A new andrographolide derivative ADA targeting SIRT3-FOXO3a signaling mitigates cognitive impairment by activating mitophagy and inhibiting neuroinflammation in Apoe4 mice.

BACKGROUND: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and mitophagy deficit was identified as the typical abnormality in early stage of AD. The neuroprotective effect of andrographolide (AGA) has been confirmed, anda acetylated derivative of AGA (3,14,19-triacetylandrographolide, ADA) was considered to have stronger efficacy. PURPOSE: The current study aims to investigate the impact of ADA on cognitive ability in a sporadic AD model and explore its potential mechanism. STUDY DESIGN/ METHODS: Apoe4 mouse was adopted for evaluating the impact of AGA on cognitive impairment through a serious of behavioral tests. The molecular mechanism of ADA involved in mitophagy and neuroinflammation was investigated in detailby Western blot, ELISA, immunofluorescence and transmission electron microscopy in Apoe4 mice, as well as Apoe4-transfected BV2 cells and HT22 cells. RESULTS: ADA application significantly improved cognitive impairment of Apoe4 mice, and lessened Aß load and neuronal damage, which has stronger activity than its prototype AGA. Accumulated mitophagy markers LC3II, P62, TOM20, PINK1 and Parkin, and decreased mitophagy receptor BNIP3 in hippocampus of Apoe4 mice were greatly reversed after ADA treatment. Meanwhile, ADA promoted the recruitment of BNIP3 to mitochondria, and the transport of damaged mitochondria to lysosome, indicating that disturbed mitophagy in AD mice was restored by ADA. Inhibited SIRT3 and FOXO3a in Apoe4 mice brains were elevated after ADA treatment. ADA also lightened the neuroinflammation caused by NLRP3 inflammasome activation. Additionally, damaged mitophagy and/or activated NLRP3 inflammasome were also observed in BV2 cells and HT22 cells transfected with Apoe4, all of which were rescued by ADA incubation. Noteworthily, SIRT3 inhibitor 3-TYP could abolish the impact of ADA on mitophagy and NLRP3 inflammasome in vitro. CONCLUSION: ADA exerted stronger cognition-enhancing ability in relative to AGA, and ADA could repaire mitophagy deficiency via SIRT3-FOXO3a pathway, and subsequently inhibite NLRP3 inflammasome to mitigate AD pathology.

Network pharmacology and experimental study of phenolic acids in salvia miltiorrhiza bung in preventing ischemic stroke.

At present, the preventive effect of ischemic stroke is not ideal, and the preventive drugs are limited. Danshen, the dried root of Salvia miltiorrhiza Bge, is a common medicinal herb in Traditional Chinese Medicine, which has been used for the treatment of cardiovascular diseases for many years. Phenolic Acids extracted from danshen, which showed multiple biological activities, have been developed as an injection for the treatment of ischemic stroke. However, its preventive effect on ischemic stroke has not been fully reported. The current study aimed to identify the potential active phenolic acids for the prevention of ischemic stroke and explore its mechanism using network pharmacology and experimental analyses. The targets of phenolic acids and ischemic stroke were obtained from public databases. Network pharmacology predicted that 35 kinds of phenolic acids had 201 core targets with ischemic stroke. The core prevention targets of ischemic stroke include IL-6, AKT1, VEGFA, etc. The signaling pathways involved in core targets include AGE-RAGE signaling pathway, HIF-1 signaling pathway, and cAMP signaling pathways, etc. Then, the antiplatelet effect of phenolic acids was screened by in vitro antiplatelet experiment. Our results showed that phenolic acids have a good inhibitory effect on ADP-induced platelet aggregation and salvianolic acid A had a good antiplatelet effect. We further demonstrated that SAA preventive administration reduced neurobehavioral scores, decreased infarct size, and protected tight junction proteins in autologous thrombus stroke model. These studies not only shed light on the potential mechanisms of phenolic acids active components on ischemic stroke, but also provided theoretical and experimental information for the development of new medicines from Danshen for the prevention of ischemic stroke. In addition, our results suggest that SAA has the potential to be a candidate for ischemic stroke prevention drug.

Salvianolic acid A improve mitochondrial respiration and cardiac function via inhibiting apoptosis pathway through CRYAB in diabetic cardiomyopathy.

Salvianolic acid A (SAA) is a traditional Chinese medicine that has a good therapeutic effect on cardiovascular disease. However, the underlying mechanisms by which SAA improves mitochondrial respiration and cardiac function in diabetic cardiomyopathy (DCM) remain unknown. This study aims to elucidate whether SAA had any cardiovascular protection on the pathophysiology of DCM and explored the potential mechanisms. Diabetes was induced in rats by 30 mg/kg of streptozotocin (STZ) treatment. After a week of stability, 5 mg/kg isoprenaline (ISO) was injected into the rats subcutaneously. 3 mg/kg SAA was orally administered for six weeks and 150 mg/kg Metformin was selected as a positive group. At the end of this period, cardiac function was assessed by ultrasound, electrocardiogram, and relevant cardiac injury biomarkers testing. Treatment with SAA improved cardiac function, glucose, and lipid levels, mitochondrial respiration, and suppressed myocardial inflammation and apoptosis. Furthermore, SAA treatment inhibits the apoptosis pathway through CRYAB in diabetic cardiomyopathy rats. As a result, this study not only provides new insights into the mechanism of SAA against DCM but also provides new therapeutic ideas for the discovery of anti-DCM compounds in the clinic.

