作者机构:
[Song, Zhiyin; Yu, Jianglong; He, He; Zhao, Huabin; Guo, Hanze; He, H; Gong, Longlong; Hao, Tianshu; Wu, Zhida; Wang, Bingjun; Jiang, Jie] Wuhan Univ, Renmin Hosp, Taikang Ctr life & Med Sci, Coll Life Sci,Frontier Sci Ctr Immunol & Metab,Dep, Wuhan 430072, Hubei, Peoples R China.;[Lu, Bin] Univ South China, Sch Basic Med Sci, Hengyang Med Sch, Dept Biochem & Mol Biol, Hengyang 421001, Hunan, Peoples R China.;[Engelender, Simone] Technion Israel Inst Technol, Rappaport Fac Med, Dept Biochem, Haifa, Israel.
通讯机构:
[He, H; Song, ZY ] W;Wuhan Univ, Renmin Hosp, Taikang Ctr life & Med Sci, Coll Life Sci,Frontier Sci Ctr Immunol & Metab,Dep, Wuhan 430072, Hubei, Peoples R China.
摘要:
Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation. Several organelle membranes make contact in the cell, with many contacts being spatially segregated sites dedicated to specific functions. Here, Hao et al. show that hypoxia increases mitochondria-lysosome contacts, leading to engulfment and degradation of the mitochondria.
摘要:
BACKGROUND AND PURPOSE: Research has revealed the involvement of mitochondrial autophagy and iron death in the pathogenesis of myocardial fibrosis. The objective of this study is to investigate whether the mitochondrial-targeted H(2)S donor AP39 inhibits mitochondrial autophagy and antagonizes myocardial cell iron death through the PINK1/Parkin pathway, thereby improving myocardial fibrosis in rats with myocardial infarction. EXPERIMENTAL APPROACH: A rat model of myocardial infarction was created by intraperitoneal injection of a high dose of isoproterenol, and H9c2 myocardial cells were subjected to hypoxic injury induced by CoCl(2). Western blot, RT-PCR, transmission electron microscopy, immunohistochemistry, as well as echocardiography, and studies on isolated hearts were employed. KEY RESULTS: In the hearts of rats with myocardial infarction, there was a significant accumulation of interstitial collagen fibers, accompanied by downregulation of CSE protein expression, activation of the PINK1/Parkin signaling pathway, and activation of mitochondrial autophagy. Intervention with AP39 resulted in a significant improvement of the aforementioned changes, which could be reversed by the addition of PAG. Similar results were observed in vitro experiments. Furthermore, the addition of CCCP reversed the antagonistic effect of AP39 on myocardial cell iron death, while the addition of RSL3 reversed the inhibitory effect of AP39 on collagen production in myocardial cells. CONCLUSION AND IMPLICATIONS: The mitochondrial-targeted H(2)S donor AP39 can inhibit mitochondrial autophagy through the PINK1/Parkin pathway, antagonize myocardial cell iron death, and improve myocardial fibrosis in rats with myocardial infarction.
通讯机构:
[Li-Chen Gao] S;School of Pharmacy, Department of Pharmacy, Phase I Clinical Trial Centre, the Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Hengyang, China<&wdkj&>Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Changsha, China
摘要:
Ferrous ion (Fe2+) is a crucial metal ion in the body and participates in the diseases related to oxidation and reduction. Golgi apparatus is the main subcellular organelle of Fe2+ transport in cells, and the stability of its structure is related to the Fe2+ at an appropriate concentration. In this work, a turn-on type Golgi-targeting fluorescent chemosensor Gol-Cou-Fe2+ was rationally designed for sensitive and selective detection of Fe2+. Gol-Cou-Fe2+ showed excellent capacity of detecting exogenous and endogenous Fe2+ in HUVEC and HepG2 cells. It was used to capture the up-regulated Fe2+ level during the hypoxia. Moreover, the fluorescence of sensor was enhanced over time under Golgi stress combining with the reduce of Golgi matrix protein GM130. However, elimination of Fe2+ or addition of nitric oxide (NO) would restore the fluorescence intensity of Gol-Cou-Fe2+ and the expression of GM130 in HUVEC. Thus, development of chemosensor Gol-Cou-Fe2+ provides a new window for tracking Golgi Fe2+ and elucidating Golgi stress-related diseases.
