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Pine pollen has been widely recognized for its comprehensive nutritional properties and health benefits, but it has also been the target of fraudulent practices. Accurate authentication of pine pollen throughout the production chain is thus of great importance to quality and safety control of pine pollen food products. Aiming at the adverse effects of excipients and DNA degradation during processes, a pretreatment method including dissolution and centrifugation steps was incorporated in DNA extraction, and the chloroplast trnL-F region was used to establish a multiplex species-specific PCR assay. The developed assay could detect 1% of intentional adulteration of cattail pollen or corn flour into pine pollen down to 0.01 ng level of template DNA and was proved to be effective for botanical origin authentication of commercial pine pollen food products. Therefore, the present study provides a simple and sensitive approach for quality control and safety monitoring of commercial pine pollen food products, and the methodology can be applied in botanical origin authenticity control of other pollen products.

Background To analyze the risk factors for hypertension in different age groups of urban and rural residents in Tianjin. Methods A total of 33,997 people (35–75 years old) from 13 community health service centers and primary hospitals in Tianjin participated in this study. They were divided into the youth group (≤ 40 years old), middle-aged group (41–65 years old), and elderly group (> 65 years old). Then, a questionnaire survey was administered, followed by physical and blood biochemical examinations. The demographic characteristics and prevalence were recorded and counted. Subsequently, risk factors were analyzed using univariate and stepwise multivariate logistic regression analysis. Results In the youth, middle-aged, and elderly groups, the prevalence rate of hypertension was 18.65, 51.80, and 76.61%, respectively. Logistic regression analysis showed that obesity(OR: 3.263, 95% CI: 1.039–1.656), men (OR: 2.117, 95% CI: 1.691–2.651), diabetes (OR: 1.978, 95% CI: 1.398–2.799), high triglycerides(OR 1.968 95% CI: 1.590–2.434) and family history of stroke (OR: 1.936, 95% CI: 1.287–2.911) are the five factors in youth. In middle-aged group, the significantly associating factors were obesity (OR: 2.478, 95% CI: 2.330–2.636), diabetes (OR: 2.173, 95% CI: 1.398–2.799), family history of stroke (OR: 1.808, 95% CI: 1.619–2.020), maleness (OR: 1.507, 95% CI: 1.412–1.609),Hypertriglyceridemia (OR 1.490 95% CI: 1.409–1.577),family history of cardiovascular disease (OR: 1.484, 95% CI: 1.307–1.684),Hypercholesterolemia (OR 1.228 95% CI: 1.160–1.299). In the elderly group, obesity (OR: 2.104, 95% CI: 1.830–2.418), family history of strokes (OR: 1.688, 95% CI: 1.243–2.292), diabetes mellitus (OR: 1.544, 95% CI: 1.345–1.773), family history of cardiovascular disease (OR: 1.470, 95% CI: 1.061–2.036), hypertriglyceridemia (OR: 1.348, 95% CI: 1.192–1.524) increased the risk for hypertension. Waist circumference (WC) and waist-to-height ratio (WHtR) increased with age, and the value of these two measures for predicting hypertension was better than BMI in middle-aged group. Conclusion Obesity is the most important risk factor for hypertension in all age groups. Diabetes, family history of strokes and high triglyceride were also significant risk factors for all age groups. There was a gender difference between the young and middle-aged groups, with men more likely to hypertension. Waist circumference (WC) and waist-to-height ratio (WHtR) were better predictors of hypertension than BMI in middle-aged group.

Atherosclerosis (AS) is a chronic disease with a complex pathology that may lead to several cardiovascular and cerebrovascular diseases; however, further research is necessary to fully elucidate its pathogenesis. The main risk factors for AS include lipid metabolism disorders, endothelial cell injury, inflammation and immune dysfunction, among which vascular endothelial cell damage is considered as the main trigger for AS occurrence and development. Endothelial cell damage leads to enhanced intimal permeability and leukocyte adhesion, promoting thrombus formation and accelerating disease progression. The function of endothelial cells is affected by glycolysis regulation, since 80% of ATP in these cells is produced via this pathway. Genes associated with AS and endothelial cell glycolysis, including AKT1, interleukin‑6, vascular endothelial growth factor A, TP53, signal transducer and activator of transcription 3, SRC and mitogen‑activated protein kinase 1, were screened. Through integrated analysis, these genes were found to play a key role in AS by regulating multiple signaling pathways associated with cell signal transduction, energy metabolism, immune function and thrombosis. In conclusion, endothelial cell injury in AS may be alleviated by glycolysis and is a potential clinical treatment strategy for AS.

This study aims to examine the medication prescriptions for hypertension in Tianjin. Patients with hypertension in Tianjin were enrolled in this study. The patients’ ages ranged from 35 to 75 years. A questionnaire survey and physical examination were completed to collect clinical data. Thereafter, a statistical analysis of the medication prescriptions was conducted with different age groups and different grades of hypertension. The results show that, in the total population, and for the young, middle-aged, and older groups, the proportions of single-drug use were 62.97%, 59.26%, 62.76%, and 63.49%, respectively, and the highest rate was for calcium channel blocker (CCB) use. The rates of the two drug classes were 24.51%, 29.63%, 25.13%, and 23.15%, respectively. The drug use rate of CCBs combined with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor antagonists (ARBs) was the highest. The rates of the three drug classes were 4.08%, 4.94%, 4.36%, and 3.52%, respectively, and the highest was ACEI/ARB and CCB combined with diuretics. The rates of the four drug classes were low. Regarding the hypertension grade, in grade 1, grade 2, and grade 3, the rates of single-drug use were 63.53%, 62.69%, and 58.38%, respectively. The rates of the two drug classes were 24.62%, 23.97%, and 25.05%, while the rates of the three drug classes were 3.86%, 4.39%, and 5.34%, respectively. The rate of single-drug use was high, and the rate of combined drug use in the youth group was slightly higher than in the middle-aged and older age groups. The combination of two drugs was common. In grades 2 and 3 hypertension, the rate of combined drug use remained low.

Gastrodiae Rhizoma is a highly valuable traditional herbal medicine commonly used to treat neurological disorders. The present study is designed to determine the antidepressant-like effect of the Gastrodiae Rhizoma water extract (GRWE) on a depression model and the potential mechanisms. The chronic unpredictable mild stress (CUMS) rat model was used to induce depression. The sucrose preference test, open field test, forced swimming test, and tail suspension test were performed to assess the depressive-like behaviors, respectively. Hypothalamic–pituitary–adrenal (HPA) function was measured via plasma corticosterone (CORT), adrenocorticotrophic hormone (ACTH), hypothalamic corticotropin-releasing factor (CRF), and glucocorticoid receptor (GR) concentrations. Plasma concentrations of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were also evaluated. The results showed that GRWE significantly attenuates the behavioral abnormalities in CUMS rats, as shown by elevated sucrose consumption, raised locomotor activity, and reduced immobility duration. Moreover, GRWE treatment reduced CORT, ACTH, CRF, and GR levels and decreased the plasma IL-1β, IL-6, and TNF-α concentrations. These findings indicate that GRWE improves depressive behaviors in a chronic stress model of rats; its effect may be ascribed to the modulation of the HPA axis activity and inflammatory response.

Rationale It remains unknown whether long-term ozone exposure can impair lung function. Objectives To investigate the associations between long-term ozone exposure and adult lung function in China. Methods Lung function results and diagnosis of small airways dysfunction (SAD) were collected from a cross-sectional study, China Pulmonary Health Study (N=50,991). We used multivariate linear and logistic regression models to examine the associations of long-term ozone exposure with lung function parameters and SAD, respectively, adjusting for demographic characteristics, individual risk factors, and longitudinal trend. We then performed a stratification analysis by chronic obstructive pulmonary disease (COPD). Measurements and main results We observed each 1-standard deviation (SD, 4.9 ppb) increase in warm-season ozone concentrations was associated with a 14.2 mL/s [95% confidence interval (CI): 8.8, 19.6] decrease in forced expiratory flow at 75th percentile of vital capacity and a 29.5 mL/s (95% CI: 19.6, 39.5) decrease in mean forced expiratory flow between the 25th and 75th percentile of vital capacity. The odds ratio of SAD was 1.09 (95% CI: 1.06, 1.11) for a 1-SD increase in warm-season ozone concentrations. Meanwhile, we observed a significant association with a decreased ratio of expiratory volume in 1 second to forced vital capacity (FEV1/FVC) but not with FEV1 or FVC. The association estimates were greater in the COPD group than in the non-COPD group. Conclusion We found independent associations of long-term ozone exposure with impaired small airways function and higher SAD risks, while the associations with airflow obstruction were weak. COPD patients appear to be more vulnerable.

