Synergistic effect of venetoclax and ibrutinib on ibrutinib-resistant ABC-type DLBCL cells

Despite the widespread use of R-CHOP therapy in diffuse large B-cell lymphoma (DLBCL), the therapeutic efficacy for this disease remains suboptimal, primarily due to the heterogeneity of refractory and/or relapsed diseases. To address this challenge, optimization of DLBCL treatment regimens has focused on the strategy of combining an additional drug "X" with R-CHOP to enhance efficacy. However, the failure of R-CHOP combined with the BTK inhibitor ibrutinib in treating ABC-type DLBCL patients has raised significant concerns regarding ibrutinib resistance. While some studies suggest that venetoclax may synergize with ibrutinib to kill ibrutinib-resistant cells, the underlying mechanisms remain unclear. Our study aimed to validate the enhanced tumor-suppressive effect of combining ibrutinib with venetoclax against ibrutinib-resistant cells and elucidate its potential mechanisms. Our experimental results demonstrated that ibrutinib-resistant cells exhibited significant cytotoxicity to the combination therapy of ibrutinib and venetoclax, inducing cell apoptosis through activation of the mitochondrial pathway and inhibition of aerobic respiration. Furthermore, we validated the inhibitory effect of this combination therapy on tumor growth in in vivo models. Therefore, our study proposes that the combination therapy of ibrutinib and venetoclax is a promising treatment strategy that can be applied in clinical practice for ABC-type DLBCL, offering a new solution to overcome the urgent challenge of ibrutinib resistance.

Role and mechanism of reactive oxygen species in tendinopathy / 中国组织工程研究

BACKGROUND:Reactive oxygen species may be closely related to the occurrence and development of tendinopathy,but its exact role and related signal transduction mechanism have not been fully summarized. OBJECTIVE:To review current clinical or preclinical original studies,summarize the role of reactive oxygen species in tendinopathy and related signal transduction pathways and to explore its characteristics and whether there is a unified downstream pathway. METHODS:Relevant original studies in PubMed,Embase,Web of Science,as well as CNKI,WanFang,and VIP databases were searched by computer and the search results were screened and excluded according to the inclusion criteria.Ninety articles were finally included for review and analysis. RESULTS AND CONCLUSION:Reactive oxygen species affects the direction of tendon healing by simultaneously acting on tendon cells and the extracellular matrix,and it exhibits a bifacial effect in the treatment of tendinopathy.Concentration of reactive oxygen species may be the key to determining its direction of action.The possibility that low-dose reactive oxygen species can participate in the normal physiological healing of tendons or that tendon tissues are adaptive to stimulations may be the underlying mechanism that produces this characteristic effect.Reactive oxygen species affect the composition and structure of the extracellular matrix and normal tendon repair as well as maintain viability in response to external stimulations through matrix metalloproteinases,mitogen-activated protein kinases,mitochondrial apoptosis,the forkhead transcription factor O family,autophagy,inflammation,and antioxidant signaling pathways.Different reactive oxygen species stimulation intensities,durations,and external environments may cause different alterations in downstream molecular pathways and thus have different effects on the tendon.Due to the large gap in the number of literature included in the evaluation of the positive and negative effects of reactive oxygen species,it may cause some analytical error in the search for factors behind the characteristics of the action of reactive oxygen species in tendon.In addition,most experimental intervention conditions and results of interest are relatively homogeneous;therefore,the temporal and quantitative mechanisms of reactive oxygen species and the synergistic effects with other intervention factors have not been clarified,and the overall system of molecular actions of reactive oxygen species in tendinopathy has not been constructed.To conclude,reactive oxygen species might be involved in the treatment and prevention of tendinopathies as a beneficial factor in the future,and facilitate the exploration of oxidative stress signaling pathways and overall molecular action systems in tendinopathies thereafter,as well as lay the foundation for research on the therapeutic strategies of different antioxidants in tendinopathies to better prevent and treat tendon injury and degeneration.

