Protective effect of Cornuside on OGD/R injury in SH-SY5Y cells and its underlying mechanism.

Apoptosis induced by oxygen-glucose deprivation/reperfusion (OGD/R) injury is the main cause of neuronal damage. Cornuside, a small-molecule cyclic enol ether terpene glycoside extracted from the dried fruit of mature Cornus officinalis Sieb. et Zucc., has vigorous anti-apoptotic and antioxidant effects. Previous studies have shown that Cornuside can reduce apoptosis and improve mitochondrial energy metabolism in cortical neurons of rats by inhibiting caspase-3 and calcium release. In this study, we treated SH-SY5Y cells with OGD/R to simulated ischemia/reperfusion (I/R) injury. Using high-throughput transcriptome sequencing, differentially expressed genes were analyzed in the OGD/R group versus the OGD/R + Cornuside (10 µmol/L) group to explore the neuroprotective mechanisms of Cornuside. The differentially expressed genes were mainly enriched in apoptosis signaling pathway, cell cycle, DNA damage and repair, and p38/JNK MAPK and p53 signaling pathways. The results showed that OGD/R significantly reduced the survival of SH-SY5Y cells, induced apoptosis, disrupted the nucleus, promoted the release of ROS, and led to cell cycle arrest. Cornuside reversed OGD/R-induced damage. By upregulating MAPK8IP1 and downregulating MAPK14, TP53INP1, and signaling pathway-related proteins (p-p38, p-JNK, and p-p53), Cornuside ameliorated cell damage induced by p38/JNK MAPK and p53 signaling pathways. Cornuside also downregulated apoptosis regulatory proteins (Bax, Bcl-2, caspase-3, caspase-9, and cytochrome c) and cell cycle regulatory proteins (cyclin B1, cyclin E, and p21).

Upregulation of A20 and TAX1BP1 contributes to the anti-neuroinflammatory and antidepressant effects of bavachalcone.

Microglia-mediated neuroinflammation is associated with a variety of disorders, including depression. Bavachalcone is a natural ingredient extracted from Psoralea corylifolia and has various pharmacological effects. However, its anti-neuroinflammatory and antidepressant effects remain unclear. In the present study, we found that bavachalcone improved lipopolysaccharide-induced depressive-like behaviors in mice and exerted an inhibitory effect on the activation of microglia in brain tissue. Further study revealed that bavachalcone inhibited the expression of TRAF6 and the activation of the NF-κB pathway in lipopolysaccharide-induced in vitro and vivo models, while bavachalcone upregulated the expression of A20 and TAX1BP1 and enhanced their interactions. In addition, bavachalcone inhibited the production of pro-inflammatory cytokines TNF-α and IL-6. Transfection with siRNA treatment showed that downregulation of A20 and TAX1BP1 weakened the anti-neuroinflammatory effect of bavachalcone. In conclusion, these results are the first to demonstrate that bavachalcone exerts anti-neuroinflammatory and antidepressant effects via inhibition of the NF-κB pathway mediated by upregulating A20 and TAX1BP1, and may be a potential candidate for the treatment of neuroinflammation-related diseases, including depression.

Effect of Dihuang Yinzi on Inflammatory Response in Cerebral Ischemia-Reperfusion Model Rats by Regulating Gut Microbiota.

Dihuang Yinzi, as a classical Chinese medicine prescription, plays an important role for the treatment of ischemic stroke. Gut microbiota play a functional role for the expression of proinflammatory cytokines and anti-inflammatory cytokines, which further affect central nervous system and change brain function. Our research confirmed that Dihuang Yinzi can exert brain protection by inhibiting inflammatory reaction. Dihuang Yinzi can significantly decrease the contents of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-17 (IL-17) in brain, serum, and colon tissues and increase the contents of transforming growth factor-ß (TGF-ß) and interleukin-10 (IL-10) in cerebral ischemia-reperfusion model rats. The results of 16s rRNA high-throughput sequencing showed that Dihuang Yinzi had a significant effect on microbiome in rats. The firmicutes, bacteroidetes, and proteobacteria were dominant in Dihuang Yinzi group. The content of firmicutes increased with the increase of dosage of Dihuang Yinzi. Especially, the content of actinomycetes in the high-dose group was higher than other groups. At the genus level, the number of bacteroides in the antibiotic groups was significantly higher than that in the other treatment groups. The results suggest that Dihuang Yinzi may play important roles in treatment of ischemic stroke by regulating the gut microbiota and the inflammatory reaction in the colon tissues, serum, and brain of the model rats, to verify the scientific nature of this prescription in relieving brain inflammatory reaction and brain injury by this way and to reveal the brain-gut related mechanism of Dihuang Yinzi in treating ischemic stroke.

