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.

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.

Epimedium for Osteoporosis Based on Western and Eastern Medicine: An Updated Systematic Review and Meta-Analysis.

Background: The efficacy of conventional pharmacotherapy on osteoporosis was limited and accompanied with serious side effects. Epimedium might have the potential to be developed as agents to treat osteoporosis. The present systematic review and meta-analysis integrating Western medicine and Eastern medicine ("WE" medicine) was to evaluate the efficacy of Epimedium on osteoporosis. Methods: Eleven electronic databases were searched to identify the randomized controlled trials (RCTs) comparing Epimedium as an adjunctive or alternative versus conventional pharmacotherapy during osteoporosis. Bone mineral density (BMD), effective rate, and Visual Analog Scale (VAS) were measured as primary outcomes. The secondary outcomes were pain relief time, bone metabolic markers, and adverse events. Research quality evaluation was conducted according to the modified Jadad scale. Review Manager 5.4 was utilized to perform analyses, and the data were pooled using a random-effect or fixed-effect model to calculate the weighted mean difference (WMD), standardized mean difference (SMD), risk ratio (RR), and 95% confidence intervals (CI). Results: Twelve RCTs recruiting 1,017 patients were eligible. Overall, it was possible to verify that, in the Epimedium plus conventional pharmacotherapy group, BMD was significantly improved (p = 0.03), effective rate was significantly improved (p = 0.0001), and VAS was significantly decreased (p = 0.01) over those in control group. When compared to conventional pharmacotherapy, Epimedium used alone improved BMD (p = 0.009) and effective rate (p < 0.0001). VAS was lower (p < 0.00001), and the level of alkaline phosphatase (ALP) was significantly decreased (p = 0.01) in patients taking Epimedium alone compared with those given conventional pharmacotherapy. Results of subgroup analyses yielded that the recommended duration of Epimedium as an adjuvant was >3 months (p = 0.03), the recommended duration of Epimedium as an alternative was ≤3 months (p = 0.002), and Epimedium decoction brought more benefits (SMD = 2.33 [1.92, 2.75]) compared with other dosage forms. No significant publication bias was identified based on statistical tests (t = 0.81, p = 0.440). Conclusions: Epimedium may improve BMD and effective rate and relieve pain as an adjuvant or alternative; Epimedium as an alternative might regulate bone metabolism, especially ALP, with satisfying clinical efficacy during osteoporosis. More rigorous RCTs are warranted to confirm these results.

Yunnan Baiyao Adjuvant Treatment for Patients with Hemoptysis: A Systematic Review and Meta-Analysis.

BACKGROUND: Yunnan Baiyao (YNBY) is a traditional Chinese medicine used to treat bleeding. We evaluated the efficacy of YNBY plus conventional pharmaceutical treatment (CPT) versus CPT alone in patients with hemoptysis. METHODS: A total of eight electronic databases were searched. The outcomes in the included studies were effective rate, hemoptysis volume, duration of hemoptysis and hospitalization, number of cases requiring endotracheal intubation, and adverse events (AEs). The studies were used to calculate risk ratios (RRs) or mean differences (MDs) with corresponding 95% confidence intervals. Risk of bias for included trials was assessed using the Cochrane risk of bias tool. RESULTS: Thirteen RCTs were analyzed consisting of a total of 1379 patients. Treatment with YNBY + CPT had a greater effective rate than CPT alone (RR: 1.18; 95% CI: 1.13 to 1.23; P < 0.001; I 2 = 0%), a lower hemoptysis volume (MD: -107.37; 95% CI: -121.69 to -93.06; P < 0.001; I 2 = 0%), a shorter duration of hemoptysis (MD: -2.70; 95% CI: -2.96 to 2.43; P < 0.001; I 2 = 0%) and hospitalization (MD: -2.38; 95% CI: -2.93 to -1.83; P < 0.001; I 2 = 9%), and a reduction in the incidence of AEs (RR: 0.34; 95% CI: 0.23 to 0.51; P < 0.001; I 2 = 0%). YNBY + CPT treatment provided no significant difference in reducing the number of cases requiring endotracheal intubation compared to CPT alone (RR: 0.49; 95% CI: 0.15 to 1.60; P=0.24; I 2 = 0%). CONCLUSION: YNBY plus CPT showed better efficacy than CPT for patients with hemoptysis. Our study provides medical evidence for the efficacy and safety of YNBY for hemoptysis.

