CURRENT ISSUES IN MOLECULAR BIOLOGY
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2025
·Vol. 47
·期 12
·991
·
IF 3
Lisha Li,Zhen Yu,Xuehua Lu,Pei Yang,Shuxia Zhang,Qinghua Lin,Junyong Han
Background: Adhesion G protein-coupled receptor G6 ( ADGRG6 ), also known as GPR126 , has been implicated in several malignancies. However, its expression pattern, clinical significance, and mechanistic role in pancreatic adenocarcinoma (PAAD) remain unclear. Methods: We combined multi-omics analyses, tissue microarray immunohistochemistry, and a series of functional experiments, including 2D and 3D spheroid cultures, zebrafish xenografts, and murine tumor models—to investigate the expression, clinical significance, and mechanism of ADGRG6 in PAAD. The association between ADGRG6 expression and immune infiltration was assessed using TIMER and GEPIA databases, followed by mechanistic validation through ADGRG6 modulation in PAAD cell lines. Results: ADGRG6 was significantly overexpressed in PAAD and correlated with larger tumor size, higher grade, advanced TNM stage, and poor overall survival. Multivariate logistic regression confirmed that high ADGRG6 expression was independently associated with higher pathological grade. Functionally, ADGRG6 silencing markedly inhibited PAAD cell proliferation, migration, and invasion in both 2D and 3D cultures, as well as in zebrafish and nude mouse xenograft models. Integrated transcriptomic and immune analyses revealed that ADGRG6 expression positively correlated with mast cells, macrophages (M1/M2), Th2/Th17 subsets, and interferon–responsive neutrophils. Mechanistically, ADGRG6 silencing reduced STAT6 phosphorylation and GATA3 expression, consistent with the suppression of the NF-κB→STAT6→GATA3 axis. Conclusions: ADGRG6 functions as an oncogenic driver in PAAD, promoting tumor progression and fostering an immunosuppressive microenvironment via NF-κB/STAT6 signaling. These findings not only broaden the mechanistic understanding of ADGRG6 function but also suggest it as a promising target for therapeutic intervention in PAAD.
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高影响因子
STEM CELLS
·
2023
·
IF 5.2
Li Zhi-hui,Chen Jun-feng,Zhang Jing,Lei Zi-ying,Wu Li-li,Meng Shi-bo,Wang Jia-lei,Xiong Jing,Lin Deng-na,Wang Jun-yi,Gao Zhi-liang,Lin Bing-liang
Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.
研究领域:
肝病学
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免疫学
·
干细胞生物学
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细胞信号传导
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高影响因子
CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
Xueting Niu,Canying Hu,Shengwei Chen,Jiaying Wen,Xiaoxi Liu,Yanhong Yong,Zhichao Yu,Xingbin Ma,Chengpeng Li,Mohamad Warda,A.M. Abd El-Aty,Ravi Gooneratne,Xianghong Ju
Heat stress (HS) has a negative impact on animal health. A modified chitosan-gentamicin conjugate (CS-GT) was prepared to investigate its potential protective effects and mechanism of action on heat stress-induced intestinal mucosa injury in IPEC-J2 cells and mouse 3D intestinal organs in a mouse model. CS-GT significantly ( P < 0.01) reversed the decline in transmembrane resistance and increased the FITC-dextran permeability of the IPEC-J2 monolayer fusion epithelium caused by heat stress. Heat stress decreased the expression of the tight binding proteins occludin , claudin1, and claudin2. However, pretreatment with CS-GT significantly increased ( P < 0.01) the expression of these tight binding proteins. Mechanistically, CS-GT inhibited the activation of the TLR4/STAT6/MYLK signaling pathway induced by heat stress. Molecular docking showed that CS-GT can bind effectively with TLR4 . In conclusion, CS-GT alleviates heat stress-induced intestinal mucosal damage both in vitro and in vivo . This effect is mediated, at least partly, by the inhibition of the TLR4/STAT6/MYLK signaling pathway and upregulation of tight junction proteins. These findings suggest that CS-GT may have therapeutic potential in the prevention and treatment of heat stress-related intestinal injury.
