Notoginsenoside R1 treatment facilitated Nrf2 nuclear translocation to suppress ferroptosis via Keap1/Nrf2 signaling pathway to alleviated high-altitude myocardial injury.

High-altitude myocardial injury (HAMI) represents a critical form of altitude illness for which effective drug therapies are generally lacking. Notoginsenoside R1, a prominent constituent derived from Panax notoginseng, has demonstrated various cardioprotective properties in models of myocardial ischemia/reperfusion injury, sepsis-induced cardiomyopathy, cardiac fibrosis, and myocardial injury. The potential utility of notoginsenoside R1 in the management of HAMI warrants prompt investigation. Following the successful construction of a HAMI model, a series of experimental analyses were conducted to assess the effects of notoginsenoside R1 at dosages of 50 mg/Kg and 100 mg/Kg. The results indicated that notoginsenoside R1 exhibited protective effects against hypoxic injury by reducing levels of CK, CK-MB, LDH, and BNP, leading to improved cardiac function and decreased incidence of arrhythmias. Furthermore, notoginsenoside R1 was found to enhance Nrf2 nuclear translocation, subsequently regulating the SLC7A11/GPX4/HO-1 pathway and iron metabolism to mitigate ferroptosis, thereby mitigating cardiac inflammation and oxidative stress induced by high-altitude conditions. In addition, the application of ML385 has confirmed the involvement of Nrf2 nuclear translocation in the therapeutic approach to HAMI. Collectively, the advantageous impacts of notoginsenoside R1 on HAMI have been linked to the suppression of ferroptosis via Nrf2 nuclear translocation signaling.

Notoginsenoside R1 protects against hypobaric hypoxia-induced high-altitude pulmonary edema by inhibiting apoptosis via ERK1/2-P90rsk-BAD ignaling pathway.

High-altitude pulmonary edema (HAPE) is a potentially fatal disease. Notoginsenoside R1 is a novel phytoestrogen with anti-inflammatory, antioxidant and anti-apoptosis properties. However, its effects and underlying mechanisms in the protection of hypobaric hypoxia-induced HAPE rats remains unclear. This study aimed to explore the protective effects and underlying mechanisms of Notoginsenoside R1 in hypobaric hypoxia-induced HAPE. We found that Notoginsenoside R1 alleviated the lung tissue injury, decreased lung wet/dry ratio, and reduced inflammation and oxidative stress. Additionally, Notoginsenoside R1 ameliorated the changes in arterial blood gas, decreased the total protein concentration in bronchoalveolar lavage fluid, and inhibited the occurrence of apoptosis caused by HAPE. In the process of further exploration of the mechanism, it was found that Notoginsenoside R1 could promote the activation of ERK1/2-P90rsk-BAD signaling pathway, and the effect of Notoginsenoside R1 was attenuated after the use of ERK1/2 inhibitor U0126. Our study indicated that the protective effects of Notoginsenoside R1 against HAPE were mainly related to the inhibition of inflammation, oxidative stress, and apoptosis. Notoginsenoside R1 may be a potential candidate for preventing HAPE.

Protective effects of Eleutheroside E against high-altitude pulmonary edema by inhibiting NLRP3 inflammasome-mediated pyroptosis.

Eleutheroside E (EE) is a primary active component of Acanthopanax senticosus, which has been reported to inhibit the expression of inflammatory genes, but the underlying mechanisms remain elusive. High-altitude pulmonary edema (HAPE) is a severe complication of high-altitude exposure occurring after ascent above 2500 m. However, effective and safe preventative measures for HAPE still need to be improved. This study aimed to elucidate the preventative potential and underlying mechanism of EE in HAPE. Rat models of HAPE were established through hypobaric hypoxia. Mechanistically, hypobaric hypoxia aggravates oxidative stress and upregulates (pro)-inflammatory cytokines, activating NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis, eventually leading to HAPE. EE suppressed NLRP3 inflammasome-mediated pyroptosis by inhibiting the nuclear translocation of nuclear factor kappa-Β (NF-κB), thereby protecting the lung from HAPE. However, nigericin (Nig), an NLRP3 activator, partially abolished the protective effects of EE. These findings suggest EE is a promising agent for preventing HAPE induced by NLRP3 inflammasome-mediated pyroptosis.

