RESUMEN
Methotrexate (MTX) is a folic acid reductase inhibitor that manages various malignancies as well as immune-mediated inflammatory chronic diseases. Despite being frequently prescribed, MTX's severe multiple toxicities can occasionally limit its therapeutic potential. Intestinal toxicity is a severe adverse effect associated with the administration of MTX, and patients are significantly burdened by MTX-provoked intestinal mucositis. However, the mechanism of such intestinal toxicity is not entirely understood, mechanistic studies demonstrated oxidative stress and inflammatory reactions as key factors that lead to the development of MTX-induced intestinal injury. Besides, MTX causes intestinal cells to express pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which activate nuclear factor-kappa B (NF-κB). This is followed by the activation of the Janus kinase/signal transducer and activator of the transcription3 (JAK/STAT3) signaling pathway. Moreover, because of its dual anti-inflammatory and antioxidative properties, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) has been considered a critical signaling pathway that counteracts oxidative stress in MTX-induced intestinal injury. Several agents have potential protective effects in counteracting MTX-provoked intestinal injury such as omega-3 polyunsaturated fatty acids, taurine, umbelliferone, vinpocetine, perindopril, rutin, hesperidin, lycopene, quercetin, apocynin, lactobacillus, berberine, zinc, and nifuroxazide. This review aims to summarize the potential redox molecular mechanisms of MTX-induced intestinal injury and how they can be alleviated. In conclusion, studying these molecular pathways might open the way for early alleviation of the intestinal damage and the development of various agent plans to attenuate MTX-mediated intestinal injury.
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Studies have identified Coenzyme Q10 (CoQ10) as a promising agent in improving idiopathic male infertility; however, its role in chemically or environmentally induced testicular dysfunction is not well-established. We investigated the potential of CoQ10 to attenuate methotrexate (MTX)-induced testicular damage and to identify molecular targets of CoQ10 effects. Wistar rats received a single intraperitoneal dose of 20 mg/kg MTX on the fifth day of the 10-day experimental protocol. 100 mg/kg CoQ10 was given orally daily for ten days, alone or combined with MTX. The testes of MTX-treated animals showed thickened tunica albuginea, distortion of seminiferous tubules with a marked reduction of germinal lining, a few primary spermatocytes with no spermatozoa, apoptotic cells, congested sub-capsular and interstitial blood vessels, and interstitial edema. Reduction of reproductive hormones and increased oxidative, inflammatory, and apoptotic biomarkers levels were also seen in the MTX-treated rats. CoQ10 + MTX-treated rats were protected against MTX-induced testicular histological changes and showed improvement in testosterone, luteinizing-, and follicle-stimulating hormone serum levels compared to the MTX group. The testes of the CoQ10 + MTX-treated rats showed reduced malondialdehyde, myloperoxidase, tumor necrosis factor -α, interleukin-6 and -1ß and Bax: Bcl2 ratio and enhanced glutathione, and catalase compared to MTX alone. CoQ10 enhanced MTX-induced downregulation of Nrf2 and PPAR-γ signaling and modulated its downstream targets, the inducible nitric oxide synthase, NF-κB, Bax, and Bcl2. In conclusion, CoQ10 targeted the Nrf2-PPAR-γ signaling loop and its downstream pathways, mitigating MTX-induced oxidative stress-related damages and alleviating the testicular dysfunction MTX caused. Our data suggest Nrf2-PPAR-γ signaling as a potential therapeutic target in testicular toxicity, where oxidative stress, inflammation, and apoptosis trigger damage.
