INFLAMMOPHARMACOLOGY
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2026
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IF 6.3
Yang Xiaoxiao,Yang Nengjie,Wang Yunan,Xiao Jun,Gu Zhifeng,Dong Chen
Background Sjogren’s Syndrome (SS) is an autoimmune disease characterized mainly by xerostomia (dry mouth), xerophthalmia (dry eyes) and damage of immune system. Recent studies have found that SS patients frequently experience neuropsychiatric symptoms such as depression and fatigue, suggesting potential underlying mechanisms involving complex immune-neural interactions. However, current therapeutic strategies targeting this immune-neuropsychiatric axis remain limited. Agomelatine (AGO), a novel antidepressant classified as a melatonin (MLT) receptor agonist and a 5-HT2C receptor antagonist, has yet to be fully investigated for its immunomodulatory potential and therapeutic application in SS. Objectives This study explores the immune–neuropsychiatric interaction in SS using Non-Obese Diabetic (NOD) mice, and investigates the therapeutic potential of AGO, highlighting its anti-inflammatory and immunomodulatory effects. Methods NOD mice were divided into blank control, hydroxychloroquine (HCQ, a basic immune regulatory drug), MLT, and AGO groups; ICR mice served as healthy controls. All received intraperitoneal injections for 4 weeks. Behavioral tests (open field and tail suspension) were conducted. Flow cytometric analysis was performed to systematically evaluate splenic T cell and B cell subsets. The results showed that only the proportions of T helper 1 (Th1) and T helper 17 (Th17) cells exhibited significant differences, whereas no obvious changes were observed in B cells or regulatory T cells (Tregs).Salivary gland tissues were assessed by Hematoxylin–Eosin (HE) staining for inflammation and damage, and by immunofluorescence for Th1-epithelial cell co-localization. Results AGO-treated mice showed significantly shorter immobility time in the tail suspension test versus untreated NOD controls, indicating reduced despair. AGO intervention also reduced splenic Th1 and Th17 cell proportions, alleviated salivary gland lymphocyte infiltration, and decreased Th1-epithelial cell co-localization, suggesting inhibition of Th1 cell migration to target tissues. Conclusion AGO significantly improved behavioral performance, reduced the proportion of Th1 cells in the spleen, and alleviated inflammatory infiltration in the salivary glands of NOD mice. These findings suggest that the drug may exert therapeutic effects by modulating immune responses and neurobehavioral functions, positioning it as a promising candidate for the treatment of SS.
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Cell Communication and Signaling
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2026
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IF 8.9
Qiu Yueping,Liu Yijie,Ding Haiying,Xin Wenxiu,Lu Shuanghui,Hu Yan,Chen Jing,Weng Qinjie,Wang Jiajia,Fang Luo
Osimertinib is a first-line treatment for advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR)-sensitive mutations; however, the severe hepatotoxicity of osimertinib is a challenge that has attracted attention. In this study, we found that osimertinib directly caused hepatocyte damage, with cells showing morphological features of vacuolization after treatment. Using transmission electron microscopy and other analytical techniques, we found that excessive activation of the autophagy-lysosome pathway was the main cause of cell vacuolation. Mechanistically, osimertinib causes dephosphorylation of transcription factor EB (TFEB), leading to its translocation into the nucleus to exert transcriptional regulatory functions. TFEB in the nucleus induces autophagy and lysosome biogenesis, thereby causing excessive activation of the autophagy-lysosome pathway subsequently leading to vacuolation-associated cell death. Through this study, we have identified S-adenosyl-L-methionine as a clinical hepatoprotective agent that could mitigate osimertinib-induced hepatocyte damage by inhibiting TFEB activation. Collectively, our findings not only lay the groundwork for addressing the clinical challenges posed by osimertinib hepatotoxicity but also broaden our understanding of drug-induced hepatocyte injury, thereby offering a novel research pathway for the study of drug-induced liver injury.
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JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY
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2023
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IF 5.4
Lan-Yi Hu,Ye Yuan,Zi-Xuan Wen,Yi-Yue Hu,Miao-Miao Yin,Yan-Jun Hu
Chloroquine (CQ) and hydroxychloroquine (HCQ) show good efficacy in the treatment of SARS-CoV-2 in the early stage, while they are no longer recommended due to their side effects. As an important drug delivery carrier, serum albumin (SA) is closely related to the efficacy of drugs . Here, the affinity behaviour of chloroquine and hydroxychloroquine with two SA were investigated through the multispectral method of biochemistry and computer simulation. The results showed that the intrinsic emission of both SA was quenched by CQ and HCQ in a spontaneous exothermic entropy reduction static process, which relied mainly on hydrogen bonding and van der Waals forces . The lower binding constants suggested weak binding between the two drugs and SA, which might lead to differences in efficacy and possibly even to varying side effects. Binding site recognition demonstrated that CQ preferred to bind to the two sites of both SA, while HCQ tended to bind to site I of SA. The results of conformational studies demonstrated that CQ and HCQ could affect the structure of both SA by slightly increasing the α -helix content of SA. Finally, we combine the results from experimental start with molecular simulations to suggest drug modifications to guide the design of drugs. This work has important implications for guiding drug design improvements to select CQ derivatives with fewer side effects for the treatment of COVID-19.
