RESUMEN
As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC50 1.87 and 2.03 µM, respectively). 17b (IC50 0.078 µM) and 17 f (IC50 0.094 µM) inhibited ACE-1 comparable to perindopril (PER) (IC50 0.048 µM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Antiinflamatorios , Antihipertensivos , Inhibidores de la Ciclooxigenasa 2 , Pirazoles , Tetrazoles , Pirazoles/farmacología , Pirazoles/química , Animales , Antihipertensivos/farmacología , Antihipertensivos/química , Antihipertensivos/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Tetrazoles/farmacología , Tetrazoles/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Ratas , Diseño de Fármacos , Masculino , Antifibróticos/farmacología , Antifibróticos/química , Ciclooxigenasa 2/metabolismo , Presión Sanguínea/efectos de los fármacos , Humanos , Peptidil-Dipeptidasa A/metabolismoRESUMEN
Alzheimer's disease (AD) is a devastating neurological condition characterized by cognitive decline, motor coordination impairment, and amyloid plaque accumulation. The underlying molecular mechanisms involve oxidative stress, inflammation, and neuronal degeneration. This study aimed to investigate the therapeutic effects of mesenchymal stem cell-derived exosomes (MSC-exos) on AD and explore the molecular pathways involved, including the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation. To assess the potential of MSC-exos for the treatment of AD, rats were treated with AlCl3 (17â¯mg/kg/once/day) for 8 weeks, followed by the administration of an autophagy activator (rapamycin), or MSC-exos with or without an autophagy inhibitor (3-methyladenin; 3-MA+ chloroquine) for 4 weeks. Memory impairment was tested, and brain tissues were collected for gene expression analyses, western blotting, histological studies, immunohistochemistry, and transmission electron microscopy. Remarkably, the administration of MSC-exos improved memory performance in AD rats and reduced the accumulation of amyloid-beta (Aß) plaques and tau phosphorylation. Furthermore, MSC-exos promoted neurogenesis, enhanced synaptic function, and mitigated astrogliosis in AD brain tissues. These beneficial effects were associated with the modulation of autophagy and the PI3K/Akt/mTOR signalling pathway, as well as the inhibition of neuroinflammation. Additionally, MSC-exos were found to regulate specific microRNAs, including miRNA-21, miRNA-155, miRNA-17-5p, and miRNA-126-3p, further supporting their therapeutic potential. Histopathological and bioinformatic analyses confirmed these findings. This study provides compelling evidence that MSC-exos hold promise as a potential therapeutic approach for AD. By modulating the PI3K/Akt/mTOR axis, autophagy, and neuroinflammation, MSC-exos have the potential to improve memory, reduce Aß accumulation, enhance neurogenesis, and mitigate astrogliosis. These findings shed light on the therapeutic potential of MSC-exos and highlight their role in combating AD.
Asunto(s)
Enfermedad de Alzheimer , Autofagia , Exosomas , Células Madre Mesenquimatosas , Transducción de Señal , Animales , Masculino , Ratas , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/terapia , Autofagia/efectos de los fármacos , Autofagia/fisiología , Modelos Animales de Enfermedad , Exosomas/metabolismo , Insulina/metabolismo , Células Madre Mesenquimatosas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Renal fibrosis is the common endpoint of nearly all chronic and progressive nephropathies. Cell death and sterile inflammation are the main characteristics of renal fibrosis, which can lead to end-stage renal failure. The inflammatory reaction triggered by tissue damage is strongly related to necroptosis, a type of caspase-independent, regulated cell death. Using an animal model of unilateral ureteral obstruction (UUO), the anti-fibrotic effects of sorafenib (SOF), a multi-kinase inhibitor, and edaravone (EDV), a potent antioxidant and free radical scavenger, were examined in rats with obstructive nephropathy. Experimentally, animals were divided randomly into five groups: sham; UUO; UUO + SOF (5 mg/kg/day, P.O.); UUO + EDV (20 mg/kg/day, P.O.); and UUO + SOF + EDV groups. The kidney function biomarkers, oxidant/antioxidant status, renal mRNA expressions of TNF-α, collagen-1α, protein expressions of RIPK-1, RIPK-3, MLKL, caspase-8, HYP, MPO, and TNF-α were all significantly modulated by UUO. Administration of either SOF or EDV significantly attenuated cellular and molecular changes induced by UUO. Also, histopathological changes were improved. Moreover, SOF in combination with EDV, significantly improved UUO-induced renal fibrosis compared with each drug alone. Collectively, administration of either SOF or EDV or both of them significantly attenuated the rats with obstructive nephropathy, possibly by blocking the RIPK-3/MLKL necroptotic pathway and suppressing renal oxidative stress and inflammation.