Eleutheroside E from pre-treatment of Acanthopanax senticosus (Rupr.etMaxim.) Harms ameliorates high-altitude-induced heart injury by regulating NLRP3 inflammasome-mediated pyroptosis via NLRP3/caspase-1 pathway.

Eleutheroside E, a major natural bioactive compound in Acanthopanax senticosus (Rupr.etMaxim.) Harms, possesses anti-oxidative, anti-fatigue, anti-inflammatory, anti-bacterial and immunoregulatory effects. High-altitude hypobaric hypoxia affects blood flow and oxygen utilisation, resulting in severe heart injury that cannot be reversed, thereby eventually causing or exacerbating high-altitude heart disease and heart failure. The purpose of this study was to determine the cardioprotective effects of eleutheroside E against high-altitude-induced heart injury (HAHI), and to study the mechanisms by which this happens. A hypobaric hypoxia chamber was used in the study to simulate hypobaric hypoxia at the high altitude of 6000 m. 42 male rats were randomly assigned to 6 equal groups and pre-treated with saline, eleutheroside E 100 mg/kg, eleutheroside E 50 mg/kg, or nigericin 4 mg/kg. Eleutheroside E exhibited significant dose-dependent effects on a rat model of HAHI by suppressing inflammation and pyroptosis. Eleutheroside E downregulated the expressions of brain natriuretic peptide (BNP), creatine kinase isoenzymes (CK-MB) and lactic dehydrogenase (LDH). Moreover, The ECG also showed eleutheroside E improved the changes in QT interval, corrected QT interval, QRS interval and heart rate. Eleutheroside E remarkably suppressed the expressions of NLRP3/caspase-1-related proteins and pro-inflammatory factors in heart tissue of the model rats. Nigericin, known as an agonist of NLRP3 inflammasome-mediated pyroptosis, reversed the effects of eleutheroside E. Eleutheroside E prevented HAHI and inhibited inflammation and pyroptosis via the NLRP3/caspase-1 signalling pathway. Taken together, eleutheroside E is a prospective, effective, safe and inexpensive agent that can be used to treat HAHI.

Pretreatment with Notoginsenoside R1 attenuates high-altitude hypoxia-induced cardiac injury via activation of the ERK1/2-P90RSK-Bad signaling pathway in rats.

High-altitude cardiac injury (HACI) is one of the common tissue injuries caused by high-altitude hypoxia that may be life threatening. Notoginsenoside R1 (NG-R1), a major saponin of Panax notoginseng, exerts anti-oxidative, anti-inflammatory, and anti-apoptosis effects, protecting the myocardium from hypoxic injury. This study aimed to investigate the protective effect and molecular mechanism of NG-R1 against HACI. We simulated a 6000 m environment for 48 h in a hypobaric chamber to create a HACI rat model. Rats were pretreated with NG-R1 (50, 100 mg/kg) or dexamethasone (4 mg/kg) for 3 days and then placed in the chamber for 48 h. The effect of NG-R1 was evaluated by changes in Electrocardiogram parameters, histopathology, cardiac biomarkers, oxidative stress and inflammatory indicators, key protein expression, and immunofluorescence. U0126 was used to verify whether the anti-apoptotic effect of NG-R1 was related to the activation of ERK pathway. Pretreatment with NG-R1 can improve abnormal cardiac electrical conduction and alleviate high-altitude-induced tachycardia. Similar to dexamethasone, NG-R1 can improve pathological damage, reduce the levels of cardiac injury biomarkers, oxidative stress, and inflammatory indicators, and down-regulate the expression of hypoxia-related proteins HIF-1α and VEGF. In addition, NG-R1 reduced cardiomyocyte apoptosis by down-regulating the expression of apoptotic proteins Bax, cleaved caspase 3, cleaved caspase 9, and cleaved PARP1 and up-regulating the expression of anti-apoptotic protein Bcl-2 through activating the ERK1/2-P90RSK-Bad pathway. In conclusion, NG-R1 prevented HACI and suppressed apoptosis via activation of the ERK1/2-P90RSK-Bad pathway, indicating that NG-R1 has therapeutic potential to treat HACI.

