JOURNAL OF MOLECULAR MEDICINE-JMM
·
2024
·
IF 4.8
Wang Pengtao,Tao Wei,Li Qiujie,Ma Wanting,Jia Wei,Kang Yuting
Indole-3-aldehyde (I3A) is an intestinal microbial metabolite that regulates inflammation in various inflammatory diseases; however, its role in chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to investigate the anti-inflammatory effects and molecular mechanisms of I3A in COPD. We constructed in vivo models using cigarette smoke (CS)-stimulated mice and in vitro models using cigarette smoke extract (CSE)-stimulated MH-S cells. The results demonstrated that I3A significantly alleviated bronchial obstruction in mice with COPD and reduced the expression of inflammatory factors such as TNF-α, IL-1β, and IL-6. Additionally, I3A decreased the levels of matrix metalloproteinases MMP2, MMP12, and inhibited the NF-κB p65/NLRP3 pathways. Further investigation revealed that I3A inhibited NF-κB activity by suppressing p65 phosphorylation and nuclear translocation in CSE-stimulated MH-S cells. The activation of the NF-κB and NLRP3 signaling pathways is mediated by histone deacetylase 5 (HDAC5) and HDAC6, both of which are inhibited by I3A. Subsequent experiments indicated that aryl hydrocarbon receptor (AHR) knockdown attenuated the inhibitory effect of I3A on pro-inflammatory cytokines and the HDACs/NF-κB/NLRP3 signaling pathways, highlighting the dependence of I3A's anti-inflammatory effects on the AHR receptor. Key messages
I3A effectively reduced lung inflammation in COPD mice by inhibiting the NF-κB pathway.
In CSE-stimulated MH-S cells, I3A suppressed p65 phosphorylation and nuclear translocation, thereby inhibiting NF-κB activity.
The activation of the NF-κB/NLRP3 pathways by HDAC5 and HDAC6 was diminished by I3A.
Through the activation of the AHR receptor, I3A suppressed the activities of HDAC5/6, leading to a decrease in inflammatory factor levels.
Graphical abstract
研究领域:
呼吸病学
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免疫学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2023
·Vol. 26
·期 1
·1-10
·
IF 2.7
Ying Deng,Jing-Shu Hong,Yi-Yun Cao,Ning Kang,Deng-Yang Han,Yi-Tong Li,Lei Chen,Zheng-Qian Li,Rui Zhan,Xiang-Yang Guo,Ning Yang,Cheng-Mei Shi
Postoperative delirium (POD), which occurs in hospital up to 1‑week post‑procedure or until discharge, is a common complication, especially in older adult patients. However, the pathogenesis of POD remains unclear. Although damage to blood‑brain barrier (BBB) integrity is involved in the neuropathogenesis of POD, the specific role of the BBB in POD requires further elucidation. Anaesthesia using 2% isoflurane for 4 h results in the upregulation of hippocampal receptor for advanced glycation end‑products (RAGE) expression and β‑amyloid accumulation in aged rats. The present study investigated the role of RAGE in BBB integrity and its mechanisms in POD‑like behaviours. The buried food, open field and Y maze tests were used to evaluate neurobehavioural changes in aged mice following 2.5% sevoflurane anaesthesia administration with exploratory laparotomy. Levels of tight junction proteins were assessed by western blotting. Multiphoton in vivo microscopy was used to observe the ultrastructural changes in the BBB in the hippocampal CA1 region. Anaesthesia with surgery decreased the levels of tight junction proteins occludin and claudin 5, increased matrix metalloproteinases (MMPs) 2 and 9, damaged the ultrastructure of the BBB and induced POD‑like behaviour. FPS‑ZM1, a specific RAGE antagonist, ameliorated POD‑like behaviour induced by anaesthesia and surgery in aged mice. Furthermore, FPS‑ZM1 also restored decreased levels of occludin and claudin 5 as well as increased levels of MMP2 and MMP9. The present findings suggested that RAGE signalling was involved in BBB damage following anaesthesia with surgery. Thus, RAGE has potential as a novel therapeutic intervention for the prevention of POD.
