CLINICAL SCIENCE
·
2025
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IF 7.7
Renzi Zhang,Yuhua Zhong,Qiudie Liu,Mengqi Zhang,Daoxin Wang,Sheng Li,Di Qi
Acute respiratory distress syndrome (ARDS) is an acute and severe disease with a high mortality rate. The outbreak of immune inflammation in the lung is an important pathogenic mechanism of ARDS. Notably, an imbalance in macrophage polarization is an important link in the occurrence and development of this inflammatory response. Recently, neuropeptides have been shown to regulate inflammation, but the role of neuropeptides in ARDS remains unclear. The aim of this study was to investigate the regulatory effect of calcitonin gene-related peptide (CGRP) on the inflammatory response in ARDS. We found that CGRP expression was increased in the serum of ARDS patients and in both in vitro and in vivo models of ARDS. CGRP can regulate the polarization of macrophages by targeting its receptor (receptor activity-modifying protein 1); reduce the proportion of M1 macrophages; increase the proportion of M2 macrophages; and reduce pathological injury, inflammation, oxidative stress, and apoptosis in lung tissue in LPS-induced ARDS both in vitro and in vivo . Additionally, we performed transcriptome sequencing and found that hypoxia-inducible factor-1α (HIF-1α) is involved in the above process and that CGRP can alleviate ARDS-related pathological damage, inflammation, and oxidative stress by inhibiting the HIF-1α pathway to regulate macrophage polarization balance. These results indicate that CGRP has good potential for clinical translation in the treatment of pulmonary infection in ARDS. Furthermore, this study provides new ideas for the treatment of inflammatory bursts in ARDS.
研究领域:
免疫学
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分子生物学
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病理学
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PubMed
高影响因子
Communications Biology
·
2025
·Vol. 8
·期 1
·1-21
·
IF 5.1
Liu Zhenghua,Xin Peng,Wu Weiwei,Jin Mingyue,Du Yang,Jiang Yuanjun,Liu Tao,Zhang Hao
Metastatic bladder cancer is characterized by its aggressive behavior and complex molecular mechanisms that remain largely undefined. This study explores the therapeutic potential of targeting peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) using liposomal nanoparticles to deliver PGC-1α siRNA to bladder cancer cells. We employed comprehensive transcriptomic, proteomic, and metabolomic analyses to investigate the impact of PGC-1α silencing. Our in vitro results demonstrate that targeting PGC-1α significantly impairs mitochondrial function and disrupts energy metabolism, affecting critical pathways such as glycolysis and the citric acid cycle, as well as altering mRNA nuclear export. In vivo experiments in animal models show that nanoparticles loaded with si-PGC-1α effectively reduce lung metastasis, indicating a significant impact on metastatic progression. These findings highlight PGC-1α as a key regulator of metabolic reprogramming in metastatic bladder cancer and suggest that its inhibition could serve as a promising therapeutic strategy. By elucidating the role of PGC-1α in cancer metabolism, this study provides new insights into the molecular underpinnings of bladder cancer metastasis and offers potential avenues for developing targeted therapies aimed at the metabolic vulnerabilities of this malignancy.
研究领域:
肿瘤学
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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
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 1
·e70054
·
IF 3.3
Lichao Ji,Yingjie Chai,Chenhao Tong,Yanxin Hu,Jiandong Li,Baochun Lu,Jianhua Yu
Gallbladder cancer is the most prevalent malignancy of the biliary tract and has a dismal overall survival even in the present day. The development of new drugs holds promise for improving the prognosis of this lethal disease. The possible anti-neoplastic role of morusin was investigated both in vitro and in vivo. Through cell viability and colony formation assays, we observed that morusin inhibited the proliferation of gallbladder cancer cells in vitro. Wound healing and transwell assays revealed that morusin impeded the migration and invasion of gallbladder cancer cells. Given the observed morphological changes, we examined epithelial-mesenchymal transition (EMT) markers. Subsequent investigations demonstrated that morusin treatment, both in vitro and in vivo, downregulated the expression of phospho-STAT3 (Signal transducer and activator of transcription 3) and HIF-1α (Hypoxia-inducible factor 1α) in gallbladder cancer cells. Furthermore, morusin effectively reversed EMT induced by phospho-STAT3 or HIF-1α. Morusin has a reversing effect on the EMT of gallbladder cancer cells by modulating STAT3/HIF-1α signaling.
