mBio
·
2025
·
IF 4.7
Kaili Duan,Shaozhe Qin,Fangling Cui,Liangyuan Zhao,Yongqing Huang,Jin-Rong Xu,Guanghui Wang
Deoxynivalenol (DON), a mycotoxin primarily produced by Fusarium species, is commonly found in cereal grains and poses risks to human and animal health, as well as global grain trade. This study demonstrates that methyl jasmonate (MeJA), a natural plant hormone, inhibits the growth and conidiation of Fusarium graminearum. Importantly, MeJA significantly reduces DON production by suppressing TRI gene expression and toxisome formation. To explore the molecular mechanism, we identified MeJA-tolerant mutants, including a transcription factor MRT1 and cAMP-PKA pathway-related genes (FgGPA1 and FgSNT1). MeJA treatment reduced PKA activity and intracellular cAMP levels in F. graminearum, suggesting it targets the cAMP-PKA pathway. Notably, the MeJA-resistant mutant FgGPA1R178H enhanced fungal growth, DON production, and cAMP levels in the presence of MeJA. Exogenous cAMP alleviated MeJA’s inhibitory effects on DON production, further supporting this pathway’s involvement. Interestingly, MeJA had no effect on all three MAP kinase pathways (Mgv1, Gpmk1, and FgHog1). Truncated and phospho-mimicking mutations in Mrt1 or FgSnt1 conferred MeJA resistance, suggesting they may act downstream of the cAMP-PKA pathway. In conclusion, MeJA presents a promising approach to control F. graminearum growth and DON production.
研究领域:
植物病理学
·
分子生物学
·
真菌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2025
·Vol. 82
·期 1
·1-16
·
IF 6.2
Zhao Xueqin,Li Yuanhao,Yang Liu,Chen Xi,Zhang Jialong,Chen Tong,Wang Haoqi,Li Fei,Cheng Chen,Wu Jingjing,Cong Jingjing,Yin Wenwei,Li Jing,Wang Xuefu
Acetaminophen (APAP) overdose induces acute liver injury and represents the most frequent cause of drug-induced liver injury worldwide. Macrophage-mediated inflammation plays detrimental roles during the early stage of liver injury. However, the potential targets regulating inflammation to improve drug-induced liver injury remains undefined. In this study, we reported that G protein-coupled receptor 35 (GPR35) improves drug-induced liver injury by blocking macrophage-mediated inflammation via the Gαs-cyclic AMP-protein kinase A (Gαs-cAMP-PKA) pathway. The ablation of GPR35 exacerbates APAP-induced liver injury, characterized by higher levels of alanine aminotransferase and aspartate aminotransferase in sera, larger damaged areas, and increased levels of pro-inflammatory cytokines. More hepatic macrophages appeared in the inflamed liver of mice with GPR35 deficiency. In contrast, the agonists of GPR35 alleviated APAP-induced liver injury. The depletion of macrophages abolished GPR35-mediated protection. Mechanistically, GPR35 ablation facilitated the activation of pro-inflammatory AKT, MAPK, and NF-κB signaling pathways at the downstream of Toll-like receptors in macrophages. GPR35 agonists activated Gαs-cAMP-PKA signaling to inhibit the activation of these pro-inflammatory signaling pathways and then suppress the inflammatory response in macrophages. Thus, our findings demonstrate that GPR35 prevents drug-induced liver injury by blocking macrophage-mediated inflammation via the Gαs-cAMP-PKA pathway, indicating that GPR35 is a potential target for the development of novel medicines that control drug-induced liver injury.