作者机构:
[Chen, Yuping; Wu, Meichun; Chen, YP] Univ South China, Hengyang Med Sch, Hengyang 410001, Hunan, Peoples R China.;[Wu, Meichun] Univ South China, Sch Nursing, Hengyang 410001, Hunan, Peoples R China.;[Chen, Yuping; Xun, Min; Chen, YP] Univ South China, Inst Pharm & Pharmacol, Sch Pharmaceut Sci, Hengyang 410001, Hunan, Peoples R China.
通讯机构:
[Chen, YP ] U;Univ South China, Hengyang Med Sch, Hengyang 410001, Hunan, Peoples R China.;Univ South China, Inst Pharm & Pharmacol, Sch Pharmaceut Sci, Hengyang 410001, Hunan, Peoples R China.
关键词:
biodegradable metal stents;vascular smooth muscle cell;stent implantation;vascular microenvironment;atherosclerosis;restenosis
摘要:
Iron-, magnesium-, or zinc-based metal vessel stents support vessel expansion at the period early after implantation and degrade away after vascular reconstruction, eliminating the side effects due to the long stay of stent implants in the body and the risks of restenosis and neoatherosclerosis. However, emerging evidence has indicated that their degradation alters the vascular microenvironment and induces adaptive responses of surrounding vessel cells, especially vascular smooth muscle cells (VSMCs). VSMCs are highly flexible cells that actively alter their phenotype in response to the stenting, similarly to what they do during all stages of atherosclerosis pathology, which significantly influences stent performance. This Review discusses how biodegradable metal stents modify vascular conditions and how VSMCs respond to various chemical, biological, and physical signals attributable to stent implantation. The focus is placed on the phenotypic adaptation of VSMCs and the clinical complications, which highlight the importance of VSMC transformation in future stent design.
摘要:
The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe(2+) and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction.
摘要:
Nasopharyngeal carcinoma (NPC) is a highly recurrent and metastatic malignant tumor affecting a large number of individuals in southern China. Traditional Chinese herbal medicine has been found to be a rich source of natural compounds with mild therapeutic effects and minimal side effects, making them increasingly popular for treating various diseases. Trifolirhizin, a natural flavonoid derived from legu-minous plants, has gained significant attention for its therapeutic potential. In this study, we confirmed that trifolirhizin could effectively inhibit the proliferation, migration and invasion of nasopharyngeal carcinoma 6-10B and HK1 cells. Furthermore, our findings demonstrated that trifolirhizin achieves this by suppressing the PI3K/Akt signaling pathway. The findings of the present study provides a valuable perspective on the potential therapeutic applications of trifolirhizin for the treatment of nasopharyngeal carcinoma.(c) 2023 Elsevier Inc. All rights reserved.
作者机构:
[Liu, Ying; Yang, Ke; He, Longwei; Wang, Peipei; Li, Songjiao] Univ South China, Hengyang Med Sch, Canc Res Inst, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang 421001, Peoples R China.;[Cheng, Dan] Univ South China, Affiliated Nanhua Hosp, Hengyang Med Sch, Clin Res Inst, Hengyang, Peoples R China.
通讯机构:
[Dan Cheng] C;[Longwei He] H;Clinical Research Institute, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, China<&wdkj&>Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Cancer Research Institute, Department of Pharmacy and Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, PR China
作者机构:
[Zhang, Taolan; Hu, Haihong; Zhan, Wendi; Zhang, TL; Zhu, HongXia] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pharm, Hengyang 421000, Hunan, Peoples R China.;[Zhang, Taolan; Yang, Xiaoyan; Hu, Haihong; Zhan, Wendi; Li, Zhicheng; Zhang, TL; Wang, Hanbin; Zhu, HongXia] Univ South China, Hengyang Med Coll, Sch Pharm, 28 Western Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Taolan; Zhang, TL] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Chinese Tradit Med CTM Res Platform Major Epidem T, Hengyang 421000, Hunan, Peoples R China.
通讯机构:
[Zhang, TL ] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pharm, Hengyang 421000, Hunan, Peoples R China.;Univ South China, Hengyang Med Coll, Sch Pharm, 28 Western Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Chinese Tradit Med CTM Res Platform Major Epidem T, Hengyang 421000, Hunan, Peoples R China.
