RESUMEN
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus, and oxidative stress and mitochondrial dysfunction play an important role in this process. It has been shown that aldose reductase (ALR2) catalyzes NADPH-dependent reduction of glucose to sorbitol, resulting in oxidative stress and mitochondrial dysfunction in diabetic patients. Astragalin (AG), a flavonoid extracted from Thesium chinense Turcz., shows an inhibitory activity on ALR2. In this study, we investigated the therapeutic effects of AG against renal injury in streptozocin (STZ)-induced diabetic mouse model. Diabetic mice were orally administered AG (5, 10 mg·kg-1·d-1) for 4 weeks. We showed that AG treatment greatly improved the proteinuria and ameliorated renal pathological damage without affecting the elevated blood glucose in diabetic mice. Furthermore, AG treatment significantly suppressed highly activated ALR2, and reduced oxidative stress in the kidney of diabetic mice and in high glucose and lipids-stimulated HK2 cells in vitro. We demonstrated that AG treatment modulated mitochondrial quality control and ameliorated apoptosis, boosting mitochondrial biogenesis, maintaining mitochondrial dynamic homeostasis, and improving energy metabolism disorder in vivo and in vitro. In high glucose and lipids-stimulated HK2 cells, we found that AG (20 µM) restored the phosphorylation level of AMPK, and upregulated the expression and transcriptional activity of PGC1α, whereas treatment with H2O2, blockade of AMPK with Compound C or knockdown of AMPKα with siRNA abolished the protective effect of AG on mitochondrial function, suggesting that antioxidant effects and activation of AMPK-dependent PGC1α pathway might be the molecular mechanisms underlying the protective effects of AG on mitochondrial quality control. We conclude that AG could be a promising drug candidate for the treatment of diabetic renal injury through activating AMPK.
Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Ratones , Animales , Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Peróxido de Hidrógeno/farmacología , Riñón/patología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Glucosa/metabolismo , Mitocondrias , LípidosRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) is an autoimmune disease. The pathogenesis of IBD is complicated and intestinal mucosal barrier damage is considered as the trigger factor for the initiation and recurrence of IBD. Total Glucosides of Paeony (TGP) has shown good inhibitory effects on immune-inflammation in clinic studies. However, its effect and mechanism on IBD are largely unknown. PURPOSE: The purpose of this study is to evaluate the effect and mechanism of TGP on IBD. STUDY DESIGN: DSS-induced colitis mouse model was used. TGP was given by gavage. Caco-2 cells were stimulated by outer membrane vesicles (OMV) to establish an in vitro model. METHODS: C57BL/6 mice were divided into normal control group, model group, mesalazine group, paeoniflorin (PA) group, high-dose group of TGP, and low-dose group of TGP. The model was induced with 2.5% DSS for 7 days, and TGP was intragastrically administered for 10 days. The therapeutic effect of TGP was evaluated by symptoms, histochemical analysis, RT-qPCR and ELISA. The mechanism was explored by intestinal permeability, Western blot and immunofluorescence in vivo and in vitro. RESULTS: Our results showed that TGP could significantly improve the symptoms and pathological changes, with reduced levels of TNF-α, IL-17A, IL-23 and IFN-γ in the colon tissues and serum under a dose-dependent manner. TGP also reduced the intestinal permeability and restored the protein expression of tight junction and adherens junction proteins of intestinal epithelial cells in vivo and in vitro. Furthermore, TGP could inhibit the expression of p-Lyn and Snail and prevent Snail nuclear localization, thereby maintaining tight and adherens junctions. CONCLUSION: TGP effectively improves the symptoms of DSS-induced colitis in mice, protects the intestinal epithelial barrier by inhibiting the Lyn/Snail signaling pathway, and maybe a promise therapeutic agent for IBD treatment.
