摘要：
Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.
期刊：
International Immunopharmacology,2021年93(2):107411 ISSN：1567-5769
通讯作者：
Hu, Sihai;Long, Dingxin
作者机构：
[Wu, Xiaoxia; Hu, Sihai; Li, Zhenyu; Li, Yumeng; Hou, Yongli; Cao, Hui] Univ South China, Inst Pathogen Biol, Coll Med, Hengyang 421001, Peoples R China.;[Wang, Yan] Univ South China, Hosp 2, Operating Room, Hengyang 421001, Peoples R China.;[Long, Dingxin] Univ South China, Sch Publ Hlth, 28 West Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Long, Dingxin] C;[Hu, Sihai] I;Institute of Pathogenic Biology, Medical College, University of South China, Hengyang 421001, China. Electronic address:;China School of Public Health, University of South China, Hengyang 421001, China. Electronic address:
关键词：
Chitosan nanoparticle;Immunopotentiators;Moucosal vaccine;NMB0315;Neisseria meningitidis serogroup B
摘要：
Neisseria meningitidis (N. meningitidis) is a human-specific pathogen and a major cause of meningitis and septicemia with a high case fatality rate. N. meningitidis may penetrate the nasopharyngeal mucosal membrane and cause severe meningitis, a mucosal immune response plays a key role in the defense against meningococcal infections. Our previous study demonstrated that N. meningitidis serogroup B 0315 (NMB0315) was a vaccine candidate against N. meningitidis serogroup B (NMB) through parenteral immunization. In this study, immunopotentiators (C48/80 or CpG-ODN) were loaded into chitosan nanoparticle (Chi NP) to form combination adjuvants (Chi-CpG NP and Chi-C48/80 NP) and adopted to enhance the immunogenicity of NMB0315 through intranasal immunization. The experimental results have indicated that both Chi-CpG NP and Chi-C48/80 NP are effective mucosal adjuvants for the induction of significantly higher rNMB0315-specific IgG, IgG1, IgG2a and sIgA antibodies. Meanwhile, Chi-CpG NP and Chi-C48/80 NP could change the ratio of IgG1/IgG2a, inducing a more balanced cellular/humoral immune response. Chi-CpG NP and Chi-C48/80 NP also boosted interleukin-4 (IL-4), interferon-γ (IFN-γ) and interleukin-17 A (IL-17A) production by splenocytes. The bactericidal antibodies have been detected in sera from mice immunized with rNMB0315+Chi-CpG NP and rNMB0315+Chi-C48/80 NP. Overall, the combination adjuvants could be applicable to the development of a mucosal vaccine against NMB.
摘要：
<jats:title>Abstract</jats:title><jats:sec><jats:title>Aim</jats:title><jats:p>Cardiorenal syndrome type 4 (CRS4) is characterized by the condition that chronic kidney disease (CKD) causes sustainable injury to heart. This study focuses on exploring the mechanism underlying CRS4 and potential treatment for CRS4.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In the present study, Sprague Dawley (SD) rats were subjected to 5/6 subtotal nephrectomy (5/6NX) for generating animal model of CKD. Cardiac hypertrophy, kidney injury, Wnt/β‐catenin signalling and serum TNF‐α were tested at eighth week after 5/6NX.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Cardiac hypertrophy and kidney injury were prominent and accompanied by Wnt/β‐catenin activation in rats at eighth week after 5/6NX. Blockade of Wnt/β‐catenin by ICG‐001 reduced 5/6NX‐stimulated fibronectin and podocalyxin in remnant kidney. Interestingly, ICG‐001 also inhibited hypertrophic markers β‐MHC and α‐actin and reduced cardiac hypertrophy. In addition, TNF‐α, as a systemic inflammation factor in blood circulation, was suggested to connect CKD to cardiac hypertrophy. It was demonstrated in vitro and in vivo studies that ICG‐001 is sufficient to counteract TNF‐α‐induced cardiac hypertrophy by sequestration of β‐catenin.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These results demonstrate that Wnt/β‐catenin to be a unified pathogenic pathway of heart disorder and kidney disease in CRS4. Based on that, Wnt/β‐catenin signalling could be a target of promising therapy for protecting both heart and kidney organs in CRS4.</jats:p></jats:sec>
作者机构：
[Li, Tony W. H.; Lu, Shelly C.; Wang, Jiaohong; Fan, Wei; Li, Yuan; Seki, Ekihiro; Zhang, Jing; Xiong, Ting; Tu, Jian; Lu, Liqing; Yang, Heping; Peng, Hui] Cedars Sinai Med Ctr, Div Digest & Liver Dis, Los Angeles, CA 90048 USA.;[Li, Yuan; Liu, Ting] Cent South Univ, Xiangya Hosp, Dept Gastroenterol, 78 Xiangya Rd, Changsha 410083, Hunan, Peoples R China.;[Xiong, Ting; Lu, Liqing; Chen, Yongheng; Liu, Ting] Cent South Univ, Xiangya Hosp, Chinese Minist Hlth, Key Lab Canc Prote, Changsha, Peoples R China.;[Tu, Jian] Univ South China, Inst Pharm & Pharmacol, Hengyang, Peoples R China.;[Zhang, Jing] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Oncol, Wuhan, Peoples R China.
