PLANT CELL AND ENVIRONMENT
·
2025
·
IF 6.3
Weiwei Liu,Qiuyue Ou,Meichang Feng,Yue Li,Linghan Huang,Xuan Peng,Xiaoqiang Zhong,Guoqiang Huang,Hengbo Wang,Jinlong Guo
Cold stress is a critical environmental factor adversely affecting plant growth and development. As a tropical-origin crop constituting the primary global source of sucrose, sugarcane ( Saccharum spp. hybrid) exhibits particular vulnerability to suboptimal temperature conditions, with chilling injury substantially compromising its yield potential. Despite its agricultural significance, the molecular mechanisms underlying cold acclimation in sugarcane remain poorly characterized. Here, we report a cold-repressed 1R-MYB gene, ScMYB7 , from sugarcane, whose promoter ( pro-ScMYB7 ) contains multiple cis -acting elements, including two cytosine—phosphate diester—guanine (CpG) islands. Bisulfite sequencing PCR (BSP) and qPCR results showed that low-temperature treatment increased the methylation level of the CpG islands in the promoter to reduce the transcription of the ScMYB7 gene. The outcomes of GUS enzyme activity measurement of the promoter also indicated that low-temperature treatment inhibits the promoter's transcriptional activity, and methylation inhibitors could alleviate this inhibition. By generating transgenic Arabidopsis lines overexpressing ScMYB7 , ScMYB7's roles in regulating cold tolerance were investigated. We observed that the transgenic plants reduced cold tolerance, featured by a decreased survival rate after recovery, fluctuated physiological traits, and significantly lower expression levels of the C-repeat binding factor (CBF)-dependent pathway genes ( AtCBFs , AtCOR15 , and AtRD29A ). Yeast one-hybrid assays demonstrated direct binding of ScMYB7 to the AtCBF1 promoter, while repression of sugarcane ScDREB1A occurred indirectly. Furthermore, the dual-luciferase reporter assay indicated that ScMYB7 was able to inhibit the expression of the AtCBF1 or ScDREB1A . Taken together, we propose a model in which ScMYB7 acts as a repressor of cold tolerance via the CBF-dependent pathway. Under low-temperature stress, increased methylation of the pro-ScMYB7 promoter reduces ScMYB7 expression, thereby alleviating its repression of sugarcane DREB/CBF-type transcription factors and enhancing cold adaptation.
研究领域:
植物分子生物学
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环境逆境生理学
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表观遗传学
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作物科学
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植物生物技术
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转录调控
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非生物胁迫响应
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PubMed
高影响因子
DIABETES OBESITY & METABOLISM
·
2026
·
IF 6.1
Yunxiao Zhang,Bo Zhu,Binhui Peng,Peng Wu,Guyu Zhong,Yongchen Wang,Zhaofeng Wang,Xinyu Feng,Dongfang Tang,Dezheng Peng,Yu Liu
Background The GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) are key targets for diabetes and obesity therapies. Pharmacological agents including GLP-1R agonists (e.g., Semaglutide), dual GLP-1R/GIPR agonists (e.g., Tirzepatide) and a GLP-1R agonist/GIPR antagonist (AMG133) have demonstrated considerable promise in anti-diabetic and weight management applications. However, a systematic comparison of the specific contributions of GIPR activation versus GIPR inhibition to weight loss within the context of GLP-1/GIP dual-targeting therapies remains unexplored. Research Design and Methods To address this, we designed three IgG4 Fc-fusion proteins: a GLP-1R agonist/GIPR agonist, (i) GLP-1(A8G)/GIP(A2G)-Fc; a GLP-1R agonist/GIPR inhibitor, (ii) GLP-1(A8G)/GIP(3–30)-Fc; and a sequential molecule that hypothesised to transition from dual GLP-1R/GIPR agonism to GLP-1R agonism/GIPR inhibition, (iii) GLP-1(A8G)/GIP(1–30)-Fc. Mono-agonist GLP-1(A8G)-Fc and dual-agonist GLP-1(A8G)/GIP(A2G)-Fc were used as controls to investigate the weight loss effects of GIPR activation and inhibition in DIO mice. Results Our findings revealed that the sequential molecule GLP-1(A8G)/GIP(1–30)-Fc produced the greatest body weight reduction (21.59%), significantly outperforming GLP-1(A8G)/GIP(3–30)-Fc (14.5%; p < 0.001). Furthermore, both GIPR activation and inhibition, when combined with GLP-1R agonism, markedly improved serum and hepatic lipid metabolism, as evidenced by reduced triglycerides and total cholesterol. Conclusion Together, these findings validate a peptide-based inhibitory strategy for synergistic weight loss and provide insights into the differential metabolic roles of GIPR activation versus inhibition, guiding the development of novel anti-obesity therapeutics.
