摘要：
Cardiovascular disease (CVD) has a high incidence and low cure rate worldwide, and atherosclerosis (AS) is the main factor inducing cardiovascular disease, of which lipid deposition in the vessel wall is the main marker of AS. Currently, although statins can be used to lower lipids and low-density lipoprotein (LDL) in AS, the cure rate for AS remains low. Therefore, there is an urgent need to develop new therapeutic approaches, and stem cells are now widely studied, while stem cells are a class of cell types that always maintain the ability to differentiate and can differentiate to form other cells and tissues, and stem cell transplantation techniques have shown efficacy in the treatment of other diseases. With the establishment of cellular therapies and continued research in stem cell technology, stem cells are also being used to address the problem of AS. In this paper, we focus on recent research advances in stem cell therapy for AS and briefly summarize the relevant factors that induce the formation of AS. We mainly discuss the efficacy and application prospects of mesenchymal stem cells (MSCs) for the treatment of AS, in addition to the partial role and potential of exosomes in the treatment of AS. Further, provide new ideas for the clinical application of stem cells.
摘要：
Cancer immunotherapy, particularly with immune checkpoint inhibitors, has revolutionized the paradigm of cancer treatment. Nevertheless, the efficacy of cancer immunotherapy remains limited in most clinical settings due to the lack of a preexisting antitumor T-cell response in tumors. Therefore, the clinical outcomes of cancer immunotherapy must be improved crucially. With increased awareness of the importance of the innate immune response in the recruitment of T cells, as well as the onset and maintenance of the T cell response, great interest has been shown in activating the cGAS-STING signaling pathway to awaken the innate immune response, thereby orchestrating both innate and adaptive immune responses to induce tumor clearance. However, tumor cells have evolved to overexpress ectonucleotide pyrophosphate phosphodiesterase 1 (ENPP1), which degrades the immunotransmitter 2',3'-cGAMP and promotes the production of immune-suppressing adenosine, resulting in inhibition of the anticancer immune response in the tumor microenvironment. Clinically, ENPP1 overexpression is closely associated with poor prognosis in patients with cancer. Conversely, depleting or inhibiting ENPP1 has been verified to elevate extracellular 2',3'-cGAMP levels and inhibit the generation of adenosine, thereby reinvigorating the anticancer immune response for tumor elimination. A variety of ENPP1 inhibitors have recently been developed and have demonstrated significant promise for cancer immunotherapy. In this review, we provide an overview of ENPP1, dissect its immunosuppressive mechanisms, and discuss the development of ENPP1 inhibitors with the potential to further improve the efficacy of cancer immunotherapy.
作者机构：
[Li, Ye; Zhang, Yuexin; Li, Chunquan; Zhao, Yu; Huang, Xuemei; Xie, Liyuan; Zhang, Guorui; Zhao, Jun; Fan, Shifan; Song, Chao] Univ South China, Hengyang Med Sch, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.;[Li, Ye; Zhang, Yuexin; Li, Chunquan; Zhao, Yu; Huang, Xuemei; Xie, Liyuan; Zhang, Guorui; Zhao, Jun; Fan, Shifan; Song, Chao] Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.;[Li, Ye; Zhang, Yuexin; Zhang, Qinyi; Li, Chunquan; Zhao, Yu; Huang, Xuemei; Xie, Liyuan; Zhang, Guorui; Fan, Shifan; Song, Chao] Univ South China, Sch Comp, Hengyang 421001, Hunan, Peoples R China.;[Li, Chunquan] Univ South China, Hunan Prov Maternal & Child Hlth Care Hosp, Hengyang Med Sch, Key Lab Birth Defect Res & Prevent,Natl Hlth Commi, Hengyang 421001, Hunan, Peoples R China.;[Li, Ye; Zhang, Yuexin; Li, Chunquan; Zhao, Yu; Huang, Xuemei; Xie, Liyuan; Zhang, Guorui; Fan, Shifan; Song, Chao] Univ South China, Affiliated Hosp 1, Cardiovasc Lab Big Data & Imaging ArtificialIntell, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Li, CQ ] U;Univ South China, Hengyang Med Sch, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Sch Comp, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hunan Prov Maternal & Child Hlth Care Hosp, Hengyang Med Sch, Key Lab Birth Defect Res & Prevent,Natl Hlth Commi, Hengyang 421001, Hunan, Peoples R China.
