Mechanism of Qili Qiangxin Capsule for Heart Failure Based on miR133a-Endoplasmic Reticulum Stress.

OBJECTIVE: To investigate the pharmacological mechanism of Qili Qiangxin Capsule (QLQX) improvement of heart failure (HF) based on miR133a-endoplasmic reticulum stress (ERS) pathway. METHODS: A left coronary artery ligation-induced HF after myocardial infarction model was used in this study. Rats were randomly assigned to the sham group, the model group, the QLQX group [0.32 g/(kg·d)], and the captopril group [2.25 mg/(kg·d)], 15 rats per group, followed by 4 weeks of medication. Cardiac function such as left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximal rate of increase of left ventricular pressure (+dp/dt max), and the maximal rate of decrease of left ventricular pressure (-dp/dt max) were monitored by echocardiography and hemodynamics. Hematoxylin and eosin (HE) and Masson stainings were used to visualize pathological changes in myocardial tissue. The mRNA expression of miR133a, glucose-regulated protein78 (GRP78), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), X-box binding protein1 (XBP1), C/EBP homologous protein (CHOP) and Caspase 12 were detected by RT-PCR. The protein expression of GRP78, p-IRE1/IRE1 ratio, cleaved-ATF6, XBP1-s (the spliced form of XBP1), CHOP and Caspase 12 were detected by Western blot. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the rate of apoptosis. RESULTS: QLQX significantly improved cardiac function as evidenced by increased EF, FS, LVSP, +dp/dt max, -dp/dt max, and decreased LVEDP (P<0.05, P<0.01). HE staining showed that QLQX ameliorated cardiac pathologic damage to some extent. Masson staining indicated that QLQX significantly reduced collagen volume fraction in myocardial tissue (P<0.01). Results from RT-PCR and Western blot showed that QLQX significantly increased the expression of miR133a and inhibited the mRNA expressions of GRP78, IRE1, ATF6 and XBP1, as well as decreased the protein expressions of GRP78, cleaved-ATF6 and XBP1-s and decreased p-IRE1/IRE1 ratio (P<0.05, P<0.01). Further studies showed that QLQX significantly reduced the expression of CHOP and Caspase12, resulting in a significant reduction in apoptosis rate (P<0.05, P<0.01). CONCLUSION: The pharmacological mechanism of QLQX in improving HF is partly attributed to its regulatory effect on the miR133a-IRE1/XBP1 pathway.

Insight into Dysmenorrhea Research from 1992 to 2022: A Bibliometric Analysis.

Dysmenorrhea, classified as primary dysmenorrhea and secondary dysmenorrhea, is a common gynecological symptom that seriously affects female daily life. At present, studies on dysmenorrhea are numerous and complex. To better reflect the trend and innovative progress of dysmenorrhea-related research, this study screened papers on the Web of Science from January 1, 1992, to December 31, 2022. A total of 1012 papers were selected and analyzed for their affiliated countries, institutions, authors, keywords, etc. China is the country with the most academic output, Beijing University of Traditional Chinese Medicine is the most influential institution, and Yang Jie, from Chengdu University of Traditional Chinese Medicine, China, is the scholar with the most papers. We consider that the current research focus is on pathogenesis, treatment, epidemiology, and self-management. With increasing research on functional connectivity between dysmenorrhea and various brain regions, functional connectivity has gradually become the forefront of research. We hope our study can promote the further study of dysmenorrhea.

Economic burden of adult patients with ß-thalassaemia major in mainland China.

BACKGROUND: ß-thalassaemia major poses a substantial economic burden, especially in adults. We aimed to estimate the economic burden of adult patients with ß-thalassaemia major from a societal perspective using the real-world data. According to the clinical guideline, we also estimated the annual medical costs for patients with the same body weight and calculated the lifetime medical costs over 50 years in mainland China. METHODS: This was a retrospective cross-sectional study. An online survey with snowball sampling covering seven provinces was conducted. We extracted patient demographics, caregiver demographics, disease and therapy information, caring burden, and costs for adult patients diagnosed with ß-thalassaemia major and their primary caregivers. In the real world, we estimated the annual direct medical cost, direct nonmedical cost, and indirect cost. In addition, we calculated the annual direct medical cost and lifetime direct medical cost by weight with discounted and undiscounted rates according to the clinical guideline. RESULTS: Direct medical costs was the main driver of total cost, with blood transfusion and iron chelation therapy as the most expensive components of direct medical cost. In addition, adult patients with ß-thalassaemia major weighing 56 kg were associated with an increase of $2,764 in the annual direct medical cost using the real-world data. The undiscounted and discounted (5% discount rate) total lifetime treatment costs were $518,871 and $163,441, respectively. CONCLUSIONS: Patients with ß-thalassaemia major often encounter a substantial economic burden in mainland China. Efforts must be made to help policymakers develop effective strategies to reduce the burden and pevalence of thalassaemia.

