Biology Direct
·
2024
·
IF 5.7
Hao Wang,Lei Zhang,Yunxiao Shang
Endoplasmic reticulum (ER) stress has been shown to play a pivotal role in the pathogenesis of asthma. DEPTOR (DEP Domain Containing MTOR Interacting Protein) is an endogenous mTOR inhibitor that participates in various physiological processes such as cell growth, apoptosis, autophagy, and ER homeostasis. However, the role of DEPTOR in the pathogenesis of asthma is still unknown. In this study, an ovalbumin (OVA)-induced mice model and IL-13 induced 16HBE cells were used to evaluate the effect of DEPTOR on asthma. A decreased DEPTOR expression was shown in the lung tissues of OVA-mice and IL-13 induced 16HBE cells. Upregulation of DEPTOR attenuated airway goblet cell hyperplasia, inhibited mucus hypersecretion, decreased the expression of mucin MUC5AC, and suppressed the level of inflammatory factors IL-4 and IL-5, which were all induced by OVA treatment. The increased protein expression of ER stress markers GRP78, CHOP, unfolded protein response (UPR) related proteins, and apoptosis markers in OVA mice were also inhibited by DEPTOR overexpression. In IL-13 induced 16HBE cells, overexpression of DEPTOR decreased IL-4, IL-5, and MUC5AC levels, preventing ER stress response and UPR process. Furthermore, from the proteomics results, we identified that SOD1 (Cu/Zn Superoxide Dismutase 1) may be the downstream factor of DEPTOR. Similar to DEPTOR, upregulation of SOD1 alleviated asthma progression. Rescue experiments showed that SOD1 inhibition abrogates the remission effect of DEPTOR on ER stress in vitro. In conclusion, these data suggested that DEPTOR attenuates asthma progression by suppressing endoplasmic reticulum stress through SOD1.
研究领域:
免疫学
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肺病学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF PHYSICAL CHEMISTRY B
·
2021
·
IF 2.991
Qin Zhang,Bingyao Wang,Yifei Zhang,Jie Yang,Bodan Deng,Bei Ding,Dongping Zhong
Transient amyloid intermediates are likely to be cytotoxic and play an essential role in amyloid-associated neurodegenerative diseases. Characterization of their structural and dynamic evolution is the key to elucidating the molecular mechanism of amyloid formation. Here, combining circular dichroism (CD), exciton couplet theory, and Fourier transform infrared spectroscopy with site-specific tryptophan (Trp) and its noncanonical derivative 5-cyano-tryptochan (Trp5CN), we developed a method to monitor strand-to-strand tertiary and sheet-to-sheet quaternary interactions in the aggregation cascades of an amyloidogenic fragment from protein SOD128–38 (with the sequence KVKVWGSIKGL). We found that the exciton couplet generated from the Bb band of Trp can be used as a probe for side chain interactions. Its sensitivity can be further improved by four times with the incorporation of Trp5CN. We further observed a red-shift of ∼2 cm–1 and a broadening of ∼2 cm–1 in the IR band generated from the CN stretch during the aggregation, which we attributed to the transition from a corkscrew-like structure to a cross-linked intermediate phase. We show here that the integration of optical methods with unique aromatic side chain-related probes is able to elucidate amyloid intermolecular interactions and even capture elusive transient intermediates on and off the amyloid assembling pathway.
