Polydatin attenuates renal fibrosis in diabetic mice through regulating the Cx32-Nox4 signaling pathway.

We previously found that polydatin could attenuate renal oxidative stress in diabetic mice and improve renal fibrosis. Recent evidence shows that NADPH oxidase 4 (Nox4)-derived reactive oxygen species (ROS) contribute to inflammatory and fibrotic processes in diabetic kidneys. In this study we investigated whether polydatin attenuated renal fibrosis by regulating Nox4 in vitro and in vivo. In high glucose-treated rat glomerular mesangial cells, polydatin significantly decreased the protein levels of Nox4 by promoting its K48-linked polyubiquitination, thus inhibited the production of ROS, and eventually decreasing the expression of fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1), the main factors that exacerbate diabetic renal fibrosis. Overexpression of Nox4 abolished the inhibitory effects of polydatin on FN and ICAM-1 expression. In addition, the expression of Connexin32 (Cx32) was significantly decreased, which was restored by polydatin treatment. Cx32 interacted with Nox4 and reduced its protein levels. Knockdown of Cx32 abolished the inhibitory effects of polydatin on the expression of FN and ICAM-1. In the kidneys of streptozocin-induced diabetic mice, administration of polydatin (100 mg·kg-1·d-1, ig, 6 days a week for 12 weeks) increased Cx32 expression and reduced Nox4 expression, decreased renal oxidative stress levels and the expression of fibrotic factors, eventually attenuating renal injury and fibrosis. In conclusion, polydatin promotes K48-linked polyubiquitination and degradation of Nox4 by restoring Cx32 expression, thereby decreasing renal oxidative stress levels and ultimately ameliorating the pathological progress of diabetic renal fibrosis. Thus, polydatin reduces renal oxidative stress levels and attenuates diabetic renal fibrosis through regulating the Cx32-Nox4 signaling pathway.

Risk factors and survival analysis of haemodialysis complicated with infective endocarditis.

The clinical features and risk factors for survival time were analysed in haemodialysis patients complicated with infective endocarditis. A total of 101 infective endocarditis (IE) patients treated at Hangzhou First People's Hospital, from January 1, 2012, to April 1, 2022, were included in the present study. Baseline demographic data and laboratory data were collected for statistical analysis of risk factors and survival time in the IE with haemodialysis group (HD-IE group, n=15) and the IE without haemodialysis group (NHD-IE group, n=86). Haemoglobin, red blood cells, C-reactive protein, procalcitonin, serum albumin, diabetes, invasive procedures, positive blood bacteria culture, heart valve calcification ratio, and left ventricular ejection fraction level were risk factors for infective endocarditis complicated with haemodialysis (P<0.05). Compared with the NHD-IE group, the HD-IE group had an obviously increased risk of mortality (χ2=6.323, P=0.012). The univariate Cox regression analysis showed that age, haemoglobin, red blood cells, serum albumin, left ventricular ejection score, longest vegetation diameter, combined hypotension and diabetes were risk factors for death; furthermore, multivariate Cox regression showed that age (HR=1.187, P=0.015), combined hypotension (HR=0.921, P=0.025) and the longest vegetation diameter (HR=9.191, P=0.004) were independent risk factors affecting the survival of patients. Collectively, the present study revealed that the mortality rate of HD-IE patients was higher than that of NHD-IE patients. Older age, hypotension, and the longest vegetation diameter were independent risk factors affecting the survival of patients. For HD-IE patients, active and effective antibiotic treatment or surgical treatment should be strongly recommended.

The role of tonifying kidney decoction and acupuncture in the treatment of Alzheimer's disease: A network meta-analysis.