研究领域:
肿瘤学
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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
PHYTOMEDICINE
·
2023
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IF 7.9
Chao Ma,Chunran Zhu,Yajun Zhang,Mei Yu,Yizhi Song,Yulong Chong,Yan Yang,Chan Zhu,Yucui Jiang,Changming Wang,Shuo Cheng,Keke Jia,Guang Yu,Jia Li,Zongxiang Tang
Background Increasing evidence highlights the involvement of metabolic disorder and calcium influx mediated by transient receptor potential channels in migraine; however, the relationship between these factors in the pathophysiology of migraine remains unknown. Gastrodin is the major component of the traditional Chinese medicine Tianma, which is extensively used in migraine therapy. Purpose Our work aimed to explore the analgesic action of gastrodin and its regulatory mechanisms from a metabolic perspective. Methods/results After being treated with gastrodin, the mice were given nitroglycerin (NTG) to induce migraine. Gastrodin treatment significantly raised the threshold of sensitivity in response to both mechanical and thermal stimulus evidenced by von Frey and hot plate tests, respectively, and decreased total contact numbers in orofacial operant behavioral assessment. We found that the expression of transient receptor potential melastatin 2 (TRPM2) channel was increased in the trigeminal ganglion (TG) of NTG-induced mice, resulting in a sustained Ca 2+ influx to trigger migraine pain. The content of succinate, a metabolic biomarker, was elevated in blood samples of migraineurs, as well as in the serum and TG tissue from NTG-induced migraine mice. Calcium imaging assay indicated that succinate insult elevated TRPM2-mediated calcium flux signal in TG neurons. Mechanistically, accumulated succinate upregulated hypoxia inducible factor-1α (HIF-1α) expression and promoted its translocation into nucleus, where HIF-1α enhanced TRPM2 expression through transcriptional induction in TG neurons, evidenced by luciferase reporter measurement. Gastrodin treatment inhibited TRPM2 expression and TRPM2-dependent Ca 2+ influx by attenuating succinate accumulation and downstream HIF-1α signaling, and thereby exhibited analgesic effect. Conclusion This work revealed that succinate was a critical metabolic signaling molecule and the key mediator of migraine pain through triggering TRPM2-mediated calcium overload. Gastrodin alleviated NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in TG neurons. These findings uncovered the anti-migraine effect of gastrodin and its regulatory mechanisms from a metabolic perspective and provided a novel theoretical basis for the analgesic action of gastrodin.
研究领域:
神经科学
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药理学
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代谢
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PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2025
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IF 4.2
Shibo Zhu,Sunwei Tang,Zijie Ye,Wei Jia
One of the most prevalent male urogenital anomalies is hypospadias. The general etiology of hypospadias is still not completely clear, despite the fact that the number of patients with the hypospadias is rising. HNF-1α was predicted as the most activated upstream regulator of severe hypospadias in our previous research. Our study aims to investigate the mechanism by which HNF-1α regulates hypospadias. We found that HNF-1α was highly expressed in hypospadias tissues, and was positively associated with fibrinogen related genes FGA and FGB, respectively. In animal experiments, silencing of HNF-1α resulted in a more narrow urethral groove, and a decreased periurethral pathologic fibrosis. Meanwhile, the inflammation cytokines and oxidative stress related factors were significantly reduced after inhibition of HNF-1α expression. In addition, the protein levels of STAT3, FGA and FGB were also depressed after HNF-1α knockdown. Mechanistically, we showed that the HNF-1α transcriptionally activated STAT3, and subsequently increased the expressions of FGA and FGB. Additionally, suppression of HNF-1α improved the murine hypospadias via inactivating the STAT3. Therefore, our findings confirmed that HNF-1α promoted hypospadias and periurethral fibrosis by activating STAT3. Targeting HNF-1α might the future direction for hypospadias treatment.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-14