RESUMEN
Liver cancer (LC) is the sixth most common disease and the third most common cause of cancer-related mortality. The WHO predicts that more than 1 million deaths will occur from LC by 2030. Hepatocellular carcinoma (HCC) is a common form of primary LC. Today, the management of LC involves multiple disciplines, and multimodal therapy is typically selected on an individual basis, considering the intricate interactions between the patient's overall health, the stage of the tumor, and the degree of underlying liver disease. Currently, the treatment of cancers, including LC, has undergone a paradigm shift in the last ten years because of immuno-oncology. To treat HCC, immune therapy approaches have been developed to enhance or cause the body's natural immune response to specifically target tumor cells. In this context, immune checkpoint pathway inhibitors, engineered cytokines, adoptive cell therapy, immune cells modified with chimeric antigen receptors, and therapeutic cancer vaccines have advanced to clinical trials and offered new hope to cancer patients. The outcomes of these treatments are encouraging. Additionally, treatment using stem cells is a new approach for restoring deteriorated tissues because of their strong differentiation potential and capacity to release cytokines that encourage cell division and the formation of blood vessels. Although there is no proof that stem cell therapy works for many types of cancer, preclinical research on stem cells has shown promise in treating HCC. This review provides a recent update regarding the impact of immunotherapy and stem cells in HCC and promising outcomes.
Asunto(s)
Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Trasplante de Células Madre , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/inmunología , Inmunoterapia/métodos , Animales , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/inmunologíaRESUMEN
Drug repurposing involves the investigation of existing drugs for new indications. It offers a great opportunity to quickly identify a new drug candidate at a lower cost than novel discovery and development. Despite the importance and potential role of drug repurposing, there is no specific definition that healthcare providers and the World Health Organization credit. Unfortunately, many similar and interchangeable concepts are being used in the literature, making it difficult to collect and analyze uniform data on repurposed drugs. This research was conducted based on understanding general criteria for drug repurposing, concentrating on liver diseases. Many drugs have been investigated for their effect on liver diseases even though they were originally approved (or on their way to being approved) for other diseases. Some of the hypotheses for drug repurposing were first captured from the literature and then processed further to test the hypothesis. Recently, with the revolution in bioinformatics techniques, scientists have started to use drug libraries and computer systems that can analyze hundreds of drugs to give a short list of candidates to be analyzed pharmacologically. However, this study revealed that drug repurposing is a potential aid that may help deal with liver diseases. It provides available or under-investigated drugs that could help treat hepatitis, liver cirrhosis, Wilson disease, liver cancer, and fatty liver. However, many further studies are needed to ensure the efficacy of these drugs on a large scale.
