RESUMO
Indirubin is the main component of the traditional Chinese medicine Indigo naturalis (IN), a potent agonist of aryl hydrocarbon receptors (AhRs). In China, IN is used to treat psoriasis and ulcerative colitis, and indirubin is used for the treatment of chronic myelogenous leukaemia. However, IN and indirubin have adverse reactions, such as abdominal pain, diarrhoea, and intussusception, and their specific mechanism is unclear.The purpose of our research was to determine the specific mechanism underlying the adverse effects of IN and indirubin. By tracking the modifications in guinea pigs after the intragastric administration of indirubin for 28 days.The results demonstrate that indirubin could accelerate bowel movements and decrease intestinal acetylcholinesterase (AchE) expression. Experiments with NCM460 cells revealed that indirubin significantly reduced the expression of AchE, and the AchE levels were increased after the silencing of AhR and re-exposure to indirubin.This study showed that the inhibition of AchE expression by indirubin plays a key role in the occurrence of adverse reactions to indirubin and that the underlying mechanism is related to AhR-mediated AchE downregulation.
Assuntos
Acetilcolinesterase , Psoríase , Cobaias , Animais , Indóis/farmacologia , Indóis/metabolismo , Índigo Carmim , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
Aims: Long non-coding RNAs (lncRNAs) contribute to the regulation of vital physiological processes and play a role in the pathogenesis of many diseases. Monocrotaline (MCT) can cause large-scale outbreaks of toxic liver disease in humans and animals in the form of hepatic sinusoidal obstruction syndrome (HSOS). Although many experiments have been carried out to explain the pathogenesis of Monocrotaline-induced hepatic sinusoidal obstruction syndrome and to develop treatments for it, no studies have examined the role of Long non-coding RNAs in this condition. This study aimed to investigate the Long non-coding RNAs-mRNA regulation network in Monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats. Main methods: We established a model for MCT-induced hepatic sinusoidal obstruction syndrome, and then carried out microarray for liver tissues of SD rats in a model of early hepatic sinusoidal obstruction syndrome (12 h Monocrotaline treatment vs. control group) to investigate the differentially expressed Long non-coding RNAs and mRNAs in early hepatotoxicity. This was followed by RT-PCR analysis of selected Long non-coding RNAs, which were markedly altered. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome analyses were also conducted. Key findings: 176 Long non-coding RNAs (63 downregulated and 113 upregulated) and 4,221 mRNAs (2,385 downregulated and 1836 upregulated) were differentially expressed in the Monocrotaline-treated group compared to the control group. The biological processes identified in GO enrichment analysis as playing a role in hepatotoxicity were positive regulation of guanosine triphosphate phosphohydrolase, liver development, and the oxidation-reduction process. Pathway analysis revealed that the metabolism pathways, gap junction, and ribosome biogenesis in eukaryotes were closely related to Monocrotaline-induced hepatotoxicity. According to these analyses, LOC102552718 might play an essential role in hepatotoxicity mechanisms by regulating the expression of inositol 1,4,5-trisphosphate receptor-1 (Itpr-1). Significance: This study provides a basis for further research on the molecular mechanisms underlying Monocrotaline-induced hepatotoxicity and its treatment, especially in the early stage, when successful treatment is critical before irreversible liver damage occurs.
RESUMO
BACKGROUND: Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CP). Vincamine (vinca alkaloid) is the source of the synthetic derivative vinpocetine (Vinpo). Worldwide, Vinpo is used as a cerebroprotective drug. As it has anti-oxidant, anti-thrombotic and anti-inflammatory effects but the power of Vinpo to prevent CP induced cystitis has not been studied. AIM OF STUDY: This research was planned to explore the effect of Vinpo (10-30 mg/kg, orally) administered 1 or 4 h before inducing cystitis by CP injection (300 mg/kg, i.p.) on the urinary bladder of mice. RESULTS: Administration of Vinpo 30 mg/kg, 4 h before CP injection ameliorated inflammatory markers. It reduced inducible nitric oxide synthase (iNOS), tumor necrosis factor- α (TNF-α), and BCL2 Associated X (Bax) expression in the bladder and increased the total antioxidant capacity level. Histological examination of the bladder has further supported these results. The present study suggests a protective effect of Vinpo (30 mg/kg, 4 h before CP injection) against CP-induced bladder inflammation. CONCLUSION: This proposes that Vinpo 30 mg/kg may become a promising pharmacological drug to prevent urinary adverse effects in patients treated with chemotherapy using CP.
Assuntos
Cistite , Alcaloides de Vinca , Camundongos , Animais , Bexiga Urinária/patologia , Ciclofosfamida/efeitos adversos , Estresse Oxidativo , Cistite/induzido quimicamente , Cistite/tratamento farmacológico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Alcaloides de Vinca/farmacologia , Alcaloides de Vinca/uso terapêutico , ApoptoseRESUMO
Atractylodes macrocephala Koidz. is one of the most frequently used traditional Chinese medicines for the treatment of ulcerative colitis (UC). The beneficial effect of polysaccharide from Atractylodes macrocephala Koidz. (PAMK) on UC has been reported, while the underlying mechanism and target remain unclear. In this study, we systematically investigated the therapeutic effect and the underlying mechanism of PAMK in UC based on a mouse model of dextran sodium sulfate (DSS)-induced colitis. PAMK treatment (100 mg/kg, 200 mg/kg and 400 mg/kg) significantly ameliorated DSS-induced colitis, manifested as a reduction in weight loss, disease activity index (DAI), colon shortening, spleen index and histological score. Moreover, PAMK treatment inhibited inflammation and improved the integrity of the intestinal barrier in colitis mice. Mechanistically, microarray analysis determined the critical role of the immunoregulatory effect of PAMK in alleviating UC. Flow cytometry analysis further demonstrated that PAMK treatment regulated the balance between T helper (Th) 17 and regulatory T (Treg) cells in the mesenteric lymph nodes (MLN) and spleen in mice with colitis. In addition, PAMK treatment downregulated the expression of IL-6 and suppressed the phosphorylation of STAT3. Together, these data revealed that PAMK treatment alleviated DSS-induced colitis by regulating the Th17/Treg cell balance, which may be dependent on the inhibition of the IL-6/STAT3 signaling pathway. Our study is the first to elucidate that the underlying mechanism by which PAMK treatment alleviates DSS-induced colitis is associated with an improved the Th17/Treg cell balance. Collectively, the study provides evidence for the potential of PAMK to treat UC.
