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AIMS: We investigated the effects of intraperitoneal injections of titanium dioxide nanoparticles (TiO2 NPs, 100 mg/kg) for 5 consecutive days on the developmental competence of murine oocytes. Furthermore, study the effects of TiO2 NPs on antioxidant and oxidative stress biomarkers, as well as their effects on expression of apoptotic and hypoxia inducing factor-1α (HIF1A) protein translation. Moreover, the possible ameliorating effects of intraperitoneal injections of fructose (2.75 mM/ml) was examined. MATERIALS AND METHODS: Thirty sexually mature (8-12 weeks old; ~ 25 g body weight) female mice were used for the current study. The female mice were assigned randomly to three treatment groups: Group1 (G1) mice were injected intraperitoneal (ip) with deionized water for 5 consecutive days; Group 2 (G2) mice were injected ip with TiO2 NPs (100 mg/kg BW) for 5 consecutive days; Group 3 (G3) mice were injected ip with TiO2 NPs (100 mg/kg BW + fructose (2.75 mM) for 5 consecutive days. RESULTS: Nano-titanium significantly decreased expression of GSH, GPx, and NO, expression of MDA and TAC increased. The rates of MI, MII, GVBD and degenerated oocytes were significantly less for nano-titanium treated mice, but the rate of activated oocytes was significantly greater than those in control oocytes. TiO2 NPs significantly increased expression of apoptotic genes (BAX, Caspase 3 and P53) and HIF1A. Intraperitoneal injection of fructose (2.75 mM/kg) significantly alleviated the detrimental effects of TiO2 NPs. Transmission electron microscopy indicated that fructose mitigated adverse effects of TiO2 NPs to alter the cell surface of murine oocytes. CONCLUSION: Results of this study suggest that the i/p infusion of fructose for consecutive 5 days enhances development of murine oocytes and decreases toxic effects of TiO2 NPs through positive effects on oxidative and antioxidant biomarkers in cumulus-oocyte complexes and effects to inhibit TiO2-induced increases in expression of apoptotic and hypoxia inducing factors.
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Nanopartículas del Metal , Nanopartículas , Ratones , Femenino , Animales , Antioxidantes/metabolismo , Hígado/metabolismo , Estrés Oxidativo , Titanio/toxicidad , Oocitos , Hipoxia/metabolismo , Hipoxia/veterinaria , Biomarcadores/metabolismo , Nanopartículas del Metal/toxicidadRESUMEN
The microstructure of the thyroid gland of the one-humped camel (Camelus dromedarius) was described using morphometric, histological, immunohistochemical staining, and ultrastructural standard techniques. The follicular secretory units of the thyroid glands displayed comparable and variable sizes where the large follicles were situated at the peripheral margins; however, the small ones were located in the central region. Semisquamous epithelium (low cuboidal) lined the large thyroid follicles, while high cuboidal (columnar) epithelium lined the small ones. Our electron microscopic findings revealed that the low-sized cuboidal follicular cells lack organelles and are hypoactive. The high cuboidal follicular cells are active cells and rich in cellular organelles such as cisternae of rough endoplasmic reticulum, mitochondria, colloid droplets, scrolled Golgi apparatus, and secretory vesicles. A few degenerate follicular cells appeared on rare occasions. The parafollicular cells appeared with a more prominent and conspicuous nucleus than the follicular cells. The follicular cells were classified as active, inactive, or degenerated using transmission electron microscopy. The follicular and parafollicular cells showed calcitonin-positive immunoreactivity. Overall, the presented results showed particular convergences of the morphostructural aspects of the thyroid gland of C. dromedarius to that of other mammals with some distinctive features to cope with their physiology and harsh niche.