Objective: This work was conducted in order to study the effect of the lower genital tract (vaginal and cervical canal) microbiota on pregnancy outcomes of reproductive-aged women receiving embryo transfer.Study design: A total of 150 reproductive-aged patients who received the first fresh in vitro fertilization-embryo transfer (IVF-ET) were included in the study. Samples from the vagina and cervical site of each patient were collected separately using sterile swabs before ET. Genomic DNA was pyrosequenced for the V3–V4 regions of the 16S ribosomal RNA gene. Further bioinformatics analysis was performed using QIIME and R package. Pregnancy outcomes were followed and analyzed to compare differences in microbial composition.Results: The cervical microbiota had a higher Shannon index than the vaginal microbiota, and the microbial composition was different between the two sites. However, the Sorenson index between the two sites within the same individual was 0.370 (0.309–0.400). A total of 89 patients achieved clinical pregnancy after ET, while 61 failed. The Shannon indices and the microbial community of both vaginal and cervical microbiota between pregnant and non-pregnant groups were not significantly different. The relative abundance of Lactobacillus in the vagina and cervical canal did not differ between the two groups. Linear discriminant analysis, random forest analysis, and receiver-operating characteristic curve analysis showed that Bifidobacterium, Prevotella, and Lactobacillus iners in the vagina, as well as Solanum torvum, Fusobacterium, and Streptococcus in the cervix, may be negatively associated with clinical pregnancy after IVF.Conclusion: The cervical microbiota was more diverse than the vaginal microbiota, but because of anatomical continuity, there was a correlation between the two sites. The microbial composition of the vagina and cervical canal may influence the outcome of IVF-ET, but more samples are needed to verify this conclusion.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic, which has resulted in more than two million deaths at 2021 February . There is currently no approved therapeutics for treating COVID-19. The SARS-CoV-2 Spike protein is considered a key therapeutic target by many researchers. Here we describe the identification of several monoclonal antibodies that target SARS-CoV-2 Spike protein. One human antibody, CA521FALA, demonstrated neutralization potential by immunizing human antibody transgenic mice. CA521FALA showed potent SARS-CoV-2-specific neutralization activity against SARS-CoV-2 pseudovirus and authentic SARS-CoV-2 infection in vitro. CA521FALA also demonstrated having a long half-life of 9.5 days in mice and 9.3 days in rhesus monkeys. CA521FALA inhibited SARS-CoV-2 infection in SARS-CoV-2 susceptible mice at a therapeutic setting with virus titer of the lung reduced by 4.5 logs. Structural analysis by cryo-EM revealed that CA521FALA recognizes an epitope overlapping with angiotensin converting enzyme 2 (ACE2)-binding sites in SARS-CoV-2 RBD in the Spike protein. CA521FALA blocks the interaction by binding all three RBDs of one SARS-CoV-2 spike trimer simultaneously. These results demonstrate the importance for antibody-based therapeutic interventions against COVID-19 and identifies CA521FALA a promising antibody that reacts with SARS-CoV-2 Spike protein to strongly neutralize its activity., Song et al describe and identify monoclonal antibodies that target the SARSCoV-2 Spike protein, including CA521FALA, which demonstrated neutralising potential in vivo and in vitro. They performed structural analysis, which revealed that CA521FALA recognizes an epitope overlapping with angiotensin converting enzyme 2 (ACE2)-binding sites in SARS-CoV-2 Spike protein therefore making it a promising therapeutic antibody.

Drug-induced liver injury is one of the main causes of drug non-approval and drug withdrawal by the Food and Drug Administration (FDA). Acetaminophen (APAP) is a widely used non-steroidal anti-inflammatory drug for treating fever and headache. APAP is considered safe at therapeutic doses; however, there have been reports of acute liver injury following the administration of APAP. To explore APAP hepatotoxicity and its mechanisms, we designed and synthesized a new click chemistry probe, APAP-P1, in our current study. We introduced the PEG-azide probe linker into the acetyl group of acetaminophen. First, we evaluated the probe toxicity in HepaRG cells and found that it still retained hepatotoxicity. We also found that this probe APAP-P1 can be metabolized by HepaRG cells. This demonstrated that the APAP-P1 probe still kept its metabolism characteristics. Using this probe, we pulled down its potential targets in vivo and in vitro. APAP can directly target TrxR1; thus, we tested for this interaction by Western blotting of pull-down proteins. The results showed that APAP-P1 can pull down TrxR1 in vivo and in vitro.

Background/Aims: Total saponins of Aralia elata (Miq) Seem (AS) from the Chinese traditional herb Long ya Aralia chinensis L. reportedly provide cardioprotective effects, but the exact mechanisms require further study. Previous studies have showed that myocardial ischemia/ reperfusion injury (MIRI) was related to calcium homeostasis imbalance and endoplasmic reticulum stress (ERS). Thus, this study aimed to demonstrate protective effects of AS on MIRI. Methods: After administrating AS for 5 days, the left anterior descending artery coronary artery of Sprague-Dawley (SD) rats was ligated for 30 min. After 48 h of reperfusion, haemodynamics, Evans blue/ 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, masson staining and the levels of lactate dehydrogenase (LDH) and creatine kinase (CK), superoxide dismutase (SOD), malondialdehyde (MDA) were detected to assess MIRI. ATPase activity and Western Blot were used to study the mechanisms. Results: Compared with IR group, AS treatment groups could significantly reduce myocardial infarct size; improve myocardial pathologic progress; decrease content of LDH, CK, and MDA; increase content of SOD; and restore the activities of Ca2+-Mg2+-ATPase, Na+-K+-ATPase, sarcoplasmic reticulum Ca2+-ATPases (SERCA), and calcineurin (CaN). AS treatment groups also significantly up-regulated the expression of GRP78, C/EBP homologous protein (CHOP), and Bax, and down-regulated the expression of Bcl-2, all similar to the effects of ERS. Conclusion: These findings illustrated that AS could prevent myocardial ischemia/reperfusion injury and reduce calcium homeostasis imbalance and ERS-related apoptosis.

The associations of long-term exposure to various constituents of fine particulate matter (≤2.5 μm in aerodynamic diameter, PM2.5) air pollution with lung function were not clearly elucidated in developing countries. The aim was to evaluate the associations of long-term exposure to main constituents of PM2.5 with lung function in China. This is a nationwide, cross-sectional analysis among 50,991 study participants from the China Pulmonary Health study. Multivariable linear regression models were used to obtain differences of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow (PEF), and forced expiratory flow at 25–75% of exhaled FVC (FEF25-75%) associated with an interquartile range (IQR) change of PM2.5 or its constituents. Residential annual PM2.5 levels varied from 26 μg/m3 to 92 μg/m3 (average: 53 μg/m3). An IQR increase of PM2.5 concentrations was associated with lower FEV1 (19.82 mL, 95% CI: 11.30–28.33), FVC (17.45 mL, 95% CI: 7.16–27.74), PEF (86.64 mL/s, 95% CI: 59.77–113.52), and FEF25-75% (31.93 mL/s, 95% CI: 16.64–47.22). Black carbon, organic matter, ammonium, sulfate, and nitrate were negatively associated with most lung function indicators, with organic matter and nitrate showing consistently larger magnitude of associations than PM2.5 mass. This large-scale study provides first-hand epidemiological evidence that long-term exposure to ambient PM2.5 and some constituents, especially organic matter and nitrate, were associated with lower large- and small- airway function.