研究领域:
神经科学
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麻醉学
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老年医学
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药理学
✓ 已验证
产品关联
DOI
高影响因子
CELL BIOLOGY INTERNATIONAL
·
2023
·
IF 3.9
Hongyang Xie,Junyu Chen,Changyan Ma,Jingjing Zhao,Manhua Cui
Dysregulation of the deubiquitinating protease, UBP43, has been implicated in many human diseases, including cancer. Here, we evaluated the functional significance and mechanism of action of UBP43 in epithelial ovarian cancer. We found that UBP43 was significantly upregulated in the tumor tissues of patients with epithelial ovarian cancer. Similar results were observed in OVCAR-3, Caov-3, TOV-112D, A2780, and SK-OV-3 cells. Furthermore, in vitro functional assays of A2780 and TOV-112D cells demonstrated that UBP43 overexpression promoted cell proliferation, migration, and invasion. Upregulation of UBP43 might result in epithelial–mesenchymal transition by inducing the nuclear transport of β-catenin, which was accompanied by enhanced N-cadherin but decreased E-cadherin expression. These malignant phenotypes were reversed by UBP43 silencing. Further investigation revealed that the knockdown of UBP43 inhibited cell proliferation by inducing a cell cycle arrest at the G2/M phase. The oncogenic characteristics of UBP43 were validated in a subcutaneous xenograft mouse model. In vivo, tumor growth was delayed in the UBP43-silenced group but accelerated after UBP43 overexpression. Finally, we demonstrated that β-catenin is a key protein in the UBP43-mediated malignant development of epithelial ovarian cancer. Specifically, overexpression of UBP43 decreased the ubiquitination degradation of β-catenin and enhanced its protein stability. Also, we observed that the downstream genes of beta-catenin such as cyclin D1, MMP2, and MMP9 were upregulated due to UBP43 overexpression. Thus, we concluded that UBP43 promoted epithelial ovarian cancer tumorigenesis and metastasis through activation of the β-catenin pathway, suggesting that UBP43 may be a potential therapeutic target for this intractable disease.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
✓ 已验证
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2021
·
IF 4.939
Xiaoxia Yang,Pengfei Shang,Jianbo Ji,Christina Malichewe,Zhiyin Yao,Jing Liao,Dandan Du,Chao Sun,Lei Wang,Ya-jie Tang,Xiuli Guo
In this study, a chitosan-based, self-assembled nanosystem that codelivered microRNA34a (miR34a) and doxorubicin (Dox) with hyaluronic acid (HA) modification (named CCmDH NPs) was developed to reverse the resistance of breast cancer (BCa) cells to Dox. The CCmDH NPs had a diameter of 180 ± 8.3 nm and a ζ potential of 16.5 mV with a slow-release effect for 96 h. The codelivery system could protect miR34a from nuclease and serum degradation and transport miR34a and Dox into drug-resistant MCF-7/A cells. In addition, the CCmDH NPs could inhibit proliferation and promote apoptosis by regulating the protein expression of B-cell lymphoma-2 (Bcl-2) and poly(ADP-ribose) polymerase (PARP) and inhibit invasion, metastasis, and adhesion by regulating E-cadherin, N-cadherin, MMP2, CD44, and Snail molecules. The CCmDH NPs induced a 73.7% tumor reduction in xenograft tumor growth in nude mice in vivo. This study provides evidence for the anticancer activity of CCmDH NPs carrying Dox and miR34a in BCa, especially metastatic Dox-resistant BCa models.
研究领域:
药学
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癌症研究
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纳米技术
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分子生物学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Longfa Kou,Rui Sun,Xinyu Jiang,Xinlu Lin,Huirong Huang,Shihui Bao,Youting Zhang,Chao Li,Ruijie Chen,Qing Yao
Tumor cells usually display metabolic, genetic, and microenvironment-related alterations, which are beneficial to tumor proliferation, tumor development, and resistance occurrence. Many transporters and enzymes, including ATB0,+, xCT, and matrix metalloproteinases (MMPs), are involved in the altered cell metabolism and tumor microenvironment and often abnormally upregulated in malignant tumors. Meanwhile, these dysregulated transporters and enzymes provide targets not only for a pharmacological blockage to suppress tumor progress but also for tumor-specific delivery. Although transporters and MMPs have been widely reported for antitumor drug delivery, the feasibility of utilizing two strategies has never been elucidated yet. Herein, we developed an MMP2-activated and ATB0,+-targeted liposome with doxorubicin and sorafenib (DS@MA-LS) loaded for optimal tumor drug delivery for cancer therapy. DS@MA-LS was designed to prolong blood circulation and deshield the PEG shell from MMP2 cleavage to expose lysine and target overexpressed ATB0,+ for enhanced tumor distribution and cancer cellular uptake. Besides the anticancer effects of loaded drugs, the endocytosed liposomes could further increase ROS production and suppress the antioxidant system to amplify oxidative stress. As expected, DS@MA-LS displayed enhanced targeted drug delivery to tumor sites with the MMP2-controlled ligand exposure and ATB0,+-mediated uptake. More importantly, DS@MA-LS successfully inhibited the tumor growth and cancer cell proliferation both in vitro and in vivo by enhancing apoptosis and ferroptosis, which thanks to the increased ROS generation and impaired GSH synthesis synergistically amplified oxidative stress. Our results suggested that the tumor microenvironment-responsive, multistaged nanoplatform, DS@MA-LS, has excellent potential for optimal drug delivery and enhanced cancer treatment.