关键词：
genes;mice;candidate disease gene;inference;multiomics;oncogenes;enhancer of transcription;cell lines;transcription factor
摘要：
Gene regulatory networks (GRNs) are interpretable graph models encompassing the regulatory interactions between transcription factors (TFs) and their downstream target genes. Making sense of the topology and dynamics of GRNs is fundamental to interpreting the mechanisms of disease etiology and translating corresponding findings into novel therapies. Recent advances in single-cell multi-omics techniques have prompted the computational inference of GRNs from single-cell transcriptomic and epigenomic data at an unprecedented resolution. Here, we present scGRN (https://bio.liclab.net/scGRN/), a comprehensive single-cell multi-omics gene regulatory network platform of human and mouse. The current version of scGRN catalogs 237 051 cell type-specific GRNs (62 999 692 TF-target gene pairs), covering 160 tissues/cell lines and 1324 single-cell samples. scGRN is the first resource documenting large-scale cell type-specific GRN information of diverse human and mouse conditions inferred from single-cell multi-omics data. We have implemented multiple online tools for effective GRN analysis, including differential TF-target network analysis, TF enrichment analysis, and pathway downstream analysis. We also provided details about TF binding to promoters, super-enhancers and typical enhancers of target genes in GRNs. Taken together, scGRN is an integrative and useful platform for searching, browsing, analyzing, visualizing and downloading GRNs of interest, enabling insight into the differences in regulatory mechanisms across diverse conditions. Graphical Abstract
作者机构：
[Li, Chun-Quan; Tang, Hui-Fang; Qian, Feng-Cui] Univ South China, Hengyang Med Sch, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.;[Li, Chun-Quan; Tang, Hui-Fang; Qian, Feng-Cui] Univ South China, Hengyang Med Sch, Hunan Prov Key Lab Multiom & Artificial Intelligen, Hengyang 421001, Hunan, Peoples R China.;[Li, Chun-Quan] Univ South China, Hengyang Med Sch, Hunan Prov Maternal & Child Hlth Care Hosp, Natl Hlth Commiss Key Lab Birth Defect Res & Preve, Hengyang 421001, Hunan, Peoples R China.;[Li, Chun-Quan; Qian, Feng-Cui] Univ South China, Sch Basic Med Sci, Dept Biochem & Mol Biol, Hengyang 421001, Hunan, Peoples R China.;[Li, Chun-Quan; Qian, Feng-Cui] Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Li, CQ ; Tang, HF ; Tang, HF] U;Univ South China, Hengyang Med Sch, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, Hunan Prov Key Lab Multiom & Artificial Intelligen, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, Hunan Prov Maternal & Child Hlth Care Hosp, Natl Hlth Commiss Key Lab Birth Defect Res & Preve, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Sch Basic Med Sci, Dept Biochem & Mol Biol, Hengyang 421001, Hunan, Peoples R China.
关键词：
chromatin;genes;software;epigenetics
摘要：
Chromatin accessibility profiles at single cell resolution can reveal cell type-specific regulatory programs, help dissect highly specialized cell functions and trace cell origin and evolution. Accurate cell type assignment is critical for effectively gaining biological and pathological insights, but is difficult in scATAC-seq. Hence, by extensively reviewing the literature, we designed scATAC-Ref (https://bio.liclab.net/scATAC-Ref/), a manually curated scATAC-seq database aimed at providing a comprehensive, high-quality source of chromatin accessibility profiles with known cell labels across broad cell types. Currently, scATAC-Ref comprises 1 694 372 cells with known cell labels, across various biological conditions, >400 cell/tissue types and five species. We used uniform system environment and software parameters to perform comprehensive downstream analysis on these chromatin accessibility profiles with known labels, including gene activity score, TF enrichment score, differential chromatin accessibility regions, pathway/GO term enrichment analysis and co-accessibility interactions. The scATAC-Ref also provided a user-friendly interface to query, browse and visualize cell types of interest, thereby providing a valuable resource for exploring epigenetic regulation in different tissues and cell types.
摘要：
Cardiovascular disease is the leading cause of death worldwide, and it's of great importance to understand its underlying mechanisms and find new treatments. Sphingosine 1-phosphate (S1P) is an active lipid that exerts its effects through S1P receptors on the cell surface or intracellular signal, and regulates many cellular processes such as cell growth, cell proliferation, cell migration, cell survival, and so on. S1PR modulators are a class of modulators that can interact with S1PR subtypes to activate receptors or block their activity, exerting either agonist or functional antagonist effects. Many studies have shown that S1P plays a protective role in the cardiovascular system and regulates cardiac physiological functions mainly through interaction with cell surface S1P receptors (S1PRs). Therefore, S1PR modulators may play a therapeutic role in cardiovascular diseases. Here, we review five S1PRs and their functions and the progress of S1PR modulators. In addition, we focus on the effects of S1PR modulators on atherosclerosis, myocardial infarction, myocardial ischaemia/reperfusion injury, diabetic cardiovascular diseases, and myocarditis, which may provide valuable insights into potential therapeutic strategies for cardiovascular disease.