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Camelus , Glándula Tiroides , Animales , Glándula Tiroides/ultraestructura , Glándula Tiroides/citología , Microscopía Electrónica de Transmisión , Inmunohistoquímica , Femenino , MasculinoRESUMEN
Gentamicin (GEN) is an aminoglycoside antibiotic used to treat gram-negative bacterial infections. Our study aimed to explore curcumin's (CMN) protective role against GEN-induced renal and cardiac toxicity. Rats were randomly classified into 4 equal groups; Control (cont), GEN (100 mg/kg b.wt, i.p.) for seven days, CMN (200 mg/kg b.wt, orally) for 21 days, and CMN + GEN groups. GEN caused renal and cardiac dysfunctions; increased urea, creatinine, uric acid, cystatin C, CK-MB, LDH, and troponin I serum levels. MDA level was elevated significantly while activities of SOD, CAT, and GSH level were reduced significantly in renal and cardiac tissues. GEN-intoxicated rats showed up-regulation of NF-κB, IL-1ß, Keap1, HMOX1, and BAX with down-regulation of Nrf2, and Bcl-2 mRNA expression in renal and cardiac tissues. Also, GEN-induced up-regulation of renal mRNA expression of KIM-1, NGAL, and intermediate filament proteins [desmin, nestin, and vimentin] as well cardiac gene expression of cMyBP-C and H-FABP. GEN-induced toxicity was significantly attenuated by CMN co-treatment as CMN improved renal and cardiac biomarkers, reduced oxidative stress and inflammatory response, and reversed alterations in mRNA expression of all tested renal and cardiac genes. These outcomes indicated that CMN could protect renal and cardiac tissues against GEN-induced oxidative stress, inflammation, and apoptosis.
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Curcumina , Gentamicinas , Ratas , Animales , Gentamicinas/toxicidad , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Curcumina/farmacología , Curcumina/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Cardiotoxicidad/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Riñón/metabolismo , Estrés Oxidativo , ARN Mensajero/metabolismo , Apoptosis , Antioxidantes/farmacología , Antioxidantes/metabolismoRESUMEN
The current study aimed to explore the possible prophylactic and therapeutic effect of Nigella sativa L. oil (NSO) against disruption of endocrine signals and injuries in the thyroid gland, ovary, and uterine tissues induced by sodium fluoride (NaF). Twenty-eight mature female Wistar rats were randomly allocated into four experimental groups (n = 7/group) as follows: control group; NaF group, orally received NaF (20 mg/kg b.wt.) daily; NSO/NaF, orally received NSO (300 mg/kg b.wt.) two weeks before being given NaF and continued throughout the experiment; and NSO+NaF group orally received NSO concurrently with NaF. Our results indicated that NSO restored hormonal balance and suppressed oxidative damage and inflammation. Moreover, the levels of triiodothyronine, thyroxine, thyroid peroxidase, estrogen (E2), progesterone, follicle-stimulating hormone, and luteinizing hormone were elevated, while prostaglandins F2-α and cortisol levels were decreased in NSO treated groups compared to NaF-intoxicated rats. As well, NSO significantly boosted levels of antioxidant molecules, and lowered lipid peroxidation of examined tissues, unlike NaF-treated group. NSO also up-regulated antioxidant enzymes, anti-apoptotic protein, zona pellucida sperm-binding protein, bone morphogenetic protein, and thyroid stimulating hormone, conversely down-regulated inflammatory cytokines, apoptotic proteins, estrogen receptor-α, estrogen receptor-ß, and thyroid stimulating hormone receptors compared to NaF-intoxicated group. Additionally, NSO ameliorated tissue damage of the thyroid gland, ovary, and uterus induced by NaF. -Overall, the prophylactic group (NSO/NaF) performed better antioxidant and anti-inflammatory activities than the treated group almost in all examined tissues, which is reflected by the improvement in the structure of the thyroid, ovarian, and uterine tissues.
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Nigella sativa , Glándula Tiroides , Ratas , Femenino , Masculino , Animales , Ratas Wistar , Antioxidantes/farmacología , Antioxidantes/metabolismo , Ovario , Fluoruro de Sodio/toxicidad , Fluoruro de Sodio/metabolismo , Aceites de Plantas/farmacología , Estrés Oxidativo , Útero/metabolismo , Receptores de Estrógenos/metabolismo , SemillasRESUMEN
Forebrain ischemia-reperfusion (IR) injury causes neurological impairments due to decreased cerebral autoregulation, hypoperfusion, and edema in the hours to days following the restoration of spontaneous circulation. This study aimed to examine the protective and/or therapeutic effects of cerebrolysin (CBL) in managing forebrain IR injury and any probable underlying mechanisms. To study the contribution of reperfusion to forebrain injury, we developed a transient dual carotid artery ligation (tDCAL/IR) mouse model. Five equal groups of six BLC57 mice were created: Group 1: control group (no surgery was performed); Group 2: sham surgery (surgery was performed without IR); Group 3: tDCAL/IR (surgery with IR via permanently ligating the left CA and temporarily closing the right CA for 30 min, followed by reperfusion for 72 h); Group 4: CBL + tDCAL/IR (CBL was given intravenously at a 60 mg/kg BW dose 30 min before IR); and Group 5: tDCAL/IR + CBL (CBL was administered i.v. at 60 mg/kg BW three hours after IR). At 72 h following IR, the mice were euthanized. CBL administration 3 h after IR improved neurological functional recovery, enhanced anti-inflammatory and antioxidant activities, alleviated apoptotic neuronal death, and inhibited reactive microglial and astrocyte activation, resulting in neuroprotection after IR injury in the tDCAL/IR + CBL mice group as compared to the other groups. Furthermore, CBL reduced the TLRs/NF-kB/cytokines while activating the Keap1/Nrf2/antioxidant signaling pathway. These results indicate that CBL may improve neurologic function in mice following IR.