Sipeimine attenuates PM2.5-induced lung toxicity via suppression of NLRP3 inflammasome-mediated pyroptosis through activation of the PI3K/AKT pathway.

Exposure to fine particulate matter (PM2.5), an environmental pollutant, significantly contributes to the incidence of and risk of mortality associated with respiratory diseases. Sipeimine (Sip) is a steroidal alkaloid in fritillaries that exerts antioxidative and anti-inflammatory effects. However, protective effect of Sip for lung toxicity and its mechanism to date remains poorly understood. In the present study, we investigated the lung-protective effect of Sip via establishing the lung toxicity model of rats with orotracheal instillation of PM2.5 (7.5 mg/kg) suspension. Sprague-Dawley rats were intraperitoneally administered with Sip (15 mg/kg or 30 mg/kg) or vehicle daily for 3 days before instillation of PM2.5 suspension to establish the model of lung toxicity. The results found that Sip significantly improved pathological damage of lung tissue, mitigated inflammatory response, and inhibited lung tissue pyroptosis. We also found that PM2.5 activated the NLRP3 inflammasome as evidenced by the upregulation levels of NLRP3, cleaved-caspase-1, and ASC proteins. Importantly, PM2.5 could trigger pyroptosis by increased levels of pyroptosis-related proteins, including IL-1ß, cleaved IL-1ß, and GSDMD-N, membrane pore formation, and mitochondrial swelling. As expected, all these deleterious alterations were reversed by Sip pretreatment. These effects of Sip were blocked by the NLRP3 activator nigericin. Moreover, network pharmacology analysis showed that Sip may function via the PI3K/AKT signaling pathway and animal experiment validate the results, which revealed that Sip inhibited NLRP3 inflammasome-mediated pyroptosis by suppressing the phosphorylation of PI3K and AKT. Our findings demonstrated that Sip inhibited NLRP3-mediated cell pyroptosis through activation of the PI3K/AKT pathway in PM2.5-induced lung toxicity, which has a promising application value and development prospect against lung injury in the future.

Pretreatment with rosavin attenuates PM2.5-induced lung injury in rats through antiferroptosis via PI3K/Akt/Nrf2 signaling pathway.

Inflammation and oxidative stress caused by fine particulate matter (PM2.5) increase the incidence and mortality rates of respiratory disorders. Rosavin is the main chemical component of Rhodiola plants, which exerts anti-oxidative and antiinflammatory effects. In this research, the potential therapeutic effect of rosavin was investigated by the PM2.5-induced lung injury rat model. Rats were instilled with PM2.5 (7.5 mg/kg) suspension intratracheally, while rosavin (50 mg/kg, 100 mg/kg) was delivered by intraperitoneal injection before the PM2.5 injection. It was observed that rosavin could prevent lung injury caused by PM2.5. PM2.5 showed obvious ferroptosis-related ultrastructural alterations, which were significantly corrected by rosavin. The pretreatment with rosavin downregulated the levels of tissue iron, malondialdehyde, and 4-hydroxynonenal, and increased the levels of glutathione. The expression of nuclear factor E2-related factor 2 (Nrf2) was upregulated by rosavin, together with other ferroptosis-related proteins. RSL3, a specific ferroptosis agonist, reversed the beneficial impact of rosavin. The network pharmacology approach predicted the activation of rosavin on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. LY294002, a potent PI3K inhibitor, decreased the upregulation of Nrf2 induced by rosavin. In conclusion, rosavin prevented lung injury induced by PM2.5 stimulation and suppressed ferroptosis via upregulating PI3K/Akt/Nrf2 signaling pathway.

