Cardiovascular Diabetology
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2024
·Vol. 23
·期 1
·1-19
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IF 8.5
Tang Yuan-juan,Zhang Zhen,Yan Tong,Chen Ken,Xu Guo-fan,Xiong Shi-qiang,Wu Dai-qian,Chen Jie,Jose Pedro A.,Zeng Chun-yu,Fu Jin-juan
Background Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia–reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. Methods and results T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. Conclusion This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.
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BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Jiawen Yang,Yifan Wu,Qiaoliang Zhu,Xiaojuan Qu,Hongyue Ou,Haixia Liu,Yongqi Wei,Di Ge,Chunlai Lu,Biao Jiang,Xiaoling Song
The c-ros oncogene 1 (ROS1), an oncogenic driver, is known to induce non-small cell lung cancer (NSCLC) when overactivated, particularly through the formation of fusion proteins. Traditional targeted therapies focus on inhibiting ROS1 activity with ROS 1 inhibitors to manage cancer progression. However, a new strategy involving the design of protein degraders offers a more potent approach by completely degrading ROS1 fusion oncoproteins, thereby effectively blocking their kinase activity and enhancing anti-tumour potential. Utilizing PROteolysis-TArgeting Chimera (PROTAC) technology and informed by molecular docking and rational design, we report the first ROS1-specific PROTAC, SIAIS039. This degrader effectively targets multiple ROS1 fusion oncoproteins (CD74-ROS1, SDC4-ROS1 and SLC34A2-ROS1) in engineered Ba/F3 cells and HCC78 cells, demonstrating anti-tumour effects against ROS1 fusion-driven cancer cells. It suppresses cell proliferation, induces cell cycle arrest, and apoptosis, and inhibits clonogenicity. The anti-tumour efficacy of SIAIS039 surpasses two approved drugs, crizotinib and entrectinib, and matches that of the top inhibitors, including lorlatinib and taletrectinib. Mechanistic studies confirm that the degradation induced by 039 requires the participation of ROS1 ligands and E3 ubiquitin ligases, and involves the proteasome and ubiquitination. In addition, 039 exhibited excellent oral bioavailability in a mouse xenograft model, highlighting its potential for clinical application. In conclusion, our study presents a promising and novel therapeutic strategy for ROS1 fusion-positive NSCLC by targeting ROS1 fusion oncoproteins for degradation, laying the foundation for the development of further PROTAC and offering hope for patients with ROS1 fusion-positive NSCLC.
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CHINESE JOURNAL OF CATALYSIS
·
2025
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IF 17.7
Shaolei Gao,Peng Lu,Liang Qi,Yingli Wang,Hua Li,Mao Ye,Valentin Valtchev,Alexis T. Bell,Zhongmin Liu
Methyl methoxyacetate (MMAc) and methyl formate (MF) can be produced directly by heterogeneous zeolite-catalyzed carbonylation and disproportionation of dimethoxymethane (DMM), with near 100% selectivity for each process. Despite continuous research efforts, the insight into the reaction mechanism and kinetics theory are still in their nascent stage. In this study, ZEO-1 material, a zeolite with up to now the largest cages comprising 16×16-MRs, 16×12-MRs, and 12×12-MRs, was explored for DMM carbonylation and disproportionation reactions. The rate of MMAc formation based on accessible Brönsted acid sites is 2.5 times higher for ZEO-1 (Si/Al = 21) relative to the previously investigated FAU (Si/Al = 15), indicating the positive effect of spatial separation of active sites in ZEO-1 on catalytic activity. A higher MF formation rate is also observed over ZEO-1 with lower activation energy (79.94 vs. 95.19 kJ/mol) compared with FAU (Si/Al = 30). Two types of active sites are proposed within ZEO-1 zeolite: Site 1 located in large cages formed by 16×16-MRs and 16×12-MRs, which is active predominantly for MMAc formation, and Site 2 located in smaller cages for methyl formate/dimethyl ether formation. Kinetics investigation of DMM carbonylation over ZEO-1 exhibit a first-order dependence on CO partial pressure and a slightly inverse-order dependence on DMM partial pressure. The DMM disproportionation is nearly first-order dependence on DMM partial pressure, while it reveals a strongly inverse dependence with increasing CO partial pressure. Furthermore, ZEO-1 exhibits good catalytic stability, and almost no deactivation is observed during the more than 70 h test with high carbonylation selectivity of above 89%, due to the well-enhanced diffusion property demonstrated by intelligent-gravimetric analysis.