Asunto(s)
Reposicionamiento de Medicamentos , Hepatopatías , Reposicionamiento de Medicamentos/métodos , Humanos , Hepatopatías/tratamiento farmacológico , Biología Computacional/métodos , Descubrimiento de Drogas/métodosRESUMEN
Heavy metals are ubiquitous environmental toxicants that have been known to have a serious effect on human and animal health. Aluminum (Al) is a widely distributed metal in nature. Al exposure has a detrimental impact on human fertility. This review focused on Al-induced male reproductive toxicity and the potential therapeutic approaches with some phytochemicals. Data from the literature showed that Al exposure is accompanied by a drastic decline in blood levels of FSH, LH, and testosterone, reduced sperm count, and affected sperm quality. Al exposure at high levels can cause oxidative stress by increasing ROS and RNS production, mediated mainly by downregulating Nrf2 signaling. Moreover, several investigations demonstrated that Al exposure evoked inflammation, evidenced by increased TNF-α and IL-6 levels. Additionally, substantial evidence concluded the key role of apoptosis in Al-induced testicular toxicity mediated by upregulating caspase-3 and downregulating Bcl2 protein. The damaging effects of Al on mitochondrial bioenergetics are thought to be due to the excessive generation of free radicals. This review helps to clarify the main mechanism involved in Al-associated testicular intoxication and the treatment strategy to attenuate the notable harmful effects on the male reproductive system. It will encourage clinical efforts to target the pathway involved in Al-associated testicular intoxication.
Asunto(s)
Aluminio , Semen , Animales , Masculino , Humanos , Aluminio/toxicidad , Semen/metabolismo , Testículo , Estrés Oxidativo , Antioxidantes/farmacología , Intoxicación por Metales Pesados/metabolismo , Reproducción , Fitoquímicos/farmacología , Fitoquímicos/metabolismoRESUMEN
BACKGROUND: The incidence of diabetes mellitus (DM) is dramatically increasing worldwide, and it is expected to affect 700 million cases by 2045. Diabetes influences health care economics, human quality of life, morbidity, and mortality, which were primarily seen extensively in developing countries. Uncontrolled DM, which results in consistent hyperglycemia, may lead to severe life-threatening complications such as nephropathy, retinopathy, neuropathy, and cardiovascular complications. METHODOLOGY: In addition to traditional therapies with insulin and oral anti-diabetics, researchers have developed new approaches for treatment, including stem cell (SC) therapy, which exhibits promising outcomes. Besides its significant role in treating type one DM (T1DM) and type two DM (T2DM), it can also attenuate diabetic complications. Furthermore, the development of insulin-producing cells can be achieved by using the different types of SCs, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and multiple types of adult stem cells, such as pancreatic, hepatic, and mesenchymal stem cells (MSC). All these types have been extensively studied and proved their ability to develop insulin-producing cells, but every type has limitations. CONCLUSION: This review aims to enlighten researchers about recent advances in stem cell research and their potential benefits in DM and diabetic complications.
RESUMEN
Cardiotoxicity is a significant adverse effect of cisplatin (CIS) that necessitates extensive medical care. The current study examines the cardioprotective effects of edaravone (EDV), obeticholic acid (OCA), and their combinations on CIS-induced cardiac damage. Rats were allocated into five groups: the normal control group, the remaining four groups received CIS (7.5 mg/kg, i.p.) as a single dose on the fifth day and were assigned to CIS, OCA (10 mg/kg/day) + CIS, EDV (20 mg/kg/day) + CIS, and the (EDV + OCA) + CIS group. Compared to the CIS-treated group, co-treating rats with EDV, OCA, or their combinations significantly decreased ALP, AST, LDH, CK-MB, and troponin-I serum levels and alleviated histopathological heart abnormalities. Biochemically, EDV, OCA, and EDV plus OCA administration mitigated cardiac oxidative stress as indicated by a marked decrease in heart MDA content with a rise in cardiac antioxidants SOD and GSH associated with upregulating Nrf2, PPARγ, and SIRT1 expression. Besides, it dampened inflammation by decreasing cardiac levels of TNF-α, IL-1ß, and IL-6, mediated by suppressing NF-κB, JAK1/STAT3, and TLR4/p38MAPK signal activation. Notably, rats co-administered with EDV plus OCA showed noticeable protection that exceeded that of EDV and OCA alone. In conclusion, our study provided that EDV, OCA, and their combinations effectively attenuated CIS-induced cardiac intoxication by activating Nrf2, PPARγ, and SIRT1 signals and downregulating NF-κB, JAK1/STAT3, and TLR4/p38MAPK signals.