Study on the synergistic effect and mechanism of curcumin combined with zerumbone on the biological behavior of non-small cell lung cancer cells / 中国药房

OBJECTIVE To investigate the synergistic effect and mechanism of curcumin （CUR） combined with zerumbone （ZER） on the biological behavior of non-small cell lung cancer （NSCLC） A549 cells. METHODS CCK-8 method and Gin’s formula were used to screen the optimal concentration combination for synergistic effect after the combination of CUR and ZER. The cells were divided into blank group， CUR group， ZER group， and CUR+ZER group. Flow cytometry was used to evaluate cell apoptosis， and clone formation experiment was used to evaluate cell proliferation ability， scratch experiment and Transwell migration experiment were used to evaluate cell migration ability， and Transwell invasion experiment was used to evaluate cell invasion ability. Western blot assay was used to detect the protein expressions of phosphorylated phosphatidylinositol-3-kinase （p- PI3K）， phosphorylated protein kinase B （p-Akt）， and vascular endothelial growth factor A （VEGF-A）. RESULTS The half inhibitory concentrations of CUR and ZER on A549 cells were approximately 16 and 12 μmol/L， respectively； the drug combination of CUR 8 μmol/L+ZER 6 μmol/L had the highest efficiency enhancement index， with the cell proliferation inhibition rate of （77.41±4.16）%， indicating the most significant synergistic effect. Compared with the CUR and ZER groups， the cell apoptosis rate in the CUR+ZER group was significantly increased （P＜0.01）， while the cell clone formation rate， cell migration rate， the number of migrating cells， the number of invading cells， and relative expression levels of p-PI3K， p-Akt， and VEGF-A proteins in the cells were significantly reduced （P＜0.05 or P＜0.01）. CONCLUSIONS The combination of CUR and ZER has a synergistic effect， significantly promoting the apoptosis of NSCLC cells， and inhibiting cell proliferation， migration， and invasion. Its potential mechanism may be closely related to the inhibition of the PI3K/Akt signaling pathway， thereby down-regulating the protein expression of VEGF-A.

Protective effects of WR-2721 combined with lentinan and cytokines against radiation damage / 中国辐射卫生

@#<b>Objective</b> To investigate the synergistic protective effects of WR-2721 combined with lentinan and cytokines against radiation damage in mice, and to provide a new treatment for acute radiation injury. <b>Methods</b> Seventy Institute of Cancer Research mice were divided into seven groups: a control group, a model group, WR-2721 group, Lentinan & cytokine group, WR-2721 & Lentinan group, WR-2721 & cytokine group and WR-2721 & Lentinan & cytokine group. All groups except the control group were irradiated with ⁶⁰Co γ-rays at a dose rate of 0.8 Gy/min and a cumulative dose of 5.0 Gy. The mice were sacrificed by cervical dislocation 14 d after irradiation to measure their spleen index, thymus index, and serum levels of superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-11 (IL-11), and tumor necrosis factor-alpha (TNF-α). <b>Results</b> For the mice treated with WR-2721, lentinan, and cytokines, the spleen index was 7.33 ± 2.84, the thymus index was 1.70 ± 0.30, the serum SOD level was 114.0 ± 8.3, the MDA level was 7.33 ± 1.16, the IL-11 level was 155.8 ± 49.4, and the TNF-α level was 174.0 ± 37.8. All these indicators except the spleen index in the combination group significantly differed from those of the model group (<i>P</i> < 0.05 or 0.01), indicating the combined treatment promoted recovery from radiation damage. <b>Conclusion</b> WR-2721 combined with lentinan and cytokines has significant synergistic protective effects, which is a promising treatment for acute radiation injury.

Guanxinning Tablet and their active substances alleviate ox-LDL-induced endothelial cell injury / 药学学报

This study investigated the intervention effect of Guanxinning Tablet on human umbilical vein endothelial cells (HUVECs) injury induced by oxidized low density lipoprotein (ox-LDL), providing experimental basis for Guanxinning Tablet in the treatment of atherosclerosis-related diseases. Under the damage of HUVECs by ox-LDL, the cell viability was detected by CCK-8 (cell counting kit-8) assay; lactate dehydrogenase (LDH) in the cell culture supernatant was detected by the corresponding kit; the cell morphology of different groups was observed by common phase contrast microscope; reactive oxygen species (ROS) and NO levels in the cells were detected by DCFH-DA and DAF-FM DA probes, respectively; monocyte adhesion assay was used to detect the recruitment of THP-1 in HUVECs, and TMRM dye was used to detect the level of mitochondrial membrane potential; interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) secretion in the cells was detected by ELISA assay. The results showed that Guanxinning Tablet had a concentration-dependent proliferative effect on HUVECs. Under the stimulation of 100 μg·mL-1 ox-LDL, the morphology of endothelial cells was significantly changed. At this time, NO level was significantly decreased, ROS level was significantly increased and accompanied by a decrease in mitochondrial membrane potential. The recruitment of THP-1 cells by endothelial cells and IL-6, ICAM-1 and MCP-1 were also significantly increased, resulting in oxidative stress and inflammatory injury. Guanxinning Tablet and its composed extracts could significantly improve cell morphology, increase NO level, decrease ROS production, and also reduce the secretion of inflammation-related proteins IL-6 and MCP-1. Salvia miltiorrhiza and Ligusticum striatum DC. have significant synergistic effects on NO. Among them, salvianolic acid B and salvianic acid A exerted the main effects, and the combined efficacy of salvianic acid A and ferulic acid was superior to that of single administration. The above results showed that Guanxinning Tablet and their active substances had the effects of improving endothelial basal function, resisting oxidative stress, and alleviating inflammatory injury, and Salvia miltiorrhiza and Ligusticum striatum DC. synergized, which may be related to their regulation of oxidative stress and inflammation and have application prospects in the treatment of atherosclerosis-related diseases.