期刊：
European Journal of Medicinal Chemistry,2024年263:115956 ISSN：0223-5234
通讯作者：
Mi, Pengbing;Yuan, Zhonghua;Zheng, X;Lin, YW
作者机构：
[Tan, Yan; Yuan, Zhonghua; Mi, Pengbing; Jiang, Jinhuan; Chen, Limei; Luo, Jianxiong; Zheng, Xing; Ye, Shiying; Lin, Yuqing; Zheng, X] Univ South China, Dept Pharm, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Lang, Jia-Jia; Lin, Ying-Wu] Univ South China, Sch Chem & Chem Engn, Hengyang 421001, Hunan, Peoples R China.;[Lang, Jia-Jia; Lin, Ying-Wu; Mi, Pengbing] Univ South China, Key Lab Prot Struct & Funct Univ Hunan Prov, Hengyang 421001, Hunan, Peoples R China.;[Zheng, Xing] Hunan Vocat Coll Sci & Technol, Dept Pharm, Changsha 410004, Hunan, Peoples R China.;[Lv, You] Shaanxi Univ Sci & Technol, Coll Bioresources Chem & Mat Engn, Xian 710021, Shaanxi, Peoples R China.
通讯机构：
[Yuan, ZH; Mi, PB; Lin, YW ; Zheng, X ] U;Univ South China, Dept Pharm, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Sch Chem & Chem Engn, Hengyang 421001, Hunan, Peoples R China.
关键词：
Human monoamine oxidase B inhibitor;Thiochromone;Thiochromone S,S-dioxide
摘要：
Developing new scaffolds for highly potent and selective inhibitors of human Monoamine Oxidase B (hMAO-B) is a crucial objective in enhancing the efficacy and safety in the clinical treatment of neurodegenerative diseases. In this study, we have identified a series of C-3 isoxazole-substituted thiochromone S,S-dioxide derivatives that exhibit strong inhibitory activity against hMAO-B. The strategy of oxidizing thiochromone to thiochromone S,S-dioxide solves the key defect of extreme insolubility observed for thiochromone analogues. In addition, the sulfone group contributes extra hydrogen(H)-bonding interactions with Tyr435, which significantly increases the activity of thiochromone S,S-dioxide derivatives against hMAO-B. Furthermore, the presence of isoxazole group provides potential H-bonding interaction and electrostatic interaction with the residue of Tyr326, while the rigid aryl ring introduces a potential steric conflict with Phe208 of hMAO-A to improve both potency and selectivity. In our investigations, several compounds (9c, 10c, 10e, 10g, 10l and 10m) demonstrate remarkable single-digit nanomolar potency. These compounds exhibit favorable cytotoxicity profiles in both differentiated SH-SY5Y and HVSMC cells, without apparent cardiotoxic effects. Moreover, compounds 10e and 10h do not lead to an increase in ROS levels in differentiated SH-SY5Y cells, further demonstrating their potential as safe and effective hMAO-B inhibitors. These findings indicate that the C-3 isoxazole substituted thiochromone S,S-dioxide analogues are potential leading compounds for the development of selective inhibitors with high potency.
摘要：
Immunotherapy has revolutionized the cancer treatment landscape by opening up novel avenues for intervention. As the use of immune checkpoint inhibitors (ICIs) has exponentially increased, so have immune-related adverse events (irAEs). The mechanism of irAEs may involve the direct damage caused by monoclonal antibodies and a sequence of immune responses triggered by T cell activation. Common side effects include dermatologic toxicity, endocrine toxicity, gastrointestinal toxicity, and hepatic toxicity. While relatively rare, neurotoxicity, cardiotoxicity, and pulmonary toxicity can be fatal. These toxicities pose a clinical dilemma regarding treatment discontinuation since they can result in severe complications and necessitate frequent hospitalization. Vigilant monitoring of irAEs is vital in clinical practice, and the principal therapeutic strategy entails the administration of oral or intravenous glucocorticoids (GSCs). It may be necessary to temporarily or permanently discontinue the use of ICIs in severe cases. Given that irAEs can impact multiple organs and require diverse treatment approaches, the involvement of a multidisciplinary team of experts is imperative. This review aims to comprehensively examine the pathogenesis, clinical manifestations, incidence, and treatment options for various irAEs.