Chemical and pharmacological research on the polyphenol acids isolated from Danshen: A review of salvianolic acids.

Danshen, the dried root of Salvia miltiorrhiza Bge, is a common medicinal herb in Traditional Chinese Medicine, which has been used for the treatment of a number of diseases for thousands of years. More than 2000 years ago, the Chinese early pharmacy monograph "Shennong Materia Medica" recorded that Danshen could be used for the treatment of gastrointestinal diseases, cardiovascular diseases, certain gynecological diseases, etc. Since then, Danshen has been widely used clinically in many different prescriptions for many different diseases, especially for the treatment of cardiovascular diseases. Nowadays, many pharmacological studies about the water-soluble components from Danshen have been reported, especially salvianolic acids. It turned out that salvianolic acids showed strong anti-lipid peroxidation and anti-thrombic activities, and among them, SalAA and SalAB were the most potent. This review focused on the achievements in research of salvianolic acids regarding their bioactivities and pharmacological effects. These studies not only shed light on the water-soluble active components of Danshen and their mechanisms at the molecular level, but also provided theoretical information for the development of new medicines from Danshen for the treatment of cardiovascular and cerebrovascular diseases, inflammatory diseases, metabolic diseases, etc.

Therapeutic effects of baicalein on rotenone-induced Parkinson's disease through protecting mitochondrial function and biogenesis.

Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD) for several decades, and disturbed mitochondrial biogenesis (mitobiogenesis) was recently found to be a common phenomenon in PD. Baicalein, a major bioactive flavone of Scutellaria baicalensis Georgi, exerted neuroprotective effects in several experimental PD models. However, the effects of baicalein in rotenone-induced PD rats and the possible mechanisms remain poorly understood. In this study, we evaluated the therapeutic effects of baicalein and explored its mechanism of action in rotenone-induced PD models. The results indicated that behavioural impairments and the depletion of dopaminergic neurons induced by rotenone were attenuated by baicalein. Furthermore, in rotenone-induced parkinsonian rats, baicalein treatment effectively restored mitochondrial function and improved mitobiogenesis, as determined by measuring the mitochondrial density and key regulators involved in mitobiogenesis. Additionally, we confirmed that baicalein enhanced mitobiogenesis through the cAMP-responsive element binding protein (CREB) and glycogen synthase kinase-3ß (GSK-3ß) pathways in rotenone-treated SH-SY5Y cells. Moreover, we demonstrated that the cytoprotective effects of baicalein could be attenuated by the mitobiogenesis inhibitor chloramphenicol as well as CREB siRNA transfection. Overall, our results suggested that baicalein partially enhanced mitobiogenesis to restore mitochondrial function, thus exerting therapeutic effects in rotenone-induced PD models.

Baicalein exerts anti-neuroinflammatory effects to protect against rotenone-induced brain injury in rats.

Baicalein, a major bioactive flavone constituent isolated from Scutellaria baicalensis Georgi, has been shown to be neuroprotective in several Parkinson's disease (PD) animal models. Since neuroinflammation has been known to play a critical role in the pathogenesis of PD, potential explanation for the neuroprotective action of anti-PD compounds involves among others reduced inflammation. Our study investigated that one of the mechanisms of protection afforded by baicalein in rotenone-induced parkinsonian rats was associated with anti-inflammatory action and explored its underlying mechanism in vivo and in vitro. The results showed that baicalein treatment improved motor impairments, attenuated brain damage, suppressed the production of proinflammatory cytokines (tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6)), modulated the astrocytes and microglia activation, and blocked the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signals in rotenone-induced rats of PD. Furthermore, treatment of baicalein prominently suppressed the generation of nitric oxide (NO) and the expression of inducible NO synthase (iNOS) protein by blocking LPS-induced IκBα phosphorylation and NF-κB translocation, and downregulated the Toll-like receptor 4 (TLR4) which functions in the upstream of NF-κB signal in the activated BV2 microglia. In conclusion, our studies suggest that baicalein may be effective in the treatment of PD through anti-neuroinflammation.

The Potential of Traditional Chinese Medicine in the Treatment and Modulation of Pain.

Pain is an unpleasant sensory and emotional experience associated with various diseases. Extensive research has been conducted to find appropriate methods of relieving pain and improving the quality of life. However, the most commonly used pain-relieving agents such as opioid therapeutics are often associated with harmful side effects; moreover, users are prone to become addicted to these agents and may develop tolerance. Often, nonopioid therapeutics is only marginally effective, thus leading to a significant unmet medical need. Scientists have studied herbal medicines, finding more than 800 kinds of traditional Chinese medicine (TCM) to be effective in relieving pain while also creating several monomeric compounds to develop novel analgesic drugs. In this review, we summarize the representative TCM currently available for the treatment and modulation of pain. Ten different natural products, mainly herbs, used in Chinese medicine to relieve pain are discussed in light of the theories of TCM and modern pharmacology. We hope that this review will provide valuable information for future studies on the potential of TCM in alleviating pain.