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Advanced Fiber Materials
·
2023
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IF 16.1
Mu Jiaxiang,Meng Zhaoxu,Liu Xinran,Guan Ping,Lian He
Photothermal therapy (PTT) has been proposed as an advanced patient-centered strategy for tumor treatment. Nevertheless, the uncertain safety of conventional photothermal conversion agents and the presence of intracellular self-protective autophagy mechanisms pose obstacles to the clinical application and efficacy of PTT. As we are deeply aware of the seriousness of these problems, we herein proposed an efficacy-enhancing strategy based on an implantable membrane platform (PPG@PB-HCQ) constructed from poly (lactic acid) (PLA), poly (ɛ-caprolactone) (PCL) and gelatin (Gel) electrospun nanofibers (PPG) and loaded with the biodegradable high-efficiency photothermal conversion agent Prussian blue (PB) and the autophagy inhibitor hydroxychloroquine sulfate (HCQ). Cellular experiments confirmed that the PPG@PB-HCQ nanofiber membrane exhibited a significantly stronger tumor cell-killing effect compared with the PTT alone. This enhancement features by of blocking the fusion of autophagosomes with lysosomes. The intracellular overexpression of the proteins microtubule-associated protein 1 light chain 3 (LC3)-II and p62 and the low expression of the proteins LC3-I and Rab7 (members of the RAS oncogene family) further demonstrated autophagic flux blockade. Importantly, the potent antitumor effect of the PPG@PB-HCQ therapeutic platform in B16 tumor-bearing model mice verified the efficacy-enhancing strategy of synergistic PTT and protective autophagy blockade. The present study provides a promising strategy for solving the difficulties of tumor treatment, as well as a new perspective for designing novel treatment platforms. Graphical Abstract
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MOLECULES
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2022
·Vol. 27
·期 16
·5175
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IF 4.927
Jingxiang Zhao,Zhiqiang Zhao,Wanting Hou,Yue Jiang,Guobin Liu,Xuelian Ren,Kun Liu,Hong Liu,Kaixian Chen,He Huang
Hydroxychloroquine (HCQ) is an autophagy inhibitor that has been used for the treatment of many diseases, such as malaria, rheumatoid arthritis, systemic lupus erythematosus, and cancer. Despite the therapeutic advances in these diseases, the underlying mechanisms have not been well determined and hinder the rational use of this drug in the future. Here, we explored the possible mechanisms and identified the potential binding targets of HCQ by performing quantitative proteomics and thermal proteome profiling on MIA PaCa-2 cells. This study revealed that HCQ may exert its functions by targeting some autophagy-related proteins such as ribosyldihydronicotinamide dehydrogenase (NQO2) and transport protein Sec23A (SEC23A), or regulating the expression of galectin-8 (LGALS8), mitogen-activated protein kinase 8 (MAPK8), and so on. Furthermore, HCQ may prevent the progression of pancreatic cancer by regulating the expression of nesprin-2 (SYNE2), protein-S-isoprenylcysteine O-methyltransferase (ICMT), and cotranscriptional regulator FAM172A (FAM172A). Together, these findings not only identified potential binding targets for HCQ but also revealed the non-canonical mechanisms of HCQ that may contribute to pancreatic cancer treatment.Keywords:hydroxychloroquine;quantitative proteomics;thermal proteome profiling
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Reproductive Sciences
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2023
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IF 2.9
Dai Yan,Sang Xiu-Bo,Bai Wen-Pei
Fetal growth restriction (FGR) seriously threatens perinatal health. The main cause of FGR is placental malperfusion, but the specific mechanism is still unclear, and there is no effective treatment for FGR. We constructed a FGR mouse model by adding exogenous asymmetric dimethylarginine (ADMA) through in vivo experiments and found that ADMA could cause placental dysplasia and induce the occurrence of FGR. Compared with the control group, reactive oxygen species (ROS) production in the placenta was increased in mice with FGR, and the expression of autophagy-related proteins p-AKT/AKT, p-mTOR/mTOR, and P62 was significantly decreased, while the expression of Beclin-1 and LC3-II was significantly increased in the FGR group. Furthermore, ADMA had a favorable effect in promoting the formation of autophagosomes. Hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) improved ADMA-induced disorders of placental development and alleviated ADMA-induced FGR. This study found that ADMA could cause excessive autophagy of trophoblasts by increasing the level of oxidative stress, ultimately leading to the occurrence of FGR, and HCQ and NAC had therapeutic effects on ADMA-induced FGR.
