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ETHNOPHARMACOLOGICAL RELEVANCE: Trifolium alexandrinum L. (TA), has traditionally been used in folk medicine for its anti-inflammatory properties against hyperuricemia and gout. However, the specific mechanisms of action of TA have not been thoroughly studied. AIM OF THE WORK: This study aimed to evaluate the protective effects of irradiated (TR25) and non-irradiated (TR0) Trifolium alexandrinum L. aqueous extract (TAAE), along with two isolated compounds, caffeine (CAF) and saponin (SAP), in a rat model of acute gouty arthritis (GA). MATERIALS AND METHODS: The GA model was established by injecting a monosodium urate (MSU) suspension into the knee joint. Synovial tissue pathology was assessed, and levels of TNF-α, IL-6, IL-1ß, NF-κB, mTOR, AKT1, PI3K, NLRP3, and ASC were measured by ELISA. mRNA expression of ERK1, JNK, and p-38 MAPK was detected using qRT-PCR, and Caspase-1 protein expression was assessed by immunohistochemical analysis. Knee swelling, uric acid levels, liver and kidney function, and oxidative stress markers were also evaluated. RESULTS: TAAE analysis identified 170 compounds, with 73 successfully identified using LC-HR-MS/MS, including caffeine citrate and theasapogenol B glycoside as the main constituents. The studied materials demonstrated significant protective effects against GA. TR25 administration significantly mitigated knee joint circumference compared to other treatments. It demonstrated potential in alleviating hyperuricemia, renal and hepatic impairments induced by MSU crystals. TR25 also alleviated oxidative stress and reduced levels of IL1ß, IL-6, TNF-α, and NF-κB. Weak Caspase-1 immune-positive staining was observed in the TR25 group. TR25 decreased NLRP3 and ASC expression, reducing inflammatory cytokine levels in GA. It effectively inhibited the PI3K, AKT, and mTOR signaling pathways, promoting autophagy. Additionally, TR25 suppressed ERK1, JNK, and p-38 MAPK gene expression in synovial tissue. These effects were attributed to various components in TAAE, such as flavonoids, phenolic acids, tannins, alkaloids, and triterpenes. CONCLUSION: Importantly, irradiation (25 KGy) enhanced the antioxidant effects and phtchemical contents of TAAE. Additionally, TR0, TR25, CAF, and SAP exhibited promising protective effects against GA, suggesting their therapeutic potential for managing this condition. These effects were likely mediated through modulation of the NLRP3/ASC/Caspase-1 and ERK/JNK/p-38 MAPK signaling pathways, as well as regulation of the PI3K/AKT/mTOR pathway. Further research is warranted to fully elucidate the underlying mechanisms and optimize their clinical applications.
Assuntos
Artrite Gotosa , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Extratos Vegetais , Animais , Artrite Gotosa/tratamento farmacológico , Artrite Gotosa/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Caspase 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ácido ÚricoRESUMO
The present study explored the effectiveness of bile-salt-based nano-vesicular carriers (bilosomes) for delivering anti-psychotic medication, Sulpiride (Su), via the skin. A response surface methodology (RSM), using a 33 Box-Behnken design (BBD) in particular, was employed to develop and optimize drug-loaded bilosomal vesicles. The optimized bilosomes were assessed based on their vesicle size, entrapment efficiency (% EE), and the amount of Sulpiride released. The Sulpiride-loaded bilosomal gel was generated by incorporating the optimized Su-BLs into a hydroxypropyl methylcellulose polymer. The obtained gel was examined for its physical properties, ex vivo permeability, and in vivo pharmacokinetic performance. The optimum Su-BLs exhibited a vesicle size of 211.26 ± 10.84 nm, an encapsulation efficiency of 80.08 ± 1.88% and a drug loading capacity of 26.69 ± 0.63%. Furthermore, the use of bilosomal vesicles effectively prolonged the release of Su over a period of twelve hours. In addition, the bilosomal gel loaded with Su exhibited a three-fold increase in the rate at which Su transferred through the skin, in comparison to oral-free Sulpiride. The relative bioavailability of Su-BL gel was almost four times as high as that of the plain Su suspension and approximately two times as high as that of the Su gel. Overall, bilosomes could potentially serve as an effective technique for delivering drugs through the skin, specifically enhancing the anti-psychotic effects of Sulpiride by increasing its ability to penetrate the skin and its systemic bioavailability, with few adverse effects.