·
IF 3.9
Tang Di,Lin Qiang,Li Pei-Wen,Wang Song,Xu Kai,Huang Yue-Sheng,Lu Qi-Ping
Chronic refractory wounds are a common, costly and recurrent complication of diabetes. Platelet-rich plasma (PRP), a new therapy for chronic wounds, is limited by a long treatment period and unstable effects. FG-4592(Roxadustat) is a new prolyl-4-hydroxylation domain(PHD) inhibitor, which can stabilize hypoxia-inducible factor-1α(HIF-1α) effectively. It is a promising drug for wound repair and needs to be demonstrated via various appropriate application scenarios. This study investigated the effects of combining FG-4592 and PRP to promote diabetic wound healing. Diabetic rats were randomly assigned to five groups: nondiabetic control, diabetic untreated, diabetic + PRP, diabetic + FG-4592, and diabetic + PRP + FG-4592. Diabetes was induced with streptozotocin (STZ). A full-thickness skin defect was created, and FG-4592 (peritoneal injection) and PRP (periwound injection) were administered alone or together. Wound healing was assessed by histological analysis (Hematoxylin-Eosin (HE) and Masson staining) and protein expression of HIF-1α, VEGF(vascular endothelial growth factor), α-SMA(α-smooth muscle actin), CoL1α1(collagen type 1 alpha 1), and SDF-1(Stromal Cell-derived Factor 1) via Western blotting and qRT-PCR(Quantitative real time polymerase chain reaction). Immunohistochemistry(IHC) and immunofluorescence(IF) were also used to evaluate CD34 (Cluster of Differentiation 34), CD31(Cluster of Differentiation 31), VEGF(vascular endothelial growth factor), SDF-1(Stromal Cell-derived Factor 1), PCNA(Proliferating Cell Nuclear Antigen), and Integrin-β1 expression. The untreated diabetic group exhibited impaired wound healing, histological damage, and reduced expression of key proteins compared to the nondiabetic control group. Both PRP and FG-4592 alone improved wound healing, reduced damage, and upregulated protein expression. However, the combination of FG-4592 and PRP showed the most significant improvement. This study suggests that FG-4592 combined with PRP accelerates diabetic wound healing by enhancing endothelial progenitor cell recruitment, neovascularization, and cell proliferation and migration via upregulation of HIF-1α and its target genes. This combination therapy may provide a novel approach for treating chronic diabetic wounds.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
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IF 2.5
Jiajia Pan,Lijun Meng,Rujun Li,Zicheng Wang,Wenjie Yuan,Yucheng Li,Lin Chen,Qinhao Shen,Weili Liu,Li Zhu
Myocardial dysfunction is a prevalent complication of sepsis (septic cardiomyopathy) with a high mortality rate and limited therapeutic options. Naringenin, a natural flavonoid compound with anti-inflammatory and antioxidant properties, holds promise as a potential treatment for sepsis-induced myocardial dysfunction. This study investigated the pharmacological effects of naringenin on septic cardiomyopathy. In vivo and in vitro experiments demonstrated that naringenin improved cardiomyocyte damage. Network pharmacology and database analysis revealed that HIF-1α is a key target protein of naringenin. Elevated expression of HIF-1α was observed in damaged cardiomyocytes, and the HIF-1α inhibitor effectively protected against LPS-induced cardiomyocyte damage. Molecular docking studies confirmed the direct binding between naringenin and HIF-1α protein. Importantly, our findings demonstrated that naringenin did not provide additional attenuation of cardiomyocyte injury on the biases of HIF-1α inhibitor treatment. In conclusion, this study proves that naringenin protects against septic cardiomyopathy through HIF-1α signaling. Naringenin is a promising therapeutic candidate for treating septic cardiomyopathy.