研究领域:
药理学
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分子生物学
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细胞生物学
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动物科学
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高影响因子
RESPIRATORY RESEARCH
·
2026
·Vol. 27
·期 1
·103
·
IF 5.7
Ge Shaobo,Li Rui,Li Yuer,Liu Jin,Yao Shiyuan,Zhang Rui,Sun Yuanliang,Zhang Tao,Zhang Jie,Zhang Ming
Background Oxidative stress contributes to airway mucus hypersecretion in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although reactive oxygen species modulator 1 (ROMO1) is involved in mitochondrial oxidative stress, its role in airway mucus hypersecretion in COPD remains unclear. Methods The protein expression of ROMO1 and mucin5AC (MUC5AC) in human airway epithelium was determined by immunohistochemistry. The effects of ROMO1 on mitochondrial injury and MUC5AC expression in cigarette smoke extract (CSE)-treated airway epithelial cells were evaluated by a series of experimental techniques, including real-time PCR, western-blot and immunofluorescent staining. Results Protein expression of ROMO1 and MUC5AC was significantly elevated in the airway epithelium of COPD patients compared with the controls. The mRNA and protein expression of ROMO1 and MUC5AC were significantly increased in concentration- and time-dependent manners when airway epithelial cells were treated with CSE. ROMO1 silencing significantly suppressed 7.5% CSE-induced mitochondrial structure damage, mitochondrial membrane potential loss, intracellular ATP depletion, mitochondrial reactive oxygen species production, signal transducer and activator of transcription 6 (STAT6) phosphorylation, and MUC5AC expression in airway epithelial cells. Moreover, pretreatment with either a mitochondrial-targeted antioxidant or STAT6 inhibitor significantly inhibited the up-regulated expression of p-STAT6/STAT6 and MUC5AC in airway epithelial cells stimulated with 7.5% CSE. Conclusion Our findings suggest that ROMO1 contributes to airway mucus hypersecretion in COPD by mediating MUC5AC expression in airway epithelial cells via the mitochondrial ROS-STAT6 pathway, thereby highlighting its potential clinical value as a therapeutic target.
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Chang Liu,Zhuoqun Wang,Linxin Zhang,Di Yang,Zhihong Zhang,Xiaoli Cui,Ali H. Eid,Mengyang Wang
Background and Purpose Fangchinoline (FAN), a bioactive bisbenzylisoquinoline alkaloid from Stephania tetrandra , shows protective potential against angiotensin II (Ang II)-induced hypertensive heart failure (HF), particularly involving mitophagy and ferroptosis, remain unclear. We investigated the effects of FAN on Ang II-induced cardiac remodelling and HF. Experimental Approach A hypertensive heart failure model was established in C57BL/6 mice via 4-week Ang II infusion. FAN was administered during the final 2 weeks. Cardiac function was assessed by echocardiography and pathological remodelling was evaluated by histological staining. RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of FAN. The potential binding proteins of FAN were verified by molecular docking, drug affinity response target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance assay (SPR). In vitro , neonatal rat ventricular myocytes (NRVMs) were used to investigate the effects of FAN on cellular hypertrophy, mitophagy and ferroptosis. Key Results In vivo , FAN treatment significantly ameliorated cardiac hypertrophy, dysfunction and fibrosis. These protective effects were independent of blood pressure-lowering actions. Mechanistically, FAN activates PGC-1α to enhance mitophagy and suppress STAT6-PPARγ signalling, thereby inhibiting ferroptosis and restoring redox homeostasis. In vitro , FAN reduced Ang II-induced NRVM hypertrophy, ROS production and mitochondrial membrane potential depolarisation, and confirmed the modulation of mitophagy and ferroptosis markers. Conclusions and Implications We demonstrate that FAN alleviates Ang II-induced HF through a mechanism involving the activation of PGC-1α-mediated mitophagy and regulation of the STAT6-PPARγ pathway, ultimately suppressing cardiomyocyte ferroptosis. These results offer new perspectives for HF treatment. Graphical FAN mitigates HF by engaging PGC-1α-mediated mitophagy and STAT6-PPARγ to counteract ferroptosis.