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Materials
·
2024
·Vol. 17
·期 8
·1812
·
IF 3.1
Wanlu Xu,Wenwu Wang,Xiaoshan Zhang,Ping Yu
Positive temperature coefficient of electrical resistivity (PTCR) materials with low Curie temperature have been paid increasing attention lately. In this study, PTCR materials with a Curie temperature of approximately −15 °C were investigated by La3+doping Ba0.55Sr0.45TiO3ceramics. It could be expected to meet the requirements of thermal management systems for low-temperature control. In addition, a trace amount of Bi0.5Na0.5TiO3(BNT) was employed to improve the resistivity and the PTCR performance. A significant PTCR effect was achieved with a high resistivity jump of nearly four orders of magnitude, a high temperature coefficient of ~28.76%/°C, and a narrow transition temperature span of 22 °C in the (Ba0.55Sr0.45)0.99875La0.00125Ti1.01O3-0.0025Bi0.5Na0.5TiO3ceramics. The PTCR enhancement mechanism of BNT is discussed.
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FREE RADICAL BIOLOGY AND MEDICINE
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2024
·
IF 7.1
Xiaowen Liu,Huamei Cai,Liang Peng,Hongli Ma,Yun Yan,Weixia Li,Jing Zhao
Remifentanil-induced hyperalgesia (RIH) represents a significant clinical challenge due to the widespread use of opioids in pain management. However, the molecular and cellular mechanisms underlying RIH remain elusive. This study aimed to unravel the role of spinal cord microglia, focusing on the Nrf2/HO-1 signaling pathway and TRPV4 channels in the development of RIH. We used both in vivo and in vitro models to investigate the activation state of spinal cord microglia, the expression of TRPV4 channels, and the modulation of the Nrf2/HO-1 pathway under remifentanil exposure. In addition, we evaluated the potential therapeutic effects of dexmedetomidine, a perioperative α2-adrenergic agonist, on RIH and its related molecular pathways. Our results revealed a prominent role of spinal cord microglia in RIH, demonstrating an apparent microglial M1 polarization and increased TRPV4 channel expression. A notable observation was the downregulation of the Nrf2/HO-1 pathway, which was associated with increased neuroinflammation and mechanical allodynia. By upregulating or overexpressing Nrf2, we confirmed its ability to inhibit TRPV4 and thereby attenuate RIH-associated mechanical allodynia, M1 polarization, and neuroinflammation. Encouragingly, dexmedetomidine demonstrated therapeutic potential by positively modulating the Nrf2-TRPV4 nexus, attenuating mechanical allodynia, and reducing microglial inflammation. Our research highlights the critical role of spinal cord microglia in RIH mediated by the Nrf2-TRPV4 axis. The ability of dexmedetomidine to modulate this axis suggests its potential as an adjunctive therapy to remifentanil in mitigating RIH. Further studies are imperative to explore the broader implications and practical applicability of our findings.
