino , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Neoplasias del Colon/metabolismo , Ratas , Diosmina/farmacología , Diosmina/administración & dosificación , Irinotecán/farmacología , Irinotecán/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/farmacología , Estrés Oxidativo/efectos de los fármacos

RESUMEN

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.

Asunto(s)

Estudios Cruzados , Diosmina , Hesperidina , Hidroxietilrutósido , Dolor Pélvico , Ultrasonografía Doppler en Color , Humanos , Femenino , Hidroxietilrutósido/análogos & derivados , Hidroxietilrutósido/uso terapéutico , Hidroxietilrutósido/farmacología , Diosmina/uso terapéutico , Diosmina/farmacología , Diosmina/administración & dosificación , Hesperidina/uso terapéutico , Dolor Pélvico/tratamiento farmacológico , Dolor Pélvico/diagnóstico por imagen , Dolor Pélvico/etiología , Adulto , Estudios Prospectivos , Proyectos Piloto , Síndrome , Adulto Joven , Resultado del Tratamiento , Ovario/efectos de los fármacos , Ovario/diagnóstico por imagen , Ovario/irrigación sanguínea , Combinación de Medicamentos

RESUMEN

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.

Asunto(s)

Cisplatino , Factor 2 Relacionado con NF-E2 , FN-kappa B , Ratas Wistar , Transducción de Señal , Testículo , Receptor Toll-Like 4 , Animales , Masculino , Cisplatino/efectos adversos , Factor 2 Relacionado con NF-E2/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patología , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Ratas , Diosmina/farmacología , Estrés Oxidativo/efectos de los fármacos

RESUMEN

Doxorubicin (DOX) is the cornerstone of chemotherapy. However, it has dose-dependent cardiotoxic events that limit its clinical use. This study was intended to investigate the efficiency of DOX as an anti-cancer against the MCF-7 cell line in the presence of diosmin (DIO) and to appraise the protective impact of DIO against DOX cardiotoxicity in vivo. In vitro study was carried out to establish the conservation of DOX cytotoxicity in the presence of DIO. In vivo study was conducted on 42 adult female Wistar rats that were equally allocated into 6 groups; control, DIO (100 mg/kg), DIO (200 mg/kg), DOX (20 mg/kg, single dose i.p.), DIO (100 mg/kg) + DOX, received DIO orally (100 mg/kg) for 30 days, then administrated with a single dose of DOX and DIO (200 mg/kg) + DOX, received DIO orally (200 mg/kg) for 30 days, then administrated with DOX. In vitro study showed preservation of cytotoxic activity of DOX on MCF-7 in the presence of DIO. In vivo study indicated that DOX altered electrocardiograph (ECG) parameters. Also, it yielded a significant rise in CK-MB, cTnT and LDH serum levels and cardiac contents of MDA, IL-1ß; paralleled by a significant drop in cardiac IL-10 and SOD. Moreover, significant upregulation of Bax, TNF-α, and HIF-1α, in concomitant with significant downregulation of Bcl-2 mRNA in cardiac tissue have been recorded in the DOX group. Furthermore, histopathological description of cardiac tissues showed that DOX alters normal cardiac histoarchitecture. On the opposite side, DIO pretreatment could ameliorate ECG parameters, suppress IL-1ß and enhanceIL-10, promote activity of SOD and repress MDA. Additionally, downregulation of Bax, TNF-α, HIF-1α and upregulation of Bcl-2 have been demonstrated in DIO-pretreated rats. Furthermore, the histopathological examination of cardiac tissues illustrated that DIO had a favorable impact on the protection of heart histoarchitecture. DIO is suggested for protection against acute cardiotoxicity caused by DOX without affecting antitumor activity.

Asunto(s)

Apoptosis , Diosmina , Doxorrubicina , Estrés Oxidativo , Ratas Wistar , Animales , Doxorrubicina/efectos adversos , Diosmina/farmacología , Ratas , Femenino , Apoptosis/efectos de los fármacos , Células MCF-7 , Estrés Oxidativo/efectos de los fármacos , Humanos , Cardiotoxicidad/prevención & control , Cardiotoxicidad/etiología , Cardiotoxicidad/tratamiento farmacológico , Electrocardiografía , Superóxido Dismutasa/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/toxicidad , Factor de Necrosis Tumoral alfa/metabolismo , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico

RESUMEN

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.

