MOLECULAR NEUROBIOLOGY
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2025
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IF 4.3
Yan Qian,Li Xiao-Jun,Wang Qi-Qi,Jia Wei,Wang Shu-Ling
Approaches of promoting a neural milieu permissive for plasticity and resilience against neuronal injury are important strategies for the treatment of a range of neurological disorders. Fibroblast growth factor 21 (FGF21) which is known for its role as a potent regulator of glucose and energy metabolism has also proved to be neuroprotective against various mental diseases. However, the underlying molecular mechanisms remain elusive. Here, we report a study of the neuroprotective effects of FGF21 by promoting 5-HT 1A R-FGFR1 heteroreceptor formation and triggering MEK 1/2 -ERK 1/2 signaling pathway in normal or abnormal neurological conditions. First, the in vitro cellular experiments demonstrated that FGF21 exerted a protective effect against glutamate-induced cytotoxicity and promoted cell differentiation and growth. Then, in wild-type and FGF21 −/− mice, exogenous FGF21 promoted FGFR1-5-HT 1A R heteromers formation in the CA3 and dentate gyrus region of the hippocampus and activated MEK 1/2 -ERK 1/2 signaling. Coordinately, FGF21 exerted similar influences in the hippocampi of IBA-induced neurological injury mice or combined stress-exposed mice. Besides, FGF21 treatment activated the phosphorylation of FGFR1 and elevated the expression of synaptophysin in these mice with neurological injury or combined stress exposure. These results illustrated that FGF21 alleviated neurological impairment through FGFR1-5-HT 1A R heteromer and ERK 1/2 signal activation and suggested that the regulation of FGFR1-5-HT 1A R heteromers and MEK 1/2 /ERK 1/2 pathway may play a key role in mediating the neuroprotective effects of FGF21 against various neurodegeneration conditions.
研究领域:
神经科学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICAL VIROLOGY
·
2025
·Vol. 97
·期 3
·e70267
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IF 4.6
Wenting Mao,Yi Wan,Yang Liu,Minmin Zhou,Xiaoying Jia,Yuxia Hou,Wei Wang
The lymphocytic choriomeningitis virus (LCMV) is a widespread pathogen that causes mild-to-severe infections to severe outcomes. In this study, we explored the potential of trametinib, a mitogen-activated protein kinase (MAPK) inhibitor, as an antiviral agent against LCMV. Trametinib demonstrated significant antiviral activity against two distinct LCMV strains, Armstrong and Cl13, with promising half-maximal inhibitory concentrations (IC 50 ) and selectivity indices (SI) indicating its potency and safety profile. Mechanistic investigations revealed that trametinib interfered with multiple stages of the LCMV life cycle, including membrane fusion and genomic replication, leading to the robust inhibition of viral proliferation. Furthermore, trametinib disrupted the MEK/ERK signaling pathway, which is crucial for LCMV infection. In both in vitro and in vivo experiments, trametinib effectively reduced viral loads and mitigated pathological damage to the spleen and liver tissues. Overall, our findings suggest that trametinib is a promising novel therapeutic option for combating LCMV infection by targeting key stages of the viral life cycle and disrupting host cellular signaling pathways. Further exploration of the antiviral properties of trametinib is likely to pave the way for its clinical development as a treatment for LCMV infections.
研究领域:
病毒学
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药物研发
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医学
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PubMed
高影响因子
Cell Reports
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2021
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IF 9.423
Ke Li,Hongguang Wu,Ao Wang,Jean Charron,Yuji Mishina,Samy L. Habib,Huijuan Liu,Baojie Li
Summary mTOR, the sensor of nutrients and growth factors, has important roles in tissue homeostasis and tumorigenesis. However, how mTOR controls gastric epithelial cell turnover and gastric cancer development, a leading malignancy, remains poorly understood. Here, we provide genetic evidence that mTOR activation promotes proliferation and inhibits differentiation of Lgr5 + gastric epithelial progenitors (GEPs) in gastric homeostasis and tumorigenesis. mTOR signaling increases MEK1 and Smad1 expression and enhances activation of MEK1-ERKs and BMP-Smad1 pathways, respectively, in GEPs and gastric tumors. Mek1 deletion or inhibition rescues hyperproliferation, whereas Bmpr1a ablation or inhibition rescues differentiation defects of Tsc1 −/− GEPs. Tsc1 deficiency in Lgr5 + GEPs accelerates gastric tumor initiation and development, which require MEK1-ERKs for hyperplasia and BMP-Smad1 for differentiation suppression. These findings reveal how mTOR signaling controls Lgr5 + GEP homeostasis and cancerization and suggest that ERKs and Smad1 signaling can be safely targeted to substitute mTOR inhibitors in gastric cancer therapy.