Myocardial ischemia is a high-risk disease among middle-aged and senior individuals. After thrombolytic therapy, heart tissue can potentially suffer further damage, which is called myocardial ischemia-reperfusion injury (MIRI). At present, the treatment methods and drugs for MIRI are scarce and cannot meet the current clinical needs. The mechanism of MIRI involves the interaction of multiple factors, and the current research hotspots mainly include oxidative stress, inflammation, calcium overload, energy metabolism disorders, pyroptosis, and ferroptosis. Traditional Chinese medicine (TCM) has multiple targets and few toxic side effects; clinical preparations containing Panax ginseng C. A. Mey., Panax notoginseng (Burk.) F. H. Chen, Aralia chinensis L., cardioprotection, and other Chinese herbal medicines have been used to treat patients with coronary heart disease, angina pectoris, and other cardiovascular diseases. Studies have shown that saponins are the main active substances in TCMs containing Panax ginseng C. A. Mey., Panax notoginseng (Burk.) F. H. Chen, Aralia chinensis L., and Radix astragali. In the present review, we sorted the saponin components with anti-MIRI effects and their regulatory mechanisms. Each saponin can play a cardioprotective role via multiple mechanisms, and the signaling pathways involved in different saponins are not the same. We found that more active saponins in Panax ginseng C. A. Mey. are mainly dammar-type structures and have a strong regulatory effect on energy metabolism. The highly active saponin components of Aralia chinensis L. are oleanolic acid structures, which have significant regulatory effects on calcium homeostasis. Therefore, saponins in Chinese herbal medicine provide a broad application prospect for the development of highly effective and low-toxicity anti-MIRI drugs.

Myocardial ischemia/reperfusion injury (MI/RI) is an urgent problem with a great impact on health globally. However, its pathological mechanisms have not been fully elucidated. Hydroxysafflor yellow A (HSYA) has a protective effect against MI/RI. This study is aimed at further clarifying the relationship between HSYA cardioprotection and calcium overload as well as the underlying mechanisms. We verified the protective effect of HSYA on neonatal rat primary cardiomyocytes (NPCMs) and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from hypoxia-reoxygenation (HR) injury. To explore the cardioprotective mechanism of HSYA, we employed calcium fluorescence, TUNEL assay, JC-1 staining, and western blotting. Finally, cardio-ECR and patch-clamp experiments were used to explain the regulation of L-type calcium channels (LTCC) in cardioprotection mediated by HSYA. The results showed that HSYA reduced the levels of myocardial enzymes and protected NPCMs from HR injury. HSYA also restored the contractile function of hiPSC-CMs and field potential signal abnormalities caused by HR and exerted a protective effect on cardiac function. Further, we demonstrated that HSYA protects cardiomyocytes from HR injury by decreasing mitochondrial membrane potential and inhibiting apoptosis and calcium overload. Patch-clamp results revealed that MI/RI caused a sharp increase in calcium currents, which was inhibited by pretreatment with HSYA. Furthermore, we found that HSYA restored contraction amplitude, beat rate, and field potential duration of hiPSC-CMs, which were disrupted by the LTCC agonist Bay-K8644. Patch-clamp experiments also showed that HSYA inhibits Bay-K8644-induced calcium current, with an effect similar to that of the LTCC inhibitor nisoldipine. Therefore, our data suggest that HSYA targets LTCC to inhibit calcium overload and apoptosis of cardiomyocytes, thereby exerting a cardioprotective effect and reducing MI/RI injury.

In this paper, the protective effect of Auricularia auricula (A. auricula) fermentation broth on the liver and stomach of mice with acute alcoholism was studied. The A. auricula fermentation broth was prepared by adding Bacillus subtilis, lactic acid bacteria, and Saccharomyces cerevisiae to A. auricula solution. The changes of physical and chemical indexes during the fermentation of A. auricula were monitored, and the results showed the content of polysaccharides and protein in the two kinds of fermentation broth after the fermentation was completed. Furthermore, the characteristic structures of active substances such as proteins, polysaccharides and phenolics were found in the A. auricula fermentation by structural analysis. Antioxidant activity test results showed that the A. auricula fermentation broth had a strong ability to scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl radicals. Cell experiments showed that the fermentation broth of A. auricula could significantly enhance the activity of NRK cells and protect NRK cells from H2O2 damage. Animal experiments showed that the A. auricula fermentation broth had protective effects on the liver and stomach of mice with acute alcoholism, and significantly reduced the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC) and triglycerides (TG) in serum. These results indicated that the A. auricula fermentation broth had protective effects on the liver and stomach of mice with acute alcoholism, and could be used as a potential functional food to prevent liver and stomach damage caused by acute alcoholism.

Calenduloside E (CE) is a saponin isolated from Aralia elata (Miq) Seem, which has anti-cardiovascular disease effects. This study aims to evaluate the anti-myocardial ischemia-reperfusion injury (MIRI) mechanisms of CE and regulation of BAG3 on calcium overload. We adopted siRNA to interfere with BAG3 expression in H9c2 cardiomyocytes and used adenovirus to interfere with BAG3 expression (Ad-BAG3) in primary neonatal rat cardiomyocytes (PNRCMs) to clarify the role of BAG3 in mitigating MIRI by CE. The results showed that CE reduced calcium overload, and Ad-BAG3 had a significant regulatory effect on L-type Ca2+ channels (LTCC) but no effects on other calcium-related proteins. And BAG3 and LTCC were colocalized in myocardial tissue and BAG3 inhibited LTCC expression. Surprisingly, CE had no regulatory effect on LTCC mRNA, but CE promoted LTCC degradation through the autophagy-lysosomal pathway rather than the ubiquitination-protease pathway. Autophagy inhibitor played a negative regulation of cardiomyocyte contraction rhythm and field potential signals. Ad-BAG3 inhibited autophagy by regulating the expression of autophagy-related proteins and autophagy agonist treatment suppressed calcium overload. Therefore, CE promoted autophagy through BAG3, thereby regulating LTCC expression, inhibiting calcium overload, and ultimately reducing MIRI.

Background Aconitine-induced cardiotoxicity limits the clinical treatment of cardiotonic, cancers and immune-related diseases. Ginsenoside Rb1 (Rb1) is an active ingredient of traditional Chinese medicine with cardioprotective effect. Purpose This study aims to study the mechanism of aconitine cardiotoxicity and the detoxification mechanism of Rb1. Study Design: Methods The regulatory effect of Rb1 on aconitine was evaluated in vitro and in vivo by myocardial enzyme indicators, pathological analysis, CardioECR detection, calcium transient analysis, western blotting and immunohistochemistry. Results Rb1 (10, 20, 40 mg/kg) alleviated apoptotic myocardial damage caused by aconitine in rats. Furthermore, Rb1 (25, 50, 100 μM) restored the contractile function and field potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) by regulating calcium channels and reduced myocardial cell damage by inhibiting the calcium transients of adult rat ventricular myocytes (ARVMs). Rb1 significantly reduced calcium levels in hiPSC-CMs, directly indicating that aconitine-induced calcium overload was alleviated by Rb1. Further, aconitine caused calcium overload by changing the expression of calcium pathway proteins, while Rb1 effectively restored calcium homeostasis. In addition, Rb1 also had a cardioprotective role by inhibiting cell pyroptosis. These results suggested that the maintenance of calcium homeostasis helped to suppress the inflammatory response related to pyroptosis of the heart. Conclusion Aconitine-induced cardiotoxicity can be alleviated by Rb1 via restoring calcium homeostasis and inhibiting apoptosis and pyroptosis.

Calcium homeostasis plays an essential role in maintaining excitation-contraction coupling (ECC) in cardiomyocytes, including calcium release, recapture, and storage. Disruption of calcium homeostasis may affect heart function, leading to the development of various heart diseases. Myocardial ischemia/reperfusion (MI/R) injury may occur after revascularization, which is a treatment used in coronary heart disease. MI/R injury is a complex pathological process, and the main cause of increased mortality and disability after treatment of coronary heart disease. However, current methods and drugs for treating MI/R injury are very scarce, not ideal, and have limitations. Studies have shown that MI/R injury can cause calcium overload that can further aggravate MI/R injury. Therefore, we reviewed the effects of critical calcium pathway regulators on MI/R injury and drew an intuitive diagram of the calcium homeostasis pathway. We also summarized and analyzed calcium pathway-related or MI/R drugs under research or marketing by searching Therapeutic Target and PubMed Databases. The data analysis showed that six drugs and corresponding targets are used to treat MI/R injury and involved in calcium signaling pathways. We emphasize the relevance of further detailed investigation of MI/R injury and calcium homeostasis and the therapeutic role of calcium homeostasis in MI/R injury, which bridges basic research and clinical applications of MI/R injury.

