Driving GABAergic neurons optogenetically improves learning, reduces amyloid load and enhances autophagy in a mouse model of Alzheimer's disease.

The changes of local field potentials (LFP, mainly gamma rhythm and theta rhythm) in the brain are closely related to learning and memory formation. Reduced gamma rhythm (20-50 Hz) and theta rhythm (4-10 Hz) has been observed in the progression of Alzheimer's disease (AD), but it is not clear whether it is related to cognition in AD. Here, we investigated behaviorally driven gamma rhythm and theta rhythm in APP/PS1 mice, and optogenetically stimulated GABAergic neurons in the brain to better understand the relationship between the changes of LFP, cognition, and cellular pathologies. Optogenetically driving GABAergic neurons rescued memory formation in a water maze task and normalized theta and gamma rhythm in the EEG. Furthermore, the optogenetic stimulation alleviated neuroinflammation and levels of amyloid-ß (Aß)1-42 fragments, and induced autophagy. GABA blockers also reversed the normalization of theta and gamma rhythms in the brain by optogenetic stimulation. The results demonstrate that stimulation of GABAergic interneurons not only rescues LFP rhythms and memory formation, but furthermore activates autophagy and reduces neuroinflammation, which have beneficial additional effects such as clearing amyloid. This is a proof of concept for a novel therapeutic approach to AD treatment.

Tanshinone IIA attenuates valvular interstitial cells' calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress.

Recent studies revealed that endoplasmic reticulum (ER) stress played an emerging role of in valve calcification. Tanshinone IIA (TanIIA) has been a research hotspot in cardiovascular diseases. Previously we found that sodium TanIIA dampened the pathological phenotype transition of valvular interstitial cells (VICs) by affecting ER stress published in Chinese Journal. Here, we test the hypothesis that TanIIA attenuates the pro-osteogenic effects of oxidized low-density lipoprotein (oxLDL) in VICs by reducing induction of ER stress. Patients' aortic valve (AV) was collected, and porcine VICs were cultured for in vitro model. ER stress markers were tested in human leaflets by immunostaining. Immunoblotting were used to test the osteoblastic factors such as Runx2, osteocalcin, and ER stress markers GRP78, CHOP, XBP1, etc. Alkakine phosphate (ALP) activity assay were used to test the activity of ALP kinase. Pro-inflammatory gene expression was detected by polymerase chain reaction. As a result, ER stress markers were elevated in patients' calcified AVs. OxLDL induced osteogenesis and inflammation via promoting ER stress. TanIIA attenuated oxLDL induced ER stress. TanIIA also inhibited theosteoblastic factors and inflammatory cytokine expressions in VICs. In conclusion, our data provide evidence that TanIIA exerts anti-inflammation and anti-osteogenic effects in VICs by attenuating ER stress, and ER stress acts as an important regulator in oxLDL induced VICs' phenotype transition.

MicroRNA-101 Targets CXCL12-Mediated Akt and Snail Signaling Pathways to Inhibit Cellular Proliferation and Invasion in Papillary Thyroid Carcinoma.

Escalating evidence suggests that microRNA-101 (miR-101) is implicated in the development and progression of various cancers, including papillary thyroid carcinoma (PTC). However, the biological function and molecular mechanisms of miR-101 in PTC are still unclear. In this study, we demonstrated that miR-101 expression was significantly decreased in PTC tissues and cell lines. Clinically, a low level of miR-101 was positively associated with advanced histological stages and lymph node and distant metastases. The expression of CXCL12 was negatively correlated with miR-101 level in PTC. CXCL12 was validated as a direct target of miR-101 in PTC cells. Functional experiments proved that miR-101 markedly reduced the proliferation, apoptosis escape, migration, and invasion of PTC cells. Moreover, CXCL12 restoration rescued the suppressive effects of miR-101 on PTC cells by activating Akt- and EMT-associated signaling pathways. Overall, miR-101 exerts oncostatic effects on PTC by downregulating CXCL12 and repressing its downstream Akt and Snail signaling pathways, suggesting that miR-101/CXCL12/Akt or Snail axis may serve as a potential therapeutic target for PTC.

Tong Luo Jiu Nao, a Chinese Medicine Formula, Reduces Inflammatory Stress in a Mouse Model of Alzheimer's Disease.

AIM: The aim of this study is to extend the molecular mechanism of Tong Luo Jiu Nao (TLJN) for Alzheimer's disease (AD), which is a modern Chinese formula that has been used to treat AD. METHODS: The senescence-accelerated mouse prone 8 strain (SAMP8) is one of the most appropriate models to study the mechanism that underlies AD. The levels of plasma amyloid ß (Aß) and the Aß deposits were measured using enzyme-linked immunosorbent assay and immunohistochemistry. Immunoblotting was used to observe the effect of TLJN on inflammatory mediator expression in an senescence-accelerated mouse model of AD. RESULTS: Our data showed that the TLJN-treated groups exhibited a reduction in plasma Aß levels and reduced Aß expression. Moreover, TLJN effectively attenuated Aß-induced activation of extracellular signal-regulated kinase and c-Jun N-terminal kinases and blocked changes in inflammatory mediator expression. CONCLUSION: These data suggest that TLJN might have protective effects and could potentially act to attenuate inflammatory stress in the pathogenesis of AD.

Antihyperlipidaemic and antioxidant effect of the total flavonoids in Selaginella tamariscina (Beauv.) Spring in diabetic mice.

OBJECTIVES: To investigate the antidiabetic, antihyperlipidaemic and antioxidant activity of total flavonoids in Selaginella tamariscina (Beauv.) Spring (TFST) in a mouse model of diabetes. METHODS: Normal mice, mice fed with a high-fat emulsion diet and streptozotocin (STZ)-induced diabetic mice were treated with TFST for 6 weeks. Serum glucose, insulin and lipid, hepatic steatosis, production of the protein visfatin and antioxidant indices were evaluated. KEY FINDINGS: TFST significantly decreased the concentration of fasting blood glucose, total cholesterol, triglycerides and low-density-lipoprotein cholesterol, while it increased the levels of insulin and high-density-lipoprotein cholesterol in diabetic mice. TFST also improved the results of the oral glucose tolerance test to a certain degree. Furthermore, both the free fatty acid levels in the liver and hepatic steatosis were ameliorated by TFST treatment. These changes may be be associated with decreased production of visfatin. Administration of TFST also significantly decreased the levels of malondialdehyde, nitric oxide and inducible nitric oxide synthase and increased the content of glutathione and the activity of superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase in the liver. No change in blood glucose levels were observed in the normal mice treated with TFST. CONCLUSIONS: TFST showed an excellent effect in reducing the high blood glucose level but had no effect on normal blood glucose level. The antidiabetic activity of TFST could be explained by its antioxidant and antihyperlipidaemic activity, which finally elevated the insulin sensitivity of liver.