研究领域:
药理学
·
肝脏病学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Animal Science and Biotechnology
·
2024
·Vol. 15
·期 1
·1-18
·
IF 6.3
Shang Lijun,Yang Fengjuan,Chen Qingyun,Dai Ziqi,Yang Guangxin,Zeng Xiangfang,Qiao Shiyan,Yu Haitao
Background The antibacterial and immunomodulatory activities of bacteriocins make them attractive targets for development as anti-infective drugs. Although the importance of the enteric nervous system (ENS) in the struggle against infections of the intestine has been demonstrated, whether it is involved in bacteriocins anti-infective mechanisms is poorly defined. Results Here, we demonstrated that the bacteriocin Microcin J25 (J25) significantly alleviated diarrhea and intestinal inflammation in piglets caused by enterotoxigenic Escherichia coli (ETEC) infection. Mechanistically, macrophage levels were significantly downregulated after J25 treatment, and this was replicated in a mouse model. Omics analysis and validation screening revealed that J25 treatment induced significant changes in the dopaminergic neuron pathway, but little change in microbial structure. The alleviation of inflammation may occur by down-regulating dopamine receptor (DR) D1 and the downstream DAG-PKC pathway, thus inhibiting arachidonic acid decomposition, and the inhibition of macrophages may occur through the up-regulation of DRD5 and the downstream cAMP-PKA pathway, thus inhibiting NF-κB. Conclusions Our studies’ findings provide insight into the changes and possible roles of the ENS in J25 treatment of ETEC infection, providing a more sophisticated foundational understanding for developing the application potential of J25.
研究领域:
微生物学
·
免疫学
·
神经科学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Virulence
·
2024
·
IF 5.5
Fen Wang,Jinping Zhang,Qian Zhang,Zhangyong Song,Caiyan Xin
Candida albicans is an opportunistic fungal pathogen that can cause systemic infections in immunocompromised individuals. Morphological transition and biofilm formation are major virulence factors of C. albicans. Moreover, biofilm enhances resistance to antifungal agents. Therefore, it is urgent to identify new and effective compounds to target the biofilm of C. albicans. In the present study, the antifungal activities of equol against C. albicans were investigated. In vitro, the microdilution analysis and spot assay result showed that equol exhibited potent inhibitory activities against C. albicans. Further investigations confirmed that the antifungal effects of equol involved interference with the transition from yeast to hypha and biofilm formation of C. albicans. In addition, transcriptome sequencing and reverse transcription-quantitative PCR (qRT-PCR) analysis showed that equol significantly downregulated the expression of several genes in the Ras1-cAMP-PKA pathway related to hyphae and biofilm formation and significantly upregulated the expression of the negative transcriptional repressors RFG1 and TUP1. Moreover, equol effectively reduced the production of cAMP, a key messenger in the Ras1-cAMP-PKA pathway, while supplementation with cAMP partly rescued the equol-induced defects in hyphal development. Furthermore, in a mouse model of systemic candidiasis (SC), equol treatment significantly decreased the fungal burden (liver, kidneys, and lung) in mice and local tissue damage, while enhancing the production of interleukin-10 (IL-10). Together, these findings confirm that equol is a potentially effective agent for treatment of SC.
研究领域:
微生物学
·
药理学
·
分子生物学
·
传染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Yan Cao,Jinpeng Lv,Yan Tan,Ruolin Chen,Xiaoxue Jiang,Duo Meng,Kun Zou,Min Pan,Liming Tang
Ethnopharmacological relevance Tribuloside, a natural flavonoid extracted from Chinese medicine Tribulus terrestris L., has shown potent efficacy in treating various diseases. In China, the fruits of Tribulus terrestris L. have long been utilized for relieving headache, dizziness , itchiness, and vitiligo . Water-based extract derived from Tribulus terrestris L. can enhance melanogenesis in mouse hair follicle melanocytes by elevating the expression of α-melanocyte stimulating hormone (α-MSH) and melanocortin-1 recepter (MC-1R). Nevertheless, there is a lack of information regarding the impact of tribuloside on pigmentation in both laboratory settings and living organisms. Aim of the study The present research aimed to examine the impact of tribuloside on pigmentation, and delve into the underlying mechanism. Materials and methods Following the administration of tribuloside in human epidermal melanocytes (HEMCs), we utilized microplate reader, Masson-Fontana ammoniacal silver stain, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) to measure melanin contents, dendrite lengths, melanosome counts; L-DOPA oxidation assay to indicate tyrosinase activity, Western blotting to evaluate the expression of melanogenic and associated phosphodiesterase (PDE)/cyclic adenosine monophosphate (cAMP)/cyclic-AMP dependent protein kinase A (PKA) pathway proteins. A PDE-Glo assay to verify the inhibitory effect of tribuloside on PDE was also conducted. Additionally, we examined the impact of tribuloside on the pigmentation in both zebrafish model and human skin samples. Results Tribuloside had a notable impact on the production of melanin in melanocytes, zebrafish, and human skin samples. These functions might be attributed to the inhibitory effect of tribuloside on PDE, which could increase the intracellular level of cAMP to stimulate the phosphorylation of cAMP-response element binding (CREB). Once activated, it induced microphthalmia-associated transcription factor (MITF) expression and increased the expression of tyrosinase, Rab27a and cell division cycle protein 42 (Cdc42), ultimately facilitating melanogenesis, melanocyte dendricity, and melanin transport. Conclusion Tribuloside acts on the PDE/cAMP/PKA pathway to enhance melanogenesis, melanocyte dendricity, and melanosome transport; meanwhile, tribuloside does not have any toxic effects on cells and may be introduced into clinical prescriptions to promote pigmentation.
