Materials Today Bio
·
2025
·
IF 10.2
Lihui Wen,Mengxin Gan,Siying Xiong,Li Dai,Wen Chen,Wen Shi
Diabetic retinopathy (DR) is characterized by pathological angiogenesis, inflammation, and retinal neurodegeneration, leading to vision loss. Current therapies, such as anti-VEGF agents, face challenges of low bioavailability and frequent invasive injections. Connexin43 (Cx43), a gap junction protein, plays a key role in DR progression through its modulation of inflammation and vascular dysfunction. A thermosensitive hydrogel composite was developed to encapsulate siRNA targeting Cx43 (si-Cx43) nanoparticles (NPs) and anti-VEGF (Avastin). The hydrogel was characterized for gelation, injectability, and degradation. In vitro studies evaluated the cytotoxicity, anti-angiogenic effects, and permeability regulation in hyperglycemic retinal cells under hyperglycemic conditions. In vivo therapeutic efficacy was assessed in a diabetic retinopathy rat model. si-Cx43-NPs demonstrated high siRNA encapsulation efficiency and stability, effectively silencing Cx43 expression in retinal endothelial cells. The hydrogel exhibited excellent injectability, temperature-sensitive gelation, and controlled degradation. In vitro, si-Cx43-NPs@Avastin-hydrogel significantly suppressed VEGF expression, reduced angiogenesis, and restored cell permeability under hyperglycemic conditions. In vivo , the hydrogel composite reduced neovascularization, inflammation, and apoptosis, restoring retinal structure and function more effectively than either single-agent treatment alone. Biocompatibility studies confirmed minimal toxicity and favorable degradation. The si-Cx43-NPs@Avastin-hydrogel provides a synergistic and minimally invasive therapeutic strategy for DR by targeting angiogenesis, inflammation, and neuroprotection with sustained drug delivery.
研究领域:
医学
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生物材料学
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分子生物学
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PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2022
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IF 6.633
Miao Zhao,Meng Han,Lina Liang,Qixue Song,Xia Li,Yimei Du,Dongping Hu,Yu Cheng,Qing K. Wang,Tie Ke
Our earlier studies identified MOG1 as a Nav1.5-binding protein that promotes Nav1.5 intracellular trafficking to plasma membranes. Genetic studies have identified MOG1 variants responsible for cardiac arrhythmias. However, the physiological functions of MOG1 in vivo remain incompletely characterized. In this study, we generated Mog1 knockout ( Mog1 −/− ) mice. Mog1 −/− mice did not develop spontaneous arrhythmias at the baseline, but exhibited a prolongation of QRS duration. Mog1 −/− mice treated with isoproterenol (ISO), but not with flecainide, exhibited an increased risk of arrhythmias and even sudden death. Mog1 −/− mice had normal cardiac morphology, however, LV systolic dysfunction was identified and associated with an increase in ventricular fibrosis. Whole-cell patch-clamping and Western blotting analysis clearly demonstrated the normal cardiac expression and function of Nav1.5 in Mog1 −/− mice. Further RNA-seq and iTRAQ analysis identified critical pathways and genes, including extracellular matrix ( Mmp2 ), gap junction ( Gja1 ), and mitochondrial components that were dysregulated in Mog1 −/− mice. RT-qPCR, Western blotting, and immunofluorescence assays revealed reduced cardiac expression of Gja1 in Mog1 −/− mice. Dye transfer assays confirmed impairment of gap-junction function; Cx43 gap-junction enhancer ZP123 decreased arrhythmia inducibility in ISO-treated Mog1 −/− mice. Transmission electron microscopy analysis revealed abnormal sarcomere ultrastructure and altered mitochondrial morphology in Mog1 −/− mice. Mitochondrial dynamics was found to be disturbed, and associated with a trend toward increased mitochondrial fusion in Mog1 −/− mice. Meanwhile, the level of ATP supply was increased in the hearts of Mog1 −/− mice. These results indicate that MOG1 plays an important role in cardiac electrophysiology and cardiac contractile function.
