Metformin decelerates aging clock in male monkeys.

In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.

HALL: a comprehensive database for human aging and longevity studies.

Diverse individuals age at different rates and display variable susceptibilities to tissue aging, functional decline and aging-related diseases. Centenarians, exemplifying extreme longevity, serve as models for healthy aging. The field of human aging and longevity research is rapidly advancing, garnering significant attention and accumulating substantial data in recent years. Omics technologies, encompassing phenomics, genomics, transcriptomics, proteomics, metabolomics and microbiomics, have provided multidimensional insights and revolutionized cohort-based investigations into human aging and longevity. Accumulated data, covering diverse cells, tissues and cohorts across the lifespan necessitates the establishment of an open and integrated database. Addressing this, we established the Human Aging and Longevity Landscape (HALL), a comprehensive multi-omics repository encompassing a diverse spectrum of human cohorts, spanning from young adults to centenarians. The core objective of HALL is to foster healthy aging by offering an extensive repository of information on biomarkers that gauge the trajectory of human aging. Moreover, the database facilitates the development of diagnostic tools for aging-related conditions and empowers targeted interventions to enhance longevity. HALL is publicly available at https://ngdc.cncb.ac.cn/hall/index.

Lineage Landscape: a comprehensive database that records lineage commitment across species.

Commitment to specific cell lineages is critical for mammalian embryonic development. Lineage determination, differentiation, maintenance, and organogenesis result in diverse life forms composed of multiple cell types. To understand the formation and maintenance of living individuals, including human beings, a comprehensive database that integrates multi-omic information underlying lineage differentiation across multiple species is urgently needed. Here, we construct Lineage Landscape, a database that compiles, analyzes and visualizes transcriptomic and epigenomic information related to lineage development in a collection of species. This landscape draws together datasets that capture the ongoing changes in cell lineages from classic model organisms to human beings throughout embryonic, fetal, adult, and aged stages, providing comprehensive, open-access information that is useful to researchers of a broad spectrum of life science disciplines. Lineage Landscape contains single-cell gene expression and bulk transcriptomic, DNA methylation, histone modifications, and chromatin accessibility profiles. Using this database, users can explore genes of interest that exhibit dynamic expression patterns at the transcriptional or epigenetic levels at different stages of lineage development. Lineage Landscape currently includes over 6.6 million cells, 15 million differentially expressed genes and 36 million data entries across 10 species and 34 organs. Lineage Landscape is free to access, browse, search, and download at http://data.iscr.ac.cn/lineage/#/home.

A dual-functional fluorescent biosensor based on enzyme-involved catalytic hairpin assembly for the detection of APE1 and miRNA-21.

Both apurinic/apyrimidinic endonuclease 1 (APE1) and microRNA-21 (miRNA-21) have been reported to be related to tumors, enabling them to be the biomarkers of several cancers. This has led to the development of various biosensors to detect APE1 or miRNA-21. However, biosensors that focus on single target detection are subject to low accuracy. In this work, a fluorescent biosensor based on enzyme-involved catalytic hairpin assembly (CHA) for the detection of APE1 and miRNA-21 was developed, aimed at improving the accuracy of early-phase diagnosis of cancers. Two hairpin structured DNA probes (H1 and H2) were utilized to concatenate the enzyme-assisted circuit and CHA circuit in the system. The stem of H1 with a blunt end was modified with an AP site, while H2 was modified with 6-FAM at the 5' terminal and Dabcyl at the 3' terminal. In the presence of APE1, H1 was cleaved from the AP site to expose the toehold sequence. Then, miRNA-21 bound with the toehold sequence to initiate the CHA reaction between H1 and H2. The assembled product of CHA triggered the 6-FAM of H2 at a distance from Dabcyl, which recovered the fluorescence signal. It is worth noting that only under the co-stimulation of APE1 and miRNA-21 can the fluorescence signal be detected, indicating that the biosensor could work as an AND logic gate. The proposed dual-functional biosensor achieved a limit of detection (LOD) of 0.016 U mL-1 for APE1 and 0.25 nM for miRNA-21 and APE1, respectively, and also exhibits good selectivity and stability for the two biomarkers. Thus, the biosensor has great potential to be applied as a new platform for cancer diagnosis.