通讯机构：
[Liu, Ting; Lu, Shelly C.; Yang, Heping] C;Cent South Univ, Xiangya Hosp, Dept Gastroenterol, 78 Xiangya Rd, Changsha 410083, Hunan, Peoples R China.;Cedars Sinai Med Ctr, Dept Med, Div Digest & Liver Dis, Davis Bldg,Room 2097,8700 Beverly Blvd, Los Angeles, CA 90048 USA.;Cedars Sinai Med Ctr, Dept Med, Div Digest & Liver Dis, Davis Bldg,Room 2094B,8700 Beverly Blvd, Los Angeles, CA 90048 USA.
摘要：
<jats:sec>
<jats:title>Background and Aims</jats:title>
<jats:p>Forkhead box M1 (FOXM1) and nuclear factor kappa B (NF‐ĸB) are oncogenic drivers in liver cancer that positively regulate each other. We showed that methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor in the liver and inhibits NF‐ĸB activity. Here, we examined the interplay between FOXM1/NF‐κB and MAT1A in liver cancer.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Approach and Results</jats:title>
<jats:p>We examined gene and protein expression, effects on promoter activities and binding of proteins to promoter regions, as well as effects of FOXM1 inhibitors T0901317 (T0) and forkhead domain inhibitory‐6 (FDI‐6) <jats:italic toggle="yes">in vitro</jats:italic> and in xenograft and syngeneic models of liver cancer. We found, in both hepatocellular carcinoma and cholangiocarcinoma, that an induction in FOXM1 and NF‐κB expression is accompanied by a fall in MATα1 (protein encoded by MAT1A). The Cancer Genome Atlas data set confirmed the inverse correlation between FOXM1 and MAT1A. Interestingly, FOXM1 directly interacts with MATα1 and they negatively regulate each other. In contrast, FOXM1 positively regulates p50 and p65 expression through MATα1, given that the effect is lost in its absence. FOXM1, MATα1, and NF‐κB all bind to the FOX binding sites in the <jats:italic toggle="yes">FOXM1</jats:italic> and <jats:italic toggle="yes">MAT1A</jats:italic> promoters. However, binding of FOXM1 and NF‐κB repressed <jats:italic toggle="yes">MAT1A</jats:italic> promoter activity, but activated the <jats:italic toggle="yes">FOXM1</jats:italic> promoter. In contrast, binding of MATα1 repressed the <jats:italic toggle="yes">FOXM1</jats:italic> promoter. MATα1 also binds and represses the NF‐κB element in the presence of p65 or p50. Inhibiting FOXM1 with either T0 or FDI‐6 inhibited liver cancer cell growth <jats:italic toggle="yes">in vitro</jats:italic> and <jats:italic toggle="yes">in vivo</jats:italic>. However, inhibiting FOXM1 had minimal effects in liver cancer cells that do not express MAT1A.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>We have found a crosstalk between FOXM1/NF‐κB and MAT1A. Up‐regulation in FOXM1 lowers MAT1A, but raises NF‐κB, expression, and this is a feed‐forward loop that enhances tumorigenesis.</jats:p>
</jats:sec>
摘要：
As a unique type of RNA, circular RNAs (circRNAs) are important regulators of multiple biological processes in the progression of cancer. However, the potential role of most circRNAs in breast cancer lung metastasis is still unknown. In this study, we characterized and further investigated circIQCH (hsa_circ_0104345) by analyzing the circRNA microarray profiling in our previous study. circIQCH was upregulated in breast cancer tissues, especially in the metastatic sites. CCK-8, transwell, wound-healing and mouse xenograft assays were carried out to investigate the functions of circIQCH. Knockdown of circIQCH inhibited breast cancer cell proliferation and migration to lung. Moreover, luciferase reporter assays and RNA immunoprecipitation assays were performed to elucidate the underlying molecular mechanism of circIQCH. The results showed that circIQCH sponges miR-145 and promotes breast cancer progression by upregulating DNMT3A. In summary, our study demonstrated the pivotal role of circIQCH-miR-145-DNMT3A axis in breast cancer growth and metastasis via the mechanism of competing endogenous RNAs. Thus, circIQCH could be a potential therapeutic target for breast cancer.
