Protective Effect of Hydroxysafflor Yellow A against Chronic Mild Stress-induced Memory Impairments by Suppressing Tau Phosphorylation in Mice.

Chronic stress plays a critical role in the etiology of sporadic Alzheimer's disease (AD). However, there are currently no effective drugs that can target chronic stress to prevent AD. In this study, we explored the neuroprotective effect of hydroxysafflor yellow A (HSYA) against chronic mild stress (CMS)-induced memory impairments in mice and the underlying mechanism. The Morris water maze test showed that HSYA significantly reduced CMS-induced learning and memory impairments in mice. HSYA increased the expression of brain-derived neurotrophic factor (BDNF) and activated downstream tropomyosin-related kinase B (TrkB) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B(Akt)/mammalian target of rapamycin (mTOR) signaling. HSYA decreased the expression of regulator of calcineurin 1-1L (RCAN1-1L) that could promote the activity of glycogen synthase kinase-3ß (GSK-3ß). HSYA also attenuated tau phosphorylation by inhibiting the activity of GSK-3ß and cyclin-dependent kinase-5 (Cdk5). Our data indicated that HSYA has protective effects against CMS-induced BDNF downregulation, tau phosphorylation and memory impairments. HSYA may be a promising therapeutic candidate for AD by targeting chronic stress.

Anti-inflammatory effects of paeoniflorin caused by regulation of the hif1a/miR-210/caspase1/GSDMD signaling pathway in astrocytes: a novel strategy for hypoxia-induced brain injury in rats.

Context: Hypoxia-induced injury is a classic symptom of obstructive sleep apnea hypopnea syndrome (OSAHS), which is a risk factor of various diseases, such as hypertension, heart failure and stroke. However, there is no effective therapy for hypoxia-induced injury or OSAHS due to the elusive mechanism involved.Objective: This study aimed to assess the effects of paeoniflorin on hypoxia-induced injury and explore the underlying mechanism.Materials and methods: Hypoxic models of SD rats and CTX-TNA2 cells were used to assess the effect of paeoniflorin, and the expressions of hif1a, miR-210, caspase1 and GSDMD were detected using western blots and RT-PCR. Plasmid transfection was performed to explore the role of miR-210 in the effect of paeoniflorin.Results: Firstly, we confirmed that hypoxia induced severe neuronal injury and an enhancement of inflammation in the rat brain, with elevated expression of caspase1, IL1b and IL18. In addition, the results showed an activation of astrocytes and an increased level of pyroptosis under hypoxic conditions, which suggested a critical role of pyroptosis in hypoxiainduced injury of the brain. Furthermore, we found that compared with the controls, paeoniflorin treatment improved hypoxia-induced pyroptosis in astrocytes. Moreover, we detected the activation of hif1a/miR-210 signaling in the effects of paeoniflorin on astrocytes. As expected, the expression of hif1a and miR-210 was significantly upregulated in astrocytes when exposed to hypoxia, while paeoniflorin treatment reversed these enhancements. After transfection of miR-210 mimics, the attenuation of pyroptosis induced by paeoniflorin was suppressed, which was accompanied by an increase of ROS levels, as well as LDH release, indicating a critical role of miR-210 in pyroptosis in astrocytes.Conclusions: Our findings demonstrated that paeoniflorin improved hypoxia-induced pyroptosis in astrocytes via depressing hif1a/miR-210/caspase1/GSDMD signaling, providing robust evidence for the treatment of hypoxic injury and OSAHS.HighlightsHypoxia induces severe injury and inflammatory response in the rat brain;Hypoxia enhanced pyroptotic level and led to an activation of astrocytes.;Paeoniflorin alleviates hypoxia-induced pyroptosis in astrocytes;Transfection of miR-210 mimics suppressed the effects of paeoniflorin on hypoxia-induced pyroptosis in astrocytes.

The Chinese Herb Codonopsis pilosula Isolate Isorhapontigenin protects against oxidative stress injury by inhibiting the activation of PI3K/Akt signaling pathway.