研究领域:
心脏病学
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分子生物学
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电生理学
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PubMed
高影响因子
International Journal of Biological Sciences
·
2021
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IF 6.582
Deng-Pan Wu,Yan Zhou,Li-Xiang Hou,Xiao-Xiao Zhu,Wen Yi,Si-Man Yang,Tian-Yu Lin,Jin-Lan Huang,Bei Zhang,Xiao-Xing Yin
Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2022
·Vol. 47
·期 12
·3761-3776
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IF 4.414
He Junhui,Li Dongmei,Wei Jie,Wang Sheng,Chu Shifeng,Zhang Zhao,He Fei,Wei Dongmei,Li Yi,Xie Jiaxiu,Lai Kedao,Chen Naihong,Wei Guining
Depression has become an important disease threatening human health. In recent years, the efficacy of Traditional Chinese Medicine (TCM) in treating the disease has become increasingly prominent, so it is meaningful to find new antidepressant TCM. Mahonia fortune (Lindl.) Fedde is a primary drug in traditional formulas for the treatment of depression, and alkaloids are the main components of it. However, the detailed mechanism of Mahonia alkaloids (MA) on depression remains unclear. This study aimed to investigate the effect of MA on gap junction function in depression via the miR-205/Cx43 axis. The antidepressant effects of MA were observed by a rat model of reserpine-induced depression and a model of corticosterone (CORT)-induced astrocytes. The concentrations of neurotransmitters were measured by ELISA, the expression of Connexin 43 (Cx43) protein was measured by Immunohistochemistry and western-blot, brain derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB) proteins were measured by western-blot, the pathological changes of prefrontal cortex were observed by hematoxylin–eosin (H&E) staining. Luciferase reporter assay was performed to verify the binding of miR-205 and Cx43. The regulation effect of Cx43 on CREB was verified by interference experiment. Gap junction dysfunction was detected by fluorescent yellow staining. The results confirmed that MA remarkably decreased miR-205 expression and increased Cx43, BDNF, CREB expression in depression rat and CORT-induced astrocytes. In addition, after overexpression of miR-205 in vitro, the decreased expression of Cx43, BDNF and CREB could be reversed by MA. Moreover, after interfering with Cx43, the decreased expression of CREB and BDNF could be reversed by MA. Thus, MA may ameliorate depressive behavior through CREB/BDNF pathway regulated by miR-205/Cx43 axis. Graphical Abstract
研究领域:
药理学
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神经科学
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分子生物学
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中药
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PubMed
高影响因子
Frontiers in Pharmacology
·
2023
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IF 5.6
Niuben Cao,Xiaomeng Liu,Yubo Hou,Yu Deng,Yu Xin,Xirui Xin,Xinchen Xiang,Xinchan Liu,Weixian Yu
Objective: Periodontitis is a common chronic inflammatory disease in which oxidative stress is one of the key pathogenic factors. Connexin43 (Cx43) is the most critical and widely distributed connexin isoform. When the organism undergoes a severe and sustained stress response, Cx43-mediated gap junctions (GJs) are believed to underlie the biology of tissue injury exacerbation and amplification. Notably, 18-α-glycyrrhetinic acid (GA) is a classical pharmacological inhibitor of GJs and has antioxidant potential. However, the regulatory role of GA in the redox signaling of periodontal tissues and the potential mechanisms of Cx43 in the pathogenesis of periodontitis remain uncertain. Methods: In this study, we evaluated the effects and mechanisms of GA in alleviating oxidative damage of periodontal tissues and cells by constructing an H 2 O 2 -induced oxidative stress model in human periodontal ligament cells (hPDLCs) and a periodontitis model in rats. Results: Cellular experiments showed that GA effectively attenuated H 2 O 2 -induced oxidative damage in hPDLCs by inhibiting the expression and function of Cx43. In addition, pretreatment of hPDLCs with either GA or SP600125 (a JNK inhibitor) inhibited the Cx43/JNK/NF-κB pathway, restored cell viability, and reduced apoptosis. Animal experiment results showed that GA intervention reduced alveolar bone resorption and periodontal tissue destruction, inhibited osteoclast differentiation, improved mitochondrial structural abnormalities and dysfunction in periodontal tissue, and decreased oxidative stress levels and apoptosis in rats with periodontitis. Conclusion: Overall, our findings suggest that the Cx43/JNK/NF-κB pathway may play a vital role to promote periodontitis progression, while GA reduces oxidative stress and apoptosis by inhibiting the interaction of Cx43 and JNK/NF-κB pathways, thus alleviating oxidative damage in the periodontal tissues.