Asunto(s)
Metotrexato , Enfermedades Testiculares , Ubiquinona/análogos & derivados , Humanos , Ratas , Masculino , Animales , Metotrexato/toxicidad , Ratas Wistar , Factor 2 Relacionado con NF-E2/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Estrés Oxidativo , Enfermedades Testiculares/inducido químicamente , Enfermedades Testiculares/tratamiento farmacológico , Enfermedades Testiculares/prevención & control , Antioxidantes/farmacologíaRESUMEN
Rheumatoid arthritis (RA) affects the joints and the endocrine system via persistent immune system activation. RA patients have a higher frequency of testicular dysfunction, impotence, and decreased libido. This investigation aimed to evaluate the efficacy of galantamine (GAL) on testicular injury secondary to RA. Rats were allocated into four groups: control, GAL (2 mg/kg/day, p.o), CFA (0.3 mg/kg, s.c), and CFA + GAL. Testicular injury indicators, such as testosterone level, sperm count, and gonadosomatic index, were evaluated. Inflammatory indicators, such as interleukin-6 (IL-6), p-Nuclear factor kappa B (NF-κB p65), and anti-inflammatory cytokine interleukin-10 (IL-10), were assessed. Cleaved caspase-3 expression was immunohistochemically investigated. Protein expressions of Janus kinase (JAK), signal transducers and activators of transcription (STAT3), and Suppressors of Cytokine Signaling 3 (SOCS3) were examined by Western blot analysis. Results show that serum testosterone, sperm count, and gonadosomatic index were increased significantly by GAL. Additionally, GAL significantly diminished testicular IL-6 while improved IL-10 expression relative to CFA group. Furthermore, GAL attenuated testicular histopathological abnormalities by CFA and downregulated cleaved caspase-3 and NF-κB p65 expressions. It also downregulated JAK/STAT3 cascade with SOCS3 upregulation. In conclusion, GAL has potential protective effects on testicular damage secondary to RA via counteracting testicular inflammation, apoptosis, and inhibiting IL-6/JAK/STAT3/SOCS3 signaling.
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Artritis Reumatoide , Interleucina-6 , Factor de Transcripción STAT3 , Proteína 3 Supresora de la Señalización de Citocinas , Humanos , Masculino , Animales , Ratas , Interleucina-10 , Caspasa 3 , Galantamina , FN-kappa B , Piroptosis , Semen , Adyuvantes Inmunológicos , Adyuvantes Farmacéuticos , Espermatogénesis , Citocinas , Apoptosis , Artritis Reumatoide/tratamiento farmacológico , TestosteronaRESUMEN
Methotrexate (MTX) is an inhibitor of folic acid reductase used in managing a variety of malignancies. Testicular injury by MTX is one of its serious adverse effects. The current investigation aims to assess the protective effects of diacerein (DIA) on testicular injury by MTX and clarify the possible underlying mechanisms. Testicular injury in rats was induced by a single injection of 20 mg/kg body weight of MTX. DIA was given in 25 mg/kg body weight/day and 50 mg/kg body weight/day doses for 10 days. Compared to the MTX group, DIA attenuated testicular intoxication as evidenced by improvement of testicular histopathological abnormalities and increased serum testosterone and luteinizing hormone. DIA attenuated testicular oxidative stress changes by lowering testicular MDA and boosting GSH content and SOD activity. Moreover, administration of DIA attenuated MTX-induced testicular inflammation, as proved by decreased TNF-α and IL-6. At the molecular level, DIA induced significant upregulation in Nrf2, HO-1, PPAR-γ, and cytoglobin protein expression. The present results proved that DIA, in a dose-dependent manner, exhibited notable amelioration of testicular toxicity induced by MTX through augmentation of anti-inflammatory and antioxidant effects combined by upregulating Nrf2/HO-1, PPAR-γ, and cytoglobin signaling.
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Acute pancreatitis (AP) is an inflammatory disorder of acinar cells. It may develop into severe chronic pancreatitis with a significant mortality rate. The current study aimed to assess the therapeutic effect of a Lactobacillus (LAB) mixture against rat AP. Six groups were created including control, taurine (300 mg/kg; i.p.) for 7 days, LAB mixture for 7 days, L-arginine (2.5 g/kg; i.p.) 2 doses with 1 h interval on 1st day, L-arginine+taurine, and L-arginine+LAB. Serum amylase and lipase activities were measured. Pancreatic tissue was used for histopathological examination, oxidative stress biomarkers including malondialdehyde (MDA) and reduced glutathione (GSH), and inflammatory biomarkers including myeloperoxidase (MPO) and interleukin (IL)-33 assessment. qRT-PCR was used for transient receptor potential vanilloid-1 (TRPV-1) investigation and Western blot analysis for measuring nuclear factor kappa-B (NF-κBp65) and the apoptosis biomarker; caspase-3. Taurine and LAB reduced lipase and significantly ameliorated induced oxidative stress by normalizing MDA and GSH contents. They counteracted inflammation by reducing MPO, IL-33, NF-κBp65, and TRPV-1. In addition, taurine and LAB counteracted apoptosis as proved by reduced caspase-3 expression. Taken together, these findings indicate that taurine and the use LAB mixture can mitigate AP by L-arginine via influencing TRPV-1/IL-33/NF-κB signaling together with exhibiting potent antioxidant and anti-inflammatory effects.
