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
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.
期刊:
European Journal of Medicinal Chemistry,2024年267:116210 ISSN:0223-5234
通讯作者:
Pengbing Mi<&wdkj&>You Lv
作者机构:
[Li, Xinhao; Mi, Pengbing; Yu, Zhixin; Chen, Limei; Lin, Yuqing; Zheng, Xing] Department of Pharmacy, Hengyang Medicinal School, University of South China, Hengyang, Hunan, 421001, China;[Tang, Yahua] The Affiliated Nanhua Hospital, Department of Pharmacy, Institute of Clinical Pharmacy, Hengyang Medical School, University of South China, Hunan, 421001, China;[Lang, Jia-Jia; Lin, Ying-Wu] School of Chemistry and Chemical Engineering, University of South China, Hengyang, Hunan, 421001, China;[Lang, Jia-Jia] Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan, 421001, China;[Zheng, Xing] Department of Pharmacy, Hunan Vocational College of Science and Technology, Changsha, Hunan, 410004, China
通讯机构:
[Pengbing Mi] D;[You Lv] C;College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science & Technology, Xi'an, Shaanxi, 710021, China<&wdkj&>Xi'an Amazinggene Co., Ltd, Xi'an, Shaanxi, 710026, China<&wdkj&>Department of Pharmacy, Hengyang Medicinal School, University of South China, Hengyang, Hunan, 421001, China<&wdkj&>Key Lab of Protein Structure and Function of Universities in Hunan Province, University of South China, Hengyang, Hunan, 421001, China
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.
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.
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.
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:
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, TaiKang Ctr Life & Med Sci,Frontier Sci Ctr Immuno, 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 Infec, 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, Macau, Peoples R China.
通讯机构:
[Song, ZY; He, H ] W;Wuhan Univ, Renmin Hosp, Coll Life Sci, TaiKang Ctr Life & Med Sci,Frontier Sci Ctr Immuno, 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 Infec, 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:
[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:
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.
摘要:
Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed.
期刊:
CHEMISTRY-AN ASIAN JOURNAL,2024年19(4):e202301036- ISSN:1861-4728
通讯作者:
Tan, Xiaofeng;Yang, QL
作者机构:
[Xiao, Hao; Yang, Qinglai; Tan, Xiaofeng; Wu, Gui-long; Yang, QL; Tan, Senyou] Univ South China, Inst Pharm & Pharmacol, Sch Pharmaceut Sci, Hengyang Med Sch, 28 West Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;[Xiao, Hao; Yang, Qinglai; Tan, Xiaofeng; Wu, Gui-long; Yang, QL; Tan, Senyou] Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, 28 West Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;[Yang, Qinglai; Tan, Xiaofeng; Yang, QL] Hunan Prov Maternal & Child Hlth Care Hosp, Key Lab Birth Defect Res & Prevent, Natl Hlth Commiss, 53 Xiangchun Rd, Changsha 410008, Hunan, Peoples R China.
通讯机构:
[Tan, XF; Yang, QL ] U;Univ South China, Inst Pharm & Pharmacol, Sch Pharmaceut Sci, Hengyang Med Sch, 28 West Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, 28 West Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;Hunan Prov Maternal & Child Hlth Care Hosp, Key Lab Birth Defect Res & Prevent, Natl Hlth Commiss, 53 Xiangchun Rd, Changsha 410008, Hunan, Peoples R China.