研究领域:
生物物理学
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生物化学
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神经退行性疾病
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分子生物学
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DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2021
·
IF 6.543
Xiao-lu Wang,Liang Wang,Fo-lan Lin,Si-si Li,Ting-xuan Lin,Ren-wang Jiang
Copper/zinc superoxide dismutase (SOD1) can clear cisplatin- (CP-) induced excessive reactive oxygen species (ROS), but exogenous SOD1 cannot enter cells because of its low biomembrane permeability. Cell-penetrating peptides (CPPs) can rapidly cross plasma membranes. This study is aimed at identifying an efficient and stable CPP-SOD1 and investigating its effects on CP-induced nephrotoxicity. We recombined SOD1 with 14 different CPPs and purified them using an NTA-Ni2+ column. In in vitro experiments, CPPs-SOD1 cell membrane penetration ability and JNK/p38 MAPK signaling pathway were evaluated using Western blotting. ROS production, mitochondrial membrane potential (MMP), and cell apoptosis were determined using flow cytometry and immunofluorescence staining in VERO and HK-2 cells. For in vivo experiments, mice were administered PSF-SOD1 for 2 h before cotreatment with a single CP injection for an additional 4 days. Blood and kidney samples were collected for renal function assessment (creatinine, urea nitrogen, histopathology, TUNEL assay, and JNK/p38 MAPK signaling pathway). Compared with TAT-SOD1, we found that PSF-SOD1 is more efficient at crossing the cell membrane and is stable after transduction into cells. Pretreatment with PSF-SOD1 inhibited CP-induced apoptosis, ROS generation, and JNK/p38 MAPK activation and restored CP-induced MMP loss in VERO and HK-2 kidney cells. Treatment of mice with PSF-SOD1 inhibited CP-induced serum creatinine, blood urea nitrogen elevation, and JNK/p38 MAPK activation. H&E staining and TUNEL assay indicated that kidney tissue damage was alleviated following PSF-SOD1 pretreatment. Overall, PSF-SOD1 ameliorated CP-induced renal damage by partially reducing oxidative stress and cell apoptosis by regulating JNK/p38 MAPK signaling pathway and might be a better cytoprotective agent than TAT-SOD1.
研究领域:
药理学
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肾病学
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分子生物学
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DOI
PubMed
高影响因子
ULTRASONICS
·
2024
·
IF 3.8
Ji Zhang,Kaili Chen,Yizhe Chen,Lingchen Hua,Siping Chen,Xin Chen,Liangyu Zou,Shupeng Li,Xifei Yang,Yuanyuan Shen
Background Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood–brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders. Objectives We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model. Methods The ALS mouse model with the SOD1 G93A mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining. Results Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord. Conclusion These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.
研究领域:
神经学
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药理学
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生物医学工程
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神经退行性疾病
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DOI
PubMed
高影响因子
JOURNAL OF NEUROSCIENCE
·
2026
·
IF 4.3
Xiaoli Su,Xingli Tan,Ying Wang,Weiwei Liang,Di Wang,Di Huo,Hongyong Wang,Yan Qi,Wenmo Zhang,Ling Han,Dongmei Zhang,Ming Wang,Jing Xu,Shuyu Wang,Jing Wang,Honglin Feng
Mutations in superoxide dismutase 1 (SOD1) compromise its metal-binding capacity, resulting in protein misfolding and aggregation, which ultimately induces cellular apoptosis in amyotrophic lateral sclerosis (ALS). Copper metabolism domain containing 1 (COMMD1), a gene implicated in copper homeostasis, has not been thoroughly characterized in the context of ALS pathogenesis. In this study, we identified elevated COMMD1 expression in ALS, potentially contributing to diminished copper incorporation into SOD1. Knockdown of COMMD1 enhanced palmitoylation of the copper chaperone for SOD1 (CCS), facilitating its membrane translocation and promoting copper loading into SOD1, thereby conferring neuroprotection in ALS. Mechanistically, we established that COMMD1 knockdown augments CCS palmitoylation via activation of the hypoxia inducible factor 1 subunit alpha (HIF-1α)/fatty acid synthase (FASN) signaling axis. In vivo investigations utilizing male hSOD1G93A transgenic mice demonstrated that COMMD1 deficiency markedly ameliorated the deterioration of motor function and prolonged survival duration. These findings collectively suggest that COMMD1 represents a potential therapeutic target for ALS intervention.Significance Statement Superoxide dismutase 1 (SOD1) was the first identified mutant gene associated with amyotrophic lateral sclerosis (ALS). Mutations in SOD1 compromise its metal-binding function, resulting in neuronal apoptosis, a hallmark of ALS pathogenesis. Utilizing the SOD1G93A models of ALS, our findings revealed that COMMD1 deficiency significantly elevates copper incorporation into SOD1, consequently attenuating cellular apoptosis. These results suggest that targeted inhibition of COMMD1 could represent a potential therapeutic strategy for ALS treatment.