摘要：
The coating of mesoporous silica nanoshells can improve the stability of gold nanorods while improving the corresponding drug‐carrying capacity. Mesoporous silica coated gold nanorod (GNR@MSN) provides the opportunity to integrate different treatments into a single nanoplatform combining cancer treatment with real‐time diagnosis. This review discusses the advancements of GNR@MSN in synthetic process, bio‐imaging techniques and tumor therapy. Abstract For unique surface plasmon absorption and fluorescence characteristics, gold nanorods have been developed and widely employed in the biomedical field. However, limitations still exist due their low specific surface area, instability and tendency agglomerate in cytoplasm. Mesoporous silica materials have been broadly applied in field of catalysts, adsorbents, nanoreactors, and drug carriers due to its unique mesoporous structure, highly comparative surface area, good stability and biocompatibility. Therefore, coating gold nanorods with a dendritic mesopore channels can effectively prevent particle agglomeration, while increasing the specific surface area and drug loading efficiency. This review discusses the advancements of GNR@MSN in synthetic process, bio‐imaging technique and tumor therapy. Additionally, the further application of GNR@MSN in imaging‐guided treatment modalities is explored, while its promising superior application prospect is highlighted. Finally, the issues related to in vivo studies are critically examined for facilitating the transition of this promising nanoplatform into clinical trials.
摘要：
The development of highly selective Janus Kinase 1 (JAK1) inhibitors is crucial for improving efficacy and minimizing adverse effects in the clinical treatment of autoimmune diseases. In a prior study, we designed a series of C-5 4-pyrazol substituted pyrrolopyridine derivatives that demonstrated significant potency against JAK1, with a 10∼20-fold selectivity over Janus Kinase 2 (JAK2). Building on this foundation, we adopted orthogonal strategy by modifying the C-5 position with 3-pyrazol/4-pyrazol/3-pyrrol groups and tail with substituted benzyl groups on the pyrrolopyridine head to enhance both potency and selectivity. In this endeavor, we have identified several compounds that exhibit excellent potency and selectivity for JAK1. Notably, compounds 12b and 12e, which combined 4-pyrazol group at C-5 site and meta-substituted benzyl tails, displayed IC(50) value with 2.4/2.2nM and high 352-/253-fold selectivity for JAK1 over JAK2 in enzyme assays. Additionally, both compounds showed good JAK1-selective in Ba/F3-TEL-JAK1/2 cell-based assays. These findings mark a substantial improvement, as these compounds are 10-fold more potent and over 10-fold more selective than the best compound identified in our previous study. The noteworthy potency and selectivity properties of compounds 12b and 12e suggest their potential utility in furthering the development of drugs for autoimmune diseases.
摘要：
BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide, and recent studies have found that CRC patients are at increased risk for cardiovascular disease (CVD). This study aimed to investigate competing causes of death and prognostic factors among a large cohort of CRC patients and to describe cardiovascular-specific mortality in relation to the US standard population. METHODS: This registry-based cohort study identified patients diagnosed with CRC between 1973 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database in the US. Cumulative mortality functions, conditional standardized mortality ratios, and cause-specific hazard ratios were calculated. RESULTS: Of the 563,298 eligible CRC patients included in this study, 407,545 died during the follow-up period. CRC was the leading cause of death, accounting for 49.8% of all possible competing causes of death. CVD was the most common non-cancer cause of death, accounting for 17.8% of total mortality. This study found that CRC patients have a significantly increased risk of cardiovascular-specific mortality compared to the US standard population, with the risk increasing with age and extended survival time. CONCLUSION: This study highlights the need to develop multidisciplinary prevention and management strategies for CRC and CVD to improve CRC patients' survival and quality of life.
期刊：
Cardiovascular Drugs and Therapy,2024年38(1):163-180 ISSN：0920-3206
通讯作者：
Guang-Hui Yi
作者机构：
[Salami, Oluwabukunmi Modupe; Habimana, Olive] Univ South China, Int Coll, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Yi, Guang-Hui; Peng, Jin-Fu] Univ South China, Hengyang Med Sch, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Yi, Guang-Hui; Peng, Jin-Fu] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Inst Pharm & Pharmacol, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Guang-Hui Yi] I;Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hengyang Medical School, University of South China, Hengyang, China<&wdkj&>Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
关键词：
Sepsis;Mitochondrial dysfunction;Cardiomyopathy;Drugs;Preclinical study
作者机构：
[Feng, Wen-Jie; Wu, Xiao-Ping; Zhu, Hong -Bo; He, Zhi-Long; Tan, Ye-Ru; Xun, Yi; Li, Yue-Hua; Jiang, Yi-Ling; Zhu, HB] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Med Oncol, Hengyang, Hunan, Peoples R China.;[Jiang, Bao-Hong] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pharm, Hengyang, Hunan, Peoples R China.