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PubMed
高影响因子
Biomaterials Science
·
2020
·Vol. 8
·期 20
·5666-5676
·
IF 6.183
Qi Wei,Na Shen,Haiyang Yu,Yue Wang,Zhaohui Tang,Xuesi Chen
Combretastatin A4 nanoparticles (CA4-NPs), which notably inhibit tumor growth, were found to cause tumor regrowth due to the intratumoral enrichment of M2-type macrophages after treatment. Since BLZ945, an inhibitor of CSF-1 receptor (CSF-1R), depletes and inhibits the proliferation of M2-type macrophages, it has the potential to relieve the immunosuppressive microenvironment and improve anti-tumor therapy of CA4-NPs. However, CSF-1R exists widely, not only in macrophages, and BLZ945 could cause potential hepatotoxicity. It is necessary to establish a tumor-targeting drug delivery system to reduce the off-target and side effects of BLZ945. In this study, FXIIIa substrate peptide A15 decorated BLZ945 nanoparticles (A15-BLZ-NPs) were developed, in which, BLZ945-poly(D,L-lactide) (BLZ945-PLA), produced by ring-opening polymerization, was encapsulated in poly(ethylene glycol)-poly(D,L-lactide) (PEG5k-PLA5k), and A15 was decorated on the surface PEG segment. A15-BLZ-NPs could crosslink with fibrin through elevated FXIIIa and specifically target intratumoral coagulation spots induced by CA4-NPs. In vivo studies showed that CA4-NPs induced enhanced distribution of BLZ945 in tumors, as the BLZ945 content was 3.75-fold in the CA4-NP + A15-BLZ-NP group compared to that of A15-BLZ-NP single treatment. Meanwhile, compared to the CA4-NP group, the combination treatment significantly reduced the proportion of M2-type macrophages (from 64.4% to 24.5%) and enriched cytotoxic T lymphocytes (from 1.5% to 18.9%) in tumors, suggesting that A15-BLZ-NPs remodeled and activated tumor immunity after CA4-NP treatment. Furthermore, the combined treatment effectively improved the tumor inhibition rate to 73.4%, which was significantly higher than that of CA4-NP (15.5%) or A15-BLZ-NP (23.9%) single treatment. This work established a novel combination strategy for anti-tumor therapy.
研究领域:
肿瘤学
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药理学
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免疫学
·
纳米技术
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2023
·
IF 3.1
Qiuxia Zhu,Yong Luo,Yuetao Wen,Ding Wang,Jing Li,Zhongcai Fan
Apoptosis is a major pathophysiological change following myocardial ischemia/reperfusion (I/R) injury. Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are widely expressed in the cardiovascular system and GLP-1/GLP-1R activates the protein kinase G (PKG)-related signaling pathway. Therefore, this study tested whether semaglutide, a new GLP-1 analog, inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. We induced myocardial I/R injury in rats and hypoxia/reoxygenation (H/R) injury in H9C2 cells and detected the effects of semaglutide, a PKG analog (8-Br-cGMP), and a PKG inhibitor (KT-5823) on the PKG/PKCε/ERK1/2 pathway and cardiomyocyte apoptosis. We found that semaglutide upregulated GLP-1R levels, and both semaglutide and 8-Br-cGMP activated the PKG/PKCε/ERK1/2 pathway, inhibited myocardial infarction (MI), decreased hs-cTNT levels, increased NT-proBNP levels, and suppressed cardiomyocyte apoptosis in I/R rats and H/R H9C2 cells. However, KT-5823 exerted contrasting effects with semaglutide and 8-Br-cGMP, and KT-5823 weakened the cardioprotective effects of semaglutide. In conclusion, semaglutide inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. The beneficial effect of GLP-1/GLP-1R, involved in the activation of the PKG/PKCε/ERK1/2 pathway, may provide a novel treatment method for myocardial I/R injury.