RESUMEN
Nephrotoxicity is a serious complication commonly encountered with gentamicin (GTM) treatment. Permeabilization of lysosomes with subsequent cytoplasmic release of GTM and cathepsins is considered a crucial issue in progression of GTM toxicity. This study was designed to evaluate the prospective defensive effect of lysosomal membrane stabilization by imipramine (IMP) against GTM nephrotoxicity in rats. GTM (30 mg/kg/h) was intraperitoneally administered over 4 h daily (120 mg/kg/day) for 7 days. IMP (30 mg/kg/day) was orally administered for 14 days; starting 7 days before and then concurrently with GTM. On 15th day, samples (urine, blood, kidney) were collected to estimate biomarkers of kidney function, lysosomal stability, apoptosis, and inflammation. IMP administration to GTM-treated rats ameliorated the disruption in lysosomal membrane stability induced by GTM. That was evidenced by enhanced renal protein expressions of LAMP2 and PI3K, but reduced cathepsin D cytoplasmic expression in kidney sections. Besides, IMP guarded against apoptosis in GTM-treated rats by down-regulation of the pro-apoptotic (tBid, Bax, cytochrome c) and the effector cleaved caspase-3 expressions, while the anti-apoptotic Bcl-2 expression was enhanced. Additionally, the inflammatory cascade p38 MAPK/NF-κB/TNF-α was attenuated in GTM + IMP group along with marked improvement in kidney function biomarkers, compared to GTM group. These findings were supported by the obvious improvement in histological architecture. Furthermore, in vitro enhancement of the antibacterial activity of GTM by IMP confers an additional benefit to their combination. Conclusively, lysosomal membrane stabilization by IMP with subsequent suppression of tBid/cytochrome c/cleaved caspase-3 apoptotic signaling could be a promising protective strategy against GTM nephrotoxicity.
Asunto(s)
Citocromos c , Imipramina , Ratas , Animales , Citocromos c/metabolismo , Imipramina/farmacología , Gentamicinas , Caspasa 3/metabolismo , Catepsina D , Regulación hacia Abajo , Estudios Prospectivos , Riñón/patología , Apoptosis , Lisosomas/metabolismo , Biomarcadores/metabolismo , Estrés OxidativoRESUMEN
Methotrexate (MTX) has long manifested therapeutic efficacy in several neoplastic and autoimmune disorders. However, MTX-associated intestinal toxicity restricts the continuation of treatment. Nifuroxazide (NIF) is an oral antibiotic approved for gastrointestinal infections as an effective antidiarrheal agent with a high safety profile. The current study was designed to explore the potential efficacy of NIF in alleviating intestinal toxicity associated with MTX chemotherapy with the elucidation of the proposed molecular mechanisms. Rats were administered NIF (50 mg/kg; p.o.) for ten days. On day five, a single i.p. injection of MTX (20 mg/kg) was given to induce intestinal intoxication. At the end of the experiment, duodenal tissue samples were isolated for biochemical, Western blotting, immunohistochemical (IHC), and histopathological analysis via H&E, PSA, and Alcian blue stains. NIF showed antioxidant enteroprotective effects against MTX intestinal intoxication through enhanced expression of the redox-sensitive signals of PPAR-γ, SIRT1, and Nrf2 estimated by IHC. Moreover, NIF down-regulated the pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6), NF-κB protein expression, and the phosphorylation of JAK1/STAT3 proteins, leading to mitigation of intestinal inflammation. In accordance, the histological investigation revealed that NIF ameliorated the intestinal pathological changes, preserved the goblet cells, and reduced the inflammatory cells infiltration. Therefore, NIF could be a promising candidate for adjunctive therapy with MTX to mitigate the associated intestinal injury and increase its tolerability.