Asunto(s)
Colitis/tratamiento farmacológico , Glucósidos/farmacología , Paeonia/química , Familia-src Quinasas/metabolismo , Animales , Células CACO-2 , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Glucósidos/química , Humanos , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Ratones Endogámicos C57BL , Monoterpenos/farmacología , Permeabilidad , Factores de Transcripción de la Familia Snail/metabolismo , Proteínas de Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismoRESUMEN
Bupleurum polysaccharides (BPs) is isolated from Bupleurum smithii var. parvifolium, a key traditional Chinese medicine. The study was to investigate the effects of BPs on diabetic kidney injury. After two intraperitoneal injections of streptozotozin (STZ) 100 mg·kg-1, renal injury in diabetic mice was induced and BPs was orally administrated at dosages of 30 and 60 mg·kg-1·d-1. The STZ injected mice developed renal function damage, renal inflammation and fibrosis known as diabetic kidney disease (DKD). BPs significantly reduced serum creatinine level and urinary albumin excretion rate, with the attenuated swelling of kidneys. BPs treatment obviously alleviated the pathological damage of renal tissue. The progression of renal injury in BPs treated mice was inhibited with less expression of type IV collagen (Col IV), fibronectin (FN) and α-smooth muscle actin (α-SMA). The inhibition of inflammation in kidney was associated with the reduced level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). BPs administration suppressed the over-expression of toll like receptor 4 (TLR4) and high-mobility group box 1 (HMGB1) with lowered activity of nuclear factor kappa B (NF-κB) in renal tissue of diabetic mice. Oral administration of BPs effectively prevented the development ofrenal injury in diabetic mice. This study suggested that the protection provided by BPs might affect through the interruption of HMGB1-TLR4 pathway, leading to the inhibition of renal inflammation and fibrotic process.
Asunto(s)
Bupleurum/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Proteína HMGB1/metabolismo , Polisacáridos/uso terapéutico , Receptor Toll-Like 4/metabolismo , Animales , Citocinas/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/inducido químicamente , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Inflamación/metabolismo , Inflamación/prevención & control , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Ratones Endogámicos C57BL , Raíces de Plantas/química , Polisacáridos/administración & dosificación , Polisacáridos/farmacología , Transducción de Señal/efectos de los fármacos , Estreptozocina/toxicidad , Factor de Transcripción ReIA/metabolismoRESUMEN
Houttuynia cordata polysaccharide (HCP) is extracted from Houttuynia cordata, a key traditional Chinese medicine. The study was to investigate the effects of HCP on intestinal barrier and microbiota in H1N1 virus infected mice. Mice were infected with H1N1 virus and orally administrated HCP at a dosage of 40 mg(kg-1(d-1. H1N1 infection caused pulmonary and intestinal injury and gut microbiota imbalance. HCP significantly suppressed the expression of hypoxia inducible factor-1α and decreased mucosubstances in goblet cells, but restored the level of zonula occludens-1 in intestine. HCP also reversed the composition change of intestinal microbiota caused by H1N1 infection, with significantly reduced relative abundances of Vibrio and Bacillus, the pathogenic bacterial genera. Furthermore, HCP rebalanced the gut microbiota and restored the intestinal homeostasis to some degree. The inhibition of inflammation was associated with the reduced level of Toll-like receptors and interleukin-1ß in intestine, as well as the increased production of interleukin-10. Oral administration of HCP alleviated lung injury and intestinal dysfunction caused by H1N1 infection. HCP may gain systemic treatment by local acting on intestine and microbiota. This study proved the high-value application of HCP.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Houttuynia/química , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Polisacáridos/uso terapéutico , Animales , Citocinas/metabolismo , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/fisiopatología , Extractos Vegetales/química , Polisacáridos/química , Polisacáridos/farmacología , Receptores Toll-Like/metabolismo , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
BACKGROUND: Neglected tropical diseases (NTDs) are closely related to poverty and affect over a billion people in developing countries. The unmet treatment needs cause high mortality and disability thereby imposing a huge burden with severe social and economic consequences. Although coordinated by the World Health Organization, various philanthropic organizations, national governments and the pharmaceutical industry have been making efforts in improving the situation, the control of NTDs is still inadequate and extremely difficult today. The lack of safe, effective and affordable medicines is a key contributing factor. This paper reviews the recent advances and some of the challenges that we are facing in the fight against NTDs. MAIN BODY: In recent years, a number of innovations have demonstrated propensity to promote drug discovery and development for NTDs. Implementation of multilateral collaborations leads to continued efforts and plays a crucial role in drug discovery. Proactive approaches and advanced technologies are urgently needed in drug innovation for NTDs. However, the control and elimination of NTDs remain a formidable task as it requires persistent international cooperation to make sustainable progresses for a long period of time. Some currently employed strategies were proposed and verified to be successful, which involve both mechanisms of 'Push' which aims at cutting the cost of research and development for industry and 'Pull' which aims at increasing market attractiveness. Coupled to this effort should be the exercise of shared responsibility globally to reduce risks, overcome obstacles and maximize benefits. Since NTDs are closely associated with poverty, it is absolutely essential that the stakeholders take concerted and long-term measures to meet multifaceted challenges by alleviating extreme poverty, strengthening social intervention, adapting climate changes, providing effective monitoring and ensuring timely delivery. CONCLUSIONS: The ongoing endeavor at the global scale will ultimately benefit the patients, the countries they are living and, hopefully, the manufacturers who provide new preventive, diagnostic and therapeutic products.