研究领域:
心脏病学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2020
·Vol. 236
·期 5
·3660-3674
·
IF 5.546
Xinxuan Cheng,Danxue He,Chunyan Liao,Sijie Lin,Liying Tang,Yuan-Liang Wang,Jiaoyue Hu,Wei Li,Zuguo Liu,Yalin Wu,Yi Liao
The underlying mechanisms of complement activation in Stargardt disease type 1 (STGD1) and age-related macular degeneration (AMD) are not fully understood. Overaccumulation of all- trans -retinal (atRAL) has been proposed as the pathogenic factor in both diseases. By incubating retinal pigment epithelium (RPE) cells with atRAL, we showed that C5b-9 membrane attack complexes (MACs) were generated mainly through complement alternative pathway. An increase in complement factor B (CFB) expression as well as downregulation of complement regulatory proteins CD46, CD55, CD59, and CFH were observed in RPE cells after atRAL treatment. Furthermore, interleukin-1β production was provoked in both atRAL-treated RPE cells and microglia/macrophages. Coincubation of RPE cells with interleukin-1 receptor antagonist (IL1Ra) and atRAL ameliorated complement activation and downregulated CFB expression by attenuating both p38 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings demonstrate that atRAL induces an autocrine/paracrine IL-1/IL-1R signaling to promote complement alternative pathway activation in RPE cells and provide a novel perspective on the pathomechanism of macular degeneration.
研究领域:
眼科学
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免疫学
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细胞生物学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Xiaojun Yan,Yulin Zhang,Wen Zeng,Yang Li,Chenhui Zhu
Tendon repair remains a major clinical challenge, largely because current strategies often fail to simultaneously achieve early inflammatory control and subsequent matrix remodeling. To address this problem, we developed a dynamically responsive nano-hydrogel, CAPP@IGF-1, composed of 3-carboxyphenylboronic acid-modified chitosan, polyvinyl alcohol, and IGF-1-loaded PLGA microspheres, which were integrated through phenylborate ester crosslinking. The hydrogel exhibited favorable self-healing behavior together with enhanced mechanical properties, with an elastic modulus of 4.5 MPa and a toughness of 15.3 MJ/m³, enabling it to maintain local structural stability under the complex dynamic conditions of tendon repair. Under the acidic inflammatory microenvironment, CAPP@IGF-1 enabled controlled local release of IGF-1 and activated the IGF-1R/AKT signaling pathway, thereby markedly promoting macrophage reprogramming from the pro-inflammatory M1 state to the pro-reparative M2 state. This was accompanied by suppression of IL-6, IL-2, and TNF-α and upregulation of IL-10, leading to the establishment of a local immune microenvironment favorable for repair. On this basis, the hydrogel further promoted tendon stem/progenitor cell migration, proliferation, extracellular matrix remodeling, and more ordered collagen deposition. In a rabbit tendon injury model, CAPP@IGF-1 notably reduced peritendinous adhesion, and enhanced the mechanical recovery of repaired tendons. Collectively, CAPP@IGF-1 achieves stage-specific intervention during tendon healing through the combined effects of a dynamically crosslinked network, enhanced mechanical properties, and intelligent IGF-1 release. This study demonstrates the feasibility of using materials design to connect inflammatory microenvironment regulation with tissue regeneration and provides a new strategic basis for the precise repair of complex tendon injuries.
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PubMed
高影响因子
iScience
·
2023
·Vol. 26
·期 6
·106918-106918
·
IF 5.8
Huixia Wang,Wanhui Hu,Tiandan Xu,Ya Yuan,Dongsheng Liu,Kurt Wüthrich
Crystal and cryo-EM structures of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) bound with their peptide ligands have been obtained with full-length constructs, indicating that the extracellular domain (ECD) is indispensable for specific ligand binding. This article complements these data with studies of ligand recognition of the two receptors in solution. Paramagnetic NMR relaxation enhancement measurements using dual labeling with fluorine-19 probes on the receptor and nitroxide spin labels on the peptide ligands provided new insights. The glucagon-like peptide-1 (GLP-1) was found to interact with GLP-1R by selective binding to the extracellular surface. The ligand selectivity toward the extracellular surface of the receptor was preserved in the transmembrane domain (TMD) devoid of the ECD. The dual labeling approach further provided evidence of cross-reactivity of GLP-1R and GCGR with glucagon and GLP-1, respectively, which is of interest in the context of medical treatments using combinations of the two polypeptides.
