DIGESTIVE DISEASES AND SCIENCES
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2022
·Vol. 67
·期 10
·4780-4796
·
IF 3.487
Duan Houyu,Ding Xiang,Luo Hesheng
Background and Aims KISS-1 is an established tumor suppressor that inhibits metastases in various malignancies. However, little is known regarding its role in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to identify the possible mechanisms of KISS-1 in ESCC metastasis. Methods The expression levels of KISS-1 mRNA and protein in ESCC samples and cell lines were analyzed by qRT-PCR, IHC, and western blotting. Bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP) were used to analyze the methylation pattern of KISS-1 promoter in ESCC cells with or without 5-Aza-dC treatment. The role of KISS-1 in the progression and metastasis of ESCC was analyzed through in vitro functional assays. Results KISS-1 mRNA and protein were markedly downregulated in ESCC tissues and cell lines compared to the respective controls. Hypermethylation of KISS-1 promoter correlated to its lower expression levels in ESCC, and KISS-1 demethylation inhibited tumor progression. Ectopic KISS-1 overexpression inhibited tumor cell metastasis in vitro. In addition, KISS-1 overexpression downregulated the matrix metalloproteinase 2 and 9 (MMP2 and 9) and inhibited epithelial–mesenchymal transition (EMT). Finally, KISS-1 downregulated phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2) and phosphorylated p38 mitogen-activated protein kinase (MAPK) without affecting their total expression levels in the ESCC cells. MAPK/ERK and p38 MAPK agonists reversed the suppressive effects of KISS-1. Conclusions The hypermethylation of KISS-1 promoter partly contributed to its downregulation in ESCC. KISS-1 inhibits the metastasis of ESCC cells by targeting the MMP2/9/ERK/p38 MAPK axis.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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DOI
PubMed
高影响因子
BMC Cardiovascular Disorders
·
2024
·Vol. 24
·期 1
·1-13
·
IF 2
Liu Hai-Hua,Wei Wei,Wu Fei-Fei,Cao Lu,Yang Bing-Jie,Fu Jia-Ning,Li Jing-Xia,Liang Xin-Yue,Dong Hao-Yu,Heng Yan-Yan,Zhang Peng-Fei
Background Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. Methods In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. Results Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. Conclusions These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.
研究领域:
心血管药理学
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炎症
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血管生物学
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分子生物学
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DOI
PubMed
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2023
·
IF 4.1
Xu Cong,Zhang Cheng,Ganesan Kumar,Qui Chen,Tang Hailin,Gao Fei,Liu Qingqing,Wu Jianming,Sui Yue,Li Peng,Zhang Jinming,Chen Jianping
Introduction: Triple-negative breast cancer (TNBC), an aggressive type of
breast cancer, remains difficult to treat. Isoliquiritigenin (ISL) is a bioactive compound
that is insoluble in water and exhibits significant anti-TNBC activity. Method: We previously
prepared oral aqueous ISL@ZLH NPs; however, they were less stable in a freezing
environment. Hence, the present study aimed to improve the stability of ISL@ZLH
NPs using cryoprotectants that can withstand long storage times and are effective in TNBC
treatment by creating an efficient oral drug delivery system. Freeze-dried ISL@ZLH
NP powder was prepared by solvent evaporation, followed by the addition of trehalose
and sucrose. The freeze-dried ISL@ZLH NP pow was optimized and characterized. The
anti-TNBC efficacy and pharmacokinetics of the ISL@ZLH NP-pow were examined in
plasma and organs, compared with those of aqueous ISL@ZLH NPs. Result: The ideal
particle size of the ISL@ZLH NP pow was 118 nm, which was not filtered out by the
glomerulus and allowed the drug to be delivered to the lesions more effectively. Cellular
uptake and biodistribution of the ISL@ZLH NP-pow in vivo and in vitro showed prolonged
storage in the organs. In addition, cryopreserved ISL@ZLH NP-treated tumors
showed significant anti-proliferative and anti-migratory effects through the downregulation
of the PI3K-Akt-mToR and MMP2/9 signaling pathways. Conclusion: These results
suggest that oral ingestion of cryopreserved ISL@ZLH NP has the potential for longterm
storage and can be employed as a clinical therapeutic approach to treat TNBC.