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BACKGROUND: Tamoxifen (TAM) is a chemotherapeutic drug widely utilized to treat breast cancer. On the other hand, it exerts deleterious cellular effects in clinical applications as an antineoplastic agent, such as liver damage and cirrhosis. TAM-induced hepatic toxicity is mainly attributed to oxidative stress and inflammation. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, is utilized to treat diabetes mellitus type-2. PIO has been reported to exert anti-inflammatory and antioxidant effects in different tissues. This research assessed the impact of PIO against TAM-induced hepatic intoxication. METHODS: Rats received PIO (10 mg/kg) and TAM (45 mg/kg) orally for 10 days. RESULTS: TAM increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT), triggered several histopathological alterations, NF-κB p65, increased hepatic oxidative stress, and pro-inflammatory cytokines. PIO protects against TAM-induced liver dysfunction, reduced malondialdehyde (MDA), and pro-inflammatory markers along with improved hepatic antioxidants. Moreover, PIO, increased hepatic Bcl-2 expression while reducing Bax expression and caspase-3 levels. In addition, PIO decreased Keap-1, Notch1, and Hes-1 while upregulated HO-1, Nrf2, and SIRT1. Molecular docking showed the binding affinity of PIO for Keap-1, NF-κB, and SIRT1. CONCLUSION: PIO mitigated TAM hepatotoxicity by decreasing apoptosis, inflammation, and oxidative stress. The protecting ability of PIO was accompanied by reducing Keap-1 and NF-κB and regulating Keap1/Nrf2/HO-1 and Sirt1/Notch1 signaling. A schematic diagram illustrating the protective effect of PIO against TAM hepatotoxicity. PIO prevented TAM-induced liver injury by regulating Nrf2/HO-1 and SIRT1/Notch1 signaling and mitigating oxidative stress, inflammation, and apoptosis.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatopatias , Ratos , Animais , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Pioglitazona/farmacologia , Pioglitazona/metabolismo , Pioglitazona/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Sirtuína 1/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Transdução de Sinais , Antioxidantes/metabolismo , Fígado/metabolismo , Estresse Oxidativo , Inflamação/metabolismo , Hepatopatias/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismoRESUMO
BACKGROUND: The use of cyclophosphamide (CP) as a chemotherapeutic agent is limited by its major complication haemorrhagic cystitis (HC). Finding preventive, safe, and efficient treatments for such problems is extensively ongoing. OBJECTIVE: This research aims to assess the uroprotective effect of pramipexole (PPX) and/or lactoferrin (LF) against CP-induced HC, in addition to shedding light on their possible molecular targets. METHODS: Adult male Sprague-Dawley rats were orally administered PPX (3 mg/kg) and/or LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg). RESULTS: Pretreatment of CP-intoxicated rats with either PPX or LF mitigated oxidative urinary bladder damage via upregulation of the Nrf2/HO-1 signalling pathway, resulting in a significant reduction in bladder MDA and 8-OHdG levels with concomitant elevations in SOD activity and GSH content. Simultaneously, both drugs markedly halted inflammation in bladder tissue through inhibition of the TLR4/NF-κB signalling pathway, followed by a significant decrease in inflammatory cytokine levels (TNF-α and IL-6). Interestingly, the PPX/LF protocol downregulated p-p38, p-ERK1/2, Sphk1, and S1P protein expression and inhibited the NLRP3/caspase1/IL-1ß axis. PPX/LF also significantly reduced BAX and caspase-3, in addition to increasing Bcl-2 levels in bladder tissue of CP-treated animals. These biochemical findings were supported by the improvement in the histological alterations induced by CP in the urinary bladder. CONCLUSIONS: The current study verified the protective effect of PPX and LF against CP-induced HC by halting oxidative stress, inflammation, and apoptosis. The molecular mechanism underlying this protective effect may involve targeting the crosstalk among Sphk1/S1P/MAPK/NF-κB, TLR-4/NF-κB, and NLRP3/caspase-1/IL-1ß signalling pathways and modulating the Nrf2/HO-1 signalling pathway.
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Cistite , Fator 2 Relacionado a NF-E2 , Animais , Masculino , Ratos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Caspase 3/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pramipexol/efeitos adversos , Lactoferrina/uso terapêutico , Caspase 1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Interleucina-6/metabolismo , Ratos Sprague-Dawley , Ciclofosfamida/efeitos adversos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Citocinas/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Ischemia-reperfusion injury (IRI) is typically associated with a vigorous inflammatory and oxidative stress response to hypoxia and reperfusion that disturbs the function of the organ. The remote effects of renal IRI on the liver, however, require further study. Renal damage associated with liver disease is a common clinical problem. Colchicine, a polymerization inhibitor of microtubules, has been used as an anti-inflammatory and anti-fibrotic drug for liver diseases. The goal of the current study was to investigate the possible protective mechanisms of colchicine on liver injury following renal IRI. Forty rats were divided randomly into four groups: sham group, colchicine-treated group, IRI group, and colchicine-treated + IRI group. Treatment with colchicine significantly reduced hepatic toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) transcription factor, myeloid differentiation factor 88 (MyD88), and tumor necrosis factor-alpha (TNF-α) contents; downregulated BCL2 associated X apoptosis regulator (BAX) gene expression, transforming growth factor-ß (TGF-ß) content, and upregulated hepatic B cell lymphoma 2 (Bcl-2) gene expression as compared with the IRI group. Finally, hepatic histopathological examinations have confirmed the biochemical results. Renal IRI-induced liver damage in rats was alleviated by colchicine through its anti-inflammatory, anti-apoptotic, and anti-fibrotic actions.
