RESUMEN
Nephrotoxicity is a common side effect arising from exposure to drugs or toxins. The study investigates the therapeutic effects of Thunbergia alata and Thunbergia erecta flowers on diclofenac-induced renal injury. Secondary metabolite characterization by positive mode high-resolution-ESI (LC-HR-ESI-MS) was followed by assessing their renal protection against diclofenac-induced damage and molecular docking studies. Using positive LC-HR-ESI-MS, 18 compounds from T. erecta and T. alata were identified. Diclofenac administration induced significant deterioration of all parameters in the kidney in addition to renal tissue contents of several inflammatory markers. The flower extracts of T. alata and T. erecta showed a clear improvement in the treated groups compared to the diclofenac-control group. The results were confirmed by histopathological examinations followed by immunohistochemical determination of vascular endothelial growth factor (VEGF), nuclear factor erythroid 2-related factor 2 (Nrf2), and transforming growth factor beta 1 (TGF-ß1) expression. Furthermore, a protein-protein network to understand the complex interplay between the target proteins and their counterparts was done in addition to a molecular docking study of the de-replicated compounds in the active sites of NF-κB, TGF-ß1, and VEGFR.
RESUMEN
Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis of lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 are considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, this study aimed to elucidate the antibacterial effect of alirocumab against E. coli in vitro. Additionally, evaluation of the potential nephroprotective effects of alirocumab against LPS-induced AKI in rats, highlighting the potential underlying mechanisms involved in these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; was a normal control group, whereas sepsis-mediated AKI was induced in groups II and III through single-dose intraperitoneal injection of LPS on day 16. In group III, animals were given alirocumab. The results revealed that LPS-induced AKI was mitigated by alirocumab, evidenced by amelioration in renal function tests (creatinine, cystatin C, KIM-1, and NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, and MDA); apoptotic markers and renal histopathological findings. Besides, alirocumab pronouncedly hindered LPS-mediated inflammatory response, confirmed by diminishing HMGB1, TNF-α, IL-1ß, and caspase-1 contents; the gene expression of PCSK9, RAGE, NF-á´B and Fractalkine/CX3CR1, along with mRNA expression of TLR4, MYD88, and NLRP3. Regarding the antibacterial actions, results showed that alirocumab displayed potential anti-bacterial activity against pathogenic gram-negative E. coli. In conclusion, alirocumab elicited nephroprotective activities against LPS-induced AKI via modulation of Nrf2/HO-1, PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-á´B/NLRP3/Caspase-1, Fractalkine/CX3R1 and apoptotic axes.
Asunto(s)
Lesión Renal Aguda , Anticuerpos Monoclonales Humanizados , Antioxidantes , Receptor 1 de Quimiocinas CX3C , Quimiocina CX3CL1 , Proteína HMGB1 , Hemo Oxigenasa (Desciclizante) , Factor 2 Relacionado con NF-E2 , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Wistar , Sepsis , Transducción de Señal , Animales , Masculino , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Proteína HMGB1/metabolismo , Quimiocina CX3CL1/metabolismo , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Hemo Oxigenasa (Desciclizante)/metabolismo , Anticuerpos Monoclonales Humanizados/farmacología , FN-kappa B/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/farmacología , Receptor 1 de Quimiocinas CX3C/metabolismo , Transducción de Señal/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Modelos Animales de Enfermedad , Lipopolisacáridos , Inhibidores de PCSK9 , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Proproteína Convertasa 9/metabolismo , Proproteína Convertasa 9/genética , Estrés Oxidativo/efectos de los fármacos , Antiinflamatorios/farmacologíaRESUMEN
Multiple sclerosis (MS) is a progressive neuro-inflammatory and neuro-autoimmune disease. Although hydrogen sulfide has recently shown potential therapeutic impacts in different neurological diseases, its effects on MS are still obscure. MiR-146a is considered a vital target for different therapeutic approaches in treating MS. The present study is directed to explore the therapeutic effects of NaHS (hydrogen sulfide donor) on cuprizone-induced MS and to explore whether NaHS can mediate its effects via regulating miR-146a expression. A total of 28 male C57Bl/6 mice were divided into 4 groups; control, cuprizone-intoxicated, NaHS control (100 µmol/kg/day, i.p), and NaHS-treated groups. Intriguingly, NaHS treatment managed to improve locomotor coordination and curb neuronal inflammation and demyelination as evidenced by hematoxylin & eosin, and Luxol fast blue staining and the increased myelin basic protein (MBP) content. Additionally, NaHS reduced interleukin-1 receptor-associated kinase-1 (IRAK-1), nuclear transcription factor kappa B (NF-κB), interleukin (IL)-17, and IL-1ß brain levels along with downregulation of miR-146a expression compared with the untreated cuprizone-intoxicated group. Furthermore, NaHS-treated animals revealed much less oxidative stress compared to the untreated animals as evidenced by elevated glutathione and reduced malondialdehyde contents. Altogether, the current work reported that NaHS could improve motor dysfunction and reduce axonal demyelination, oxidative stress, as well as neuro-inflammation in mice with MS. Thus, using H2S-releasing compounds could be a promising approach in MS treatment strategies. The mechanism of these beneficial effects may involve the regulation of miR-146a/NF-κB/IL-1ß axis.