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Journal of Orthopaedic Translation
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2021
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IF 5.191
Rongliang Wang,Jiawei Li,Xingquan Xu,Jia Xu,Huiming Jiang,Zhongyang Lv,Rui Wu,Ziying Sun,Wenjie Guo,Yang Sun,Shiro Ikegawa,Qing Jiang,Dongquan Shi
Background Synovial inflammation plays a major role in the pathogenesis of osteoarthritis (OA). This study investigated the effect of andrographolide (Andro) on synovial inflammation mediated by tumor necrosis factor-alpha receptor 2 (TNFR2) trafficking and its utility in attenuating OA progression. Methods Knee joints were harvested from rats subjected to radial transection of the medial collateral ligament (MCLT) and medial meniscus (MMT) to examine the effect of Andro on synovial inflammation and OA progression. Quantitative real-time polymerase chain reaction was used to evaluate the expression of inflammatory factors in primary fibroblast-like synoviocytes (FLSs) after Andro treatment in vitro . The mechanism underlying Andro-mediated regulation of TNFR2 distribution and nuclear factor-κB (NF-κB) expression was verified using endosome maturation inhibitor hydroxychloroquine (HCQ) through flow cytometry, immunofluorescence, and western blot analysis. Results Andro treatment was found to reduce synovial inflammation and OA progression in vivo . Furthermore, a decrease in pain hypersensitivity and dorsal horn neuron activation was observed after treatment. Andro also downregulated the expression of inflammatory mediators and TNFR2 in FLSs. TNFR2 is crucial for the activation of the NF-κB signaling pathway, and Andro-induced degradation of TNFR2 was associated with lysosomal function, which in turn, reduced the downstream phosphorylation of p65 in the NF-κB signaling pathway. Conclusions Andro could suppress synovial inflammation via regulation of TNFR2 trafficking and degradation. This also suggests it could be a potential treatment for the prevention of synovial inflammation and OA progression. The translational potential of this article This study provides strong evidence that Andro reduces NF-κB activation and inflammatory responses in OA FLSs via regulation of TNFR2 trafficking. The inhibition of TNFR2 and Andro could be a novel therapeutic approach for OA and pain management.
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Frontiers in Cell and Developmental Biology
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2021
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IF 6.684
Zhang Man,Bai Yang,Xu Chang,Qi Yiying,Meng Jiahong,Zhang Wenkan,Su Hang,Yan Weiqi
Accumulating evidence suggests that extracellular signal-regulated kinase (ERK) is a valuable target molecule for cancer. However, antitumor drugs targeting ERK are still in their clinical phase and no FDA-approved medications exist. In this study, we identified an ERK inhibitor (ERKi; Vx-11e) with potential antitumor activities, which was reflected by the inhibition in the survival and proliferation of Osteosarcoma (OS) cells. Mechanistically, the ERKi regulated autophagic flux by promoting the translocation of transcription factor EB (TFEB) in OS cells, thereby increasing the dependence of OS cells on autophagy and sensitivity to treatment with autophagy inhibitors in OS. Besides, we also found that the ERKi could regulate mitochondrial apoptosis through the ROS/mitochondria pathway and aerobic glycolysis in OS, which also increases the dependence of OS cells on autophagy to clear metabolites to a certain extent. These results may provide a reference for the clinically improved efficacy of ERKis in combination with autophagy inhibitors in the treatment of OS and indicate its potential as a therapeutic agent.
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FASEB JOURNAL
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2020
·Vol. 34
·期 6
·8402-8415
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IF 4.966
Xingquan Xu,Rongliang Wang,Rui Wu,Wenjin Yan,Tianshu Shi,Qing Jiang,Dongquan Shi
Bone loss is a severe complication of primary biliary cirrhosis (PBC). Trehalose was intermittently administered in bile duct-ligated (BDL) male rats, a PBC-related osteoporosis model, for 4 weeks to reduce osteoporosis. Femoral bones were assessed ex vivo by micro computed tomography (CT) and histomorphometry. The potential mechanisms related to the reduction of osteoporosis were explored by evaluating the effect of trehalose on osteoblast autophagy, osteogenesis, osteoclastogenesis, and ERK phosphorylation. The results demonstrated that trehalose reduced osteoporosis of BDL rats and decreased osteoblast-mediated osteoclast differentiation by enhancing osteoblast autophagy to regulate osteoprotegerin (OPG) secretion. Hydroxychloroquine (HCQ) increased the expression of OPG and OPG /receptor activator genes for nuclear factor-κB ligand (RANKL) ratio, and reduced osteoblast-mediated osteoclastogenesis by inhibiting autophagy flux and inducing autophagosome formation. Furthermore, trehalose increased the phosphorylation of ERK1/2 in MC3T3-E1 cells, and the ERK inhibitor PD98059 reversed the upregulation of OPG gene and reduction of trehalose-induced osteoclastogeneis. The treatment with HCQ markedly increased the ERK phosphorylation. The correlation between autophagosome formation and ERK phosphorylation was confirmed in autophagy proteins (ATG) 4B or ATG5-deficient cells. Thus, trehalose could decrease osteoblast-mediated osteoclastogenesis and reduce PBC-related bone loss by regulating ERK phosphorylation via autophagosome formation.