Asunto(s)
Descubrimiento de Drogas , Enfermedades Desatendidas , Medicina Tropical , Humanos , Enfermedades Desatendidas/tratamiento farmacológico , Enfermedades Desatendidas/prevención & controlRESUMEN
Diabetic nephropathy (DN) is one of the common microvascular complications of diabetes mellitus. Renal fibrosis is closely related to the deterioration of renal function. The present study aimed to investigate protective effect of Taxus chinensis on high-fat diet/streptozotocin-induced DN in rats and explore the underlying mechanism of action. The rat DN model was established via feeding high fat diet for 4 weeks and subsequently injecting streptozotocin (30 mg·kg-1 body weight) intraperitoneally. The rats with blood glucose levels higher than 16.8 mmol·L-1 were selected for experiments. The DN rats were treated with Taxus chinensis orally (0.32, 0.64, and 1.28 g·kg-1) once a day for 8 weeks. Taxus chinensis significantly improved the renal damage, which was indicated by the decreases in 24-h urinary albumin excretion rate, blood serum creatinine, and blood urea nitrogen. Histopathological examination confirmed the protective effect of Taxus chinensis. The thickness of glomerular basement membrane was reduced, and proliferation of mesangial cells and podocytes cells and increase in mesangial matrix were attenuated. Further experiments showed that Taxus chinensis treatment down-regulated the expression of TGF-ß1 and α-SMA, inhibited phosphorylation of Smad2 and Smad3. These results demonstrated that Taxus chinensis alleviated renal injuries in DN rats, which may be associated with suppressing TGF-ß1/Smad signaling pathway.
Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Medicamentos Herbarios Chinos/administración & dosificación , Proteínas Smad/metabolismo , Taxus/química , Factor de Crecimiento Transformador beta1/metabolismo , Albúminas , Animales , Glucemia/metabolismo , Creatinina/sangre , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/orina , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Fosforilación , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Proteínas Smad/genéticaRESUMEN
AIM: To investigate the effect of recombined human glucagon-like peptide 1 (rhGLP-1 [7-36]) on the secretion and expression of amylin in Goto-Kakizaki (GK) rats. METHODS: The GK rats were treated with rhGLP-1 (7-36) 56 and 133 mug/kg subcutaneously for 12 weeks. The fasting and post-prandial blood glucose levels were measured. The plasma amylin concentration was measured by ELISA. The transcription levels of amylin and insulin mRNA were evaluated by fluorescent-quantitative- PCR. Immunohistochemistry was utilized to detect the amylin protein. Histological examination was assayed by light microscopy. RESULTS: Treatment with rhGLP-1 (7-36) caused a significant reduction of post-prandial blood glucose levels in the GK rats (P<0.05). The plasma amylin levels of the GK rats were lower than those of Wistar rats after the glucose administration (P<0.01). Treatment with rhGLP-1 (7-36) exhibited a marked elevation of the glucose-stimulated plasma amylin level (P<0.05) and slight histological amelioration. The amylin expression was augmented in the rhGLP-1 (7-36)-treated GK rat pancreas. Amylin and insulin mRNA were also highly expressed in the treated GK rats (P<0.05). However, the ratio of amylin to insulin mRNA was significantly decreased by treatment with rhGLP-1 (7-36). CONCLUSION: RhGLP-1 (7-36) stimulates the secretion and expression of amylin, and exerts a beneficial effect on the ratio of amylin to insulin mRNA. These findings suggest that GLP-1 and GLP-1 analogs are ideal candidates for the treatment of type 2 diabetes.