Summary Background Small airway dysfunction is a common but neglected respiratory abnormality. Little is known about its prevalence, risk factors, and prognostic factors in China or anywhere else in the world. We aimed to estimate the prevalence of small airway dysfunction using spirometry before and after bronchodilation, both overall and in specific population subgroups; assess its association with a range of lifestyle and environmental factors (particularly smoking); and estimate the burden of small airway dysfunction in China. Methods From June, 2012, to May, 2015, the nationally representative China Pulmonary Health study invited 57 779 adults to participate using a multistage stratified sampling method from ten provinces (or equivalent), and 50 479 patients with valid lung function testing results were included in the analysis. We diagnosed small airway dysfunction on the basis of at least two of the following three indicators of lung function being less than 65% of predicted: maximal mid-expiratory flow, forced expiratory flow (FEF) 50%, and FEF 75%. Small airway dysfunction was further categorised into pre-small airway dysfunction (defined as having normal FEV1 and FEV1/forced vital capacity [FVC] ratio before bronchodilator inhalation), and post-small airway dysfunction (defined as having normal FEV1 and FEV1/FVC ratio both before and after bronchodilator inhalation). Logistic regression yielded adjusted odds ratios (ORs) for small airway dysfunction associated with smoking and other lifestyle and environmental factors. We further estimated the total number of cases of small airway dysfunction in China by applying present study findings to national census data. Findings Overall the prevalence of small airway dysfunction was 43·5% (95% CI 40·7–46·3), pre-small airway dysfunction was 25·5% (23·6–27·5), and post-small airway dysfunction was 11·3% (10·3–12·5). After multifactor regression analysis, the risk of small airway dysfunction was significantly associated with age, gender, urbanisation, education level, cigarette smoking, passive smoking, biomass use, exposure to high particulate matter with a diameter less than 2·5 μm (PM2·5) concentrations, history of chronic cough during childhood, history of childhood pneumonia or bronchitis, parental history of respiratory diseases, and increase of body-mass index (BMI) by 5 kg/m2. The ORs for small airway dysfunction and pre-small airway dysfunction were similar, whereas larger effect sizes were generally seen for post-small airway dysfunction than for either small airway dysfunction or pre-small airway dysfunction. For post-small airway dysfunction, cigarette smoking, exposure to PM2·5, and increase of BMI by 5 kg/m2 were significantly associated with increased risk, among preventable risk factors. There was also a dose-response association between cigarette smoking and post-small airway dysfunction among men, but not among women. We estimate that, in 2015, 426 (95% CI 411–468) million adults had small airway dysfunction, 253 (238–278) million had pre-small airway dysfunction, and 111 (104–126) million had post-small airway dysfunction in China. Interpretation In China, spirometry-defined small airway dysfunction is highly prevalent, with cigarette smoking being a major modifiable risk factor, along with PM2·5 exposure and increase of BMI by 5 kg/m2. Our findings emphasise the urgent need to develop and implement effective primary and secondary prevention strategies to reduce the burden of this condition in the general population. Funding Ministry of Science and Technology of China; National Natural Science Foundation of China; National Health Commission of China.

Calenduloside E (CE) is a natural triterpenoid saponin isolated from Aralia elata (Miq.) Seem., a well-known traditional Chinese medicine. Our previous studies have shown that CE exerts cardiovascular protective effects both in vivo and in vitro. However, its role in myocardial ischemia/reperfusion injury (MIRI) and the mechanism involved are currently unknown. Mitochondrial dynamics play a key role in MIRI. This study investigated the effects of CE on mitochondrial dynamics and the signaling pathways involved in myocardial ischemia/reperfusion (MI/R). The MI/R rat model and the hypoxia/reoxygenation (H/R) cardiomyocyte model were established in this study. CE exerted significant cardioprotective effects in vivo and in vitro by improving cardiac function, decreasing myocardial infarct size, increasing cardiomyocyte viability, and inhibiting cardiomyocyte apoptosis associated with MI/R. Mechanistically, CE restored mitochondrial homeostasis against MI/R injury through improved mitochondrial ultrastructure, enhanced ATP content and mitochondrial membrane potential, and reduced mitochondrial permeability transition pore (MPTP) opening, while promoting mitochondrial fusion and preventing mitochondrial fission. However, genetic silencing of OPA1 by siRNA abolished the beneficial effects of CE on cardiomyocyte survival and mitochondrial dynamics. Moreover, we demonstrated that CE activated AMP-activated protein kinase (AMPK) and treatment with the AMPK inhibitor, compound C, abolished the protective effects of CE on OPA1 expression and mitochondrial function. Overall, this study demonstrates that CE is effective in mitigating MIRI by modulating AMPK activation-mediated OPA1-related mitochondrial fusion.

Gastrodia elata is a traditional herbal medicine that has been used for centuries to treat rheumatism. Previous studies have confirmed that ethanol extracts of Gastrodia elata have anti-inflammatory and antioxidant activities, and the n-butanol fraction exerts a higher inhibitory effect. However, the in vivo anti-inflammatory effects of Gastrodia elata have not been evaluated. Thus, we assessed the therapeutic effect of the n-butanol extract of Gastrodia elata (BGE) on complete Freund’s adjuvant- (CFA-) induced arthritis rats which were separated into six groups (NOR; MODEL; CFA + dexamethasone (DEX); CFA + 25, 50, 100 mg/kg BGE). The paw swelling, joint radiology, and histology were used to analyze the effect of BGE on delaying the progression of rheumatoid arthritis. Furthermore, serum levels of inflammatory cytokines were analyzed via ELISA. In addition, the effect of BGE on nitric oxide (NO) production, expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2(COX-2), and inflammatory cytokines were detected in lipopolysaccharide- (LPS-) stimulated RAW264.7 macrophage cells. Lastly, the impacts of BGE on the activation of the mitogen-activated protein kinases (MAPK) pathway in CFA rats and LPS-stimulated RAW264.7 macrophage were examined by western blot analysis. The results show that BGE can significantly reduce paw swelling without losing the body weight of rats. Imaging assessment confirms that BGE can protect cartilage from destruction, as well as reducing inflammatory cell infiltration and synovial proliferation. Moreover, BGE suppresses the production of inflammatory cytokines in serum and inhibits the activation of the phosphorylation of p38 and ERK in CFA rats. BGE was also demonstrated to decrease the production of NO and inflammatory cytokines in LPS-stimulated RAW264.7 cells. The effect of BGE in LPS-induced expression leads to reduced p38 and ERK phosphorylation and also downregulates the protein expression of iNOS and COX-2. Taken together, BGE exhibits a potential therapeutic effect on CFA rats, and its anti-inflammatory and antioxidant effects were possibly exerted by regulation of ERK/p38MAPK.

Hydroxysafflor yellow A (HSYA) is an effective therapeutic agent that alleviates myocardial ischaemia/reperfusion injury (MIRI), but the exact mechanisms remain elusive. The aim of this study was to investigate the potential protective effect of HSYA against MIRI through mechanisms related to NLRP3 inflammasome regulation. In this study, hypoxia/reoxygenation (H/R)-induced H9c2 cardiomyocytes were treated with HSYA or the AMPK inhibitor, compound C (CC). Our results showed that HSYA pretreatment improved cardiomyocyte viability, maintained mitochondrial membrane potential, reduced apoptotic cardiomyocytes, decreased caspase-3 activity, and inhibited NOD-like receptor 3 (NLRP3) inflammasome activation during H/R injury. Moreover, the inhibition of AMPK activation by the CC inhibitor partially abolished the effects of HSYA treatment, including suppressing the upregulation of NLRP3 inflammasome components (NLRP3, caspase-1 and interleukin-1β) and promoting autophagy (LC3-II/LC3-I and p62). In conclusion, the protective mechanism of HSYA in H/R-induced cardiomyocyte injury is associated with inhibiting NLRP3 inflammasome activation through the AMPK signalling pathway.