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Colchicina/farmacologia , Colchicina/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Nefropatias/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Animais , Anti-Inflamatórios , Antifibróticos , Apoptose/efeitos dos fármacos , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologiaRESUMO
INTRODUCTION: Parkinsonism is a neurodegenerative disorder. Pomegranate (POM) has been previously shown to have a dopaminergic neuroprotective effect against parkinsonism. OBJECTIVE: The aim of the current study is to investigate the possible effect of POM in combination with each of vinpocetine, propolis, or cocoa in the treatment of parkinsonism disease even without being given as adjuvant to L-dopa . METHODS: Rats were divided into seven groups, one normal and six RT model groups. One of the RT groups (2.5 mg/kg/48 h/10 doses sc), for 20 days served as non-treated parkinsonism model, whereas the others were treated with either L-dopa (10 mg/kg, p.o./day) or with POM (150 mg/kg, p.o./day) together with each of the following; vinpocetine (VIN) (20 mg/kg, p.o./day), propolis (300 mg/kg, p.o./day), cocoa (24 mg/kg, p.o./day). Motor and cognitive performances were examined using four tests (catalepsy, swimming, Y-maze, open field). Striatal dopamine, norepinephrine, serotonin, GABA, glutamate, acetylcholinesterase, GSK-3ß, BDNF levels were assessed as well as MDA, SOD, TAC, IL-1ß, TNF-α, iNOs, and caspase-3. Also, histopathological examinations of different brain regions were determined. RESULTS: Treatment with L-dopa alone or with all POM combination groups alleviated the deficits in locomotor activities, cognition, neurotransmitter levels, acetylcholinesterase activity, oxidative stress, and inflammatory markers as well as caspase-3 expression induced by RT. CONCLUSION: Combinations of POM with each of VIN, propolis, or cocoa have a promising disease-modifying antiparkinsonian therapy even without being given as an adjuvant to L-dopa.
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Doença de Parkinson , Transtornos Parkinsonianos , Punica granatum , Própole , Acetilcolinesterase/efeitos adversos , Envelhecimento , Animais , Caspase 3/uso terapêutico , Glicogênio Sintase Quinase 3 beta , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Extratos Vegetais/efeitos adversos , Própole/efeitos adversos , Ratos , Alcaloides de VincaRESUMO
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease that is exacerbated by social isolation (SI) and protein malnutrition (PM). Antioxidants, physical and mental activities (Ph&M) can maintain cognitive functions and protect against dementia. OBJECTIVE: To investigate the impact of Epigallocatechin-3-gallate (EGCG), Vitamin E (VE), Vitamin C (VC), and Selenium (Se), in enhancing the potential effect of Ph&M versus SI&PM as risk factors in the progression of AD in rats. METHODS: Aluminum chloride (70 mg/kg, I.P for 5 weeks) was used to induce AD in rats that either normally fed or socially isolated and protein malnourished (SI&PM). Simultaneously, rats were weekly exposed to Ph&M either alone or in combination with EGCG (10 mg/kg, I.P), VC (400 mg/kg, P.O), VE (100 mg/kg, P.O), and Se (1 mg/kg, P.O). RESULTS: The combination protocol of EGCG, VE, VC, and Se together with Ph&M significantly increased brain monoamines, superoxide dismutase (SOD), total antioxidant capacity (TAC) and brain-derived neurotrophic factor (BDNF) in AD, SI&PM and SI&PM/AD groups. Additionally, this regimen significantly mitigated brain acetylcholine esterase (ACHE), ß-amyloid (Aß), Tau protein, ß-secretase, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and Interleukin 1ß (IL-1ß) as well as DNA fragmentation. These biochemical findings were supported by the histopathological examinations of brain tissue. CONCLUSION: The combination protocol of antioxidants with Ph&M activities mitigated SI&PM-induced progressive risk of AD.
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Doença de Alzheimer/tratamento farmacológico , Ácido Ascórbico/farmacologia , Catequina/análogos & derivados , Saúde Mental/normas , Condicionamento Físico Animal , Selênio/farmacologia , Vitamina E/farmacologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Animais , Antioxidantes/farmacologia , Catequina/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de RiscoRESUMO
Ischemia-reperfusion injury (IRI) induces an inflammatory response and production of reactive oxygen species, which affects the organs remote to the sites of renal IR. However, remote effects of renal IRI on the liver need further investigations. Renal injury associated with liver disease is a common clinical problem. Colchicine is an established drug for microtubule stabilization that may reduce tissue injury and has antioxidant and antiinflammatory effects. The aim of the present study was (i) to assess the hepatic changes after induction of renal IRI, (ii) to explore the possible protective effect of colchicine on liver injury following renal IRI, and (iii) to investigate the possible mechanisms underlying the potential effect. Forty rats were randomly divided into four groups: sham operation group, colchicine-treated group, IR group, and colchicine-treated IR group. Colchicine treatment improved liver function (ALT/AST) after renal IRI, decreased hepatic oxidative stress and cell apoptosis by reducing hepatic MDA, upregulating hepatic total antioxidant capacity, Nrf2, and HO-1. Furthermore, colchicine inhibited inflammatory responses by downregulating hepatic NLRP3 inflammasome, IL-1ß, and caspase-1. Colchicine attenuates renal IRI-induced liver injury in rats. This effect may be due to reducing inflammation and oxidative stress markers.