研究领域:
癌症生物学
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细胞信号传导
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胃肠病学
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DOI
PubMed
高影响因子
Cancers
·
2022
·Vol. 14
·期 9
·2338
·
IF 6.575
Chunyuan Tang,Ying Zhou,Wen Sun,Haihong Hu,Yuxi Liu,Lu Chen,Fengting Ou,Su Zeng,Nengming Lin,Lushan Yu
Simple SummaryColorectal cancer (CRC) claimed more than 900,000 lives globally in 2020. Therefore, its pathogenetic landscape calls for in-depth investigation. Recently, more attention has been paid to oncogenesis driven by noncoding RNAs and even peptides encoded by noncoding RNAs. Here, we report aLINC01234-encoded peptide named MEK1-binding oncopeptide (MBOP), which exists endogenously and is highly expressed in CRC. Through in vivo and in vitro migration and proliferation assays, we demonstrated the oncogenic role of MBOP. In addition, we performed immunoprecipitation assays to identify the interacting proteins and pathways, and MBOP was found to interact with MEK1 and activate the MEK1/pERK/MMP2/MMP9 signaling pathway. Moreover, the ubiquitin–protease-system-mediated degradation of MBOP was elucidated, where the E3 ubiquitin-protein transferase MAEA and RMND5A play vital roles. In conclusion, oncopeptide MBOP plays a substantial role in the tumorigenesis of CRC, and it could be a candidate prognostic biomarker for clinical treatment.AbstractColorectal cancer (CRC) ranks third in incidence rate and second in mortality rate of malignancy worldwide, and the diagnosis and therapeutics of it remain to be further studied. With the emergence of noncoding RNAs (ncRNAs) and potential peptides derived from ncRNAs across various biological processes, we here aimed to identify a ncRNA-derived peptide possible for revealing the oncogenesis of CRC. Through combined predictive analysis of the coding potential of a batch of long noncoding RNAs (lncRNAs), the existence of an 85 amino-acid-peptide, named MEK1-binding oncopeptide (MBOP) and encoded fromLINC01234was confirmed. Mass spectrometry and Western blot assays indicated the overexpression of MBOP in CRC tissues and cell lines compared to adjacent noncancerous tissues and the normal colonic epithelial cell line. In vivo and in vitro migration and proliferation assays defined MBOP as an oncogenic peptide. Immunoprecipitation trials showed that MEK1 was the key interacting protein of MBOP, and MBOP promoted the MEK1/pERK/MMP2/MMP9 axis in CRC. Two E3-ligase enzymes MAEA and RMND5A mediated the ubiquitin–protease-system-related degradation of MBOP. This study indicates that MBOP might be a candidate prognostic indicator and a potential target for clinical therapy of CRC.Keywords:peptide;MBOP;LncRNA;colorectal cancer;MAPK signaling pathway
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2019
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IF 3.775
Jie Zhang,Yifan Song,Yuan Liang,Haoyang Zou,Peng Zuo,Mi Yan,Siyuan Jing,Tiezhu Li,Yongjun Wang,Da Li,Tiehua Zhang,Zhengyi Wei
Cucurbitacin IIa (CuIIa), a tetracyclic triterpenoid harboring anticancer activity, was investigated in A549 cells to reveal its mechanism of targeting on epidermal growth factor receptor (EGFR) signaling pathway. Results showed that CuIIa was capable of inducing apoptosis and cell cycle arrest at G2/M phase. The transcription of EGFR pathway genes and their proteins accumulation was inconsistently influenced by CuIIa. Notably, transcription of Raf1 was significantly upregulated, nevertheless, MEK1 and ERK1 were significantly downregulated. On the other hand, the accumulation of the total and phosphorylated proteins of the most members in EGFR-mitogen-activated protein kinase (MAPK) pathway, as well as CylclinB1 and survivin were also shifted by CuIIa treatment. Remarkably, total MEK remained constant but survivin completely degraded. Moreover, phosphorylated BRAF continuously increased while Raf1 and MEK decreased continuously. CuIIa was further confirmed to be a tyrosine kinase inhibitor (TKI) of EGFR by kinase inhibition assay. The results of molecular simulation showed that the long side chain of CuIIa occupied the binding pocket of EGFR and the ligand was stabilized at the active site of EGFR. In view of the results above, it is suggested that CuIIa inhibits cell proliferation by interfering the EGFR-MAPK signaling pathway.