关键词:
Tumor microenvironment factors;NIR-II phototheranostic agents;Simultaneous activation;Integration of diagnosis and treatment
摘要:
This review examines the recent advances in developing dual‐functional NIR‐II activatable phototheranostic agents over the past years. It systematically presents NIR‐II phototheranostic agents activated by various TME factors such as acidity (pH), hydrogen peroxide (H2O2), glutathione (GSH), hydrogen sulfide (H2S), enzymes, as well as multiple TME factors. Abstract Malignant tumors seriously threaten human life and well‐being. Emerging Near‐infrared II (NIR‐II, 1000–1700 nm) phototheranostic nanotechnology integrates diagnostic and treatment modalities, offering merits including improved tissue penetration and enhanced spatiotemporal resolution. This remarkable progress has opened promising avenues for advancing tumor theranostic research. The tumor microenvironment (TME) differs from normal tissues, exhibiting distinct attributes such as hypoxia, acidosis, overexpressed hydrogen peroxide, excess glutathione, and other factors. Capitalizing on these attributes, researchers have developed TME‐activatable NIR‐II phototheranostic agents with diagnostic and therapeutic attributes concurrently. Therefore, developing TME‐activatable NIR‐II phototheranostic agents with diagnostic and therapeutic activation holds significant research importance. Currently, research on TME‐activatable NIR‐II phototheranostic agents is still in its preliminary stages. This review examines the recent advances in developing dual‐functional NIR‐II activatable phototheranostic agents over the past years. It systematically presents NIR‐II phototheranostic agents activated by various TME factors such as acidity (pH), hydrogen peroxide (H2O2), glutathione (GSH), hydrogen sulfide (H2S), enzymes, and their hybrid. This encompasses NIR‐II fluorescence and photoacoustic imaging diagnostics, along with therapeutic modalities, including photothermal, photodynamic, chemodynamic, and gas therapies triggered by these TME factors. Lastly, the difficulties and opportunities confronting NIR‐II activatable phototheranostic agents in the simultaneous diagnosis and treatment field are highlighted.
作者机构:
[Zhang, Yuexin; Mu, Xinxin; Zhang, Qinyi; Li, Chunquan; Song, Shuang; Zhang, Guorui; Song, Chao; Tang, Huifang; Yin, Mingxue; Zhang, Hang] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Yuexin; Mu, Xinxin; Zhang, Qinyi; Li, Chunquan; Song, Shuang; Zhang, Guorui; Song, Chao; Tang, Huifang; Yin, Mingxue; Zhang, Hang] Univ South China, Hengyang Med Sch, Hunan Prov Key Lab Multiom & Artificial Intelligen, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Qinyi; Li, Chunquan; Song, Shuang; Zhang, Guorui; Yin, Mingxue] Univ South China, Sch Basic Med Sci, Dept Biochem & Mol Biol, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Qinyi; Li, Chunquan; Song, Shuang; Zhang, Guorui; Yin, Mingxue] Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, 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, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Li, CQ ; Tang, HF ; Tang, HF] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, 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, Sch Basic Med Sci, Dept Biochem & Mol Biol, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Hengyang Med Sch, MOE Key Lab Rare Pediat Dis, Hengyang 421001, Hunan, Peoples R China.
关键词:
gated blood-pool imaging;chromatin;genetics;mice;enhancer of transcription;candidate disease gene;single nucleotide polymorphism;crispr;genes;rna;genome;methylation
摘要:
Enhancer RNAs (eRNAs) transcribed from distal active enhancers serve as key regulators in gene transcriptional regulation. The accumulation of eRNAs from multiple sequencing assays has led to an urgent need to comprehensively collect and process these data to illustrate the regulatory landscape of eRNAs. To address this need, we developed the eRNAbase (http://bio.liclab.net/eRNAbase/index.php) to store the massive available resources of human and mouse eRNAs and provide comprehensive annotation and analyses for eRNAs. The current version of eRNAbase cataloged 10 399 928 eRNAs from 1012 samples, including 858 human samples and 154 mouse samples. These eRNAs were first identified and uniformly processed from 14 eRNA-related experiment types manually collected from GEO/SRA and ENCODE. Importantly, the eRNAbase provides detailed and abundant (epi)genetic annotations in eRNA regions, such as super enhancers, enhancers, common single nucleotide polymorphisms, expression quantitative trait loci, transcription factor binding sites, CRISPR/Cas9 target sites, DNase I hypersensitivity sites, chromatin accessibility regions, methylation sites, chromatin interactions regions, topologically associating domains and RNA spatial interactions. Furthermore, the eRNAbase provides users with three novel analyses including eRNA-mediated pathway regulatory analysis, eRNA-based variation interpretation analysis and eRNA-mediated TF-target gene analysis. Hence, eRNAbase is a powerful platform to query, browse and visualize regulatory cues associated with eRNAs. Graphical Abstract