The Effects of Enriched Rehabilitation on Cognitive Function and Serum Glutamate Levels Post-stroke.

Aim: This study aimed to explore the effect of enriched rehabilitation (ER) on cognitive function and serum glutamate levels in patients with stroke. Methods: Forty patients diagnosed with post-stroke cognitive impairment (PSCI), according to the inclusion criteria, and undergoing inpatient rehabilitation were enrolled in the study. Patients were randomly assigned to receive 8 weeks of ER treatment (ER group; n = 20) or conventional medical treatment (CM group; n = 20). In addition, 20 age-matched healthy subjects who were outpatients in our hospital during the same period formed the healthy control (HC) group. In- and between-group differences in cognitive function were assessed during pre-intervention and post-intervention based on the Montreal Cognitive Assessment (MoCA), the Symbol Digit Modalities Test (SDMT), and the Trail Making Test (TMT). The serum levels of glutamate, tumor necrosis factor (TNF), and malondialdehyde (MDA) levels were also detected pre-intervention and post-intervention. Results: Pre-intervention cognitive function and the levels of all the serum parameters assessed significant difference between the HC group and the PSCI group (both ER and CM groups) (p < 0.05), but not between the two groups of patients with PSCI (p > 0.05). Significant improvements were observed in cognitive function in both the ER and the CM groups post-intervention compared with pre-intervention, as evidenced by the measured improvement in MoCA, SDMT, and TMT scores. Similar improvements were seen for serum glutamate, the degree of oxidative damage, and the level of inflammation in both the treatment groups (p < 0.05). More enhancements in cognitive function, including MoCA, SDMT, TMT scores, and the serum levels of glutamate, the degree of oxidative damage, and the level of inflammation were shown in the ER group compared with the CM group post-intervention (p < 0.05). Conclusions: ER can improve cognitive function in patients with PSCI. The associated mechanism may be related to the negative regulatory effect of ER on serum glutamate, TNF, and MDA levels, which is likely to enhance synaptic plasticity and alleviate oxidative stress- and inflammation-related damage, at least to some extent.

Alteronol Enhances the Anti-tumor Activity and Reduces the Toxicity of High-Dose Adriamycin in Breast Cancer.

The first-line chemotherapy drug adriamycin (ADM) is widely used for the treatment of breast cancer, but the acquired drug resistance and the normal tissue toxicity remain clinical challenges. Alteronol has been reported to exert wide-ranging anti-tumor activity. In this study, we firstly examined the synergistic anti-tumor effects and the underlying mechanisms of alteronol combined with ADM in breast cancer. We have found that the combination of alteronol and ADM significantly suppressed the expression levels of the cell cycle-related proteins (CDC2 and Cyclin B1) and induced cell cycle arrest at the G2/M phase, leading to cell proliferation inhibition in breast cancer 4T1 cells. Moreover, co-treatment of alteronol and ADM (i) remarkably activated p38 and JNK kinases, (ii) elevated ROS levels, (iii) triggered mitochondrial dysfunction, (iv) released cytochrome c into the cytoplasm, (v) upregulated apoptosis-related proteins, e.g., cleaved PARP, Bax, and cleaved caspase-3/9, and (vi) downregulated the expression of Bcl-2, followed by apoptosis. Furthermore, our in vivo studies showed that the low-dose combination of alteronol (2 mg/kg) and ADM (1 mg/kg) significantly inhibited tumor growth in tumor bearing mice, and the anti-tumor effect of the combination was the same as that of high-dose ADM (8 mg/kg). In addition, the low-dose combination group showed lower toxicities to major organs than the high-dose ADM group. Taken together, these data demonstrate that the low-dose combination of alteronol and ADM could notably improve the anti-tumor activity and have lower toxicities to major organs than those in high-dose ADM group.