Background: Shuxuening injection (SXNI) has a good effect on cardiovascular and cerebrovascular diseases. Here, our study aims to investigate whether SXNI have the protective effect on myocardial ischemia-reperfusion injury (MIRI) and elucidate the mechanism of SXNI’s cardiac protection. Methods: In this experiment, the coronary arteries of Sprague-Dawley (SD) rats were ligated for the induction of a MIRI model. TTC staining and haematoxylin-eosin (HE), as well as troponin I (TnI), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), creatine kinase (CK) and CK-MB levels, were used to detect the protective effect of SXNI. In rat cardiac tissue, superoxide dismutase, catalase, glutathione and malondialdehyde (MDA) activities and glucose-regulated protein 78 (GRP78), calreticulin (CRT), CCAAT/enhancer binding protein homologous protein (CHOP) and caspase-12 expression levels were detected. In rat serum, the levels of inflammatory factors, including high-sensitivity C-reactive protein, monocyte chemoattractant protein-1, tumour necrosis factor-α, interleukin-6 (IL-6) and IL-1β, were measured by Elisa. In the rat arterial tissue, Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) expression was measured by western blot. In the rat plasma, ELISA was used to assay the levels of coagulation and plasmin system indicators, including platelet activating factor, endothelin, tissue factor (TF), plasminogen inhibitor, thromboxane B2, plasma fibrinogen. Results: The results showed that SXNI can reduce the infarct size of myocardial tissue, decrease the myocardial enzyme and TnI levels and decrease the degree of myocardial damage compared with the model group. Additionally, SXNI can increase the activity of antioxidant enzymes, reduce the MDA level and decrease the GRP78, CRT, CHOP and caspase-12 expression levels. SXNI also decreased the levels of inflammatory cytokines in rat serum, lowered the level of procoagulant molecules in plasma and reduced the TLR4/NF-κB expression. Conclusions: SXNI has protective effect on MIRI mainly by inhibiting oxidative stress and endoplasmic reticulum stress (ERS), thereby regulating TLR4/NF-κB pathway to reduce inflammation, and lowing procoagulant-related factors levels to reduce the risk of thrombosis.

Summary Background Although exposure to cigarette smoking and air pollution is common, the current prevalence of chronic obstructive pulmonary disease (COPD) is unknown in the Chinese adult population. We conducted the China Pulmonary Health (CPH) study to assess the prevalence and risk factors of COPD in China. Methods The CPH study is a cross-sectional study in a nationally representative sample of adults aged 20 years or older from ten provinces, autonomous regions, and municipalities in mainland China. All participants underwent a post-bronchodilator pulmonary function test. COPD was diagnosed according to 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Findings Between June, 2012, and May, 2015, 57 779 individuals were invited to participate, of whom 50 991 (21 446 men and 29 545 women) had reliable post-bronchodilator results and were included in the final analysis. The overall prevalence of spirometry-defined COPD was 8·6% (95% CI 7·5–9·9), accounting for 99·9 (95% CI 76·3–135·7) million people with COPD in China. Prevalence was higher in men (11·9%, 95% CI 10·2–13·8) than in women (5·4%, 4·6–6·2; p 3 (1·85, 1·23–2·77) or 75 μg/m 3 or higher (2·00, 1·36–2·92), underweight (body-mass index 2 ; 1·43, 1·03–1·97), sometimes childhood chronic cough (1·48, 1·14–1·93) or frequent cough (2·57, 2·01–3·29), and parental history of respiratory diseases (1·40, 1·23–1·60). A lower risk of COPD was associated with middle or high school education (OR 0·76, 95% CI 0·64–0·90) and college or higher education (0·47, 0·33–0·66). Interpretation Spirometry-defined COPD is highly prevalent in the Chinese adult population. Cigarette smoking, ambient air pollution, underweight, childhood chronic cough, parental history of respiratory diseases, and low education are major risk factors for COPD. Prevention and early detection of COPD using spirometry should be a public health priority in China to reduce COPD-related morbidity and mortality. Funding Ministry of Health and Ministry of Science and Technology of China.

The aberrant proliferation of nucleus pulposus (NP) cells has been reported to be implicated in the pathogenesis of intervertebral disc degeneration (IDD). Previous studies have demonstrated that microRNAs (miRNAs), which are a group of small noncoding RNAs, are critical regulators of cell proliferation in various pathologies. However, the role of miRNA‑96 (miR‑96) in the proliferation of NP cells remains to be determined. In the present study, reverse transcription‑quantitative polymerase chain reaction was used to investigate the expression of miR‑96 in NP tissues from patients with IDD and healthy tissues from patients with traumatic lumbar fracture as the control. A dual‑luciferase reporter assay was used to investigate whether AT‑rich interaction domain 2 (ARID2) may be a direct target gene for miR‑96. Furthermore, isolated NP cells from patients with IDD were transfected with miR‑96 mimics and ARID2‑targeting small interfering RNAs; cell proliferation, and the protein expression of Akt, phosphorylated Akt and ARID2 were examined, whereas the effects of an Akt inhibitor on NP cell proliferation were also evaluated. The present results demonstrated that miR‑96 expression was significantly upregulated in IDD samples, and the level of miR‑96 expression was positively associated with disc degeneration grade, which was evaluated by a modified Pfirrmann grading system. In addition, the current study identified ARID2 as a direct gene target of miR‑96. Furthermore, it was demonstrated that ARID2 mRNA expression was inversely correlated with the expression of miR‑96 in NP tissues. In addition, miR‑96 overexpression promoted NP cell proliferation and induced Akt phosphorylation, which led to increased cyclin D1 translation. Notably, overexpression of ARID2 or treatment with an Akt inhibitor decreased the effect of miR‑96 on NP cell proliferation. In conclusion, the results of the present study indicate that miR‑96 may promote the proliferation of human degenerated NP cells by targeting ARID2 via activation of the Akt pathway, and potentially serves as a therapeutic target for IDD.

γδ T cells has been shown to exhibit profound antitumor effects in a broad range of tumor entities, including OS. However, resistance to γδ T cells is a serious problem in the management of OS. This study investigates the impact of celastrol on the expression of death receptors 4/5 (DR4/5) on OS cell lines (HOS, U2OS) and cancer cell lysis by γδ T cells. The results showed that celastrol increased transcription of DR4/5 in HOS and U2OS, leading to increased cell surface, and total DR4/5 protein expression. Celastrol sensitizes OS cell lines or autologous OS cells to healthy donors-derived or OS patient-derived γδ T cell cytotoxicity in vitro. The induction of DR4/5 molecules increased lysis of HOS and U2OS by γδ T cells which was abolished by addition of a blocking TRAIL antibody. Importantly, the cytotoxic activity of γδ T cells was unaltered by small-dose celastrol. Taken together, our data show that celastrol up-regulated DR4/5 on OS cells to be responsible for intercellular TRAIL/APO-2L crosslink that confers increased cancer cell lysis by γδ T cells. These results suggest the clinical evaluation of celastrol in OS, especially in combination with immunotherapy approaches employing adoptive γδ T cell transfer.

Araloside C (AsC) has potential cardioprotective properties. However, the underlying mechanism of AsC-mediated cardioprotection, especially the role of mitochondrial function, remains largely unknown. Here, we used H9c2 cardiomyocytes to study the cardioprotective mechanisms of AsC through H2O2-induced oxidative stress. Cell viability, lactate dehydrogenase release, mitochondrial functions and bioenergetics were evaluated. Western blot analysis was used to measure the protein expression levels of apoptosis and the phosphorylation of AMP-activated protein kinase (AMPK). Results revealed that AsC increased cell viability, improved mitochondrial membrane potential disruption, decreased mitochondrial reactive oxygen species level, elevated cellular ATP levels and alleviated impaired mitochondrial respiration in H2O2-induced H9c2 cardiomyoblasts injury. Furthermore, AsC modulated apoptosis-associated protein expression and AMPK pathway in H9c2 cells under oxidative stress. In conclusion, AsC potentially protects H9c2 cardiomyoblasts against oxidative stress by regulating mitochondrial function and AMPK activation. AsC may be an effective therapeutic agent for the prevention of oxidative stress in cardiac injury.

Currently, hundreds of herbal products with potential hepatotoxicity were available in the literature. A comprehensive summary and analysis focused on these potential hepatotoxic herbal products may assist in understanding herb-induced liver injury (HILI). In this work, we collected 335 hepatotoxic medicinal plants, 296 hepatotoxic ingredients, and 584 hepatoprotective ingredients through a systematic literature retrieval. Then we analyzed these data from the perspectives of phylogenetic relationship and structure-toxicity relationship. Phylogenetic analysis indicated that hepatotoxic medicinal plants tended to have a closer taxonomic relationship. By investigating the structures of the hepatotoxic ingredients, we found that alkaloids and terpenoids were the two major groups of hepatotoxicity. We also identified eight major skeletons of hepatotoxicity and reviewed their hepatotoxic mechanisms. Additionally, 15 structural alerts (SAs) for hepatotoxicity were identified based on SARpy software. These SAs will help to estimate the hepatotoxic risk of ingredients from herbs. Finally, a herb-ingredient network was constructed by integrating multiple datasets, which will assist to identify the hepatotoxic ingredients of herb/herb-formula quickly. In summary, a systemic analysis focused on HILI was conducted which will not only assist to identify the toxic molecular basis of hepatotoxic herbs but also contribute to decipher the mechanisms of HILI.

