Novel Combination Therapy for Heart Failure: Trimebutine-Methoxsalen Identified through Synergistic Network Virtual Screening and Experimental Validation.

Combination therapy is increasingly favored by pharmaceutical companies and researchers as an effective way to quickly discover new drugs with excellent efficacy, especially in the treatment of complex diseases. Previously, we successfully developed a computational screening method to identify such combinations, although it fell short in elucidating their synergistic mechanisms. In this work, we have transitioned to a highest single agent (HSA) synergy model for network screening, which streamlines the discovery of promising combinations and facilitates the investigation of their synergistic effects. Through this refined approach, the trimebutine-methoxsalen combination emerged as a promising candidate for heart failure (HF) treatment, exhibiting significant in vitro cardioprotective effects and effectively mitigating isoproterenol (ISO)-induced structural remodeling in the mouse heart. Further mechanistic studies have demonstrated that trimebutine and methoxsalen could synergistically inhibit intracellular calcium overload in myocardial cells and reduce the production of ROS, thus exerting cardioprotective effects. Overall, this study introduces an advanced computational strategy that not only identifies a novel combination therapy against HF but also sheds light on its underlying synergistic mechanisms.

Rational design of a high-affinity fluorescent probe for visualizing monitoring the amyloid ß clearance effect of anti-Alzheimer's disease drug candidates.

Beta-amyloid (Aß), the most pivotal pathological hallmark for Alzheimer's disease (AD) diagnosis and drug evaluation, was recognized by TZ095, a high-affinity fluorescent probe developed by rational molecular design. With a TICT mechanism, TZ095 exhibited remarkable affinity with Aß aggregates (Kd = 81.54 nM for oligomers; Kd = 66.70 nM for fibril) and substantial fluorescence enhancement (F/F0 = 44), enabling real-time monitoring of Aß in live cells and nematodes. Significantly, this work used TZ095 to construct a new protocol that can quickly and conveniently monitor Aß changes at the cellular and nematode levels to evaluate the anti-AD efficacy of candidate compounds, and four reported Aß-lowering drug candidates were administrated for validation. Imaging data demonstrated that TZ095 can visually and quantitatively track the effect of Aß elimination after drug treatment. Furthermore, TZ095 excelled in ex vivo histological staining of 12-month-old APP/PS1 mouse brains, accurately visualizing Aß plaques. Integrating CUBIC technology, TZ095 facilitated whole-brain, 3D imaging of Aß distribution in APP/PS1 mice, enabling high-resolution in situ analysis of Aß plaques. Collectively, these innovative applications of TZ095 offer a promising strategy for rapid, convenient, and real-time monitoring of Aß levels in preclinical therapeutic assessments.

A Senomorphlytic Three-Drug Combination Discovered in Salsola collina for Delaying Aging Phenotypes and Extending Healthspan.

The pursuit of pharmacological interventions in aging aims focuses on maximizing safety and efficacy, prompting an exploration of natural products endowed with inherent medicinal properties. Subsequently, this work establishes a unique library of plant extracts sourced from Yunnan Province, China. Screening of this herbal library herein revealed that Salsola collina (JM10001) notably enhances both lifespan and healthspan in C. elegans. Further analysis via network pharmacology indicates that the p53 signaling pathway plays a crucial role in mediating the anti-aging effects of JM10001. Additionally, this work identifies that a composition, designated as JM10101 and comprising three chemical constituents of JM10001, preserves the original lifespan-extending activity in C. elegans. Both JM10001 and JM10101 mitigate aging symptoms in senescence-accelerated mice treated with doxorubicin and in naturally aged mice. Notably, JM10101 exhibits a more sophisticated senomorphlytic role encompassing both senomorphic and senolytic functions than JM10001 in the modulation of senescent cells, offering a promising strategy for the discovery of combination drugs in the rational development of anti-aging therapies.

Assessing trends and burden of occupational exposure to asbestos in the United States: a comprehensive analysis from 1990 to 2019.