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Antioxidantes , Daño por Reperfusión , Ratones , Animales , Antioxidantes/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Transducción de Señal , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Modelos Animales de Enfermedad , Prosencéfalo/metabolismo , Estrés OxidativoRESUMEN
AIMS: The objective of this study was to compare the effects of finasteride, a medication used to treat benign prostatic hyperplasia (BPH), and laser irradiated silver nanoparticles (AgNPs), a potential candidate for BPH therapy (Sanchez-Salas, 2017; Marghani et al., 2022) [1,2], on the sex hormone profiles, sperm quality, steroidogenesis, testicular oxidative stress, and histomorphology changes in BPH rats. MATERIALS AND METHODS: BPH was induced in male Sprague-Dawley (SD) rats via intramuscular (i.m.) injection of 5 mg/kg BW testosterone propionate (TP) for 14 days. Once the BPH model was induced, rats were divided into four groups (n = 6) as follows: the control group; the BPH group; the BPH/Fina group, which received 5 mg/kg BW finasteride by oral gavage daily for 14 days; and the BPH/AgNPs group, which received a daily intraperitoneal (i.p.) injection of 50 mg/kg BW AgNPs, followed by 5min of exposure to a 532 nm NIR laser in the prostatic area for the constitutive 14 days. KEY FINDINGS: On day 14, the BPH rats had a significant increase in prostate specific antigen (PSA), dihydrotestosterone, and prostate weights, while testicular weights and sperm quality were significantly lower than in the control rats. On day 28, laser irradiated AgNps treated BPH rats showed improved sex hormone balance, testicular weights, sperm quality, steroidogenesis, and an ameliorative effect on testicular histopathology compared to finasteride. SIGNIFICANCE: Surprisingly, these findings suggest that laser irradiated AgNPs can be used as an alternative therapy to finasteride for the treatment of BPH without causing negative effects on the testes.
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Nanopartículas del Metal , Hiperplasia Prostática , Humanos , Masculino , Ratas , Animales , Hiperplasia Prostática/inducido químicamente , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/patología , Testosterona , Finasterida/farmacología , Plata , Ratas Sprague-Dawley , Extractos Vegetales/farmacología , SemenRESUMEN
The potential reproductive toxic effects of oral TiO2 NPs in adult male rats as well as the possible alleviation of chitosan administration was investigated. Animals were allocated to four groups; the first group received deionized water and was assigned as a control group. In the second group, rats received chitosan at a dose of 5 mg/kg BW/day. The third group was designed for administration of TiO2 NPs at a dose of 150 mg/kg BW/day (1/80 LD50). Rats in the fourth group received both TiO2 NPs and chitosan. After 14 days, TiO2 NPs induced testicular lipid peroxidation as well as oxidative stress. Nano-titanium significantly upregulated genes that encode apoptosis and inflammation in testicular tissue. Moreover, it induced histological alteration in the testicular structure with impairment in spermatogenesis via reduction of PCNA immune-staining. Chitosan administration significantly improved the activities of testicular GPx, SOD, and CAT enzymes. In addition, it significantly down-regulated the relative expressions of pro-apoptotic and pro-inflammatory testicular genes. Chitosan was able to improve the testicular architecture as well as spermatogenesis. The current study revealed the capability of chitosan to ameliorate nano-titanium induced testicular toxicity. Thus, attention should be given to the extensive consumption of nano-titanium particles.