Mechanism of Ethyl Acetate Extract of Gentianopsis paludosa in Treatment of Ulcerative Colitis Based on Bcl-2/Bax Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of ethyl acetate extract of Tibetan medicine dampness bud Gentianopsis paludosa in the prevention and treatment of recurrent ulcerative colitis （UC） in rats with dampness-heat in large intestine syndrome based on the apoptotic pathway mediated by the B-cell lymphoma-2 （Bcl-2） and Bcl-2-associated X protein （Bax）. MethodUsing the disease-syndrome combination method， a recurrent UC model of dampness-heat in large intestine syndrome was constructed in rats. Seventy SPF-grade male SD rats were randomly divided into control group， model group， high-， medium-， and low-dose ethyl acetate of G.paludosa groups （150， 75， 37.5 mg·kg-1）， and mesalazine group （135 mg·kg-1）. The rats were orally administered with respective drugs for 14 days. The general conditions of the rats were recorded， and colon length and mucosal damage were observed. The colon wet weight index and organ coefficients of the liver， spleen， and thymus were calculated. Enzyme-linked immunosorbent assay （ELISA） was used to measure the levels of interleukin-6 （IL-6） and interleukin-1β （IL-1β） in the serum of each group. Hematoxylin-eosin （HE） staining was performed to observe pathological changes in the colon. Terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） was used to detect apoptosis in colonic epithelial cells. Western blot was used to measure the expression levels of Bcl-2， Bax， Caspase-3， Caspase-9， Zona Occludens-1 （ZO-1）， Claudin3， and Occludin in colonic tissue. Immunohistochemistry （IHC） was used to observe the expression of Bax and Caspase-3 in colonic epithelial cells. ResultCompared with the control group， the model group showed significant increases in the disease activity index （DAI） score， colonic mucosal damage index （CMDI）， intestinal epithelial apoptosis， liver and spleen indexes， and levels of inflammatory factors IL-1β and IL-6 in the serum （P<0.01）， decreased expression of intestinal mucosal protective proteins ZO-1， Claudin3， and Occluding （P<0.01）， increased expression of pro-apoptotic proteins Bax， Caspase-3， and Caspase-9 （P<0.01）， and decreased expression of anti-apoptotic protein Bcl-2 （P<0.01）. Compared with the model group， the high-， medium-， and low-dose ethyl acetate of G.paludosa groups all significantly improved the general condition of the rats， reduced colonic lesions， decreased intestinal epithelial cell apoptosis， reduced liver and spleen indexes， upregulated the expression of ZO-1， Claudin3， Occludin， and Bcl-2 proteins， and downregulated the expression of Bax， Caspase-3， and Caspase-9 proteins， with the high- and medium-dose ethyl acetate of G.paludosa groups showing the superior effects （P<0.05， P<0.01）. ConclusionEthyl acetate of G.paludosa can alleviate colonic mucosal damage and exert a therapeutic effect on UC by regulating the Bcl-2/Bax signaling pathway.

Rapid determination of the total content of oleanolic acid and ursolic acid in Chaenomelis Fructus using near-infrared spectroscopy.

Chaenomelis Fructus is a widely used traditional Chinese medicine with a long history in China. The total content of oleanolic acid (OA) and ursolic acid (UA) is taken as an important quality marker of Chaenomelis Fructus. In this study, quantitative models for the prediction total content of OA and UA in Chaenomelis Fructus were explored based on near-infrared spectroscopy (NIRS). The content of OA and UA in each sample was determined using high-performance liquid chromatography (HPLC), and the data was used as a reference. In the partial least squares (PLS) model, both leave one out cross validation (LOOCV) of the calibration set and external validation of the validation set were used to screen spectrum preprocessing methods, and finally the multiplicative scatter correction (MSC) was chosen as the optimal pretreatment method. The modeling spectrum bands and ranks were optimized using PLS regression, and the characteristic spectrum range was determined as 7,500-4,250 cm-1, with 14 optimal ranks. In the back propagation artificial neural network (BP-ANN) model, the scoring data of 14 ranks obtained from PLS regression analysis were taken as input variables, and the total content of OA and UA reference values were taken as output values. The number of hidden layer nodes of BP-ANN was screened by full-cross validation (Full-CV) of the calibration set and external validation of the validation set. The result shows that both PLS model and PLS-BP-ANN model have strong prediction ability. In order to evaluate and compare the performance and prediction ability of models, the total content of OA and UA in each sample of the test set were detected under the same HPLC conditions, the NIRS data of the test set were input, respectively, to the optimized PLS model and PLS-BP-ANN model. By comparing the root-mean-square error (RMSEP) and determination coefficient (R 2) of the test set and ratio of performance to deviation (RPD), the PLS-BP-ANN model was found to have better performance with RMSEP of 0.59 mg·g-1, R 2 of 95.10%, RPD of 4.53 and bias of 0.0387 mg·g-1. The results indicated that NIRS can be used for the rapid quality control of Chaenomelis Fructus.