Eleutheroside B ameliorated high altitude pulmonary edema by attenuating ferroptosis and necroptosis through Nrf2-antioxidant response signaling.

High altitude pulmonary edema (HAPE) is a potentially fatal condition induced by exposure to high-altitude environment. Eleutheroside B is a naturally active polyphenolic substance that has previously demonstrated anti-inflammatory, antioxidant and antidepressant properties. However, the effects of eleutheroside B on HPAE are unknown. Here, eleutheroside B (50 mg/kg and 100 mg/kg) was applied to HAPE rats. Eleutheroside B alleviated lung edema and decreased levels of tumor necrosis factor-α, interleukin-1ß, vascular endothelial growth factor, and total proteins in the bronchoalveolar lavage fluid. Eleutheroside B reversed the acid-base disturbances by HAPE. In addition, eleutheroside B reversed the oxidative stress. Eleutheroside B pretreatment facilitated the translocation of nuclear factor E2-related factor 2 (Nrf2) into the nucleus, contributing to the inhibition of ferroptosis and necroptosis. ML385 confirmed the role of Nrf2 in ferroptosis and necroptosis. Collectively, the beneficial effects of eleutheroside B against HAPE were associated with the inhibition of ferroptosis and necroptosis through Nrf2-antioxidant response signaling.

Probiotics ameliorates pulmonary inflammation via modulating gut microbiota and rectifying Th17/Treg imbalance in a rat model of PM2.5 induced lung injury.

The imbalance of intestinal microbiota and inflammatory response is crucial in the development of lung injury induced by PM2.5. In recent years, probiotics have attracted great attention for their health benefits in inflammatory diseases and regulating intestinal balance, but their intricate mechanisms need further experiments to elucidate. In our research, a rat lung damage model induced by PM2.5 exposure in real environment was established to explore the protective properties of probiotics on PM2.5 exposure injury and its related mechanism. The results indicated that compared with the AF control group, rats in the PM2.5 group gained weight slowly, ate less and had yellow hair. The results of pathological and immunohistochemical examinations showed that the inflammatory infiltration of lung tissue was alleviated after probiotic treatment. The Lung function results also showed the improvement effects of probiotics administration. In addition, probiotics could promote the balance of Th17 and Treg cells, inhibit cytokines expression (TNF-α, IL-6, IL-1ß, IL-17A), and increase the concentration of anti-inflammatory factors (IL-10, TGF-ß). In addition, 16 S rRNA sequence analysis showed that probiotic treatment could reduce microbiota abundance and diversity, increase the abundance of possible beneficial bacteria, and decrease the abundance of bacteria associated with inflammation. In general, probiotic intervention was found to have preventive effects on the occurrence of PM2.5 induced pathological injury, and the mechanism was associate with to the inhibition of inflammatory response, regulation of Th17/Treg balance and maintenance of intestinal internal environment stability.

Efficacy and Safety of Shenfu Injection for Severe Pneumonia in the Elderly: A Systematic Review and Meta-Analysis Based on Western and Eastern Medicine.