通讯机构：
[Zhu, HB ] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Med Oncol, Hengyang, Hunan, Peoples R China.
关键词：
AIFM2;GPX4;circRNAs;hepatocellular cancer (HCC);miR-6085
摘要：
BACKGROUND: Circular RNAs (circRNAs) represent a subset of non-coding RNAs implicated in the regulation of diverse biological processes, including tumorigenesis. However, the expression and functional implications of circ0060467 in hepatocellular carcinoma (HCC) remain elusive. In this study, we aimed to elucidate the role of circ0060467 in modulating the progression of HCC. METHODS: Differentially expressed circRNAs in HCC tissues were identified through circRNA microarray assays. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays revealed the upregulation of circ0060467 in both HCC cell lines and tissues. Various assays were conducted to investigate the roles of circ0060467 in HCC progression. Additionally, RNA immunoprecipitation (RIP) assays and luciferase assays were carried out to assess the interactions between circ0060467, microRNA-6085 (miR-6085), apoptosis-inducing factor mitochondria-associated 2 (AIFM2), and glutathione peroxidase 4 (GPX4) in HCC. RESULTS: Microarray and qRT-PCR analyses demonstrated a marked elevation of circ0060467 in HCC tissues and cell lines. Knockdown of circ0060467 suppressed HCC cell proliferation. Luciferase reporter and RIP assays confirmed the binding of circ0060467, AIFM2, and GPX4 to miR-6805. Subsequent experiments revealed that circ0060467 competes with AIFM2 and GPX4, thereby inhibiting cancer cell ferroptosis by binding to miR-6085 and promoting hepatocellular carcinoma progression. CONCLUSIONS: Collectively, circ0060467 modulates the levels of AIFM2 and GPX4, crucial regulators of tumor cell ferroptosis, by acting as a sponge for miR-6085 in HCC. Thus, circ0060467 may represent a novel diagnostic marker and therapeutic target for HCC.
摘要：
Curcumin, derived from the popular spice turmeric, is a pharmacologically active polyphenol. Curcumin's therapeutic activity has been extensively studied in recent decades, with reports implicating curcumin in many biological activities, particularly, its significant anticancer activity. However, its potential as an oral administration product is hampered by poor bioavailability, which is associated with a variety of factors, including low water solubility, poor intestinal permeability, instability, and degradation at alkaline pH. To improve its bioavailability, modifying β-diketone curcumin with heterocycles, such as pyrazole, isoxazole and triazole is a powerful strategy. Derivatives are synthesized while maintaining the basic skeleton of curcumin. The β-diketone cyclized curcumin derivatives are regulators of multiple molecular targets, which play vital roles in a variety of cellular pathways. In some literatures, structurally modified curcumin derivatives have been compared with curcumin, and the former has enhanced biological activity, improved water solubility and stability. Therefore, the scope of this review is to report the most recently synthesized heterocyclic derivatives and to classify them according to their chemical structures. Several of the most important and effective compounds are reviewed by introducing different active groups into the β-diketone position to achieve better therapeutic efficacy and bioavailability.
作者机构：
[Wu, Min; Song, Zhiyin; He, H; Chen, Li; He, He; Liu, Bing; Meng, Qingtao; Ye, Fei; Dong, Jun; Lin, Jiacheng; Tang, Junhui; Zhou, Pang-Hu] Wuhan Univ, Renmin Hosp, Coll Life Sci,Dept Anesthesiol, TaiKang Ctr Life & Med Sci,Frontier Sci Ctr Immun, Wuhan, Hubei, Peoples R China.;[Song, Zhiyin; He, H; Chen, Li; He, He] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Basic Med, Dept Pathol, Wuhan, Hubei, Peoples R China.;[Song, Zhiyin; He, H; Chen, Li; He, He] Huazhong Univ Sci & Technol, State Key Lab Diag & Treatment Severe Zoonot Infe, Wuhan, Hubei, Peoples R China.;[Lu, Bin] Univ South China, Sch Basic Med Sci, Hengyang Med Sch, Dept Biochem & Mol Biol, Hengyang, Hunan, Peoples R China.;[Lu, Jia-Hong] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China.
