Biology Direct
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2024
·Vol. 19
·期 1
·1-18
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IF 5.7
Liu Xiao-Mei,Wang Zi-Hao,Wei Qian-Xue,Song Yang,Ma Xiao-Xin
Choriocarcinoma is a malignant cancer that belongs to gestational trophoblastic neoplasia (GTN). Herein, serum metabolomic analysis was performed on 29 GTN patients and 30 healthy individuals to characterize the metabolic variations during GTN progression. Ultimately 24 differential metabolites (DMs) were identified, of which, Equol was down-regulated in GTN patients, whose VIP score is the 3rd highest among the 24 DMs. As an intestinal metabolite of daidzein, the anticancer potential of Equol has been demonstrated in multiple cancers, but not choriocarcinoma. Hence, human choriocarcinoma cell lines JEG-3 and Bewo were used and JEG-3-derived subcutaneous xenograft models were developed to assess the effect of Equol on choriocarcinoma. The results suggested that Equol treatment effectively suppressed choriocarcinoma cell proliferation, induced cell apoptosis, and reduced tumorigenesis. Label-free quantitative proteomics showed that 136 proteins were significantly affected by Equol and 20 proteins were enriched in Gene Ontology terms linked to protein degradation. Tripartite motif containing 21 (TRIM21), a E3 ubiquitin ligase, was up-regulated by Equol. Equol-induced effects on choriocarcinoma cells could be reversed by TRIM21 inhibition. Annexin A2 (ANXA2) interacted with TRIM21 and its ubiquitination was modulated by TRIM21. We found that TRIM21 was responsible for proteasome-mediated degradation of ANXA2 induced by Equol, and the inhibitory effects of Equol on the malignant behaviors of choriocarcinoma cells were realized by TRIM21-mediated down-regulation of ANXA2. Moreover, β-catenin activation was inhibited by Equol, which also depended on TRIM21-mediated down-regulation of ANXA2. Taken together, Equol may be a novel candidate for the treatment for choriocarcinoma.Graphical abstract
研究领域:
肿瘤学
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分子生物学
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代谢组学
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蛋白质组学
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癌症生物学
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高影响因子
Cancer Communications
·
2023
·Vol. 43
·期 4
·480-502
·
IF 16.2
Daojia Miao,Qi Wang,Jian Shi,Qingyang Lv,Diaoyi Tan,Chuanyi Zhao,Zhiyong Xiong,Xiaoping Zhang
Background The mechanism of metabolism reprogramming is an unsolved problem in clear cell renal cell carcinoma (ccRCC). Recently, it was discovered that the Hippo pathway altered tumor metabolism and promoted tumor progression. Thus, this study aimed at identifying key regulators of metabolism reprogramming and the Hippo pathway in ccRCC and pinpointing potential therapeutic targets for ccRCC patients. Methods Hippo-related gene sets and metabolic gene sets were used to screen potential regulators of the Hippo pathway in ccRCC. Public databases and samples from patients were applied to investigate the association of dihydrolipoamide branched chain transacylase E2 ( DBT ) with ccRCC and Hippo signaling. The role of DBT was confirmed by gain or loss of function assays in vitro and in vivo. Mechanistic results were yielded by luciferase reporter assay, immunoprecipitation, mass spectroscopy, and mutational studies. Results DBT was confirmed as a Hippo-related marker with significant prognostic predictive value, and its downregulation was caused by methyltransferase-like-3 (METTL3)-mediated N6-methyladenosine (m 6 A) modification in ccRCC. Functional studies specified DBT as a tumor suppressor for inhibiting tumor progression and correcting the lipid metabolism disorder in ccRCC. Mechanistic findings revealed that annexin A2 (ANXA2) interacted with the lipoyl-binding domain of DBT to activate Hippo signaling which led to decreased nuclear localization of yes1-associated transcriptional regulator (YAP) and transcriptional repression of lipogenic genes. Conclusions This study demonstrated a tumor-suppressive role for the DBT/ANXA2/YAP axis-regulated Hippo signaling and suggested DBT as a potential target for pharmaceutical intervention in ccRCC.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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代谢组学
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表观遗传学
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BRITISH JOURNAL OF PHARMACOLOGY
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2025
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IF 7.7
Wenjing Wei,Abudureyimu Alimujiang,Zehua Zhang,Zulipikaer Wusiman,Xiangran Liu,Yong Zhu,Yipeng Bai,Ziqi Zhu,Zhijian Li,Dengqiu Xu,Shixia Huo
