Myricetin improves pathological changes in 3×Tg-AD mice by regulating the mitochondria-NLRP3 inflammasome-microglia channel by targeting P38 MAPK signaling pathway.

BACKGROUND: Alzheimer's disease (AD) represents the common neurodegenerative disease featured by the manifestations of cognitive impairment and memory loss. AD could be alleviated with medication and improving quality of life. Clinical treatment of AD is mainly aimed at improving the cognitive function of patients. Donepezil, memantine and galantamine are commonly used drug. But they could only relieve AD, not cure it. Therefore, new treatment strategies focusing on AD pathogenesis are of great significance and value. Myricetin (Myr) is a natural flavonoid extracted from Myrica rubra. And it shows different bioactivities, such as anti-inflammation, antioxidation as well as central nervous system (CNS) activities. Nonetheless, its associated mechanism in treating AD remains unknown. PURPOSE: Here we focused on investigating Myr's effect on treating AD and exploring if its protection on the nervous system activity was associated with specifically inhibiting P38 MAPK signaling pathway while regulating mitochondria-NLRP3 inflammasome-microglia. STUDY DESIGN AND METHODS: This work utilized triple transgenic mice (3 × Tg-AD) as AD models and Aß25-35 was used to induce BV2 cells to build an in vitro AD model. Behavioristics, pathology and related inflammatory factors were examined. Molecular mechanisms are investigated by western-blot, immunofluorescence staining, CETSA, molecular docking, network pharmacology. RESULTS: According to our findings, Myr could remarkably improve memory loss, spatial learning ability, Aß plaque deposition, neuronal and synaptic damage in 3 × Tg-AD mice through specifically inhibiting P38 MAPK pathway activation while restraining microglial hyperactivation. Furthermore, Myr promoted the transformation of microglial phenotype, restored the mitochondrial fission-fusion balance, facilitated mitochondrial biogenesis, and restrained NLRP3 inflammasome activation and neuroinflammation. For the in-vitro experiments, P38 agonist dehydrocorydaline (DHC) was utilized to confirm the key regulatory role of P38 MAPK signaling pathway on the mitochondria-NLRP3 inflammasome-microglia channel. CONCLUSIONS: Our results revealed the therapeutic efficacy of Myr in experimental AD, and implied that the associated mechanism is possibly associated with inhibiting tmitochondrial dysfunction, activating NLRP3 inflammasome, and neuroinflammation which was mediated by P38 MAPK pathway. Myr is the drug candidate in AD therapy via targeting P38 MAPK pathway.

Loganin alleviated cognitive impairment in 3×Tg-AD mice through promoting mitophagy mediated by optineurin.

ETHNOPHARMACOLOGICAL RELEVANCE: Corni Fructus is a traditional Chinese herb and widely applied for treatment of age-related disorders in China. Iridoid glycoside was considered as the active ingredient of Corni Fructus. Loganin is one of the major iridoid glycosides and quality control components of Corni Fructus. Emerging evidence emphasized the beneficial effect of loganin on neurodegenerative disorders, such as Alzheimer's disease (AD). However, the detailed mechanism underlying the neuroprotective action of loganin remains to be unraveled. AIM OF THE STUDY: To explore the improvement of loganin on cognitive impairment in 3 × Tg-AD mice and reveal the potential mechanism. MATERIALS AND METHODS: Eight-month 3 × Tg-AD male mice were intraperitoneally injected with loganin (20 and 40 mg/kg) for consecutive 21 days. Behavioral tests were used to evaluated the cognition-enhancing effects of loganin, and Nissl staining and thioflavine S staining were performed to analyze neuronal survival and Aß pathology. Western blot analysis, transmission electron microscopy and immunofluorescence were utilized to explore the molecular mechanism of loganin in AD mice involved mitochondrial dynamics and mitophagy. Aß25-35-induced SH-SY5Y cells were applied to verify the potential mechanism in vitro. RESULTS: Loganin significantly mitigated the learning and memory deficit and amyloid ß-protein (Aß) deposition, and recovered synaptic ultrastructure in 3 × Tg-AD mice. Perturbed mitochondrial dynamics characterized by excessive fission and insufficient fusion were restored after loganin treatment. Meanwhile, loganin reversed the increase of mitophagy markers (LC3II, p62, PINK1 and Parkin) and mitochondrial markers (TOM20 and COXIV) in hippocampus of AD mice, and enhanced the location of optineurin (OPTN, a well-known mitophagy receptor) to mitochondria. Accumulated PINK1, Parkin, p62 and LC3II were also revealed in Aß25-35-induced SH-SY5Y cells, which were ameliorated by loganin. Increased OPTN in Aß25-35-treated SH-SY5Y cells was further upregulated by loganin incubation, along with the reduction of mitochondrial ROSand elevation ofmitochondrial membrane potential (MMP). Conversely, OPTN silence neutralized the effect of loganin on mitophagy and mitochondrial function, which is consistent with the finding that loganin presented strong affinity with OPTN measured by molecular docking in silico. CONCLUSIONS: Our observations confirmed that loganin enhanced cognitive function and alleviated AD pathology probably by promoting OPTN-mediated mitophagy,. Loganin might be a potential drug candidate for AD therapy via targeting mitophagy.

Research Progress of Traditional Chinese Medicine Monomers in Reversing Multidrug Resistance of Breast Cancer.

Breast cancer is a malignant disease with an increasing incidence. Chemotherapy is still an important means for breast cancer treatment, but multidrug resistance (MDR) greatly limits its clinical application. Therefore, the high-efficiency MDR reversal agents are urgently needed. Traditional Chinese medicine (TCM) monomers have unique advantages in reversing chemotherapeutic MDR because of its low toxicity, high efficiency, and ability to impact multiple targets. This review firstly summarizes the major mechanisms of MDR in breast cancer, including the reduced accumulation of intracellular chemotherapeutic drugs, the promoted inactivation of intracellular chemotherapeutic drugs, and the enhanced damage repair ability of DNA, etc., and secondly highlights the research progress of 15 kinds of TCM monomers, including curcumin, resveratrol, emodin, apigenin, tetrandrine, gambogic acid, matrine, paeonol, schisandrin B, [Formula: see text]-elemene, astragaloside IV, berberine, puerarin, tanshinone IIA, and quercetin, in reversing MDR of breast cancer. This review also provides the suggestion for the future research of MDR reversal agents in breast cancer.