Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

Microbubble-enhanced transcranial MR-guided focused ultrasound brain hyperthermia: heating mechanism investigation using finite element method.

Recently, our group developed a synergistic brain drug delivery method to achieve simultaneous transcranial hyperthermia and localized blood-brain barrier opening via MR-guided focused ultrasound (MRgFUS). In a rodent model, we demonstrated that the ultrasound power required for transcranial MRgFUS hyperthermia was significantly reduced by injecting microbubbles (MBs). However, the specific mechanisms underlying the power reduction caused by MBs remain unclear. The present study aims to elucidate the mechanisms of MB-enhanced transcranial MRgFUS hyperthermia through numerical studies using the finite element method. The microbubble acoustic emission (MAE) and the viscous dissipation (VD) were hypothesized to be the specific mechanisms. Acoustic wave propagation was used to model the FUS propagation in the brain tissue, and a bubble dynamics equation for describing the dynamics of MBs with small shell thickness was used to model the MB oscillation under FUS exposures. A modified bioheat transfer equation was used to model the temperature in the rodent brain with different heat sources. A theoretical model was used to estimate the bubble shell's surface tension, elasticity, and viscosity losses. The simulation reveals that MAE and VD caused a 40.5% and 52.3% additional temperature rise, respectively. Compared with FUS only, MBs caused a 64.0% temperature increase, which is consistent with our previous animal experiments. Our investigation showed that MAE and VD are the main mechanisms of MB-enhanced transcranial MRgFUS hyperthermia.

Synthesis and biological evaluation of novel benzothiazole derivatives as potential anticancer and antiinflammatory agents.

Introduction: Cancer, a significant global health concern, necessitates innovative treatments. The pivotal role of chronic inflammation in cancer development underscores the urgency for novel therapeutic strategies. Benzothiazole derivatives exhibit promise due to their distinctive structures and broad spectrum of biological effects. This study aims to explore new anti-tumor small molecule drugs that simultaneously anti-inflammatory and anticancer based on the advantages of benzothiazole frameworks. Methods: The compounds were characterized by nuclear magnetic resonance (NMR), liquid chromatograph-mass spectrometer (LC-MS) and high performance liquid chromatography (HPLC) for structure as well as purity and other related physicochemical properties. The effects of the compounds on the proliferation of human epidermoid carcinoma cell line (A431) and human non-small cell lung cancer cell lines (A549, H1299) were evaluated by MTT method. The effect of compounds on the expression levels of inflammatory factors IL-6 and TNF-α in mouse monocyte macrophages (RAW264.7) was assessed using enzyme-linked immunosorbent assay (ELISA). The effect of compounds on apoptosis and cell cycle of A431 and A549 cells was evaluated by flow cytometry. The effect of compounds on A431 and A549 cell migration was evaluated by scratch wound healing assay. The effect of compounds on protein expression levels in A431 and A549 cells was assessed by Western Blot assay. The physicochemical parameters, pharmacokinetic properties, toxicity and drug similarity of the active compound were predicted using Swiss ADME and admetSAR web servers. Results: Twenty-five novel benzothiazole compounds were designed and synthesized, with their structures confirmed through spectrogram verification. The active compound 6-chloro-N-(4-nitrobenzyl) benzo[d] thiazol-2-amine (compound B7) was screened through a series of bioactivity assessments, which significantly inhibited the proliferation of A431, A549 and H1299 cancer cells, decreased the activity of IL-6 and TNF-α, and hindered cell migration. In addition, at concentrations of 1, 2, and 4 µM, B7 exhibited apoptosis-promoting and cell cycle-arresting effects similar to those of the lead compound 7-chloro-N-(2, 6-dichlorophenyl) benzo[d] thiazole-2-amine (compound 4i). Western blot analysis confirmed that B7 inhibited both AKT and ERK signaling pathways in A431 and A549 cells. The prediction results of ADMET indicated that B7 had good drug properties. Discussion: This study has innovatively developed a series of benzothiazole derivatives, with a focus on compound B7 due to its notable dual anticancer and anti-inflammatory activities. B7 stands out for its ability to significantly reduce cancer cell proliferation in A431, A549, and H1299 cell lines and lower the levels of inflammatory cytokines IL-6 and TNF-α. These results position B7B7 as a promising candidate for dual-action cancer therapy. The study's mechanistic exploration, highlighting B7's simultaneous inhibition of the AKT and ERK pathways, offers a novel strategy for addressing both the survival mechanisms of tumor cells and the inflammatory milieu facilitating cancer progression.