IMPORTANCE: As one of the chronic neurological degenerative diseases with the highest incidence of amnesia and dementia, Alzheimer's disease (AD) carried out the clinical treatment based on the 2 traditional Chinese medicine (TCM) of Chinese herbal compound and acupuncture (AP). With the vigorous development of TCM, doctors are facing the problem of choosing TCM or western medicine in clinical work. Hence there is an urge to make pairwise comparisons among these interventions to provide evidence for clinical practice. OBJECTIVE: The used efficacy of the 2 TCM methods and combined with donepeziline were compared to compile the best treatment through network meta-analysis. METHODS: Patients diagnosed with AD were included in the randomized clinical trial, who were treated with tonifying kidney decoction (TKD) or AP combined with donepezil hydrochloride (DH) as an intervention measure, while the control group was treated with DH. The total effective rate was the primary outcome, and mini-mental state examination (MMSE) score and activities of daily living (ADCS-ADL) scores were the secondary indicators. RESULTS: Eventually 30 studies reporting 2236 patients underwent TKD or AP combined with DH were enrolled. In terms of total efficiency, compared with TKD and DH, TKD + DH was significantly preferable. In addition, TKD were classified into 2 categories, namely tonifying kidney with reducing phlegm formulas (TKRP) and tonifying kidney with filling lean marrow (TKFLM). Regarding to MMSE score of TKD, of the 3 interventions, only TKRP + DH (standard mean difference [SMD] = 4.84, 95% confidence interval [CI]: 0.86-8.82) and TKFLM + DH (SMD = 3.93, 95% CI: 1.06-6.80) had significant efficacy over TKFLM (SMD = 4.25, 95%CI: -2.58 to 11.08). Although no difference between TKRP and other groups, its effectiveness was higher than TKFLM + DH and TKFLM (surface under the cumulative ranking curve (SUCRA) = 61.5%). For the ADL score, compared with TKFLM + DH and DH, TKRP + DH had more effective (SUCRA = 70.2%). Regarding to the total effective rates, AP + DH was more statistically better than AP, and AP was statistically better than DH. CONCLUSION: TKD or AP in combination with DH are significantly superior in treating AD.

Efficacy and safety of hypoglycemic drugs in improving cognitive function in patients with Alzheimer's disease and mild cognitive impairment: A systematic review and network meta-analysis.

Objective: The purpose of this study was to compare the effects of oral hypoglycaemic drugs (HDs) on cognitive function and biomarkers of mild cognitive impairment (MCI) and Alzheimer's disease (AD) through a network meta-analysis of randomized controlled trials (RCTs). Methods: We conducted systematic searches for English- and Chinese-language articles in the PubMed, Medline, Embase, Cochrane Library and Google Scholar databases, with no date restrictions. We performed a network meta-analysis, which we report here according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The 16 studies included a total of 3,081 patients. We selected the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-Cog), the Alzheimer's Disease Cooperative Study Activities of Daily Living section (ADCS-ADL) and amyloid beta (Aß) 42 as the outcome measures for analysis and comparison. Result: We selected seven treatments and assessed the clinical trials in which they were tested against a placebo control. Of these treatments, intranasal insulin 20 IU (ITSN20), glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase 4 inhibitor (DPP-4) were associated with significantly improved MMSE scores (7 RCTs, 333 patients, 30≥MMSE score≥20: mild) compared with placebo [standardized mean difference (SMD) 1.11, 95% confidence interval (CI) (0.87, 1.35); SMD 0.75, 95% CI (0.04, 1.41); and SMD 4.08, 95% CI (3.39, 4.77), respectively]. Rosiglitazone 4 mg (RLZ4), rosiglitazone 10 mg (RLZ10), intranasal insulin 40 IU (ITSN40), and ITSN20 significantly decreased ADAS-Cog scores (11 RCTs, 4044 patients, 10 ≤ ADAS-Cog scores ≤ 30: mild and moderate) compared with placebo [SMD -1.40, 95% CI (-2.57, -0.23), SMD -3.02, 95% CI (-4.17, -1.86), SMD -0.92, 95% CI (-1.77, -0.08), SMD -1.88, 95% CI (-3.09, -0.66)]. Additionally, ITSN20 and ITSN40 significantly improved ADCS-ADL scores (2 RCTs, 208 patients, ADCS-ADL scale score ≤ 10: mild) compared with placebo [SMD 0.02, 95% CI (0.01, 0.03), and SMD 0.04, 95% CI (0.03, 0.05), respectively]. In the 16 included studies, the degree of AD was classified as mild or moderate. For mild cognitive impairment, DPP-4 performed best, but for mild to moderate impairment, ITSN40 had excellent performance. Conclusion: Various HDs can improve the cognitive function of MCI and AD patients. Different drug regimens brought different degrees of improvement, which may be related to their dosage, duration, and mechanism of action. Systematic review registration: www.crd.york.ac.uk/prospero.

Pharmacokinetic Profiling of Butylidenephthalide and Alisol B in Danggui-Shaoyao-San in Rats.

BACKGROUND AND OBJECTIVE: Danggui-Shaoyao-San (DSS), a famous Chinese formula, has been widely used to treat gynecological disorders since ancient times and has recently showed efficacy in treating Alzheimer's disease. Butylidenephthalide (BDPH) and alisol B (ALI) are recognized as the primary active ingredients of DSS. The objectives of the present study were to evaluate the pharmacokinetic comparative study of BDPH and ALI in herbal extracts and their purified forms. METHOD: A sensitive and specific high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) methodology was developed to determine the concentration level of BDPH and ALI in rat plasma. This approach enables a real-time pharmacokinetics profiling of BDPH and ALI in DSS extracts as well as their purified forms in rats after oral administration. RESULTS: The validated method showed an evident linearity over a wide range of dosages (r > 0.99) with sensitivity down to 1.0 ng/mL for each analyte. The extraction recovery of the analyte ranged from 80.8 to 99.1%. The pharmacokinetic parameters were significantly different in herbal extracts and their purified forms. The results showed that the absorption of both BDPH and ALI from DSS extracts was significantly greater compared with their purified forms. CONCLUSIONS: A highly specific, sensitive and rapid HPLC-MS/MS method was developed and applied for the determination of BDPH and ALI in rat plasma. It was found that BDPH and ALI had higher bioavailability in the DSS extract compared with their purified forms.

