Human-like adrenal features in Chinese tree shrews revealed by multi-omics analysis of adrenal cell populations and steroid synthesis

The Chinese tree shrew(Tupaia belangeri chinensis)has emerged as a promising model for investigating adrenal steroid synthesis,but it is unclear whether the same cells produce steroid hormones and whether their production is regulated in the same way as in humans.Here,we comprehensively mapped the cell types and pathways of steroid metabolism in the adrenal gland of Chinese tree shrews using single-cell RNA sequencing,spatial transcriptome analysis,mass spectrometry,and immunohistochemistry.We compared the transcriptomes of various adrenal cell types across tree shrews,humans,macaques,and mice.Results showed that tree shrew adrenal glands expressed many of the same key enzymes for steroid synthesis as humans,including CYP11B2,CYP11B1,CYB5A,and CHGA.Biochemical analysis confirmed the production of aldosterone,cortisol,and dehydroepiandrosterone but not dehydroepiandrosterone sulfate in the tree shrew adrenal glands.Furthermore,genes in adrenal cell types in tree shrews were correlated with genetic risk factors for polycystic ovary syndrome,primary aldosteronism,hypertension,and related disorders in humans based on genome-wide association studies.Overall,this study suggests that the adrenal glands of Chinese tree shrews may consist of closely related cell populations with functional similarity to those of the human adrenal gland.Our comprehensive results(publicly available at http://gxmujyzmolab.cn:16245/scAGMap/)should facilitate the advancement of this animal model for the investigation of adrenal gland disorders.

Glycolytic potential enhanced by blockade of pyruvate influx into mitochondria sensitizes prostate cancer to detection and radiotherapy

Objective:This study aimed to evaluate the effects of mitochondrial pyruvate carrier(MPC)blockade on the sensitivity of detection and radiotherapy of prostate cancer(PCa).Methods:We investigated glycolysis reprogramming and MPC changes in patients with PCa by using metabolic profiling,RNASeq,and tissue microarrays.Transient blockade of pyruvate influx into mitochondria was observed in cellular studies to detect its different effects on prostate carcinoma cells and benign prostate cells.Xenograft mouse models were injected with an MPC inhibitor to evaluate the sensitivity of 18F-fluorodeoxyglucose positron emission tomography with computed tomography and radiotherapy of PCa.Furthermore,the molecular mechanism of this different effect of transient blockage towards benign prostate cells and prostate cancer cells was studied in vitro.Results:MPC was elevated in PCa tissue compared with benign prostate tissue,but decreased during cancer progression.The transient blockade increased PCa cell proliferation while decreasing benign prostate cell proliferation,thus increasing the sensitivity of PCa cells to 18F-PET/CT(SUVavg,P=0.016;SUVmax,P=0.03)and radiotherapy(P<0.01).This differential effect of MPC on PCa and benign prostate cells was dependent on regulation by a VDAC1-MPC-mitochondrial homeostasis-glycolysis pathway.Conclusions:Blockade of pyruvate influx into mitochondria increased glycolysis levels in PCa but not in non-carcinoma prostate tissue.This transient blockage sensitized PCa to both detection and radiotherapy,thus indicating that glycolytic potential is a novel mechanism underlying PCa progression.The change in the mitochondrial pyruvate influx caused by transient MPC blockade provides a critical target for PCa diagnosis and treatment.

Causal Relationship Between Complement C3,C4,and Nonalcoholic Fatty Liver Disease:Bidirectional Mendelian Randomization Analysis

The complement system is activated during the development of nonalcoholic fatty liver disease(NAFLD).We aimed to evaluate the causal relationship between serum C3 and C4 levels and NAFLD.After exclusion criteria,a total of 1600 Chinese Han men from the Fangchenggang Area Male Health and Examination Survey cohort were enrolled in cross-sectional analysis,while 572 participants were included in the longitudinal analysis(average follow-up of 4 years).We performed a bidirectional Mendelian randomization(MR)analysis using two C3-related,eight C4-related and three NAFLD-related gene loci as instrumental variables to evaluate the causal associations between C3,C4,and NAFLD risk in cross-sectional analysis.Per SD increase in C3 levels was significantly associated with higher risk of NAFLD(OR=1.65,95%CI 1.40,1.94)in cross-sectional analysis while C4 was not(OR=1.04,95%CI 0.89,1.21).Longitudinal analysis produced similar results(HR_(C3)=1.20,95%CI 1.02,1.42;HR_(C4)=1.10,95%CI 0.94,1.28).In MR analysis,there were no causal relation-ships for genetically determined C3 levels and NAFLD risk using unweighted or weighted GRS_C3(β_(E_unweighted)=−0.019,95%CI−0.019,−0.019,p=0.202;β_(E_weighted)=−0.019,95%CI−0.019,−0.019,p=0.322).Conversely,serum C3 lev-els were significantly effected by the genetically determined NAFLD(β_(E_unweighted)=0.020,95%CI 0.020,0.020,p=0.004;β_(E_weighted)=0.021,95%CI 0.020,0.021,p=0.004).Neither the direction from C4 to NAFLD nor the one from NAFLD to C4 showed significant association.Our results support that the change in serum C3 levels but not C4 levels might be caused by NAFLD in Chinese Han men.

Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study

Exposures to copper have become a health concern.We aim to explore the broad clinical effects of blood copper concentrations.A total of 376,346 Caucasian subjects were enrolled.We performed a Mendelian randomization and phenome-wide association study(MR-PheWAS)to evaluate the causal association between copper and a wide range of outcomes in UK Biobank,and we constructed a protein-protein interaction network.We found association between blood copper concentrations and five diseases in the overall population and nine diseases in male.MR analysis implicated a causal role of blood copper in five diseases(overall population),including prostate cancer(OR=0.87,95%CI 0.77-0.98),malignant and unknown neoplasms of the brain and nervous system(OR=0.58,95%CI 0.38-0.89),and hypertension(OR=0.94,95%CI 0.90-0.98),essential hypertension(OR=0.94,95%CI 0.90-0.98)and cancer of brain and nervous system(OR=0.63,95%CI 0.41-0.98).For male,except for dysphagia being newly associated with blood copper(OR=1.39,95%CI 1.18-1.63),other MR results were consistent with the overall population.In addition,the PPI network showed possible relationship between blood copper and four outcomes,namely brain cancer,prostate cancer,hypertension,and dysphagia.Blood copper may have causal association with prostate cancer,malignant and unknown neoplasms of the brain and nervous system,hypertension,and dysphagia.Considering that copper is modifiable,exploring whether regulation of copper levels can be used to optimize health outcomes might have public health importance.

Single-cell transcriptomics reveals cell type diversity of human prostate

Extensive studies have been performed to describe the phenotypic changes occurring during malignant transformation of the prostate.However,the cell types and associated changes that contribute to the development of prostate diseases and cancer remain elusive,largely due to the heterogeneous composition of prostatic tissues.Here,we conduct a comprehensive evaluation of four human prostate tissues by singlecell RNA sequencing(sc RNA-seq)to analyze their cellular compositions.We identify 18 clusters of cell types,each with distinct gene expression profiles and unique features;of these,one cluster of epithelial cells(Ep)is found to be associated with immune function.In addition,we characterize a special cluster of fibroblasts and aberrant signaling changes associated with prostate cancer(PCa).Moreover,we provide insights into the epithelial changes that occur during the cellular senescence and aging.These results expand our understanding of the unique functional associations between the diverse prostatic cell types and the contributions of specific cell clusters to the malignant transformation of prostate tissues and PCa development.