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Quitosano , Nanopartículas , Enfermedades Testiculares , Humanos , Masculino , Ratas , Animales , Titanio/química , Enfermedades Testiculares/inducido químicamenteRESUMEN
Osteoporosis (OP) is a serious health problem, and the most popular therapeutic strategy for OP is hormone replacement (estrogen); however, it increases the risk of reproductive cancers. Hydroxyapatite (HA) nanoparticles have a similar chemical structure to the bone mineral component and can be used as a new remedy for OP. This study was designed to investigate the osteoporosis-protective potential of nano zinc hydroxyapatite (ZnHA-NPs) and/or estradiol (E2) combined therapy. A total of 35 adult female rats were assigned into five groups (n = 7): 1) control group; 2) ovariectomized group (OVX); 3) OVX received oral estradiol replacement therapy (OVX/E2); 4) OVX received ZnHA replacement therapy (OVX/ZnHA); and 5) OVX received both estradiol and ZnHA-NPs combined therapy (OVX/E2+ZnHA). After 3 months of treatment, serum bone markers and estrogen level, oxidative/antioxidant, and inflammatory cytokines were determined. Additionally, femoral expression of estrogen receptors alpha and beta (ESR1; ESR2), receptor activator of nuclear factor-kappa B (RANKL) ligand, osteoprotegerin (OPG), bone mineral density (BMD), histological alterations, and immunohistochemical expression of vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) were assessed. ALP, PINP, Ca, and P concentrations improved significantly (p < 0.05) in all treatment groups, especially in the OVX/E + ZnHA group. MDA and NO were higher in OVX rats, while SOD activity and GSH were lower (p < 0.05). E2 alone or with ZnHA-NPs restored the estimated antioxidant molecules and cytokines toward normal levels in OVX rats (p < 0.05). On the other hand, E2 and ZnHA increased OPG and OC expression in femurs while decreasing ESR1, ESR2, and NF-kB expression (p < 0.05). The combination treatment was superior in the restoration of normal femoral histoarchitecture and both cortical and trabecular BMD (p < 0.05). Overall, the combined therapy of OVX/E2+ZnHA was more effective than the individual treatments in attenuating excessive bone turnover and preventing osteoporosis.
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This study aims to see if Ginseng® can reduce the hepatorenal damage caused by malathion. Four groups of forty male Wistar albino rats were alienated. Group 1 was a control group that got orally supplied corn oil (vehicle). Group 2 was intoxicated by malathion dissolved in corn oil orally at 135 mg/kg/day. Group 3 orally received both malathion + Panax Ginseng® (300 mg/kg/day). Group 4 was orally given Panax Ginseng® at a 300 mg/kg/day dose. Treatments were administered daily and continued for up to 30 consecutive days. Malathion's toxic effect on both hepatic and renal tissues was revealed by a considerable loss in body weight and biochemically by a marked increase in liver enzymes, LDH, ACP, cholesterol, and functional renal markers with a marked decrease in serum TP, albumin, and TG levels with decreased AchE and Paraoxonase activity. Additionally, malondialdehydes, nitric oxide (nitrite), 8-hydroxy-2-deoxyguanosine, and TNFα with a significant drop in the antioxidant activities were reported in the malathion group. Malathion upregulated the inflammatory cytokines and apoptotic genes, while Nrf2, Bcl2, and HO-1 were downregulated. Ginseng® and malathion co-treatment reduced malathion's harmful effects by restoring metabolic indicators, enhancing antioxidant pursuit, lowering the inflammatory reaction, and alleviating pathological alterations. So, Ginseng® may have protective effects against hepatic and renal malathion-induced toxicity on biochemical, antioxidant, molecular, and cell levels.
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Rosemary oil (ROO) is known to have multiple pharmacological effects: it is an antioxidant, anti-inflammatory, and cytoprotective. In the present study, we examined the effects of ROO on Human olfactory bulb neuronal stem cells (hOBNSCs) after their transplantation into rats, with the ibotenic (IBO) acid-induced cognitive deficit model. After 7 weeks, cognitive functions were assessed using the Morris water maze (MWM). After two months blood and hippocampus samples were collected for biochemical, gene expression, and histomorphometric analyses. Learning ability and memory function were significantly enhanced (P < 0.05) after hOBNSCs transplantation and were nearly returned to normal in the treated group. The IBO acid injection was associated with a significant decline (P < 0.05) of total leukocyte count (TLC) and a significant increase (P < 0.05) in total and toxic neutrophils. As well, the level of IL-1ß, TNF-α CRP in serum and levels of MDA and NO in hippocampus tissue were significantly elevated (P < 0.05), while antioxidant markers (CAT, GSH, and SOD) were reduced (P < 0.05) in treated tissue compared to controls. The administration of ROO before or with cell transplantation attenuated all these parameters. In particular, the level of NO nearly returned to normal when rosemary was administrated before cell transplantation. Gene expression analysis revealed the potential protective effect of ROO and hOBNSCs via down-expression of R-ßAmyl and R- CAS 3 and R-GFAP genes. The improvement in the histological organization of the hippocampus was detected after the hOBNSCs transplantation especially in h/ROO/hOBNSCs group.