Background: Although increasing clinical trials studying Shenfu injection (SFI) comprising panaxoside 0.8 mg/ml extracted from Panax ginseng C.A. Mey. and aconitine 0.1 mg/ml extracted from Aconitum carmichaeli Debeaux for elderly patients with severe pneumonia on biomarkers associated with COVID-19 progression are emerging, there is no evidence-based evaluation for the effect of SFI on elderly severe pneumonia. Objectives: To evaluate the effect of SFI on elderly patients with severe pneumonia providing hints for treating critical COVID-19, we conducted a systematic review and meta-analysis. Methods: Nine databases, namely, PubMed, EMBASE, Web of Science, Science Direct, Google Scholar, Wanfang, Chongqing VIP Database, CNKI, and SinoMed were used to search clinical trials reporting the effect of SFI as an adjuvant for elderly severe pneumonia on outcomes of interest. Primary outcomes were total effective rate, Acute Physiology and Chronic Health Evaluation (APACHE) II score, mortality, and safety. Secondary outcomes were predictors associated with COVID-19 progression. Duplicated or irrelevant articles with unavailable data were excluded. Cochrane Collaboration's tool was used to evaluate the risk of bias by two reviewers independently. All data were analyzed by Rev Man 5.4. Continuous variables were shown as weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence intervals (95% CI), whereas dichotomous data were calculated as the risk ratio (RR) with 95% CI. Results: We included 20 studies with 1, 909 participants, and the pooled data showed that compared with standard control, SFI could improve the total effective rate (RR = 1.25, 95% CI = 1.14-1.37, and n = 689), APACHE II score (WMD = -2.95, 95% CI = -3.35, -2.56, and n = 809), and predictors associated with COVID-19 progression (brain natriuretic peptide, creatine kinase, stroke volume, cardiac output, left ventricular ejection fraction, cardiac index, sE-selectin, von Willebrand factor, activated partial thromboplastin time, platelet counts, D-Dimer, procalcitonin, and WBC count). SFI may reduce mortality (RR = 0.52, 95% CI = 0.37-0.73, and n = 429) and safety concerns (RR = 0.29, 95% CI = 0.17-0.51, and n = 150) for elderly severe pneumonia. Conclusion: SFI as an adjuvant may improve the total effective rate, APACHE II score, gas exchange, and predictors associated with COVID-19 progression, reducing mortality and safety concerns for elderly patients with severe pneumonia.

Sipeimine ameliorates PM2.5-induced lung injury by inhibiting ferroptosis via the PI3K/Akt/Nrf2 pathway: A network pharmacology approach.

Fine particulate matter (PM2.5) exposure can cause lung injury and a large number of respiratory diseases. Sipeimine is a steroidal alkaloid isolated from Fritillaria roylei which has been associated with anti-inflammatory, antitussive and antiasthmatic properties. In this study, we explored the potential effects of sipeimine against PM2.5-induced lung injury in Sprague Dawley rats. Sipeimine alleviated lung injury caused by PM2.5 and decreased pulmonary edema, inflammation and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the bronchoalveolar lavage fluid. In addition, sipeimine upregulated the glutathione (GSH) expression and downregulated the expression of 4-hydroxynonenal (4-HNE), tissue iron and malondialdehyde (MDA). The downregulation of proteins involved in ferroptosis, including nuclear factor E2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1) and solute carrier family 7 member 11 (SLC7A11) was reversed by sipeimine. The administration of RSL3, a potent ferroptosis-triggering agent, blocked the effects of sipeimine. Using network pharmacology, we found that the effects of sipeimine were presumably mediated through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. A PI3K inhibitor (LY294002) blocked the PI3K/Akt signaling pathway and reversed the effects of sipeimine. Overall, this study suggested that the protective effect of sipeimine against PM2.5-induced lung injury was mainly mediated through the PI3K/Akt pathway, ultimately leading to a reduction in ferroptosis.

Astragaloside IV alleviates PM2.5-caused lung toxicity by inhibiting inflammasome-mediated pyroptosis via NLRP3/caspase-1 axis inhibition in mice.

Exposure to particulate matter (PM)2.5 in air pollution is a serious health issue worldwide. At present, effective prevention measures and modalities of treatment for PM2.5-caused lung toxicity are lacking. This study elucidated the protective effect of astragaloside IV (Ast), a natural product from Astragalus membranaceous Bunge, against PM2.5-caused lung toxicity and its possible molecular mechanisms. The mice model of lung toxicity was performed by intratracheal instillation of PM2.5 dust suspension. The investigation was performed with Ast or in combination with nigericin, which is a NOD-like receptor protein 3 (NLRP3) activator. The results revealed that PM2.5 lead significant lung inflammation and promoted the pyroptosis pattern of cell death by upregulating pro-inflammatory cytokines and causing oxidative stress related to the NLRP3 inflammasome-mediated pyroptosis pathway. Ast protected against PM2.5 resulted lung toxicity via suppressing NLRP3 inflammasome-mediated pyroptosis via NLRP3/caspase-1 axis inhibition, thereby protecting the lung against PM2.5-induced lung inflammation and oxidative damage, eventually resulting in prolonged survival in mice. Nigericin partially reversed the protective effects of Ast. The present research provides new insights into the therapeutic potential of Ast, demonstrating that it might be a possible candidate for the prevention of PM2.5-caused respiratory diseases. Targeting the NLRP3 inflammasome might be a novel therapeutic tactic for PM2.5-caused respiratory diseases.

