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Crataegus monogyna fruit aqueous extract as a protective agent against doxorubicin-induced reproductive toxicity in male rats

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Objective: Doxorubicin (DOX) is a broad spectrum chemotherapeutic agent used in the treatment of several malignancies. The use of DOX in clinical chemotherapy has been restricted due to its diverse toxicities, including reproductive toxicity. Crataegus monogyna (C. monogyna) is one of the oldest medicinal plants that have been shown to be cytoprotective because of scavenging free radicals. The present study was undertaken to determine whether C. monogyna fruits aqueous extract could serve as a protective agent against reproductive toxicity during DOX treatment in a rat model through antioxidant-mediated mechanisms. Materials and Methods: Male Wistar rats were allocated to four groups. Two groups of rats were treated with DOX at a dose of 4 mg/kg intraperitoneally on days 1, 7, 14, 21, and 28 (accumulated dose of 20 mg/kg). One of the groups received C. monogyna fruits aqueous extract at a dose of 20 mg/kg per day orally for 28 days along with DOX. A vehicle-treated control group and a C. monogyna control group were also included. Results: The DOX-treated group showed significant decreases in the body and organ weights and spermatogenic activities as well as many histological alterations. DOX treatment also caused a significant decrease in sperm count and motility with an increase in dead and abnormal sperms. Moreover, significant decrease in serum levels of testosterone and increased serum concentrations of FSH, LH, LDH, CPK, and SGOT were observed in DOX-treated rats. Notably, Crataegus co-administration caused a partial recovery in above-mentioned parameters. Conclusion: These findings indicated that doxorubicin can adversely damage the testicular tissue, while Crataegus co-administration could effectively prevent these adverse effects by effective inhibiting oxidative processes and restoration of antioxidant defense system.
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... The underlying mechanism through which DOX induces tissue toxicity has been proposed but is not yet fully elucidated. Moreover, documented studies indicate oxidative stress [10,11] as a critical interplay in the induction of its toxicities. In view of this reports, much focus is steered on investigations of the usage of compounds or agents from natural origins that exhibits antioxidant properties. ...
... Toxicity induced by the usage of Doxorubicin has been well reported even though the exact mechanism behind these DOX-induced toxicities remains not fully elucidated, the induction of oxidative damage, and lipid peroxidation of the membranes is perceived to be contributing factor to DOX toxicities [10,14]. Phytochemicals are bioactive compounds found in fruits and vegetables; their consumption is greatly associated with a decrease in risk of chronic diseases due to their antioxidant potentials [11,20,24]. C. volubile leaf extracts have been documented to perform an important role in attenuating oxidative stress, scavenging free radicals and boosting of antioxidant defense systems [23,24,36]. ...
Article
Objectives Doxorubicin (DOX) is a commonly used chemotherapeutic drug. However, its non-target organ toxicities pose a serious problem. This study is to assess the protective role of Clerodendrum volubile leaf extract (CVE) against DOX-induced toxicities in rats. In addition, the inhibitory activities of three phytochemical compounds (Rutin, Gallic acid and Rosmarinic acid ) from CVE against Carbonyl reductase 1 (CBR1) were examined. Methods Rats were randomly divided into 5 groups: (a) Control group rats were given 0.9% NaCl as vehicle, (b) DOX group: A single dose of DOX (25 mg/kg; i.p.) was administered and rats were sacrificed 4 days after DOX injection, while groups (c–e) CVE-treated DOX rat groups were given 125, 250 and 500 mg/kg body weight of extracts orally for 12 consecutive days; 8 days before, and 4 days after the DOX administration. Computational techniques were used to determine the inhibitory activities of the compounds against CBR1. Results DOX intoxication caused a significant increase (p<0.05) in serum marker enzymes: ALT, AST, ALP, LDH, CK activities. The levels of liver and heart tissues antioxidant parameters: GPx, SOD, CAT, and GSH were significantly (p<0.05) decreased in DOX-intoxicated rats with concomitant elevation of malondialdehyde levels. Pretreatment with CVE reversed the above trends. From the structural analysis, Rutin and RSA exhibited the highest binding free energies against CBR1, and also exhibited structural stability when bound with CBR1. Conclusions Our study indicates the protective effect of CVE when used in combination with doxorubicin thus improving its chemotherapeutic application via inhibition of CBR-mediated metabolism.