摘要:
Breast cancer and diabetes are significant health challenges, and effective treatments for both diseases are lacking. Proton pump inhibitors (PPIs) have demonstrated anticancer and hypoglycemic effects, but their mechanisms of action are not yet fully understood. We used the GeneCards and PharmMapper databases to identify therapeutic targets for diabetes, breast cancerand PPIs. We identified common targets and constructed a regulatory network of diseases and drugs using the STRING database and Cytoscape software. We also explored the binding between small molecule ligands and protein receptors using Discovery Studio software. We identified 33 shared targets for breast cancer, diabetes, and PPIs including lansoprazole, omeprazole, and pantoprazole, which play a critical role in fatty acid transport, insulin resistance, apoptosis, and cancer-related signaling pathways. Our findings demonstrated that PPIs had a strong affinity for AKT1 and MMP9. This study provides insights into the mechanisms of action of PPIs in breast cancer and diabetes and identifies AKT1 and MMP9 as critical targets for future drug development. Our findings highlight the potential of PPIs as a novel therapeutic approach for these challenging diseases.
期刊:
Drug Development Research,2023年84(3):406-422 ISSN:0272-4391
通讯作者:
Tang, G.;Wang, Z.
作者机构:
[Xie, Zhizhong; Zhao, Yin; Lei, Xiaoyong; Sun, Xueyan; Zhao, Jingduo; Tang, Guotao] Heng Yang Med Sch, Inst Pharm & Pharmacol, Hunan Prov Key Lab Tumor Microenvironm Respons Dru, Hengyang, Hunan, Peoples R China.;[Li, Yong; Liu, Xingyun] Univ South China, Nanhua Hosp, Hengyang Med Sch, Hengyang, Hunan, Peoples R China.;[Huang, Sheng] Jiuzhitang Co Ltd, Changsha, Hunan, Peoples R China.;[Wang, Zhe] Univ South China, Affiliated Hosp 2, Hengyang Med Sch, Dept Pharm, Hengyang, Hunan, Peoples R China.;[Wang, Zhe] Univ South China, Affiliated Hosp 2, Dept Pharm, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Zhe Wang] T;[Guotao Tang] I;The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hunan, Hengyang, China<&wdkj&>Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, HengYang Medicial School, Hengyang, Hunan, China
摘要:
Treatment of Klebsiella pneumoniae causing pyogenic infections is challenging. The clinical and molecular characteristics of Klebsiella pneumoniae causing pyogenic infections are poorly understood, and antibacterial treatment strategies are limited. We analyzed the clinical and molecular characteristics of K. pneumoniae from patients with pyogenic infections and used time-kill assays to reveal the bactericidal kinetics of antimicrobial agents against hypervirulent K. pneumoniae (hvKp). A total of 54 K. pneumoniae isolates were included, comprising 33 hvKp and 21 classic K. pneumoniae (cKp) isolates, and the hvKp and cKp isolates were identified using five genes (iroB, iucA, rmpA, rmpA2, and peg-344) that have been applied as hvKp strain markers. The median age of all cases was 54 years (25th and 75th percentiles, 50.5 to 70), 62.96% of individuals had diabetes, and 22.22% of isolates were sourced from individuals without underlying disease. The ratios of white blood cells/procalcitonin and C-reactive protein/procalcitonin were potential clinical markers for the identification of suppurative infection caused by hvKp and cKp. The 54 K. pneumoniae isolates were classified into 8 sequence type 11 (ST11) and 46 non-ST11 strains. ST11 strains carrying multiple drug resistance genes have a multidrug resistance phenotype, while non-ST11 strains carrying only intrinsic resistance genes are generally susceptible to antibiotics. Bactericidal kinetics revealed that hvKp isolates were not easily killed by antimicrobials at susceptible breakpoint concentrations compared with cKp. Given the varied clinical and molecular features and the catastrophic pathogenicity of K. pneumoniae, it is critical to determine the characteristics of such isolates for optimal management and effective treatment of K. pneumoniae causing pyogenic infections.IMPORTANCE Klebsiella pneumoniae may cause pyogenic infections, which are potentially life-threatening and bring great challenges for clinical management. However, the clinical and molecular characteristics of K. pneumoniae are poorly understood, and effective antibacterial treatment strategies are limited. We analyzed the clinical and molecular features of 54 isolates from patients with various pyogenic infections. We found that most patients with pyogenic infections had underlying diseases, such as diabetes. The ratio of white blood cells to procalcitonin and the ratio of C-reactive protein to procalcitonin were potential clinical markers for differentiating hypervirulent K. pneumoniae strains from classical K. pneumoniae strains that cause pyogenic infections. K. pneumoniae isolates of ST11 were generally more resistant to antibiotics than non-ST11 isolates. Most importantly, hypervirulent K. pneumoniae strains were more tolerant to antibiotics than classic K. pneumoniae isolates. Klebsiella pneumoniae may cause pyogenic infections, which are potentially life-threatening and bring great challenges for clinical management. However, the clinical and molecular characteristics of K. pneumoniae are poorly understood, and effective antibacterial treatment strategies are limited.