摘要:
BACKGROUND: The cellular endoplasmic reticulum (ER) is responsible for various functions, including protein synthesis, folding, distribution, and calcium ion storage. Studies have linked ER stress with acute lung injury (ALI), which can result in oxidative stress and even cell death. Peroxynitrite (ONOO(-)) is a well-known reactive oxygen species (ROS) that contributes to various physiological and pathological processes in oxidative stress diseases. To understand the role of ER ONOO(-) in ALI, it is crucial to accurately measure its level in the ER. Unfortunately, there is currently no probe available to detect ER ONOO(-) in an ALI model. RESULTS: To address this, we developed three near-infrared (NIR) fluorescent probes (DCM-F-ONOO, DCM-Cl-ONOO, and DCM-Br-ONOO) for the detection of ONOO(-) using pentafluorobenzenesulfonate (PFBS) moieties as fluorescence quenchers. Through comprehensive testing, we selected DCM-Br-ONOO as the best NIR fluorescent probe due to its rapid response (within 3min), high selectivity, good sensitivity (LOD=2.3nM), and approximately 66-fold enhanced response to ONOO(-) in fluorescence intensity. The probe was successfully applied to detect changes in ONOO(-) levels induced by different drugs in the ER of living cells. Importantly, a significant increase in the level of ONOO(-) was observed in the ER of an ALI cell model (4.5-fold) and an ALI mouse model (2.5-fold) using the probe, which is essential for understanding the role of ONOO(-) in ER-associated diseases. SIGNIFICANCE: Using DCM-Br-ONOO as a probe, present work further validated that the elevated levels of ONOO(-) secretion were accompanied by the ALI progressed. These findings may provide valuable results for figuring out the biological roles that ONOO(-) played in ALI.
摘要:
The signal pathway of TNF‐α inducing human umbilical vascular endothelial cells apoptosis. Abstract Endothelial cell apoptosis driven by inflammation (TNF‐α) plays a critical role in the pathogenesis of atherosclerosis, but the exact molecular mechanisms are not clearly elucidated. MicroRNA (miR)‐29 families (a/b/c) take important roles in pathophysiological processes of atherosclerosis, also the underlying mechanisms have not been fully clarified. The aims are to explore whether or not miR‐29 families mediate the apoptotic effects of TNF‐α on endothelial cells and uncover the underlying molecular mechanisms. In this study, MTT assay and flow cytometer analysis were employed respectively to determine the proliferation and apoptosis of human umbilical vascular endothelial cells (HUVECs) under TNF‐α exposure. Real‐time quantitative PCR and western blot were performed to detect the levels of target RNAs and proteins/their phosphorylation in HUVECs. TNF‐α could inhibit HUVEC proliferation and induce HUVEC apoptosis in a positive dose‐ and time‐dependent manner, with a similar way of miR‐29a upregulation, but no effects on miR‐29b/c. Upregulation of miR‐29a with its mimics enhanced the apoptotic effect of TNF‐α on HUVECs, but downregulation of miR‐29a using anti‐miR‐29a blocked up its apoptotic effect. MiR‐29a inhibited the expression of PI3Kp85α and Bcl‐2 and blocked up the signal transduction of PI3K/AKT/Bcl‐2 axis to mediate the apoptotic effect of TNF‐α on HUVECs. Mediating the inflammation‐driven endothelial cell apoptosis is an important biology mechanism by which miR‐29a promotes atherosclerosis and its complications. MiR‐29a will be a potential diagnostic and therapeutic target for atherosclerotic cardiovascular diseases; it is worthwhile to further study.
摘要:
BACKGROUND: With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression. METHODS: Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma. RESULTS: We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes. CONCLUSIONS: These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.
期刊:
Journal of Hazardous Materials,2024年464:132986 ISSN:0304-3894
通讯作者:
Wang, JK
作者机构:
[Zhu, Yanli] Hunan Univ Technol & Business, Sch Resources & Environm, Changsha 410205, Hunan, Peoples R China.;[Wang, Jikai; Xie, Zhulan; Wang, JK; Sun, Yiyang; Zeng, Pengfei] Univ South China, Inst Pharm & Pharmacol, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Chen, Danjun; Fu, Chengxiao] Univ South China, Affiliated Hosp 1, Hengyang Clin Pharmacol Res Ctr, Hengyang Med Sch,Dept Pharm, Hengyang 421001, Hunan, Peoples R China.;[Jiang, Yuehua] Hengyang Anim Husb & Aquaculture Affairs Ctr, Dept Anim Husb & Aquaculture Prod Qual Control, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Wang, JK ] U;Univ South China, Inst Pharm & Pharmacol, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.