Inhibitory effects of simeprevir on Staphylococcusepidermidis and itsbiofilm in vitro / 中南大学学报(医学版)

OBJECTIVES@#Staphylococcus epidermidis (S. epidermidis) is a Gram-positive opportunistic pathogen that often causes hospital infections. With the abuse of antibiotics, the resistance of S. epidermidis gradually increases, and drug repurposing has become a research hotspot in the treating of refractory drug-resistant bacterial infections. This study aims to study the antimicrobial and antibiofilm effects of simeprevir, an antiviral hepatitis drug, on S. epidermidis in vitro.@*METHODS@#The micro-dilution assay was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of simeprevir against S. epidermidis. Crystal violet staining assay was used to detect the biofilm inhibitory effect of simeprevir. The antimicrobial activity of simeprevir against S. epidermidis and its biofilm were explored by SYTO9/PI fluorescent staining. The combined effect between simeprevir and gentamycin was assessed by checkerboard assay and was confirmed by time-inhibition assay.@*RESULTS@#Simeprevir showed significant antimicrobial effects against S. epidermidis type strains and clinical isolates with the MIC and MBC at 2-16 μg/mL and 4-32 μg/mL, respectively. The antimicrobial effects of simeprevir were confirmed by SYTO9/PI staining. Simeprevir at MIC could significantly inhibit and break the biofilm on cover slides. Similarly, simeprevir also significantly inhibit the biofilm formation on the surface of urine catheters either in TSB [from (0.700±0.020) to (0.050±0.004)] (t=54.03, P<0.001), or horse serum [from (1.00±0.02) to (0.13±0.01)] (t=82.78, P<0.001). Synergistic antimicrobial effect was found between simeprevir and gentamycin against S. epidermidis with the fractional inhibitory concentration index of 0.5.@*CONCLUSIONS@#Simeprevir shows antimicrobial effect and anti-biofilm activities against S. epidermidis.

Joint effects of meteorological factors and PM2.5 on age-related macular degeneration: a national cross-sectional study in China

BACKGROUND@#Weather conditions are a possible contributing factor to age-related macular degeneration (AMD), a leading cause of irreversible loss of vision. The present study evaluated the joint effects of meteorological factors and fine particulate matter (PM2.5) on AMD.@*METHODS@#Data was extracted from a national cross-sectional survey conducted across 10 provinces in rural China. A total of 36,081 participants aged 40 and older were recruited. AMD was diagnosed clinically by slit-lamp ophthalmoscopy, fundus photography, and spectral domain optical coherence tomography (OCT). Meteorological data were calculated by European Centre for Medium-Range Weather Forecasts (ECMWF) reanalysis and were matched to participants' home addresses by latitude and longitude. Participants' individual PM2.5 exposure concentrations were calculated by a satellite-based model at a 1-km resolution level. Multivariable-adjusted logistic regression models paired with interaction analysis were performed to investigate the joint effects of meteorological factors and PM2.5 on AMD.@*RESULTS@#The prevalence of AMD in the study population was 2.6% (95% CI 2.42-2.76%). The average annual PM2.5 level during the study period was 63.1 ± 15.3 µg/m3. A significant positive association was detected between AMD and PM2.5 level, temperature (T), and relative humidity (RH), in both the independent and the combined effect models. For PM2.5, compared with the lowest quartile, the odds ratios (ORs) with 95% confidence intervals (CIs) across increasing quartiles were 0.828 (0.674,1.018), 1.105 (0.799,1.528), and 2.602 (1.516,4.468). Positive associations were observed between AMD and temperature, with ORs (95% CI) of 1.625 (1.059,2.494), 1.619 (1.026,2.553), and 3.276 (1.841,5.830), across increasing quartiles. In the interaction analysis, the estimated relative excess risk due to interaction (RERI) and the attributable proportion (AP) for combined atmospheric pressure and PM2.5 was 0.864 (0.586,1.141) and 1.180 (0.768,1.592), respectively, indicating a synergistic effect between PM2.5 and atmospheric pressure.@*CONCLUSIONS@#This study is among the first to characterize the coordinated effects of meteorological factors and PM2.5 on AMD. The findings warrant further investigation to elucidate the relationship between ambient environment and AMD.