研究领域:
药学
·
纳米技术
·
癌症研究
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2021
·
IF 6.53
Miaolin Zeng,Huifen Zhou,Yu He,Haixia Du,Junjun Yin,Yongchun Hou,Jiaqi Zhu,Yangyang Zhang,Chongyu Shao,Jiehong Yang,Haitong Wan
Mannitol, a representative of hyperosmolar therapy, is indispensable for the treatment of malignant cerebral infarction, but its therapeutic effect is limited by its exacerbation of blood-brain barrier (BBB) disruption. This study was to explore whether Danhong injection (DHI), a standardized product extracted from Salvia miltiorrhiza Bunge and Carthamus tinctorius L ., inhibits the destructive effect of mannitol on BBB and thus enhancing the treatment of hemispheric ischemic stroke. SD rats were subjected to pMCAO followed by intravenous bolus injections of mannitol with/without DHI intervention. Neurological deficit score, brain edema, infarct volume at 24 h after MCAO and histopathology, microvascular ultrastructure, immunohistochemistry and immunofluorescence staining of endothelial cell junctions, energy metabolism in the ischemic penumbra were assessed. Intravenous mannitol after MCAO resulted in a decrease in 24 h mortality and cerebral edema, whereas no significant benefit on neurological deficits, infarct volume and microvascular ultrastructure. Moreover, mannitol led to the loss of endothelial integrity, manifested by the decreased expression of occludin, junctional adhesion molecule-1 (JAM-1) and zonula occluden-1 (ZO-1) and the discontinuity of occludin staining around the periphery of endothelial cells. Meanwhile, after mannitol treatment, energy-dependent vimentin and F-actin, ATP content, and ATP5D expression were down-regulated, while MMP2 and MMP9 expression increased in the ischemic penumbra. All the insults after mannitol treatment were attenuated by addition of intravenous DHI. The results suggest DHI as a potential remedy to attenuate mannitol-related BBB disruption, and the potential of DHI to upregulate energy metabolism and inhibit the activity of MMPs is likely attributable to its effects observed.
研究领域:
神经学
·
药理学
·
中风研究
·
血管生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
·
2022
·
IF 4.336
Mengdi Lv,Xiaoting Qian,Shijie Li,Jie Gong,Qun Wang,Yong Qian,Zhi Su,Xuling Xue,Hong-Ke Liu
It is a major challenge to design novel multifunctional metal-based chemotherapeutic agents for anti-tumor and anti-metastasis applications. Two complexes ( OA-Ir and OA-Ru ) were synthesized via CuAAC (copper-catalyzed azide-alkyne cycloaddition) reaction from nontoxic Ir - N 3 or Ru - N 3 species and low toxic alkynyl precursor OA-Alkyne, and exhibited satisfactory anti-tumor and anti-metastasis pharmacological effects . Conjugation of Oleanolic acid (OA) and metal-arene species significantly enhanced the cytotoxicity in A2780 cells compared to the precursors through mitochondrial-induced autophagy pathway. Moreover, the two complexes could inhibit the cell metastasis and invasion through damage of actin dynamics and down-regulation of MMP2/MMP9 proteins. Combination of two precursors improved the lipophilicity and biocompatibility, simultaneously enhanced the cell uptake and the mitochondrial accumulation of metal-arene complexes, which caused mitochondrial membrane potential damage, oxidative phosphorylation , ATP depletion and autophagy. Besides, OA-Ir and OA-Ru displayed excellent activity to disintegrate the 3D multicellular tumor spheroids , showing potential for the treatment of solid tumors. This work provides a new way for developing novel metal-based complexes via CuAAC reaction for simultaneously inhibiting tumor proliferation and metastasis.
研究领域:
化学
·
药理学
·
癌症研究
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）