Supplementation of Lycium barbarum Polysaccharide Combined with Aerobic Exercise Ameliorates High-Fat-Induced Nonalcoholic Steatohepatitis via AMPK/PPARα/PGC-1α Pathway.

Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease (NAFLD). Either Lycium barbarum polysaccharide (LBP) or aerobic exercise (AE) has been reported to be beneficial to hepatic lipid metabolism. However, whether the combination of LBP with AE improves lipid accumulation of NASH remains unknown. Our study investigated the influence of 10 weeks of treatment of LBP, AE, and the combination (LBP plus AE) on high-fat-induced NASH in Sprague-Dawley rats. The results showed that LBP or AE reduced the severity of the NASH. LBP plus AE treatment more effectively ameliorated liver damage and lowered levels of serum lipid and inflammation. In addition, the combination can also regulate genes involved in hepatic fatty acid synthesis and oxidation. LBP plus AE activated AMPK, thereby increasing the expression of PPARα which controls hepatic fatty acid oxidation and its coactivator PGC-1α. Our study demonstrated the improvement of LBP plus AE on NASH via enhancing fatty acid oxidation (FAO) which was dependent on AMPK/PPARα/PGC-1α pathway.

Effect of acupressure combined with Yinzhihuang granules on neonatal jaundice: a systematic review and meta-analysis of randomized controlled trials.

Background: With the improvement of living standards in recent years, people are paying increasing attention to neonatal jaundice. Yinzhihuang granule is a common Chinese herbal drug for the treatment of neonatal jaundice. The aim of this paper was to study the efficacy of acupressure-assisted Yinzhihuang granule in the treatment of neonatal jaundice by meta-analysis. Methods: We performed a search in the databases of PubMed, Embase, Cochrane Library, Chinese Journal Full-text Database (CNKI), VIP, Wanfang Science and Technology Journal Full-text Database, and Chinese Biomedical Literature Search Database (CBM) for articles on the therapeutic effect of acupressure-assisted Yinzhihuang granule on neonatal jaundice from database establishment to October 2021. The software Endnote X9 was used to check and eliminate the articles, screen the articles according to the required inclusion and exclusion criteria, extract the data, and perform quality evaluation according to the risk of bias tool of Cochrane Collaboration. The software Stata 15.1 and RevMan 5.3 were used to record the data, and a meta-analysis was performed on the effective rate of acupressure-assisted Yinzhihuang granule in the treatment of neonatal jaundice, according to serum total bilirubin values after treatment and duration of jaundice. And show the efficacy of Yinzhihuang particles through these results. The reliability of the results was assessed by sensitivity analysis. Funnel plots were used to test the publication bias of the articles. Results: A total of 3 articles were included. The results of meta-analysis showed that when acupressure-assisted Yinzhihuang granule was used to treat neonatal jaundice, the effective rate of the test group was not significantly different from that in the control group; the serum total bilirubin level in the test group was significantly lower than that in the control group after treatment; the duration of jaundice in the test group was significantly shorter than that in the control group. Discussion: Acupressure combined with Yinzhihuang granule is effective in treating neonatal jaundice, which has a positive effect on reducing the level of serum total bilirubin and reducing the duration of jaundice.