Astragaloside IV pre-treatment attenuates PM2.5-induced lung injury in rats: Impact on autophagy, apoptosis and inflammation.

BACKGROUND: Fine particulate matter (PM2.5) with an aerodynamic diameter of less than 2.5 µm, exerts serious lung toxicity. At present, effective prevention measures and treatment modalities for pulmonary toxicity caused by PM2.5 are lacking. Astragaloside IV (AS-IV) is a natural product that has received increasing attention from researchers for its unique biological functions. PURPOSE: To investigate the protective effects of AS-IV on PM2.5-induced pulmonary toxicity and identify its potential mechanisms. METHODS: The rat model of PM2.5-induced lung toxicity was created by intratracheal instillation of PM2.5 dust suspension. The investigation was performed with AS-IV or in combination with autophagic flux inhibitor (Chloroquine) or AMP-sensitive protein kinase (AMPK)-specific inhibitor (Compound C). Apoptosis was detected by terminal deoxy-nucleotidyl transferase dUTP nick end labeling (TUNEL) and western blotting. Autophagy was detected by immunofluorescence staining, autophagic flux measurement, western blotting, and transmission electron microscopy. The AMPK/mTOR pathway was analyzed by western blotting. Inflammation was analyzed by western blotting and suspension array. RESULTS: AS-IV prevented histopathological injury, inflammation, autophagy dysfunction, apoptosis, and changes in AMPK levels induced by PM2.5. AS-IV increased autophagic flux and inhibited apoptosis and inflammation by activating the AMPK/ mammalian target of rapamycin (mTOR) pathway. However, AS-IV had no protective effect on PM2.5-induced lung injury following treatment with Compound C or Chloroquine. CONCLUSION: AS-IV prevented PM2.5-induced lung toxicity by restoring the balance among autophagy, apoptosis, and inflammation in rats by activating the AMPK/mTOR signaling pathway.

Oral Chinese Herbal Medicine on Immune Responses During Coronavirus Disease 2019: A Systematic Review and Meta-Analysis.

BACKGROUND: Cellular immune responses including lymphocyte functions and immune effector cells are critical for the control of coronavirus infection. Chinese herbal medicine (CHM) potentially has a therapeutic effect for treatment of coronavirus disease 2019 (COVID-19). Nevertheless, there are limited clinical practice suggestions on immunogenicity of the CHM against SARS-CoV-2. To assess the effect of oral CHM on immunogenicity and whether oral CHM improves the clinical parameters through the immunity profile during COVID-19, we performed the present study. METHODS: For this systematic review and meta-analysis, 11 databases were searched for relevant studies assessing oral CHM for COVID-19 on November 20, 2020 (updated March 9, 2021). Primary outcomes mainly included immunity profiles. Secondary outcomes included all-cause mortality; the remission time of fever, cough, chest tightness, and fatigue. The random effect was used to estimate the heterogeneity of the studies. Summary relative risks, weight mean difference and standardized mean difference were measured with 95% confidence intervals. Modified Jadad scale and Newcastle-Ottawa Scale were used to assess the risk of bias of randomized controlled trials (RCTs) and observational studies, respectively. The certainty of evidence was evaluated using the GRADE approach. RESULTS: We analyzed findings from 3,145 patients in 30 eligible studies. Compared with routine treatment, oral CHM, as an adjuvant medicine, improved lymphocyte counts, CD4+, and CD4+/CD8+ ratio with low quality of evidence; improved CD3+ with moderate quality of evidence; and reduced TNF-α with low certainty of evidence. Besides, oral CHM, as an adjuvant medicine reduced the time to clinical symptoms remission with a lower risk of all-cause mortality, compared with routine treatment alone. CONCLUSION: CHM may be recommended as an adjuvant immunotherapy for disease modification and symptom relief in COVID-19 treatment. However, large RCTs objectively assessing the efficacy of CHM on immune responses in COVID-19 are needed to confirm our findings.