Synergistic mechanisms of ferroptosis in anaplastic thyroid cancer induced by dihydroartemisinin and sorafenib / 中华内分泌代谢杂志

Objective:To investigate the synergistic effects and molecular mechanisms of dihydroartemisinin(DHA) and sorafenib(SOR) in inducing ferroptosis in anaplastic thyroid cancer(ATC) cells.Methods:CCK-8 and flow cytometry assays were performed to detect the effects of DHA and SOR on the proliferation and ferroptosis of ATC cells(CAL-62). Real-time fluorescence quantitative PCR and Western blotting assays were performed to detect the expressions of ferroptosis-related genes glutathione peroxidase 4(GPX4), solute carrier family 7 member 11 gene(SCL7A11), lipoxygenase-15(LOX-15), and p53. The levels of iron death intermediate metabolites including lactate dehydrogenase(LDH), glutathione(GSH), malondialdehyde(MDA), ferrous ion(Fe 2+ ), nitric oxide(NO), and reactive oxygen species(ROS)were measured by corresponding assay kits. The corresponding inhibition of DHA and SOR on ATC in vivo was analyzed in a tumor model in nude mice. Results:Compared with the control group, DHA, SOR, and DHA+ SOR treatment significantly inhibited cell proliferation and apoptosis in a dose-dependent manner( P<0.001), with increased LDH, Fe 2+, MDA, and ROS contents and reduced GSH activity( P<0.001), which were promoted by ferrous sulfate(FeSO 4)and reversed by ferroptosis inhibitor-1. Compared with the control group and the drug monotherapy group, 15-LOX-2 and p53 expressions were upregulated in DHA+ SOR group while GPX4 and SCL7A11 expressions were decreased( P<0.001), without significant difference in 15-LOX-1 protein content. In addition, NO level was significantly increased in DHA+ SOR group( P<0.001). DHA and SOR inhibited tumor growth of ATC in vivo. Conclusion:DHA and SOR synergistically induced ferroptosis via upregulating the expression of 15-LOX-2 gene and inhibiting NO synthesis in ATC cells.

The interaction between social psychology and workload factors of neck work-related musculoskeletal disorders / 中国职业医学

{L-End}Objective To explore the interaction between social psychology and workload factors on neck work-related musculoskeletal disorders (WMSDs) in manual workers. {L-End}Methods Manual workers in Henan Province and Hubei Province were selected as the research subjects using typical sampling method. The Chinese Musculoskeletal Questionnaire was used to investigate the prevalence of neck WMSDs in the research subjects. A total of 4 327 workers with neck WMSDs were selected as the case group, and 4 327 workers without neck WMSDs were selected as the control group in a 1∶1 pairing. Conditional logistic regression analysis was used to compare the relevant risk factors in the two groups, and the additive interaction model was established to analyze the interactions between the risk factors. {L-End}Results The univariate conditional logistic analysis results showed that dynamic load, static load, power load and psychosocial factors increased the risk of neck WMSDs in manual workers (all P<0.05). In terms of the social psychological factors, insufficient rest time had the greatest impact workers, with the odds ratio (OR) and 95% confidence interval (CI) of 1.799 (1.647-1.965). In terms of dynamic load, static load and power load, repeated similar movements of the head per minute (bending, twisting), forward bending of the neck or maintaining this posture for a long time, and lifting heavy objects>20 kg had the greatest impact, with the OR and 95%CI of 1.599 (1.470-1.739), 1.984 (1.805-2.181) and 1.241 (1.093-1.408), respectively. There was a synergistic interaction between insufficient rest time and forward bending of the neck or maintaining this posture for a long time, and the relative excess risk due to interaction (95%CI) and attributable proportion (95%CI) were 0.420 (0.187-0.652) and 0.171 (0.066-0.276), respectively. There is no interaction between insufficient rest time and repeated similar movements of the head per minute (bending, twisting), and lifting heavy objects >20 kg. {L-End}Conclusion The interaction between insufficient rest time and forward bending of the neck or maintaining this posture for a long time (static load) can increase the risk of neck WMSDs in manual workers, which is an additive synergistic effect.