... Sperm motility were assessed as previously discriped. 25,26 Briefly, a modified ringer solution (sodium chloride: 68.00 g, potassium chloride: 17.33 g, calcium chloride: 6.42 g, magnesium sulfate: 2.50 g, sodium bicarbonate: 24.50 g and distilled water 10,000 mL) was used for semen dilution (1:200). Sperm motility was evaluated by using light microscope (Model CHT; Olympus Optical Co. Ltd., Tokyo, Japan) at 400× magnification. ...
... Histological parameters including TDI and SPI can also give information on the degree of testicular damage as a consequence of germ cell loss. 25 This study indicated that the percentage of seminiferous tubules without sperm in the control group was higher than groups fed on diets supplemented with nano-selenium. Accordingly, the percentage of degenerated testicular germinal epithelium in the control group was higher than that of groups fed on diets supplemented with nano-selenium. ...
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It is well documented that aging has negative effects on fertility. With increasing age, the activity of antioxidant enzymes are reduced and because of roosters sperm composition, a high proportion of polyunsaturated fatty acids (PUFAs), the probability of sperm damage increases. The objective of the present study was to compare the effects of nano-selenium and sodium selenite on fertility in aged male broiler breeder chickens. Thirty-five male broiler breeders (Cobb 500)® at 50 weeks of age were randomly divided into five equal groups: The control group was fed on a commercial diet, group T1 was fed on a commercial diet supplemented with sodium selenite (0.30 mg kg-1 feed), group T2, T3 and T4 were fed on a commercial diet supplemented with nano-selenium (0.15, 0.30 and 0.60 mg kg-1 feed, respectively). Sperm characteristics (sperm count, motility, viability, and maturity) as well as testicular histomorphometric features [tubule differentiation (TDI), spermiation (SPI), Sertoli cell (SCI) and meiotic (MI) indices] were assessed. The results showed that sperm characteristics were gradually decreased with age in the control group, however, it increased in group T3. Also, TDI, SPI, SCI, and MI in group T3 were higher than those of other groups. Our findings revealed that dietary supplementations with nano-selenium boosted fertility in aged male broiler breeders and the best results were obtained when the roosters received 0.30 mg kg-1 nano-selenium. Supplementation of nano-selenium in aged broiler breeder males might be effective to maintain flock fertility and/or increase the flock fertility.
... These properties have appeared to be linked to the presence of phytochemicals generally maintaining the appropriate cell redox balance through diverse mechanisms, including antioxidant activity [27]. Studies on the genus have shown that phytochemicals such as oligomeric procyanidins, flavonoids, triterpenes, polysaccharides, catecholamines and many of these compounds have been evaluated for biological functions [20,[58][59][60]. In this context, several studies have revealed that the C. monogyna fruit represents a great source and one of the highest in terms of phenolic content with a value up to 30.63 mg gallic acid equivalent (GAE) g −1 in fully ripe fruit [61]. ...
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Hawthorn (Crataegus monogyna Jacq.) is a wild edible fruit tree of the genus Crataegus, one of the most interesting genera of the Rosaceae family. This review is the first to consider, all together, the pharmaceutical, phytochemical, functional and therapeutic properties of C. monogyna based on numerous valuable secondary metabolites, including flavonoids, vitamin C, glycoside, anthocyanin, saponin, tannin and antioxidants. Previous reviews dealt with the properties of all species of the entire genera. We highlight the multi-therapeutic role that C. monogyna extracts could have in the treatment of different chronic and degenerative diseases, mainly focusing on flavonoids. In the first part of this comprehensive review, we describe the main botanical characteristics and summarize the studies which have been performed on the morphological and genetic characterization of the C. monogyna germplasm. In the second part, the key metabolites and their nutritional and pharmaceutical properties are described. This work could be an essential resource for promoting future therapeutic formulations based on this natural and potent bioactive plant extract.
... Elevated FSH level can be a sign of spermatogenesis destruction related to numerous causes including: testicular damage, genetic aberrations, and toxic disclosure such as radiation and chemotherapy 47 . Leydig cells are of great significance for the development of the spermatogenic process 48 , and the decrease of the hormone levels showed changes in structure and function of these cells 49 . ...
