摘要:
Capsaicin is the main active ingredient of chili peppers and the most pungent alkaloid. It is reported that capsaicin has many pharmacological effects such as analgesia, anticancer, anti-inflammatory, antibacterial, and anti-obesity. However, the application of capsaicin is limited by its adverse side effects, such as stomach irritation, stomach cramps, and burning sensation. In recent years, many capsaicin derivatives have been synthesized and their biological activities have been evaluated. Some capsaicin derivatives have shown promising activities in cells and animal models. Herein, we described the synthesis and biological activity of capsaicin and its derivatives. It is hoped that the insights obtained in this perspective will facilitate the synthesis of a second generation of capsaicin analogs with improved biological activities.
期刊:
Cancer Cell International,2024年24(1):1-21 ISSN:1475-2867
通讯作者:
Tan, Yeru;Li, YH
作者机构:
[Jiang, Baohong] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Pharm, Hengyang, Hunan, Peoples R China.;[Zeng, Lijun; Tan, Yeru; Li, YH; Li, Yuehua; Tang, Yuanbin; Luo, Lunqi; Ouyang, Lianjie; Feng, Wenjie; Tan, YR; Wu, Sixuan] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Oncol, Hengyang, Hunan, Peoples R China.;[Wu, Sixuan] Fujian Med Univ, Fujian Canc Hosp, Clin Oncol Sch, Fuzhou, Fujian, Peoples R China.
通讯机构:
[Li, YH ; Tan, YR] U;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Dept Oncol, Hengyang, Hunan, Peoples R China.
关键词:
Breast cancer;NDUFAF6;NRF2;PD-L1;Immune infiltration;Prognosis
摘要:
Breast cancer is a major global health concern, and there is a continuous search for novel biomarkers to predict its prognosis. The mitochondrial protein NDUFAF6, previously studied in liver cancer, is now being investigated for its role in breast cancer. This study aims to explore the expression and functional significance of NDUFAF6 in breast cancer using various databases and experimental models. We analyzed breast cancer samples from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Human Protein Atlas (HPA) databases, supplemented with immunohistochemistry (IHC) staining to assess NDUFAF6 expression. A breast cancer cell xenograft mouse model was used to evaluate tumor growth, apoptosis, and NDUFAF6 expression. Survival probabilities were estimated through Kaplan–Meier plots and Cox regression analysis. A Protein–Protein Interaction (PPI) network was constructed, and differentially expressed genes related to NDUFAF6 were analyzed using GO, KEGG, and GSEA. The relationship between NDUFAF6 expression, immune checkpoints, and immune infiltration was also evaluated. NDUFAF6 was found to be overexpressed in breast cancer patients and in the xenograft mouse model. Its expression correlated with worse clinical features and prognosis. NDUFAF6 expression was an independent predictor of breast cancer outcomes in both univariate and multivariate analyses. Functionally, NDUFAF6 is implicated in several immune-related pathways. Crucially, NDUFAF6 expression correlated with various immune infiltrating cells and checkpoints, particularly promoting PD-L1 expression by inhibiting the NRF2 signaling pathway. The study establishes NDUFAF6 as a potential prognostic biomarker in breast cancer. Its mechanism of action, involving the inhibition of NRF2 to upregulate PD-L1, highlights its significance in the disease's progression and potential as a target for immunotherapy.
摘要:
Canopy FGF signaling regulator 2 (CNPY2) is a novel angiogenic growth factor. In recent years, increasing evidence highlights that CNPY2 has important functions in health and disease. Many new blood vessels need to be formed to meet the nutrient supply in the process of tumor growth. CNPY2 can participate in the development of tumors by promoting angiogenesis. CNPY2 also enhances neurite outgrowth in neurologic diseases and promotes cell proliferation and tissue repair, thereby improving cardiac function in cardiovascular diseases. Regrettably, there are few studies on CNPY2 in various diseases. At the same time, its biological function and molecular mechanism in the process and development of disease are still unclear. This paper reviews the recent studies on CNPY2 in cervical cancer, renal cell carcinoma, prostate cancer, colorectal cancer, lung cancer, gastric cancer, hepatocellular carcinoma, cerebral ischemia-reperfusion injury, spinal cord ischemia-reperfusion injury, Parkinson's disease, ischemic heart disease, myocardial ischemia-reperfusion injury, myocardial infarction, heart failure, and non-alcoholic fatty liver disease. The biological function and molecular mechanism of CNPY2 in these diseases have been summarized in this paper. Many drugs that play protective roles in tumors, cardiovascular diseases, non-alcoholic fatty liver disease, and neurologic diseases by targeting CNPY2, have also been summarized in this paper. In addition, the paper also details the biological functions and roles of canopy FGF signaling regulator 1 (CNPY1), canopy FGF signaling regulator 3 (CNPY3), canopy FGF signaling regulator 4 (CNPY4), and canopy FGF signaling regulator 5 (CNPY5). The mechanism and function of CNPY2 should be continued to study in order to accelerate disease prevention in the future.