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.

Astragaloside IV Protects from PM2.5-Induced Lung Injury by Regulating Autophagy via Inhibition of PI3K/Akt/mTOR Signaling in vivo and in vitro.

INTRODUCTION: Prolonged exposure to air polluted with airborne fine particulate matter (PM2.5) can increase respiratory disease risk. Astragaloside IV (AS-IV) is one of the main bioactive substances in the traditional Chinese medicinal herb, Astragalus membranaceus Bunge. AS-IV has numerous pharmacological properties; whereas there are few reports on the prevention of PM2.5-induced lung injury by AS-IV through modulation of the autophagic pathway. This study aimed to investigate the protective effects and the underlying mechanisms of AS-IV in PM2.5-induced lung injury rats and rat alveolar macrophages (NR8383 cells). METHODS: The pneumotoxicity model was established by intratracheal injection of PM2.5 in rats, and PM2.5 challenge in NR8383 cells. The severity of lung injury was evaluated by wet weight to dry weight ratio and McGuigan pathology scoring. Inflammatory factors and oxidative stress were detected through ELISA. The expressions of p-PI3K, p-Akt, and p-mTOR proteins were analyzed by immunohistochemistry. Immunofluorescence and transmission electron microscopy were used to detect autophagosomes. The expressions of autophagy marker protein (LC3B and p62), PI3K/Akt/mTOR signaling and NF-κB translocation were detected by Western blot in lung tissue and NR8383 cells. RESULTS: After PM2.5 stimulation, rats showed severe inflammation and oxidative stress, along with inhibition of autophagy in lung tissue. AS-IV not only decreased pulmonary inflammation and oxidative stress by inhibiting nuclear factor kappa B translocation, but also regulated autophagy by inhibiting PI3K/Akt/mTOR signaling. After treatment with 3-methyladenine (a classic PI3K inhibitor, blocking the formation of autophagosomes), the protective effect of AS-IV on PM2.5-induced lung injury was further strengthened. In parallel, using Western blot, immunohistochemistry, and transmission electron microscopy, we demonstrated that AS-IV restore autophagic flux mainly through regulating the degradation of autophagosomes rather than suppressing the formation in vivo and in vitro. CONCLUSION: Our data indicated that AS-IV protects from PM2.5-induced lung injury in vivo and in vitro by inhibiting the PI3K/Akt/mTOR pathway to regulate autophagy and inflammation.

The effect of Chinese herbal medicine on digestive system and liver functions should not be neglected in COVID-19: An updated systematic review and meta-analysis.

Gastrointestinal symptoms and liver injury are common in patients with coronavirus disease 2019 (COVID-19). However, profiles of different pharmaceutical interventions used are relatively underexplored. Chinese herbal medicine (CHM) has been increasingly used for patients with COVID-19, but the efficacy of CHM used in COVID-19 on gastrointestinal symptoms and liver functions has not been well studied with definitive results based on the updated studies. The present study aimed at testing the efficacy of CHM on digestive symptoms and liver function (primary outcomes), the aggravation of COVID-19, and the time to viral assay conversion (secondary outcomes), among patients with COVID-19, compared with standard pharmacotherapy. The literature search was undertaken in 11 electronic databases from December 1, 2019 up to November 8, 2020. Appraisal of the evidence was conducted with Cochrane risk of bias tool or Newcastle Ottawa Scale. A random-effects model or subgroup analysis was conducted when significant heterogeneity was identified in the meta-analysis. The certainty of the evidence was assessed with the grading of recommendations assessment, development, and evaluation approach. Forty-eight included trials involving 4,704 participants were included. Meta-analyses favored CHM plus standard pharmacotherapy for COVID-19 on reducing the aggravation of COVID-19 and the time to viral assay conversion compared with standard pharmacotherapy. However, the present CHM as a complementary therapy for treating COVID-19 may not be beneficial for improving most gastrointestinal symptoms and liver function based on the current evidence. More well-conducted trials are warranted to confirm the potential efficacy of CHM furtherly.