Article
Background: Hormones play a vital role in initiating and maintenance of male reproductive or testicular function which includes the production of androgens and spermatozoa. Testosterone is essential for the initiation and maintenance of spermatogenesis. FSH is responsible for the stimulation of spermatogenesis. Semen analysis and hormone evaluation are essential parameters in the diagnosis of infertility in males. Objective: The aim of the present study is to evaluate the effect of sorafenib on FSH and intratesticular testosterone levels in male Swiss albino mice. Materials and Methods: The animals were segregated into control, positive control, and treatment groups (n=6). Treatment group received 25, 50 and 100 mg/kg body weight of sorafenib orally for seven consecutive days at intervals of 24 hours between two administrations. Positive control group received 100 mg/kg body weight of imatinib. The animals were sacrificed at the end of 1 st , 2 nd , 4 th , 5 th , 7 th and 10 th week after the last exposure to sorafenib. Results: The intratesticular testosterone level was significantly (P<0.05) reduced in treated groups and severe effect was observed on week 4 th and 5 th weeks. FSH level was increased significantly (P<0.05) in sorafenib treated groups of mice. Conclusion: The administration of sorafenib does affect testosterone and FSH level significantly, but this effect is reversible once the drug is withdrawn. This finding may help the clinicians to plan and address the fertility-related issues in young patients of reproductive age who are being treated with sorafenib for advanced renal cell carcinoma, hepatocellular carcinoma and differentiated thyroid carcinoma.
... 36 rats were randomly separated into six groups (n=6) and placed in individual steel cages. The study procedure was arranged according to former studies (van Acker et al., 2000, Jalali and Hasanzadeh, 2013, Sakr et al., 2011 with slight adjustments. ...
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Doxorubicin (DOX) is an anthracycline drug used for cancer treatment. However, its treatment is contiguous with toxic effects. We examine the nephroprotective potential of A. hydaspica polyphenol-rich ethyl acetate extract (AHE) against DOX persuaded nephrotoxicity. 36 male Sprague Dawley rats were randomly assorted into 6 groups. Control group received saline; DOX group: 3 mg/kg b.w. dosage of DOX intraperitoneally for 6 weeks (single dose/week). In co-treatment groups, 200 and 400 mg/kg b.w AHE was given orally for 6 weeks in concomitant with DOX (3 mg/kg b.w, i.p. injection per week) respectively. Standard group received silymarin 400 mg/kg b.w daily + DOX (single dose/week). Biochemical kidney function tests, oxidative stress markers, genotoxicity, antioxidant enzyme status, and histopathological changes were examined. DOX caused significant body weight loss and decrease kidney weight. DOX-induced marked deterioration in renal function indicators in both urine and serum, i.e., PH, specific gravity, total protein, albumin, urea, creatinine, uric acid, globulin, blood urea nitrogen, etc. Also, DOX treatment increases renal tissue oxidative stress markers, while lower antioxidant enzymes in tissue along with degenerative alterations in the renal tissue compared to control rats. AHE co-treatment ameliorates DOX-prompted changes in serum and urine chemistry. Likewise, AHE treatment decreases sensitive markers of oxidative stress and prevented DNA damages by enhancing antioxidant enzyme levels. DOX induction in rats also caused DNA fragmentation which was restored by AHE co-treatment. Moreover, the histological observations evidenced that AHE effectively rescued the kidney tissue from DOXinterceded oxidative damage. Our results suggest that co-treatment of AHE markedly improve DOX-induced deleterious effects in a dose-dependent manner. The potency of AHE co-treatment at 400mg/kg dose is similar to silymarin. These outcomes revealed that A. hydaspica AHE extract might serve as a potential adjuvant that avoids DOX-induced nephrotoxicity.
... HPLC-DAD-ESI/MS analyzes of the extracts revealed a predominance of F (Rodrigues et al., 2012). An interesting fact is that, in addition to not producing toxicity in non-tumor cells, the aqueous extract of C. monogyna is capable of exerting a protective effect against the toxicity caused by doxorubicin, a broad-spectrum chemotherapeutic drug whose use has been restricted (Shalizar Jalali & Hasanzadeh, 2013). ...