Synergistic effect of Hsp90 inhibitor ginkgolic acids C15 ꞉1 combined with paclitaxel on nasopharyngeal carcinoma / 中南大学学报(医学版)

OBJECTIVES@#Nasopharyngeal cracinoma is a kind of head and neck malignant tumor with high incidence and high mortality. Due to the characteristics of local recurrence, distant metastasis, and drug resistance, the survival rate of patients after treatment is not high. Paclitaxel (PTX) is used as a chemotherapy drug in treating nasopharyngeal carcinoma, but nasopharyngeal carcinoma cells are easy to develop resistance to PTX. Inhibition of heat shock protein 90 (Hsp90) can overcome common signal redundancy and resistance in many cancers. This study aims to investigate the anti-tumor effect of ginkgolic acids C15꞉1 (C15:1) combined with PTX on nasopharyngeal carcinoma CNE-2Z cells and the mechanisms.@*METHODS@#This experiment was divided into a control group (without drug), a C15:1 group (10, 30, 50, 70 μmol/L), a PTX group (5, 10, 20, 40 nmol/L), and a combination group. CNE-2Z cells were treated with the corresponding drugs in each group. The proliferation of CNE-2Z cells was evaluated by methyl thiazolyl tetrazolium (MTT). Wound-healing assay and transwell chamber assay were used to determine the migration of CNE-2Z cells. Transwell chamber was applied to the impact of CNE-2Z cell invasion. Annexin V-FITC/PI staining was used to observe the effect on apoptosis of CNE-2Z cells. The changes of proteins involved in cell invasion, migration, and apoptosis after the combination of C15꞉1 and PTX treatment were analyzed by Western blotting.@*RESULTS@#Compared with the control group, the C15꞉1 group and the PTX group could inhibit the proliferation of CNE-2Z cells (all P<0.05). The cell survival rates of the C15꞉1 50 μmol/L combined with 5, 10, 20, or 40 nmol/L PTX group were lower than those of the single PTX group (all P<0.05), the combination index (CI) value was less than 1, suggesting that the combined treatment group had a synergistic effect. Compared with the 50 μmol/L C15꞉1 group and the 10 nmol/L PTX group, the combination group significantly inhibited the invasion and migration of CNE-2Z cells (all P<0.05). The results of Western blotting demonstrated that the combination group could significantly down-regulate Hsp90 client protein matrix metalloproteinase (MMP)-2 and MMP-9. The results of double staining showed that compared with the 50 μmol/L C15꞉1 group and the 10 nmol/L PTX group, the apoptosis ratio of CNE-2Z cells in the combination group was higher (both P<0.05). The results of Western blotting suggested that the combination group could decrease the Hsp90 client proteins [Akt and B-cell lymphoma-2 (Bcl-2)] and increase the Bcl-2-associated X protein (Bax).@*CONCLUSIONS@#The combination of C15꞉1 and PTX has a synergistic effect which can inhibit cell proliferation, invasion, and migration, and induce cell apoptosis. This effect may be related to the inhibition of Hsp90 activity by C15꞉1.

Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.

Fas cell surface death receptor/Fas ligand genetic variants in gastric cancer patients: A case-control study

Background & objectives: Various studies have suggested a correlation between Fas cell surface death receptor/Fas ligand (FAS/FASL) variants and multiple types of cancers. The present study aimed to investigate the association between FAS-670A/G and FASL-844C/T and the synergistic effects of both variants on the risk of gastric cancer (GC) in the Kurdish population of west of Iran. Methods: This study was conducted by polymerase chain reaction-restriction fragment length polymorphism technique using MvaI and BsrDI restriction enzymes in 98 GC patients and 103 healthy control individuals. Results: According to the obtained results, a significant association (P=0.008) of FASL polymorphism among GC patients and the control group was detected. Furthermore, no significant differences were found in the FAS polymorphism frequencies between GC patients and the control group. Codominant and dominant models in FASL polymorphism showed significant protective effects against GC [odds ratio (OR)=0.307, 95% confidence interval (CI) (0.134-0.705), P=0.005; OR=0.205, 95% CI (0.058-0.718), P=0.013 and OR=0.295, 95% CI (0.129-0.673), P=0.004 for models of codominant CC vs. CT, codominant CC vs. TT and dominant, respectively]. Furthermore, the presence of both FAS-670G and FASL-844T alleles represented a significant protective effect against GC occurrence [OR=0.420, 95% CI (0.181-0.975), P=0.043]. Interpretation & conclusions: So far, we believe this is the first study, the results of which suggest that FASL gene variation and its synergistic effects with FAS gene could be associated with the risk of GC in the Kurdish population in the west of Iran

Systematic review of synergistic effect between air pollutants and temperature on human mortality in China / 环境与职业医学