研究领域:
肿瘤学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR ENDOCRINOLOGY
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2026
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IF 3.4
Yanbing Lou,Tingting Yang,Chenglong Xia,Shijun Yang,Huidan Deng,Yanqiu Zhu,Jing Fang,Zhicai Zuo,Hongrui Guo
CCS and ATOX1 is a specific target of copper in hormone secretion of ovarian granulosa cells. • MEK1-ERK1/2 pathway is involved in copper-affected hormone secretion. • Copper affects hormones secretion through CCS and ATOX1 dependent MEK1-ERK1/2 pathway. Steroid hormone synthesis in granulosa cells (GCs) is crucial for normal follicular development and ovulation. Emerging evidence suggests that copper (Cu), a trace element, influences hormone secretion in yak granulosa cells (YGCs); however, the underlying mechanisms remain unclear. In this study, we demonstrated that Cu supplementation upregulates estradiol (E2) and progesterone (P4) secretion in YGCs through the activation of the MEK1-ERK1/2 signaling pathway. Our findings indicate that the Cu chaperones ATOX1 and CCS, but not the Cu-dependent enzyme LOX, are essential for Cu-induced MEK1-ERK1/2 activation and subsequent hormone secretion. Gene silencing of ATOX1 or CCS resulted in reduced MEK1-ERK1/2 phosphorylation and steroidogenesis, highlighting their regulatory roles in this pathway. Although LOX influenced hormone secretion, it did not affect MEK-ERK phosphorylation, suggesting a MEK-independent mechanism. These findings reveal that Cu regulates steroid hormone synthesis in YGCs via a CCS- and ATOX1-dependent MEK1–ERK1/2 pathway, providing new insights into the molecular basis of Cu-associated reproductive disorders in yaks. Download: Download high-res image (289KB) Download: Download full-size image
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DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2026
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IF 4
Zhang Xiaojuan,Song Yingying,Han Xinyan,Wang Mengxue,Chen Yufeng,Weng Yue,Li Yaxin,Huang Fei,Shi Hailian,Wu Hui,Wu Xiaojun
White peony root ( Paeonia lactiflora Pall.) is the dried root of peony. White peony root has a long history in Traditional Chinese Medicine (TCM) and is primarily used to treat various conditions, including pain, inflammation, and immune system disorders. Paeoniflorin (PF) is one of the main active components of white peony root, and it has multiple functions such as anti-inflammation, immune regulation, and neuroprotection. However, the impact of PF on multiple sclerosis (MS) remains to be fully elucidated. In this study, we observed that PF treatment markedly attenuated neurological symptoms in experimental autoimmune encephalomyelitis (EAE) mice, reduced disease severity, and alleviated spinal cord inflammation and demyelination, indicating a significant neuroprotective effect. PF administration was accompanied by reduced CD4 + T cell infiltration, decreased Th17 cell proportions, and increased Treg cell frequency in vivo. It also balanced Th17/Treg-associated cytokine secretion by suppressing IL-17 and promoting IL-10 expression. In addition, PF modulated the expression of differentiation-related proteins in lymphoid tissues and inhibited inflammatory gene and protein levels. In primary murine CD4 + T cells, PF enhanced Treg differentiation under Treg-polarizing conditions. In Jurkat cells, PF induced phosphorylation of Raf, MEK 1/2 , and ERK 1/2 , together with increased expression of Egr-1 and Foxp3. These findings indicate that PF treatment is associated with modulation of the Treg/Th17 balance in EAE mice and with changes in Raf/MEK 1/2 /ERK 1/2 /Egr-1 signaling in Jurkat cells. In summary, PF treatment ameliorated EAE manifestations, together with restoration of Treg/Th17 homeostasis and activation of the Raf/MEK 1/2 /ERK 1/2 /Egr-1 pathway. However, whether the Raf/MEK 1/2 /ERK 1/2 /Egr-1 signaling axis directly contributes to PF-induced Treg differentiation in primary T cells or to the therapeutic effects of PF in vivo remains to be determined. Graphical abstract PF treatment ameliorated EAE manifestations and was associated with reduced CD4 + T-cell infiltration, restoration of the Th17/Treg balance, and attenuation of CNS inflammation and demyelination in EAE mice. PF also enhanced Treg differentiation in primary murine CD4 + T cells and was associated with the activation of the Raf/MEK 1/2 /ERK 1/2 /Egr-1 signaling axis in Jurkat cells. The causal contribution of this signaling axis to Treg differentiation and the therapeutic effects of PF remains to be determined.
