From virus to immune system: Harnessing membrane-derived vesicles to fight COVID-19 by interacting with biological molecules.

Emerging and re-emerging viral pandemics have emerged as a major public health concern. Highly pathogenic coronaviruses, which cause severe respiratory disease, threaten human health and socioeconomic development. Great efforts are being devoted to the development of safe and efficacious therapeutic agents and preventive vaccines to combat them. Nevertheless, the highly mutated virus poses a challenge to drug development and vaccine efficacy, and the use of common immunomodulatory agents lacks specificity. Benefiting from the burgeoning intersection of biological engineering and biotechnology, membrane-derived vesicles have shown superior potential as therapeutics due to their biocompatibility, design flexibility, remarkable bionics, and inherent interaction with phagocytes. The interactions between membrane-derived vesicles, viruses, and the immune system have emerged as a new and promising topic. This review provides insight into considerations for developing innovative antiviral strategies and vaccines against SARS-CoV-2. First, membrane-derived vesicles may provide potential biomimetic decoys with a high affinity for viruses to block virus-receptor interactions for early interruption of infection. Second, membrane-derived vesicles could help achieve a balanced interplay between the virus and the host's innate immunity. Finally, membrane-derived vesicles have revealed numerous possibilities for their employment as vaccines.

Hyperbaric Oxygen Boosts Antitumor Efficacy of Copper-Diethyldithiocarbamate Nanoparticles against Pancreatic Ductal Adenocarcinoma by Regulating Cancer Stem Cell Metabolism.

Cuproptosis-based cancer nanomedicine has received widespread attention recently. However, cuproptosis nanomedicine against pancreatic ductal adenocarcinoma (PDAC) is severely limited by cancer stem cells (CSCs), which reside in the hypoxic stroma and adopt glycolysis metabolism accordingly to resist cuproptosis-induced mitochondria damage. Here, we leverage hyperbaric oxygen (HBO) to regulate CSC metabolism by overcoming tumor hypoxia and to augment CSC elimination efficacy of polydopamine and hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@PH NPs). Mechanistically, while HBO and CuET@PH NPs inhibit glycolysis and oxidative phosphorylation, respectively, the combination of HBO and CuET@PH NPs potently suppresses energy metabolism of CSCs, thereby achieving robust tumor inhibition of PDAC and elongating mice survival importantly. This study reveals novel insights into the effects of cuproptosis nanomedicine on PDAC CSC metabolism and suggests that the combination of HBO with cuproptosis nanomedicine holds significant clinical translation potential for PDAC patients.

Investigation into the characteristics of electron beam-aged microplastics and adsorption behavior of dibutyl phthalate.

Microplastics are increasingly prevalent in the environment, and their ability to adsorb various organic additives, posing harm to organisms, has attracted growing attention. Currently, there are no effective methods to age microplastics, and there is limited discussion on the subsequent treatment of aged microplastics. This study focuses on micro polyethylene (PE) and employs electron beam technology for aging treatment, investigating the adsorption and leaching behavior between PE and dibutyl phthalate (DBP) before and after aging. Experimental results indicate that with increasing doses of electron beam irradiation, the surface microstructure of PE worsens, inducing the generation of oxygen-containing functional groups on the surface of polyethylene. Comparative evaluations between electron beam aging and existing methods show that electron beam technology surpasses existing aging methods, achieving a level of aging exceeding 0.7 within an extremely short period of 1 min at doses exceeding 350 kGy. Adsorption experiments demonstrate that the adsorption between PE and DBP conforms to pseudo-second-order kinetics and the Freundlich model both before and after aging. The adsorption capacity of microplastics for DBP increases from 76.8 mg g-1 to 167.0 mg g-1 after treatment, exceeding that of conventional DBP adsorbents. Electron beam irradiation causes aging of microplastics mainly through the generation of ·OH, which lead to the formation of oxygen-containing functional groups on the microplastics' surface, thereby enhancing their adsorption capacity for DBP. This provides a new perspective for the degradation of aged microplastics and composite pollutants.

Biotransformation of chenodeoxycholic acid by human intestinal fungi and the agonistic effects on FXR.