Arsenic trioxide (ATO) has been verified as a breakthrough with respect to the management of acute promyelocytic leukemia (APL) in recent decades but associated with some serious adverse phenomena, particularly cardiac functional abnormalities. Salvianolic acid A (Sal A) is a major effective component in treating ATO-induced cardiotoxicity. Therefore, the objective of our study was to assess whether Sal A had protective effects by the regulation of calcium homeostasis and endoplasmic reticulum (ER) stress. For the in vivo study, BALB/c mice were treated with ATO and/or Sal A via daily tail vein injections for two weeks. For the in vitro study, we detected the effects of ATO and/or Sal A in real time using adult rat ventricular myocytes (ARVMs) and an IonOptix MyoCam system. Our results showed that Sal A pretreatment alleviated cardiac dysfunction and Ca2+ overload induced by ATO in vivo and vitro. Moreover, Sal A increased sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) activity and expression, alleviated [Ca2+]ER depletion, and decreased ER stress-related protein expression. Sal A protects the heart from ATO-induced injury and its administration correlates with the modulation of SERCA, the recovery of Ca2+ homeostasis, and the down-regulation of ER stress-mediated apoptosis.

Background Cardiotoxicity remains an important concern in drug discovery and clinical medication. Meanwhile, Sophora tonkinensis Gapnep. (S. tonkinensis) held great value in the clinical application of traditional Chinese medicine, but cardiotoxic effects were reported, with matrine, oxymatrine, cytisine, and sophocarpine being the primary toxic components. Methods In this study, impedance and extracellular field potential (EFP) of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were recorded using the cardio non-labeled cell function analysis and culture system (Cardio-NLCS). The effects of matrine, oxymatrine, cytisine, and sophocarpine (2, 10, 50 μM) on cell viability; level of lactate dehydrogenase (LDH), creatine kinase MB isoenzyme (CK-MB), and cardiac troponin I (CTn-I); antioxidant activities; production of reactive oxygen species (ROS) and malondialdehyde (MDA); and disruption of intracellular calcium homeostasis were also added into the integrated assessment. Results The results showed that matrine and sophocarpine dose-dependently affected both impedance and EFP, while oxymatrine and cytisine altered impedance significantly. Our study also indicated that cardiotoxicity of matrine, oxymatrine, cytisine, and sophocarpine was related to the disruption of calcium homeostasis and oxidative stress. Four alkaloids of S. tonkinensis showed significant cardiotoxicity with dose dependence and structural cardiotoxicity synchronized with functional changes of cardiomyocytes. Conclusions This finding may provide guidance for clinical meditation management. Furthermore, this study introduced an efficient and reliable approach, which offers alternative options for evaluating the cardiotoxicity of the listed drugs and novel drug candidates. Electronic supplementary material The online version of this article (10.1186/s13287-018-1126-4) contains supplementary material, which is available to authorized users.

Atherosclerosis is an arterial disease associated with inflammation. Hence, the discovery of novel therapeutic agents for suppressing inflammatory responses is urgent and vital for the treatment of atherosclerosis in cardiovascular diseases. The total saponins of Aralia elata (Miq.) Seem. (TAS) are the main components extracted from the Chinese traditional herb Longya Aralia chinensis L., a folk medicine used in Asian countries for treating numerous diseases, enhancing energy and boosting immunity. However, the protective effects of TAS against inflammation-triggered vascular endothelial dysfunction, a critical early event during the course of atherosclerosis, and the potential mechanisms of this protection have been not demonstrated. Accordingly, the aim of this study was to investigate the anti-inflammatory and anti-apoptotic effects and the protective mechanisms of TAS, and show how TAS ameliorates human umbilical vein endothelial cell (HUVEC) damage caused by tumour necrosis factor-&alpha, (TNF-&alpha, ). The results indicated that TAS exerted cytoprotective effects by inhibiting TNF-&alpha, triggered HUVEC apoptosis, mitochondrial membrane potential depolarisation, and the regulation of inflammatory factors (IL-6, MCP-1, and VCAM-1) while suppressing NF-&kappa, B transcription. Furthermore, this phenomenon was related to activation of the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway. Blocking the Akt pathway with LY294002, a PI3K inhibitor, reversed the cytoprotective effect of TAS against TNF-&alpha, induced endothelial cell death. Moreover, LY294002 partially abolished the effects of TAS on the upregulation of the Bcl-2 family of proteins and the downregulation of Bax protein expression. In conclusion, the results of our study suggest that TAS suppresses the inflammation and apoptosis of HUVECs induced by TNF-&alpha, and that PI3K/Akt signalling plays a key role in promoting cell survival and anti-inflammatory reactions during this process.

Patients with diabetes mellitus (DM) suffer more risks from diabetic encephalopathy such as cognitive dysfunction and depressive-like behaviors. Numerous studies show that ER (endoplasmic reticulum) stress and inflammation play important roles in the development of diabetic encephalopathy. Gastrodin (Gas), one major component of Gastrodia elata, is traditionally used in central nervous system disorders and is believed to possess anti-inflammatory, anti-apoptotic, and other neuroprotective effects. This present study aims to explore the protective effects of Gas on diabetic encephalopathy. Gas was administrated daily (70 and 140 mg/Kg) for 12 weeks. Meanwhile, the fasting blood glucose and body weight of db/db mice were measured every two weeks. After Gas treatment, the Morris water maze (MWM) test and novel object recognition (NOR) test were performed to assess the learning and memory functions of db/db mice, and the forced swim test was performed to evaluate depressive-like behaviors of db/db mice. Additionally, the expression of ER stress and Nucleotide binding and oligomerization domain-like (Nod) receptor family pyrin domain-containing 3 (NLRP3) inflammasome related proteins were evaluated by using Western blot. Our study suggested that Gas attenuated blood glucose levels and dyslipidemia of db/db mice. It has been shown that Gas could improve learning and memory function and depressive-like behaviors of db/db mice. Moreover, Gas inhibited ER stress and NLRP3 inflammasome activation in the hippocampus. Taken together, this study demonstrates that Gas attenuates the diabetic encephalopathy by inhibiting ER stress and NLRP3 inflammasome activation.

Elderly populations with underlying chronic diseases are more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and have higher mortality. Parkinson’s disease (PD) is a neurodegenerative disease that occurs more often in elderly people. Currently, little is known about whether patients with PD are more susceptible to novel coronavirus disease 2019 (COVID-19) and whether the treatment of PD would affect the management of COVID-19 or vice versa. Here, we report a case of a PD patient with severe COVID-19 pneumonia in Wuhan, China. After diagnosis of COVID-19, this PD patient had worsening of motor symptoms, complicated with acute hypoxemic respiratory failure, urinary tract infection, and acute encephalopathy. In addition to treatment for COVID-19 and urinary tract infection, we adjusted anti-PD medicine by stepwise increasing of dose, resulting in better control of her mobility symptoms and non-motor symptoms.

Panaxatriol (PT) is a natural product derived from ginseng that possesses cardioprotective effects in isolated rat hearts. To develop more potent therapeutic agents against myocardial ischemia/reperfusion (MI/R) injury from natural products, a novel series of heterocycle ring-fused panaxatriol derivatives were designed and synthesized. In vitro results showed that approximately half of them exhibited increased cytoprotective activity compared with PT in a cardiomyocyte model of oxygen-glucose deprivation and reperfusion (OGD/R) injury. Furthermore, the in vitro activity of the representative derivative, compound 18, was also confirmed in a rat model of MI/R injury. In vivo results showed that 18 can markedly reduce myocardial infarction size, decrease circulating cardiac troponin I (cTnI) leakage, and alleviate cardiac tissue damage in the rats. Therefore, these findings provide the basis for further development of novel anti-MI/R injury agents.