期刊:
CURRENT MOLECULAR MEDICINE,2023年23(7):668-677 ISSN:1566-5240
通讯作者:
Long, Shuanglian;Mo, Zhongcheng;He, WG
作者机构:
[Luo, Min; Liu, Jiang; He, Weiguo; Mo, Zhongcheng; Gui, Zihao; Long, Shuanglian] Univ South China, Clin Anat & Reprod Med Applicat Inst, Hengyang Med Sch, Hengyang 421001, Peoples R China.;[Li, Tangluo] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Inst Pharm & Pharmacol, Hengyang 421001, Peoples R China.;[Peng, Mindan; Liu, Jiang] Univ South China, Hunan Prov Innovat Training Base Med Postgrad, Yueyang 416000, Hunan, Peoples R China.;[Peng, Mindan; Liu, Jiang] Yueyang Women & Childrens Med Ctr, Yueyang 416000, Hunan, Peoples R China.;[Mo, Zhongcheng] Guilin Med Univ, Guangxi Key Lab Diabet Syst Med, Guilin 541000, Guangxi, Peoples R China.
通讯机构:
[He, WG ; Mo, ZC; Long, SL] U;Univ South China, Clin Anat & Reprod Med Applicat Inst, Hengyang Med Sch, Hengyang 421001, Peoples R China.
关键词:
CPP;Central precocious puberty;GnRH.;MKRN3;Makorin RING finger protein 3;Puberty initiation
摘要:
Puberty is initiated from the continuous and growing pulsatile secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus and then the activation of the hypothalamic-pituitary-gonadal (HPG) axis. Numerous factors involve pubertal initiation, whose abnormality may come from the dysfunction of these regulators. Makorin RING finger protein 3 (MKRN3) inhibits the secretion of GnRH and plays indispensable roles during the development of pubertal onset, and mutations of MKRN3 showed the commonest genetic cause of central precocious puberty (CPP). Recently, growing studies have revealed the functional mechanisms of MKRN3 in the pubertal initiation and the occurrence of CPP. In this review, we mainly summarized the research advances on the roles of MKRN3 in the development of pubertal onset and their underpinning mechanisms, contributing to a better understanding of the precise mechanisms of pubertal initiation and the pathogenesis of CPP.
关键词:
Breast cancer;Lead compounds;Multidrug resistance
摘要:
Chemotherapy is the mainstay in the treatment of breast cancer. However, many drugs that are commonly used in clinical practice have a high incidence of side effects and multidrug resistance (MDR), which is mainly caused by overexpression of drug transporters and related enzymes in breast cancer cells. In recent years, researchers have been working hard to find newer and safer drugs to overcome MDR in breast cancer. In this review, we provide the molecule mechanism of MDR in breast cancer, categorize potential lead compounds that inhibit single or multiple drug transporter proteins, as well as related enzymes. Additionally, we have summarized the structure-activity relationship (SAR) based on potential breast cancer MDR modulators with lower side effects. The development of novel approaches to suppress MDR is also addressed. These lead compounds hold great promise for exploring effective chemotherapy agents to overcome MDR, providing opportunities for curing breast cancer in the future.
作者机构:
[Zhang, Jing; Xie, Zhizhong; Lei, Xiaoyong; Ouyang, Chenglin; Tang, Guotao] Univ South China, Inst Pharm & Pharmacol, Hengyang Medicial Sch, Hunan Prov Key Lab Tumor Microenvironm Respons Dru, Hengyang 421001, Hunan, Peoples R China.;[Wang, Zhe] Univ South China, Affiliated Hosp 2, Hengyang Med Sch, Dept Pharm, Hengyang 421001, Hunan, Peoples R China.;[Li, Yong; Liu, Xingyun] Univ South China, Affiliated Nanhua Hosp, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Huang, Sheng] Jiuzhitang Co Ltd, Changsha 410007, Hunan, Peoples R China.