研究领域:
结构生物学
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分子生物学
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药理学
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PubMed
高影响因子
Current Pharmaceutical Analysis
·
2021
·Vol. 17
·期 9
·1197-1205
·
IF 0.89
Wang Jie,Lu Ping,Zhang Shengting,Li Wanwan,Ji Xiuling,Li Jing,Zhang Hui,Wei Yunlin,Liang Chenggang
Background: Current methods for assaying bioactivity of GLP-1 analogues are costly and time consuming, mainly dependent on AlphaScreen luminous beads, based on fluorescent resonance energy transfer technology, and cAMP-GloTM Max assay kit, and on ATP to generate a negative- association
curve. Objective: To establish a sensitive, stable, and low-cost method for the determination of biological activity of therapeutic glucagon-like peptide-1(GLP-1) and their analogous drugs in vitro in quality control. Methods: An applicable fluorescent high-content system (fHCS)
method was developed in U2OS cell, which was stably transfected with green fluorescent protein (GFP) labeled at the C-terminal of glucagon-like peptide-1 receptor (GLP-1R). HCS was firstly used to measure per unit area of fluorescent intensity changes as a result of drug-stimulated receptor
endocytosis. Results: The detection sensitivity improved at least 30 folds than the other reported methods. This method showed a wide detection range with a good linear regression of R2>0.98. In five scgs from 50~150% SCG, the accuracy achieved the standard of the 41st United States
Pharmacopoeia with all biases being less than 7.5%. The precision attained the 9.0th European Pharmacopoeia standard with all relative standard deviations (RSDs) below 10%. This assay result can be kept stable over 100 h at room temperature. Furthermore, the U2OS/GLP-1R cells showed a sharp
specificity towards GLP-1 analogues during detecting activities in a mixture of different ligands. Conclusion: These results suggested that the GLP-1R/fHCS method can be employed broadly in the bioactivity determination of GLP-1 analogous drugs and as a platform for screening GLP-1 similar
active ingredients in natural products.
研究领域:
药理学
·
药物开发
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生物技术
·
细胞生物学
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DOI
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2019
·
IF 2.12
Qiang Fu,Hai-Dong Lu,Yi-Fei Xie,Jia-You Liu,Yang Han,Ning-Bo Gong,Fang Guo
Indomethacin ( Indo ) and naproxen ( Nap ) belong to Biopharmaceutical Classification System (BCS) class II drugs, which permeate membranes well but are poorly soluble. Two pharmaceutical salts hydrate of Indo and Nap with (1R,2R)-1,2-diphenylethylenediamine ( DPEN ) were obtained using solution crystallization. Both salts, (DPEN) 2 ·(Indo) 2 ·(H 2 O) 2 and (DPEN) 1 ·(Nap) 1 ·(H 2 O) 0.5 , were characterised using various solid-state characterisation techniques such as single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and Raman spectra . The structure analysis shows that DPEN is monocation as only one amine is protonated into ammonium. The Indo , DPEN and water molecules form one-dimensional hydrogen bond chains through extensive N H⋯O, N H⋯N and O H⋯N interactions. The solubility study shows that the two salts are more soluble in pH 1.2, 4.5 and 6.8 buffer mediums compared with pure raw materials. Solubility thermodynamics calculation was carried out to further understand the solubility properties of two salts.