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PubMed
高影响因子
ANTIOXIDANTS & REDOX SIGNALING
·
2024
·
IF 5.9
Siyu Lu,Yiming Zhou,Mincong Liu,Lijun Gong,Li Liu,Zhigui Duan,Keke Chen,Frank J. Gonzalez,Fang Wei,Rong Xiang,Guolin Li
Aims: Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber hypertrophy due to the lack of strategies to precisely regulate individual oxidants in vivo. In this study, we used tetrathiomolybdate (TM) to dissociate the link between superoxide (O2•−) and hydrogen peroxide and thereby to specifically explore the role of O2•− in muscle hypertrophy in C2C12 cells and mice.Results: TM can linearly regulate intracellular O2•− levels by inhibition of superoxide dismutase 1 (SOD1). A 70% increase in O2•− levels in C2C12 myoblast cells and mice is necessary and sufficient for triggering hypertrophy of differentiated myotubes and can enhance exercise performance by more than 50% in mice. SOD1 knockout blocks TM-induced O2•− increments and thereby prevents hypertrophy, whereas SOD1 restoration rescues all these effects. Scavenging O2•− with antioxidants abolishes TM-induced hypertrophy and the enhancement of exercise performance, whereas the restoration of O2•− levels with a O2•− generator promotes muscle hypertrophy independent of SOD1 activity.Innovation and Conclusion: These findings suggest that O2•− is an endogenous initiator of myofiber hypertrophy and that TM may be used to treat muscle wasting diseases. Our work not only suggests a novel druggable mechanism to increase muscle mass but also provides a tool for precisely regulating O2•− levels in vivo.
研究领域:
生理学
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药理学
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运动科学
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DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2019
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IF 4.367
Chunting Zhang,Weiwei Liang,Hongyong Wang,Yueqing Yang,Tianhang Wang,Shuyu Wang,Xudong Wang,Ying Wang,Honglin Feng
Oxidative stress plays a critical role in mutant copper/zinc superoxide dismutase 1 ( SOD1 )-linked amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by selective loss of motor neurons . Thus, an anti-oxidative stress remedy might be a promising means for the treatment of ALS. The aim of the present study is to investigate the neuroprotective effects of γ-oryzanol (Orz) and elucidate its relevant molecular mechanisms in mutant hSOD1 -linked Drosophila and cell models of ALS. Orz treatment provided neuroprotection in flies with expression of hSOD1-G85R in motor neurons, as demonstrated by the prolonged survival, improvement of motor deficits, reduced oxidative damage and regulated redox homeostasis when compared with those in controls. Moreover, Orz significantly decreased neuronal apoptosis and upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutamate-cysteine ligase catalytic subunit (GCLC) antioxidant pathway via activating Akt in hSOD1-G93A -expressing NSC-34 cells. In addition, our results showed that both in vivo and in vitro , Akt served as an upstream regulator of signal transducers and activators of transcription (Stat) 3 stimulated by Orz, which further increased the level of another anti-oxidative stress factor heat-shock protein 70 (HSP70). Altogether, these findings provide evidence that Orz has potential neuroprotective effects that may be beneficial in the treatment of ALS disease with SOD1 mutations.
研究领域:
神经科学
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分子生物学
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药理学
·
神经退行性疾病
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2026
·
IF 11
Xiaoling Liu,Run Huang,Ling Zou,Lu Yang,Yonghui Wu,Dandan Li,Jinbao Li,Jian He,Xiaochao Yang
Oxidative stress caused by the excessive accumulation of reactive oxygen species (ROS) plays a critical role in the development of acute respiratory distress syndrome (ARDS). Current antioxidant therapies using organic ROS scavengers fail in decreasing mortality due to the low ROS scavenging activity and fast metabolic rate. Inorganic ROS scavenging nanoparticles provide potential options for investigating ARDS antioxidant therapy. However, previous studies mainly focus on the ROS scavenging activity of these nanoparticles, while their capability to modulate the endogenous antioxidant system remains largely unexplored. Herein, mesoporous Ce–Mn–O bimetallic oxide nanoparticles (NP CeMn ) are designed and synthesized to activate the endogenous antioxidant system for ARDS therapy. Morphologically similar ceria nanoparticles (NP Ce ) and manganese oxide nanoparticles (NP Mn ) are used for comparison. In vivo and in vitro results demonstrate that NP Ce and NP Mn can promote the expression of SOD1 and SOD2, respectively, while NP CeMn can promote the expression of both SOD1 and SOD2. Mechanism studies establish a Keap1/Nrf2/SOD axis through which NP CeMn acts to activate the endogenous antioxidant system. Based on this property, NP CeMn can effectively alleviate oxidative stress and inflammation in the lung of the murine ARDS model. These findings suggest that activating the endogenous antioxidant system via inorganic nanoparticles is a promising ARDS therapeutic strategy.