Asunto(s)
Sulfuro de Hidrógeno , MicroARNs , Esclerosis Múltiple , Masculino , Ratones , Animales , Sulfuro de Hidrógeno/farmacología , Esclerosis Múltiple/tratamiento farmacológico , FN-kappa B/metabolismo , Cuprizona , Inflamación , Ratones Endogámicos C57BLRESUMEN
Ivermectin is a US Food and Drug Administration (FDA)-approved antiparasitic agent with antiviral and anti-inflammatory properties. Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries, its potential therapeutic effect on pulmonary fibrosis (PF) has not been investigated. This study aimed to explore the ability of ivermectin (0.6 mg/kg) to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model. This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF. The results showed that ivermectin mitigated the bleomycin-evoked pulmonary injury, as manifested by the reduced infiltration of inflammatory cells, as well as decreased the inflammation and fibrosis scores. Intriguingly, ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-|ß1 (TGF-|ß1) and fibronectin protein expression, highlighting its anti-fibrotic activity. This study revealed for the first time that ivermectin can suppress the nucleotide-binding oligomerization domain (NOD)|-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, as manifested by the reduced gene expression of NLRP3 and the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), with a subsequent decline in the interleukin|-|1ß (IL|-|1ß) level. In addition, ivermectin inhibited the expression of intracellular nuclear factor-|κB (NF|-|κB) and hypoxiainducible factor1α (HIF|-|1α) proteins along with lowering the oxidative stress and apoptotic markers. Altogether, this study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin. These beneficial effects were mediated, at least partly, via the downregulation of TGF-|ß1 and fibronectin, as well as the suppression of NLRP3 inflammasome through modulating the expression of HIF1α and NF-|κB.
Asunto(s)
Inflamasomas , Fibrosis Pulmonar , Animales , Ratas , Antiinflamatorios , Bleomicina/toxicidad , Fibronectinas/metabolismo , Fibrosis , Inflamasomas/metabolismo , Ivermectina/efectos adversos , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológicoRESUMEN
Background and Objectives: Fibrotic lung disease is one of the main complications of many medical conditions. Therefore, the use of anti-fibrotic agents may provide a chance to prevent, or at least modify, such complication. The aim of this study was to evaluate the protective pulmonary anti-fibrotic and anti-inflammatory effects of Dinebra retroflexa. Materials and methods: Dinebra retroflexa methanolic extract and its synthesized silver nanoparticles were tested on bleomycin-induced pulmonary fibrosis. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/5 mL/kg-Saline) as a supposed model for induced lung fibrosis. The weed evaluation was performed by intratracheal instillation of Dinebra retroflexa methanolic extract and its silver nanoparticles (35 mg/100 mL/kg-DMSO, single dose). Results: The results showed that both Dinebra retroflexa methanolic extract and its silver nanoparticles had a significant pulmonary fibrosis retraction potential, with Ashcroft scores of three and one, respectively, and degrees of collagen deposition reduction of 33.8 and 46.1%, respectively. High-resolution UHPLC/Q-TOF-MS/MS metabolic profiling and colorimetrically polyphenolic quantification were performed for further confirmation and explanation of the represented effects. Such activity was believed to be due to the tentative identification of twenty-seven flavonoids and one phenolic acid along with a phenolic content of 57.8 mg/gm (gallic acid equivalent) and flavonoid content of 22.5 mg/gm (quercetin equivalent). Conclusion: Dinebra retroflexa may be considered as a promising anti-fibrotic agent for people at high risk of complicated lung fibrosis. The results proved that further clinical trials would be recommended to confirm the proposed findings.
Asunto(s)
Nanopartículas del Metal , Fibrosis Pulmonar , Humanos , Ratas , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Bleomicina/efectos adversos , Nanopartículas del Metal/uso terapéutico , Plata/farmacología , Suiza , Espectrometría de Masas en Tándem , Fitoterapia , Pulmón/patologíaRESUMEN
Insulin resistance is known to be a risk factor for cognitive impairment, most likely linked to insulin signaling, microglia overactivation, and beta amyloid (Aß) deposition in the brain. Exenatide, a long lasting glucagon-like peptide-1 (GLP-1) analogue, enhances insulin signaling and shows neuroprotective properties. Pioglitazone, a peroxisome proliferated-activated receptor-γ (PPAR-γ) agonist, was previously reported to enhance cognition through its effect on Aß accumulation and clearance. In the present study, insulin resistance was induced in male rats by drinking fructose for 12 weeks. The effect of monotherapy with pioglitazone (10 mg·kg(-1)) and exenatide or their combination on memory dysfunction was determined and some of the probable underlying mechanisms were studied. The current results confirmed that (1) feeding male rats with fructose syrup for 12 weeks resulted in a decline of learning and memory registered in eight-arm radial maze test; (2) treatment with pioglitazone or exenatide enhanced cognition, reduced hippocampal neurodegeneration, and reduced hippocampal microglia expression and beta amyloid oligomer deposition in a manner that is equal to monotherapies. These results may give promise for the use of pioglitazone or exenatide for ameliorating the learning and memory deficits associated with insulin resistance in clinical setting.