通讯机构：
[Song, ZY; He, H ] W;Wuhan Univ, Renmin Hosp, Coll Life Sci,Dept Anesthesiol, TaiKang Ctr Life & Med Sci,Frontier Sci Ctr Immun, Wuhan, Hubei, Peoples R China.;Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Basic Med, Dept Pathol, Wuhan, Hubei, Peoples R China.;Huazhong Univ Sci & Technol, State Key Lab Diag & Treatment Severe Zoonot Infe, Wuhan, Hubei, Peoples R China.
摘要：
Endoplasmic reticulum (ER)-mitochondria contacts are critical for the regulation of lipid transport, synthesis, and metabolism. However, the molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, we show that Mic19, a key subunit of MICOS (mitochondrial contact site and cristae organizing system) complex, regulates ER-mitochondria contacts by the EMC2-SLC25A46-Mic19 axis. Mic19 liver specific knockout (LKO) leads to the reduction of ER-mitochondrial contacts, mitochondrial lipid metabolism disorder, disorganization of mitochondrial cristae and mitochondrial unfolded protein stress response in mouse hepatocytes, impairing liver mitochondrial fatty acid beta-oxidation and lipid metabolism, which may spontaneously trigger nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice. Whereas, the re-expression of Mic19 in Mic19 LKO hepatocytes blocks the development of liver disease in mice. In addition, Mic19 overexpression suppresses MCD-induced fatty liver disease. Thus, our findings uncover the EMC2-SLC25A46-Mic19 axis as a pathway regulating ER-mitochondria contacts, and reveal that impairment of ER-mitochondria contacts may be a mechanism associated with the development of NASH and liver fibrosis. The molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, authors uncover a role for the EMC2- SLC25A46-Mic19 axis in mitochondrial lipid metabolism and liver disease
期刊：
Clinical Drug Investigation,2024年44(3):199-207 ISSN：1173-2563
通讯作者：
Fu, CX
作者机构：
[Pan, Wei; Li, Dan; Chen, Danjun; Fu, Chengxiao; Yang, Bo; Yang, Xiongwen] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pharm, Hengyang 421001, Hunan, Peoples R China.;[Pan, Wei; Li, Dan; Chen, Danjun; Wang, Lili; Fu, Chengxiao; Yang, Bo; Yang, Xiongwen] Univ South China, Hengyang Med Sch, Inst Pharm & Pharmacol, Coll Basic Med Sci, Hengyang 421200, Hunan, Peoples R China.;[Fu, Chengxiao] Univ South China, Affiliated Hosp 1, Clin Pharmacol Res Ctr, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Tong, Qin] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Oncol, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Fu, CX ] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pharm, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, Inst Pharm & Pharmacol, Coll Basic Med Sci, Hengyang 421200, Hunan, Peoples R China.;Univ South China, Affiliated Hosp 1, Clin Pharmacol Res Ctr, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.
摘要：
Background and ObjectivesAlthough thromboembolic events (TEEs) have been reported with the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), their association remains largely unknown. In this study, we aimed to provide a comprehensive review of TEEs associated with EGFR-TKIs.MethodsWe collected EGFR-TKIs (gefitinib, erlotinib, afatinib, and osimertinib) adverse reaction reports from 2015 Q1 to 2023 Q1 from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Disproportionality analysis was conducted to identify thromboembolic adverse events associated with EGFR-TKIs by comparing them with the overall FAERS database according to the reporting odds ratio (ROR). Associated factors were explored using univariate logistic regression.ResultsWe identified 1068 reports of TEEs associated with EGFR-TKIs (1.24% accounts for all TEEs). Affected patients were females (49.72%) and those older than 65 years (41.20%). The reported TEE case fatality was 30.24%. The median time to onset (TTO) of all cases was 39 days [interquartile range (IQR) 11-161], and the median TTO of fatalities [31 days (IQR 10-116)] was significantly shorter than that of non-fatal cases [46 days (IQR 12-186)].ConclusionThis study yielded three key findings. Firstly, EGFR-TKIs seem to exhibit prothrombotic effects, elevating the risk of TEEs. Secondly, the clinical outcomes of TEEs associated with EGFR-TKIs were poor. Thirdly, most TEEs occurred within the initial 3 months, and fatal cases occurred earlier than non-fatal cases.