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PubMed
高影响因子
WORLD JOURNAL OF MICROBIOLOGY & BIOTECHNOLOGY
·
2013
·Vol. 30
·期 4
·1251-1260
·
IF 1.262
Zhou Gang,Shi Qing-shan,Ouyang You-sheng,Chen Yi-ben
Isothiazolones are used as preservatives in various modern industrial products. Although microorganisms that exhibit resistance towards these biocides have been identified, the underlying resistance mechanisms are still unclear. Therefore, we investigated the resistance properties of the following Burkholderia cepacia strains to Kathon (a representative of isothiazolones): a wild-type (WT) strain; a laboratory resistance strain (BC-IR) induced from WT; and an isolated strain (BC-327) screened from industrial contamination samples. The bacterial cell structure was disrupted by 50 μg ml −1 Kathon treatment. BC-IR and BC-327 did not display resistance in the presence of 1 ml L −1 Tween 80, 1 ml L −1 Triton X-100, 0.1 % sodium dodecyl sulfate or 1 mmol L −1 EDTA-2Na. Additionally, BC-IR and BC-327 exhibited lower relative conductivity from 10 to 180 min. The types as well as the levels of outer-membrane proteins (OMPs) were altered among WT, BC-IR and BC-327. Finally, the two Kathon-resistance strains BC-IR and BC-327 presented higher resistance capacity to H 2 O 2 . We measured the levels of peroxide-sensor genes and observed that the transcriptional activator oxyR , superoxide dismutase sod1 , sod2 , catalase cat1 and cat3 were all up-regulated under oxidative conditions for all strains. Taken together, OMPs and peroxide-sensor genes in B. cepacia contributed to isothiazolone resistance; However, the laboratory strain BC-IR exhibited a different resistance mechanism and properties compared to the isolated strain BC-327.
研究领域:
微生物学
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分子生物学
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工业生物技术
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DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2025
·
IF 12
Qian Yu,Ke Jiang,Siyu Ma,Quan Zheng,Serena Tondi,Chiara Reina,Berina Šabanović,Chenlei Wen,Baiyong Shen,Alexandra Aicher,Haiyun Song,Yinxing Ma,Christopher Heeschen
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, partly due to cancer stem cells (CSCs) that drive progression and treatment resistance. We explored the therapeutic potential of inducing cuproptosis, a copper-dependent regulated cell death, in CSC-enriched PDAC models. Using human and murine PDAC models, we evaluated elesclomol, a copper transport enhancer. Elesclomol alone had minimal effects; combined with copper chloride (CuCl 2 ), it significantly and irreversibly reduced CSC phenotypes without affecting non-transformed cells. Mechanistically, only the combination raised intracellular copper ions 2–4-fold, decreased iron–sulfur cluster proteins, and caused fatty acylated DLAT accumulation in mitochondria, triggering cuproptosis, particularly in CSCs. It also selectively inhibited copper-dependent antioxidant SOD1 in PDAC cells, impairing oxidative stress defense and sensitizing them to copper-induced death. To enhance clinical relevance, CuCl 2 was replaced with hollow mesoporous copper sulfide nanoparticles releasing copper ions. Either combined with or loaded with elesclomol, these nanoparticles similarly increased copper levels and inhibited PDAC spheroid formation. In vivo , in aggressive immunocompetent murine PDAC models, this nanoparticle-based treatment significantly improved gemcitabine response. These findings identify nanoparticle-mediated cuproptosis induction, combined with standard chemotherapy, as an innovative CSC-targeting strategy to improve PDAC outcomes, offering new hope for PDAC patients.
研究领域:
肿瘤学
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分子生物学
·
癌症治疗学
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纳米医学
·
细胞死亡机制
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Xinrui Meng,Jingjing Liu,Jia Kang,Menghan Wang,Zhanghui Guan,Dong Tian,Xinping Chen
Gastric ulcer is a highly prevalent digestive tract disease across the world, which is recurrent and hard to cure, sometimes transforming into gastric cancer if left untreated, posing great threat to human health. To develop new medicines for gastric ulcer, we ran a series of screens with ethanol stress model in GES-1 cells, and we uncovered that lamivudine rescued cells from ethanol toxicity. Then, we confirmed this discovery using the well-established ethanol-induced gastric ulcer model in mice and our findings suggest that lamivudine can directly activate phosphoglycerate kinase 1 (PGK1, EC 2.7.2.3), which binds and stimulates superoxide dismutase 1 (SOD1, EC 1.15.1.1) to inhibit ferroptosis and ultimately improve gastric ulcer. Moreover, AAV-PGK1 exhibited comparable gastroprotective effects to lamivudine. The findings are expected to offer novel therapeutic strategies for gastric ulcer, encompassing both lamivudine and AAV-PGK1.