Asunto(s)

Medicamentos Herbarios Chinos , Farmacología en Red , Animales , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Farmacología en Red/métodos , Ratas , Ratas Sprague-Dawley , Frutas/química , Masculino , Control de Calidad , Citrus/química , Biomarcadores/sangre , Medicina Tradicional China , Diosmina/farmacología , Diosmina/sangre , Cumarinas/sangre , Cumarinas/farmacología , Espectrometría de Masas/métodos , Flavonoides

RESUMEN

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.

Asunto(s)

Diosmina , Enfermedades Renales , Sirtuina 3 , Humanos , Animales , Ratones , FN-kappa B , Diosmina/farmacología , Factor de Crecimiento Transformador beta1 , Interleucina-6 , Factor de Necrosis Tumoral alfa , Enfermedades Renales/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Fibrosis , ARN Mensajero , ARN Interferente Pequeño

RESUMEN

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.

Asunto(s)

Diosmina , FN-kappa B , Humanos , FN-kappa B/metabolismo , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Diosmina/farmacología , Diosmina/metabolismo , Lipopolisacáridos/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Corteza Prefrontal/metabolismo , Antidepresivos/uso terapéutico , Estrés Oxidativo , Microglía/metabolismo

RESUMEN

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.

Asunto(s)

Arsénico , Diosmina , Humanos , Ratas , Ratones , Animales , Antioxidantes/farmacología , Diosmina/farmacología , Diosmina/metabolismo , Arsénico/farmacología , Arsénico/toxicidad , Ratas Wistar , Estrés Oxidativo , Riñón , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/prevención & control , Glutatión/metabolismo

RESUMEN

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.

Asunto(s)

Diosmina , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Diosmina/metabolismo , Diosmina/farmacología , Inteligencia Artificial , Proliferación Celular , Mioblastos , Diferenciación Celular , Desarrollo de Músculos

RESUMEN

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.

Asunto(s)

Enfermedades Cardiovasculares , Diosmina , Humanos , Diosmina/farmacología , Diosmina/uso terapéutico , Factor A de Crecimiento Endotelial Vascular , Interleucina-12 , Factores de Crecimiento de Fibroblastos , Hipoxia , Inflamación , Interleucina-6 , Ácido Láctico , Homeostasis , Oxígeno

RESUMEN

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.

Asunto(s)

Enfermedades Cardiovasculares , Diosmina , Humanos , Antioxidantes/farmacología , Glucurónidos/farmacología , Diosmina/farmacología , Peróxido de Hidrógeno , Interleucina-8 , Antiinflamatorios/farmacología , Inflamación

RESUMEN

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.

Asunto(s)

Diosmina , Enfermedades Renales , Humanos , Simulación del Acoplamiento Molecular , Metaloproteinasa 9 de la Matriz , Caspasa 3 , Diosmina/farmacología , Farmacología en Red , Fosfatidilinositol 3-Quinasas , Fibrosis

RESUMEN

BACKGROUND: Necessity of new and alternative treatments in traumatic facial nerve injury. AIMS/OBJECTIVE: In this experimental study, we aimed to evaluate the histopathologic and functional effects of methylprednisolone, hyperbaric oxygen and hesperidin + diosmin treatments on traumatic facial nerve regeneration in rats. METHODS: After facial nerve injury, five groups were formed with eight rats in each group: Group 1 (negative control), 2 (operation), 3 (corticosteroid), 4 (hyperbaric oxygen), 5 (hesperidin + diosmin). Blink reflex of rats evaluated a day after the operation and at the first, second and third weeks. Facial nerve samples from sacrificed animals were examined under a light microscope. RESULTS: According to our results, in group 4; axonal degeneration and vascular congestion were significantly lower than group 2 and 3, and myelin sheath thickness was significantly higher than group 3. In group 5; axonal degeneration was significantly lower than group 2 and vascular congestion was significantly lower than group 2 and 3. In terms of functional recovery; there was no statistically significant difference between the groups. CONCLUSIONS AND SIGNIFICANCE: It has been shown that both hyperbaric oxygen and hesperidin + diosmin treatments have positive effects on facial nerve regeneration. Both treatments may be good alternatives for ameliorating traumatic nerve injury, but these treatment modalities need to be further explored.