BACKGROUND: This study aimed to analyze the trends and burden of occupational exposure to asbestos in the United States (U.S.) from 1990 to 2019, focusing on mortality rates, geographic distribution, age and sex patterns, and causes of death. METHODS: Data on the number of deaths attributable to occupational exposure to asbestos were collected from 1990 to 2019 in the U.S. Joinpoint analysis was conducted to assess trends over time, and regression models were applied to calculate annual percentage changes (APC) and annual average percentage changes (AAPC). Geographic distribution was examined using mapping techniques. Age and sex patterns were analyzed, and causes of death were identified based on available data. RESULTS: From 1990 to 2019, the overall number of deaths due to occupational exposure to asbestos in the U.S. increased by 20.2%. However, age-standardized mortality rates (ASMR) and age-standardized disability-adjusted life years (DALYs) rates (ASDR) exhibited a decline over the same period. Geographic analysis revealed differences in the number of deaths across states in 2019, with California reporting the highest number of fatalities. Age-specific mortality and DALYs showed an increase with age, peaking in older age groups. Tracheal, bronchus, and lung cancer were the leading causes of death attributed to asbestos exposure, with increasing trends observed over the past five years. CONCLUSION: The study highlights significant trends and burden in occupational exposure to asbestos in the U.S., including overall increases in mortality rates, declining ASMR and ASDR, geographic disparities, age and sex patterns, and shifts in causes of death. These findings underscore the importance of continued monitoring and preventive measures to mitigate the burden of asbestos-related diseases.

The Burden of Cardiovascular Diseases Attributed to Diet High in Sugar-Sweetened Beverages in 204 Countries and Territories From 1990 to 2019.

This study examines the impact of sugar-sweetened beverage (SSB) consumption on cardiovascular diseases (CVDs) and aims to provide evidence for preventive measures. The analysis involved a comprehensive scrutiny of CVD-related data from 1990 to 2019. Temporal trends of ASMR and ASDR were assessed using the Estimated Annual Percentage Change (EAPC). Globally, there was an increase in deaths and DALYs from 1990 to 2019, despite decreasing ASMR and ASDR. In 2019, SSB-related CVDs accounted for approximately 193.1 thousand deaths and 3973.2 thousand DALYs. China had the highest number of deaths, Tajikistan had the highest ASMR, and Yemen had the highest ASDR in 2019. ASMR and ASDR increased with age and were higher in males. Deaths and DALYs increased overall, except in high Socio-demographic Index (SDI) regions. ASMR and ASDR declined across SDI regions, with the steepest decline in high SDI regions (EAPC: -2.8 for ASMR, -2.36 for ASDR). ASDR increased in low SDI countries but decreased in high SDI countries. This study provides comprehensive insights into the global burden of SSB-related CVDs. Urgent interventions and policies are needed to reduce SSB consumption and mitigate the impact on cardiovascular health.

Global, Regional, and National Burden of COPD Attributable to Occupational Particulate Matter, Gases, and Fumes, 1990-2019: Findings from the Global Burden of Disease Study 2019.

Background: A study aimed to estimate the burden of Chronic obstructive pulmonary disease (COPD) caused by occupational exposure to particulate matter, gases, and fumes in 204 countries from 1990 to 2019. Methods: Data on the deaths number, age-standardized mortality rates (ASMR), and age-standardized disability-adjusted life years (DALYs) rates (ASDR) of COPD attributable to occupational particulate matter, gases, and fumes were collected from the GBD study 2019. We also investigated the association between the ASDR and SDI. Results: There were 517.7 thousand deaths [95% UI: 413.9 to 634.5] in 2019. The number of deaths increased from 1990 to 2019. The ASMR and ASDR were 6.61 (5.24 to 8.17) and 143.02 (118.56 to 168.69) in 2019, respectively, representing a 46% and 44.5% decrease since 1990. China had the highest number of deaths [200,748.4 (151,897.6 to 260,703.9)], while Nepal had the highest ASMR [39 (27.7 to 50)] and ASDR [724.5 (549 to 894.2)]. Males and females 75-79 and 80-84 years old had the highest number of COPD deaths. A negative correlation was observed when SDI > 0.4, whereas a positive correlation was found when SDI < 0.4. Conclusion: From 1990 to 2019, there was an increase in the number of deaths, but a decline in ASMR and ASDR globally. Besides, there was a heterogeneous burden of COPD attributable to occupational particulate matter, gases, and fumes across regions and countries. It is important to develop and implement strategies to prevent and reduce the burden of COPD attributable to occupational particulate matter, gases, and fumes.