IL-1ß functionally attenuates ABCG2 and PDZK1 expression in HK-2 cells partially through NF-ĸB activation.

Long-standing untreated hyperuricemia could lead to gout. Several recent studies have demonstrated a significant decrease of serum urate during acute gout attack, which is an aseptic inflammation process focusing on IL-1ß. However, how IL-1ß, by itself, alters the expression and the functional activity of urate transporters in renal tubular epithelial cells is still unclear. Herein, we revealed that IL-1ß could attenuate the mRNA and protein levels of ABCG2, a major urate efflux pump, in HK-2 cells by real-time PCR and Western-blot assays. Moreover, using an ABCG2 specific inhibitor and a new sensitive and specific detection system, it was found that IL-1ß also reduced the ABCG2 transporter activities. Incubation with specific inhibitors of the NF-κB pathway partly dampened the inhibitory effect of IL-1ß on ABCG2, indicating that IL-1ß reduced the ABCG2 expression partially through the NF-ĸB pathway. Furthermore, the decreased expression of PDZK1 induced by IL-1ß, which is dependent on the NF-κB pathway, could account for the imbalance between the functions and expressions of ABCG2 on this status. These findings demonstrated a new role for IL-1ß, whereby it leads to the inhibition of ABCG2 in renal tubular epithelial cells; this new role probably does not encompass its involvement in the process of renal urate excretion mediated by inflammation. Therefore, other regulation mechanisms of urate reabsorption in renal tubular epithelial cells deserve to be examined in further studies.

Meta-analysis: compared with anti-CCP and rheumatoid factor, could anti-MCV be the next biomarker in the rheumatoid arthritis classification criteria?

Background Previous reviews of the diagnosis for rheumatoid arthritis (RA) have not compared anti-mutated citrullinated vimentin (MCV) with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) in respect of sensitivity, specificity and the area under the curve (AUC) against disease controls for differential diagnosis. This meta-analysis aims to evaluate the value of anti-MCV in the diagnosis for RA, the combined sensitivity of anti-MCV and anti-CCP, and certain clinical characteristics related to the performance of anti-MCV. Methods Medline, Embase, Cochrane Library and Web of Science were searched for articles published up to 25 August 2018. A total of 33 studies including 6044 RA patients and 5094 healthy or disease controls achieved inclusive criteria. QUADAS-2 was applied to evaluate the quality of the included studies. The bivariate random effects model was employed in primary data synthesis to evaluate the diagnostic performance. Results The sensitivity of anti-MCV, anti-CCP and RF in RA diagnosis against a disease control group was 0.71, 0.71, 0.77, with the specificity of 0.89, 0.95, 0.73, and the AUC of the SROC of 0.89, 0.95, 0.82, respectively. The predesign of the primary study and diagnostic criteria were statistically significant as sources of heterogeneity. Anti-MCV and anti-CCP tests demonstrated a sensitivity of 0.77 when performed in parallel, with a sensitivity of 0.60 when performed in series; whereas, the combination of anti-MCV and RF presented a sensitivity of 0.64 when used in series. Conclusions Anti-MCV demonstrates comparable diagnostic value to anti-CCP and RF, thus it can be an effective diagnostic marker for RA and may be written into the next authoritative criteria.

Extraperiosteal segmental excision for osteofibrous dysplasia of tibia with reconstruction by liquid nitrogen-treated recycled autograft.