Asunto(s)
Hidroxibenzoatos , Metotrexato , FN-kappa B , Nitrofuranos , Ratas , Animales , FN-kappa B/metabolismo , Metotrexato/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , PPAR gamma/metabolismo , Sirtuina 1/metabolismo , Antioxidantes/farmacología , Estrés OxidativoRESUMEN
Ulcerative colitis (UC) is one of the most common subtypes of inflammatory bowel disease (IBD) that affects the colon and is characterized by severe intestinal inflammation. Canagliflozin is a widely used antihyperglycemic agent, a sodium-glucose cotransporter-2 (SGLT2) inhibitor that enhances urinary glucose excretion. This study aims to provide insights into the potential benefits of canagliflozin as a treatment for UC by addressing possible cellular signals. Acetic acid (AA; 4% v/v) was administered intrarectally to induce colitis. Canagliflozin is given orally at a dose of 10 mg/kg/day. Canagliflozin attenuates inflammation in AA-induced colitis, evidenced by significant and dose-dependently downregulation of p38 MAPK, NF-κB-p65, IKK, IRF3, and NADPH-oxidase as well as colonic levels of IL-6 and IL-1ß and MPO enzymatic activity. Canagliflozin mitigates colonic oxidative stress by decreasing MDA content and restoring SOD enzymatic activities and GSH levels mediated by co-activating of Nrf2, PPARγ, and SIRT1 pathways. Moreover, an in-silico study confirmed that canagliflozin was specific to all target proteins in this study. Canagliflozin's binding affinity with its target proteins indicates and confirms its effectiveness in regulating these pathways. Also, network pharmacology analysis supported that canagliflozin potently attenuates UC via a multi-target and multi-pathway approach.
Asunto(s)
Colitis Ulcerosa , FN-kappa B , Humanos , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Glucosa/metabolismo , Inflamación/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , PPAR gamma/metabolismo , Transducción de Señal , Sirtuina 1/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Amphotericin B (AmB)-induced acute kidney injury (AKI) is a common health problem having an undesirable impact on its urgent therapeutic utility for fatal systemic fungal infections. Tadalafil (TAD), a phosphodiesterase-5 (PDE-5) inhibitor, has been observed to have a wide range of pharmacological actions, including nephroprotection. The study's objective was to examine the possible underlying protective mechanism of TAD against AmB-induced nephrotoxicity. Experimentally, animals were divided randomly into four groups: control, TAD (5 mg/kg/day; p.o.), AmB (18.5 mg/kg/day; i.p.), and TAD+AmB groups. Sera and tissue samples were processed for biochemical, molecular, and histological analyses. The biochemical investigations showed that TAD significantly ameliorated the increase of kidney function biomarkers (creatinine, urea, CysC, KIM-1) in serum, renal nitric oxide (NO), lipid peroxidation (MDA), and inflammatory cytokines (TNF-α, IL-6) in AmB-treated rats. Meanwhile, TAD significantly retarded AmB-induced decrease in serum magnesium, sodium, potassium, and renal glutathione content. Molecular analysis revealed that TAD reduced AmB-induced imbalance in the protein expression of eNOS/iNOS, which explains its regulatory effect on renal NO content. These results were also supported by the down-regulation of nuclear NF-κB p65 and cleaved caspase-3 protein expressions, as well as the improvement of histological features by TAD in AmB-treated rats. Therefore, it can be suggested that TAD could be a promising candidate for renoprotection against AmB-induced AKI. That could be partly attributed to its regulatory effect on renal eNOS/iNOS balance and NO, the inhibition of NF-κB p65 nuclear translocation, its downstream inflammatory cytokines and iNOS, and ultimately the inhibition of caspase-3-induced renal apoptosis.