研究领域:
牙科学
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药理学
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细胞生物学
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分子生物学
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炎症
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氧化应激
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PubMed
高影响因子
Cells
·
2021
·Vol. 10
·期 2
·237
·
IF 6.6
Guobin Li,Lan Zhang,Kaiting Ning,Baoqiang Yang,Francisca M. Acosta,Peng Shang,Jean X. Jiang,Huiyun Xu
Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences.Keywords:osteocytes;Cx43;gap junctions;hemichannels;bone–muscle crosstalk
研究领域:
生物力学
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分子生物学
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生理学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2022
·
IF 5.895
Ying-Xin Zhao,Yi-Xi Tang,Xiao-Han Sun,Shi-Yong Zhu,Xue-Yan Dai,Xue-Nan Li,Jin-Long Li
Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in plastic products, consumer products, and packaging materials. It is of great health concern in both animals and humans as it released into the environment and entered into the body from plastic products over time, thereby resulting in neurotoxicity. As a pivotal regulator of the central nervous system (CNS), astrocytes, are crucial for maintaining brain homeostasis. Nevertheless, the underlying reason for astrocyte neurotoxicity due to DEHP exposure remains incompletely understood. Here, using an in vivo model of neurotoxicity in quail, this study summarizes that Cx43 is internalized by phosphorylation and translocated to the nucleus as a consequence of DEHP exposure in astrocytes. This study further demonstrated that astrocytes transformed to pro-inflammatory status and induced the formation of autophagosomes. Of note, integrated immunofluorescent codetection approaches revealed an overexpression of the glial fibrillary acidic protein (GFAP) and down-expression of Cx43 in astrocytes. Therefore, in terms of neurotoxicity, this experiment in vivo models directly linked Cx43 internalization to autophagy and neuroinflammation and ultimately locked these changes to the astrocytes of the brain. These findings unveil a potential approach targeting Cx43 internalization for the treatment of neurodegeneration caused by DEHP exposure in astrocytes.
研究领域:
神经科学
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毒理学
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细胞生物学
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PubMed
高影响因子
Cell Death & Disease
·
2025
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IF 9.6
Ye Junrui,Wang Hongyun,Peng Ye,Wang Shasha,Zheng Ruifang,Chen Yuqi,Yuan Ruolan,Wang Zhenzhen,Yan Xu,He Wenbin,Li Gang,Sun Hongshuo,Feng Zhongping,Chu Shifeng,Zhang Zhao,Chen Naihong
Depression remains a pervasive global health challenge, compounded by limited therapeutic efficacy that is partly attributed to incompletely understood metabolic underpinnings. In this study, we reveal a noncanonical mitochondrial function of astrocytic connexin 43 (Cx43) whereby it directly inhibits isocitrate dehydrogenase 3α (IDH3α), thereby sustaining glycolytic metabolism and lactate production essential for neuronal excitability. Astrocyte-specific deletion of Cx43 in the prelimbic cortex (PrL) recapitulates hallmark depressive phenotypes, characterized by reduced lactate synthesis, diminished neuronal excitability, and depressive-like behaviors. Loss of Cx43 enhances IDH3α activity, prompting a metabolic reprogramming from aerobic glycolysis toward oxidative phosphorylation (OXPHOS) driven by glutamine-fueled anaplerosis, resulting in suppressed glucose uptake and decreased lactate output. This metabolic impairment restricts astrocytic lactate supply, depriving neurons of a critical energetic substrate. Importantly, this reprogramming occurs independently of gap junction intercellular communication, as demonstrated using a channel function-deficient dominant-negative Cx43 mutant. Restoration of mitochondrial Cx43 in astrocytes rescues neuronal excitability and ameliorates depressive-like phenotypes. Collectively, our findings identify mitochondrial Cx43 as a vital regulator of IDH3α activity, essential for astrocyte-neuron metabolic coupling, and highlight a promising target for therapeutic intervention in depression.