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Enfermedad de Alzheimer , Células-Madre Neurales , Síndromes de Neurotoxicidad , Rosmarinus , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Antioxidantes/uso terapéutico , Suplementos Dietéticos , Humanos , Ácido Iboténico/metabolismo , Ácido Iboténico/farmacología , Ácido Iboténico/uso terapéutico , Aprendizaje por Laberinto , Células-Madre Neurales/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Aceites Volátiles , Bulbo Olfatorio , RatasRESUMEN
In the current study, we aimed to investigate the neurotoxic effect of oral titanium dioxide nanoparticles (TiO2 NPs) as well as the possible neuroprotective effect of carboxymethyl chitosan in adult rats for 14 days. The results revealed that TiO2 NPs inhibited the activity of the acetylcholine esterase enzyme and the levels of serotonin, dopamine, and norepinephrine neurotransmitters. Additionally, it induced neuro-oxidative stress and neuroinflammation via an elevation in MDA levels and IL-6, while GSH concentration, as well as GPx and GST activities, were decreased. TiO2 NPs induced neuronal apoptosis through upregulation of the expression of caspase-8 and -9 that was further confirmed by increasing caspases-3 and -8 proteins in the hippocampus, cerebral cortex, and cerebellum. The expression of the immediate-early gene BDNF was increased in response to TiO2 NPs, while that of Arc was reduced. Chitosan significantly attenuated the TiO2 NPs-induced neurotoxicity regarding AChE, serotonin, MDA, GSH, GPx, GST, IL-6, caspases-8, -9, and -3. Chitosan inhibited the expression of Arc and alleviated the effect of TiO2 NPs on BDNF expression. Collectively, TiO2 NPs induced neurotoxicity via their action on vital neuronal biomarkers that might in turn cause brain dysfunction. Despite the neuroprotection of chitosan, its inhibitory effect on Arc expression should be considered.
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Quitosano , Nanopartículas del Metal , Nanopartículas , Animales , Encéfalo , Nanopartículas/toxicidad , Estrés Oxidativo , Ratas , Titanio/toxicidadRESUMEN
5-Fluorouracil (5-FU), a chemotherapeutic drug, has adverse effects on heart and kidney functions. Ficus Carica (fig) and extra virgin olive oil (EVOO) are natural sources which have antioxidant effects. This study investigated the synergistic effects of fig extract and EVOO against cardiac and renal damage induced by 5-FU. Forty rats were equally divided into five groups and treated with physiological saline (control), five intravenous injections of 5-FU (40 mg/kg b.w) (5-FU), fig (1 g/kg b.w/day, orally) with 5-FU (Fig/5-FU), EVOO (7 g/kg b.w/day, orally) with 5-FU (EVOO/5-FU), combined treatment of fig and EVOO with five 5-FU injections (Fig/EVOO/5-FU). After 30 days, blood and tissue samples (Heart and kidney) were collected to be used in the examinations. 5-FU significantly increased serum creatine kinase activity, renal biomarkers, cholesterol, triglycerides, C-reactive protein, tumor necrosis factor-α, and interleukin-1ß as well as cardiac and renal lipid peroxides (malondialdehyde). Meanwhile, serum levels of immunoglobulins, interleukins (IL-10, IL-12), and antioxidants of heart and kidney tissues were significantly decreased in 5-FU group. It also downregulated cardiac and renal Bcl2, and upregulated cardiac troponin and renin gene expressions. As well, histological alterations clarified that 5-FU induced cardiac cell damage, distorted renal corpuscles and tubules, inflammatory cell infiltrations, and severe congestion and hemorrhage in the blood vessels. The treatment with fig and olive oil, especially the combined treatment, modulated the toxic effect of 5-FU on the heart and kidney. Our results revealed that fig extract and EVOO have a powerful antioxidant and many protective effects against cardiac and renal toxicity induced by 5-FU, especially when using fig and EVOO together as a combined treatment.
