Butylphthalide combined with donepezil for the treatment of vascular dementia: a meta-analysis.

OBJECTIVE: To systematically evaluate the efficacy and safety of butylphthalide combined with donepezil versus butylphthalide monotherapy for the treatment of vascular dementia. METHODS: Randomized controlled trials were searched in electronic databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database (VIP), Wan Fang, and China Biology Medicine from inception to 29 November 2022. Two reviewers independently screened the papers and extracted data from the included studies. The data were processed using RevMan5.4 statistical software. RESULTS: Nine randomized controlled trials (n = 1024) were included in this meta-analysis. Regarding the primary outcomes, compared with butylphthalide monotherapy, combined butylphthalide and donepezil treatment exhibited significantly greater total clinical efficacy (relative risk = 1.24, 95% confidence interval [1.17, 1.31]) and did not increase the adverse event rate (relative risk = 1.39, 95% confidence interval [0.91, 2.14]). Regarding the secondary outcomes, the meta-analysis results for the Mini-Mental State Examination, abilities of daily living, and Montreal Cognitive Assessment scores and the interleukin-6, tumor necrosis factor-α, and superoxide dismutase blood levels all supported combined butylphthalide and donepezil treatment. CONCLUSION: Butylphthalide combined with donepezil may be a better treatment strategy than donepezil alone for the treatment of vascular dementia in clinical practice.

Efficacy and Possible Mechanisms of Astragali Radix and its Ingredients in Animal Models of Osteoporosis: A Preclinical Review and Metaanalysis.

BACKGROUND: Astragali Radix (AR) has a long history as a traditional Chinese medicine for anti-osteoporosis (OP) treatment. The aim of the study was to explore the effect and optimal regimens of AR and its main ingredients (IAR) in OP treatment. METHODS: Eligible animal studies were searched in seven databases (PubMed, Web of Science, MEDLINE, SciELO Citation Index, Cochrane Library, China National Knowledge Infrastructure and Wanfang). The primary outcomes were bone metabolic indices. The secondary outcome measure was the anti-OP mechanism of IAR. RESULTS: 21 studies were enrolled in the study. The primary findings of the present article illustrated that IAR could significantly increase the bone mineral density (BMD), bone volume over the total volume, trabecular number, trabecular thickness, bone maximum load and serum calcium, while trabecular separation and serum C-terminal telopeptide of type 1 collagen were remarkably decreased (P < 0.05). In subgroup analysis, the BMD in the long treatment group (≥ 10 weeks) showed better effect size than the short treatment group (< 10 weeks) (P < 0.05). Modeling methods and animal sex were factors affecting serum alkaline phosphatase and osteocalcin levels. CONCLUSION: The findings suggest the possibility of developing IAR as a drug for the treatment of OP. IAR with longer treatment time may achieve better effects regardless of animal strain and age.

Sinomenine ameliorates fibroblast-like synoviocytes dysfunction by promoting phosphorylation and nuclear translocation of CRMP2.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and arthritic pain. Sinomenine (SIN), derived from the rhizome of Chinese medical herb Qing Teng (scientific name: Sinomenium acutum (Thunb.) Rehd. Et Wils), has a longstanding use in Chinese traditional medicine for treating rheumatoid arthritis. It has been shown to possess anti-inflammatory, analgesic, and immunosuppressive effects with minimal side-effects clinically. However, the mechanisms governing its effects in treatment of joint pathology, especially on fibroblast-like synoviocytes (FLSs) dysfunction, and arthritic pain remains unclear. AIM: This study aimed to investigate the effect and underlying mechanism of SIN on arthritic joint inflammation and joint FLSs dysfunctions. MATERIALS AND METHODS: Collagen-induced arthritis (CIA) was induced in rats and the therapeutic effects of SIN on joint pathology were evaluated histopathologically. Next, we conducted a series of experiments using LPS-induced FLSs, which were divided into five groups (Naïve, LPS, SIN 10, 20, 50 µg/ml). The expression of inflammatory factors was measured by qPCR and ELISA. The invasive ability of cells was detected by modified Transwell assay and qPCR. Transwell migration and cell scratch assays were used to assess the migration ability of cells. The distribution and content of relevant proteins were observed by immunofluorescence and laser confocal microscopy, as well as Western Blot and qPCR. FLSs were transfected with plasmids (CRMP2 T514A/D) to directly modulate the post-translational modification of CRMP2 protein and downstream effects on FLSs function was monitored. RESULTS: SIN alleviated joint inflammation in rats with CIA, as evidenced by improvement of synovial hyperplasia, inflammatory cell infiltration and cartilage damage, as well as inhibition of pro-inflammatory cytokines release from FLSs induced by LPS. In vitro studies revealed a concentration-dependent suppression of SIN on the invasion and migration of FLSs induced by LPS. In addition, SIN downregulated the expression of cellular CRMP2 that was induced by LPS in FLSs, but increased its phosphorylation at residue T514. Moreover, regulation of pCRMP2 T514 by plasmids transfection (CRMP2 T514A/D) significantly influenced the migration and invasion of FLSs. Finally, SIN promoted nuclear translocation of pCRMP2 T514 in FLSs. CONCLUSIONS: SIN may exert its anti-inflammatory and analgesic effects by modulating CRMP2 T514 phosphorylation and its nuclear translocation of FLSs, inhibiting pro-inflammatory cytokine release, and suppressing abnormal invasion and migration. Phosphorylation of CRMP2 at the T514 site in FLSs may present a new therapeutic target for treating inflammatory joint's destruction and arthritic pain in RA.