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SENSORS AND ACTUATORS B-CHEMICAL
·
2024
·
IF 8
Jiao Jiao,Chunyang Du,Hongfang Zhang
Accurate detection of cancer biomarkers like mucin 1 (MUC-1) is significantly important for diagnosis and prognosis of tumor. Herein, a self-correction electrochemical immunoassay for MUC-1 detection was developed based on bioinspired nanochannels and electrochemistry of molybdophosphate. MUC-1 can be captured in the bioinspired polymer nanochannels via the formation of immunocomplex. Then, diffusion of MoO 4 2− in the nanochannels would be sterically hindered and the in-situ generation of phosphomolybdic acid onto the electrode surface which was modified with phosphate chitosan hydrogel, would be influenced. Therefore, the two well-defined redox peaks of phosphomolybdic acid can be applied to the detection of the antigen. To improve detection sensitivity, the phosphate chitosan was incorporated with carbon nanotubes. Moreover, the occurrence in nanochannels was amplified by hybridization chain reaction, which enhanced the hindrance for transport of MoO 4 2− by increasing steric effect, electrostatic repulsion as well as anchoring sites. Under optimized conditions, currents of the both anodic peaks on square wave voltametric voltammograms decreased linearly with the logarithm of the concentration of MUC-1 ranging from 10 fg∙mL −1 to 100 ng∙mL −1 with a detection limit of 6.0 fg∙mL −1 . And thus, the detection results can be self-corrected by the results acquired from the two peaks, which had valuable implications for the reliable MUC-1 detection in disease diagnosis and therapy application.
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BIOSENSORS & BIOELECTRONICS
·
2019
·
IF 9.518
Liying Zhao,Huaixia Yang,Xiaoke Zheng,Jinge Li,Lihe Jian,Weisheng Feng,Jinming Kong
Cytokeratin fragment antigen 21–1 (CYFRA 21–1) DNA is a crucial biomarker closely associated with non-small cell lung cancer. Here, we fabricated a novel electrochemical biosensor for ultrasensitive detection of CYFRA 21–1 DNA via polysaccharide and electrochemically mediated atom transfer radical polymerization (eATRP) dual signal amplification . Specifically, thiolated peptide nucleic acid (PNA) probes at 5′-terminals are immobilized on the gold electrode surface for specific recognition of CYFRA 21–1 DNA (tDNA). After hybridization, hyaluronic acid (HA) is linked to the hybridized PNA/DNA duplexes via the recognized carboxylate-Zr 4+ -phosphate chemistry . Then multiple initiators of the polymerization reaction are introduced via esterification reaction. Lastly, large numbers of electro-active monomers are successfully grafted from the initiation sites of functionalized HA by eATRP reaction, significantly amplifying the electrochemical signal. Under optimal conditions, the constructed sensor can detect as low as 9.04 aM tDNA. Further, this proposed biosensor can also be applied to the direct detection of double-stranded DNA (dsDNA), obtaining 0.12 fM as the detection limit. Besides, this strategy shows high selectivity for mismatched bases and excellent applicability for CYFRA 21–1 DNA detection in the serum samples. Given its high sensitivity, selectivity, ease of operation, low cost and environmental friendliness , this biosensor has considerable potential in early diagnosis and biomedical application .
