RESUMEN
Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1ß, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.
Asunto(s)
Disfunción Cognitiva , Metformina , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Sirtuina 1 , Animales , Metformina/farmacología , Metformina/uso terapéutico , Sirtuina 1/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Ratones , Masculino , Transducción de Señal/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/etiología , Enfermedades Neuroinflamatorias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Alzheimer's disease is a neurodegenerative disease that leads to dementia and poses a serious threat to the health of the elderly. Traditional Chinese medicine (TCM) presents as a promising novel therapeutic therapy for preventing and treating dementia. Studies have shown that natural products derived from kidney-tonifying herbs can effectively inhibit AD. Furthermore, endoplasmic reticulum (ER) stress is a critical factor in the pathology of AD. Regulation of ER stress is a crucial approach to prevent and treat AD. Thus, in this study, we first collected kidney-tonifying herbs, integrated chemical ingredients from multiple TCM databases, and constructed a comprehensive drug-target network. Subsequently, we employed the endophenotype network (network proximity) method to identify potential active ingredients in kidney-tonifying herbs that prevented AD via regulating ER stress. By combining the predicted outcomes, we discovered that 32 natural products could ameliorate AD pathology via regulating ER stress. After a comprehensive evaluation of the multi-network model and systematic pharmacological analyses, we further selected several promising compounds for in vitro testing in the APP-SH-SY5Y cell model. Experimental results showed that echinacoside and danthron were able to effectively reduce ER stress-mediated neuronal apoptosis by inhibiting the expression levels of BIP, p-PERK, ATF6, and CHOP in APP-SH-SY5Y cells. Overall, this study utilized the endophenotype network to preliminarily decipher the effective material basis and potential molecular mechanism of kidney-tonifying Chinese medicine for prevention and treatment of AD.
RESUMEN
BACKGROUND: Cognitive behavioral therapy (CBT) is the recommended treatment for depression in patients with epilepsy (PWE). However, there are no studies that calculate the effect size of CBT on depression and quality of life (QoL) in PWE. METHODS: We searched seven electronic databases (PubMed, Web of Science, Embase, Cochrane Library, Clinical Trials, Ovid Medline, and PsycINFO). We included 13 studies examining CBT for depression in PWE and calculated its effect size. RESULTS: A total of 13 studies met the criteria. After treatment, CBT improves depression in PWE (g = 0.36, 95%CI: 0.18 to 0.54, I2 = 50%), and the efficacy maintains during follow-up (g = 0.47, 95%CI: 0.04 to 0.89, I2 = 80%). Subgroup analysis has shown that individual CBT (g = 0.47, 95%CI: 0.20 to 0.73, I2 = 0%) had a greater effect size than group CBT (g = 0.30, 95%CI: 0.07 to 0.53, I2 = 62%) in the treatment of depression. Likewise, CBT has a positive effect on the QoL improvement of PWE (g = 0.34, 95%CI: 0.11 to 0.57, I2 = 64%). In controlling seizures, CBT did not differ from the control group (g = -0.06, 95%CI: -0.32 to 0.19, I2 = 0%). CONCLUSIONS: Cognitive behavioral therapy interventions were effective in improving depression and QoL in PWE, but not effective in controlling seizures. The efficacy of CBT interventions targeting seizure control seems to be uncertain.