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.
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:
Naunyn-Schmiedeberg's Archives of Pharmacology,2024年397(1):627-627 ISSN:0028-1298
通讯作者:
Xiao, Junhui;Li, R
作者机构:
[Shen, Lixian; Tang, Lijing; Li, Rong; Li, R; Xiao, Junhui; Wang, Mei; Xiao, JH; Liu, Meng] Univ South China, Affiliated Hosp 2, Hengyang Med Sch, Dept Pharm, Hengyang 421001, Hunan, Peoples R China.;[Wang, Mei; Liu, Meng] Univ South China, Sch Pharmaceut Sci, Hengyang Med Sch, Dept Pharm & Pharmacol, Hengyang 421000, Hunan, Peoples R China.
通讯机构:
[Li, R ; Xiao, JH] U;Univ South China, Affiliated Hosp 2, Hengyang Med Sch, Dept Pharm, Hengyang 421001, Hunan, Peoples R China.
关键词:
Doxorubicin;Ferroptosis;Liquiritin;Solute carrier family 7 member;Glutathione peroxidase 4
摘要:
Solute carrier family 7 member (SLC7A11) and glutathione peroxidase 4 (GPX4) mediated ferroptosis in doxorubicin-induced cardiotoxicity. Based on the bioinformatics analysis, liquiritin, a flavonoid isolated from the rhizome part of Glycyrrhiza glabra with activities of anti-inflammatory and anti-oxidant, is forecasted to synchronously with ferroptosis-relevant protein. This study aims to investigate the effect of liquiritin on doxorubicin-induced cardiotoxicity and the underlying mechanisms. The C57BL/6 J mice heart or cardiomyocytes were subjected to doxorubicin in vivo or in vitro, which were treated with liquiritin at different dosages. The heart or H9c2 cell cardiotoxicity, relevant protein levels, and ferroptosis were measured by methods of biochemistry, flow cytometry, or Western blot. The mice treated with doxorubicin showed evident cardiotoxicity, concomitant with the downregulation of SLC7A11 and GPX4, and accelerate ferroptosis. Administration of liquiritin could relieve the heart injury, accompanied by restoration of the levels of SLC7A11 and GPX4, and inhibit ferroptosis. And liquiritin ameliorated similar effects in doxorubicin-treated H9c2 cells. Based on these findings, we conclude that liquiritin can protect the doxorubicin-induce mice's cardiotoxicity, and its beneficial effect is related to the reduction of ferroptosis through a mechanism involving the regulation of the SLC7A11/GPX4 pathway.
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:
BACKGROUND: Potassium bismuth citrate is a gastric mucosal protector and a key drug for treating peptic ulcers. OBJECTIVE: To evaluate the pharmacokinetic characteristics and safety of 120-mg bismuth potassium citrate formulations administered orally under fasting conditions in healthy Chinese subjects. METHOD: A single-center open two-cycle trial was conducted on 12 healthy subjects who received a single oral dose of 120 mg of bismuth potassium citrate. The plasma concentration of bismuth was determined using a validated inductively coupled plasma mass spectrometry (ICP‒MS) method. The pharmacokinetic parameters, including maximum serum concentration (C(max)) and area under the curve concentration-time curve (AUC(0-t) and AUC(0-∞)), and safety were evaluated via noncompartment analysis. RESULTS: The ratios of the least square geometric mean ratio between the test (T) and reference (R) formulations for C(max), AUC(0-t), and AUC(0-∞) were 44.8%, 55.5%, and 64.4%, respectively; the bilateral 95% confidence intervals (Cis) for these parameters were 20.2-99.6%, 24.1-127.5%, and 23.7-175.0%, respectively, and the non-inferior limits for these parameters were 169.4%, 198.8%, and 200.5%, respectively. The upper limits of the one-sided 97.5% confidence interval for the least squares geometric mean ratio (T/R) were lower than the non-inferior limits. No serious adverse reactions or adverse reactions leading to detachment were observed among the subjects. CONCLUSION: The concentration of bismuth in the blood of healthy subjects in the T formulation was not greater than that in the R formulation. Similarly, the safety of oral administration of 120 mg of bismuth potassium citrate formulations to healthy subjects was good. The trial registration number (TRN) was [2018] 013, 6 December 2018.
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.