Glaucocalyxin A impairs tumor growth via amplification of the ATF4/CHOP/CHAC1 cascade in human oral squamous cell carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: The natural extract glaucocalyxin A (GLA), purified from the aboveground sections of the Chinese traditional medicinal herb Rabdosia japonica (Burm. f.) Hara var. glaucocalyx (Maxim.) Hara, has various pharmacological benefits, such as anti-bacterial, anti-coagulative, anti-neoplastic, and anti-inflammatory activities. Although GLA has shown anti-tumor activity against various cancers, the therapeutic potential and biological mechanisms of GLA remain to be further explored in oral squamous cell carcinoma (OSCC). AIM OF THE STUDY: This study aimed to elucidate the therapeutic potential and regulatory mechanisms of GLA in OSCC. MATERIALS AND METHODS: The cell proliferation and apoptosis effects of GLA were analyzed by CCK-8, clone formation, Annexin V/PI staining, and apoptotic protein expression in vitro. An OSCC xenograft model was applied to confirm the anti-neoplastic effect in vivo. Furthermore, the changes of reactive oxygen species (ROS) were determined by DCFH-DA probe and GSH/GSSG assay, and inhibited by the pan-caspase inhibitor Z-VAD(OMe)-FMK and the ROS scavenger N-acetylcysteine (NAC). The modulation of GLA on mitochondria and ER-dependent apoptosis pathways was analyzed by JC-1 probe, quantitative real-time PCR, and Western blot. Finally, public databases, clinical samples, and transfection cells were analyzed to explore the importance of GLA's indirect targeting molecule CHAC1 in OSCC. RESULTS: GLA significantly inhibited cell proliferation and induced apoptosis in vitro and in vivo. GLA perturbed the redox homeostasis, and cell apoptosis was totally rescued by Z-VAD(OMe)-FMK and NAC. Furthermore, GLA activated the mitochondrial apoptosis pathway. Simultaneously, the overexpression and knockdown of CHAC1 dramatically affected GLA-mediated apoptosis. The endoplasmic reticulum stress-associated ATF4/CHOP signal was identified to participate in GLA-upregulated CHAC1 expression. Finally, we found that CHAC1 expression was lower in OSCC compared with normal tissues and positively correlated with 4-Hydroxynonenal (4-HNE) level. High CHAC1 expression also indicated better overall survival. Moreover, CHAC1 selectively regulated the viability of oral cancer cells. CONCLUSION: GLA is a promising therapeutic agent that activates the ROS-mediated ATF4/CHOP/CHAC1 axis in OSCC patients.

Oral Arsenic-Containing Qinghuang Powder: A Potential Drug for Myelodysplastic Syndromes.

Qinghuang Powder (QHP), an oral arsenic, has become an effective drug in the treatment of myelodysplastic syndromes (MDS) in Xiyuan Hospital, China Academy of Chinese Medical Sciences for many years, and the action mechanism of the compound or active ingredient As2S2 of QHP has been elucidated. Considering the relatively safety, chemotherapy-free and convenient oral profile, QHP is widely used in the clinical treatment for MDS patients, especially for elderly patients. In this review, the authors document the efficacy and safety of oral arsenic-containing compound QHP in the treatment of MDS, with a special focus on the association of efficacy of QHP with the cytogenetics, prognostic risk, DNA methylation, gene mutation, blood arsenic concentration, mechanism of action of As2S2 and the countermeasures against adverse reactions of gastrointestinal tract.

The active ingredients and mechanisms of Longchai Jiangxue Formula in treating PV, based on UPLC/Q-TOF-MS/MS, systematic pharmacology, and molecular biology validation.

BACKGROUND: Polycythemia vera (PV) is a refractory hematological disease that lack of effective therapy. Chinese traditional medicine Longchai Jiangxue formula (LCJX) has showed the powerful effects on PV. However, the active ingredients and mechanisms of this formula have not been elucidated. We explored the active ingredients and mechanisms of LCJX for treating PV. METHODS: The chemical constituents of LCJX were qualitatively analyzed by UPLC/Q-TOF-MS/MS. On this basis, the TCMSP, ETCM, PubChem BioAssay and ChEMBL databases were searched to predict the potential targets of chemical components of LCJX. Then Genecards, GEO, DisGeNET, and OMIM databases were used to retrieve data of targets related to PV. Drug-disease-target network and protein-protein-interaction (PPI) network were built. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed. Finally, Molecular docking, CCK-8 assay, Annexin V-FITC/PI staining and western blot were processed so as to screen the active components related to PV and elucidate its mechanisms. RESULTS: A total of 84 compounds were identified from LCJX by UPLC/Q-TOF-MS/MS. After removed duplicate items, there were 143 targets linked to both disease and drugs. Crucial genes, such as MTOR, HIF1A, JAK2, VEGFA, STAT3, AKT1, TERT, MAPK1, were shown in PPI network. GO enrichment indicated that oxidative stress process, tyrosine kinase activity and phosphatase binding function, and cell membrane structure were in reference to LCJX against PV. KEGG enrichment showed that JAK-STAT signaling pathway and PI3K-Akt signaling pathway, were put in an important position of the treatment. Furthermore, Molecular docking, CCK-8 assay, Annexin V-FITC/PI staining and western blot technique proved the therapeutic effect of Saikosaponin A, main ingredient of LCJX. CONCLUSION: This study, combined with UPLC/Q-TOF-MS/MS, network pharmacology and molecular biology, provides a reference for the identification of effective components, screening of quality markers and analysis of its action mechanism of LCJX.