RESUMEN
Cadmium (Cd) is one of the most abundant toxic heavy metals, and its exposure is linked to serious kidney intoxication, a major health problem. Evidence reported that inflammatory damage is a key factor in Cd renal intoxication. Perindopril (PER) is an angiotensin-converting enzyme inhibitor approved for treating hypertension and other cardiovascular problems. Significantly, RAS activation results in inflammatory damage. Our study aimed to examine the renoprotective effects of PER in Cd-induced nephrotoxicity, the impact of inflammation, and the underlying molecular mechanisms. PER was given at a dose of 1 mg/kg per day. Cd was injected at a dose of 1.2 mg/kg, as a single dose. Treatment with PER led to a significant decrease in serum levels of urea, creatinine, uric acid, and urine albumin/creatinine ratio. PER effectively mitigated inflammation by decreasing MPO, NO, IL-1ß, IL-6, and INF-γ levels mediated by downregulating NF-κB expression and suppressing JAK-1 and STAT3 phosphorylation. PER modulates Ang II/Ang 1-7 axis in Cd-intoxicated rats by decreasing Ang II expression and increasing Ang-(1-7) expression. PER inhibits Cd-induced apoptosis by lowering Bax, cytochrome c, and cleaved caspase 3 expressions while increasing Bcl-2 expression. In conclusion, PER dampens Cd-induced kidney intoxication by modulating Ang II/Ang 1-7 axis, suppressing NF-κB, JAK-1/STAT3, and apoptosis signals.
RESUMEN
Cisplatin is a chemotherapeutic agent usually used in treating different patterns of malignancies. One of the significant apparent complications of cisplatin chemotherapy is brain toxicity. The present study was conducted to evaluate the protective effects of lansoprazole on cisplatin-induced cortical intoxication. Thirty-two rats were allocated into four groups (8 rats/group); group I: received only a vehicle for 10 days, group II: lansoprazole was administered (50 mg/kg) via oral gavage for 10 days, group III: On 5th day of the experiment, rats were given cisplatin (10 mg/kg) i.p. once to induce cortical injury. Group IV: rats were given lansoprazole for 5 days before cisplatin and 5 days afterward. Lansoprazole administration significantly improved cisplatin-induced behavioral changes, as evidenced by decreasing the immobility time in forced swimming and open field tests. Besides, lansoprazole improved cortical histological changes, restored cortical redox balance, enhanced Nrf2/ARE expression, cisplatin-induced neuronal apoptosis, and dampened cisplatin inflammation. In addition, lansoprazole modulated cortical Akt/p53 signal. The present work was the first to show that lansoprazole co-administration reduced cortical toxicity in cisplatin-treated rats via multiple signaling pathways. The current findings provided crucial information for developing novel protective strategies to reduce cisplatin cortical toxicity.
Asunto(s)
Cisplatino , Fármacos Neuroprotectores , Ratas , Animales , Cisplatino/toxicidad , Fármacos Neuroprotectores/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Lansoprazol/farmacología , Lansoprazol/uso terapéutico , Transducción de Señal , Apoptosis , Encéfalo/metabolismo , Estrés OxidativoRESUMEN
Intestinal injury is a common adverse effect of methotrexate (MTX) therapy, limiting its clinical use. Despite oxidative stress and inflammation being the most embedded mechanism of injury, pharmacological agents that exhibit antioxidant and anti-inflammatory impacts could prevent such toxicities. This study aimed to assess the enteroprotective effect of lactobacillus acidophilus (LB) and/or umbelliferone (UMB) against MTX-induced intestinal injury. Histologically, pretreatment with LB, UMB, or their combinations preserve the intestinal histological structure and mucin content with superior effect in combination therapy. In addition, oral pretreatment with UMB, LB, or their combinations significantly restored oxidant/antioxidant status, as evidenced by the upregulation of Nrf2, SOD3, HO-1, GSH, and GST levels concurrent with a decline in MDA contents. Besides, they suppressed the inflammatory burden by inhibiting STAT3, MPO, TLR4, NF-κB, TNF-α, and IL-6 levels. Moreover, LB, UMB, or their combinations significantly upregulated Wnt and ß-catenin expression. Notably, pretreatment with the combination therapy is superior to monotherapy in protecting rats' small intestines from MTX-induced enteritis. In conclusion, combined pretreatment with LB and UMB could be a novel therapeutic regimen for conditions of intestinal injury induced by MTX via restoring oxidant/antioxidant balance and suppressing inflammatory burden.