Global burden of ischemic heart disease associated with high red and processed meat consumption: an analysis of 204 countries and territories between 1990 and 2019.

BACKGROUND: Multiple studies have indicated an association between red and processed meat consumption and the incidence of ischemic heart disease (IHD). In this study, we aimed to assess the burden of IHD caused by a diet high in red and processed meat in 204 countries and territories between 1990 and 2019, using data from the Global Burden of Disease (GBD) 2019. METHODS: We extracted data from the GBD 2019, which included the number of deaths, age-standardized mortality rates (ASMR), disability-adjusted life years (DALYs), and age-standardized DALYs rates (ASDR) attributed to IHD caused by a diet high in red and processed meat. We then calculated the burden of IHD attributable to a high intake of red and processed meat in each country and territory, stratified by age, sex, and socio-demographic index (SDI). RESULTS: Globally, a high intake of red meat was responsible for 351,200 (95% uncertainty interval (UI): 559,000-642,700) deaths from IHD in 2019, while a high intake of processed meat was associated with 171,700 (95% UI: 30,100-320,000) deaths from IHD. Between 1990 and 2019, while the corresponding age-standardized rates declined, the numbers of deaths and DALYs increased. China had the highest number of deaths [98,386.9 (95% UI: 14,999.3-189,812.7)] caused by a high intake of red meat, while United States of America [33,129.6 (95% UI: 7,150-59,593.8)] was associated with the highest number of deaths caused by high intake of processed meat for IHD in 2019. Males experienced a greater burden of IHD caused by a high intake of red and processed meat than females. The ASMR and ASDR of IHD attributed to a high intake of red meat decreased in countries with high SDI, high-middle SDI and low SDI, while the ASMR and ASDR of IHD attributed to a high intake of processed meat decreased only in countries with high SDI and high-middle SDI. CONCLUSION: Although there is a decline in the ASMR and ASDR of IHD caused by a high intake of red and processed meat, there is also an increase in deaths and DALYs number globally. Additionally, there is a heterogeneous burden of IHD related to a high intake of red and processed meat across regions and countries, with males experiencing a greater burden than females. Implementing targeted policies and interventions is required to reduce the burden of IHD caused by a high intake of red and processed meat.

A Mendelian randomization study revealed a causal link between napping and deep vein thrombosis (DVT).

BACKGROUND: Numerous individuals opt for napping to achieve adequate rest, and several studies have linked napping to various health conditions. Consequently, we aimed to investigate the potential effect of napping on the development of deep vein thrombosis (DVT). METHODS: We used the publicly available summary statistics data sets of genome-wide association studies (GWAS) meta-analyses for napping in individuals included in the UK Biobank as the exposure and a GWAS for DVT from the individuals included in the FinnGen Biobank as the outcome. The two-sample MR research approach was utilized to explore the causative link between napping and DVT. Single nucleotide polymorphisms (SNPs) data strongly related to napping were found and used as instrumental factors. Inverse variance weighting (IVW), weighted median and MR-Egger regression, and weighted mode approaches were four statistical techniques. RESULTS: There were 86 SNPs in all that were discovered to be strongly related to napping (P < 5 × 10-8, linkage disequilibrium r2 < 0.1). Consistent association between napping and DVT (IVW: odds ratio (OR) 0.508, 95% confidence interval (CI) 0.280-0.921; MR-Egger regression: OR 0.988, 95% CI 0.118-8.303; weighted median estimates: OR 0.419, 95% CI 0.181-0.974; weighted mode: OR 0.442, 95% CI 0.080-2.427) suggested that napping correlated with decreased risk of DVT. There was no evidence that genetic pleiotropy affected the link between napping and DVT (MR-Egger intercept - 6.7 × 10-3; P = 0.525). CONCLUSION: The results of the Mendelian randomization study suggested a potential causal relationship between napping and a reduced incidence of DVT.