Bile acids play a vital role in modulating host metabolism, with chenodeoxycholic acid (CDCA) standing out as a primary bile acid that naturally activates farnesoid X receptor (FXR). In this study, we investigated the microbial transformations of CDCA by seven human intestinal fungal species. Our findings revealed that hydroxylation and dehydrogenation were the most prevalent metabolic pathways. Incubation of CDCA with Rhizopus microspores (PT2906) afforded eight undescribed compounds (6-13) alongside five known analogs (1-5) which were elucidated by HRESI-MS and NMR data. Notably, compounds 8, 12 and 13 exhibited an inhibitory effect on FXR in contrast to the FXR activation observed with CDCA in vitro assays. This study shone a light on the diverse transformations of CDCA by intestinal fungi, unveiling potential modulators of FXR activity with implications for host metabolism.

Research advances of tissue-derived extracellular vesicles in cancers.

BACKGROUND: Extracellular vesicles (EVs) can mediate cell-to-cell communication and affect various physiological and pathological processes in both parent and recipient cells. Currently, extensive research has focused on the EVs derived from cell cultures and various body fluids. However, insufficient attention has been paid to the EVs derived from tissues. Tissue EVs can reflect the microenvironment of the specific tissue and the cross-talk of communication among different cells, which can provide more accurate and comprehensive information for understanding the development and progression of diseases. METHODS: We review the state-of-the-art technologies involved in the isolation and purification of tissue EVs. Then, the latest research progress of tissue EVs in the mechanism of tumor occurrence and development is presented. And finally, the application of tissue EVs in the clinical diagnosis and treatment of cancer is anticipated. RESULTS: We evaluate the strengths and weaknesses of various tissue processing and EVs isolation methods, and subsequently analyze the significance of protein characterization in determining the purity of tissue EVs. Furthermore, we focus on outlining the importance of EVs derived from tumor and adipose tissues in tumorigenesis and development, as well as their potential applications in early tumor diagnosis, prognosis, and treatment. CONCLUSION: When isolating and characterizing tissue EVs, the most appropriate protocol needs to be specified based on the characteristics of different tissues. Tissue EVs are valuable in the diagnosis, prognosis, and treatment of tumors, and the potential risks associated with tissue EVs need to be considered as therapeutic agents.

Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke.

While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, Ncase/Ncontrol=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMTmax-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09-1.79; cIMTmean-AS: HR = 1.39, 95%CI = 1.09-1.78; cIMTmin-AS: HR = 1.32, 95%CI = 1.04-1.68). A positive global genetic correlation was observed (cIMTmax-AS: [Formula: see text]=0.23, P=9.44 × 10-5; cIMTmean-AS: [Formula: see text]=0.21, P=3.00 × 10-4; cIMTmin-AS: [Formula: see text]=0.16, P=6.30 × 10-3). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMTmax-AS: odds ratio (OR)=1.12, 95%CI=0.97-1.28; cIMTmean-AS: OR=1.09, 95%CI=0.93-1.26; cIMTmin-AS: OR=1.03, 95%CI = 0.90-1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMTmax: beta=0.07, 95%CI = 0.01-0.13; AS-cIMTmean: beta=0.08, 95%CI = 0.01-0.15; AS-cIMTmin: beta = 0.08, 95%CI = 0.01-0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.

High-Performance Thin-Layer Chromatography Coupled with Single Quadrupole: Application the Identification and Differentiation of Rehmanniae Radix and Its Different Processing Products from Raw Materials to Commercial Products.

The authentication of ingredients in formulas is crucial yet challenging, particularly for constituents with comparable compositions but vastly divergent efficacy. Rehmanniae Radix and its derivatives are extensively utilized in food supplements, which contain analogous compositions but very distinct effects. Rehmanniae Radix, also a difficult-to-detect herbal ingredient, was chosen as a case to explore a novel HPTLC-QDa MS technique for the identification of herbal ingredients in commercial products. Through systematic condition optimization, including thin layer and mass spectrometry, a stable and reproducible HPTLC-QDa MS method was established, which can simultaneously detect oligosaccharides and iridoids. Rehmannia Radix and its processed products were then analyzed to screen five markers that could distinguish between raw and prepared Rehmannia Radix. An HPTLC-QDa-SIM method was further established for formula detection by using the five markers and validated using homemade prescriptions and negative controls. Finally, this method was applied to detect raw and prepared Rehmannia Radix in 12 commercial functional products and supplements.

A prospective cohort study of exposure to household pesticide with cardiovascular diseases mortality in older adults.