研究领域:
药理学
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心脏病学
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分子生物学
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DOI
PubMed
高影响因子
MATERIALS & DESIGN
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2024
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IF 7.6
Jinmei Cheng,Yushun Dou,Jiaxin Li,Tingting You,Yihai Wang,Mengchuan Wang,Shengjun Shi,Chun-hui Cui,Xiaopin Duan,Jisheng Xiao
Critical limb ischemia (CLI) remains a significant clinical challenge with high morbidity and mortality. Considering the critical role of hypoxia-inducible factor 1α (HIF-1α) in hypoxic site to induce angiogenesis by regulating the expression of growth factors, we prepared a cooperative composite (P-F-HKUST-1) by mixing thermo-responsive hydrogel (PPCN) with folic acid modified copper-based MOFs (F-HKUST-1) for the hindlimb ischemia therapy. The gelation of P-F-HKUST-1 in hindlimb muscle generated a more serious ischemia environment and subsequently induced the expression of HIF-1α, while the slowly released Cu 2+ from P-F-HKUST-1 increased HIF-1α stability by inactivating the factor-inhibiting hypoxia-inducible factor 1 (FIH-1), which synergistically induced the productions of downstream growth factors and finally restored the blood perfusion rapidly. In addition, P-F-HKUST-1 hydrogel exhibited a long in vivo retention time, which endowed the sustaining action on HIF-1α to reduce the frequency of administration. The rapid blood flow recovery, together with the good biocompatibility suggested that P-F-HKUST-1 could be a potential novel combined therapy (HIF-1α stimulation and stabilization) for critical limb ischemia.
研究领域:
生物医学工程
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药学
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组织工程
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分子生物学
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DOI
高影响因子
DIGESTIVE DISEASES AND SCIENCES
·
2025
·
IF 2.5
Gao Tao,Zhang Huaisheng,Xu Yuan,He Guosong,Ma Huicong,Zheng Chuanming,Li Lei,Cheng Feng,Dou Hehe,Zhang Fulong,Zhao Heng,Qiu Zhaolei
Background Severe Acute Pancreatitis (SAP) is associated with significant intestinal injury and inflammation. Hypoxia-Inducible Factor-1α (HIF-1α) and NLRP3 inflammasome have been implicated in this process, but their specific roles remain unclear. Objective This study aims to elucidate the roles of HIF-1α and NLRP3 in the pathogenesis of SAP and their effects on intestinal injury, barrier function, and inflammatory responses. Methods A SAP rat model was established, and histological changes were assessed via HE staining. Western blot was used to analyze HIF-1α and NLRP3 expression in intestinal mucosa. The effects of HIF-1α modulation were examined using the activator DMOG and inhibitor BAY87-2243. Immunohistochemistry, ELISA, and TUNEL staining were used to evaluate intestinal barrier function, permeability markers, and apoptosis. Results HIF-1α and NLRP3 expression significantly increased in SAP rats, peaking at 72 h. HIF-1α activation aggravated intestinal injury and barrier dysfunction, decreasing tight junction protein levels and increasing epithelial apoptosis. Enhanced intestinal permeability and elevated pro-inflammatory cytokines were also observed. Furthermore, HIF-1α activation promoted NLRP3 inflammasome assembly, resulting in increased caspase-1 and IL-1β expression. Conclusion HIF-1α exacerbates intestinal injury and inflammation in SAP, likely through NLRP3 inflammasome activation. Targeting HIF-1α may offer a potential therapeutic approach for SAP-induced damage and inflammation.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
FITOTERAPIA
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2024
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IF 2.5
Ye-Fang Lu,Chuang Liu,Juan Ma,Hu-Ri Piao,Changhao Zhang,Xuejun Jin,Cheng-Hua Jin
Hypoxia-inducing factor-1α (HIF-1α) is overexpressed in variety of tumor patients and plays an important role in the regulation of hypoxia response in tumor cells. Therefore, its inhibitors have become one of the targets for the treatment of a variety of cancers. Two series of panaxadiol (PD) ester derivatives containing pyrazole ( 18a–j ) and pyrrole ( 19a–n ) moiety were synthesized and their HIF-1α inhibitory activities were evaluated. Among all the target compouds, compounds 18c , 19d , and 19n (IC 50 = 8.70 – 10.44 μM) showed better HIF-1α inhibitory activity than PD (IC 50 = 13.35 μM). None of these compounds showed cytotoxicity above 100 μM and inhibited HIF-1α transcription in a dose-dependent manner. These compounds showed good antitumor activity and provide lead compounds for further design and activity study of PD ester derivatives.