Trends of the Global, Regional and National Incidence, Mortality, and Disability-Adjusted Life Years of Malaria, 1990-2019: An Analysis of the Global Burden of Disease Study 2019.

Background: Malaria remains a substantial concern in the realm of public health on a worldwide level. Using information from the global burden of disease (GBD) 2019 for 204 countries and territories between 1990 and 2019, we assessed the burden of malaria. Methods: Data on malaria were derived from the GBD 2019 study between 1990 and 2019. We evaluated the number of incidence, deaths, disability-adjusted life years (DALYs), age-standardized incidence rates (ASIR), age-standardized mortality rates (ASMR), and age-standardized DALY rates (ASDR), examining them across variables such as age, year, gender, country, region, and socio-demographic index (SDI). Results: The burden of malaria decreased globally between 1990 and 2019. There were 2313.57×105 incident cases and 6.43×105 deaths in 2019, contributing to 464.38×105 DALYs. Largest incident cases were observed in Western Sub-Saharan Africa [1151.72 (95% UI: 890.01-1527.17)] ×105 in 2019. The only region where deaths increased between 1990 and 2019 was Western Sub-Saharan Africa. ASRs of malaria are distributed heterogeneously in different regions. The highest ASIR was observed in Central Sub-Saharan Africa [21,557.65 (95% UI: 16,639.4-27,491.48)] in 2019. From 1990 to 2019, the ASMR of malaria declined. Compared to other age cohorts, the ASIR, ASMR, and ASDR for children aged between 1 to 4 years were found to be higher. Worst-affected regions by malaria infection were the low-middle SDI region and low SDI region. Conclusion: Malaria threatens global public health, especially in Central Sub-Saharan Africa and Western Sub-Saharan Africa. Children 1-4 years old continue to bear the most significant burden of malaria. The study's results will guide efforts to reduce malaria's impact on the global population.

Photoactivatable senolysis with single-cell resolution delays aging.

Strategies that can selectively eliminate senescent cells (SnCs), namely senolytics, have been shown to promote healthy lifespan. However, it is challenging to achieve precise, broad-spectrum and tractable senolysis. Here, we integrate multiple technologies that combine the enzyme substrate of senescence-associated ß-galactosidase (SA-ß-gal) with fluorescence tag for the precise tracking of SnCs, construction of a bioorthogonal receptor triggered by SA-ß-gal to target and anchor SnCs with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy (PDT). We generate KSL0608-Se, a photosensitive senolytic prodrug, which is selectively activated by SA-ß-gal. In naturally-aged mice, KSL0608-Se-mediated PDT prevented upregulation of age-related SnCs markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice. We therefore provide a strategy to monitor and selectively eliminate SnCs to regulate aging.

Trends in the Burden of COPD Attributable to Ambient PM2.5 Exposure in China 1990-2019: An Age-Period-Cohort Analysis.