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Antineoplásicos , Pancreatitis , Animales , Ratas , Enfermedad Aguda , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Arginina/efectos adversos , Biomarcadores/metabolismo , Caspasa 3/metabolismo , Interleucina-33/inmunología , Interleucina-33/metabolismo , Lipasa/metabolismo , FN-kappa B/metabolismo , Páncreas/metabolismo , Pancreatitis/inducido químicamente , Pancreatitis/tratamiento farmacológico , Pancreatitis/patologíaRESUMEN
Benign prostatic hyperplasia (BPH) is one of the most prevalent clinical disorders in the elderly. Probenecid (Prob) is a well-known FDA-approved therapy for gout owing to its uricosuric effect. The present study evaluated the use of Prob for BPH as a COX-2 inhibitor. Prob (100 and 200 mg/kg) was intraperitoneally injected into male Wistar rats daily for 3 weeks. In the second week, testosterone (3 mg/kg) was subcutaneously injected to induce BPH. Compared with BPH-induced rats, Prob treatment reduced prostate weight and index and improved histopathological architecture. The protease activity of ADAM-17/TACE and its ligands (TGF-α and TNF-α) were regulated by prob, which in turn abolished EGFR phosphorylation, and several inflammatory mediators (COX-2, PGE2, NF-κB (p65), and IL-6) were suppressed. By reducing the nuclear import of extracellular regulated kinase protein 1/2 (ERK1/2), Prob helped re-establish the usual equilibrium between antiapoptotic proteins like Bcl-2 and cyclin D1 and proapoptotic proteins like Bax. All of these data point to Prob as a promising treatment for BPH because of its ability to inhibit COX-2-syntheiszed PGE2 and control the ADAM-17/TGF-α-induced EGFR/ERK1/2 signaling cascade. These findings might help to repurpose Prob for the treatment of BPH.
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Hiperplasia Prostática , Testosterona , Humanos , Ratas , Masculino , Animales , Anciano , Testosterona/efectos adversos , Hiperplasia Prostática/inducido químicamente , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/metabolismo , Probenecid/efectos adversos , Dinoprostona/metabolismo , Factor de Crecimiento Transformador alfa/efectos adversos , Factor de Crecimiento Transformador alfa/metabolismo , Proteína ADAM17/metabolismo , Ciclooxigenasa 2/metabolismo , Sistema de Señalización de MAP Quinasas , Ratas Sprague-Dawley , Ratas Wistar , Receptores ErbB/metabolismoRESUMEN
Lung carcinoma is one of the most prevalent and deadly neoplasia worldwide. Numerous synthetic medications have been used in the treatment of cancer. However, there are several drawbacks, such as side effects and inefficiency. The current study focused on the potential anti-cancer effectiveness of tangeretin, an antioxidant flavonoid, on lung cancer induced experimentally in BALB/c mice and explored the involvement of NF-κB/ICAM-1, JAK/STAT-3, and caspase-3 signaling in its anti-cancer effect. BALB/c mice were injected with urethane (1.5 mg/kg) twice; on the first day and on the 60th day of the experiment, then treated with 200 mg/kg tangeretin orally once daily for the last 4 weeks of the experiment. Compared with urethane group, tangeretin normalized oxidative stress markers; MDA, GSH, and SOD activity. Moreover, it had an anti-inflammatory effect by decreasing lung MPO activity, ICAM-1, IL-6, NF-ÒB, and TNF-α expressions. Interestingly, tangeretin decreased cancer metastasis by reducing p-JAK, JAK, p-STAT-3, and STAT-3 protein expression levels. Furthermore, it increased the apoptotic marker, caspase-3, indicating enhanced apoptosis of cancer cells. Finally, histopathology confirmed the anti-cancer effect of tangeretin. In conclusion, tangeretin could have a promising effect in counteracting lung cancer via modulation of NF-κB/ICAM-1, JAK/STAT-3, and caspase-3 signaling.