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DOI
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Guoxin Jing,Zhaojie Wang,Xizhen Zhuang,Xiaolie He,Huijun Wu,Qingxiu Wang,Liming Cheng,Zhongmin Liu,Shilong Wang,Rongrong Zhu
Graphene oxide (GO), with good hydrophilicity and biocompatibility, is widely explored as a carrier for various factors in the field of stem cell differentiation . However, its function of sustaining the stemness of mouse embryonic stem cells (mESCs) and the underlying mechanisms of this process remains undiscovered. Herein, we explored the biofunction of GO on mESCs and revealed the involved signaling pathways and key gene. The alkaline phosphatase activity detection, pluripotency genes quantification and the teratomas formation in vivo confirmed that GO nanosheets could sustain the self-renewal ability of mESCs instead of influencing its pluripotency . The underlying signaling pathways were uncovered by RNA-seq that integrin signaling pathway was involved in the biofunction of GO on mESCs and Vinculin turned to be a key gene for the effect of GO. Further experiments confirmed that the downregulation of Vinculin influenced the fate of mESCs through decreasing the expression of MEK1. Altogether, the study demonstrated for the first time that GOs hold the potential in sustaining the self-renewal of mESCs and clarified the mechanism of this function, which make it play a new role in stem cell research and regenerative medicine .
研究领域:
干细胞生物学
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纳米技术
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再生医学
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分子生物学
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DOI
PubMed
高影响因子
NEUROGASTROENTEROLOGY AND MOTILITY
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2022
·Vol. 35
·期 2
·e14488
·
IF 3.96
Mengjuan Lin,Guiying Hu,Baoping Yu
Background Hydrogen sulfide (H 2 S), an important endogenous gasotransmitter, is involved in the modulation of gastrointestinal motility, but whether it mediates the intestinal dysmotility in irritable bowel syndrome (IBS) is not known. This study explored the significance of cystathionine-β-synthase (CBS)/H 2 S signaling in stress-induced colonic dysmotility. Methods A rat model of IBS was established using chronic water avoidance stress (WAS). Colonic pathological alterations were detected histologically. Intestinal motility was determined by intestinal transit time (ITT) and fecal water content (FWC). Visceral sensitivity was assessed using the visceromotor response (VMR) to colorectal distension (CRD). Real-time PCR, Western blotting, and immunostaining were performed to identify the expression of CBS in the colon. The contractions of distal colon were studied in an organ bath system and H 2 S content was measured by ELISA. The effects of SAM, a selective CBS activator, on colonic dysmotility were examined. MEK1 was tested as a potential upstream effector of CBS/H 2 S loss. Key Results After 10 days of WAS, the ITT was decreased and FWC was increased, and the VMR magnitude in response to CRD was enhanced. The colonic CBS expression and H 2 S levels were significantly declined in WAS-exposed rats, and the density of CBS-positive enteric neurons in the myenteric plexus in WAS-treated rats was lower than that in controls. SAM treatment relieved WAS-induced colonic hypermotility via increased H 2 S production. AZD6244, a selective inhibitor of MEK1, partially reversed CBS downregulation and colonic hypermotility in WAS-treated rats. Conclusions & Inferences Decreased CBS/H 2 S signaling through increased MEK1 signaling might be important in the pathogenesis of chronic stress-induced colonic hypermotility. SAM could be administered for disorders associated with intestinal hypermotility.