Association between gaseous air pollutants and biomarkers of systemic inflammation: A systematic review and meta-analysis.

BACKGROUND: Studies have linked gaseous air pollutants to multiple health effects via inflammatory pathways. Several major inflammatory biomarkers, including C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) have also been considered as predictors of cardiovascular disease. However, there has been no meta-analysis to evaluate the associations between gaseous air pollutants and these typical biomarkers of inflammation to date. OBJECTIVES: To evaluate the overall associations between short-term and long-term exposures to ambient ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon dioxide (CO) and major inflammatory biomarkers including CRP, fibrinogen, IL-6 and TNF-α. METHODS: A meta-analysis was conducted for publications from PubMed, Web of Science, Scopus and EMBASE databases up to Feb 1st, 2021. RESULTS: The meta-analysis included 38 studies conducted among 210,438 participants. Generally, we only observed significant positive associations between short-term exposures to gaseous air pollutants and inflammatory biomarkers. For a 10 µg/m3 increase in short-term exposure to O3, NO2, and SO2, there were significant increases of 1.05% (95%CI: 0.09%, 2.02%), 1.60% (95%CI: 0.49%, 2.72%), and 10.44% (95%CI: 4.20%, 17.05%) in CRP, respectively. Meanwhile, a 10 µg/m3 increase in NO2 was also associated with a 4.85% (95%CI: 1.10%, 8.73%) increase in TNF-α. Long-term exposures to gaseous air pollutants were not statistically associated with these biomarkers, but the study numbers were relatively small. Subgroup analyses found more apparent associations in studies with better study design, higher quality, and smaller sample size. Meanwhile, the associations also varied across studies conducted in different geographical regions. CONCLUSION: Short-term exposure to gaseous air pollutants is associated with increased levels of circulating inflammatory biomarkers, suggesting that a systemic inflammatory state is activated upon exposure. More studies on long-term exposure to gaseous air pollutants and inflammatory biomarkers are warranted to verify the associations.

Short-Term Ambient Particulate Air Pollution and Hospitalization Expenditures of Cause-Specific Cardiorespiratory Diseases in China: A Multicity Analysis.

BACKGROUND: Ambient air pollution is leading risk factor for health burden in China. Few studies in China have investigated the economic loss related to short-term exposure to ambient PM2.5, which could trigger acute onset of cardiorespiratory diseases within a few days. METHODS: Daily ambient air pollutants data are obtained for each city from the National Air Quality Monitoring System and daily hospitalization data are obtained from the urban employee-based basic medical insurance scheme database in 74 Chinese cities with an average coverage of 88.5 million urban employees during 2016-2017. A three-stage time-series analytic approach is used in this study to investigate the impact of short-term exposure to ambient fine particulate (PM2.5) air pollution on hospital admissions, expenses and hospital stays of three cause-specific cardiorespiratory diseases, including lower respiratory infections (LRI), coronary heart disease (CHD) and stroke in the included cities. FINDINGS: Based on the time-series analysis using daily hospitalization data, 28,560 LRI cases, 54,600 CHD cases, and 23,989 stroke cases are attributable to ambient PM2.5 in the 74 cities during the study period, and the related attributable expenses are 220 million CNY (US$ 32.9 million) for LRI, 458 million CNY (US$ 68.5 million) for CHD, and 410 million CNY (US$ 65.8 million) for stroke, respectively. These attributable numbers account for 1.45% to 2.05% of total hospital admissions and 1.10% to 1.51% of total expenses for the three diseases during 2016-2017, respectively. The attributable numbers for the three cause-specific cardiorespiratory diseases would increase to 362,007 hospital admission cases and 3.68 billion CNY expenses ($US550 million) in the entire urban employee population (299 million) in China during 2016-2017, and the related direct economic loss of absence from work would be 798 million CNY (US$ 119.3 million). INTERPRETATION: Our results support that short-term exposure to ambient PM2.5 pollution could lead to significant health and economic impacts in China. Reducing levels of ambient PM2.5 can avoid substantial health damage and expenditures, and generate appreciable economic benefits from decreasing absence from work. FUNDING: Natural Science Foundation of China (82073509, 71903010, 71903011), and the National Key Research and Development Program of China (2017YFC0211600, 2017YFC0211601).