Inflammation is a major contributing factor to the progression of atherosclerosis. Ginsenoside Rb1 (Rb1), an active saponin of Panax notoginseng, has been found to exert beneficial effects on inflammation and oxidative stress. This study investigated the ability of Rb1 to inhibit the formation of atherosclerotic plaques and the potential mechanisms. In this study, the effects of Rb1 on the development of atherosclerosis were investigated in ApoE-/- deficient mice fed with a western diet. Mice were intragastrically administrated with Rb1 (10 mg/kg) for 8 weeks. This study is that ginsenoside Rb1 exerted an inhibitory effect on early atherosclerosis in ApoE-/- mice via decreasing body weight and food intake daily, upregulating the lipid levels of serum plasma, including those of TC, TG and LDL-C and HDL-C and reducing the atherosclerotic plaque area, suppressing inflammatory cytokines (levels of IL-1&beta, IL-6 and TNF-&alpha, ) in the serum of ApoE-/- mice, changing the expression levels of BCL-2, BAX, cleaved caspase-3 and cleaved caspase-9 and weakening apoptosis associated with anti-inflammatory activity. Hence, all these effects against atherosclerosis were tightly associated with regulation of necrosis or apoptosis associated with anti-inflammatory activity. Additionally, the results found that ginsenoside Rb1 increased autophagy flux to inhibit apoptosis via acceleration of autophagy by promoting transformation of LC3 from type I to type II in high-fat diet-induced atherosclerosis in ApoE-/- mice. This finding, along with those of the previous study, provides evidence that Rb1 promotes the process of autophagy to protect against atherosclerosis via regulating BCL-2 family-related apoptosis. These results indicate that Rb1 exhibits therapeutic effects in atherosclerosis by reversing the imbalance between apoptosis and autophagy.

Background Small airways dysfunction (SAD) is common but neglected respiratory abnormality. However, little is known about its prevalence, risk factors, and prognosis in the general population of China. Methods The nationally representative China Pulmonary Health study included more than 50 000 adults during 2012–15 using multistage stratified cluster sampling method, with valid spirometry measurements. Ten Chinese provinces, autonomous regions, and municipalities in mainland China were selected from six geographical regions, and all assessments were done in community health centres. SAD was defined as two of the three measures (ie, maximal mid-expiratory flow, forced expiratory flow 50%, and forced expiratory flow 75%) having below 65% of the predicted pre-bronchodilator values. Early-stage SAD was defined as SAD with normal forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), peak expiratory flow, and FEV1/FVC, whereas pre-SAD was defined as early-stage SAD before bronchodilator inhalation, and pre-SAD plus post-SAD as early-stage SAD before and after bronchodilator inhalation. Logistic regression yielded adjusted odds ratios (aORs) for SAD associated with lifestyle and environmental factors. We estimated the total number of SAD in China using data from the present study and national census. Findings Overall the prevalence of SAD, pre-SAD, and pre-SAD plus post-SAD was 43·5%, 21·4%, and 10·8%, respectively. The risk of SAD, especially pre-SAD plus post-SAD, was significantly associated with several factors, including cigarette smoking (aOR 1·16, 95% CI 1·04–1·28), exposure to particulate matter 2·5 (1·27 [1·12–1·44] at 50–74 μg/m3, and 1·48 [1·30–1·69] at ≥75 μg/m3), adiposity (1·37 [1·26–1·48] per 5 kg/m2 higher body-mass index) and parental history of respiratory diseases (1·11, 1·02–1·21). In 2015, an estimated 426 million (95% CI 411–467), 211 million (191–242), and 104 million (94–126) adults had SAD, pre-SAD, and pre-SAD plus post-SAD, respectively, in China. Interpretation In China, spirometry-defined SAD is highly prevalent, with cigarette smoking, air pollution, and adiposity being major modifiable risk factors. Our findings highlight the need for early screening of SAD to reduce the health burden associated with chronic lung diseases in general populations. Funding National Natural Science Foundation of China, National Key R&D Program of China, and the Special Research Foundation for Public Welfare of Health, Ministry of Health of China.

Patients with diabetes mellitus (DM) are at high risk for cognitive dysfunction. Endoplasmic reticulum stress (ERS) and inflammation play crucial roles in DM. Gastrodin (Gas), the main component of Gastrodia elata, possesses anti-oxidative stress, anti-inflammatory, and neuroprotective effects. This present study aims to investigate whether Gas could ameliorate cognitive dysfunction in DM and to explore its underlying mechanisms. Rats with streptozotocin-induced type 2 DM were used in this study. After administration of Gas for 5 weeks, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) in serum, TNF-α, IL-1β, MDA and SOD in the hippocampus were measured. Morris water maze, hematoxylin and eosin (HE) and Nissl staining were performed to assess the effects of Gas on cognitive function and hippocampal neuronal apoptosis. Protein levels of GLUT3, brain derived neurotrophic factor (BDNF), GRP78, PERK, P-PERK, TXNIP, ASC, NLRP3, CHOP, Bcl-2 and Bax were measured by using Western blot. The results showed that Gas could improve hyperglycemia and dyslipidemia in DM rats, as the levels of TC, TG LDL-C in serum were decreased. TNF-α, IL-1β, MDA contents in the hippocampus were decreased, and SOD contents was increased in the hippocampus of DM rats. Inflammation, oxidative stress, ERS, and apoptosis were observed in the hippocampus of DM rats, accompanied with decreased expression of BDNF and GLUT3. Gas improved the cognitive deficits caused by diabetes and inhibited inflammation, oxidative stress, ERS, and apoptosis in the hippocampus. Furthermore, Gas substantially increased the expression of GLUT3, and inhibited hippocampal ERS and ERS-mediated apoptosis. Additionally, Gas increased the expression of BDNF and decreased the activation of NLRP3 inflammasome. These results suggested that by inhibiting ERS and NLRP3 inflammasome activation and increasing the expression of BDNF and GLUT3, Gas exhibits neuroprotective effects against cognitive dysfunction in DM.

Human mesotrypsin is highly homologous to other mammalian trypsins, and yet it is functionally unique in possessing resistance to inhibition by canonical serine protease inhibitors and in cleaving these inhibitors as preferred substrates. Arg-193 and Ser-39 have been identified as contributors to the inhibitor resistance and cleavage capability of mesotrypsin, but it is not known whether these residues fully account for the unusual properties of mesotrypsin. Here, we use human cationic trypsin as a template for engineering a gain of catalytic function, assessing mutants containing mesotrypsin-like mutations for resistance to inhibition by bovine pancreatic trypsin inhibitor (BPTI) and amyloid precursor protein Kunitz protease inhibitor (APPI), and for the ability to hydrolyze these inhibitors as substrates. We find that Arg-193 and Ser-39 are sufficient to confer mesotrypsin-like resistance to inhibition; however, compared with mesotrypsin, the trypsin-Y39S/G193R double mutant remains 10-fold slower at hydrolyzing BPTI and 2.5-fold slower at hydrolyzing APPI. We identify two additional residues in mesotrypsin, Lys-74 and Asp-97, which in concert with Arg-193 and Ser-39 confer the full catalytic capability of mesotrypsin for proteolysis of BPTI and APPI. Novel crystal structures of trypsin mutants in complex with BPTI suggest that these four residues function cooperatively to favor conformational dynamics that assist in dissociation of cleaved inhibitors. Our results reveal that efficient inhibitor cleavage is a complex capability to which at least four spatially separated residues of mesotrypsin contribute. These findings suggest that inhibitor cleavage represents a functional adaptation of mesotrypsin that may have evolved in response to positive selection pressure.

Mesotrypsin is an isoform of trypsin that is uniquely resistant to polypeptide trypsin inhibitors and can cleave some inhibitors rapidly. Previous studies have shown that the amyloid precursor protein Kunitz protease inhibitor domain (APPI) is a specific substrate of mesotrypsin and that stabilization of the APPI cleavage site in a canonical conformation contributes to recognition by mesotrypsin. We hypothesized that other proteins possessing potential cleavage sites stabilized in a similar conformation might also be mesotrypsin substrates. Here we evaluated a series of candidate substrates, including human Kunitz protease inhibitor domains from amyloid precursor-like protein 2 (APLP2), bikunin, hepatocyte growth factor activator inhibitor type 2 (HAI2), tissue factor pathway inhibitor-1 (TFPI1), and tissue factor pathway inhibitor-2 (TFPI2), as well as E-selectin, an unrelated protein possessing a potential cleavage site displaying canonical conformation. We find that Kunitz domains within APLP2, bikunin, and HAI2 are cleaved by mesotrypsin with kinetic profiles of specific substrates. TFPI1 and TFPI2 Kunitz domains are cleaved less efficiently by mesotrypsin, and E-selectin is not cleaved at the anticipated site. Cocrystal structures of mesotrypsin with HAI2 and bikunin Kunitz domains reveal the mode of mesotrypsin interaction with its canonical substrates. Our data suggest that major determinants of mesotrypsin substrate specificity include sequence preferences at the P1 and P′2 positions along with conformational stabilization of the cleavage site in the canonical conformation. Mesotrypsin up-regulation has been implicated previously in cancer progression, and proteolytic clearance of Kunitz protease inhibitors offers potential mechanisms by which mesotrypsin may mediate pathological effects in cancer.