BACKGROUND: Osteofibrous dysplasia usually progresses until ten years of age and occasionally regresses spontaneously after puberty. Patients with osteofibrous dysplasia usually require close observation. Surgery is an option considered only for extensive, deforming lesions and those with pathological fractures and rapid progression prior to puberty. If surgery is indicated, the traditional intra-lesional curettage or subperiosteal resection usually leads to high recurrence. Hence, extraperiosteal wide excision and various methods of reconstruction after resection have been advocated for this lesion. We reviewed the clinical results of patients managed with extraperiosteal segmental excision and reconstruction by liquid nitrogen-treated tumor-bearing autograft combined with allograft. METHODS: From January 2010 to December 2014, twelve patients with final diagnosis of tibial osteofibrous dysplasia were studied retrospectively. All these patients were treated with extraperiosteal segmental excision and reconstruction by liquid nitrogen-treated tumor-bearing autograft combined with allograft. RESULTS: The patient group consisted of 5 males and 7 females, with a median age of 13 years (6-24 years). 3 lesions were located in left tibia and 9 in right. The median length of resected segment was 8 cm (5-11 cm). The patients were followed for 36-84 months (median 52 months). Follow-up radiographs showed that the median time for complete union of the grafted bone was 9 months (6-15 months). There was no evidence of recurrence. All patients had full range of motion in the knee and ankle joints after surgery. CONCLUSIONS: Extraperiosteal segmental excision for osteofibrous dysplasia of tibia with reconstruction by liquid nitrogen-treated recycled autograft and allograft is a good surgical option to prevent recurrence and fill bone defects in this rare lesion.

Hybrid Molecular Container Based on Glycoluril and Triptycene: Synthesis, Binding Properties, and Triggered Release.

We designed and synthesized a "hybrid" molecular container 1, which is structurally related to both cucurbit[n]uril (CB[n]) and pillar[n]arene type receptors. Receptor 1 was fully characterized by 1 H NMR, 13 C NMR, IR, MS and X-ray single crystal diffraction. The self-association behavior, host-guest recognition properties of 1, and the [salt] dependence of Ka were investigated in detail by 1 H NMR and isothermal titration calorimetry (ITC). Optical transmittance and TEM measurements provide strong evidence that receptor 1 undergoes co-assemble with amphiphilic guest C10 in water to form supramolecular bilayer vesicles (diameter 25.6±2.7 nm, wall thickness ≈3.5 nm) that can encapsulate the hydrophilic anticancer drug doxorubicin (DOX) and the hydrophobic dye Nile red (NR). The release of encapsulated DOX or NR from the vesicles can be triggered by hexamethonium (8 c) or spermine (10) which leads to the disruption of the supramolecular vesicles.

A glycoluril dimer-triptycene hybrid receptor: synthesis and molecular recognition properties.

The strategic combination of the methylene bridged glycoluril dimer and triptycene skeletons delivers acyclic water soluble hybrid receptor 1 which is analogous to cucurbit[6]uril. The molecular recognition properties of host 1 toward hydrophobic cationic guests are investigated in detail by a combination of 1H NMR spectroscopy and isothermal titration calorimetry (ITC) studies. The fluorescence emission of 1 can be selectively and efficiently quenched upon the formation of 1·26 and 1·28 complexes.

Blurring the Lines between Host and Guest: A Chimeric Receptor Derived from Cucurbituril and Triptycene.

We report the synthesis and X-ray crystal structure of a cucurbituril-triptycene chimeric receptor (1). Host 1 binds to guests typical of CB[6]-CB[8], but also binds to larger guests such as blue box (20) and the Fujita square (22). Intriguingly, the geometries of the 1⋅20 and 1⋅22 complexes blur the lines between host and guest in that both components fulfill both roles within each complex. The fluorescence output of 1 is fully quenched by the formation of complexes with pyridinium-derived guests.

Cucurbit[7]uril as a Supramolecular Artificial Enzyme for Diels-Alder Reactions.

The ability to mimic the activity of natural enzymes using supramolecular constructs (artificial enzymes) is a vibrant scientific research field. Herein, we demonstrate that cucurbit[7]uril (CB[7]) can catalyse Diels-Alder reactions for a number of substituted and unreactive N-allyl-2-furfurylamines under biomimetic conditions, without the need for protecting groups, yielding powerful synthons in previously unreported mild conditions. CB[7] rearranges the substrate in a highly reactive conformation and shields it from the aqueous environment, thereby mimicking the mode of action of a natural Diels-Alderase. These findings can be directly applied to the phenomenon of product inhibition observed in natural Diels-Alderase enzymes, and pave the way toward the development of novel, supramolecular-based green catalysts.