OBJECTIVES: We examined the associations of self-reported exposures, and urinary metabolites related to household pesticide with cardiovascular disease (CVD) mortality in older adults based on the 2007 to 2014 waves of National Health and Nutrition Examination Survey (NHANES). METHODS: Information on application and urinary metabolites related to household pesticide exposure were collected. We estimated the risks of household pesticide exposure, urinary metabolites with subsequent incident CVD death using Cox proportional hazards regression models. The indirect effects of urinary metabolites and effect modifications were examined. RESULTS: The participants who reported exposure to household pesticide had a higher risk of incident CVD death (adjusted HR 1.40, 95% CI 1.08 to 1.81). Per 1-log10 increase in urinary N, N-diethyl-3-methylbenzamide (DEET) related to household insect repellents was associated with a higher risk of incident CVD death (adjusted HR 1.97, 95% CI 1.14 to 3.40). Urinary DEET explained 4.21% of the total association between household pesticide exposure and CVD death risk. The participants who persisted a low level of health diet exhibited pronounced CVD death risks with household pesticide exposures. CONCLUSIONS: Exposure to household pesticide, especially household insect repellents, was consistently associated with an elevated CVD death risk in older adults. A heatlhy diet could partly attenuate the associations.

The effects of Nardosinone on levodopa intervention in the treatment of Parkinson's disease.

BACKGROUND: The roots and rhizomes of Nardostachys jatamansi DC. are reported to be useful for the treatment of Parkinson's disease (PD). Previous research has also shown that Nardosinone, the main active component isolated from Nardostachys jatamansi DC., exhibits the potential to treat PD. AIM OF THE STUDY: To investigate how the effects of Nardosinone could assist levodopa in the treatment of PD, how this process changes the intestinal flora, and to explore the effective forms of Nardosinone in the intestinal flora. MATERIAL AND METHODS: We used behavioral experiments, and hematoxylin-eosin staining and immunohistochemical staining, to investigate the effects of a combination of Nardosinone and levodopa on rotenone-induced PD rats. In addition, we used LC/MS-MS to determine the levels of levodopa, 5-hydroxytryptamine, dopamine and its metabolite 3, 4-dihydroxyphenylacetic acid, and homovanillic acid, to investigate the effect of the intestinal flora on co-administration in the treatment of PD. LC/MS-MS was also used to detect the metabolites of Nardosinone on the gastrointestinal tract and intestinal flora. RESULTS: The behavioral disorders and neuronal damage associated with PD were significantly improved following the co-administration. Analysis also revealed that the co-administration increased the levels of five neurotransmitters in the striatum, plasma and feces. In vitro experiments further demonstrated that the levels of dopamine and levodopa were increased in the intestinal flora. In total, five metabolites of Nardosinone were identified. CONCLUSION: Our findings indicate that Nardosinone and its metabolites might act as a potential adjutant to enhance the efficacy of levodopa via the intestinal flora, thus expanding the therapeutic potential of the combination of Chinese and Western medicine as a treatment method for PD.

Hydrogen Spillover Phenomenon at the Interface of Metal-Supported Electrocatalysts for Hydrogen Evolution.