Rehmapicroside ameliorates cerebral ischemia-reperfusion injury via attenuating peroxynitrite-mediated mitophagy activation.

Peroxynitrite (ONOO-)-mediated mitophagy activation represents a vital pathogenic mechanism in ischemic stroke. Our previous study suggests that ONOO- mediates Drp1 recruitment to the damaged mitochondria for excessive mitophagy, aggravating cerebral ischemia/reperfusion injury and the ONOO--mediated mitophagy activation could be a crucial therapeutic target for improving outcome of ischemic stroke. In the present study, we tested the neuroprotective effects of rehmapicroside, a natural compound from a medicinal plant, on inhibiting ONOO--mediated mitophagy activation, attenuating infarct size and improving neurological functions by using the in vitro cultured PC12 cells exposed to oxygen glucose deprivation with reoxygenation (OGD/RO) condition and the in vivo rat model of middle cerebral artery occlusion (MCAO) for 2 h of transient cerebral ischemia plus 22 h of reperfusion. The major discoveries include following aspects: (1) Rehmapicroside reacted with ONOO- directly to scavenge ONOO-; (2) Rehmapicroside decreased O2- and ONOO-, up-regulated Bcl-2 but down-regulated Bax, Caspase-3 and cleaved Caspase-3, and down-regulated PINK1, Parkin, p62 and the ratio of LC3-II to LC3-I in the OGD/RO-treated PC12 cells; (3) Rehmapicroside suppressed 3-nitrotyrosine formation, Drp1 nitration as well as NADPH oxidases and iNOS expression in the ischemia-reperfused rat brains; (4) Rehmapicroside prevented the translocations of PINK1, Parkin and Drp1 into the mitochondria for mitophagy activation in the ischemia-reperfused rat brains; (5) Rehmapicroside ameliorated infarct sizes and improved neurological deficit scores in the rats with transient MCAO cerebral ischemia. Taken together, rehmapicroside could be a potential drug candidate against cerebral ischemia-reperfusion injury, and its neuroprotective mechanisms could be attributed to inhibiting the ONOO--mediated mitophagy activation.

Therapeutic targets of oxidative/nitrosative stress and neuroinflammation in ischemic stroke: Applications for natural product efficacy with omics and systemic biology.

Oxidative/nitrosative stress and neuroinflammation are critical pathological processes in cerebral ischemia-reperfusion injury, and their intimate interactions mediate neuronal damage, blood-brain barrier (BBB) damage and hemorrhagic transformation (HT) during ischemic stroke. We review current progress towards understanding the interactions of oxidative/nitrosative stress and inflammatory responses in ischemic brain injury. The interactions between reactive oxygen species (ROS)/reactive nitrogen species (RNS) and innate immune receptors such as TLR2/4, NOD-like receptor, RAGE, and scavenger receptors are crucial pathological mechanisms that amplify brain damage during cerebral ischemic injury. Furthermore, we review the current progress of omics and systematic biology approaches for studying complex network regulations related to oxidative/nitrosative stress and inflammation in the pathology of ischemic stroke. Targeting oxidative/nitrosative stress and neuroinflammation could be a promising therapeutic strategy for ischemic stroke treatment. We then review recent advances in discovering compounds from medicinal herbs with the bioactivities of simultaneously regulating oxidative/nitrosative stress and pro-inflammatory molecules for minimizing ischemic brain injury. These compounds include sesamin, baicalin, salvianolic acid A, 6-paradol, silymarin, apocynin, 3H-1,2-Dithiole-3-thione, (-)-epicatechin, rutin, Dl-3-N-butylphthalide, and naringin. We finally summarize recent developments of the omics and systematic biology approaches for exploring the molecular mechanisms and active compounds of Traditional Chinese Medicine (TCM) formulae with the properties of antioxidant and anti-inflammation for neuroprotection. The comprehensive omics and systematic biology approaches provide powerful tools for exploring therapeutic principles of TCM formulae and developing precision medicine for stroke treatment.