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.

Effect of Ganduqing on common cold: A protocol for systematic review and meta-analysis based on existing evidence.

BACKGROUND: The common cold is an infectious viral disease of the upper respiratory tract that has become the most frequent infectious disease in humans. Currently there is no cure for the common cold, and treatment typically focuses on alleviating symptoms. Although antiviral treatment is an important focus of current research, more than 200 viral strains have been associated with the common cold, making antiviral drug interventions difficult. Ganduqing is a Chinese medicinal preparation composed of Astragalus and Shegan. Several randomized controlled trials have been conducted to evaluate treatment of the common cold, but their effectiveness and safety have not been scientifically evaluated. In this study, we will systematically examine the efficacy and safety of Ganduqing in patients with common cold. METHODS: The following electronic databases will be systematically and comprehensively searched: Cochrane Library, EMBASE, PubMed, Science Network, China National Knowledge Infrastructure, China Biomedical Literature Database, Wanfang Database and Chinese Journal Database, for randomized controlled trials that used Ganduqing for treating the common cold through June 2020. The primary outcomes were signs and symptoms of the common cold, including cough, sore throat, fever, nasal congestion and runny nose. Secondary outcomes included changes in the percentage of neutrophils and lymphocytes, and recurrence. Study selection, data extraction and quality assessment will be independently conducted by 2 researchers. Meta-analyses incorporating data derived from the literature will conduct using Review Manager (RevMan) v.5.3 and Stata 14 software. The Grading of Recommendations, Assessment, Development and Evaluations framework will be used to assess the quality of evidence derived from the meta-analyses. RESULTS: This systematic review and meta-analysis aims to provide an evidence of Ganduqing for the common cold and will be disseminated through publications in peer-reviewed journals and/or presentations at scientific conferences. CONCLUSIONS: This systematic review will provide evidence for the efficacy and safety of Ganduqing in treating common colds. TRIAL REGISTRATION NUMBER: INPLASY202060073.

Effect of myrtol on chronic bronchitis or chronic obstructive pulmonary disease: A protocol for systematic review and meta-analysis.

BACKGROUND: The key to the management of chronic obstructive (CB) and chronic obstructive pulmonary disease (COPD) is to control symptoms of the disease and to prevent deterioration in the health of affected patients. Myrtol has been proved to be effective in treating the symptoms of patients with CB and COPD and preventing the deterioration in their health. However, there has been no systematic review of the efficacy and safety of myrtol in the treatment of CB or COPD. The purpose of this study is going to evaluate the effects of myrtol on the management of CB or COPD based on randomized controlled trials. METHODS: Electronic literature and other ongoing studies will be searched before November 31, 2019. Randomized controlled trials that report the use of myrtol in the treatment of CB or COPD (in the absence and presence of concurrent treatments) will be selected for inclusion regardless of language. Primary outcomes will include cumulative numbers of exacerbation events and the number of days of disability including days in bed, days off work due to breathing complications, and days on which the participant was unable to undertake normal activities due to breathing complications. Study selection, data extraction, and deviation the derivation risk assessment will be carried out by 2 independent investigators. Meta-analysis will be carried out by the RevMan5.3 software. RESULTS: The study will provide summary results for estimating the efficacy and safety of myrtol for future treatments of CB or COPD. CONCLUSIONS: This systematic review will determine if myrtol is an effective and a safe intervention on the symptoms and the prevention of exacerbation of CB or COPD. ETHICS AND DISSEMINATION: Ethical approval will not be required for this study because no identifying patient data will be used. The review will be published as an article or a conference presentation in a peer-reviewed journal. REGISTRATION: OSF registration number: DOI 10.17605/OSF.IO/PXRBV.