作者机构：
[Chu, Chun] Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China,Hengyang,Hunan Province 421001,China;[Nie, Liangui; Hu, Hongming; Liu, Shengquan] Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China,Hengyang,Hunan Province 421001,China;[Liu, Yi] Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China,Hengyang,Hunan Province 421001,China. Electronic address: xiziju48262422@163.com;[Yang, Jun] Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China,Hengyang,Hunan Province 421001,China. Electronic address: weidongyang@mailfence.com
通讯机构：
[Yi Liu; Jun Yang] D;Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province 421001, China<&wdkj&>Department of Pharmacy, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province 421001, China
摘要：
BACKGROUND: Through bioinformatics analysis, this study explores the interactions and biological pathways involving metabolomic products in patients diagnosed with coronary heart disease (CHD). METHODS: A comprehensive search for relevant studies focusing on metabolomics analysis in CHD patients was conducted across databases including CNKI, Wanfang, VIP, CBM, PubMed, Cochrane Library, Nature, Web of Science, Springer, and Science Direct. Metabolites reported in the literature underwent statistical analysis and summarization, with the identification of differential metabolites. The pathways associated with these metabolites were examined using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Molecular annotation of metabolites and their relationships with enzymes or transporters were elucidated through analysis with the Human Metabolome Database (HMDB). Visual representation of the properties related to these metabolites was achieved using Metabolomics Pathway Analysis (metPA). RESULTS: A total of 13 literatures satisfying the criteria for enrollment were included. A total of 91 metabolites related to CHD were preliminarily screened, and 87 effective metabolites were obtained after the unrecognized metabolites were excluded. A total of 45 pathways were involved. Through the topology analysis (TPA) of pathways, their influence values were calculated, and 13 major metabolic pathways were selected. The pathways such as Phenylalanine, tyrosine, and tryptophan biosynthesis, Citrate cycle (TCA cycle), Glyoxylate and dicarboxylate metabolism, and Glycine, serine, and threonine metabolism primarily involved the regulation of processes and metabolites related to inflammation, oxidative stress, one-carbon metabolism, energy metabolism, lipid metabolism, immune regulation, and nitric oxide expression. CONCLUSION: Multiple pathways, including Phenylalanine, tyrosine, and tryptophan biosynthesis, Citrate cycle (TCA cycle), Glyoxylate and dicarboxylate metabolism, and Glycine, serine, and threonine metabolism, were involved in the occurrence of CHD. The occurrence of CHD is primarily associated with the regulation of processes and metabolites related to inflammation, oxidative stress, one-carbon metabolism, energy metabolism, lipid metabolism, immune regulation, and nitric oxide expression.
作者机构：
[Hsia, Yi-Jan] Buddhist Tzu Chi Med Fdn, Dent Dept, New Taipei 23142, Taiwan.;[Hsia, Yi-Jan] Buddhist Tzu Chi Med Fdn, Taipei Tzu Chi Hosp, Div Oral & Maxillofacial Surg, New Taipei 23142, Taiwan.;[Chou, Tz-Chong; Lin, Zhang-Min] Cathay Gen Hosp, Cathay Med Res Inst, Lane 160,32 Jiancheng Rd, New Taipei 22174, Taiwan.;[Zhang, Taolan] Univ South China, Dept Pharm, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Taolan] Univ South China, Sch Pharm, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Chou, TC ] C;Cathay Gen Hosp, Cathay Med Res Inst, Lane 160,32 Jiancheng Rd, New Taipei 22174, Taiwan.
关键词：
butyrate;glyoxalases;methylglyoxal;nuclear factor erythroid 2‑related factor2;prostate cancer;signal transducer and activator of transcription 3
摘要：
Cancer cells are characterized by increased glycolysis, known as the Warburg effect, which leads to increased production of cytotoxic methylglyoxal (MGO) and apoptotic cell death. Cancer cells often activate the protective nuclear factor erythroid 2‑related factor2 (Nrf2)/glyoxalase1 (Glo1) system to detoxify MGO. The effects of sodium butyrate (NaB), a product of gut microbiota, on Nrf2/Glos/MGO pathway and the underlying mechanisms in prostate cancer (PCa) cells were investigated in the present study. Treatment with NaB induced the cell death and reduced the proliferation of PCa cells (DU145 and LNCap). Moreover, the protein kinase RNA-like endoplasmic reticulum kinase/Nrf2/Glo1 pathway was greatly inhibited by NaB, thereby accumulating MGO-derived adduct hydroimidazolone (MG-H1). In response to a high amount of MGO, the expression of Nrf2 and Glo1 was attenuated, coinciding with an increased cellular death. NaB also markedly inhibited the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (Stat3) pathway. Conversely, co‑treatment with Colivelin, a Stat3 activator, significantly reversed the effects of NaB on Glo1 expression, MG-H1 production, and the cell migration and viability. As expected, overexpression of Stat3 or Glo1 reduced NaB‑induced cell death. The activation of calcium/calmodulin dependent protein kinase II gamma and reactive oxygen species production also contributed to the anticancer effect of NaB. The present study, for the first time, demonstrated that NaB greatly increases MGO production through suppression of the JAK2/Stat3/Nrf2/Glo1 pathway in DU145 cells, a cell line mimicking castration‑resistant PCa (CRPC), suggesting that NaB may be a potential agent for PCa therapy.