Jiao-Tai-Wan Improves Cognitive Dysfunctions through Cholinergic Pathway in Scopolamine-Treated Mice.

Cognitive dysfunction is characterized as the gradual loss of learning ability and cognitive function, as well as memory impairment. Jiao-tai-wan (JTW), a Chinese medicine prescription including Coptis chinensis and cinnamon, is mainly used for the treatment of insomnia, while the effect of JTW in improving cognitive function has not been reported. In this study, we employed a scopolamine- (SCOP-) treated learning and memory deficit model to explore whether JTW could alleviate cognitive dysfunction. In behavioral experiments, Morris water maze, Y-maze, fearing condition test, and novel object discrimination test were conducted. Results showed that oral administration of JTW (2.1 g/kg, 4.2 g/kg, and 8.4 g/kg) can effectively promote the ability of spatial recognition, learning and memory, and the memory ability of fresh things of SCOP-treated mice. In addition, the activity of acetylcholinesterase (AChE) was effectively decreased; the activity of choline acetyltransferase (ChAT) and concentration of acetylcholine (Ach) were improved after JTW treatment in both hippocampus and cortex of SCOP-treated mice. JTW effectively ameliorated oxidative stress because of decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) and increased the activities of superoxide dismutase (SOD) and catalase (CAT) in hippocampus and cortex. Furthermore, JTW promotes the expressions of neurotrophic factors including postsynaptic density protein 95 (PSD95) and synaptophysin (SYN) and brain-derived neurotrophic factor (BDNF) in both hippocampus and cortex. Nissl's staining shows that the neuroprotective effect of JTW was very effective. To sum up, JTW might be a promising candidate for the treatment of cognitive dysfunction.

Neuroprotective effect of ß-asarone against Alzheimer's disease: regulation of synaptic plasticity by increased expression of SYP and GluR1.

AIM: ß-asarone, an active component of Acori graminei rhizome, has been reported to have neuroprotective effects in Alzheimer's disease. As the underlying mechanism is not known, we investigated the neuroprotective effects of ß-asarone in an APP/PS1 double transgenic mouse model and in NG108 cells. MATERIALS AND METHODS: APPswe/PS1dE9 double transgenic male mice were randomly assigned to a model group, ß-asarone treatment groups (21.2, 42.4, or 84.8 mg/kg/d), or donepezil treatment group (2 mg/kg/d). Donepezil treatment was a positive control, and background- and age-matched wild-type B6 mice were an external control group. ß-asarone (95.6% purity) was dissolved in 0.8% Tween 80 and administered by gavage once daily for 2.5 months. Control and model animals received an equal volume of vehicle. After 2.5 months of treatment, behavior of all animals was evaluated in a Morris water maze. Expression of synaptophysin (SYP) and glutamatergic receptor 1 (G1uR1) in the hippocampus and cortex of the double transgenic mice was assayed by Western blotting. The antagonistic effects of ß-asarone against amyloid-ß peptide (Aß) were investigated in vitro in the NG108-15 cell line. After 24 hours of incubation, cells were treated with 10 µm Aß with or without ß-asarone at different concentrations (6.25, 12.5, or 25 µM) for an additional 36 hours. The cytotoxicity of ß-asarone was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay of cell viability, and cell morphology was evaluated by bright-field microscopy after 24 hours of treatment. The expression of SYP and GluR1 in cells was detected by Western blot assay in the hippocampus and brain cortex tissues of mice. RESULTS: ß-asarone at a high dose reduced escape latency and upregulated SYP and GluR1 expression at both medium and high doses. Cell morphology evaluation showed that ß-asarone treatment did not result in obvious cell surface spots and cytoplasmic granularity. ß-asarone had a dose-dependent effect on cell proliferation. CONCLUSION: ß-asarone antagonized the Aß neurotoxicity in vivo, improved the learning and memory ability of APP/PS1 mice, and increased the expression of SYP and GluR1 both in vivo and in vitro. Thus, ß-asarone may be a potential drug for the treatment of Alzheimer's disease.