摘要：
<jats:p>The chlamydial plasmid, an essential virulence factor, encodes plasmid proteins that play important roles in chlamydial infection and the corresponding immune response. However, the virulence factors and the molecular mechanisms of <jats:italic>Chlamydia psittaci</jats:italic> are not well understood. In the present study, we investigated the roles and mechanisms of the plasmid-encoded protein CPSIT_P7 of <jats:italic>C. psittaci</jats:italic> in regulating the inflammatory response in THP-1 cells (human monocytic leukemia cell line). Based on cytokine arrays, CPSIT_P7 induces the expression of interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1) in THP-1 cells. Moreover, the expression levels of IL-6, IL-8, and MCP-1 stimulated by CPSIT_P7 declined after silencing of the Toll-like receptor 4 (TLR4) gene using small interfering RNA and transfection of a dominant negative plasmid encoding TLR4 (pZERO-hTLR4). We further demonstrated that transfection with the dominant negative plasmid encoding MyD88 (pDeNy-hMyD88) and the dominant negative plasmid encoding Mal (pDeNy-hMal) could also abrogate the expression of the corresponding proteins. Western blot and immunofluorescence assay results showed that CPSIT_P7 could activate nuclear factor κB (NF-κB) signaling pathways in THP-1 cells. Altogether, our results indicate that the CPSIT_P7 induces the TLR4/Mal/MyD88/NF-κB signaling axis and therefore contributes to the inflammatory cytokine response.</jats:p>
摘要：
In this study, we investigated the association between TP53 somatic mutations and immunotherapeutic outcomes in non-small cell lung cancer (NSCLC) patients. Kaplan-Meier survival curve analysis of the MSK-IMPACT cohort of 350 NSCLC patients shows that overall survival (OS) is significantly lower for patients with truncating TP53 mutations than those with wild-type TP53 (OS: 9 months vs. 14 months; P=0.019). Multivariate analysis shows that truncating TP53 mutations are an independent predictor of immunotherapeutic outcomes. Moreover, among NSCLC patients with lower tumor mutation burden (TMB), those with TP53 truncating mutations showed significantly lower OS than those with wild-type TP53 [hazard ratio (HR) = 1.40, confidence interval (CI) = 1.13-1.73; P = 0.002]. TP53 mutations correlate with higher infiltration of CD8(+) T cells, neutrophils and dendritic cells in lung adenocarcinoma tissues. A prognostic model with TP53 mutational status shows better survival prediction than the model without TP53 mutational status 1-year [area under curve (AUC): 64.9% vs. 60.2%; P = 0.052] and 2-years (AUC: 70.9% vs. 66.1%; P = 0.098) post-immunotherapy. These findings demonstrate that truncating TP53 mutations correlate with poor immunotherapy outcomes in NSCLC patients with low TMB. TP53 mutation status also improves the prognostic prediction in NSCLC patients that underwent immunotherapy.
作者机构：
[Tian, Xiao-Ting; Ba, Hui-Xue; Cao, Yuan-Yuan; Li, Xiao-Hui] Cent South Univ, Xiangya Sch Pharmaceut Sci, Dept Pharmacol, Changsha 410013, Peoples R China.;[Li, Ke] Hunan Acad Tradit Chinese Med, Changsha 410013, Hunan, Peoples R China.;[Li, Ying] Cent South Univ, Xiangya Hosp 3, Dept Hlth Management, Changsha, Peoples R China.;[Li, Xiao-Hui] Hunan Key Lab Bioanal Complex Matrix Samples, Changsha, Peoples R China.;[Wang, Aiping] Univ South China, Nanhua Affiliated Hosp, Inst Clin Res, Hengyang, Peoples R China.