研究领域:
肿瘤学
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药剂学
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纳米技术
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药物递送系统
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癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2019
·Vol. 18
·期 4
·2385-2392
·
IF 1.448
Li Li,Qiuhong Li,Lei Wei,Zhongfu Wang,Wei Ma,Fangying Liu,Yanhua Shen,Shanfang Zhang,Xiulian Zhang,Huiping Li,Yechang Qian
Pulmonary fibrosis (PF) is a heterogeneous pathological process in lung tissues with a considerable mortality rate. Currently, combination therapy represents an effective approach to treat PF. Dexamethasone (Dxs) and berberine (BBR) are widely applied to inhibit the progression of PF. Dxs plus penehyclidine hydrochloride or alfacalcidol have been reported more effective in therapy compared with any single drug treatment. However, whether Dxs plus BBR induces an increased antifibrotic effect remains unknown. The current study aimed to evaluate the therapeutic effect of BBR plus Dxs in bleomycin (BLM)‑induced PF. A PF model in rats was established and rats were divided into control, BLM, BBR, Dxs and BBR plus Dxs groups (n=9/group). On days 3, 7 and 14, blood samples were collected from the eyes of the rats (n=6/group). CXC chemokine ligand 14 (CXCL14), collagen I, collagen III, matrix metalloproteinase (MMP)2 and MMP9 serum levels were measured by ELISA. On day 14, all rats were sacrificed. Hematoxylin and eosin analysis, Masson staining and hydroxyproline (Hyp) assessment were performed to observe histopathological changes and collagen deposition. mRNA and protein levels of CXCL14, CXC chemokine receptor 4 (CXCR4), collagen I/III, α‑smooth muscle actin (α‑SMA), MMP2/9 and phosphorylated‑Smad 2/3 in lung tissue were further evaluated. Similar effects in preventing lung damage were observed histopathologically for Dxs and BBR compared with the BLM group. These treatments further reduced levels of Hyp, CXCL14, CXCR4, collagen I/III, MMP2/9, α‑SMA and p‑Smad 2/3. The combination of Dxs and BBR exhibited increased effectiveness compared with the single treatments. Results further suggested that antifibrotic mechanisms were involved in inhibiting CXCL14 and MMP2/MMP9 expression, and preventing the activation of Smad2/3 and hedgehog signaling pathways. The combined use of Dxs and BBR may represent a potential therapeutic approach for PF.
研究领域:
药理学
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呼吸医学
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病理学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Ting Wang,Jie Chen,Chuandong Shu,Xinkun Shen,Yuanyuan Fu,Menghuan Li,Zhong Luo
Ulcerative colitis (UC) is a prevalent gastrointestinal disease characterized by the chronical and refractory inflammation of colorectal mucosa and walls, which severely impairs overall well-being of individuals. Probiotics has shown tremendous promise for UC therapy due to its multifaceted mucosal barrier restoration and immunomodulation capabilities. Nevertheless, the successful administration of probiotics remains a clinical obstacle. Herein, we report a multifunctional supramolecular probiotic capsule based on clinically-tested biopolymers for UC therapy, which not only allow colon-targeted probiotic delivery via oral route but also enable concurrent delivery of hemostatic and anti-inflammatory drugs. Specifically, Clostridium butyricum (CB) was first engineered with protective norepinephrine (NE) coating and then encapsulated by self-assembled gelatin-based nanocomplexes modified with balsalazide and matrix metalloproteinase 2/9 (MMP2-/9)-responsive fibronectin peptides. The released balsalazide and fibronectin could induce rapid hemostasis and anti-inflammation actions to alleviate inflammation damage of the UC-affected colons in the short term, while CB could restore gut microbiota homeostasis to remodel intestinal immunocomposition and repair mucosal barrier for reducing UC risk in the long term. Overall, this study provides a promising option for UC treatment with good efficacy and minimal invasiveness. Statement of significance This study reports a supramolecular probiotic capsule with nanointegrative hemostatic and anti-inflammatory capacities for ulcerative colitis (UC) therapy, which could be orally administrated and activated in the inflamed colorectal sites. The probiotic capsules enable immediate UC symptom relief while also accelerating mucosal repair and preventing UC relapse in the long-term, offering an approach for UC treatment in the clinic.
研究领域:
胃肠病学
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药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
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