ConspectusHydrogen spillover, as a well-known phenomenon for thermal hydrogenation, generally involves the migration of active hydrogen on the surface of metal-supported catalysts. For thermocatalytic hydrogenation, hydrogen spillover generally takes place from metals with superiority for dissociating hydrogen molecules to supports with strong hydrogen adsorption under a H2 environment with high pressures. The former can bring high hydrogen chemical potential to largely reduce the kinetic barrier of the migration of active hydrogen species from metals to supports. At the same time, the latter can make H* migration thermodynamically spontaneous. For these reasons, hydrogen spillover is a common interfacial phenomenon occurring on metal-supported catalysts during thermocatalysis. Recently, this phenomenon has been observed for the exceptionally enhanced electrocatalytic performance for hydrogen evolution and other electrocatalytic organic synthesis. Different from hydrogen spillover for thermocatalysis under high H2 pressure, hydrogen spillover for electrocatalysis involves the migration of active hydrogen species (H*) from metals with strong hydrogen adsorption to supports with weak hydrogen adsorption, thereby suffering from a thermodynamically unfavorable process accompanied by a high kinetic barrier. Thus, the occurrence of hydrogen spillover at the electrocatalytic interface is not easy, and successful cases are rare. Understanding the underlying nature of hydrogen spillover at the electrocatalytic interface of metal-supported catalysts is critical to the rational design of advanced electrocatalysts.In this Account, we provide in-depth insights into recent advances in hydrogen spillover at the electrocatalytic interface for a significantly enhanced hydrogen evolution performance. Electron accumulation at the metal-support interface induces severe interfacial H* trapping and is recognized as the main factor in the failed hydrogen spillover. Given this, we developed two novel strategies to promote the occurrence of hydrogen spillover at the electrocatalytic interface. These strategies include (i) the introduction of ligand environments to enrich the local hydrogen coverage on metals and lower the barrier for interfacial hydrogen spillover and (ii) the minimization of work function difference between metals and supports (ΔΦ) to relieve electron accumulation and lower the kinetic barrier for hydrogen spillover. Also, we summarize the previously reported strategy of shortening the metal-support interface distance to lower the kinetic barrier for interfacial hydrogen spillover. Afterward, some criteria and methodologies are proposed to identify the hydrogen spillover phenomenon at the electrocatalytic interface. Finally, the remaining challenges and future perspectives are also discussed. Based on this Account, we aim to provide new insights into electrocatalysis, particularly the targeted control of hydrogen spillover at the electrocatalytic interface, and then to offer guidelines for the rational design of advanced electrocatalysts.

miR-29a-KLF4 signaling inhibits breast tumor initiation by regulating cancer stem cells.

Cancer stem cells (CSCs) are known for their potent ability to drive tumor initiation and recurrence, yet the molecular mechanisms regulating CSCs are still unclear. Our study found a positive correlation between increased levels of miR-29a and better survival rates in early-stage breast cancer patients, but a negative correlation in late-stage patients, suggesting a dual function of miR-29a in regulating breast cancer. Furthermore, miR-29a showed significant downregulation in the ALDH+ breast cancer stem cell population compared to non-stem cancer cells. Overexpression of miR-29a in human breast cancer cells reduced the proportion of CSCs, suppressed their ability to form mammospheres, and inhibited the expression of stemness genes SOX2, KLF4, and hTERT in vitro. Conversely, knockdown of miR-29a in breast cancer cells showed opposite effects. Tumor xenograft experiments revealed that miR-29a overexpression significantly inhibited tumorigenesis initiated by MDA-MB-231 cell transplantation in nude mice. We further demonstrated that Krüppel-like factor 4 (KLF4), a key gene that regulates cell stemness, was a direct target of miR-29a in breast cancer cells. miR-29a suppressed the expression of KLF4 at both mRNA and protein levels. Reintroduction of KLF4 into breast cancer cells rescued the miR-29a-induced CSC suppression phenotype. In summary, our study is the first to demonstrate that miR-29a-KLF4 signaling inhibits breast tumor initiation by regulating CSCs, which provides novel therapeutic targets for preventing breast tumor initiation.

Risk factors for prostate cancer: An umbrella review of prospective observational studies and mendelian randomization analyses.