We investigated the effects of the Chinese herb Codonopsis pilosula isolate isorhapontigenin on antioxidant factor and the PI3K/Serine/Akt signaling pathway in Parkinson's disease. This research was, therefore, carried out to explore a possible protective mechanism of isorhamnetin in Parkinson's disease. The results support that isorhapontigenin could effectively inhibit isorhapontigenin restored myeloperoxidase + induced reduction of antioxidant levels. Also, 1-Methyl-4-phenylpyridine up-regulated the expression of phosphorylated-Akt, phosphorylated-PI3K, and phosphorylated mammalian target of rapamycin, while isorhapontigenin inhibited the expression of phosphorylated-Akt, phosphorylated-PI3K, and phosphorylated- mammalian target of rapamycin. Furthermore, LY294002 improved the antioxidant effect of isorhapontigenin in PC12 cells, and insulin-like growth factor 1 inhibited the antioxidant effect of isorhapontigenin in PC12 cells. Our results support the finding that isorhamnetin enhanced the antioxidant effect induced by 1-Methyl-4-phenylpyridine in PC12 cells by suppressing the activation of the PI3K/Akt signaling pathway.

Chemerin-9 Peptide Enhances Memory and Ameliorates Aß1-42-Induced Object Memory Impairment in Mice.

Accumulating evidence suggests that the inhibition of neuroinflammation is a potential target for therapeutic or preventive strategies for Alzheimer's disease (AD). Chemerin has attracted particular attention for its role in the regulation of inflammation. In addition, amyloid ß1-42 (Aß1-42) can interact with chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, and induce microglial chemotaxis. Meanwhile, CMKLR1 is expressed in the brain, and both chemerin and Aß1-42 share the same receptor. Thus, we hypothesized that chemerin (C9), a chemerin-derived nonapeptide, may have the potential to ameliorate Aß1-42 mediated AD disease progression. The results showed that an intracerebroventricular (i.c.v.) injection of C9 (8 µg/kg) facilitated memory formation and improved memory retention, as evidenced by the results of both the novel object recognition test (NOR) and object location recognition (OLR) tasks. These memory-enhancing effects of C9 were also observed after C9 (2 µg/kg) was infused into the hippocampus. Moreover, we found that treatment with C9 reversed the deficits in memory and learning ability induced by oligomeric Aß1-42. Meanwhile, C9 also significantly inhibited Aß1-42-induced increases in the levels of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the hippocampus. The same results were obtained for Western blotting and enzyme-linked immunosorbent assay (ELISA) experiments. Finally, we observed that C9 did not affect locomotor activity, suggesting that its improvement of memory is not a false positive induced by hypolocomotion. In conclusion, C9 may facilitate memory formation, prolong memory retention, and ameliorate Aß1-42-induced memory impairment, suggesting that C9 may potentially represent a novel strategy for the treatment of AD.

Losartan protects against intermittent hypoxia-induced peritubular capillary loss by modulating the renal renin-angiotensin system and angiogenesis factors.

Obstructive sleep apnea is characterized by chronic intermittent hypoxia (CIH), which is a risk factor for renal peritubular capillary (PTC) loss, and angiotensin II receptor blockers can alleviate PTC loss. However, the mechanism by which losartan (an angiotensin II receptor blocker) reduces CIH-induced PTC loss and attenuates kidney damage is still unknown. Thus, in this study, we examined the protective effects of losartan against CIH-induced PTC loss and explored the underlying mechanisms in rat CIH model. The immunohistochemical staining of CD34 and morphological examination showed that CIH reduced PTC density and damaged tubular epithelial cells. Immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR, and western blot analysis results revealed that CIH increased the expression of hypoxia inducible factor-1α (HIF-1α), angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R), pro-angiogenesis factor vascular endothelial growth factor (VEGF), and anti-angiogenesis factor thrombospondin-1 (TSP-1) in the renal cortex of rats. CIH may up-regulate VEGF expression and simultaneously increase TSP-1 production. By histopathological, immunohistochemistry, ELISA, RT-qPCR, and western blot analysis, we found that the expressions of renal renin-angiotensin system (RAS), HIF-1α, VEGF, and TSP-1 were decreased, and PTC loss and tubular epithelial cell injury were attenuated with losartan treatment. Losartan ameliorated CIH-induced PTC loss by modulating renal RAS to improve the crosstalk between endothelial cells and tubular epithelial cells and subsequently regulate the balance of angiogenesis factors. Our study provided novel insights into the mechanisms of CIH-induced kidney damage and indicated that losartan could be a potential therapeutic agent for renal protection by alleviating CIH-induced PTC loss.