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Plants have been traditionally used for the treatment of different types of illness, due to biomolecules with recognised benefits. Rosaceae family is used in traditional Galician medicine. The following plants Agrimonia eupatoria, Crataegus monogyna, Filipendula ulmaria, Geum urbanum, Potentilla erecta and Rosa canina are usually found in treatments. The aim of this study is to perform an ethnobotanical review about the bioactive compounds of these plants and their different bioactivities, both studied in vitro and in vivo. The nature of the bioactive compounds is varied, highlighting the presence of different phenolic compounds, such as phenolic acids, flavonoids or tannins. Understanding the beneficial effects of the administration of the whole plant or target tissues from A. eupatoria, C. monogyna, F. ulmaria, G. urbanum, P. erecta and R. canina as well as those from their individual compounds could lead to the development of new drugs based on the use of natural ingredients.
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Background Crataegus aronia (C. aronia) extracts have been used medicinally since ancient times and are often utilized in traditional Arab medicine. An extensive study has revealed that Crataegus species have antioxidant, antibacterial, anti-inflammatory, and hypotensive properties. Objectives This work was performed to explore the phytochemical contents of C. aronia extract, as well as its antioxidant and antibacterial properties, and to assess the lipid peroxidation level as an oxidative stress biomarker in erythrocytes. Methods Chemical constituents in the methanolic extract of C. aronia were identified by gas chromatography-mass spectrometry and their relative concentrations were determined. The antioxidant activity of C. aronia extract was determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. The effect of C. aronia on the concentration of malondialdehyde (MDA) in the erythrocyte hemolysates was studied. Also, the crude extract was assessed for its antimicrobial activity through agar diffusion and microbroth dilution assays. Key findings The DPPH IC50 value of the extract showed that the antioxidants activity was equal to (14.3 μg/ml) and according to FRAP assay, the antioxidant activity was in the range of 33.9 μmol–82.86μmol Fe⁺²/g dw. The extract exerts a protective effect against oxidative stress in RBCs and shows a 50% inhibition of Malonyldialdehyde (MDA) at 39.48 μg/ml extract. Minimum inhibitory concentrations were found in the range of 800–1000 μg/ml of leave extracts. The phytochemical analysis showed that the total phenols, flavonoids, and flavonols content were 494.071mg GAE/g extract, 155.251mg RE/g extract, and 103.2049 mg RE/g extract). C. aronia extract contains alkaloids, flavonoids, terpenoids, and steroids. Crude extract of C. aronia was more potent in inhibiting the growth of B. subtilis, S. aureus and M. luteus with MIC and MBC values of 800,800 and 1000 μg/mL, respectively. According to GC-MS, 20 compounds were identified: dihydro-3-methylene-5-methyl-2-furanone (14.71%), hexanoic acid (6.57%), ethyl 3,5-ditert-butyl-4-hydroxybenzoate (6.4%), N, N-dimethylheptadecan-1-amine (4.91%), methyl 2-oxobutanoate (4.14%), glyceraldehyde (3.98%), and 2-methoxy-1-(2-nitroethenyl)-3-phenylmethoxybenzene (3.16%), were the major constituents. Conclusion This study may open a window of hope for children with Glucose-6-phosphate dehydrogenase disorder by possible utilization of the active ingredients of C. aronia to minimize both oxidative stress and infection which negatively impact the disease sequelae. According to these in vitro experiments, this plant extract has a significant amount of natural antioxidants, which may aid in the protection of various oxidative stresses. As a result, employing the active components of C. aronia to minimize oxidative stress and infection, both of which have a detrimental impact on disease sequelae, may bring hope to children with Glucose-6-phosphate dehydrogenase disorder.
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Doxorubicin is an extensively used anti-neoplastic drug used for solid and hematogenous cancer since the 1950s, and its usage is limited due to its toxic effects upon various organs. The main reason behind the toxicity is the production of free radicals. It is evident that the first and foremost organ affected by the doxorubicin is the heart, and further, it causes toxic effects in hepatic, kidney, reproductive organs, adipose tissue, and brain. This review aims to bring up recent findings on the molecular mechanisms underlying doxorubicin-induced toxicity among different organs via the regulation of various signaling and biochemical events. • Highlights • The review focuses on the multiorgan toxicity due to doxorubicin treatment explained among various animal models and cell lines. • The heart has been reported as the primary organ, which is highly vulnerable to doxorubicin therapy through multiple pathways, eventually emanating cardiotoxicity. • Apart from the heart, the mechanisms underlying multiorgan toxicity, which include liver, kidney, adipose tissue, reproductive systems of both male and female, and the nervous system were also affected during the doxorubicin therapy. • The most common mechanism of toxicity among all the organs includes imbalances in the redox potential of the cell due to the free radicals produced during the metabolism of doxorubicin treatment. • Besides the use of doxorubicin for malignancies, the patients are prone to developing serious side effects at an off-target site.