Glycoluril-Derived Molecular Clips are Potent and Selective Receptors for Cationic Dyes in Water.

Molecular clip 1 remains monomeric in water and engages in host-guest recognition processes with suitable guests. We report the Ka values for 32 1⋅guest complexes measured by 1 H NMR, UV/Vis, and fluorescence titrations. The cavity of 1 is shaped by aromatic surfaces of negative electrostatic potential and therefore displays high affinity and selectivity for planar and cationic aromatic guests that distinguishes it from CB[n] receptors that prefer aliphatic over aromatic guests. Electrostatic effects play a dominant role in the recognition process whereby ion-dipole interactions may occur between ammonium ions and the C=O groups of 1, between the SO3- groups of 1 and pendant cationic groups on the guest, and within the cavity of 1 by cation-π interactions. Host 1 displays a high affinity toward dicationic guests with large planar aromatic surfaces (e.g. naphthalene diimide NDI+ and perylene diimide PDI+) and cationic dyes derived from acridine (e.g. methylene blue and azure A). The critical importance of cation-π interactions was ascertained by a comparison of analogous neutral and cationic guests (e.g. methylene violet vs. methylene blue; quinoline vs. N-methylquinolinium; acridine vs. N-methylacridinium; neutral red vs. neutral red H+ ) the affinities of which differ by up to 380-fold. We demonstrate that the high affinity of 1 toward methylene blue (Ka =3.92×107 m-1 ; Kd =25 nm) allows for the selective sequestration and destaining of U87 cells stained with methylene blue.

Uptake of Hydrocarbons in Aqueous Solution by Encapsulation in Acyclic Cucurbit[n]uril-Type Molecular Containers.

The ability of two water-soluble acyclic cucurbit[n]uril (CB[n]) type containers, whose hydrophobic cavity is defined by a glycoluril tetramer backbone and terminal aromatic (benzene, naphthalene) sidewalls, to act as solubilizing agents for hydrocarbons in water is described. (1) H NMR spectroscopy studies and phase-solubility diagrams establish that the naphthalene-walled container performs as well as, or better than, CB[7] and CB[8] in promoting the uptake of poorly soluble hydrocarbons into aqueous solution through formation of host-hydrocarbon complexes. The naphthalene-walled acyclic CB[n] container is able to extract large hydrocarbons from crude oil into aqueous solution.

On the nature of the transition state characterizing gated molecular encapsulations.

Gated molecular encapsulations, with baskets of type 1, are postulated to occur by the mechanism in which solvent molecule penetrates the inner space of 1, through one of its apertures, while the residing guest simultaneously departs the cavity. In the transition state of the exchange, three pyridine-based gates are proposed to assume an open position with both incoming solvent and departing guest molecules interacting with the concave surface of the host. The More O'Ferrall-Jencks diagram and linear free energy relationships (LFERs) suggest a more advanced departure of the guest when bigger solvents partake in the displacement.

Numerical studies on lutetium isotopic selective photoionization based on a three-step ionization scheme.

Numerical studies of lutetium selective photoionization have been carried out based on a three-step photoionization scheme, 5d6s2 2D3/2 â†’ 5d6s6p4Fo5/2 â†’ 5d6s7s4D3/2 → (53,375 cm-1)1/2 → Lu+, by the density matrix theory. Atomic hyperfine structures and magnetic sublevels are considered in our photoionization dynamics model. To examine the effectiveness of this model, the simulated 176Lu ion strengths are compared with the experimental results, and the simulated excitation cross sections of 176Lu excitation channels are compared with the analytical and experimental results. Semi-quantitative agreements are acquired for these two cases. On this basis, selective photoionization processes of two lutetium isotopes are simulated and discussed. Considering the ionization probability and abundance of target isotope, the 8.5-9.5-8.5 two-step excitation channel is optimal for 176Lu enrichment from natural lutetium. The influences of laser parameters and atomic Doppler broadening are presented numerically and optimization excitation conditions are identified. For the co-propagating excitation lasers, extra-narrow laser bandwidth (at the magnitude of 0.1 GHz) and atomic Doppler broadening (smaller than 0.3 GHz) is required. A new time-delayed configuration is proposed to implement multiple counter-propagating laser exposures for high target isotope abundance at the larger atomic Doppler broadening.