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Neoplasias Pulmonares , FN-kappa B , Ratones , Animales , FN-kappa B/metabolismo , Caspasa 3 , Uretano , Molécula 1 de Adhesión Intercelular , Ratones Endogámicos BALB C , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , ApoptosisRESUMEN
Rebamipide is a quinolone derivative that has been commonly used for the treatment of gastric and duodenal ulcers. However, the molecular mechanisms of rebamipide against acetic acid-evoked colitis have not been adequately examined. Hence, the current study aimed to investigate the ameliorative effect of rebamipide in a rat model of acetic acid-evoked ulcerative colitis and the linked mechanisms pertaining to SIRT1/FoxO3a/Nrf2 and PI3K/AKT pathways. Herein, colitis was induced by the intrarectal administration of 3% acetic acid solution in saline (v/v) while rebamipide was administered by oral gavage (100 mg/kg/day) for seven days before the colonic insult. The colonic injury was examined by macroscopical and microscopical examination. The current findings demonstrated that rebamipide significantly improved the colonic injury by lowering the colonic disease activity index and macroscopic mucosal injury score. Moreover, it mitigated the histopathological aberrations and microscopical damage score. The favorable outcomes of rebamipide were driven by combating inflammation evidenced by dampening the colonic expression of NF-κBp65 and the pro-inflammatory markers CRP, TNF-α, and IL-6. In the same context, rebamipide curtailed the colonic pro-inflammatory PI3K/AKT pathway as seen by downregulating the immunostaining of PI3K and p-AKT(Ser473) signals. In tandem, rebamipide combated the colonic pro-oxidant events and augmented the antioxidant milieu by significantly diminishing the colonic TBARS and replenishing GSH, SOD, GST, GPx, and CAT. In the same regard, rebamipide stimulated the colonic upstream SIRT1/FoxO3a/Nrf2 axis by upregulating the expression of SIRT1, FoxO3a, and Nrf2, alongside downregulating Keap-1 gene expression. These antioxidant actions were accompanied by upregulation of the protein expression of the cytoprotective signal PPAR-γ in the colons of rats. In conclusion, the present findings suggest that the promising ameliorative features of rebamipide against experimental colitis were driven by combating the colonic inflammatory and oxidative responses. In perspective, augmentation of colonic SIRT1/FoxO3a/Nrf2 and inhibition of PI3K/AKT pathways were engaged in the observed favorable outcomes.
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Edaravone (ED) is a neuroprotective drug with beneficial effects against several disorders due to its prominent antioxidant activity. However, its effect against methotrexate (MTX)-induced testicular damage was not previously investigated. Therefore, we aimed to investigate the ability of ED to prevent the oxidative stress, inflammation, and apoptosis induced by MTX on the rat testis and to examine whether ED administration modulated the Akt/p53 signaling and steroidogenesis process. Rats were allocated into; Normal, ED (20 mg/kg, PO, for 10 days), MTX (20 mg/kg, i.p., on the 5th day), and ED + MTX groups. The results showed that MTX group exhibited higher serum activities of ALT, AST, ALP, and LDH in addition to histopathological alterations in the rat testis, compared to normal group. Furthermore, MTX induced down-regulation of the steroidogenic genes; StAR, CYP11a1, and HSD17B3 and reduced FSH, LH, and testosterone levels. The MTX group also showed higher levels of MDA, NO, MPO, NF-kB, TNF-α, IL-6, IL-1ß, Bax, and caspase 3, as well as, lower levels of GSH, GPx, SOD, IL-10, Bcl2 compared to normal rats, p < 0.05. In addition, MTX treatment resulted in increased p53 expression and decreased p-Akt expression. Remarkably, ED administration significantly prevented all the biochemical, genetic, and histological damage induced by MTX. Hence, ED treatment protected the rat testis from apoptosis, oxidative stress, inflammation, and impaired steroidogenesis induced by MTX. This novel protective effect was mediated by decreasing p53 while increasing p-Akt protein expression.