通讯机构:
[Zhe Wang] T;[Guotao Tang] I;The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China<&wdkj&>Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medicial School, University of South China, Hengyang, Hunan 421001, China
摘要:
Generally, hypoxia-inducible factor-1 alpha (HIF-1 alpha) is highly expressed in solid tumors, it plays a key role in the occurrence and development of tumors, hindering cancer treatment in various ways. The antitumor activity and pharmacological mechanism of YC-1 [3-(5 '-hydroxymethyl-2 '-furyl)-1-benzyl indazole], an HIF-1 alpha inhibitor, and the design and synthesis of its derivatives have attracted tremendous attention in the field of antitumor research. YC-1 is a potential drug candidate and a lead compound for tumor therapy. Hence, the multifaceted mechanism of action of YC-1 and the structure activity relationship (SAR) of its derivatives are important factors to be considered for the development of HIF-1 alpha inhibitors. Therefore, this review aimed to provide a comprehensive overview of the various antitumor mechanisms of YC-1 in antitumor research and an in-depth summary of the SAR for the development of its derivatives. A full understanding and discussion of these aspects are expected to provide potential ideas for developing novel HIF-1 alpha inhibitors and antitumor drugs belonging to the YC-1 class. The review also highlighted the application prospects of the YC-1 class of potential antitumor candidates, and provided some unique insights about these antitumor agents.
摘要:
Impaired endothelium-dependent vasodilation in atherosclerosis is a high-risk factor for myocardial infarction and ischemic stroke, and inflammation, necroptosis and apoptosis contribute to endothelial dysfunction in atherosclerosis. Although DL-3-n-butylphthalide (NBP) has been widely used in treating ischemic stroke, its effect on endothelium-dependent vasodilation remains unknown. This study aims to explore whether NBP is able to improve endothelium-dependent vasodilation in atherosclerosis and the underlying mechanisms. Male ApoE(-/-) mice were fed with a high-fat diet (HFD) for 9-16 weeks to establish a model of atherosclerosis. NBP were given to the mice after eating HFD for 6 weeks and atorvastatin served as a positive control. The endothelium-dependent vasodilation, the blood flow velocity, the atherosclerotic lesion area, the serum levels of lipids, inflammatory cytokines and necroptosis-relevant proteins (RIPK1, RIPK3 and MLKL), and the endothelial necroptosis and apoptosis within the aorta were measured. Human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low-density lipoprotein (ox-LDL) for 48h to mimic endothelial injury in atherosclerosis, lactate dehydrogenase release, the ratio of necroptosis and apoptosis and the expression of necroptosis-relevant proteins were examined. Similar to atorvastatin, NBP improves endothelium-dependent vasodilation, decreases aortic flow velocity and reduces atherosclerotic lesion area in HFD-fed ApoE(-/-) mice, concomitant with a reduction in serum lipids, inflammatory cytokines and necroptosis-relevant proteins, and endothelial necroptosis and apoptosis. Consistently, NBP inhibited necroptosis and apoptosis in ox-LDL-treated HUVECs. Based on these observations, we conclude that NBP exerts beneficial effects on improving the endothelium-dependent vasodilation in atherosclerosis via suppressing inflammation, endothelial necroptosis and apoptosis.
摘要:
With the continuous cognition of the relationship between tumor cells and tumor immune microenvironment, immunotherapy based on the immune checkpoint blockade has achieved great breakthroughs, led to improved clinical outcomes, and prolonged survival for cancer patients in recent years. Nevertheless, the de novo or acquired resistance to immunotherapy has greatly counteracted the efficacy, leading to a 20%-40% overall response rate. Thus, further in-depth understanding of the regulation of the tumor microenvironment and antitumor immunity is urgently warranted. Ubiquitination-mediated protein degradation plays vital roles in protein stabilization, activation, and dynamics as well as in cellular homeostasis modulation. The dysregulated ubiquitination and deubiquitination are closely related to the changes in physiological and pathological processes, which subsequently result in a variety of diseases including cancer. In this review, the authors first summarize the current knowledge about the involvement of the ubiquitin-proteasome system in tumor development with the ubiquitin conjugation-regulated stability of p53, phosphatase and tensin homolog, and Myc protein as examples, then dissect the potential implications of ubiquitination-mediated immune checkpoints degradation in tumor microenvironment and immune responses, and finally discuss the effects of therapeutically targeting the ubiquitin-proteasome pathway on immunotherapy, with the goal of providing deep insights into the exploitation of more precise and effective combinational therapy against cancer.
