Identification of (E)-1-((1H-indol-3-yl)methylene)-4-substitute-thiosemicarbazones as potential anti-hepatic fibrosis agents.

Liver fibrosis remains a global health challenge due to its rapidly rising prevalence and limited treatment options. The orphan nuclear receptor Nur77 has been implicated in regulation of autophagy and liver fibrosis. Targeting Nur77-mediated autophagic flux may thus be a new promising strategy against hepatic fibrosis. In this study, we synthesized four types of Nur77-based thiourea derivatives to determine their anti-hepatic fibrosis activity. Among the synthesized thiourea derivatives, 9e was the most potent inhibitor of hepatic stellate cells (HSCs) proliferation and activation. This compound could directly bind to Nur77 and inhibit TGF-ß1-induced α-SMA and COLA1 expression in a Nur77-dependent manner. In vivo, 9e significantly reduced CCl4-mediated hepatic inflammation response and extracellular matrix (ECM) production, revealing that 9e is capable of blocking the progression of hepatic fibrosis. Mechanistically, 9e induced Nur77 expression and enhanced autophagic flux by inhibiting the mTORC1 signaling pathway in vitro and in vivo. Thus, the Nur77-targeted lead 9e may serve as a promising candidate for treatment of chronic liver fibrosis.

Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma.

Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77's Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (KD = 445.3 nM) and could activate Nur77's transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.

Discovery of bipyridine amide derivatives targeting pRXRα-PLK1 interaction for anticancer therapy.

Retinoid X receptor alpha (RXRα) is an important therapeutic target of cancer. Recently, small molecules (e.g.,XS-060 and its derivatives), which can significantly induce RXRα-dependent mitotic arrest by inhibiting pRXRα-PLK1 interaction, have been demonstrated as excellent anticancer agents. To further obtain novel RXR-targeted antimitotic agents with excellent bioactivity and drug-like properties, we herein synthesized two new series of bipyridine amide derivatives with XS-060 as the lead compound. In the reporter gene assay, most synthesized compounds showed antagonistic activity against RXRα. The most active compound, bipyridine amide B9 (BPA-B9), showed better activity than XS-060, with excellent RXRα-binding affinity (KD = 39.29 ± 1.12 nM) and anti-proliferative activity against MDA-MB-231 (IC50 = 16 nM, SI > 3). Besides, a docking study revealed a proper fitting of BPA-B9 into the coactivator binding site of RXRα, rationalizing its potent antagonistic effect on RXRα transactivation. Further, the mechanism studies revealed that the anticancer activity of BPA-B9 was dependent on its cellular RXRα-targeted mechanism, such as inhibiting pRXRα-PLK1 interaction and inducing RXRα-dependent mitotic arrest. Besides, BPA-B9 displayed better pharmacokinetics than the lead XS-060. Further, animal assays indicated BPA-B9 had significant anticancer efficacy in vivo with no considerable side effects. Together, our study reveals a novel RXRα ligand BPA-B9 targeting the pRXRα-PLK1 interaction, with great potential as a promising anticancer drug candidate for further development.

A label-free LC/MS-based enzymatic activity assay for the detection of PDE5A inhibitors.

Phosphodiesterase type 5 (PDE5), a cyclic nucleotide phosphodiesterase, controls the duration of the cyclic guanosine monophosphate (cGMP) signal by hydrolyzing cGMP to GMP. Inhibiting the activity of PDE5A has proven to be an effective strategy for treating pulmonary arterial hypertension and erectile dysfunction. Current enzymatic activity assay methods for PDE5A mainly use fluorescent or isotope-labeled substrates, which are expensive and inconvenient. Here, we developed an LC/MS-based enzymatic activity assay for PDE5A without labeling, which detects the enzymatic activity of PDE5A by quantifying the substrate cGMP and product GMP at a concentration of 100 nM. The accuracy of this method was verified by a fluorescently labeled substrate. Moreover, a new inhibitor of PDE5A was identified by this method and virtual screening. It inhibited PDE5A with an IC50 value of 870 nM. Overall, the proposed strategy provides a new method for screening PDE5A inhibitors.