Influence of progestational stress on BDNF and NMDARs in the hippocampus of male offspring and amelioration by Chaihu Shugan San.

BACKGROUND: Progestational stress has been proven to be a risk for the neural development of offspring, especially in the hippocampus. However, whether Chaihu Shugan San (CSS) can ameliorate hippocampal neural development via the regulation of brain-derived neurotrophic factor (BDNF), and N-methyl-D-aspartate receptors (NMDAR) 2A (NR2A) and 2B (NR2B), and the mechanism of such action remains unclear. METHODS: Thirty-six female rats were randomly allocated into control, chronic immobilization stress (CIS) and CSS groups according to the random number table, respectively. The male offspring were fed for 21 days after birth then randomly divided into the same three groups (6 rats/group) as the female rats. Female rats, except for the control group, underwent 21-day CIS to established a progestational stress anxiety-like model which was evaluated by body weight, the elevated plus-maze (EPM) test and serum dopamine (DA) measured using an enzyme-linked immunosorbent assay (ELISA). The expression levels of estrogen receptors (ERα/ERß) and progesterone receptor (PR) in female rat ovaries were quantified by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The hippocampal tissue in the 21-day offspring was observed by hematoxylin-eosin (HE) staining. The concentration of BDNF, NR2A, and NR2B were measured by RT-qPCR and immunohistochemistry in the CA3 and dentate gyrus (DG) regions of offsprings' hippocampus. RESULTS: Compared with the female control group, significant differences in body weight, EPM test and DA concentration were observed in the CIS group, meanwhile, the concentration of ERα (P < 0.05), PR (P < 0.05) and ERß in the ovaries were decreased. In the offsprings' hippocampus of the CIS group, the chromatin of the nucleus was edge set and with condensed and irregular morphology nucleus, and the cytoplasm was unevenly stained with spaces around the cells, moreover, the expression levels of BDNF, NR2A, and NR2B were also declined (P < 0.05). However, Chaihu Shugan San reversed these changes, especially the BDNF in the DG region (P < 0.05), and NR2A and NR2B in the CA3 and DG region (P < 0.05). CONCLUSIONS: CSS could ameliorate the neural development of the hippocampus in offspring damaged by anxiety-like progestational stress in female rats via regulating the expression levels of ERα, ERß, and PR in female rat ovaries and BDNF, NR2A, and NR2B in the hippocampus of their offspring.

ALDH2 deficiency induces atrial fibrillation through dysregulated cardiac sodium channel and mitochondrial bioenergetics: A multi-omics analysis.

Point mutation in alcohol dehydrogenase 2 (ALDH2), ALDH2*2 results in decreased catalytic enzyme activity and has been found to be associated with different human pathologies. Whether ALDH2*2 would induce cardiac remodeling and increase the attack of atrial fibrillation (AF) remains poorly understood. The present study evaluated the effect of ALDH2*2 mutation on AF susceptibility and unravelled the underlying mechanisms using a multi-omics approach including whole-genome gene expression and proteomics analysis. The in-vivo electrophysiological study showed an increase in the incidence and reduction in the threshold of AF for the mutant mice heterozygous for ALDH2*2 as compared to the wild type littermates. The microarray analysis revealed a reduction in the retinoic acid signals which was accompanied by a downstream reduction in the expression of voltage-gated Na+ channels (SCN5A). The treatment of an antagonist for retinoic acid receptor resulted in a decrease in SCN5A transcript levels. The integrated analysis of the transcriptome and proteome data showed a dysregulation of fatty acid ß-oxidation, adenosine triphosphate synthesis via electron transport chain, and activated oxidative responses in the mitochondria. Oral administration of Coenzyme Q10, an essential co-factor known to meliorate mitochondrial oxidative stress and preserve bioenergetics, conferred a protection against AF attack in the mutant ALDH2*2 mice. The multi-omics approach showed the unique pathophysiology mechanisms of concurrent dysregulated SCN5A channel and mitochondrial bioenergetics in AF. This inspired the development of a personalized therapeutic agent, Coenzyme Q10, to protect against AF attack in humans characterized by ALDH2*2 genotype.

Lignans from Schisandra chinensis ameliorate alcohol and CCl4-induced long-term liver injury and reduce hepatocellular degeneration via blocking ETBR.