Prevalence of cervicovaginal human papillomavirus infection and genotypes in the pre-vaccine era in China: A nationwide population-based study.

OBJECTIVE: The HPV vaccine has been licensed in mainland China since 2017. This study aimed to assess the epidemiological characteristics of HPV genotypes in the pre-vaccine era in China. METHODS: We conducted a multicentric population-based study nested in the largest health clinic chain in China. Between January 1, 2017 and December 31, 2017, 427,401women aged 20 years or older with polymerase chain reaction-based HPV genotyping tests were included in the study. The cervicovaginal infection of 14 high-risk HPV genotypes and 9 low-risk genotypes was assessed using adjusted prevalence, multivariable logistic regression, cluster analysis, and heatmap. RESULTS: HPV prevalence was 15.0% (95% confidence interval [CI]: 14.1-15.9%) in China, with high- and low-risk genotypes being 12.1% (95%CI: 11.4-12.7%) and 5.2% (95%CI: 4.8-5.7%), respectively. The prevalence of HPV genotypes corresponding to bivalent, quadrivalent, and nonavalent vaccines were 2.1%, 2.4%, and 8.3%, respectively, whereas the prevalence of non-vaccine high-risk genotypes was 5.7%. The most common high-risk genotypes were HPV-52 (3.5%), HPV-58 (2.1%), and HPV-16 (1.6%), and the prevalence of HPV-18 (0.6%), HPV-6 (0.1%), and HPV-11 (0.2%) were relatively low. Infection with HPV genotypes differed significantly across age groups and geographic locations. CONCLUSION: HPV prevalence was high in the pre-vaccine era in China, and a population-based HPV vaccination strategy is needed in the future.

Associations of adverse pregnancy outcomes with high ambient air pollution exposure: Results from the Project ELEFANT.

BACKGROUND: Investigations on the potential effects of high air pollution exposure before pregnancy on adverse pregnancy outcomes are limited, and it is unknown whether air quality standards looser than that set by World Health Organization (WHO) still can provide sufficient protection pregnant women from adverse pregnancy outcomes. OBJECTIVES: To evaluate the potential effects of high ambient air pollution around pregnancy on preterm birth (PTB) and low birth weight (LBW), and assess the risk of PTB and LBW associated with air pollutants with reference to different air quality standards of WHO and China. METHODS: Our study leveraged 10,960 pregnant women from the Project ELEFANT. Daily average particulate matter with an aerodynamic diameter of ≤2.5 µm (PM2.5) and ≤10 µm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO) and ozone (O3) concentrations were collected based on Chinese Air Quality Reanalysis datasets. Hazard ratios (HR) of PTB and LBW were estimated for maternal PM2.5, PM10, NO2, SO2, CO and O3 exposures and related proportions of days with daily average air pollution concentrations exceeding air quality standards of WHO and China around pregnancy using Cox proportional hazards regression models with adjustment for potential confounders. RESULTS: Ambient PM2.5, PM10, NO2, SO2 and CO exposure during the before pregnancy and pregnancy period were both significantly and positively associated with increased risk of PTB, PTB subtypes and LBW. A 10% increase in proportion of days with daily average PM2.5 exceeding 25 µg/m3 over the entire pregnancy was most apparently associated with risk of PTB (HR, 12.66; 95% CI, 8.20-19.53) and LBW (HR, 17.42; 95% CI, 6.88-44.10) among all PM2.5 proportion variables based on different air quality standards. CONCLUSION: Air quality standards of WHO are necessary to be implemented to control for risks of adverse pregnancy outcomes associated with ambient air pollution in areas with high air pollution levels.