BACKGROUND: The incidence of prostate cancer is increasing in older males globally. Age, ethnicity, and family history are identified as the well-known risk factors for prostate cancer, but few modifiable factors have been firmly established. The objective of this study was to identify and evaluate various factors modifying the risk of prostate cancer reported in meta-analyses of prospective observational studies and mendelian randomization (MR) analyses. METHODS AND FINDINGS: We searched PubMed, Embase, and Web of Science from the inception to January 10, 2022, updated on September 9, 2023, to identify meta-analyses and MR studies on prostate cancer. Eligibility criteria for meta-analyses were (1) meta-analyses including prospective observational studies or studies that declared outcome-free at baseline; (2) evaluating the factors of any category associated with prostate cancer incidence; and (3) providing effect estimates for further data synthesis. Similar criteria were applied to MR studies. Meta-analysis was repeated using the random-effects inverse-variance model with DerSimonian-Laird method. Quality assessment was then conducted for included meta-analyses using AMSTAR-2 tool and for MR studies using STROBE-MR and assumption evaluation. Subsequent evidence grading criteria for significant associations in meta-analyses contained sample size, P values and 95% confidence intervals, 95% prediction intervals, heterogeneity, and publication bias, assigning 4 evidence grades (convincing, highly suggestive, suggestive, or weak). Significant associations in MR studies were graded as robust, probable, suggestive, or insufficient considering P values and concordance of effect directions. Finally, 92 selected from 411 meta-analyses and 64 selected from 118 MR studies were included after excluding the overlapping and outdated studies which were published earlier and contained fewer participants or fewer instrument variables for the same exposure. In total, 123 observational associations (45 significant and 78 null) and 145 causal associations (55 significant and 90 null) were categorized into lifestyle; diet and nutrition; anthropometric indices; biomarkers; clinical variables, diseases, and treatments; and environmental factors. Concerning evidence grading on significant associations, there were 5 highly suggestive, 36 suggestive, and 4 weak associations in meta-analyses, and 10 robust, 24 probable, 4 suggestive, and 17 insufficient causal associations in MR studies. Twenty-six overlapping factors between meta-analyses and MR studies were identified, with consistent significant effects found for physical activity (PA) (occupational PA in meta: OR = 0.87, 95% CI: 0.80, 0.94; accelerator-measured PA in MR: OR = 0.49, 95% CI: 0.33, 0.72), height (meta: OR = 1.09, 95% CI: 1.06, 1.12; MR: OR = 1.07, 95% CI: 1.01, 1.15, for aggressive prostate cancer), and smoking (current smoking in meta: OR = 0.74, 95% CI: 0.68, 0.80; smoking initiation in MR: OR = 0.91, 95% CI: 0.86, 0.97). Methodological limitation is that the evidence grading criteria could be expanded by considering more indices. CONCLUSIONS: In this large-scale study, we summarized the associations of various factors with prostate cancer risk and provided comparisons between observational associations by meta-analysis and genetically estimated causality by MR analyses. In the absence of convincing overlapping evidence based on the existing literature, no robust associations were identified, but some effects were observed for height, physical activity, and smoking.

Comprehensive HRMS Screening and Risk Assessments of Aristolochic Acid Analogues in Asari Radix et Rhizoma and Related Commercial Health Products.

Aristolochic acid analogues (AAAs) are well-known toxins. We performed the first comprehensive screening on AAAs in Asari Radix et Rhizoma (underground part of Asarum heterotropoides Schmidt), the only Aristolochiaceae plant widely used in clinical practice. LC-HRMS revealed 70 trace AAAs using polygonal mass defect filtering and precursor ion list strategies, 38 of which were newly discovered in A. heterotropoides. UHPLC-QTrap-MS/MS was then utilized for quantitative/semiquantitative analysis of 26 abundant compounds. Seventeen AAAs were detected from 91 batches of A. heterotropoides and 20 AAAs from 166 consumable products. For 141 Asari-containing proprietary products, aristolactam I and aristolactam II-glucoside exhibited the widest distribution, present in 98% products. AA IVa was the most abundant, detected in 91%. Notably, 60% of the products contained AA I (0.03-0.79 ppm). The safety was assessed using linear extrapolation, permitted daily exposure, cumulative amount, and the margin of exposure. It is recommended that AA I content be limited to 3 ppm.

Integration of machine learning for developing a prognostic signature related to programmed cell death in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) presents a significant global health burden, characterized by a heterogeneous molecular landscape and various genetic and epigenetic alterations. Programmed cell death (PCD) plays a critical role in CRC, offering potential targets for therapy by regulating cell elimination processes that can suppress tumor growth or trigger cancer cell resistance. Understanding the complex interplay between PCD mechanisms and CRC pathogenesis is crucial. This study aims to construct a PCD-related prognostic signature in CRC using machine learning integration, enhancing the precision of CRC prognosis prediction. METHOD: We retrieved expression data and clinical information from the Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets. Fifteen forms of PCD were identified, and corresponding gene sets were compiled. Machine learning algorithms, including Lasso, Ridge, Enet, StepCox, survivalSVM, CoxBoost, SuperPC, plsRcox, random survival forest (RSF), and gradient boosting machine, were integrated for model construction. The models were validated using six GEO datasets, and the programmed cell death score (PCDS) was established. Further, the model's effectiveness was compared with 109 transcriptome-based CRC prognostic models. RESULT: Our integrated model successfully identified differentially expressed PCD-related genes and stratified CRC samples into four subtypes with distinct prognostic implications. The optimal combination of machine learning models, RSF + Ridge, showed superior performance compared with traditional methods. The PCDS effectively stratified patients into high-risk and low-risk groups, with significant survival differences. Further analysis revealed the prognostic relevance of immune cell types and pathways associated with CRC subtypes. The model also identified hub genes and drug sensitivities relevant to CRC prognosis. CONCLUSION: The current study highlights the potential of integrating machine learning models to enhance the prediction of CRC prognosis. The developed prognostic signature, which is related to PCD, holds promise for personalized and effective therapeutic interventions in CRC.