Background Air pollutants and extreme temperature both pose significant threats to human health, but the synergistic effect between air pollutants and temperature on health is inconsistent. Objective To explore a potential synergistic effect between air pollutants and temperature on the mortality in China through literature review. Methods Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure, VIP Information Chinese Journal Service Platform, PubMed, Web of Science, Science Direct, and Embase databases were searched. "Temperature" "air pollution" "mortality" were selected as keywords to collect literature on synergistic effect between air pollutants and temperature on mortality in China. Literature was published from 2000-01-01 to 2022-07-31 in Chinese or English. Two researchers screened the literature independently according to the inclusion criteria, and the results were integrated and analyzed after data extraction. The "meta" package of R software was used for meta-analysis. Results Twenty-seven studies met the inclusion criteria and associated air pollutants included PM10, PM2.5, O3, SO2, NO2, and CO. The impact of PM10 and PM2.5 on mortality in high temperature days was higher than that in moderate temperature days. In high temperature days, a 10 μg·m−3 increment in PM10 concentration corresponded to pooled estimates of 2.30% (95%CI: 1.34%-3.26%), 1.23% (95%CI: 0.64%-1.82%), and 1.42% (95%CI: 0.63%-2.22%) increase in non-accidental, cardiovascular, and respiratory mortalities, respectively. A 10 μg·m−3 increment in PM2.5 concentration corresponded to pooled estimates of 2.56% (95%CI: 2.00%-3.13%), 2.37% (95%CI: 1.64%-3.12%), and 2.14% (95%CI: 1.03%-3.25%) increase in non-accidental, cardiovascular, and respiratory mortalities, respectively. The synergistic effect of SO2 and NO2 on cardiovascular and respiratory mortalities in low temperature days was higher than that in moderate temperature days. Conclusion The synergistic effects of air pollutants and temperature on mortality in low temperature days or in high temperature days are higher than that in moderate temperature days. The health protection related to these pollutants should be strengthened in these days.

He-Wei Granule enhances anti-tumor activity of cyclophosphamide by changing tumor microenvironment / 中草药·英文版

Objective: He-Wei Granule (HWKL) is a modern product derived from the modified formulation of traditional Chinese medicine Banxia Xiexin Decoction (BXD), which remarkedly enhanced the anti-proliferation activity of cyclophosphamide (CTX) on HepG2 and SGC-7901 cell lines in vitro in our previous research. The aim of the study was to investigate the synergistic effects of HWKL and CTX using a transplanted H22 hepatocellular carcinoma mouse model. Methods: The CTX-toxic-reducing efficacy of HWKL was evaluated by hematology indexes, organ indexes and marrow DNA detection. To investigate the underlying mechanisms, histopathology test, immunohistochemistry test and TUNEL staining were conducted. The efficacy of HWKL on the micro-vessel density (MVD) in tumor tissue was also evaluated by measuring CD34 level. Results: High dose HWKL (6.75 g/kg) markedly attenuated CTX-induced hepatotoxicity and myelosuppression while significantly enhanced CTX anticancer efficacy in vivo. Further mechanism investigation suggested that high dose HWKL significantly increased cleaved Caspase 3 level and promoted apoptosis in tumor tissue by up-regulating Bax expression and down-regulating Bcl-2 and FasL expressions. Compared with CTX alone group, the decrease in LC-3B and Beclin 1 levels suggested that the autophagy in H22 carcinoma was significantly inhibited with addition of high dose HWKL. ELISA assay results indicated that the autophagy inhibition was achieved by decreasing p53 expression, blocking PI3K/AKT/mTOR pathway and recovering Th1/Th2 cytokine balance. In addition, CD34 and EGFR immunohistochemistry assay suggest that high dose HWKL could significantly decrease micro-vessel density (MVD) and inhibit angiogenesis in H22 carcinoma. Conclusion: It can be concluded that high-dose HWKL enhanced CTX efficacy by promoting apoptosis, inhibiting autophagy and angiogenesis in tumor tissue while significantly alleviated CTX-induced toxicity, and could be applied along with CTX in clinical treatment as a supplement agent.

Regulation of Nrf2 signaling factor in cadmium combined with bacitracin induced endoplasmic reticulum stress in testes and ovaries of rats / 中国职业医学