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The anticancer drug Doxorubicin has been associated with several adverse side-effects including reproductive toxicity in both genders. The current review has complied the mechanisms of doxorubicin induced reproductive toxicity. The articles cited in the review were searched using Google Scholar, PubMed, Scopus, Science Direct. Doxorubicin treatment have been found to cause decrease in testicular mass along with histopathological deformities, oligospermia and abnormalities in sperm morphology. Apart from severely affecting the normal physiological role of both leydig cells and Sertoli cells, doxorubicin also causes chromosome abnormalities and affects DNA methylase enzymes. Testicular lipid metabolism has been found to be negatively affected by doxorubicin treatment resulting is altered profile of sphingolipids glycerophospholipids and neutral lipids. Dysregulation of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β- hydroxysteroid dehydrogenase (17β-HSD) is strongly linked to testicular exposure to doxorubicin. Further, oxidative stress along with endoplasmic reticulum stress also found to aggravates the male reproductive functioning in doxorubicin treated conditions. Several antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase (GPx) are downregulated by doxorubicin. It also disturbs the hormones of the hypothalamic-pituitary-gonadal (HPG)-axis including testosterone, luteinizing hormone, follicle stimulating hormone etc. In female, the drug disturbs folliculogenesis and oogenesis leading to failure of ovulation and uterine cycle. In rodent model the drug shortened pro-estrous and estrous phases. It was also found that doxorubicin causes mitochondrial dysfunction in oocytes with impaired calcium signalling along with ER stress. The goal of the present review is to comprehends the various pathways due to which doxorubicin treatment promotes toxicity in male and female reproductive system.
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Causes of Primary Testicular DiseaseChemotherapeutic Agents and X-Irradiation TherapyThe Clinical Features of Primary Testicular DiseaseTesticular Biopsy and its Place in the Management of Primary Testicular DiseaseThe Treatment of Primary Testicular DiseaseReferences
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Doxorubicin (DOX), one of the anthracycline antibiotic drugs isolated from the soil fungus Streptomyces peucetius caesius , which has been widely used to treat cancer effectively. It has also been known to induce reproductive abnormalities in males. The implication of natural phenolic compounds in the prevention of many pathologic diseases has been reported. Herein, the ability of polyphenolic-rich Grapefruit Seed Extracts (GSE), to protect rat testis against DOX-induced histomorphometric impairment was investigated. Four groups of Wistar rats were used; The GSE- alone group received intraperitoneal (i.p.) Normal Saline (NS) 2.5 mg kg<SUP>-1</SUP> b.wt. followed by orally GSE 10 mg kg<SUP>-1</SUP> b.wt. daily for 16 weeks. The DOX-alone group were given i.p., DOX 20 mg kg<SUP>-1</SUP> b.wt. as a single dose. The GSE plus DOX-group were similarly given DOX, but also had oral GSE 10 mg kg<SUP>-1</SUP> b.wt. post-treatment for 16 weeks. Another group of rats were each given orally 2.5 mL kg<SUP>-1</SUP> b.wt. peanut oil (vehicle) daily for 16 weeks, after 2.5 mL kg<SUP>-1</SUP> b.wt. normal saline was given as a single dose i.p., to serve as the control. The animals were sacrificed 16 weeks after DOX or NS injections. The testicular toxicity induced by DOX was assessed by histologic and stereologic evaluation of the testis. Present results demonstrated that post-treatment with GSE was capable of reversing the reduction of body and testicular weights as well as the testicular histomorphometric evidences of high dose and delayed DOX toxicity in the animals. The GSE was therefore shown to exert testicular cytorejuvinative effects on rats challenged with DOX.