Tandem Electrocatalytic Alkyne Semihydrogenation over Bicomponent Catalysts through Hydrogen Spillover.

Electrocatalytic alkyne semihydrogenation under mild conditions is a more attractive approach for alkene production than industrial routes but suffers from either low production efficiency or high energy consumption. Here, we describe a tandem catalytic concept that overcomes these challenges. Component (i), which can trap hydrogen effectively, is partnered with component (ii), which can readily release hydrogen for hydrogenation, to enable efficient generation of active hydrogen on component (i) at low overpotentials and timely (i)-to-(ii) hydrogen spillover and facile desorptive hydrogenation on component (ii). We examine this concept over bicomponent palladium-copper catalysts for the production of representative 2-methyl-3-butene-2-ol (MBE) from 2-methyl-3-butyne-2-ol (MBY) and achieve a record high MBE production rate of 1.44 mmol h-1 cm-2 and a Faraday efficiency of ~88.8 % at a low energy consumption of 1.26 kWh kgMBE -1. With these catalysts, we further achieve 60 h continuous production of MBE with record high profit space.

Diastereomers of Steroidal Alkaloids with Cytotoxic Activities against Non-Small-Cell Lung Cancer from the Bulbs of Fritillaria sinica.

Eleven new steroidal alkaloids, along with nine known related compounds, were isolated from the bulbs of Fritillaria sinica. Seven pairs of diastereomers were identified, including six and four 20-deoxy cevanine-type steroidal alkaloid diastereomers with molecular weights of 413 and 415, respectively. Structures were elucidated based on spectroscopic data analysis, chemical derivatization, and single-crystal X-ray diffraction analysis. Compounds 5, 9, 11, 12, 16, and 20 exhibited significant in vitro cytotoxic activity against non-small-cell lung cancer with CC50 values from 6.8 ± 3.9 to 12 ± 5 µM.

Targeting the PHF8/YY1 axis suppresses cancer cell growth through modulation of ROS.

High levels of mitochondrial reactive oxygen species (mROS) are linked to cancer development, which is tightly controlled by the electron transport chain (ETC). However, the epigenetic mechanisms governing ETC gene transcription to drive mROS production and cancer cell growth remain to be fully characterized. Here, we report that protein demethylase PHF8 is overexpressed in many types of cancers, including colon and lung cancer, and is negatively correlated with ETC gene expression. While it is well known to demethylate histones to activate transcription, PHF8 demethylates transcription factor YY1, functioning as a co-repressor for a large set of nuclear-coded ETC genes to drive mROS production and cancer development. In addition to genetically ablating PHF8, pharmacologically targeting PHF8 with a specific chemical inhibitor, iPHF8, is potent in regulating YY1 methylation, ETC gene transcription, mROS production, and cell growth in colon and lung cancer cells. iPHF8 exhibits potency and safety in suppressing tumor growth in cell-line- and patient-derived xenografts in vivo. Our data uncover a key epigenetic mechanism underlying ETC gene transcriptional regulation, demonstrating that targeting the PHF8/YY1 axis has great potential to treat cancers.

Social support and cognitive activity and their associations with incident cognitive impairment in cognitively normal older adults.