关键词:
Desorption ionization mechanism;Environmental analysis;MALDI-MS;Nano-matrix;Two-dimensional material
摘要:
Laser desorption ionization mass spectrometry (LDI-MS) aroused intensive concerns for the merits of label-free and high-throughput analysis. Here, we designed a silver nanoparticles (AgNP)-modified indium vanadate nanosheets with doping samarium (AgNP@InVO(4):Sm) nanosheets. The developed AgNP@InVO(4):Sm nanosheets (AIVON) were synthesized based on the microemulsion-mediated solvothermal method and ultraviolet-assisted in situ formation of AgNP, then for the first time applied as a matrix in LDI-MS analysis. With the advantages including enhanced MS signal, little matrix-related background, high reproducibility, and good salt tolerance, AIVON exhibited much better prospect than non-modified indium vanadate nanosheets with doping samarium (IVON) and traditional organic matrix, thus allowing sensitive MS detection for a wide range of low-molecular-weight (LMW) molecules. Moreover, by coupling with headspace sampling thin-film microextraction (TFME), a kind of representative pollutant chlorophenols were identified and quantified via AIVON-assisted LDI-MS in environmental and biological samples. Volatile LMW pollutants could be preconcentrated after TFME, hence a sensitive and rapid assay with negligible sample matrix effect was realized by using AIVON-assisted LDI-MS. It is anticipated that this novel nano-matrix AIVON and the proposed TFME coupling detection strategy were of competitive merits for LDI-MS analysis in the fields of environment, biomedicine, and agriculture.
摘要:
Chemodynamic therapy (CDT), as an emerging therapeutic strategy, kills cancer cells by converting in-tracellular hydrogen peroxide (H2O2) into cytotoxic oxidizing hydroxyl radicals ( center dot OH). However, the ther-apeutic efficiency of CDT is compromised due to the insufficient endogenous H2O2 and metal catalysts in tumor cells. The use of multivalent polyphenols with multiple hydroxyl functions provides a facile yet robust means for efficient CDT augmentation. For this purpose, we reported herein the construc-tion of polyphenol-metal nanoparticles (NPs) via a phenol-metal coordination strategy. The unique-ness of this study is the preparation of only one polymer construct with multivalency that can afford various supramolecular interactions for simultaneous "one-pot" loading of different therapeutic species, i.e., doxorubicin (DOX), glucose oxidases (GOD), and Fe3 + and further co-self-assembly into a stabilized nanomedicine for cascade amplified chemo-chemodynamic therapy. Specifically, the tumor intracellular acidic pH-triggered DOX release could serve for chemotherapy as well as enhance the intracellular H2O2 level. Together with the extra H2O2 and gluconic acid produced by the GOD-triggered glucose consump-tion, DOX@POAD-Fe@GOD NPs promoted Fe3+participation in the Fe-mediated Fenton reaction for cascade amplified chemo-chemodynamic therapy. Notably, this formulation displayed a greater anti-tumor effect with a tumor inhibition ratio 1.6-fold higher than that of free DOX in a BALB/c mice model bearing 4T1 tumors. Overall, the multivalent polyphenol-metal nanoplatform developed herein integrates chemother-apy, starvation therapy, and CDT for synergistic enhanced anticancer efficiency, which shows great poten-tial for clinical translations. Statement of significance Chemodynamic therapy (CDT) generally suffers from compromised therapeutic efficiency due to insuf-ficient endogenous H2O2 and metal catalysts in tumor cells. To develop a facile yet robust strategy for efficient CDT augmentation, we reported herein construction of a multivalent polyphenol-metal nanoplat-form, DOX@POAD-Fe@GOD nanoparticles (NPs) via a phenol-metal coordination strategy. This nanoplat-form integrates multiple supramolecular dynamic interactions not only for simultaneously safe encapsu-lation of doxorubicin (DOX), Fe3 +, and glucose oxidases (GOD), but also for cascade amplified chemo-chemodynamic therapy. Specifically, the intracellular acidic pH-triggered dissociation of DOX@POAD-Fe@GOD NPs promoted the release of Fe3 +, DOX, and GOD for significantly increased ROS levels that can accelerate Fenton reactions for cascaded chemotherapy, starvation therapy, and CDT with amplified antitumor efficiency in vivo .(c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.