研究领域:
神经科学
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细胞生物学
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代谢学
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精神病学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Cardiovascular Medicine
·
2022
·
IF 5.846
Kai-Wen Ren,Xiao-Hong Yu,Yu-Hui Gu,Xin Xie,Yu Wang,Shi-hao Wang,Hui-Hua Li,Hai-Lian Bi
Atrial fibrosis and atrial inflammation are associated with the pathogenesis of atrial fibrillation (AF). Basic helix–loop–helix family member E40 (Bhlhe40) is an important transcription factor, which is involved in tumors, inflammation, apoptosis, viral infection, and hypoxia. However, its role and molecular mechanism in AF remain unclear. In this study, a mouse model of AF was induced by Ang II infusion. The atrial diameter was evaluated using echocardiography. Induction and duration of AF were measured by programmed electrical stimulation. Atrial structural remodeling was detected using routine histologic examinations. Our results showed that Bhlhe40 was significantly upregulated in angiotensin II (Ang II)-stimulated atrial cardiomyocytes and atrial tissues and in tissues from patients with AF. Cardiac-specific knockdown of Bhlhe40 in mice by a type 9 recombinant adeno-associated virus (rAAV9)-shBhlhe40 significantly ameliorated Ang II-induced atrial dilatation, atrial fibrosis, and atrial inflammation, as well as the inducibility and duration of AF. Mechanistically, cardiac-specific knockdown of Bhlhe40 attenuated Ang II-induced activation of NF-κB/NLRP3, TGF-1β/Smad2 signals, the increased expression of CX43, and the decreased expression of Kv4.3 in the atria. This is the first study to suggest that Bhlhe40 is a novel regulator of AF progression, and identifying Bhlhe40 may be a new therapeutic target for hypertrophic remodeling and heart failure.
研究领域:
心脏病学
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分子生物学
·
转化医学
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PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2020
·
IF 5.186
Chen Xiao,Liang Huaibin,Xi Zhiyu,Yang Yong,Shan Huimin,Wang Baofeng,Zhong Zhihong,Xu Canxin,Yang Guo-Yuan,Sun Qingfang,Sun Yuhao,Bian Liuguan
Intracerebral hemorrhage (ICH) is a particularly severe form of stroke, and reactive astrogliosis is a common response following injury to the central nervous system (CNS). Mesenchymal stem cells (MSCs) are reported to promote neurogenesis and alleviate the late side effects in injured brain regions. Gap junctions (Gjs) are abundant in the brain, where the richest connexin (Cx) is Cx43, most prominently expressed in astrocytes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor regulating antioxidant reactions. Here, we aimed to explore whether bone marrow MSCs (BM-MSCs) could alleviate brain injury and protect astrocytes from apoptosis, by regulating Cx43 and Nrf2. We validated the effect of BM-MSC transplantation in an ICH model in vivo and in vitro and detected changes using immunofluorescence, as well as protein and mRNA expression of glial fibrillary acidic protein (GFAP), vimentin (VIM), Cx43, Nrf2, and heme oxygenase-1 (HO-1). Our results showed that BM-MSC transplantation attenuated brain injury after ICH and upregulated VIM expression in vivo and in vitro. Additionally, Cx43 upregulation and Nrf2 nuclear translocation were observed in astrocytes cocultured with BM-MSC. Knockdown of Cx43 by siRNA restrained Nrf2 nuclear translocation. Cx43 and Nrf2 had a connection as determined by immunofluorescence and coimmunoprecipitation. We demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and have anti-apoptotic abilities after BM-MSC transplantation, where Cx43 upregulation triggers Nrf2 nuclear translocation and promotes its phase II enzyme expression. The Cx43/Nrf2 interaction of astrocytes after BM-MSC transplantation may provide an important therapeutic target in the management of ICH.