Asunto(s)
Antioxidantes , Metotrexato , Ratas , Animales , Antioxidantes/farmacología , Antioxidantes/metabolismo , Metotrexato/toxicidad , Transducción de Señal , Lactobacillus acidophilus/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Oxidantes/farmacología , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
The present study was designed to evaluate the potential renoprotective impacts of apocynin (APC) against nephrotoxicity induced by methotrexate (MTX) administration. To fulfill this aim, rats were allocated into four groups: control; APC (100 mg/kg/day; orally); MTX (20 mg/kg; single intraperitoneal dose at the end of the 5th day of the experiment); and APC +MTX (APC was given orally for 5 days before and 5 days after induction of renal toxicity by MTX). On the 11th day, samples were collected to estimate kidney function biomarkers, oxidative stress, pro-inflammatory cytokines, and other molecular targets. Compared to the MTX control group, treatment with APC significantly decreased urea, creatinine, and KIM-1 levels and improved kidney histological alterations. Furthermore, APC restored oxidant/antioxidant balance, as evidenced by a remarkable alleviation of MDA, GSH, SOD, and MPO levels. Additionally, the iNOS, NO, p-NF-κB-p65, Ace-NF-κB-p65, TLR4, p-p38-MAPK, p-JAK1, and p-STAT-3 expressions were reduced, while the IκBα, PPAR-γ, SIRT1, and FOXO3 expressions were significantly increased. In NRK-52E cells, MTX-induced cytotoxicity was protected by APC in a concentration-dependent manner. In addition, increased expression of p-STAT-3 and p-JAK1/2 levels were reduced in MTX-treated NRK-52E cells by APC. The in vitro experiments revealed that APC-protected MTX-mediated renal tubular epithelial cells were damaged by inhibiting the JAK/STAT3 pathway. Besides, our in vivo and in vitro results were confirmed by predicting computational pharmacology results using molecular docking and network pharmacology analysis. In conclusion, our findings proved that APC could be a good candidate for MTX-induced renal damage due to its strong antioxidative and anti-inflammatory bioactivities.
Asunto(s)
Metotrexato , FN-kappa B , Ratas , Animales , Metotrexato/toxicidad , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Interleucina-6/metabolismo , PPAR gamma/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Sirtuina 1/metabolismo , Simulación del Acoplamiento Molecular , Transducción de Señal , Antioxidantes/farmacología , Antioxidantes/metabolismo , Estrés OxidativoRESUMEN
Cardiac toxicity is a public health issue that can be caused by both environmental and occupational exposures. The current study aimed to investigate the effectiveness of carvedilol (CV), Acetovanillone (ACET), and their combination for ameliorating cadmium (Cd)-induced oxidative stress, inflammation, and necroptosis. Rats were assigned to; the normal group, Cd group (2 mg/kg; i.p., single dose), and the other three groups received orally CV (10 mg/kg), ACET (25 mg/kg), and CV plus ACET, respectively and a single dose of Cd. Oral administration of CV, ACET, and their combination significantly dampens cardiac oxidative injury by increasing antioxidants GSH and SOD levels, while it decreases MDA and NADPH oxidase levels mediated by decreasing cardiac abundance of Nrf2, HO-1, and SIRT1 and downregulating KEAP-1 and FOXO-3 levels. Also, they significantly attenuated inflammatory response as indicated by reducing MPO and NOx as well as proinflammatory cytokines TNF-α and IL-6 mediated by downregulating TLR4, iNOS, and NF-κB proteins expression as well as IκB upregulation. Moreover, they potently counteracted cardiac necroptosis by downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins expression. Of note, the combination of CV and ACET have marked protection that exceeded each drug alone. Conclusively, CV ad ACET potently mitigated Cd-induced cardiac intoxication by regulating NADPH oxidase, KEAP-1/Nrf2/HO-1, SIRT1/FOXO-3, TLR4/NF-κB/iNOS, and RIPK1/RIPK3/MLKL signals.