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Metotrexato , Enfermedades Testiculares , Masculino , Humanos , Ratas , Animales , Metotrexato/toxicidad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Edaravona , Proteína p53 Supresora de Tumor/metabolismo , Ratas Wistar , Antioxidantes/farmacología , Inflamación/tratamiento farmacológico , Inflamación/patología , Estrés OxidativoRESUMEN
BACKGROUND: Irinotecan is a chemotherapeutic agent used to treat a variety of tumors, including colorectal cancer (CRC). In the intestine, it is transformed into SN-38 by gut microbial enzymes, which is responsible for its toxicity during excretion. OBJECTIVE: Our study highlights the impact of Irinotecan on gut microbiota composition and the role of probiotics in limiting Irinotecan-associated diarrhea and suppressing gut bacterial ß-glucuronidase enzymes. MATERIAL AND METHODS: To investigate the effect of Irinotecan on the gut microbiota composition, we applied 16S rRNA gene sequencing in three groups of stool samples from healthy individuals, colon cancer, and Irinotecan treated patients (n = 5/group). Furthermore, three Lactobacillus spp.; Lactiplantibacillus plantarum (L. plantarum), Lactobacillus acidophilus (L. acidophilus), Lacticaseibacillus rhamnosus (L. rhamnosus) were used in a single and mixed form to in-vitro explore the effect of probiotics on the expression of ß-glucuronidase gene from E. coli. Also, probiotics were introduced in single and mixed forms in groups of mice before the administration of Irinotecan, and their protective effects were explored by assessing the level of reactive oxidative species (ROS) as well as studying the concomitant intestinal inflammation and apoptosis. RESULTS: The gut microbiota was disturbed in individuals with colon cancer and after Irinotecan treatment. In the healthy group, Firmicutes were more abundant than Bacteriodetes, which was the opposite in the case of colon-cancer or Irinotecan treated groups. Actinobacteria and Verrucomicrobia were markedly present within the healthy group, while Cyanobacteria were noted in colon-cancer and the Irinotecan-treated groups. Enterobacteriaceae and genus Dialister were more abundant in the colon-cancer group than in other groups. The abundance of Veillonella, Clostridium, Butryicicoccus, and Prevotella were increased in Irinotecan-treated groups compared to other groups. Using Lactobacillus spp. mixture in mice models significantly relieved Irinotecan-induced diarrhea through the reduction of both ß-glucuronidase expression and ROS, in addition to guarding gut epithelium against microbial dysbiosis and proliferative crypt injury. CONCLUSIONS: Irinotecan-based chemotherapy altered intestinal microbiota. The gut microbiota participates greatly in determining both the efficacy and toxicity of chemotherapies, of which the toxicity of Irinotecan is caused by the bacterial ß-glucuronidase enzymes. The gut microbiota can now be aimed and modulated to promote efficacy and decrease the toxicity of chemotherapeutics. The used probiotic regimen in this study lowered mucositis, oxidative stress, cellular inflammation, and apoptotic cascade induction of Irinotecan.
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Neoplasias del Colon , Microbioma Gastrointestinal , Animales , Ratones , Irinotecán/efectos adversos , Escherichia coli , ARN Ribosómico 16S/genética , Especies Reactivas de Oxígeno , Glucuronidasa/genética , Diarrea/inducido químicamente , Diarrea/prevención & controlRESUMEN
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.
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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/metabolismoRESUMEN
Worldwide, the most frequently diagnosed cancer is female breast cancer, and it poses a serious global health threat. Traditional cancer therapies are associated with various side effects, so developing better therapies for breast cancer is necessary, such as laser therapy which could be a promising treatment option. The aim of the current study was to investigate the femtosecond laser irradiation effect on breast cancer using T47D cell line as an in vitro model. Cells were seeded at a density of 5 × 104 cells/well in 96-well plates and incubated overnight. After that, the cells were exposed to femtosecond laser irradiation at various wavelengths falling in the UV, visible, and IR ranges for 3, 5, or 10 min and at a constant power of 100 mW. Cell viability was measured directly and 24 h after femtosecond laser irradiation using MTT assay. When using different femtosecond laser irradiation parameters, especially the 380 and 400 nm femtosecond laser irradiation, there was significant inhibition of breast cancer cell growth, either directly or 24 h after femtosecond laser exposure. Also, 420 and 440 nm significantly affected the viability of the cells. It was also observed that increasing exposure time enhances the observed effect, so 10 min exposure time was the best time of exposure. However, 700, 720, 750, and 780 nm did not significantly affect the cells viability with different exposure times. It was possible to conclude from the aforementioned results that femtosecond laser irradiation exerted a significant anticancer effect against T47D cells. Consequently, the femtosecond laser could be used successfully for breast cancer management.