Background and Purpose Vitiligo, a common depigmenting skin disorder, is characterised by the selective loss of melanocytes, which leads to distinctive non-scaly, chalky-white macules. Galangin is a flavonoid found in galangal and propolis; our previous study highlighted the therapeutic potential of galangin. However, the contributions of galangin to restoring skin pigmentation and maintaining immune homeostasis, as well as its detailed molecular roles in vitiligo management, have not been fully elucidated. Experimental Approach We used C57BL/6J mice with H 2 O 2 -induced vitiligo or imiquimod-induced erythema, to test the anti-vitiligo effects and anti-inflammatory effects of galangin. Other techniques used included immunoprecipitation-mass spectrometry, pull-down assays, Autodock and surface plasmon resonance (SPR) analysis in cultured cells. Key Results Galangin exerted anti-inflammatory and antioxidant effects through two mechanisms, promoting melanocyte proliferation while inhibiting macrophage proliferation. Using immunoprecipitation-mass spectrometry, pull-down assays, Autodock and SPR analyses, we found that galangin bound to annexin A2 and promoted its degradation in macrophages. This interaction led to inhibition of macrophage proliferation, activation and polarisation. In vivo, galangin significantly improved skin conditions in mice with H 2 O 2 -induced vitiligo or imiquimod-induced erythema. Furthermore, annexin A2 knockout abolished the protective effects of galangin in these models. Conclusions and Implications Galangin bound to annexin A2 and promoted its degradation in macrophages, decreasing release of inflammatory factors and chemokines. These findings provide experimental evidence supporting the potential application of galangin in clinical treatments for vitiligo and highlight ANXA2 as a promising therapeutic target for managing this condition.
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Advanced Science
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2026
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IF 14.1
Yong Luo,Tianlong Luo,Lingfeng Li,Qi Sun,Dongquan Li,Shanhe Huang,Zonglin Li,Weilong Lin,Yuan Ou,Tao Du,Shengmeng Peng,Kewei Xu,Bisheng Cheng,Hai Huang
Resistance to second-generation antiandrogens like enzalutamide (ENZ) in castration-resistant prostate cancer (CRPC) is a major clinical challenge, yet the role in the tumor microenvironment remains poorly understood. This study identifies a unique AR-positive tumor-associated macrophages (AR + TAMs) subpopulation, enriched in ENZ-resistant patients and correlated with poor prognosis, which acquires functional AR protein not through endogenous expression but via ANXA2-dependent phagocytosis of tumor cells. The internalized AR protein translocates to the macrophage nucleus, directly binds the IL-6 promoter to enhance its transcription and secretion. Macrophage-derived IL-6 subsequently activates the JAK2/STAT3 pathway in cancer cells, suppressing ENZ-induced apoptosis and conferring therapeutic resistance. Genetic or pharmacological blockade of IL-6 signaling restored ENZ sensitivity in vitro and in vivo, and combining an anti-IL-6 antibody with ENZ synergistically overcomes resistance in patient-derived xenograft and orthotopic models. These findings reveal a novel phagocytosis-mediated, paracrine mechanism of ENZ resistance orchestrated by AR + TAMs, challenging the tumor-centric view of therapy failure and providing a strong rationale for co-targeting the IL-6 pathway to improve outcomes of AR-directed therapy in CRPC.
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VETERINARY RESEARCH
·
2025
·Vol. 56
·期 1
·1-13
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IF 3.5
Wang Zengbao,Li Taifeng,Jiang Yingying,Wang Xue,Li Hongmei,Zhao Xiaomin,Zhang Xiao,Zhao Ningning
Serpin protease inhibitors (SERPIN) in protozoa play crucial roles in various biological processes, including the invasion of host cells. However, the precise roles and molecular mechanisms underlying SERPIN-mediated invasion of parasite remain poorly understand. In this study, we provide evidence that surface-expressed Eimeria tenella SERPIN1 (EtSERPIN1) on sporozoites is involved in adhesion and invasion processes. To elucidate the molecular target responsible for mediating EtSERPIN1-induced invasion, we utilized GST pull-down and yeast two-hybrid assays to identify host cell membrane proteins interacting with EtSERPIN1. Our findings revealed an interaction between EtSERPIN1 and a membrane protein called annexin A2 (ANXA2). Furthermore, recombinant GgANXA2 was shown to bind to the sporozoite surface. Pre-treatment with anti-GgANXA2-specific antibody or recombinant GgANXA2 protein significantly inhibited EtSERPIN1 binding to host cells. Pre-incubation with recombinant GgANXA2 also reduced sporozoite infection in both DF-1 cells and chickens. These results suggest that the interaction between EtSERPIN1 and GgANXA2 plays a critical role in both adhesion and invasion processes of E. tenella sporozoites. Finally, we investigated the impact of recombinant GgANXA2 and EtSERPIN1 proteins on E. tenella infection. Our results demonstrate that incubation with GgANXA2 protein significantly attenuated sporozoite infectivity, as evidenced by a significant reduction in parasite burden within the chicken cecum. Immunization with recombinant EtSERPIN1 exhibited potent anti- E. tenella activity, with higher body weight gains, lower cecal lesions and oocyst output, as well as elevated levels of cecal mucosa antibodies. These findings suggest that targeting GgANXA2 through EtSERPIN1 mediates adhesion and invasion processes of E. tenella , highlighting its potential as a novel therapeutic target.