Objective: Exposure to ambient particulate matter (PM2.5) is the leading risk factor for developing chronic obstructive pulmonary disease (COPD) in China. The present study aimed to investigate the trends in COPD mortality attributable to ambient PM2.5 exposure in China from 1990 to 2019. Methods: Data on COPD burden attributable to ambient PM2.5 exposure in China were extracted from the Global Burden of Disease (GBD) study 2019. The estimated annual percentage change (EAPC) was used to assess COPD mortality from 1990 to 2019. The APC model was used to analyze the temporal trends in the rate of COPD mortality attributable to ambient PM2.5 exposure according to age, period, and cohort. Results: Exposure to ambient PM2.5 contributed to 192.4 thousand deaths in 1990 and 263.6 thousand deaths in 2019. The age-standardized mortality rate (ASMR) and the age-standardized disability-adjusted life year rate (ASDR) due to ambient PM2.5 exposure showed a gradual downward trend, the ASMR and ASDR in 2019 decreased to 16.6 per 100,000 with an EAPC of -2.82 (95% CI: -8.61 to 3.34) and 278.6 per 100,000 with an EAPC of -2.02 (95% CI: -7.85 to 4.19), compared to those in 1990, respectively. The relative risk (RR) of COPD increased with age in females, while in males, mortality significantly increased from the levels among those in the 60-64 age group to that among those in the 90-94 age group. In the period group, the RR of COPD in males remained above 1.0 from the 2000 to 2004 period, but it gradually decreased in females. The cohort effect showed an overall downward trend. Conclusion: Although the ASMR and ASDR are decreasing in Chinese patients with COPD, the number of deaths due to COPD is increasing. Ambient PM2.5 exposure is more harmful in males and older people above 60 years of age.

The global, regional, and national burden of tuberculosis in 204 countries and territories, 1990-2019.

BACKGROUND: Tuberculosis (TB) is the leading cause of death from a single infectious disease and ranks 13th among the leading causes of death worldwide. In this study, we aimed to report the burden of TB in 204 countries and territories from 1990 to 2019 by sex, age, and socio-demographic index (SDI). METHODS: Annual death number, age-standardized mortality rates (ASMR), and age-standardized disability-adjusted life year (DALY) rates (ASDR) with a 95% uncertainty interval (UI) of TB were derived from the global burden of disease (GBD) 2019 for the time period between 1990 and 2019. The association between the burden of TB and SDI was also investigated. RESULTS: The total death number related to TB decreased by 33.6%, from 1777.5 in 1990-1179.8 in 2019, per 1000 individuals. The global ASMR and ASDR for TB were 14.64 (13.39-16.03) and 590.42 (536.85-646.42), which were 63.5% and 62.8% lower than in 1990, respectively. South Asia, Eastern Sub-Saharan Africa, Southeast Asia, and Western Sub-Saharan Africa had the largest number of TB deaths in 2019. Central Sub-Saharan Africa was the region with the highest ASMR and ASDR in 2019. India had the highest number of TB deaths, and the Central African Republic and Switzerland had the highest and lowest ASMR per 100,000 individuals, respectively. The number of deaths and DALYs were higher in males than in females and the ASDR significantly increased from the 10-14-year-old age group to the 80-84-year-old age group in both sexes. Most cases of TB were caused by drug-susceptible TB. A negative association between the regional SDI and the ASDR of TB was found. CONCLUSIONS: From 1990-2019, TB death number, ASMR, and ASDR decreased. It is important to note that, despite the decreasing burden of TB, it remains a major public health problem, especially in low SDI countries. It is necessary to design and implement suitable strategies to address the current situation.

Ferroptosis related genes participate in the pathogenesis of spinal cord injury via HIF-1 signaling pathway.

BACKGROUND: Spinal cord injury (SCI) is a crushing disease without a effective and specific therapeutic strategy. Therefore, it is crucial to uncover underlying mechanism in order to identify potential treatments for SCI. Current studies show ferroptosis might pay important role in SCI. METHODS: In this study, we aimed to identify the key ferroptosis-related genes providing therapeutic targets for SCI. GSE45006, GSE19890 and GSE156999 from Gene Expression Omnibus (GEO) database were analyzed. RESULTS: A total of 61 ferroptosis-related DEGs were identified, followed by bioinformatics enrichment analyses and PPI network construction. Ten key ferroptosis-related genes were identified by Cytoscape (Cytohubba), most of which were enriched in the HIF-1 signaling pathway. Then we constructed a clip SCI rat model and qPCR was performed to assess the expressions of five genes enriched in HIF-1 signaling pathway (Stat3, Tlr4, Hmox1, Hif1a and Cybb). Finally, a ceRNA network, Stat3, Tlr4, Hmox1/miR127, miR383, miR485/rno-Mut_0003, rno-Pwwp2a_0002 was constructed and expression of mentioned molecules were validated by chip data. CONCLUSIONS: Five hub genes from HIF-1 signaling pathway were identified and might play a central role in SCI, which indicated that ferroptosis was correlated with HIF-1 signaling pathway. These results can provide a new insight into molecular mechanisms and identify potential therapeutic targets for SCI.