Cervical Cancer Screening Coverage - China, 2018-2019.

What is already known about this topic?: The World Health Organization set a 2030 target of 70% cervical cancer screening coverage for women aged 35-45 years. Coverage stood at 37% in China in 2015. What is added by this report?: In 2018-2019, China's cervical cancer screening coverage reached 43.4% in women aged 35-44 years and 36.8% in women aged 35-64 years. Screening coverage was still lower in rural areas as well as central and western regions; large variations existed across provincial-level administrative divisions. What are the implications for public health practice?: National and local policy and financial support should be maintained for cervical cancer screening, along with more targeted health education and outreach efforts and strengthened accessibility of health services in the rural areas and central and western regions.

Breast Cancer Screening Rates Among Women Aged 20 Years and Above - China, 2015.

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?: Breast cancer is the most common cancer in women in China and around the world. By 2019, 121 countries have instituted a national screening program as a secondary prevention measure for breast cancer. WHAT IS ADDED BY THIS REPORT?: Breast cancer screening rates in China were 18.9% in women aged 20 years and above, and 25.7% in women aged 35-64 years in 2015. The screening rate for women aged 20 years and above was significantly higher in urban areas than in rural areas (24.6% vs. 15.0%), and in the eastern region than in the central and western regions (24.0% vs. 15.1% and 15.3%). WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE?: Continued efforts should be made to strengthen national and local policy initiatives and financial support for population-based, organized screening programs for breast cancer. Health education and accessibility of screening services to women across the country should be strengthened, especially for women aged 50 years and above.

The effects of indoor air pollution from solid fuel use on cognitive function among middle-aged and older population in China.

OBJECTIVES: Growing evidence has linked outdoor air pollution exposure with higher risk of cognitive impairments. However, the role of indoor air pollution in cognitive decline is not well elaborated. By using nationally representative longitudinal data, this study aimed to explore the effects of indoor air pollution from solid fuel use on cognitive function among middle-aged and older individuals in China. METHODS: Data were obtained from 2011 to 2015 waves of CHARLS (China Health and Retirement Longitudinal Study). Scores from the Telephone Interview of Cognitive Status and figure drawing/word recall tests were used to measure cognitive function in 39,482 individuals. Exposure to indoor air pollution was measured as use of solid fuel for cooking. Solid fuel was defined as coal, biomass charcoal, wood, and straw; clean fuel was defined as liquefied gas, natural gas, and electricity. Linear mixed effect models were applied to examine the effect of indoor air pollution from solid fuel use on cognitive function. RESULTS: Participants had an average global cognitive function of 9.67 (SD = 4.13). Solid fuel users made up 49.71% of participants, but this proportion was much greater among those living in rural areas (64.22%). Compared with clean fuel users, solid fuel users had worse cognitive function. On average, solid fuel users had a 0.81 (95%CI: -0.89, -0.73) lower global cognition score, 0.63 (95%CI: -0.69, -0.57) lower mental health score, and 0.16 (95%CI: -0.22, -0.14) lower episodic memory score. These effects were stronger among participants who are female, aged 65 years old and above, have education level of primary school and below, or have cardiovascular diseases. CONCLUSIONS: These results provide evidence for the role of indoor air pollution in neurobehavioral disorders in China. Promotion of practices like expanded use of clean fuel and improved stoves in households may be crucial to significantly reduce indoor air pollution and protect mental health.

Cervical Cancer Screening Rates Among Chinese Women - China, 2015.

What is already known about this topic? Cervical cancer is the fourth most common cancer of women around the world. Age-adjusted incidence and mortality rates of cervical cancer were 11.78 and 3.29 per 100,000, respectively, in China in 2015. What is added by this report? Cervical cancer screening rates were 25.7% for women aged 20-64 years old and 31.4% for women aged 35-64 years old in China in 2015. Screening rates were lower in rural areas than in urban areas and varied across provinces. What are the implications for public health practice? Efforts should be made to continue to strengthen national and local policy initiatives, financial support, health education, and accessibility to women in rural areas for cervical cancer screening coverage.