期刊:
Macromolecular Chemistry and Physics,2024年225(4):2300335- ISSN:1022-1352
通讯作者:
Shi, YF;Wei, H
作者机构:
[Zhang, Xianshuo; Shi, YF; Wang, Peipei; Shi, Yunfeng; Hou, Shuo; Niu, Wenxu] Anyang Normal Univ, Henan Prov Engn & Technol Res Ctr Precise Synth Fl, Henan Prov Key Lab New Optoelect Funct Mat, Anyang 455000, Henan, Peoples R China.;[Zhang, Xianshuo; Shi, YF; Wang, Peipei; Shi, Yunfeng; Hou, Shuo; Niu, Wenxu] Anyang Normal Univ, Sch Chem & Chem Engn, Anyang 455000, Henan, Peoples R China.;[Wei, Hua; Ma, Wei; Wei, H; Yu, Cui-Yun] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang 421001, Peoples R China.;[Wei, Hua; Ma, Wei; Wei, H; Yu, Cui-Yun] Univ South China, Dept Pharm & Pharmacol, Hengyang 421001, Peoples R China.;[Kang, Guiying] Tianshui Normal Univ, Coll Chem Engn & Technol, Tianshui 741000, Gansu, Peoples R China.
通讯机构:
[Wei, H ] U;[Shi, YF ] A;Anyang Normal Univ, Henan Prov Engn & Technol Res Ctr Precise Synth Fl, Henan Prov Key Lab New Optoelect Funct Mat, Anyang 455000, Henan, Peoples R China.;Anyang Normal Univ, Sch Chem & Chem Engn, Anyang 455000, Henan, Peoples R China.;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dru, Hengyang 421001, Peoples R China.
关键词:
micelle, controlled drug release;poly(tertiary amine-oxide);reduction sensitivity;zwitterionic
摘要:
Poly(tertiary amine-oxide)-based polymeric nanocarriers have showed more functionalities than stealthy PEG-based analogs due to the structure of phospholipid affinitive N-oxides groups, which has attracted considerable attention to the synthesis of various zwitterionic copolymers with tertiary amine-oxide grafts for enhanced anticancer drug delivery. However, poly(tertiary amine-oxide)-based amphiphilic copolymers with tumor intracellular microenvironment sensitivities, to the knowledge, have been rarely reported likely due to the lack of a controlled synthetic strategy. Herein, a reducible zwitterionic copolymer, poly(epsilon-caprolactone)25-SS-poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)30 (PCL25-SS-OPDEA30) is designed and synthesized successfully via combination of controlled polymerization techniques and post polymerization modification. Specifically, postoxidation of poly(tertiary amine) is confirmed to be a better synthetic strategy toward a well-defined polymer structure relative to direct polymerization of N,N-diethylaminoethyl methacrylate (ODEA). The effect of disulfide bridges on the self-assembly behaviors, in vitro drug loading and drug release properties is investigated in detail. Notablely, the resulting micelles self-assembled from PCL25-SS-OPDEA30 show much greater colloidal stability, higher drug loading content (DLC), and better in vitro tumor cell inhibition than the reduction-insensitive counterparts. Overall, this study reports a robust strategy toward zwitterionic nanomedicines for on-demand anticancer drug delivery. A reducible zwitterionic block copolymer, poly(epsilon-caprolactone)25-SS-poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)30 (PCL25-SS-OPDEA30) is synthesized via atom transfer radical polymerization and post polymerization modification. Postoxidation is confirmed to be a synthetic strategy better than direct monomer polymerization for a well-defined polymer structure. The resulting self-assembled zwitterionic nanomedicines show much greater colloidal stability, higher drug loading content, and better in vitro tumor cell inhibition than the reduction-insensitive counterparts.image
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.
期刊:
Computational and Structural Biotechnology Journal,2024年23:77-86 ISSN:2001-0370
通讯作者:
Zhang, Jian;Zhu, J;Li, CQ
作者机构:
[Zhang, Jian; Gao, Yu; Zhao, Jun; Zhu, Jiang; Zhang, J] Harbin Med Univ, Sch Med Informat, Daqing Campus, Daqing 163319, Peoples R China.;[Wang, Qiuyu; Li, Chunquan; Song, Chao] Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Cardiovasc Lab Big Data & Imaging Artificial Intel, Hengyang 421001, Hunan, Peoples R China.;[Feng, Chenchen; Wang, Qiuyu; Song, Chao; Yin, Mingxue; Li, Chunquan] Univ South China, Sch Comp, Hengyang 421001, Hunan, Peoples R China.;[Wang, Qiuyu; Song, Chao; Yin, Mingxue; Li, Chunquan] Univ South China, Hunan Prov Key Lab Multiomics&Artificial Intellige, Hengyang 421001, Hunan, Peoples R China.;[Wang, Qiuyu; Yin, Mingxue; Li, Chunquan] Univ South China, Sch Basic Med Sci, Hengyang Med Sch, Dept Biochem & Mol Biol, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Li, CQ ] U;[Zhang, J; Zhu, J ] H;Harbin Med Univ, Sch Med Informat, Daqing Campus, Daqing 163319, Peoples R China.;Univ South China, Affiliated Hosp 1, Hengyang Med Sch, Cardiovasc Lab Big Data & Imaging Artificial Intel, Hengyang 421001, Hunan, Peoples R China.