通讯机构:
[Yu, CY; Wei, H ] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang 421001, Peoples R China.;Univ South China, Dept Pharm & Pharmacol, Hengyang 421001, Peoples R China.
摘要:
Cyclic polymers with cleavable backbones triggered by either external or internal stimuli can realize simultaneous extracellular stability and intracellular destabilization of cyclic polymer-based nanocarriers but remain seldom reported. To this end, we prepared herein cyclic-ONB-P(OEGMA-st-DMAEMA) (c-ONB-P(OEGMA-st-DMAEMA)) with a light-cleavable junction in the polymer backbone based on oligo (ethylene glycol) monomethyl ether methacrylate (OEGMA) and N,N-dimethylaminoethyl methacrylate (DMAEMA) using a light-cleavable atom transfer radical polymerization (ATRP) initiator containing an o-nitrobenzyl (ONB) ester group. Together with the pH-sensitivity of DMAEMA, c-ONB-P(OEGMA-st-DMAEMA) shows a light-cleavable mainchain and pH-sensitive side chains. Notably, doxorubicin (DOX)-loaded c-ONB-P(OEGMA(4)-st-DMAEMA(38)) (C2) micelles mediated an IC(50) value of 2.28 μg/mL in Bel-7402 cells, which is 1.7-fold lower than that acquired without UV irradiation. This study thus reported the synthesis of a cyclic copolymer with a UV-cleavable backbone and uncovered the effects of topological modulation on the in vitro controlled release properties of cyclic polymers.
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.
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
作者机构:
[Wu, Yimou; Li, Yuehua; Wu, YM] Univ South China, Inst Pathogen Biol, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;[Zeng, Lijun; Zhu, Hongbo; Li, Yuehua; Tang, Yuanbin; Feng, Wenjie; Wan, Zhixing; Qi, Xiaowen; Xie, Liming; Zhu, HB] Univ South China, Affiliated Hosp 1, Dept Med Oncol, Hengyang 421001, Hunan, Peoples R China.;[Jiang, Baohong] Univ South China, Affiliated Hosp 1, Dept Pharm, Hengyang 421001, Hunan, Peoples R China.;[He, Rongfang] Univ South China, Affiliated Hosp 1, Dept Pathol, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Wu, YM ; Zhu, HB ] U;Univ South China, Inst Pathogen Biol, Hengyang Med Sch, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Affiliated Hosp 1, Dept Med Oncol, Hengyang 421001, Hunan, Peoples R China.
关键词:
CircCRIM1;Environmental factors;Exosomes;Immune infiltration;OGA;Triple-negative breast cancer
摘要:
Triple-negative breast cancer (TNBC) has an escalating morbidity and a dismal prognosis. Obesity has been reported to be strongly linked to adverse TNBC outcomes. Exosomes (Exos) transport RNA and proteins between cells and serve as intermediaries for cell-to-cell communication. Accumulated evidence suggests that adipose-secreted circular RNAs (circRNAs) can modulate protein glycosylation in TNBC to facilitate tumor cell outgrowth. Herein, exo-circCRIM1 expression was found to be elevated in TNBC patients with a high body fat percentage. Functional experiments demonstrated that by inhibiting miR-503-5p, exo-circCRIM1 enhanced TNBC evolution and metastasis while activating glycosylation hydrolase OGA. Furthermore, OGA negatively regulates FBP1 by decreasing its protein stability. Moreover, the levels of OGA and FBP1 were positively related to the infiltration level of some immune cells in TNBC. These findings indicate that exo-cirCRIM1 secreted by adipocytes contributes to TNBC progression by inhibiting miR-503-5p and activating the OGA/FBP1 signaling pathway. The findings reveal a novel intercellular signaling pathway mediated by adipose-derived exosomes and suggest that treatment targeting the secreted exosome-circCRIM1 may reverse TNBC progression.