A senolysis-based theragnostic prodrug strategy towards chronic renal failure.

Selective elimination of senescent cells (senolysis) has become a promising therapeutic strategy for the management of chronic renal failure (CRF), but the senolytic molecular pathways towards CRF therapy are limited. Here, we present for the first time a senescence-associated ß-galactosidase (SA-ß-gal) activatable theragnostic prodrug strategy to pertinently and effectively treat CRF in mice with the aid of fluorescence-guided senolysis. The signs of premature senescence, including the overexpression of ß-gal, have been found in kidneys of mice with CRF, making this enzyme particularly suitable as a trigger of prodrugs for CRF therapy. With this unique design, our pioneering prodrug TSPD achieved the activation of a fluorophore for tracking and the specific release of the parent drug, gemcitabine, in ß-gal-enriched cells after activation with SA-ß-gal. In mice with CRF, abdominal administration of TSPD was effective for improvement of the kidney functions, supporting the feasibility of the SA-ß-gal-dependent senolysis therapy towards CRF.

Trends in incidence and mortality of esophageal cancer in China 1990-2019: A joinpoint and age-period-cohort analysis.

Background: The incidence and mortality trends of esophageal cancer (EC) remain unknown in China. This study aimed to describe the trend in incidence and mortality of EC in China. Methods: We extracted age-standardized rates and numbers of EC in China for 1990-2019 from the Global Burden of Disease study 2019. The age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) were calculated to describe the trends, while the annual percentage of change and the average annual percent change (AAPC) were analyzed by the joinpoint regression analysis. The incidence and mortality data were analyzed via age-period-cohort model analysis. Results: The ASIR and ASMR decreased slightly before 1999, then increased from 1999 to 2004, and decreased again thereafter, with overall AAPC values of -2.5 (-2.8, -2.1) for females and -0.9 (-1.1, -0.8) for males regarding incidence, with overall AAPC values of -3.1 (-3.3, -2.9) for females and -1.2 (-1.3, -1.1) for males regarding mortality. As a whole, the relative risk (RR) of EC increased with age in both females and males regarding incidence and mortality, except for the 80-84-year-old age group in females and the 85-89-year-old age group in males regarding incidence, where they began to decrease. The RR of EC increased with age in females and males regarding mortality, except for the 85-89-year-old age group in males. The time period showed a trend of first rising and then decreasing, and the RR of time period effect was lower in 2015 than that in 1990 in females regarding both incidence and mortality, whereas males showed a significant upward trend in both incidence and mortality. The birth cohort effect showed an overall downward trend. Conclusions: The overall incidence and mortality of EC in China shows an increased and then decreased trend from 1990 to 2019. The AAPC decreased in incidence and mortality from 1990 to 2019. The RR of incidence and mortality of EC in China is greatly affected by age in both sexes, by time period in male, we should be paid more attention to.

Health Inequality in the Global Burden of Chronic Obstructive Pulmonary Disease: Findings from the Global Burden of Disease Study 2019.