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Neoplasias de la Mama , Terapia por Láser , Terapia por Luz de Baja Intensidad , Femenino , Humanos , Neoplasias de la Mama/radioterapia , Rayos Láser , Proliferación Celular/efectos de la radiaciónRESUMEN
OBJECTIVE AND DESIGN: Prostatic inflammation is the driving force in benign prostatic hyperplasia (BPH). This work investigated the potential modulatory effect of COX-2 inhibition on ADAM-17/EGFR/ERK1/2 axis. MATERIALS OR SUBJECTS: Adult male Wistar rats were used. TREATMENT: Celecoxib (10 and 20 mg/kg; i.p.) was injected i.p. daily for three weeks. Testosterone (TST) (3 mg/kg; s.c.) was used to induce BPH. METHODS: Prostatic inflammation and hyperplasia were assessed by organ weight and histopathology. Inflammatory mediators were measured using ELISA technique. Protein analysis was performed using western blotting and immunohistochemistry. Gene expression analysis was performed using qRT-PCR. Statistical analyses included one-way ANOVA and Tukey's multiple comparison test. RESULTS: Testosterone-treated rats had a marked increase in COX-2, prostate weight, and index. Moreover, TST-induced COX-2 was inferred from cytoskeletal changes and was attributable to the overexpression of PGE2, NF-κB (p65), and IL-6. COX-2-derived PGE2 increased the activity of ADAM-17, TGF-α, and TNF-α. Consequently, EGFR-ERK1/2 pathway was over-activated, disrupting anti-apoptotic Bcl-2, cyclin D1, and pro-apoptotic Bax. Celecoxib reversed these effects. CONCLUSION: COX-2 stimulates the ERK1/2 pathway via PGE2-ADAM-17-catalyzed shedding of TGF-α in testosterone-induced BPH. The results indicate a functional correlation between inflammation and hyperplasia in BPH.
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Hiperplasia Prostática , Testosterona , Animales , Masculino , Ratas , Proteína ADAM17/metabolismo , Celecoxib/efectos adversos , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Receptores ErbB/metabolismo , Hiperplasia , Inflamación/patología , Sistema de Señalización de MAP Quinasas , Hiperplasia Prostática/metabolismo , Ratas Sprague-Dawley , Ratas Wistar , Testosterona/efectos adversos , Factor de Crecimiento Transformador alfa/efectos adversos , Factor de Crecimiento Transformador alfa/metabolismoRESUMEN
Idiopathic pulmonary fibrosis is a terminal lung ailment that shares several pathological and genetic mechanisms with severe COVID-19. Thymol (THY) is a dietary compound found in thyme species that showed therapeutic effects against various diseases. However, the effect of THY against bleomycin (BLM)-induced lung fibrosis was not previously investigated. The current study investigated the ability of THY to modulate oxidative stress, inflammation, miR-29a/TGF-ß expression, and PI3K/phospho-Akt signaling in lung fibrosis. Mice were divided into Normal, THY (100 mg/kg, p.o.), BLM (15 mg/kg, i.p.), BLM + THY (50 mg/kg, p.o.), and BLM + THY (100 mg/kg, p.o.) groups and treated for four weeks. The obtained results showed that BLM + THY (50 mg/kg) and BLM + THY (100 mg/kg) reduced fibrotic markers; α-SMA and fibronectin, inflammatory mediators; TNF-α, IL-1ß, IL-6, and NF-kB and oxidative stress biomarkers; MDA, GSH, and SOD, relative to BLM group. Lung histopathological examination by H&E and Masson's trichrome stains confirmed the obtained results. Remarkably, expression levels of TGF-ß, PI3K, and phospho-Akt were decreased while miR-29a expression was elevated. In conclusion, THY effectively prevented BLM-induced pulmonary fibrosis by exerting significant anti-oxidant and anti-inflammatory effects. Our novel findings that THY upregulated lung miR-29a expression while decreased TGF-ß and PI3K/Akt signaling are worthy of further investigation as a possible molecular mechanism for THY's anti-fibrotic actions.