研究领域:
胃肠病学
·
药理学
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分子生物学
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DOI
PubMed
高影响因子
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
·
2018
·Vol. 48
·期 6
·2503-2516
·
IF 5.5
Zhao Yixiu,Zhang Xin,Luan Jing,Zhao Buchang,An Na,Sun Na,Wang Xinhui,Zhao Tao,Sun Yanhong,Fu Zidong Donna,Zhang Yan,Zhang Yan
Background/Aims: Shenxian-shengmai (SXSM) oral liquid, a Chinese patent compound medicine, has been used to treat sinus bradyarrhythmias induced by mild sick sinus syndrome in clinical practice. Myocardial ischemia, in particular in serious or right coronary-related heart diseases, can cause bradyarrhythmias and cardiac dysfunction. Moreover, reperfusion of ischemic myocardium is associated with additional myocardial damage known as myocardial ischemia-reperfusion (I/R) injury. This study was designed to evaluate the effects of SXSM on bradyarrhythmias and cardiac dysfunction induced by myocardial I/R injury, and to explore the underlying mechanisms. Methods: Administration of SXSM to adult male Sprague Dawley (SD) rats was achieved orally by gavage and control rats were given equivalent deionized water every day for 14 days. After the last administration, the heart was connected with the Langendorff perfusion apparatus and both groups were subjected to ischemia for 20 min followed by reperfusion for 40 min to induce myocardial I/R injury. Heart rate (HR), left ventricular developed pressure (LVDP), the maximal increase rate of left ventricular pressure (+dp/dtmax) and the maximal decrease rate of left ventricular pressure (-dp/dtmax) were recorded by a physiological signal acquisition system. The heart treated with ischemic preconditioning (IPC) for 3 times at a range of 5 min/time before ischemia served as a positive control group. The hearts without I/R injury served as control group. After reperfusion, superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-Px) activities in the myocardium were determined by appropriate assay kits. Myocardial SOD1 and glutamate cysteine ligase catalytic subunit (GCLC) expression were assessed by western blot analysis. For the in vitro study, SXSM serum was prepared according to the serum pharmacological method and neonatal rat cardiomyocytes were isolated from the heart of new born SD rats. Neonatal rat cardiomyocytes were pretreated with SXSM serum and subjected to H2O2 or anoxia/ reoxygenation (A/R) treatment to induce oxidative damage. Cell viability was evaluated using a Cell Counting Kit-8 (CCK8) assay. Levels of reactive oxygen species (ROS), SOD, GSH and GSH-Px in cardiomyocytes were determined by appropriate assay kits. SOD1 and GCLC expression were assessed by western blot analysis. Buthionine-[S, R]-sulfoximine (BSO), a GCLC inhibitor, and SOD1 siRNA were also used for identifying the cardiac protective targets of SXSM. Results: SXSM and ischemic preconditioning (IPC) significantly increased heart rate during myocardial reperfusion and protected cardiac function against myocardial I/R injury, including an increase in left ventricular diastolic pressure (LVDP), the maximal increase rate of left ventricular pressure (+dp/dtmax) and the maximal decrease rate of left ventricular pressure (-dp/dtmax). We also found that SXSM and IPC improved the expansion of myocardial interstitium, the structural abnormality and morphological changes of cardiomyocytes induced by I/R injury. Meanwhile, SXSM protected cardiomyocytes against the oxidative damage induced by H2O2 and A/R injury through reducing intracellular ROS levels. Moreover, SXSM increased SOD activity through enhancing SOD1 expression and increased GSH content through promoting GCLC expression as well as GSH-Px activity. BSO and SOD1 siRNA counteracted anti-arrhythmic and cardiac protective effect of SXSM, suggesting that the therapeutic targets of SXSM might be SOD1 and GCLC. Conclusion: SXSM is effective in protecting the myocardium from I/R injury, with myocardial SOD1 and GCLC being the potential therapeutic targets
研究领域:
药理学
·
心脏病学
·
分子生物学
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DOI
PubMed
高影响因子
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