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高影响因子
BIOMACROMOLECULES
·
2024
·
IF 5.5
Yaxing Li,Heng Gong,Tingjiang Gan,Xikun Ma,Qirui Geng,Shijiu Yin,Hui Zhang,Ye Wu
Chronic diabetic wounds struggle to heal due to drug-resistant bacterial infections, oxidative stress microenvironment, and immune dysfunction. At present, the disease has become a huge clinical challenge. Multifunctional hydrogels with antibacterial, antioxidant, and anti-inflammatory properties are becoming an emerging trend in the treatment of chronic wounds. However, matching different bioactive functions with the wound healing process to sequentially exert antibacterial, antioxidant, anti-inflammatory, and immunomodulatory functions remains a significant challenge. In this research, a hydrogel dressing with bactericidal and anti-inflammatory properties was synthesized by crafting a pH/ROS-responsive scaffold from phenylboronic acid-grafted hyaluronic acid (HA-PBA) and 4-arm-PEG-dopamine (4A-PEG-Dopa), employing dynamic borate ester bonds. This structure was then infused with the antimicrobial peptide (AMP) and ROS-sensitive micelle mPEG-TK-PLGA loaded with quercetin (QC). This dressing embodied a dual-barrier drug delivery mechanism, engineered for the prolonged and consistent liberation of QC. In the experiment, the hydrogel dissociated within the acidic microenvironment of diabetic wounds, thereby liberating the encapsulated micelles and AMP. Upon further dissociation, the micelles release QC due to the ROS-abundant microenvironment, which could relieve oxidative stress and encourage M2 polarization of macrophage via the Akt/STAT6 signaling pathway. Therefore, this smart delivery system, developed through our innovative approach, holds promise for treating chronic infectious diabetic wounds.
研究领域:
生物材料学
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药剂学
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医学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Zhencong Yang,Xue Feng,Philippe Madjirebaye,Yuting Fan,Li Yan,Zhoujin Xu,Xuli Wu
Although sodium nitrite (SN) is broadly used as a food preservative, its immunomodulatory effects on food allergy pathogenesis remain poorly understood. This study examined how subchronic SN exposure influences dendritic cell (DC)-mediated sensitization and T-cell polarization in an Ovalbumin (OVA)-induced mouse food allergy (FA) model. Our findings reveal that SN exacerbated allergic responses manifested by increased clinical symptoms, reduced weight gain, and elevated serum histamine, MCP-1, and IgE levels compared to those of OVA-sensitization alone. Mechanistically, SN promoted Th2 polarization through T-bet/GATA3 imbalance, Treg suppression, and enhanced DC activation. In vitro studies have demonstrated augmented antigen uptake by SN, MHC II expression, and selectively activated MAPK (p-JNK/ERK1/2) and STAT6 pathways, amplifying Th2 cytokine production and IgE class switching. These findings indicate that SN might disrupt immune homeostasis through coordinated modulation of DC function, Th2 polarization, and regulatory mechanisms, which highlights the potential of SN to exacerbate FA via multiple immunomodulatory pathways.
研究领域:
免疫学
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过敏与免疫学
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分子免疫学
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营养免疫学
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黏膜免疫学
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信号转导
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食品毒理学
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Aihua Xu,Yang Yang,Yang Shao,Manyu Jiang,Yongxin Sun,Bo Feng
Neuronal apoptosis and inflammation exacerbate the secondary injury after spinal cord injury (SCI). Four and a half domains 2 (FHL2) is a multifunctional scaffold protein with tissue- and cell-type specific effects on the regulation of inflammation, but its role in SCI remains unclear. The T10 mouse spinal cord contusion model was established, and the mice were immediately injected with lentiviruses carrying FHL2 shRNA after SCI. The results showed that FHL2 expression was increased following SCI, and then gradually decreased. Moreover, FHL2 depletion aggravated functional impairment, neuronal necrosis, and enlarged lesion cavity areas in the injured spinal cord. FHL2 deficiency facilitated neuronal apoptosis by elevating cleaved caspase 3/9 expression, neuroinflammation by regulating microglia polarization, and bone loss. Indeed, FHL2 deficiency increased the secretion of TNF-α and IL-6, M1 microglia polarization, and the activation of STAT1 pathway but decreased the secretion of IL-10 and IL-4, M2 microglia polarization, and the activation of the STAT6 pathway in the spinal cord. In vitro , FHL2 silencing promoted LPS + IFN-γ-induced microglia M1 polarization through activating the STAT1 pathway and alleviated IL-4-induced microglia M2 polarization via inhibiting the STAT6 pathway. FHL2 positively regulated the expression of poly (ADP-ribose) polymerase family member 14 (PARP14) by promoting its transcription. PARP14 overexpression inhibited FHL2 silencing-induced microglia M1 polarization and relieved the inhibitory effect of FHL2 silencing on microglia M2 polarization. Collectively, the study suggests that FHL2 reduces the microglia M1/M2 polarization-mediated inflammation via PARP14-dependent STAT1/6 pathway and thereby improves functional recovery after SCI.