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COVID-19 , MicroARNs , Fibrosis Pulmonar , Ratones , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/genética , Bleomicina/toxicidad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Timol/uso terapéutico , Factor de Crecimiento Transformador beta/metabolismo , COVID-19/patología , Inflamación/metabolismo , Pulmón/metabolismo , Estrés Oxidativo , Fibrosis , MicroARNs/metabolismoRESUMEN
Kidney diseases are major health problem and understanding the underlined mechanisms that lead to kidney diseases are critical research points with a marked potential impact on health. Cadmium (Cd) is a heavy metal that occurs naturally and can be found in contaminated food. Kidneys are the most susceptible organ to heavy metal intoxication as it is the main route of waste excretion. The harmful effects of Cd were previously well proved. Cd induces inflammatory responses, oxidative injury, mitochondrial dysfunction and disturbs Ca2+ homeostasis. The nuclear factor-kappa B (NF-κB) is a cellular transcription factor that regulates inflammation and controls the expression of many inflammatory cytokines. Therefore, great therapeutic benefits can be attained from NF-κB inhibition. In this review we focused on certain compounds including cytochalasin D, mangiferin, N-acetylcysteine, pyrrolidine dithiocarbamate, roflumilast, rosmarinic acid, sildenafil, sinapic acid, telmisartan and wogonin and certain plants as Astragalus Polysaccharide, Ginkgo Biloba and Thymus serrulatus that potently inhibit NF-κB and effectively counteracted Cd-associated renal intoxication. In conclusion, the proposed NF-κB involvement in Cd-renal intoxication clarified the underlined inflammation associated with Cd-nephropathy and the beneficial effects of NF-κB inhibitors that make them the potential to substantially optimize treatment protocols for Cd-renal intoxication.
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Enfermedades Renales , FN-kappa B , Acetilcisteína/uso terapéutico , Cadmio/toxicidad , Citocalasina D/uso terapéutico , Citocinas/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/metabolismo , FN-kappa B/metabolismo , Polisacáridos/uso terapéutico , Citrato de Sildenafil/uso terapéutico , Telmisartán/uso terapéuticoRESUMEN
Coagulation is a main pathway in various diseases pathogenesis including testicular damage. This study evaluated rivaroxaban (RVX) protective effects in testicular impairment by cisplatin (CP). Rats were randomly allocated into five groups: Control, RVX (7 mg/kg/day), CP (10 mg/kg), RVX 5 mg + CP and RVX 7 mg + CP. Serum testosterone and testicular ALT, AST, and ALP were assessed. Testicular oxidative stress and antioxidant parameters and inflammatory indicators including interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) were assessed. qRT-PCR was used to determine mRNA expression of 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 17ß-hydroxysteroid dehydrogenase (17ß-HSD), and steroidogenic acute regulatory protein (stAR). Protein expressions of p-Nuclear factor kappa B (p- NF-κB) and vascular cell adhesion protein-1 (VCAM-1) were analyzed by Western blot analysis. Tissue factor (TF) expression was immunohistochemically analyzed. Results revealed that RVX significantly increased serum testosterone and sperm count while significantly reduced IL-1ß and TNF-α. It significantly decreased tissue MDA and NO contents while increased SOD and GPx. In addition, RVX attenuated CP-induced histopathological aberrations and normalized TF. It also decreased the VCAM-1 and p-NF-κB expression and showed strong expression of 3ß-HSD, 17ß-HSD, and stAR, indicating improvement of steroidogenesis. In conclusion, RVX counteracted testicular damage by CP via suppressing oxidative stress, inflammation, and coagulation and downregulating p-NF-κB/VCAM-1 signaling.