Background: This study assessed health inequality in the global burden of chronic obstructive pulmonary disease (COPD) between 1990 and 2019 using data extracted from the Global Burden of Diseases (GBD 2019) study. Methods: Data were extracted from the GBD 2019 study. A series of comparative and descriptive analyses of the disease burden between women and men in countries with different socioeconomic development (SDI) status were performed. The slope index of inequality (SII), relative index of inequality (RII), and concentration index (CI) were calculated to measure the socioeconomic-related cross-national health inequity between 1990 and 2019. Results: The global health burden caused by COPD increased by 25.7% in terms of disability-adjusted life years (DALY) from 59.2 million years in 1990 to 74.4 million years in 2019. Global age-standardized DALY rate (ASDR) associated with COPD decreased by 40.0%, from 1537.7 per 100,000 population in 1990 to 926.1 per 100,000 population in 2019. The highest sex-specific DALY number was at age 70-74 in male and female, and female is lower than male. However, after controlling for population size, the burden of COPD is more concentrated in the population living in low SDI countries, relative health inequality indicators (RII and CI) supported this conclusion. Conclusion: The health inequalities caused by the disparity of socioeconomic status are increasing, and the increasing concentration of wealth worldwide is likely to aggravate health inequalities associated with COPD.

The Burden of Trachea, Bronchus, and Lung Cancer Attributable to Occupational Exposure From 1990 to 2019.

Objectives: Occupational exposure to carcinogens is associated with trachea, bronchus, and lung (TBL) cancer. The objective of this study was to provide global and regional estimates of the burden of TBL cancer associated with occupational carcinogens (OCs) between 1990 and 2019. Methods: Age-standardized mortality rates (ASMR) and age-standardized disability-adjusted life years (DALYs) rates (ASDR) of TBL cancer related to exposure to OCs at the global and regional levels were extracted for 1990-2019 from the Global Burden of Disease 2019. Joinpoint regression was used to analyze trends in the ASMR and ASDR of TBL cancer burden related to OCs, and the annual percent change and the average annual percent change (AAPC) were recorded. Results: The mortality from TBL cancer related to exposure to OCs increased globally. The ASMR and ASDR decreased in both sexes and in men between 1990 and 2019. The AAPC of ASMR and ASDR decreased in men between 1990 and 2019, but increased in women. Asbestos accounted for the highest death number and beryllium accounted for the lowest; diesel engine exhaust caused the largest percentage change in death number (145.3%), in ASDR (14.9%), and in all ages DALY rates (57.6%). Asbestos accounted for the largest death number in high social development index (SDI) countries, whereas low-middle SDI countries had the largest percent change (321.4%). Asbestos was associated with decreased ASDR in high SDI countries and increased ASDR in low-middle SDI countries, and similar changes were observed for other OCs. Conclusions: The overall mortality and DALYs of TBL cancer burden related to OCs showed a decreasing trend between 1990 and 2019, whereas death number increased. Asbestos accounted for the highest death number. TBL cancer burden related to OCs decreased to different degrees in high, low, low-middle, and middle SDI countries, which showed variable levels of TBL cancer burden related to exposure to OCs (except asbestos).

Identification of Guaifenesin-Andrographolide as a Novel Combinatorial Drug Therapy for Epilepsy Using Network Virtual Screening and Experimental Validation.

Combinatorial drug therapy has attracted substantial attention as an emerging strategy for the treatment of diseases with complex pathological mechanisms. We previously developed a potentially universal computational screening approach for combination drugs and used this approach to successfully identify some beneficial combinations for the treatment of heart failure. Herein, this screening approach was used to identify novel combination drugs for the treatment of epilepsy in an approved drug library. The combination of guaifenesin-andrographolide was first discovered as a promising therapy with synergistic anticonvulsant activities in maximal electroshock (MES)- and subcutaneous pentylenetetrazol (sc-PTZ)-induced epilepsy models in vivo. The studies of network analysis, fluorescence imaging, and N-methyl-d-aspartate (NMDA)-induced cytotoxicity further revealed that guaifenesin-andrographolide might synergistically affect NMDA receptors and then alleviate the pathogenesis of epilepsy. Therefore, we report that the combination of guaifenesin-andrographolide exerts effects against epilepsy through a novel synergistic mechanism and is thus a potential treatment for epilepsy, providing a promising mechanism for the design of novel combinatorial drug treatments against epilepsy.