Assuntos
Atractylodes , Colite Ulcerativa , Colite , Camundongos , Animais , Linfócitos T Reguladores/patologia , Interleucina-6/farmacologia , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/patologiaRESUMO
The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates a wide range of biological and toxicological effects by binding to specific ligands. AhR ligands exist in various internal and external ecological systems, such as in a wide variety of hydrophobic environmental contaminants and naturally occurring chemicals. Most of these ligands have shown differential responses among different species. Understanding the differences and their mechanisms helps in designing better experimental animal models, improves our understanding of the environmental toxicants related to AhR, and helps to screen and develop new drugs. This review systematically discusses the species differences in AhR activation effects and their modes of action. We focus on the species differences following AhR activation from two aspects: (1) the molecular configuration and activation of AhR and (2) the contrast of cis-acting elements corresponding to AhR. The variations in the responses seen in humans and other species following the activation of the AhR signaling pathway can be attributed to both factors.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Sequência de Aminoácidos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Humanos , Ligantes , Receptores de Hidrocarboneto Arílico/química , Alinhamento de Sequência , Especificidade da EspécieRESUMO
Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-ß1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-ß1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular.
Assuntos
Autofagia , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Células-Tronco Mesenquimais/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Smad/metabolismo , Transplante de Células-Tronco/métodos , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antineoplásicos/toxicidade , Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/patologia , Cisplatino/toxicidade , Feminino , Masculino , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genéticaRESUMO
OBJECTIVE: Although cisplatin (CIS) acts as potent chemotherapy, nephrotoxicity still its major life-threatening side effect. The purpose of this study was to discuss and compare the renoprotective effects of curcumin (CUR) and etoricoxib (ETB) against CIS-induced nephrotoxicity. MATERIALS & METHODS: Thirty six adult female rats were divided equally into 6 groups: Group I (control), Group II (CIS) received cisplatin (7.5 mg/kg i.p), Group III (CUR) and group IV (ETB) received curcumin (200 mg/kg/day) or etoricoxib (10 mg/kg/day) respectively via gavage for seven continuous days. Group V (CIS + CUR) and Group VI (CIS + ETB) received curcumin (200 mg/kg/day) or etoricoxib (10 mg/kg/day) via gavage for seven continuous days. On the 4th day, the rats received cisplatin (7.5 mg/kg i.p) as a single injection 1 h after last curcumin or etoricoxib administration. At the assigned time, blood and tissue samples were collected for biochemical, histochemical, histopathological, immunohistochemical, and RT-PCR gene expression studies. RESULTS: Curcumin administration significantly decreased CIS-induced elevation of serum creatinine and blood urea nitrogen (BUN), and reversed oxidative stress markers; glutathione (GSH) and malondialdehyde (MDA) to control level. Suppression of inflammatory and apoptotic responses by CUR co-treatment was evidenced by decreased iNOS and BAX immunohistochemical reactions, and TNF-α and Caspase3 gene expressions which were detected by RT-PCR in kidney tissues. To our knowledge, this is the first time to discuss the effect of ETB on CIS induced nephrotoxicity. Although ETB reduced the previously mentioned inflammatory and apoptotic markers, its effect was less than that of CUR. Administration of ETB couldn't modify the disturbed levels of creatinine, BUN, GSH, and MDA. CONCLUSION: In conclusion, CUR provided a promising renoprotective effect against CIS induced nephrotoxicity. Further studies are recommended to approve or disapprove the protective role of ETB in CIS induced nephrotoxicity.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Curcumina/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Etoricoxib/farmacologia , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RatosRESUMO
Reported cases of uni-leaflet mitral valve (MV) were related to the absence or dysplasia of the posterior mitral leaflet with ample anterior mitral leaflet. We present here a new entity of uni-leaflet MV where the MV appears as a membrane-like structure with a single slit-like orifice at its lateral part with no commissures. CASE REPORT: Continuous Doppler flow revealed a mean pressure gradient of 19 mmHg across the mitral valve indicating severe mitral stenosis. In 3D images from the left atrial view, the MV appeared like a membrane with a single orifice in its lateral part toward the left atrial appendage, the area of this orifice by 3D was 0.52 cm2, there were no commissures or even any residual lines at the site where commissures should be. The diagnosis of congenital severe mitral stenosis due to acommissural MV was confirmed. During surgery, the surgical appearance of the MV confirmed our diagnosis by 3D. CONCLUSION: Isolated congenital severe mitral stenosis presenting in adulthood is rare, uni-leaflet MV as a cause is only reported in a few cases. MV replacement is usually indicated due to the abnormal anatomy of MV leaflets and the subvalvular apparatus.