摘要：
BACKGROUND: Curcumin nicotinate (Curtn), derived from curcumin and niacin, reduces serum LDL-C levels, partly due to its influence on PCSK9. This study investigates IDOL's role in Curtn's lipid-lowering effects. OBJECTIVE: To elucidate Curtn's regulation of the IDOL/LDLR pathway and potential molecular mechanisms in hepatocytes. METHODS: Differential metabolites in Curtn-treated HepG2 cells were identified via LC-MS. Molecular docking assessed Curtn's affinity with IDOL. Cholesterol content and LDLR expression effects were studied in high-fat diet Wistar rats. In vitro evaluations determined Curtn's influence on IDOL overexpression's LDL-C uptake and LDLR expression in hepatocytes. RESULTS: Lipids were the main differential metabolites in Curtn-treated HepG2 cells. Docking showed Curtn's higher affinity to IDOL's FERM domain compared to curcumin, suggesting potential competitive inhibition of IDOL's binding to LDLR. Curtn decreased liver cholesterol in Wistar rats and elevated LDLR expression. During in vitro experiments, Curtn significantly enhanced the effects of IDOL overexpression in HepG2 cells, leading to increased LDL-C uptake and elevated expression of LDL receptors. CONCLUSION: Curtn modulates the IDOL/LDLR pathway, enhancing LDL cholesterol uptake in hepatocytes. Combined with its PCSK9 influence, Curtn emerges as a potential hyperlipidemia therapy.
摘要：
As an important characteristic of tumor, acidic tumor microenvironment (TME) is closely related to immune escape, invasion, migration and drug resistance of tumor. The acidity of the TME mainly comes from the acidic products produced by the high level of tumor metabolism, such as lactic acid and carbon dioxide. pH regulators such as monocarboxylate transporters (MCTs), carbonic anhydrase IX (CA IX), and Na+/H+ exchange 1 (NHE1) expel protons directly or indirectly from the tumor to maintain the pH balance of tumor cells and create an acidic TME. We review the functions of several pH regulators involved in the construction of acidic TME, the structure and structure-activity relationship of pH regulator inhibitors, and provide strategies for the development of small-molecule antitumor inhibitors based on these targets.
通讯机构：
[Li, CQ ] U;[Guo, MZ ] B;Univ South China, Natl Hlth Commiss, Key Lab Birth Defect Res & Prevent, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Sch Comp, Hengyang 421001, Hunan, Peoples R China.;Beijing Univ Civil Engn & Architecture, Sch Elect & Informat Engn, Beijing 100044, Peoples R China.
关键词：
chromatin;gene expression profiling;methylation;single nucleotide polymorphism;genetics;mice;candidate disease gene;enhancer of transcription;basic local alignment search tool;datasets;arabidopsis;maize;rna-seq;transcription factor;genes;pathologic processes
摘要：
Transcription factors (TFs), transcription co-factors (TcoFs) and their target genes perform essential functions in diseases and biological processes. KnockTF 2.0 (http:////www.licpathway.net//KnockTF//index.html) aims to provide comprehensive gene expression profile datasets before//after T(co)F knockdown//knockout across multiple tissue//cell types of different species. Compared with KnockTF 1.0, KnockTF 2.0 has the following improvements: (i) Newly added T(co)F knockdown//knockout datasets in mice, Arabidopsis thaliana and Zea mays and also an expanded scale of datasets in humans. Currently, KnockTF 2.0 stores 1468 manually curated RNA-seq and microarray datasets associated with 612 TFs and 172 TcoFs disrupted by different knockdown//knockout techniques, which are 2.5 times larger than those of KnockTF 1.0. (ii) Newly added (epi)genetic annotations for T(co)F target genes in humans and mice, such as super-enhancers, common SNPs, methylation sites and chromatin interactions. (iii) Newly embedded and updated search and analysis tools, including T(co)F Enrichment (GSEA), Pathway Downstream Analysis and Search by Target Gene (BLAST). KnockTF 2.0 is a comprehensive update of KnockTF 1.0, which provides more T(co)F knockdown//knockout datasets and (epi)genetic annotations across multiple species than KnockTF 1.0. KnockTF 2.0 facilitates not only the identification of functional T(co)Fs and target genes but also the investigation of their roles in the physiological and pathological processes. Graphical Abstract