ETHNOPHARMACOLOGICAL RELEVANCE: Chemical hepatotoxicity, especially alcoholic liver injury (ALI), commonly occurs in young and middle-aged people who drink heavily. ALI is extremely harmful and can induce severe disease states, such as hepatitis, liver fibrosis, cirrhosis, or liver cancer, which are similar to CCl4-induced liver disease states in animals. In recent studies, the pathological changes of hepatocytes and the hepatic stellate cell have shown a significant connection between endoplasmic reticulum (ER) stress and the development of liver pathology in patients. However, the detailed pathological mechanism needs to be further studied. Schisandra chinensis, (S. chinensis), a fruit-bearing vine used in Traditional Chinese Medicine (TCM), has been used to treat chronic or acute diseases, including liver disease. S. chinensis-derived lignans (SCDLs) in particular have been shown to alleviate liver pathological changes. AIM OF THE STUDY: This study sought to elucidate the mechanisms underlying SCDL-mediated hepatoprotection. MATERIALS AND METHODS: We first used in silico target prediction and computational simulation methods to identify putative lignan-binding targets relative to the hepatoprotective effect. A gene microarray analysis was performed to identify differently expressed genes that might have significance in the disease pathological process. We then used histological analyses in a mice hepatotoxicity model to test the effectiveness of SCDLs in vivo, and a hepatocellular toxicity model to analyze the candidate-compound-mediated hepatoprotection and expression states of the key targets in vitro. RESULTS: The in silico analysis results indicated that endothelin receptor B (ETBR/EDNRB) is likely a significant node during the liver pathological change process and a promising key target for the SCDL compound schisantherin D on the hepatoprotective effect; experimental studies showed that schisantherin D alleviated the EtOH- and ET-1-induced HL-7702 cell (belongs to liver parenchymal cell lines) injury ratio, decreased the expression of ETBR, and inhibited ECMs and ET-1 secretion in LX-2 cells (one form of hepatic stellate cells). SCDLs ameliorated EtOH- and CCl4-induced fibrosis formation in mice liver tissue. Liver tissue western blots of SCDL-treated mice showed downregulated α-SMA, ETBR, PLCß, CHOP, Bax, and the apoptotic factors of cleaved-caspase 12, cleaved-caspase 9, and cleaved-caspase 3 hinted at an anti-apoptosis and hepatoprotective effect. The SCDL treatment also elevated serum glutathione (GSH) and reduced the serum-transforming growth factor-ß1 (TGF-ß1) level. CONCLUSION: The findings indicated that SCDLs prevent hepatotoxicity via their anti-fibrotic, anti-oxidant, and anti-apoptosis properties. ETBR may be the key factor in promoting chemical hepatotoxicity.

Andrographolide attenuates oxidative stress injury in cigarette smoke extract exposed macrophages through inhibiting SIRT1/ERK signaling.

Andrographolide (AG), an ingredient extracted from traditional Chinese herbal medicine Andrographis paniculata, has been demonstrated to have potent anti-inflammatory and anti-oxidative stress properties. The purpose of this study was to investigate whether and how AG attenuated CSE-induced mitochondrial dysfunction, inflammation and oxidative stress in RAW 264.7 cells (a mouse macrophages line). The results showed that AG significantly reduced CSE-induced upregulation of pro-inflammatory cytokines (i.e., TNF-α and IL-1ß) in the RAW 264.7 cells. AG inhibited CSE-induced production of reactive oxygen species (ROS) and prevented the reduction of superoxide dismutase (SOD) and glutathione/oxidized glutathione (GSH/GSSG) ratio, indicating the anti-oxidative stress effects of AG in macrophages. AG also improved mitochondrial function and mitochondrial membrane potential. In addition, AG inhibited CSE-induced increase of heme oxygenase (HO)-1, matrix metalloproteinase (MMP)-9 and MMP-12. Moreover, AG increased SIRT1 transcription and expression, suggesting AG inhibits mitochondrial dysfunction, inflammation and oxidative stress via a SIRT1 dependent signaling. We also demonstrated that AG inhibited CSE-induced ERK phosphorylation, and treatment with PD980589, a ERK inhibitor, reversed CSE-induced inflammation and oxidative stress. These results indicated that AG may prevent COPD via the inhibition of SIRT1/ERK signaling pathway, and subsequently inhibition of mitochondrial dysfunction, inflammation, and oxidative stress in macrophages.

Relation of Blood Arsenic Concentration with Effect and Safety of Arsenic-Containing Qinghuang Powder () in Patients with Myelodysplastic Syndrome.