研究领域:
神经科学
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干细胞研究
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神经病学
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分子生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2026
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IF 6.6
Haitao Zhang,Chaofeng Chen,Dayu Wang,Yiwei Huang,Yang Liu,Zhiyuan Wang,Furui Fu,Hongyu Wang,Senjie Shi,Yijin Li,Jianchun Zeng,Caiping Shen,Chudan Zhong,Xiaozhou Liu,Jinlun Chen,Jie Li,Shufen Liu,Jin Huang,Yirong Zeng,Wenjun Feng
As an emerging environmental contaminant, N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone (6PPD-Q) poses a potential threat to public health. However, the potential link between 6PPD-Q exposure and bone health remains largely unexplored. This study aims to systematically investigate the toxic effects of 6PPD-Q on bone metabolism and elucidate the underlying mechanisms by integrating transcriptomic sequencing, network toxicology, single-cell RNA, Molecular docking, molecular dynamics with both in vivo and in vitro experiments. Integrative analysis converged on mitophagy as a central mechanism in 6PPD-Q-induced osteoporosis, with single-cell sequencing identifying bone marrow-derived mesenchymal stem cells (BMSCs) as the key cell type and revealing CX43, MMP2, PDGFRB, and FYN as the principal targets. Molecular docking and MD simulations confirmed the targeted binding of 6PPD-Q to CX43. RNA-seq analysis of rat tibiae validated the differential expression of CX43 and the critical role of mitophagy. Both in vivo and in vitro experiments demonstrated that 6PPD-Q-induced bone loss was associated with the downregulation of CX43 and concomitant mitophagy dysregulation. In conclusion, this study elucidates that 6PPD-Q induces bone loss was associated with the downregulation of CX43 and concomitant mitophagy dysregulation. Our work establishes a comprehensive mechanistic framework for 6PPD-Q-induced bone damage and offers novel insights for future research into its bone toxicity. The 1 or 10 mg/kg dose used in this study, although higher than the typical environmental exposure level, is consistent with the effects observed in cadmium exposure and is close to the 8 mg/kg dose used in studies on mouse bone toxicity. Additionally, the 5 ng/mL concentration of 6PPD-Q used in the in vitro experiments is comparable to the concentration detected in freshwater, indicating its environmental relevance.
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高影响因子
Journal of Clinical and Translational Hepatology
·
2022
·
IF 5.065
Yuzhu Cao,Yawen Xia,Yufei Wang,Hang Shi,Yuanyuan Wu,Yin Lu
Background and Aims Oxaliplatin is widely used in cancer chemotherapy with adverse effects such as liver toxicity. Magnesium isoglycyrrhizinate (MgIG) has hepatoprotective effects, but the underlying mechanism remains elusive. The study’s aim was to investigate the mechanism underlying the hepatoprotective effects of MgIG against oxaliplatin-induced liver injury. Methods A xenografted colorectal cancer mouse model was established with MC38 cells. Mice were given oxaliplatin (6 mg/kg/week) for 5 weeks to mimic oxaliplatin-induced liver injury in vivo . LX-2 human hepatic stellate cell s(HSCs) were employed for in vitro studies. Serological tests, hematoxylin and eosin staining, oil red O staining and transmission electron microscopy were used for histopathological examinations. Real-time PCR, western blotting, immunofluorescence and immunohistochemical staining were used to determine Cx43 mRNA or protein levels. Flow cytometry was used to assay reactive oxygen species (ROS) and mitochondrial membrane. Short hairpin RNA targeting Cx43 was lentivirally transduced in LX-2 cells. Ultra-high performance liquid chromatography-tandem mass spectrometry was used to determine MgIG and metabolite concentration. Results MgIG (40 mg/kg/day) treatment significantly reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) levels in the mouse model, and alleviated liver pathological changes, including necrosis, sinusoidal expansion, mitochondrial damage, and fibrosis. MgIG reduced the abnormal expression of Cx43 in the mitochondria and nuclei of HSCs. MgIG inhibited the activation of HSCs via reducing ROS generation, mitochondrial dysfunction, and N-cadherin transcription. MgIG’s inhibition of HSCs activation was abolished after knockdown of Cx43 in LX-2 cells. Conclusions Cx43 mediated MgIG’s hepatoprotective effects against oxaliplatin-induced toxicity.
研究领域:
药理学
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肝病学
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细胞生物学
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分子生物学
·
癌症研究
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）