关键词:
Single cell integration database;Cell heterogeneity;Multi-method automatic cell-type annotation;Cell to cell communication
摘要:
Single-cell RNA sequencing (scRNA-seq), which profiles gene expression at the cellular level, has effectively explored cell heterogeneity and reconstructed developmental trajectories. With the increasing research on diseases and biological processes, scRNA-seq datasets are accumulating rapidly, highlighting the urgent need for collecting and processing these data to support comprehensive and effective annotation and analysis. Here, we have developed a comprehensive Single -Cell transcriptome integration database for human and mouse (SCInter, https://bio.liclab.net/SCInter/index.php), which aims to provide a manually curated database that supports the provision of gene expression profiles across various cell types at the sample level. The current version of SCInter includes 115 integrated datasets and 1016 samples, covering nearly 150 tissues/cell lines. It contains 8016,646 cell markers in 457 identified cell types. SCInter enabled comprehensive analysis of cataloged single-cell data encompassing quality control (QC), clustering, cell markers, multi-method cell type automatic annotation, predicting cell differentiation trajectories and so on. At the same time, SCInter provided a user-friendly interface to query, browse, analyze and visualize each integrated dataset and single cell sample, along with comprehensive QC reports and processing results. It will facilitate the identification of cell type in different cell subpopulations and explore developmental trajectories, enhancing the study of cell heterogeneity in the fields of immunology and oncology.
摘要:
In recent years, there has been a growing interest in antimicrobial peptides as innovative antimicrobial agents for combating drug-resistant bacterial infections, particularly in the fields of biofilm control and eradication. In the present study, a novel cationic antimicrobial peptide, named LC-AMP-F1, was derived from the cDNA library of the Lycosa coelestis venom gland. The sequence, physicochemical properties and secondary structure of LC-AMP-F1 were predicted and studied. LC-AMP-F1 was tested for stability, cytotoxicity, drug resistance, antibacterial activity, and antibiofilm activity in vitro compared with melittin, a well-studied antimicrobial peptide. The findings indicated that LC-AMP-F1 exhibited inhibitory effects on the growth of various bacteria, including five strains of multidrug-resistant bacteria commonly found in clinical settings. Additionally, LC-AMP-F1 demonstrated effective inhibition of biofilm formation and disruption of mature biofilms. Furthermore, LC-AMP-F1 exhibited favorable stability, minimal hemolytic activity, and low toxicity towards different types of eukaryotic cells. Also, it was found that the combination of LC-AMP-F1 with conventional antibiotics exhibited either synergistic or additive therapeutic benefits. Concerning the antibacterial mechanism, scanning electron microscopy and SYTOX Green staining results showed that LC-AMP-F1 increased cell membrane permeability and swiftly disrupted bacterial cell membranes to exert its antibacterial effects. In summary, the findings and studies facilitated the development and clinical application of novel antimicrobial agents.
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.
通讯机构:
[Wang, PY; Liu, XL ] C;Chinese Acad Sci, Key Lab Design & Assembly Funct Nanostruct, Fujian Inst Res Struct Matter, Fuzhou 350002, Peoples R China.;Fujian Agr & Forestry Univ, Coll Life Sci, Fuzhou 350002, Peoples R China.;Hosp Fujian Med Univ, United Innovat Mengchao Hepatobiliary Technol Key, Mengchao Hepatobiliary, Fuzhou 350025, Peoples R China.
摘要:
Triggering the healing process of drug-resistant bacteria-infected wounds has attracted great attention due to global morbidity that may induce gangrene, amputation, and even death. Here, a chitin derivative, carboxymethyl chitosan (CMC), tannic acid (TA), and Cu(2+) were used for hydrogel engineering. Using sodium bicarbonate as the neutralizer and reductant, hydrogen bonds between CMC and TA and in situ Cu(OH)(2) generation via ion coordination force between Cu(2+) and TA facilitated the synthesis of CMC/TA/Cu hydrogel. Cu(2+) and TA release, cytotoxicity, in vitro cell migration, angiogenesis, and antidrug-resistant bacteria were measured. Besides, wound closure was evaluated in vivo using the methicillin-resistant Staphylococcus aureus (MRSA)-infected excisional dermal wound mouse model. Negligible toxicity was observed both in vitro and in vivo. Dermal cell migration and angiogenesis were significantly enhanced. In vivo, the CMC/TA/Cu hydrogel induced effective re-epithelialization, collagen deposition, inflammatory alleviation, and MRSA inhibition during wound repair in mice. All these results confirmed that the CMC/TA/Cu hydrogel is a promising novel dressing for chronic wound healing in clinic.
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.