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Ficus , Animales , Antioxidantes , Citocinas , Fluorouracilo , Inflamación , Masculino , Aceite de Oliva , Estrés Oxidativo , Extractos Vegetales/farmacología , RatasRESUMEN
AIMS: This study was designed to evaluate the protective and therapeutic efficacy of platelet-rich plasma (PRP) against testicular degeneration and germ cell apoptosis after induced spermatic cord torsion/detorsion (TD) in rats. MATERIALS: Forty rats were allocated into 5 groups: 1) control, 2) short torsion/detorsion (STD), 3) long torsion detorsion (LTD), 4) protective (PRP/P) and 5) treatment (PRP/T). Testicular ischemia was induced by twisting the right testis 1080° clockwise for 2.5 h. PRP (10 µl) was injected intra-testicular 5 min before (PRP/P) and 3 h after (PRP/T) detorsion. At the end of the experiment, rats were euthanized at 2, 30, 2, and 30 days for groups 2-5 respectively. Nitric oxide, malondialdehyde, catalase, total antioxidant capacity, reduced glutathione, glutathione-S-transferase, interleukin1 beta, tumor necrosis factor, caspase-3, and B-cell lymphoma 2 expressions were assessed in the testes. Moreover, histological examination was performed. KEY FINDINGS: PRP treatment significantly mitigated the torsion-detorsion induced testicular degeneration. Particularly, by improving the state of oxidative stress (NO, P = 0.0001) and antioxidant markers (TAC, GSH, GST, P = 0.0001-0.01) and decreasing the expression of IL-1ß, TNF-α and cas 3 and increase the BCL2 fold changes (P = 0.0001). The protective use of PRP is superior to the therapeutic use of PRP in the restoration of the testicular histoarchitecture following TD. SIGNIFICANCE: This study illustrates the cyto-protective role of PRP against TD induced testicular cell injury that highlight possible application of PRP as a complementary therapy in different testicular degenerative diseases which might attribute to its ability to ameliorate the oxidative stress and inhibit induced apoptosis.
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Plasma Rico en Plaquetas/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Torsión del Cordón Espermático/metabolismo , Torsión del Cordón Espermático/prevención & control , Testículo/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Daño por Reperfusión/patología , Torsión del Cordón Espermático/patología , Testículo/patología , Resultado del TratamientoRESUMEN
Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 ± 2.88%), neuron-like (52.63 ± 4.16%), and astrocyte -like (22.36 ± 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease.
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Células-Madre Neurales/trasplante , Bulbo Olfatorio/citología , Enfermedad de Parkinson/terapia , Trasplante de Células Madre/métodos , Animales , Regulación de la Expresión Génica/fisiología , Humanos , Masculino , Factor de Crecimiento Nervioso/genética , Factor de Crecimiento Nervioso/metabolismo , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Ratas , Ratas WistarRESUMEN
In this study, we aim to demonstrate the fate of allogenic adult human olfactory bulb neural stem/progenitor cells (OBNSC/NPCs) transplanted into the rat hippocampus treated with ibotenic acid (IBO), a neurotoxicant specific to hippocampal cholinergic neurons that are lost in Alzheimer's disease. We assessed their possible ability to survive, integrate, proliferate, and differentiate into different neuronal and glial elements: we also evaluate their possible therapeutic potential, and the mechanism(s) relevant to neuroprotection following their engraftment into the CNS milieu. OBNSC/NPCs were isolated from adult human olfactory bulb patients, genetically engineered to express GFP and human nerve growth factor (hNGF) by lentivirus-mediated infection, and stereotaxically transplanted into the hippocampus of IBO-treated animals and controls. Stereological analysis of engrafted OBNSCs eight weeks post transplantation revealed a 1.89 fold increase with respect to the initial cell population, indicating a marked ability for survival and proliferation. In addition, 54.71 ± 11.38%, 30.18 ± 6.00%, and 15.09 ± 5.38% of engrafted OBNSCs were identified by morphological criteria suggestive of mature neurons, oligodendrocytes and astrocytes respectively. Taken together, this work demonstrated that human OBNSCs expressing NGF ameliorate the cognitive deficiencies associated with IBO-induced lesions in AD model rats, and the improvement can probably be attributed primarily to neuronal and glial cell replacement as well as the trophic influence exerted by the secreted NGF.