OBJECTIVES: To explore the associations of social support, and cognitive activity with cognitive impairment incidence, and further examine the mediation effect of cognitive activity on the association between social support and cognitive impairment incidence based on a nationwide elderly Chinese cohort. METHODS: We collected the participants from an ongoing cohort of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). A total of 9394 older adults aged 65 or more years and free of cognitive impairment who participated in the CLHLS between 2008 and 2018 were included. The information on social support and cognitive activity was collected through a questionnaire. The incident cognitive impairment cases were identified through the Mini-Mental State Examination scale (MMSE). Cox proportional hazard regression models were conducted to calculate the hazard ratios (HRs) and 95% confidence interval (CI) of social support and cognitive activity associated with cognitive impairment. We used casual mediation models to assess the indirect association of cognitive activities underlying the association between social support and cognitive impairment. RESULTS: The adjusted HRs (95% CI) of incident cognitive impairment were 0.956 (0.932 to 0.980), and 0.895 (0.859 to 0.933) associated with per 1 score increase in social support and cognitive activity score, respectively. Better adherence to social support was associated with a higher cognitive activity score (adjusted ß = 0.046, 95% CI[0.032-0.060]). The baseline cognitive activity, as well as the mean cognitive activity at baseline and during the first follow-up wave, mediate the association between social support and the incidence of cognitive impairment, accounting for 11.4% and 12.6% of the total association, respectively. The participants who were aged 80 years or older, or those with mild daily functional limitations gained more benefits in the development of cognitive activity related to social support, leading to a reduction in the risks of cognitive impairment. CONCLUSION: The results of this nationwide cohort provide consistent evidence linking social support, and cognitive activity to reduced risk of subsequent cognitive impairment incidence. These findings provide additional evidence to inform the social strategies to prevent cognitive impairment incidence in elderly people.

Epidemiological and Genetic Analyses of Schizophrenia and Breast Cancer.

BACKGROUND AND HYPOTHESIS: While the phenotypic association between schizophrenia and breast cancer has been observed, the underlying intrinsic link is not adequately understood. We aim to conduct a comprehensive interrogation on both phenotypic and genetic relationships between schizophrenia and breast cancer. STUDY DESIGN: We first used data from UK Biobank to evaluate a phenotypic association and performed an updated meta-analysis incorporating existing cohort studies. We then leveraged genomic data to explore the shared genetic architecture through a genome-wide cross-trait design. STUDY RESULTS: Incorporating results of our observational analysis, meta-analysis of cohort studies suggested a significantly increased incidence of breast cancer among women with schizophrenia (RR = 1.30, 95% CIs = 1.14-1.48). A positive genomic correlation between schizophrenia and overall breast cancer was observed (rg = 0.12, P = 1.80 × 10-10), consistent across ER+ (rg  = 0.10, P = 5.74 × 10-7) and ER- subtypes (rg = 0.09, P = .003). This was further corroborated by four local signals. Cross-trait meta-analysis identified 23 pleiotropic loci between schizophrenia and breast cancer, including five novel loci. Gene-based analysis revealed 27 shared genes. Mendelian randomization demonstrated a significantly increased risk of overall breast cancer (OR = 1.07, P = 4.81 × 10-10) for genetically predisposed schizophrenia, which remained robust in subgroup analysis (ER+: OR = 1.10, P = 7.26 × 10-12; ER-: OR = 1.08, P = 3.50 × 10-6). No mediation effect and reverse causality was found. CONCLUSIONS: Our study demonstrates an intrinsic link underlying schizophrenia and breast cancer, which may inform tailored screening and management of breast cancer in schizophrenia.

Thyroid-stimulating hormone-thyroid hormone signaling contributes to circadian regulation through repressing clock2/npas2 in zebrafish.

Thyroid-stimulating hormone (TSH) is important for the thyroid gland, development, growth, and metabolism. Defects in TSH production or the thyrotrope cells within the pituitary gland cause congenital hypothyroidism (CH), resulting in growth retardation and neurocognitive impairment. While human TSH is known to display rhythmicity, the molecular mechanisms underlying the circadian regulation of TSH and the effects of TSH-thyroid hormone (TH) signaling on the circadian clock remain elusive. Here we show that TSH, thyroxine (T4), triiodothyronine (T3), and tshba display rhythmicity in both larval and adult zebrafish and tshba is regulated directly by the circadian clock via both E'-box and D-box. Zebrafish tshba-/- mutants manifest congenital hypothyroidism, with the characteristics of low levels of T4 and T3 and growth retardation. Loss or overexpression of tshba alters the rhythmicity of locomotor activities and expression of core circadian clock genes and hypothalamic-pituitary-thyroid (HPT) axis-related genes. Furthermore, TSH-TH signaling regulates clock2/npas2 via the thyroid response element (TRE) in its promoter, and transcriptome analysis reveals extensive functions of Tshba in zebrafish. Together, our results demonstrate that zebrafish tshba is a direct target of the circadian clock and in turn plays critical roles in circadian regulation along with other functions.