@#Objective To investigate the effect of acute exposure to cadmium combined with bacitracin on the endoplasmic reticulum stress (ERS) in testes and ovaries of rats and its regulation by nuclear factor erythroid-2-related factor 2 (Nrf2). Methods According to the 4×2 factorial design model, 48 specific pathogen free adult SD rats were divided into four groups: the control group and the low-, medium- and high- dose cadmium chloride exposure groups. Each group was further divided into with- or without bacitracin combined subgroup. There were six rats in each subgroup with 3 males and 3 females. The low-, medium- and high- dose groups were intraperitoneally injected with 5, 10, 20 mg/kg body weight of cadmium chloride solution, respectively. The control group was intraperitoneally injected with the same amount of 0.9% sodium chloride solution. Among them, rats in the bacitracin combined subgroup were given a one-time intraperitoneal injection of bacitracin at a dose of 20 mg/kg body weight two hours before cadmium chloride exposure. After 48 hours, the rats were sacrificed. The mRNA expression of glucose regulated protein78 kD (Grp78), protein kinase R-like endoplasmic reticulum kinase (Perk), Nrf2 in testes and ovaries of rats was determined using quantitative real-time polymerase chain reaction. The protein expression of GRP78, PERK, NRF2 was determined using Western blotting. Results The mRNA expression of Grp78, Perk, Nrf2 and the protein expression of GRP78, PERK, NRF2 in testes and ovaries of rats in the no bacitracin combined subgroups of the three dose groups showed different degrees of up-regulated changes compared with the no bacitracin combined subgroup of the control group (all P<0.05). Among them, the expression of the three kinds of mRNAs and proteins in the testes and ovaries of rats in the no bacitracin combined subgroups of the high-dose group was up-regulated (all P<0.05), and most of them were higher than those in the no bacitracin combined subgroups of the low- and medium-dose groups (all P<0.05). The expression of most of the three kinds of mRNAs and proteins in testes of rats showed different degrees of down-regulated changes (all P<0.05), but the expression of the three kinds of mRNAs and proteins showed different degrees of up-regulated changes in ovaries (all P<0.05) in the bacitracin combined subgroups of the three doses groups than that in the bacitracin combined subgroups of the control group, and especially in the bacitracin combined subgroups of the high-dose subgroup. The expression of the three kinds of mRNAs and proteins in testes and ovaries of rats in the bacitracin combined subgroups of the three doses groups showed different degrees of changes (all P<0.05) compared with the no bacitracin combined subgroup in the same group, and the expression in the bacitracin combined subgroups of the medium- and high-dose groups showed mainly down-regulated changes (all P<0.05). Conclusion Acute exposure to cadmium can induce different degrees of ERS, activate PERK/NRF2 signaling pathway, and improve the toxicity to testis and ovary. Bacitracin can inhibit cadmium-induced ERS, thereby inhibiting the activation of PERK/NRF2 signaling pathway, and enhancing the synergistic effect of cadmium on testis and ovary toxicity. The higher the exposure dose of cadmium, the more obvious the inhibitory effect.

Effect of Homoharringtonine as a Combined Regimen for Acute Myeloid Leukemia

Homoharringtonine (HHT), a cephalotaxus alkaloid has shown promising results in the treatment of several hematological disorders such as chronic myeloid leukemia, acute myeloid leukemia (AML), and myelodysplastic syndrome. It is known for its unique mechanism of action by which it prevents the initial elongation step of protein biosynthesis. Hence, it is used in hematological malignancies where it synergistically potentiates the action of other drugs and induces apoptosis. The relevant studies published were searched using an electronic database from 2002 to 2019. The articles published in English were only considered. Search engines such as PubMed, MEDLINE, Google Scholar, and Semantic scholar were used. In this review, we have discussed the effect of HHT in combination with other chemotherapeutic agents for AML with or without genetic mutation specification and the future perspective of these regimens. Although standard treatment options exist for most of these diseases, still cure rates are low with reported morbidity and the drug resistance emergence is pervasive. Thus, novel treatment approaches are crucial for better outcome. Alternative regimens together with HHT have not been a standard practice, although they have shown a very good potential in AML patients. Many of the combinations were also proved to be safe and effective with very low toxic potential. All these data outcomes of various combinations under different scenarios exhibit that HHT has promising results in the treatment of AML which may lead to its approval in the upcoming years.

Effect of co-exposure of low-level benzene derivatives and noise on hearing loss of workers / 中国职业医学