Diabetes mellitus is associated with rapid cognitive decline. Currently, there is no effective treatment for cognitive dysfunction induced by diabetes. L-3-n-Butylphthalide (L-NBP) is a nerve protective drug extracted from seeds of celery, which has been proved to improve learning and memory in vascular dementia animal models by improving microcirculation, protecting mitochondria and increasing long-term potentiation (LTP). NR2B, one of the subunits of N-methyl-D-aspartate receptor, has been proved to be an important factor for the formation of LTP. The study aimed to investigate the role of NR2B in cognitive dysfunction in the rats with type 1 diabetes and define the protective effects of L-NBP on cognition. A rat model of type 1 diabetes was established by a single intraperitoneal injection of streptozotocin at 60 mg/kg. Animals were randomly allocated to four groups: normal control (NC); diabetic control (DC); diabetic + low L-NBP (DL, administered L-NBP 60 mg/kg per day for 12 weeks); and diabetic + high L-NBP (DH, administered L-NBP 120 mg/kg per day, for 12 weeks). After 12 weeks, cognitive and memory changes were investigated in the Morris water maze. The expression of NR2B was assessed by real-time polymerase chain reaction, Western blotting, and immunohistochemistry. Our results indicated that the escape latency was significantly increased and the number of crossing platform was significantly decreased in DC group compared to NC group. Also, the expression of NR2B was significantly declined in DC group. However, compared to DC group, the expression of NR2B of the L-NBP-treated groups was significantly increased and the escape latency was shortened with the DH group being the most obvious. Therefore, L-NBP can improve the cognitive function by up-regulating the expression of NR2B in STZ-diabetic rats, which may provide the direction for future diabetic encephalopathy therapy.

Peripheral mechanical neuropathic pain is a serious side effect of docetaxel chemotherapy for cancer. However, the underlying mechanism for this side effect is unknown. In the present study, we found that docetaxel treatment induced mechanical allodynia in rats. We further revealed that the transient receptor potential ankyrin subtype 1 protein (TRPA1) protein level is upregulated and the TRPA1 activator allyl isothiocyanate induced larger ion currents in the dorsal root ganglion neurons from the docetaxel treated rats. In addition, application the TRPA1 blocker Ap18 reversed the docetaxel-induced mechanical hypersensitivity. We suggest that the docetaxel-induced mechanical allodynia is mediated by upregulation of TRPA1 in dorsal root ganglion neurons.

Increasing evidence demonstrates an association between diabetes and hippocampal neuron damage. This study aimed to determine the effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits (GCLM and GCLC) in the hippocampus of streptozotocin-induced type 1 diabetes mellitus (T1DM) rats. At 12weeks after streptozotocin injection, T1DM rats were randomly divided into 4 groups (n=15 each group) to receive no treatment (T1DM), saline (T1DM+saline), alpha-lipoic acid (T1DM+alpha-lipoic acid), and troxerutin (T1DM+troxerutin), respectively, for 6weeks. Meanwhile, 10 control animals (NC group) were assessed in parallel. Learning performance was evaluated by the Morris water maze. After treatment, hippocampi were collected for pathological examination by hematoxylin and eosin (H&E) staining. Next, hippocampal superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and glutathione (GSH) levels were assessed. Finally, glutamate cysteine ligase catalytic (GCLC) and glutamate cysteine ligase modifier (GCLM) subunit mRNA and protein levels were quantified by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Compared with T1DM and T1DM+saline groups, escape latency was overtly reduced in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Significantly increased GCLM and GCLC mRNA levels, GCLC protein amounts, SOD activity, and GSH levels, and reduced MDA amounts were observed in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. In T1DM and T1DM+saline groups, H&E staining showed less pyramidal cells in the hippocampus, with disorganized layers, karyopyknosis, decreased endochylema, and cavitation, effects relieved in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Troxerutin alleviates oxidative stress and promotes learning in streptozotocin-induced T1DM rats, a process involving GCLC expression.

Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.

To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts.A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rho-kinase inhibitor fasudil hydrochloride hydrate (10 mg·kg(-1)·d(-1), ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting.In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved.The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.

The aim of the study was to explore the relationship between the concentration of C-telopeptide fragments of type II collagen (CTX-II), Zn2+, and Ca2+ in urine and knee osteoarthritis (KOA). Eighty-two patients with KOA and 20 healthy volunteers were enrolled. Anteroposterior and lateral position x-rays of knee joints were collected. The images were classified according to Kellgren-Lawrence radiographic grading criterion. The patients were divided into group grade I, group grade II, group grade III, and grade IV. The concentration of CTX-II in the urine was detected by enzyme-linked immunosorbent assay. The concentration of Zn2+ and Ca2+ in urine was detected by inductively coupled plasma atomic emission spectrometry. Compared with the healthy individuals, the concentration of CTX-II was significantly higher in KOA patients. The concentration of CTX-II in KOA patients from high to low was as follows: group IV, group III, group II, and group I. There was no significant difference between group I and healthy individuals. The concentration of Zn2+ and Ca2+ in urine of KOA patients was higher than that in healthy individuals. There was no difference in each KOA group. The concentration of CTX-II is instrumental to diagnose the progress of KOA. The concentration of Zn2+ and Ca2+ in urine is helpful for early diagnosis of KOA.

Aims Several studies have shown associations between the composition of polyunsaturated fatty acids (PUFAs) in various tissues and type 2 diabetes mellitus (T2DM) development in European populations. Genetic variants of fatty acid desaturase (FADS) contribute to the variations of PUFA composition. Here we have explored whether similar correlations are also true among Chinese Han people. Methods A case–control study was employed to examine this correlation in Han Chinese people. The study included 421 healthy adults and 331 T2DM patients. Results The ratio of arachidonic acid/linoleic acid (AA/LA), which reflects Δ6 desaturase activity, was significantly increased in T2DM patients. Furthermore, the ratio of eicosapentaenoic acid/α-linolenic acid (EPA/ALA), which reflects Δ5 desaturase activity, was markedly decreased in T2DM patients. Importantly, among four single nucleotide polymorphisms (rs174545, rs2072114, rs174602 and rs174616) in the FADS1-FADS2 gene cluster, only minor allele (T) of rs174616 was associated with decreased risk of T2DM in both codominant and dominant models after adjustment for age, gender and BMI. Furthermore, the ratio of AA/LA in both controls and T2DM was reduced in T carriers while an increased proportion of LA was seen in T2DM patients compared with control patients. Conclusion These data suggest that in northern Han Chinese people, the minor allele (T) of rs174616 in the FADS1-FADS2 gene cluster is associated with a decreased conversion rate of LA to AA, which may contribute to decreased reduced risk of developing T2DM.

The association between dyslipidemia and elevated fasting glucose in type 2 diabetes is well known. In non-diabetes, whether this association still exists, and whether dyslipidemia is an independent risk factor for high fasting plasma glucose (FPG) levels are not clear. This cross-sectional study recruited 3460 non-diabetic Chinese subjects (1027 men, and 2433 women, aged 35-75 years old) who participated in a health survey. Men and women were classified into tertiles by levels of plasma lipids respectively. In women, the prevalence of impaired fasting glucose (IFG) was decreased with increased HDL-C. A stepwise increase in HDL-C was associated with decreasing FPG levels (lowest tertiles, FPG: 5.376 ± 0.018; middle tertiles, 5.324 ± 0.018; highest tertiles, 5.276 ± 0.018 mmol/L; P = 0.001). Reversely, FPG levels increased from lowest tertiles to highest tertiles of LDL-C, TC, and TG. we found that women in the first tertile with lower HDL-C level had a 1.75-fold increase in risk of IFG compared with non-diabetic women in the third tertile with higher HDL-C level (OR: 1.75; 95% CI: 1.20-2.56). In men, no significant association was found. We took age, BMI, waist/hip ratio, education, smoking, alcohol drinking, and physical exercise as adjusted variables. In Chinese non-diabetic women, dyslipidemia is independently associated with high levels of FPG; TG, HDL-C, and LDL-C are predictors of IFG independent of BMI and waist/hip ratio.