OBJECTIVE: To investigate the relation of blood arsenic concentration (BAC) with clinical effect and safety of arsenic-containing Qinghuang Powder (, QHP) in patients with myelodysplastic syndrome (MDS). METHODS: Totally 163 patients with MDS were orally treated with QHP for 2 courses of treatment, 3 months as 1 course. The BACs of patients were detected by atomic fluorescence spectrophotometry at 1, 3, and 6 months during the treatment, and the effective rate, hematological improvement and safety in patients after treatment with QHP were analyzed. RESULTS: After 2 courses of treatment, the total effective rate was 89.6% (146/163), with 31.3% (51/163) of hematological improvement and 58.3% (95/163) of stable disease. The hemoglobin increased from 73.48 ± 19.30 g/L to 80.39 ± 26.56 g/L (P<0.05), the absolute neutrophil count increased from 0.81 ± 0.48 × 109/L to 1.08 ± 0.62 × 109/L (P<0.05), and no significant changes were observed in platelet counts (P>0.05). Among 46 patients previously depended on blood transfusion, 28.3% (13/46) completely got rid of blood transfusion and 21.7% (10/46) reduced the volume of blood transfusion by more than 50% after treatment. The BACs were significantly increased in patients treated for 1 month with 32.17 ± 18.04 µ g/L (P<0.05), 3 months with 33.56 ± 15.28 µ g/L (P<0.05), and 6 months with 36.78 ± 11.92 µ g/L (P<0.05), respectively, as compared with those before treatment (4.08 ± 2.11 µ g/L). There were no significant differences of BACs among the patients treated for 1, 3 and 6 months (P>0.05). The adverse reactions of digestive tract during the treatment were mild abdominal pain and diarrhea in 14 cases (8.6%), and no patients discontinued the treatment. The BACs of patients with gastrointestinal adverse reactions were significantly lower than those without gastrointestinal adverse reactions (22.39 ± 10.38 vs. 37.89 ± 11.84, µ g/L, P<0.05). The BACs of patients with clinical effect were significantly higher than those failed to treatment (40.41 ± 11.69 vs. 23.84 ± 12.03, µ g/L, P<0.05). CONCLUSION: QHP was effective and safe in the treatment of patients with MDS and the effect was associated with BACs of patients.

Intervention of artemisinin in macular edema associated with retinal vein occlusion: A protocol for a systematic review and meta-analysis.

BACKGROUND: Artemisinin was discovered to be highly effective antimalarial drugs shortly after the isolation of the parent artemisinin in 1971 in China. It is derived from extracts of sweet wormwood (Artemisia annua) and are well established for the treatment of malaria. Recently, artemisinin has been shown that it might have therapeutic value for several other diseases. The purpose of this review is to assess the efficacy of artemisinin as a treatment for macular edema associated with retinal vein occlusion. METHODS AND ANALYSIS: A systematic literature search will be performed in all available databases to quantitatively review eligible studies and identify all relevant data. We will include randomized controlled trials assessing efficacy of artemisinin as a treatment for macular edema associated with retinal vein occlusion. The methodological qualities, including the risk of bias, will be evaluated using the Cochrane risk of bias assessment tool, while confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. ETHICS AND DISSEMINATION: Ethical approval is not required, as this study is based on the review of published research. This review will be published in a peer-reviewed journal and disseminated both electronically and in print. PROSPERO REGISTRATION NUMBER: The protocol for this systematic review has been registered on PROSPERO under the number CRD42019131408.

[Acupuncture combined with cinesiotherapy cupping for knee osteoarthritis with qi stagnation and blood stasis syndrome: a randomized controlled trial].