研究领域:
神经科学
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炎症
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细胞生物学
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分子生物学
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PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2020
·Vol. 30
·期 52
·2006454
·
IF 16.836
Zujian Feng,Qi Su,Chuangnian Zhang,Pingsheng Huang,Huijuan Song,Anjie Dong,Deling Kong,Weiwei Wang
Wound management remains a major concern in clinical care. Conventional dressings and hydrogels delivering drugs or cells can drive wound healing. However, these approaches are limited either by unnecessary bleeding and tissue tearing, or sophisticated fabrication, high cost, and drug-related side effects. Herein, a novel bioinspired glycopeptide hydrogel is rationally designed to mimic the glycoprotein components and nanofibrous architecture of cutaneous extracellular matrix (ECM) for self-accelerating the wound healing by regulating macrophage polarization without any additional therapeutic agents. The glycopeptide hydrogel, termed as GM-peptide hybrid hydrogel (GP gel ), is established by the self-assembly of β-sheet Q11 peptide-grafted glucomannan, with nanofibrous structure, high water content, porosity, and self-healing properties. It is observed that GP gel displays remarkable capability of polarizing primary macrophages to M2-type phenotype in vitro and in vivo by inducing the activation of mannose receptors through ERK/STAT6 pathway. GP gel unprecedentedly expedites the wound closure rate and the regeneration of epidermis tissues in full-thickness skin excision models without drugs, exogenous cytokines, or seeded cells. More significantly, GP gel could promote angiogenesis in the repaired skin tissues. Collectively, such a novel ECM-mimicking glycopeptide hydrogel provides a highly effective treatment approach for skin wounds and may serve as a promising scaffold in regenerative medicine.
研究领域:
生物医学工程
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材料科学
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组织工程
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伤口愈合
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高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2025
·
IF 4.2
Xiaoqi Wang,Shuang Liu,Di Su,Jiayu Sui,Xiangyu Yan,Jia Yang,Ziqi Zheng,Penghe Wang,Weijun Song,Zexi Jin,Mingyan E,Maomao Zhang,Bo Yu
Background and aims Viral myocarditis is an inflammatory pathology of the myocardium that involves innate immune responses, especially those involving neutrophils. However, strategies targeting neutrophils to alleviate inflammation have not achieved complete success. Alpha lipoic acid (ALA), a natural organosulfur compound, has the capacity to modulate immune cell behavior. This study aimed to investigate whether ALAs can regulate innate immunity to provide protection against coxsackievirus B3 (CVB3)-induced myocarditis. Methods and results Abdominal administration of ALA improved cardiac dysfunction and reduced mortality in a CVB3-induced mouse model of myocarditis (VM). ALA treatment induced neutrophils and inhibited Ly6C hi pro-inflammatory macrophages, favoring a reparatory environment in the myocardium. However, depleting neutrophils with anti-Ly6G antibodies increased Ly6C hi pro-inflammatory macrophage recruitment in blood and heart in ALA-treated VM mice. Further flow cytometry analysis indicated that ALA promoted Ym-1 expression of neutrophils. Blocking Ym-1 significantly reversed ALA-mediated cardiac reparative macrophages infiltration and cardiac function improvement post-VM. Recombinant Ym-1 drives macrophages toward a reparative phenotype and attenuates CVB3-induced viral myocarditis. Mechanistically, ALA reprogrammed neutrophil metabolic patterns, leading to increased production of the metabolite acetyl-CoA, thereby increasing the transcription of Ym-1 by promoting STAT6 acetylation. Conclusions ALA protects against VM by activating metabolic reprogramming/STAT6 acetylation/Ym-1 axis in neutrophils. These results highlight the heterogeneity of neutrophils and suggest that ALA might represent a feasible strategy to improve the prognosis of VM patients.