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高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Yang Xiaohua,Zhang Min,Lu Zhihong,Zhi Linping,Xue Huan,Liu Tao,Liu Mengmeng,Cui Lijuan,Liu Zhihong,He Peifeng,Liu Yunfeng,Zhang Yi
Glucagon-like peptide-1 receptor (GLP-1R) agonist-based therapeutics for type 2 diabetes mellitus have attracted worldwide attention. However, there are challenges in the development of small molecule GLP-1R agonists owing to the complexity of ligand recognition and signal induction mechanisms. Here, we attained S6 using virtual screening and fluorescent imaging plate reader (FLIPR)-based calcium assays. The purpose of this study was to identify and characterize S6, a novel small molecule GLP-1R agonist. Data from cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI) indicated that S6 could bind potently with GLP-1R. Radioimmunoassay data showed that S6 potentiated insulin secretion in a glucose-dependent manner and the insulinotropic effect was mediated by GLP-1R. Calcium imaging techniques suggested that S6 elevated the intracellular calcium concentration [(Ca2+)i] by activating GLP-1R. In patch-clamp experiments, we demonstrated that S6 inhibited voltage-dependent K+ (Kv) channels in a GLP-1R-dependent fashion. Besides, S6 significantly prolonged action potential duration but had no effect on voltage-dependent Ca2+ channels. In summary, these findings indicate that S6 stimulates glucose-dependent insulin secretion mainly by acting on GLP-1R, inhibiting Kv channels, increasing (Ca2+)i. This study will provide direction for the screening and development of novel small-molecule agents targeting GLP-1R in the future.
研究领域:
药理学
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内分泌学
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糖尿病
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Yu Zou,Quan Zhou,Yinan Zhao,Defu Zhi,Huiying Chen,Rui Wang,Benzhi Ju,Shubiao Zhang
Ionizable lipids are the leading vectors for gene therapy. Understanding the effects of molecular structure on efficient gene delivery is one of the most important challenges for maximizing the utility of such lipid vectors. We synthesized an array of pH-responsive and ionizable lipids to investigate the relationship between lipid structure and activity. The optimized lipid (EDM) has double tertiary amines in the headgroup and an ester linker. EDM exhibited efficient DNA and siRNA delivery to, and gene silencing of, A549 cells. EDM has a p K a value of 6.67, which enabled it to quickly escape from the endosome after entering the cell; the ester linkages rapidly degraded and enabled gene release into the cytoplasm. EDM also delivered IGF-1R siRNA to inhibit tumor growth and induce cancer cell apoptosis by efficient inhibition of IGF-1R expression in mice. Our study on the structure–activity relationships of ionizable lipids will facilitate clinical applications.
研究领域:
药学
·
基因治疗
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分子生物学
·
癌症研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Xin Gao,Zhen-Zi Shang,Qiang-Ming Li,Feng-Yun Zhang,Xue-Qiang Zha,Jian-Ping Luo
Ethnopharmacological relevance Dendrobium huoshanense has been long used to treat gastrointestinal disorders including ulcerative colitis (UC) in traditional Chinese medicine. Polysaccharides as its main active components can alleviate UC by reducing inflammation, and promote the secretion of glucagon-like peptide-1 (GLP-1), which possesses anti-inflammatory effects via GLP-1 receptor (GLP-1R). However, it remains unclear whether polysaccharides from different parts of this herb are equally effective in alleviating UC and whether polysaccharides function via GLP-1/GLP-1R axis. Aim of the study To identify the part in which the polysaccharide is most effective in alleviating UC and to explore its mechanism of action through GLP-1/GLP-1R axis. Materials and methods The physicochemical properties of polysaccharides were analyzed. A dextran sulfate sodium (DSS)-induced UC mouse model was used to assess colitis-associated damage via morphological scoring, histopathological evaluation and inflammatory examination with multi-cytokine array and western blotting. Gut microbiota compositions, short-chain fatty acid contents and GLP-1 levels were measured, and their roles were checked using antibiotic mixture and GLP-1R antagonist Exendin (9-39). Results Stem, leaf and flower polysaccharides, with different molecular weight, monosaccharide composition and spatial conformation, differentially alleviated UC symptoms, and stem polysaccharide (DHPS) showed the strongest efficacy, as evidenced by improved epithelial integrity, mucus barrier and inflammatory disorder. DHPS-alleviated UC was independent of DHPS-altered gut microbiota and positively correlated with DHPS-elevated GLP-1 levels, which could be abolished by Exendin (9-39), suggesting that GLP-1-activated GLP-1R signaling mediated the effects of DHPS against UC. Conclusions DHPS is the most effective polysaccharide for alleviating DSS-induced UC through GLP-1/GLP-1R axis, proposing DHPS is a valid candidate for UC treatment using D. huoshanense .
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高影响因子
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