Asunto(s)

Diosmina , Traumatismos del Nervio Facial , Hesperidina , Oxigenoterapia Hiperbárica , Ratas , Animales , Metilprednisolona/farmacología , Hesperidina/farmacología , Diosmina/farmacología , Modelos Animales , Nervio Facial/patología , Regeneración Nerviosa

RESUMEN

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.

Asunto(s)

Diosmina , Humanos , Diosmina/farmacología , Compuestos de Sulfhidrilo/metabolismo , Bromelaínas/farmacología , Eritrocitos/metabolismo , Estrés Oxidativo , Glutatión/metabolismo , Marcadores de Spin

RESUMEN

Bendiocarb is a carbamate insecticide, which is used more in indoor areas, especially against scorpions, spiders, flies, mosquitoes and cockroaches. Diosmin is an antioxidant flavonoid found mostly in citrus fruits. In this study, the efficacy of diosmin against the adverse effects of bendiocarb was investigated in rats. For this purpose, 60, 2-3 month-old male Wistar albino rats, weighing 150-200 g, were used. The animals were assigned to six groups, one of which was maintained for control purposes and five of which were trial groups. The control rats received only corn oil, which was used as a vehicle for diosmin administration in the trial groups. Groups 2, 3, 4, 5 and 6 were administered with 10 mg/kg.bw bendiocarb, 10 mg/kg.bw diosmin, 20 mg/kg.bw diosmin, 2 mg/kg.bw bendiocarb plus 10 mg/kg.bw diosmin, and 2 mg/kg.bw bendiocarb plus 20 mg/kg.bw diosmin, respectively, using an oral catheter, for 28 days. At the end of the study period, blood and organ (liver, kidneys, brain, testes, heart and lungs) samples were collected. Body weight and organ weights were determined. Compared to the control group, in the group given bendiocarb alone, firstly, body weight and liver, lung and testicular weights decreased. Secondly, tissue/plasma malondialdehyde (MDA) and nitric oxide (NO) levels increased, and glutathione (GSH) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) (except for lung tissue), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PD) activities decreased in all tissues and erythrocytes. Thirdly, catalase (CAT) activity decreased in erythrocytes and the kidney, brain, heart and lung tissues and increased in the liver and testes. Fourthly, while GST activity decreased in the kidneys, testes, lung and erythrocytes, an increase was observed in the liver and heart tissues. Fifthly, while serum triglyceride levels and lactate dehydrogenase (LDH), alkaline phosphatase (ALP) and pseudo-cholinesterase (PchE) activities decreased, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and blood urea nitrogen (BUN), creatinine and uric acid levels increased. Lastly, liver caspase 3, caspase 9 and p53 expression levels significantly increased. When compared to the control group, the groups treated with diosmin alone showed no significant difference for the parameters investigated. On the other hand, it was observed that the values of the groups treated with a combination of bendiocarb and diosmin were closer to the values of the control group. In conclusion, while exposure to bendiocarb at a dose of 2 mg/kg.bw for 28 days caused oxidative stress/organ damage, diosmin administration at doses of 10 and 20 mg/kg.bw reduced this damage. This demonstrated that diosmin has pharmaceutical benefits, when used for supportive treatment as well as radical treatment, against the potential adverse effects of bendiocarb.

Asunto(s)

Diosmina , Animales , Ratas , Masculino , Diosmina/farmacología , Ratas Wistar , Antioxidantes/metabolismo , Estrés Oxidativo , Glutatión/metabolismo , Peso Corporal , Hígado , Riñón