Endovascular Interventional Procedure is a Significant Risk Factor of Postsurgical Gout: A Retrospective Cohort Study.

INTRODUCTION: Surgery is a risk factor for flares in people with gout. However, gout flares after endovascular interventional procedures are not well understood. The aim of this study was to evaluate the clinical features and risk factors for gout flare that develop during the postsurgical period including endovascular procedures. METHODS: We enrolled 222 patients with gout who developed postsurgical gout and 196 controls who had histories of gout but did not develop gout flares after surgery within 20 days. Clinical characteristics of patients who developed a postsurgical gout flare were compared with the controls. RESULTS: The rate of endovascular interventional procedures was higher (38.74% vs. 13.48%, P < 0.001) in the flare group than in the no-flare group and lower in orthopedic surgery (13.96% vs. 41.84%, P < 0.001). The Cox model showed that endovascular interventional procedures (HR, hazard ratio 1.752; 95% CI, confidence interval 1.126-2.724, P = 0.013) and presurgical uric acid levels of ≥ 7 mg/dl (HR 1.489; 95% CI 1.081-2.051, P = 0.015) were significantly associated with increased risks of postsurgical gout flare, and taking colchicine before surgery were significantly associated with decreased risk of postsurgical gout flare (HR 0.264; 95% CI 0.090-0.774, P = 0.015). There was no significant difference in the types of endovascular interventional procedures between the flare group and the no-flare group. CONCLUSIONS: Patients with a history of gout should be more alert to recurrence gout flares after endovascular interventional procedures. Adequate presurgical control of serum uric acid levels and/or prophylactic treatment with colchicine will help prevent gout flares during the postsurgical period.

Dietary anthocyanin is associated with a lower prevalence of hyperuricemia independently of metabolic syndrome among females: Results from NHANES 2007-2010 and 2017-2018.

OBJECTIVE: Known for anti-inflammatory and antioxidant properties, flavonoid has phytoestrogenic effects, but it is unclear whether its role in hyperuricemia and metabolic syndrome (MetS) differs by gender. Moreover, given the strong association between hyperuricemia and MetS, we aimed to explore whether flavonoid is a protective factor for hyperuricemia, independently of MetS, in different genders. METHODS: Data for 2007-2010 and 2017-2018 were obtained from the National Health and Nutrition Examination Survey (NHANES) and the Food and Nutrient Database for Dietary Studies (FNDDS). To assess the association among flavonoid, hyperuricemia, and MetS, multivariate logistic regression and subgroup analyses were conducted. Besides, to investigate whether the association between flavonoid and hyperuricemia was independent of MetS, multivariate logistic regression models were further conducted to explore the association between flavonoid and MetS among females with hyperuricemia and to investigate the association between flavonoid and hyperuricemia among females after excluding MetS. RESULT: Among 5356 females, anthocyanin intake was inversely associated with the prevalence of hyperuricemia (Q4 vs. Q1: OR 0.49, 95% CI 0.31 to 0.76), and MetS (Q4 vs. Q1: OR 0.68, 95% CI 0.50 to 0.93). Furthermore, subgroup analyses showed the beneficial association between anthocyanin and hyperuricemia among females aged 40 to 59 years and menopausal. However, among 5104 males, no significant association was observed after adjustment for covariates (Q4 vs. Q1: OR 0.81, 95% CI 0.56 to 1.18). While in 372 females with hyperuricemia, no significant association was found between MetS and anthocyanin (Q4 vs. Q1: OR 0.88, 95% CI 0.31 to 2.49). Meanwhile, among 3335 females after excluding MetS, there was still a significant association between anthocyanin and a lower prevalence of hyperuricemia (Q4 vs. Q1: OR 0.38, 95% CI 0.17 to 0.85). CONCLUSION: Dietary anthocyanin is associated with a lower prevalence of hyperuricemia independently of MetS among females. Foods rich in anthocyanin should be emphasized for females, especially those aged 40 to 59 years and menopausal, which may be of potential significance in the prevention of hyperuricemia.