OBJECTIVE: To explore the effects of combined exposure to low-level benzene derivatives and noise on hearing loss of workers. METHODS: A total of 216 employees from nine wood furniture factories and four printing factories were selected as research subjects by typical sampling method. Those without exposure to occupational hazardous factors were set as the control group, those exposed to noise alone were set as the noise group, and those exposed to benzene derivatives and noise were set as the combined exposure group. The normalization of equivalent continuous A-weighted sound pressure level to a nominal 8 hours working day(L_(EX,8 h)) and the exposure concentration of time weighted average(C_(TWA)) of benzene, toluene, xylene, ethylbenzene in the workplace air of the three groups were detected, and the hearing threshold of 0.5-8.0 kHz in both ears of the research subjects were measured by pure tone audiometry. RESULTS: No benzene was detected in the workplace air of the combined exposure group, and the C_(TWA) of toluene, xylene and ethylbenzene were all lower than the occupational exposure limits. The L_(EX,8 h) of the noise group and combined exposure group were all higher than that of the control group [(85.6±2.5) vs(68.7±4.4) dB(A),(84.3±3.1) vs(68.7±4.4) dB(A), all P<0.05], while the L_(EX,8 h) of the noise group was higher than that of the combined exposure group [(85.6±2.5) vs(84.3±3.1) dB(A), P<0.05]. Compared with the control group, the individual frequency hearing thresholds, average hearing threshold of speech frequency and average hearing threshold of high frequency in both ears in the noise group and the combined exposure group were increased(all P<0.05), and the detection rates of speech frequency hearing loss and high frequency hearing loss were increased(all P<0.02). The hearing thresholds of right ear of 0.5, 1.0 kHz and left ear of 0.5 kHz were increased in the combined exposure group(all P<0.05), and the detection rate of speech frequency hearing loss was increased(16.7% vs 40.8%, P<0.02), when compared with the noise group. Multivariate logistic regression analysis results showed that the risk of speech frequency hearing loss and high frequency hearing loss in the combined exposure group were higher than that in the control group and the noise group(all P<0.05), after excluding the influence of confounding factors such as education level and smoking.CONCLUSION: The combined exposure to low-level benzene derivatives and noise may have a synergistic effect on the hearing loss in workers.

Research progress on dual PDE3/4 inhibitors for the treatment of respiratory diseases / 药学学报

Chronic obstructive pulmonary disease and asthma are complex inflammatory diseases with airway obstruction as the main characteristics, and have become common respiratory diseases that seriously affect human health. Compared with the clinical use of PDE3 or PDE4 inhibitors alone, dual PDE3/4 inhibitors have synergistic anti-inflammatory and bronchodilator effects, and have attracted widespread attention in recent years. This article reviews the representative research results of dual PDE3/4 inhibitors currently in the preclinical and clinical research stages, summarizing their latest progress and their potential for the treatment of chronic obstructive pulmonary disease and asthma.

Study on the synergistic effects of aspirin and atorvastatin on cell proliferation of non-small cell lung cancer cells / 药学实践杂志

Objective To study the synergistic effects of aspirin and atorvastatin on cell proliferation of non-small cell lung cancer cell A549 and NCI-H460 and the mechanism of these actions. Methods The proliferation of A549 and NCI-H460 cells treated by aspirin or/and atorvastatin were determined by MTS assay. The migration of A549 and NCI-H460 cells were conducted by wound-healing assay. The expression of relevant protein in mTOR and NFκB signaling pathway were detected by western blotting. The mRNA expression of TNF-α and IL-1β were detected by quantitative real-time PCR. Results Aspirin or/and atorvastatin inhibited the proliferation and migration of A549 and NCI-H460 at concentration of 100 and 5 μmol/L or greater. The effect was enhanced by the combination of aspirin and atorvastatin. Aspirin or/and atorvastatin inhibited the protein expression of the phosphorylation of mTOR and NFκB, and down-regulated anti-apoptotic regulators Bcl-2 and Mcl-1 in NCI-H460 cells. The combination treatment of aspirin and atorvastatin was more efficacious than the single treatment. Atorvastatin decreased the mRNA expression of TNF-α. The combination of atorvastatin with aspirin decreased the mRNA expression of IL-1β by nearly 50 percent compared to the control (P<0.05). Conclusion Aspirin and atorvastatin have synergistic inhibitory effects on cell growth of non-small cell lung cancer cell A549 and NCI-H460 by suppressing mTOR and NFκB signaling pathway.

Research progress on antibacterial activity of herbal volatile oil / 中国中药杂志

Due to worldwide abuse of chemical antibiotics and continuous emergence of "superbugs", the harm of bacterial drug resistance to human beings has become more and more serious. Therefore, it is of great significance to look for green antibiotics with a wide range of sources, broad antibacterial spectrum, non-toxicity or low toxicity, environmentally friendliness, diverse active components and low drug resistance. The volatile oil of traditional Chinese medicine is a kind of volatile oily liquid that exists in plants and can be distilled with steam and immiscible with water. Because of its good potential to resist drug-resistant pathogens, it is widely used in food, medicine and other fields. This paper summarized the antibacterial advantages and characteristics of volatile oil of traditional Chinese medicine, and the antibacterial effect and antibacterial mechanism of combined application of volatile oil of traditional Chinese medicine, in order to provide some theoretical basis and study ideas for solving the problem of bacterial drug resistance and developing natural and green antibiotics.