研究领域:
药理学
·
细胞生物学
·
分子生物学
·
民族药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Dun Liu,Runyan Niu,Siliang Wang,Lihua Shao,Xian Yang,Xuexue Liu,Xiaolong Ma,Zezhang Zhu,Jinping Zhang,Benlong Shi,Huanyu Ni,Xiao Du
Neural stem cell (NSCs) transplantation is a promising therapeutic strategy for spinal cord injury (SCI), but its efficacy is greatly limited by the local inhibitory microenvironment. In this study, based on l-arginine (l-Arg)-loaded mesoporous hollow cerium oxide (AhCeO2) nanospheres, we constructed an injectable composite hydrogel (AhCeO2-Gel) with microenvironment modulation capability. AhCeO2-Gel protected NSCs from oxidative damage by eliminating excess reactive oxygen species while continuously delivering Nitric Oxide to the lesion of SCI in a pathological microenvironment, the latter of which effectively promoted the neural differentiation of NSCs. The process was confirmed to be closely related to the up-regulation of the cAMP-PKA pathway after NO-induced calcium ion influx. In addition, AhCeO2-Gel significantly promoted the polarization of microglia toward the M2 subtype as well as enhanced the regeneration of spinal nerves and myelinated axons. The prepared bioactive hydrogel system also efficiently facilitated the integration of transplanted NSCs with host neural circuits, replenished damaged neurons, alleviated neuroinflammation, and inhibited glial scar formation, thus significantly accelerating the recovery of motor function in SCI rats. Therefore, AhCeO2-Gel synergized with NSCs transplantation has great potential as an integrated therapeutic strategy to treat SCI by comprehensively reversing the inhibitory microenvironment.
研究领域:
生物医学工程
·
神经科学
·
组织工程
·
再生医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Applied Physiology Nutrition and Metabolism
·
2018
·Vol. 44
·期 1
·
IF 2.518
Yu Qiao,Guoqiang Fan,Jun Guo,Shixing Gao,Ruqian Zhao,Xiaojing Yang
Zinc-α2-glycoprotein (ZAG) has been demonstrated to play a role in stimulating lipid mobilization under normal conditions. However, further studies are required to determine whether ZAG overexpression can alleviate the reduction in plasma lipid levels under stress conditions. In the present study, we investigated the effects of ZAG on lipometabolism in white adipose tissue (WAT) after dexamethasone (DEX) stimulation using C57BL/6 male mice as the experimental models. Transcript and protein levels of genes associated with the β-adrenoreceptor (β-AR)/cyclic adenosine monophosphate/protein kinase a (PKA) pathway, lipid mobilization, and energy metabolism were determined by quantitative real-time polymerase chain reaction and Western blotting. Plasma levels of nonesterified fatty acid (NEFA) were measured using an automatic biochemical analyzer. Results indicated that plasma NEFA levels were decreased in the DEX group, but NEFA levels were rescued by ZAG overexpression. ZAG overexpression resulted in the upregulation of β3-AR and phosphorylated PKA protein relative to those of the DEX group. Analysis of lipometabolism showed that protein levels of phosphorylated hormone-sensitive lipase was reduced upon DEX treatment but were restored by ZAG overexpression. For energy metabolism, ZAG significantly upregulated the protein expression of carnitine palmitoyltransferase1a and cytochrome c oxidase subunit 1 relative to those of the DEX group. In conclusion, ZAG could alleviate DEX-induced decrease in plasma NEFA levels and this could be associated with the promoting lipid mobilization in WAT.
研究领域:
药理学
·
内分泌学
·
代谢
✓ 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）