SHMT as a Potential Therapeutic Target for Renal Cell Carcinoma.

BACKGROUND: Serine hydroxymethyltransferase (SHMT) is a serine-glycine-one-carbon metabolic enzyme in which SHMT1 and SHMT2 encode the cytoplasmic and mitochondrial isoenzymes, respectively. SHMT1 and SHMT2 are key players in cancer metabolic reprogramming, and thus are attractive targets for cancer therapy. However, the role of SHMT in patients with renal cell carcinoma (RCC) has not been fully elucidated. We aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of SHMT1 and SHMT2 in patients with kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), and kidney renal papillary cell carcinoma (KIRP); elucidate the association between SHMT expression and RCC; and identify potential new targets for clinical RCC treatment. METHODS: Several online databases were used for the analysis, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. RESULTS: SHMT1 and SHMT2 transcript levels were significantly down- and upregulated, respectively, in patients with KICH, KIRC, and KIRP, based on sample type, individual cancer stage, sex, and patient age. Compared to men, women with KIRC and KIRP showed significantly up- and downregulated SHMT1 transcript levels, respectively. However, SHMT2 transcript levels were significantly upregulated in the patients mentioned above. KIRC and KIRP patients with high SHMT1 expression had longer survival periods than those with low SHMT1 expression. In patients with KIRC, the findings were similar to those mentioned above. However, in KICH patients, the findings were the opposite regarding SHMT2 expression. SHMT1 versus SHMT2 were altered by 9% versus 3% (n = 66 KICH patients), 4% versus 4% (n = 446 KIRC patients), and 6% versus 7% (n = 280 KIRP patients). SHMT1 versus SHMT2 promoter methylation levels were significantly up- and downregulated in patients with KIRP versus KIRC and KIRP, respectively. SHMT1, SHMT2, and their neighboring genes (NG) formed a complex network of interactions. The molecular functions of SHMT1 and its NG in patients with KICH, KIRC, and KIRP, included clathrin adaptor, metalloendopeptidase, and GTPase regulator activities; lipid binding, active transmembrane transporter activity, and lipid transporter activity; and type I interferon receptor binding, integrin binding, and protein heterodimerization, respectively. Their respective Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were involved in lysosome activity, human immunodeficiency virus 1 infection, and endocytosis; coronavirus disease 2019 and neurodegeneration pathways (multiple diseases); and RIG-I-like receptor signaling pathway, cell cycle, and actin cytoskeleton regulation. The molecular functions of SHMT2 and its NG in patients with KICH, KIRC, and KIRP included cell adhesion molecule binding and phospholipid binding; protein domain-specific binding, enzyme inhibitor activity, and endopeptidase activity; and hormone activity, integrin binding, and protein kinase regulator activity, respectively. For patients with KIRC versus KIRP, the KEGG pathways were involved in cAMP and calcium signaling pathways versus microRNAs (MiRNAs) in cancer cells and neuroactive ligand-receptor interactions, respectively. We identified the key transcription factors of SHMT1 and its NG. CONCLUSIONS: SHMT1 and SHMT2 expression levels were different in patients with RCC. SHMT1 and SHMT2 may be potential therapeutic and prognostic biomarkers in these patients. Transcription factor (MYC, STAT1, PPARG, AR, SREBF2, and SP3) and miRNA (miR-17-5P, miR-422, miR-492, miR-137, miR-30A-3P, and miR-493) regulations may be important strategies for RCC treatment.

Systematic analysis of the BET family in adrenocortical carcinoma: The expression, prognosis, gene regulation network, and regulation targets.