Mulberroside A ameliorates CCl4-induced liver fibrosis in mice via inhibiting pro-inflammatory response.

Liver fibrosis is caused by a variety of pathogenic factors. It is mainly characterized by chronic liver damage mediated by the imbalance between extracellular matrix synthesis and degradation. If the injury factor cannot be removed for a long time, fibrosis will progress to cirrhosis or even cancer. The development of liver fibrosis is a very complex process which is related to the activation of hepatic stellate cells (HSCs), oxidative stress, and cytokines produced by immune cells. At present, screening of substances with anti-inflammatory activity from natural plant extracts has become a new research focus in the prevention and treatment of liver fibrosis. Mulberry twig is a commonly used traditional Chinese medicine. Pharmacological studies have shown that mulberry twig has anti-inflammatory and antioxidant activities. Thus, it is likely that Mulberry twig contains active substances with liver protection functions. The present study aimed to explore the effect of Mulberroside A (MulA), the main active ingredient from Mulberry twig, on acute liver injury induced by CCl4 in mice. MulA treatment could significantly alleviate the CCl4-induced liver injury, as evidenced by histological analysis and Masson staining. However, we observed that MulA inhibited the expressions of collagen I and α-SMA in livers of CCl4-treated mice but did not directly inhibit the proliferation and activation of HSCs. Finally, we analyzed the anti-inflammatory effect of MulA and demonstrated that it could markedly inhibit the pro-inflammatory cytokines release in liver tissues and in cultured macrophages, thereby alleviating liver fibrosis. Our findings suggest MulA as a potential therapeutic candidate for liver injury and inflammatory diseases.

NAD induces astrocyte calcium flux and cell death by ART2 and P2X7 pathway.

Mono-ADP-ribosyltransferase 2 (ART2) is found in mouse T cells and has mediated NAD-induced cell death (NICD) alongside the P2X7 pathway. We determined whether ART2 was expressed in mouse brain astrocytes and the possible function of the NAD-ART2-P2X7 pathway in astrocytes. Our results demonstrate that ART2 existed both in cultured mouse astrocytes and mouse brain slices. Exposure of astrocytes to the ART2 substrate, NAD, induced calcium elevation, which was blocked by ART2 and P2X7 inhibitors. ATP and NAD had an additive effect on calcium elevation. NICD in low-calcium conditions was blocked by ART2 and P2X7 inhibitors. The harmful effect of ATP on astrocytes was inhibited by P2X7 and ART2 inhibitors, meaning that endogenous NAD release may occur. Both NICD function and oxygen-glucose deprivation injury in mouse brain slices were also involved in the ART2-P2X7 pathway. Collectively, to our knowledge, our study provides the first evidence that ART2 exists in mouse brain astrocytes and NAD induces calcium elevation and astrocyte death by an ART2 and P2X7-mediated mechanism. The results suggest a novel approach for manipulating astrocyte death.