研究领域:
胃肠病学
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神经胃肠病学
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药理学
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应激生物学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Xiaolie He,Yanjing Zhu,Mei Wang,Guoxin Jing,Rongrong Zhu,Shilong Wang
Major depression is a complex neuropsychiatric disorder with few treatment approaches. The use of nontargeted antidepressants induced many side effects with their low efficacy. A more precise targeting strategy is to develop nanotechnology-based drug delivery systems; hence, we employed solid lipid nanoparticles (SLNs) to encapsulate HU-211 and curcumin (Cur). The antidepressant effects of the dual-drug nanoparticles (Cur/SLNs-HU-211) for major depression treatment were investigated in corticosterone-induced cellular and animal models of major depression. Cur/SLNs-HU-211 can effectively protect PC12 cells from corticosterone-induced apoptosis and can release more dopamine, which may be associated with the higher uptake of Cur/SLNs-HU-211 shown by cellular uptake behavior analysis. Additionally, Cur/SLNs-HU-211 significantly reduced the immobility time in forced swim test, enhanced fall latency in rotarod test, and improved the level of dopamine in mice blood. Cur/SLNs-HU-211 can deliver more Cur to the brain and thus produce a significant increase in neurotransmitters level in brain tissue, especially in the hippocampus and striatum. The results of Western blot and immunofluorescence revealed that Cur/SLNs-HU-211 can significantly enhance the expression of CB1, p-MEK1, and p-ERK1/2. Our study suggests that Cur/SLNs-HU-211 may have great potential for major depression treatment.
研究领域:
药理学
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纳米技术
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神经科学
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精神病学
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产品关联
DOI
PubMed
高影响因子
Environmental Science-Nano
·
2026
·
IF 5.1
Hong Yang,Peng Zhao,Xiaolei Wei,Chao Huang,Wu-Hong Lv,Yu-Chen Zhou,Zhi Luo
Copper oxide nanoparticles (CuO NPs) are widely used in industry and agriculture, leading to their persistent occurrence and accumulation in aquatic environments and posing potential environmental risks. However, the specific role and underlying mechanisms of CuO NPs on the health risks of aquatic organisms remain unclear. This study revealed that dietary exposure to high levels of CuO NPs elevated hepatic Cu content, induced oxidative stress and mitochondrial dysfunction that exacerbate hepatic lipotoxicity. Mechanistically, high dietary CuO NPs enhanced the interaction between domains 1 and 3 of the Cu chaperone for superoxide dismutase (Ccs) and mitogen-activated protein kinase kinase 1 (Mek1), which subsequently activated the phosphorylation of extracellular signal-regulated protein kinase 1/2 (Erk1T202/Y204 and Erk2T185/Y187). The activated Erk1/2 mediated CuO NPs-induced lipotoxicity by suppressing the expression of peroxisome proliferator-activated receptor α (Pparα) and promoting its phosphorylation at the S77 site. Further investigation demonstrated that Pparα phosphorylation impaired fatty acid β-oxidation by downregulating the promoter activities of long chain acyl-coA dehydrogenase (acadl) and carnitine palmitoyl transferase Ia1b (cptIa1b). For the first time, this study elucidated the novel mechanism by which CuO NPs induced metabolic disorder via the Ccs/Mek1/Erk1/2/Pparα signaling axis. These findings provide critical evidence for the toxicological and environmental risk assessment of nanoparticles, while also deepen the mechanistic understanding of nanometal exposure-induced health effects in aquatic animals within complex environments.
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高影响因子
INFECTION GENETICS AND EVOLUTION
·
2021
·
IF 3.342
M.A. Abo-Kadoum,Mohammed Assad,Moure UAE,Stech A.E. Nzaou,Zhen Gong,Asmaa Moaaz,Samson Teweldebrhan,Adel Eltoukhy,Ai Xuefeng,Yu Chen,Jianping Xie
Mycobacterium tuberculosis (Mtb) survival and virulence largely reside on its ability to manipulate the host immune response . We have previously shown that M. tuberculosis Raf kinase inhibitor protein (RKIP) Rv2140c regulates diverse phosphorylation events in M. smegmatis . However, its role during infection is unknown. In this report, we show that Rv2140c can mimic the mammalian RKIP function. Rv2140c inhibit the activation of extracellular signal-regulated kinase (ERK) and nuclear factor κB (NF-κB) via decreasing the phosphorylation capacity of upstream mediators MEK1, ERK1/2, and IKKα/β, thus leading to a reduction in pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. This effect can be reversed by RKIP inhibitor locostatin. Furthermore Rv2140c mediates apoptosis associated with activation of caspases cascades. This modulation enhances the intracellular survival of M. smegmatis within macrophage. We propose that Rv2140c is a multifunctional virulence factor and a promising novel anti-Tuberculosis drug target.
研究领域:
微生物学
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免疫学
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传染病学
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DOI
PubMed
高影响因子
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