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Molecular Catalysis
·
2024
·
IF 3.9
Kaixuan Ke,Ling Guo,Zhipeng Qi,Dou Dou,Han Ma,Xianying Fang,Linguo Zhao
Carotenoid cleavage dioxygenases (CCDs) play a pivotal role in the biosynthesis of volatile apocarotenoids, which have significant industrial applications due to their aromatic and bioactive properties. This study focuses on the molecular cloning and biochemical characterization of the LbCCD1 from Lycium barbarum . The LbCCD1 gene was successfully cloned and heterologously expressed in Escherichia coli and several carotenoids were using as substrates for investigate its specificity by in vitro and in vivo experiment. The LbCCD1 protein was able to cleave a variety of carotenoids including β-carotene, zeaxanthin, astaxanthin, and β-apo-8′-carotenal, at the 9, 10 (9′, 10′) double bond to produce β-ionone, 3‑hydroxy-4-oxo-β-ionone, and 3‑hydroxy-β-ionone, respectively in vitro. LbCCD1 could also cleave zeaxanthin and β-carotene at the 9, 10 (9′, 10′) double bond to produce β-ionone, respectively, in E. coli accumulating carotenoids. Interestingly, LbCCD1 did not exhibit cleavage activity on lycopene either in vivo or in vitro unlike other CCD1 family enzymes. In the previous experiment, it was confirmed that LbCCD1 exhibits cleavage activity towards β-apo-8′-carotenal in vitro, so we used β-apo-8′-carotenal as the substrate for characterizing the enzymatic properties. The expression of LbCCD1 was optimized at such conditions (temperature 24 °C, IPTG 0.1 mM, induction time 24 h). The biochemical characterization of LbCCD1 revealed the optimal activities were at pH 9 and 55 °C. The addition of 10 % ethanol could increase enzyme activity to above 15 %. However, the concentration of Fe 2+ has a minimal effect on enzyme activity. The V max for β-apo-8′-carotenal was 8.6 U/mg, while the K m was 0.27 mM. To preliminarily verify the potential of LbCCD1 as a biological component for β-ionone production. By introducing LbCCD1 into the β-carotene-high-producing chassis cell and optimizing the conditions (temperature 30 °C, IPTG 0.01 mM, Fe 2+ concentration 0.05 mM), the β-ionone yield reached 21.45 mg/L. This study focused on one of the CCDs derived from woody plants, which have been relatively underexplored. It lays the groundwork for expanding the CCD enzyme library, identifying suitable CCDs, and investigating the structure-function relationship of CCDs. Furthermore, it sets the stage for engineering novel CCD genes and developing advanced applications of CCDs as biocatalysts and platforms for synthetic biology. These advancements will enable the efficient production of volatile aroma compounds from carotenoids.
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HISTOLOGY AND HISTOPATHOLOGY
·
2024
·
IF 2.5
Zhou Hua,Jiuhong Deng,Guiying Wang
Objective: Diabetic nephropathy (DN) is a prevalent cause of end-stage kidney disease worldwide. Moringa isothiocyanate-1 (MIC-1) has shown potential for DN management, however, the exact mechanisms remain unclear. This research intended to evaluate the impact and mechanism of MIC-1 on DN. Methods: Six C57BLKS/J-db/m mice served as controls. Eighteen C57BLKS/J-db/db mice were randomly separated into three groups: db/db, db/db + irbesartan (IBS), and db/db + MIC-1. Three weeks post-drug administration, the body weight and kidney weight of mice in each group were measured. Concurrently, serum creatinine (Scr), urine albumin, insulin, glycosylated hemoglobin (GHb), oxidative stress-, and inflammatory-related factors were determined. Additionally, the pathological injury, apoptosis, apoptosis-related markers, NLRP3, and ASC levels in the kidney tissues were examined utilizing H&E, Masson, PAS, TUNEL staining, and Western blot. Results: MIC-1 decreased the body weight, kidney weight, the levels of Glu, Scr, and urine albumin in db/db mice. Moreover, MIC-1 significantly suppressed the levels of MDA, insulin, GHb, TNF-α, IL-1β, and IL-6, while increased the activities of SOD, CAT, and GPX in the serum of db/db mice. MIC-1 also mitigated the kidney tissue injury in db/db mice. Western blot assay showed that MIC-1 enhanced the Bcl-2 level and suppressed the Bax, cleaved caspase-3, cleaved caspase-9, NLRP3, ASC, and caspase-1 levels of the kidney tissues in db/db mice. Conclusions: MIC-1 ameliorated the kidney injury in DN mice, and its mechanism may be associated with the suppression of renal cell apoptosis, oxidative stress, and inflammatory responses.