通讯机构：
[Ke Li] H;[Xiao-Hui Li] D;Hunan Academy of Traditional Chinese Medicine, Hunan, China<&wdkj&>Department of Pharmacology, Xiangya School of Pharmaceutical Science, Central South University, Changsha, China<&wdkj&>Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, China
期刊：
Journal of Neuroinflammation,2020年17(1):1-16 ISSN：1742-2094
通讯作者：
Hou, Lin;Yuan, Zengqiang;Cheng, Jinbo
作者机构：
[Dong, Yuan; Hou, Lin] Qingdao Univ, Med Coll, Dept Biochem, Qingdao 266071, Shandong, Peoples R China.;[Li, Shuoshuo] Chinese Acad Sci, Inst Biophys, State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China.;[Li, Shuoshuo] Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China.;[Lu, Yiming] Beijing Inst Radiat Med, Beijing 100850, Peoples R China.;[Dong, Yuan; Li, Xiaoheng; Yuan, Zengqiang; Cheng, Jinbo; Yuan, ZQ] Beijing Inst Basic Med Sci, Brain Sci Ctr, 27 Taiping Rd, Beijing 100850, Peoples R China.
通讯机构：
[Hou, Lin] Q;[Yuan, ZQ; Cheng, JB] B;[Cheng, Jinbo] M;Qingdao Univ, Med Coll, Dept Biochem, Qingdao 266071, Shandong, Peoples R China.;Beijing Inst Basic Med Sci, Brain Sci Ctr, 27 Taiping Rd, Beijing 100850, Peoples R China.
关键词：
Fear memory;PTSD;NLRP3 inflammasome;Neuroinflammation;Postsynaptic density
摘要：
Persistent inflammation dysregulation and cognitive decline have been associated with several trauma- and stress-related disorders such as posttraumatic stress disorder (PTSD) and anxiety disorder. Despite the abundant discoveries of neuroinflammation in such disorders, the underlying mechanisms still remain unclear. Wild-type and Nlrp3−/− mice were exposed to the electric foot shocks in the contextual fear memory paradigm. Three hours after the electric foot shocks, activation of the NLRP3 inflammasome was investigated through immunoblotting and ELISA. Microglia were isolated and analyzed by quantitative real-time PCR. Hippocampal tissues were collected 3 h and 72 h after the electric foot shocks and subjected to RNA sequencing. MCC950 was administrated to mice via intraperitoneal (i.p.) injection. Interleukin-1 receptor antagonist (IL-ra) and interleukin-1β (IL-1β) were delivered via intracerebroventricular (i.c.v.) infusion. Contextual fear responses of mice were tested on 4 consecutive days (test days 1-4) starting at 48 h after the electric foot shocks. Anxiety-like behaviors were examined by elevated plus maze and open-field test. We demonstrated that, in the contextual fear memory paradigm, the NLRP3 inflammasome was activated 3 h after electric foot shocks. We also found an upregulation in toll-like receptor and RIG-I-like receptor signaling, and a decrease in postsynaptic density (PSD) related proteins, such as PSD95 and Shank proteins, in the hippocampus 72 h after the electric foot shocks, indicating an association between neuroinflammation and PSD protein loss after stress encounter. Meanwhile, Nlrp3 knockout could significantly prevent both neuroinflammation and loss of PSD-related proteins, suggesting a possible protective role of NLRP3 deletion during this process. For further studies, we demonstrated that both genetic knockout and pharmaceutical inhibition of the NLRP3 inflammasome remarkably enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior caused by electric foot shocks. Moreover, cytokine IL-1β administration inhibited the extinction of contextual fear memory. Meanwhile, IL-1ra significantly enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior. Taken together, our data revealed the pivotal role of NLRP3 inflammasome activation in the regulation of fear memory and the development of PTSD and anxiety disorder, providing a novel target for the clinical treatment of such disorders.
摘要：
Gastric cancer (GC) is the fifth most common primary malignancy in humans. Rho GDP dissociation inhibitor 2 (RhoGDI2) is overexpressed in multiple cancer types, but the role of RhoGDI2 in GC has not been elucidated. This study aims to determine the level of RhoGDI2 in GC and to confirm the effect of its inhibition or overexpression on GC cell migration, invasion and chemosensitivity. RhoGDI2 level is significantly enhanced in human GC tissue samples in comparison with normal gastric epithelium and corresponding para-cancerous samples. The expression of RhoGDI2 is correlated with clinicopathological parameters and prognosis. Transfection in combination with miRNA targeting of RhoGDI2 in GC cell lines remarkably downregulates GC cell migration and invasion and reduces the mRNA levels of Rac1, Pak1 and LIMK1. The inhibition of RhoGDI2 downregulates GC cell migration and invasion by attenuating the EMT cascade via the Rac1/Pak1/LIMK1 pathway. Knockdown of RhoGDI2 is a potential therapeutic strategy for GC.