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Antineoplásicos , Coagulación Sanguínea , Cisplatino , FN-kappa B , Estrés Oxidativo , Rivaroxabán , Enfermedades Testiculares , Testículo , Molécula 1 de Adhesión Celular Vascular , Animales , Masculino , Ratas , Cisplatino/toxicidad , Interleucina-1beta/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Rivaroxabán/farmacología , Rivaroxabán/uso terapéutico , ARN Mensajero/metabolismo , Semen/metabolismo , Superóxido Dismutasa/metabolismo , Testículo/efectos de los fármacos , Testosterona/metabolismo , Tromboplastina/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Enfermedades Testiculares/inducido químicamente , Enfermedades Testiculares/prevención & control , Antineoplásicos/toxicidad , Coagulación Sanguínea/efectos de los fármacosRESUMEN
Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins that occurs in chronic liver injury. Inflammation and oxidative stress play a key role in fibrogenesis which can develop into cirrhosis and carcinoma. Low-level laser therapy (LLLT) has promising therapeutic effects against fibrogenesis; however, the specific underlying mechanism is not fully elucidated. We investigated the potential of LLLT to attenuate carbon tetrachloride (CCl4)-induced liver fibrosis in rats, focusing on oxidative injury, inflammatory response, and the possible role of PPARγ and Nrf2/HO-1 signaling. Rats were given CCl4 and exposed to LLLT twice/week for 6 weeks and blood and liver samples were collected for analysis. CCl4 caused liver injury and fibrosis manifested by hepatocyte injury, steatosis, inflammatory cell infiltration, and accumulation of collagen, elevated serum transaminases and bilirubin, and decreased albumin. ROS, MDA, NO, NF-κB p65, TNF-α, iNOS, TGF-ß1, and IL-6 were increased in the liver of CCl4-administered rats. Exposure to LLLT ameliorated histopathological alterations, collagen deposition, and liver function markers, and downregulated hepatic α-SMA, collagen 1A1, and collagen 3A1. In Addition, LLLT decreased ROS, MDA, NO, NF-κB p65, TGF-ß1, and pro-inflammatory mediators, and enhanced antioxidant defenses. These effects were associated with upregulated PPARγ, Nrf2, and HO-1, both gene and protein expression. In conclusion, LLLT attenuated liver fibrosis by suppressing ECM production and deposition, oxidative injury and inflammation, and upregulating PPARγ and Nrf2/HO-1 signaling.
Asunto(s)
Inflamación , Rayos Láser , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Animales , Ratas , Albúminas/metabolismo , Antioxidantes/farmacología , Bilirrubina/metabolismo , Tetracloruro de Carbono/toxicidad , Hemo Oxigenasa (Desciclizante)/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Hígado/metabolismo , Cirrosis Hepática/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transaminasas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcers represent a significant clinical concern and adversely affect the quality of life. Inducible nitric oxide synthase/endothelial nitric oxide synthase (iNOS/eNOS) and asymmetric dimethylarginine/ dimethylarginine dimethylaminohydrolase-1 (ADMA/DDAH-1) signaling are key players in gastric ulcer pathogenesis. This work was planned to explore the role of iNOS/eNOS and ADMA/DDAH-1 signaling in rats with indomethacin-induced gastric ulcer, as potential pathways for the gastro-protective effect of tadalafil. Split into 5 separate groups, rats were assigned to control, tadalafil (10 mg/kg, p.o), indomethacin (single oral dose of 60 mg/kg), indomethacin + pantoprazole (40 mg/kg, p.o), and indomethacin + tadalafil (10 mg/kg, p.o). The results indicated that pretreatment with tadalafil significantly reduced ulcer index (UI), increased preventive index (PI), and counteracted indomethacin-induced histopathological aberrations. Tadalafil significantly reduced the gastric content of NO while it significantly elevated that of GSH and enhanced SOD activity. It significantly reduced the gastric expression of TNF-α and ADMA while it significantly elevated that of COX-2, PGE-2, and DDAH-1. Western blot analysis revealed that pretreatment with tadalafil significantly reduced iNOS protein expression while it significantly elevated that of eNOS. Collectively, these data suggest that tadalafil exerts potential protective effect against indomethacin-induced ulcer through suppression of inflammation, attenuation of oxidative stress, and boosting of antioxidants. Moreover, tadalafil protective effects are mediated via upregulation of PGE-2 with modulating the signaling pathways of ADMA/DDAH-1, and iNOS/eNOS. As a result, the current evidence corroborates the use of tadalafil in controlling gastric ulcers and preventing NSAID gastric side effects.