Alpinia oxyphylla Miq. and Its Active Compound P-Coumaric Acid Promote Brain-Derived Neurotrophic Factor Signaling for Inducing Hippocampal Neurogenesis and Improving Post-cerebral Ischemic Spatial Cognitive Functions.

Alpinia oxyphylla Miq. (AOM) is a medicinal herb for improving cognitive functions in traditional Chinese medicine for poststroke treatment, but its efficacies and underlying mechanisms remain unknown. In the present study, we tested the hypothesis that AOM could induce adult hippocampal neurogenesis and improve poststroke cognitive impairment via inducing brain-derived neurotrophic factor (BDNF) signaling pathway. In order to test the hypothesis, we performed both in vivo rat experiments using transient middle cerebral artery occlusion (MCAO) model and in vitro neural stem cell (NSC) experiments using oxygen-glucose deprivation plus reoxygenation. First, AOM treatment significantly up-regulated the expression of BDNF, tropomycin receptor kinase B (TrkB), and phosphorylated AKT (p-AKT) in the hippocampus, enhanced adult hippocampal neurogenesis, and improved the spatial learning/memory and cognitive functions in the post-MCAO ischemic rats in vivo. Next, in vitro studies confirmed p-coumaric acid (P-CA) to be the most effective compound identified from AOM extract with the properties of activating BDNF/TrkB/AKT signaling pathway and promoting NSC proliferation. Cotreatment of BDNF/TrkB-specific inhibitor ANA12 abolished the effects of P-CA on inducing BDNF/TrkB/AKT activation and the NSC proliferation. Finally, animal experiments showed that P-CA treatment enhanced the neuronal proliferation and differentiation in the hippocampus, improved spatial learning and memory functions, and reduced anxiety in the transient MCAO ischemic rats. In conclusion, P-CA is a representative compound from AOM for its bioactivities of activating BDNF/TrkB/AKT signaling pathway, promoting hippocampal neurogenesis, improving cognitive functions, and reducing anxiety in post-ischemic stroke rats.

Bis-spirolabdane diterpenoids from Leonurus japonicus and their anti-platelet aggregative activity.

Six bis-spirolabdane diterpenoids along with four known analogues were isolated from the aerial parts of Leonurus japonicus. Their structures and absolute configurations were elucidated by spectroscopic analyses, single-crystal X-ray diffraction, and a modified Mosher's method. The inhibitory activity of the compounds against the abnormal increase in platelet aggregation induced by adenosine diphosphate was investigated. Only the (13R)-bis-spirolabdane diterpenoids exhibited a significant effect.

Penthorin A and B, two unusual 2,4'-epoxy-8,5'-neolignans from Penthorum chinese.

Two new 2,4'-epoxy-8,5'-neolignans (1 and 2), together with five known 7,9';7',9-diepoxylignans (3-7), were isolated from an ethyl acetate soluble portion of a hepatoprotective water decoction of Penthorum chinese. Their structures and absolute configurations were elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. This is the second report of 2,4'-epoxy-8,5'-neolignans from plants. Compounds 2, 6, and 7 showed in vitro protective activities against acetaminophen-induced hepatocyte injury at 5 µM.

New amino butenolides from the bulbs of Fritillaria unibracteata.

Five new amino γ-butenolides, fritenolide A (1), B (2), C (3), D (4), and E (5), along with four known compounds, were isolated from the bulbs of Fritillaria unibracteata. Their structures were determined by spectroscopic analysis, including 1D NMR, 2D NMR, HRESIMS, HRESIMS/MS, IR, and CD techniques. All isolates were evaluated for the protective activity on injured hepatocytes and cytotoxic activity on human cancer cells in vitro. The unusual amino butenolides were isolated from the Liliaceae family for the first time.