Asunto(s)
Cadmio , Lesiones Cardíacas , Ratas , Animales , Carvedilol/farmacología , Cadmio/toxicidad , FN-kappa B/metabolismo , Sirtuina 1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Receptor Toll-Like 4/metabolismo , Estrés Oxidativo , Transducción de Señal , Antioxidantes/farmacología , Antioxidantes/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , NADPH Oxidasas/metabolismoRESUMEN
One of the significant health issues in the world is the prevalence of ulcerative colitis (UC). UC is a chronic disorder that mainly affects the colon, beginning with the rectum, and can progress from asymptomatic mild inflammation to extensive inflammation of the entire colon. Understanding the underlying molecular mechanisms of UC pathogenesis emphasizes the need for innovative therapeutic approaches based on identifying molecular targets. Interestingly, in response to cellular injury, the NLR family pyrin domain containing 3 (NLRP3) inflammasome is a crucial part of the inflammation and immunological reaction by promoting caspase-1 activation and the release of interleukin-1ß. This review discusses the mechanisms of NLRP3 inflammasome activation by various signals and its regulation and impact on UC.
Asunto(s)
Colitis Ulcerosa , Colitis , Humanos , Inflamasomas , Colitis Ulcerosa/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR , InflamaciónRESUMEN
Renal ischemia/reperfusion (IR) injury is characterized by an unexpected impairment of blood flow to the kidney. Azilsartan is an angiotensin receptor blocker that is approved for the management of hypertension. The present study aimed to investigate, on molecular basics, the nephroprotective activity of azilsartan on renal IR injury in rats. Rats were assigned into four groups: (1) Sham group, (2) Azilsartan group, (3) IR group, and (4) IR/Azilsartan-treated group. Histological examination and renal function were evaluated. Levels of KIM-1, HMGB1, caspase 3, GPX, SOD, NF-κB, and p53 proteins were investigated using ELISA. mRNA levels of IL-1ß, IL6, IL10, TNF-α, NF-κB, p53, and bax were assessed by qRT-PCR. Expression of p38, JNK, and ERK1/2 proteins was investigated by Western blotting. IR injury resulted in tissue damage, elevation of creatinine, BUN, KIM-1, HMGB1, caspase 3, NF-κB, and p53 levels, decreasing GPX and SOD activities, and up-regulation of NF-κB, IL-1ß, IL6, TNF-α, p53, and bax genes. Furthermore, it up-regulated the expression of phosphorylated/total ratio of p38, ERK1/2, and JNK proteins. Interestingly, treatment of the injured rats with azilsartan significantly alleviated IR injury-induced histopathological and biochemical changes. It reduced the creatinine, BUN, KIM-1, HMGB1, caspase-3, NF-κB, and p53 levels, elevated GPX and SOD activities, down-regulated the expression of NF-κB, IL-1ß, IL6, TNF-α, p53, and bax genes, and up-regulated IL10 gene expression. Furthermore, it decreased the phosphorylated/total ratio of p38, ERK1/2, and JNK proteins. Azilsartan exhibited nephroprotective activity in IR-injured rats via its antioxidant effect, suppression of inflammation, attenuation of apoptosis, and inhibition of HMGB1/NF-κB/p38/ERK1/2/JNK signaling pathway.