Background: Bromodomain and extracellular terminal (BET) family (including BRD2, BRD3, and BRD4) is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Currently, more than 30 targeted inhibitors have shown significant inhibitory effects against various tumors in preclinical and clinical trials. However, the expression levels, gene regulatory networks, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in adrenocortical carcinoma (ACC) have not been fully elucidated. Therefore, this study aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in patients with ACC, and elucidated the association between BET family expression and ACC. We also provided useful information on BRD2, BRD3, and BRD4 and potential new targets for the clinical treatment of ACC. Methods: We systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of BRD2, BRD3, and BRD4 in ACC using multiple online databases, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. Results: The expression levels of BRD3 and BRD4 were significantly upregulated in ACC patients at different cancer stages. Moreover, the expression of BRD4 was significantly correlated with the pathological stage of ACC. ACC patients with low BRD2, BRD3, and BRD4 expressions had longer survival than patients with high BRD2, BRD3, and BRD4 expressions. The expression of BRD2, BRD3, and BRD4 was altered by 5%, 5%, and 12% in 75 ACC patients, respectively. The frequency of gene alterations in the 50 most frequently altered BRD2, BRD3, and BRD4 neighboring genes in these ACC patients were ≥25.00%, ≥25.00%, and ≥44.44%, respectively. BRD2, BRD3, and BRD4 and their neighboring genes form a complex network of interactions mainly through co-expression, physical interactions, and shared protein domains. Molecular functions related to BRD2, BRD3, and BRD4 and their neighboring genes mainly include protein-macromolecule adaptor activity, cell adhesion molecule binding, and aromatase activity. Chemokine signaling pathway, thiamine metabolism, and olfactory transduction were found to be enriched as per the KEGG pathway analysis. SP1, NPM1, STAT3, and TP53 are key transcription factors for BRD2, BRD4, and their neighboring genes. MiR-142-3P, miR-484, and miR-519C were the main miRNA targets of BRD2, BRD3, BRD4, and their neighboring genes. We analyzed the mRNA sequencing data from 79 patients with ACC and found that ZSCAN12, DHX16, PRPF4B, EHMT1, CDK5RAP2, POMT1, WIZ, ZNF543, and AKAP8 were the top nine genes whose expression were positively associated with BRD2, BRD3, and BRD4 expression. The expression level of BRD2, BRD3, and BRD4 positively correlated with B cell and dendritic cell infiltration levels. BRD4-targeted drug PFI-1 and (BRD2, BRD3, and BRD4)-targeted drug I-BET-151 may have good inhibitory effects on the SW13 cell line. Conclusions: The findings of this study provide a partial basis for the role of BRD2, BRD3, and BRD4 in the occurrence and development of ACC. In addition, this study also provides new potential therapeutic targets for ACC, which can serve as a reference for future basic and clinical research.

Determining a multimodal aging clock in a cohort of Chinese women.

BACKGROUND: Translating aging rejuvenation strategies into clinical practice has the potential to address the unmet needs of the global aging population. However, to successfully do so requires precise quantification of aging and its reversal in a way that encompasses the complexity and variation of aging. METHODS: Here, in a cohort of 113 healthy women, tiled in age from young to old, we identified a repertoire of known and previously unknown markers associated with age based on multimodal measurements, including transcripts, proteins, metabolites, microbes, and clinical laboratory values, based on which an integrative aging clock and a suite of customized aging clocks were developed. FINDINGS: A unified analysis of aging-associated traits defined four aging modalities with distinct biological functions (chronic inflammation, lipid metabolism, hormone regulation, and tissue fitness), and depicted waves of changes in distinct biological pathways peak around the third and fifth decades of life. We also demonstrated that the developed aging clocks could measure biological age and assess partial aging deceleration by hormone replacement therapy, a prevalent treatment designed to correct hormonal imbalances. CONCLUSIONS: We established aging metrics that capture systemic physiological dysregulation, a valuable framework for monitoring the aging process and informing clinical development of aging rejuvenation strategies. FUNDING: This work was supported by the National Natural Science Foundation of China (32121001), the National Key Research and Development Program of China (2022YFA1103700 and 2020YFA0804000), the National Natural Science Foundation of China (81502304), and the Quzhou Technology Projects (2022K46).