研究领域:
免疫学
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病毒学
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心脏病学
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药理学
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分子生物学
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高影响因子
ACS Nano
·
2024
·
IF 15.8
Zhixiang Mu,Tianxi Shen,Hui Deng,Bairui Zeng,Chen Huang,Zhengjin Mao,Yuyu Xie,Yu Pei,Liting Guo,Rongdang Hu,Limin Chen,Yunlong Zhou
Modulating the properties of biomaterials in terms of the host immune response is critical for tissue repair and regeneration. However, it is unclear how the preference for the cellular microenvironment manipulates the chiral immune responses under physiological or pathological conditions. Here, we reported that in vivo and in vitro oligopeptide immunosuppressive modulation was achieved by manipulation of macrophage polarization using chiral tetrapeptide (Ac-FFFK-OH, marked as FFFK) supramolecular polymers. The results suggested that chiral FFFK nanofibers can serve as a defense mechanism in the restoration of tissue homeostasis by upregulating macrophage M2 polarization via the Src-STAT6 axis. More importantly, transiently acting STAT6, insufficient to induce a sustained polarization program, then passes the baton to EGR2, thereby continuously maintaining the M2 polarization program. It is worth noting that the L-chirality exhibits a more potent effect in inducing macrophage M2 polarization than does the D-chirality, leading to enhanced tissue reconstruction. These findings elucidate the crucial molecular signals that mediate chirality-dependent supramolecular immunosuppression in damaged tissues while also providing an effective chiral supramolecular strategy for regulating macrophage M2 polarization and promoting tissue injury repair based on the self-assembling chiral peptide design.
研究领域:
生物材料
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免疫学
·
组织工程
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分子生物学
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生物医学工程
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高影响因子
EUROPEAN JOURNAL OF HISTOCHEMISTRY
·
2020
·
IF 2.172
Li Wu,Dan Han,Jie Jiang,Xiaojie Xie,Xunran Zhao,Tengfei Ke,Wen Zhao,Liu Liu,Wei Zhao
After the facial nerve axotomy (FNA), the distal end of the axon would gradually decay and disappear. Accumulated evidence shows that transplantation of bone marrow mesenchymal stem cells (BMSCs) reveals potential in the treatment of nervous system diseases or injuries. This study is aimed at investigating the therapeutic effects of co-transplantation of BMSCs and monocytes in FNA. We found that co-culture significantly elevated the CD4+/CD8+ ratio and CD4+ CD25+ T cell proportion compared with monocytes transplantation, and enhanced the differentiation of BMSCs into neurons. After the cell transplantation, the lowest apoptosis in the facial nerve nucleus was found in the co-transplantation group 2 (BMSCs:monocytes= 1:30). Moreover, the lowest expression levels of pro-inflammatory cytokines and the highest expression levels of anti-inflammatory cytokines were observed in the co-transplantation group 2 (BMSCs: monocytes= 1:30). The highest expression levels of protein in the JAK/STAT6 pathway and the SDF-1/CXCR4 axis were found in the co-transplantation group 2. BMSC/monocyte co-transplantation significantly improves the microenvironment in the facial nerve nucleus in FNA rats; therefore these findings suggest that it could promote the anti-/pro-inflammatory balance shift towards the anti-inflammatory microenvironment, alleviating survival conditions for BMSCs, regulating BMSC the chemotaxis homing, differentiation, and the section of BMSCs, and finally reducing the neuronal apoptosis. These findings might provide essential evidence for the in-hospital treatment of FNA with co-transplantation of BMSCs and monocytes.
研究领域:
神经科学
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干细胞生物学
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再生医学
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PubMed
高影响因子
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