研究领域:
寄生虫学
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分子生物学
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兽医学
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International Journal of Nanomedicine
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2026
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IF 8.7
Pongsigeraxi Borjigin,Caixia Deng,Rilaga Su,Juan Li,Ying Ying,Yingsong Chen,Tegexibaiyin Wang
Purpose This study aimed to enzymatically synthesize pearl powder fluorescent carbon dots (PFCDs) and investigate their neuroprotective potential against cerebral ischemia/reperfusion injury (CIRI) by modulating the Anxa2/NF-κB signaling pathway.Methods PFCDs were synthesized through enzymatic digestion and characterized. Neuroprotective effects were assessed using an in vitro oxygen–glucose deprivation/reoxygenation (OGD/R) model in PC12 cells and a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model. Cell viability, neurological function, cerebral infarct volume, and neuronal injury were evaluated. Expression of Anxa2/NF-κB signaling pathway proteins and inflammatory cytokines (TNF-α, IL-6, IL-1β) was analyzed by Western blot, immunofluorescence, and ELISA.Results The synthesized PFCDs exhibited an organic–inorganic hybrid structure, uniform particle size below 10 nm, and distinctive optical properties. In vitro, PFCDs enhanced cell viability under OGD/R conditions, inhibited phosphorylation of Anxa2 and NF-κB p65, and reduced secretion of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). In vivo, treatment with PFCDs in MCAO/R rats improved neurological function, reduced cerebral infarct volume, and alleviated neuronal injury. These protective effects were linked to downregulation of the Anxa2/NF-κB signaling pathway and reduced serum levels of inflammatory cytokines.Conclusion We successfully achieved the enzymatic synthesis of carbon dots from pearl powder, characterized by a unique organic–inorganic hybrid structure. PFCDs effectively alleviated CIRI-induced neuroinflammation by suppressing the Anxa2/NF-κB signaling pathway, highlighting their therapeutic potential as a nanomedicine derived from natural products.
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CELL
·
2024
·
IF 45.5
Kaili Fu,Alvin Ho Kwan Cheung,Chi Chun Wong,Weixin Liu,Yunfei Zhou,Feixue Wang,Pingmei Huang,Kai Yuan,Olabisi Oluwabukola Coker,Yasi Pan,Danyu Chen,Nga Man Lam,Mengxue Gao,Xiang Zhang,He Huang,Ka Fai To,Joseph Jao Yiu Sung,Jun Yu
Summary Streptococcus anginosus ( S. anginosus ) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse stomach and induced acute gastritis. S. anginosus infection spontaneously induced progressive chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in conventional mice, and the findings were confirmed in germ-free mice. In addition, S. anginosus accelerated GC progression in carcinogen-induced gastric tumorigenesis and YTN16 GC cell allografts. Consistently, S. anginosus disrupted gastric barrier function, promoted cell proliferation, and inhibited apoptosis. Mechanistically, we identified an S. anginosus surface protein, TMPC, that interacts with Annexin A2 (ANXA2) receptor on gastric epithelial cells. Interaction of TMPC with ANXA2 mediated attachment and colonization of S. anginosus and induced mitogen-activated protein kinase (MAPK) activation. ANXA2 knockout abrogated the induction of MAPK by S. anginosus . Thus, this study reveals S. anginosus as a pathogen that promotes gastric tumorigenesis via direct interactions with gastric epithelial cells in the TMPC-ANXA2-MAPK axis.
研究领域:
微生物学
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肿瘤学
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胃肠病学
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分子生物学
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