OBJECTIVE: To compare the clinical efficacy between acupuncture combined with cinesiotherapy cupping and acupuncture combined with conventional cupping for knee osteoarthritis (KOA) with qi stagnation and blood stasis syndrome, and to seek a better solution for KOA. METHODS: A total of 78 patients of KOA with qi stagnation and blood stasis syndrome were randomly divided into an observation group and a control group, 39 cases in each group (3 cases in the observation group and 2 cases in the control group lost contact). Both groups were treated with acupuncture at Neixiyan (EX-LE 4), Dubi (ST 35), Xuehai (SP 10), Liangqiu (ST 34), Heding (EX-LE 2), Zusanli (ST 36), Yinlingquan (SP 9), Yanglingquan (GB 34) and Xuanzhong (GB 39). Based on the acupuncture treatment, the control group was treated with conventional cupping. The No. 4 cupping glass was used for Xuehai (SP 10), Liangqiu (ST 34) and Fengshi (GB 31), while the No. 3 cupping glass was used for Yinlingquan (SP 9), while the cupping with appropriate size was used for ashi points; the cupping glass was retained for 5 min. Based on the acupuncture treatment, the observation group was treated with cinesiotherapy cupping. The selection of acupoint and cupping glass was identical as the control group. The patients were instructed to perform knee flexion-extension, hip abduction-adduction, weight-bearing and other active exercise while cupping; the treatment was given once a day, 10 times as a course of treatment; totally three courses were given with an interval of 2 days between the courses. The patient's symptom scores, pain scores and knee function scores were recorded before and after treatment. The amount of joint effusion was measured by ultrasound; the level of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) in joint effusion were measured by ELISA. RESULTS: After treatment, the total effective rate in the observation group was 94.4% (34/36), which was significantly higher than 86.5% (32/37) in the control group (P<0.05). Compared before treatment, the symptom scores, pain scores, amount of joint effusion and the levels of IL-1, IL-6, TNF-α in joint fluid in both groups all were decreased after treatment, whereas the knee function scores were increased (P<0.05). Compared with the control group, the symptom scores, pain scores, and the levels of IL-1, TNF-α and the amount of joint effusion all were significantly decreased, whereas the knee function scores were increased in the observation group (P<0.05). The level of IL-6 in joint effusion was not significantly different between the observation group and the control group (P>0.05). CONCLUSION: The acupuncture combined with cinesiotherapy cupping could alleviate pain, improve joint function and reduce joint effusion, which is superior to acupuncture combined with conventional cupping.

Epigenetic silencing of the synthesis of immunosuppressive Siglec ligand glycans by NF-κB/EZH2/YY1 axis in early-stage colon cancers.

Normal colonic epithelial cells express sialyl 6-sulfo Lewisx and disialyl Lewisa on their cell surface, which are ligands for the immunosuppressive molecule Siglec-7. Expression of these normal glycans is frequently lost upon malignant transformation by silencing DTDST and ST6GalNAc6 at the early stage of colorectal carcinogenesis, and leads to production of inflammatory mediators that facilitate carcinogenesis. Indeed, by querying The Cancer Genome Atlas datasets, we confirmed that the level of DTDST or ST6GalNAc6 mRNA is substantially decreased at the early stage of colorectal carcinogenesis. Cultured colon cancer cell lines were used in this study including DLD-1, HT-29, LS174T and SW620. Their promoter regions were strongly marked by repressive mark H3K27me3, catalyzed by EZH2 that was markedly upregulated in early stage of colorectal carcinogenesis. Suppression of EZH2 substantially downregulated H3K27me3 mark and upregulated DTDST and ST6GalNAc6 as well as expression of normal glycans and Siglec-binding activities. Transcription factor YY1 was vital for the recruitment of PRC2-containing EZH2 to both promoters. Inhibition of NF-κB substantially reduced EZH2 transcription and restored their mRNAs as well as the production of normal Siglec ligand glycans in the results obtained from in vitro studies on cultured colon cancer cell lines. These findings provide a putative mechanism for promotion of carcinogenesis by loss of immunosuppressive molecules by epigenetic silencing through NF-κB-mediated EZH2/YY1 axis.

Induction of Oxidative Stress Through Inhibition of Thioredoxin Reductase 1 Is an Effective Therapeutic Approach for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generation of reactive oxygen species (ROS). Increased antioxidant-producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS, and we demonstrate that it is vital for HCC growth as it maintains intracellular reduction-oxidation (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant overexpression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathological features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid-derived 2)-like 2, the master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 through genetic inhibition hindered the proliferation of HCC cells and induced apoptosis in vitro. Administration of the pharmacological TXNRD1 inhibitor auranofin (AUR) effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells toward the conventional therapeutic sorafenib. Conclusion: Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage; targeting TXNRD1 resulted in dramatic accumulation of ROS, which was found to be an effective approach for the suppression of HCC tumor growth.

Association of Gene Mutations with Response to Arsenic-Containing Compound Qinghuang Powder () in Patients with Myelodysplastic Syndromes.

OBJECTIVES: To investigate the relationship between gene mutations and response to Compound Qinghuang Powder (, CQHP) in patients with myelodysplastic syndrome (MDS). METHODS: Forty-three MDS patients were genotyped by ultra-deep targeted sequencing and the clinical data of patients were collected and the relationship between them was analyzed. RESULTS: Up to 41.86% of patients harbored genet mutations, in most cases with more than one mutation. The most common mutations were in SF3B1, U2AF1, ASXL1, and DNMT3A. After treatment with CQHP, about 88.00% of patients no longer required blood transfusion, or needed half of prior transfusions. CONCLUSIONS: CQHP is an effective treatment for patients with MDS, especially those with gene mutations in SF3B1, DNMT3A, U2AF1, and/or ASXL1.