Association between short-term exposure to ambient particulate air pollution and biomarkers of oxidative stress: A meta-analysis.

BACKGROUND: Exposure to ambient particulate air pollution contributes substantially to the mortality and morbidity due to cardiovascular diseases (CVD), respiratory diseases and neurodegenerative diseases. Several hypothetical mechanisms have been proposed to explain these associations, particularly oxidative stress. Malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and Superoxide Dismutase (SOD) are typical biomarkers of oxidative stress and have been frequently investigated. However, the association between exposure to ambient particulate matter (PM) and these biomarkers has not been well established. OBJECTIVES: Evaluate the association between ambient particulate air pollution and biomarkers of oxidative stress based on existing epidemiological studies. METHODS: A systematic literature search was conducted in databases of Science Direct, PubMed, Web of Science, and Scopus up to April 24, 2020 to summarize epidemiological studies reporting the association between exposure to ambient PM (PM2.5, PM10, or both) and biomarkers of oxidative stress, and a meta-analysis was performed for the associations reported in individual studies using a random-effect model. RESULTS: This meta-analysis included 23 epidemiological studies (13 identified for 8-OHdG, 11 identified for MDA and 5 identified for SOD). A 10 µg/m3 increase in short-term exposure to ambient PM2.5 was associated with pooled percent changes of 2.10% (95% CIs: -0.13%, 4.38%), 1.60% (95% CIs: 0.21%, 3.01%) and -0.61% (95% CIs: -1.92%, 0.72%) in 8-OHdG, MDA and SOD, respectively. CONCLUSION: Short-term exposure to ambient PM2.5 was associated with a significantly increased level of MDA, indicating that ambient particulate air pollution may contribute to increased oxidative stress.

[Chemotactic response of ginseng endophyte to ginseng root exudates].

The ginseng endophytic bacteria F1 is a potential biocontrol agent for ginseng bacterial soft rot. In this paper,the chemotactic response of ginseng endophytic bacteria F1 on 8 kinds of sugar and amino acids was detected by capillary method to explore its biocontrol mechanism. The chemotactic response of F1 strain to 4 kinds of better chemotaxis substances such as glucose,glycine,L-rhamnoseand L-glutamic acid under parameters( concentration,time,temperature and pH) was studied. The results showed that under the same experimental conditions( incubation temperature 25 ℃,incubation time 60 min,chemotaxis concentration 1 mg·L~(-1)),ginseng endophytic bacteria F1 showed different degrees of response to the eight substances tested. The phenomenon of positive chemotaxis of the measured sugars and amino acids was obvious,and the chemotactic response to total ginsenosides was low. The degree of chemotaxis response is positively correlated with the chemotaxis index within a certain range of parameters,but as the temperature,p H,time,concentration and other factors continue to increase,the chemotaxis effect decreases,and F1 optimizes the chemotaxis of the four substances. The parameters are as follows: glucose: 25 ℃,10 mg·L~(-1),45 min,pH 7; glycine: 30 ℃,10 mg·L~(-1),75 min,pH7; L-rhamnose: 30 ℃,1 mg·L~(-1),30 min,pH 6; L-glutamic acid: 25 ℃,0. 1 mg·L~(-1),45 min,pH 8. The chemotactic response is more sensitive to low concentrations of chemotactic substances.