研究领域:
药理学
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肿瘤学
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药物化学
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DOI
PubMed
高影响因子
INFLAMMATION
·
2018
·Vol. 41
·期 6
·2068-2078
·
IF 2.884
Zhou Qin,Gong Xia,Kuang Ge,Jiang Rong,Xie Tianjun,Tie HongTao,Chen XiaHong,Li Ke,Wan JingYuan,Wang Bin
Ferulic acid (FA), derived from fruits and vegetables, is well-known as a potent antioxidant of scavenging free radicals. However, the role and underlying mechanism of FA on kidney ischemia reperfusion (I/R) injury are limited. Here, we explored the effects of FA on kidney I/R injury. The kidney I/R injury models were carried out by clamping bilateral pedicles for 35 min followed by reperfusion for 24 h. Mice were orally pretreated with different doses of FA for three times 24 h before I/R. The renal function was assessed by serum creatine (Scr) and blood urea nitrogen (BUN). Kidney histology was examined by hematoxylin and eosin (HE) staining and terminal deoxynucleotidly transferased UTP nick-end labeling (TUNEL) assay. Proinflammatory cytokines, caspase-3 activity, adenosine generation, adenosine signaling molecules, and hypoxia inducible factor-1 alpha (HIF-1α) were also detected, respectively. The siHIF-1α adenovirus vectors were in vivo used to inhibit the expression of HIF-1α. The results showed that FA significantly attenuated kidney damage in renal I/R-operated mice as indicated by reducing levels of Scr and BUN, ameliorating renal pathological structural changes, and tubular cells apoptosis. Moreover, FA pretreatment inhibited I/R-induced renal proinflammatory cytokines and neutrophils recruitment. Interestingly, the levels of HIF-α, CD39, and CD73 mRNA and protein as well as adenosine production were all significantly increased after FA pretreatment in the kidney of I/R-performed mice, and inhibiting HIF-α expression using siRNA abolished this protection of FA on I/R-induced acute kidney injury as evidenced by more severe renal damage and reduced adenosine production. Our findings indicated that FA protected against kidney I/R injury by reducing apoptosis, alleviating inflammation, increasing adenosine generation, and upregulating CD39 and CD73 expression, which might be mediated by HIF-1α.
研究领域:
药理学
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分子生物学
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肾脏病学
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DOI
PubMed
高影响因子
ACTA NEUROPSYCHIATRICA
·
2024
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IF 2.6
Shan Xing,Shuyi Xu,Linjiao Wang,Liyuan Guo,Xin Zhou,Haoxin Wu,Wei Wang,Lanying Liu
Depression is one of the major mental disorders, which seriously endangers human health, brings a serious burden to patients’ families. In this study, we intended to further explore the antidepressant-like effect and possible molecular mechanisms of Salidroside (SAL). We built corticosterone (CORT)-induced depressive mice model and used behavioural tests to evaluate depression behaviour. To explore the molecular mechanisms of SAL, we employed a variety of methods such as immunofluorescence, western blot, pharmacological interference, etc. The results demonstrated that SAL both at 25 mg/kg and 50 mg/kg can reduce immobility time in the tail suspension test (TST). At the same time, SAL treatment could restore the reduced sugar water intake preference in the sucrose preference test (SPT) in CORT-induced depressive mice and reduce the immobility time in TST and forced swimming experiments (FST). In addition, SAL treatment reversed the reduction in the number of Ki-67, BrdU, and NeuN in the hippocampus due to CORT treatment. SAL treatment also restored the expression of SIRT1, PGC-1α, brain-derived neurotrophic factor (BDNF) and other proteins in the hippocampus. In addition, after blocking SIRT1 signalling with EX527, we found that the treatment with SAL failed to reduce the immobility time in TST and FST, the level of SIRT1 and PGC-1α activity were correspondingly downregulated, and the expression of DCX and Ki-67 in the hippocampus failed to be activated. These findings suggested that SAL exerts antidepressant-like effects by promoting hippocampal neurogenesis through the SIRT1/PGC-1α signalling pathway.
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
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