RESUMEN

BACKGROUND: Chronic exposure to high concentrations of inorganic arsenic (NaAsO2) in drinking water is related to an increase in the risk of liver toxicity and diabetes. Diosmin has various pharmacological properties, including antioxidant and anti-inflammatory properties. This study was designed to investigate the protective effects of diosmin on diabetes and hepatotoxicity caused by NaAsO2. METHODS: Sixty male 8-week-old NMRI mice, weighing 25 ± 2 g, were randomly selected and put into six groups. The control (Group 1) was treated orally with distilled water, group 2 was treated with diosmin (100 mg/kg, p.o), group 3 received NaAsO2 (10 mg/kg, p.o), and groups 4, 5, 6 received diosmin (25, 50, 100 mg/kg, p.o), respectively and NaAsO2 (10 mg/kg, p.o). After 29 days, fasting blood sugar (FBS) measurement and glucose tolerance test were done. The mice were sacrificed on day 31, and blood and tissue (liver and pancreas) samples were taken. Then, serum and tissue samples were studied for biochemical and histological evaluations. RESULTS: The results demonstrated that diosmin ameliorated glucose intolerance and decreased FBS compared to the NaAsO2 group. Diosmin (50 and 100 mg/kg) improved the serum factors of liver function (alanine aminotransferase, aspartate transaminase, and alkaline phosphatase) in the groups receiving NaAsO2. Moreover, increased levels of nitric oxide, tumor necrosis factor-alpha, and thiobarbituric acid reactive substances in liver tissue induced by NaAsO2 were diminished by diosmin treatment. Administration of diosmin increased total thiol and enzymatic activities of catalase, superoxide dismutase, and glutathione peroxidase in liver tissue. Furthermore, treatment with diosmin reduced the increase in protein amount of Sirtuin 3 and nuclear factor kappa B in the groups receiving NaAsO2. Also, the liver and pancreas histological lesions induced by NaAsO2 were attenuated by diosmin treatment. CONCLUSION: Diosmin has a preventive effect against hepatotoxicity and diabetes induced by NaAsO2 in mice through its antioxidant and anti-inflammatory properties.

Asunto(s)

Enfermedad Hepática Inducida por Sustancias y Drogas , Diosmina , Ratones , Masculino , Animales , Antioxidantes/metabolismo , Diosmina/farmacología , Diosmina/uso terapéutico , Estrés Oxidativo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Hipoglucemiantes/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico

RESUMEN

Secondary osteoporosis is commonly caused by long-term intake of glucocorticoids (GCs), such as dexamethasone (DEX). Diosmin, a natural substance with potent antioxidant and anti-inflammatory properties, is clinically used for treating some vascular disorders. The current work targeted exploring the protective properties of diosmin to counteract DEX-induced osteoporosis in vivo. Rats were administered DEX (7 mg/kg) once weekly for 5 weeks, and in the second week, vehicle or diosmin (50 or 100 mg/kg/day) for the next four weeks. Femur bone tissues were collected and processed for histological and biochemical examinations. The study findings showed that diosmin alleviated the histological bone impairments caused by DEX. In addition, diosmin upregulated the expression of Runt-related transcription factor 2 (Runx2) and phosphorylated protein kinase B (p-AKT) and the mRNA transcripts of Wingless (Wnt) and osteocalcin. Furthermore, diosmin counteracted the rise in the mRNA levels of receptor activator of nuclear factor-kB ligand (RANKL) and the reduction in osteoprotegerin (OPG), both were induced by DEX. Diosmin restored the oxidant/antioxidant equilibrium and exerted significant antiapoptotic activity. The aforementioned effects were more pronounced at the dose level of 100 mg/kg. Collectively, diosmin has proven to protect rats against DEX-induced osteoporosis by augmenting osteoblast and bone development while hindering osteoclast and bone resorption. Our findings could be used as a stand for recommending supplementation of diosmin for patients chronically using GCs.

Asunto(s)

Conservadores de la Densidad Ósea , Diosmina , Osteoporosis , Animales , Ratas , Antioxidantes/metabolismo , Conservadores de la Densidad Ósea/farmacología , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Dexametasona/farmacología , Diosmina/farmacología , Diosmina/uso terapéutico , Glucocorticoides/toxicidad , Ligandos , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Estrés Oxidativo , Ligando RANK/metabolismo , ARN Mensajero/metabolismo

RESUMEN

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.

Asunto(s)

Diosmina , Enfermedades Renales , Ratas , Animales , Cisplatino/farmacología , Interleucina-6/metabolismo , Diosmina/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Ratas Wistar , Riñón , Enfermedades Renales/inducido químicamente , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/prevención & control , Estrés Oxidativo , Antioxidantes/farmacología , Citocinas/metabolismo , Superóxido Dismutasa/metabolismo , Glutatión Peroxidasa/metabolismo