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POLYMER
·
2025
·
IF 4.5
Xiangyuan Meng,Huifang Ma,Yaping Ma,Chenguang Liu,Aihua He
High-temperature resistant shape memory polyolefins, which also exhibit resistances to creep and raw petroleum, are highly crucial for the pipelines in severe environments, like high temperature, high pressure and petroleum medium. Herein, a series of crosslinked polybutene-1 alloys (PBA-X) were firstly fabricated, which presented excellent high-temperature resistances to creep and raw petroleum at 85 °C, as well as outstanding shape memory behaviors like 93.7-100.0 % shape recovery ratio ( R r ), 90.6-98.4 % shape fixation ratio ( R f ), and easy recovered from varied programmed three-dimensional (3D) shapes through thermal stimulation. PBA-X are anticipated to offer significant potential as innovative pipeline lining materials for deep-ocean petroleum transportation systems.
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Kaifang Wang,Danlin Chen,Jiali Tang,Zihao Hong,Zhongtai Zhu,Ziyi Yuan,Zhihong Lin,Yuqi Liu,Raphael Semiat,Xuezhong He
Membrane gas separation technologies have emerged as highly prospective avenues for the selective separation of CO 2 . In this research, a novel array of mixed-matrix membranes (MMMs) was engineered, integrating two-dimensional nanosheets of MXene, specifically Ti 3 C 2 T x , into polymers of intrinsic microporosity (PIMs) to selectively separate CO 2 from N 2 . The inclusion of Ti 3 C 2 T x nanosheets, rich in polar functional groups, significantly increases the affinity between CO 2 molecules and the fabricated MMMs. Additionally, the precise modulation of the molecular diffusion channels for CO 2 and N 2 is achievable due to the interlayer spacing between MXene layers (∼0.35 nm) within the PIM-1 matrix. This innovation is predicated on the synergistic effect of solution-diffusion and molecular sieving mechanisms that underpin the gas separation process, leading to a marked improvement in both selectivity for CO 2 over N 2 and the permeability of CO 2 . Among the series, the MMMs with a 0.5 wt% MXene display exceptional separation efficiency, achieving a CO 2 permeability of 12475.3 barrer and a CO 2 /N 2 selectivity of 32.7. Notably, all the PIM-1/MXene membranes prepared with different compositions in this study exceed the Robeson upper bound defined in 2019, indicating their substantial promise for CO 2 separation and capture in industrial applications.
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LIFE SCIENCES
·
2024
·
IF 5.2
Kai Yang,Xiaoxiao Yu,Zihao Guo,Zhihao Fang,Hongyu Zhang,Wanyangchuan Zhang,Changxu Liu,Yanchao Ji,Zhichao Dong,Qiang Gu,Jiahao Yao,Chang Liu
Aims Non-alcoholic fatty liver disease (NAFLD) has risen as a significant global public health issue, for which vertical sleeve gastrectomy (VSG) has become an effective treatment method. The study sought to elucidate the processes through which PIM1 mitigates the advancement of NAFLD. The Pro-viral integration site for Moloney murine leukemia virus 1 (PIM1) functions as a serine/threonine kinase. Bioinformatics analysis revealed that reduced PIM1 expression in NAFLD. Methods To further prove the role of PIM1 in NAFLD, an in-depth in vivo experiment was performed, in which male C57BL/6 mice were randomly grouped to receive a normal or high-fat diet for 19 weeks. They were operated or delivered the loaded adeno-associated virus which the PIM1 was overexpressed (AAV-PIM1). In an in vitro experiment, AML12 cells were treated with palmitic acid to induce hepatic steatosis. Key findings The results revealed that the VSG surgery and virus delivery of mice alleviated oxidative stress, and apoptosis in vivo. For AML12 cells, the levels of oxidative stress, apoptosis, and lipid metabolism were reduced via PIM1 upregulation. Moreover, ML385 treatment resulted in the downregulation of the NRF2/HO-1/NQO1 signaling cascade, indicating that PIM1 mitigates NAFLD by targeting this pathway. Significance PIM1 alleviated mice liver oxidative stress and NAFLD induced by High-fat diet by regulating the NRF2/HO-1/NQO1 signaling Pathway.
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