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ENVIRONMENTAL RESEARCH
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2024
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IF 7.7
Zhipeng Zhang,Huizi Zheng,Ying Liu,Shuang Ma,Qi Feng,Jiao Qu,Xiaolin Zhu
Global outbreaks and the spread of viral diseases in the recent years have led to a rapid increase in the usage of antiviral drugs (ATVs), the residues and metabolites of which are discharged into the natural environment, posing a serious threat to human health. There is an urgent need to develop sensitive and rapid detection tools for multiple ATVs. In this study, we developed a highly sensitive electrochemical sensor comprising a glassy carbon electrode (GCE) modified with graphitized hydroxylated multi-walled carbon nanotubes (G-MWCNT-OH) and 1-butyl-3-methylimidazolium hexafluorophosphate (BMIMPF 6 , IL) for the detection of six ATVs including famciclovir (FCV), remdesivir (REM), favipiravir (FAV), hydroxychloroquine sulfate (HCQ), cepharanthine (CEP) and molnupiravir (MOL). The morphology and structure of the G-MWCNT-OH/IL nanocomposites were characterized comprehensively, and the electroactive surface area and electron conductivity of G-MWCNT-OH/IL/GCE were determined using cyclic voltammetry and electrochemical impedance spectroscopy. The thermodynamic stability and non-covalent interactions between the G-MWCNT-OH and IL were evaluated through quantum chemical simulation calculations, and the mechanism of ATV detection using the G-MWCNT-OH/IL/GCE was thoroughly examined. The detection conditions were optimized to improve the sensitivity and stability of electrochemical sensors. Under the optimal experimental conditions, the G-MWCNT-OH/IL/GCE exhibited excellent electrocatalytic performance and detected the ATVs over a wide concentration range (0.01–120 μM). The limit of detections (LODs) were 42.3 nM, 55.4 nM, 21.9 nM, 15.6 nM, 10.6 nM, and 3.2 nM for FCV, REM, FAV, HCQ, CEP, and MOL, respectively. G-MWCNT-OH/IL/GCE was also highly stable and selective to the ATVs in the presence of multiple interfering analytes. This sensor exhibited great potential for enabling the quantitative detection of multiple ATVs in actual water environment.
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DALTON TRANSACTIONS
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2024
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IF 3.5
Linming Li,Yan Chen,Ming Zhang,Suying Li,Shuaiqi Feng,Yan-Qin He,Ning Zhang,Zhifang Liu,Meifeng Liu,Qing-Peng Wang
Protective autophagy is a promising target for antitumor drugs exploration. A hydroxychloroquine (HCQ) platinum(IV) complex with autophagy suppressing potency was developed, which displayed potent antitumor activities with a TGI of 44.2% against 4T1 tumors in vivo and possessed rather lower toxicity than cisplatin. Notably, it exhibited satisfactory antimetastatic activities toward lung pulmonary metastasis models with inhibition rate of 49.6%, which was obviously more potent than CDDP (21.6%). Mechanism detection revealed that it caused serious DNA damage and upregulated the expression of γ-H2AX and p53. More importantly, the incorporation of autophagy inhibitor HCQ endowed platinum(IV) complex with potent autophagy impairing properties by perturbing lysosomal function in tumor cells, which promoted apoptosis synergistically with the DNA injury. Then, the impaired autophagy further led to the suppression of hypoxia and inflammation in tumor microenvironment by downregulating ERK1/2, HIF-1α, iNOS, caspase1 and COX-2. Adaptive immune response was improved by inhibiting immune checkpoint PD-L1, and further increasing CD4+ and CD8+ T cells in tumors. Then, tumor metastasis was effectively inhibited by restraining angiogenesis through inhibiting VEGFA, MMP-9, and CD34.
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SEPARATION AND PURIFICATION TECHNOLOGY
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2024
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IF 8.1
Boqiang Gao,Haoge Liang,Jie Wang,Yan Huang,Jingzhen Wang,Jia Song,Pan Hu,Hu Yang,Shuanglong Ma
Hydroxychloroquine (HCQ) as an antiviral pharmaceutical has been widely detected in the aquatic environment. Adsorption is an effective method for removal of HCQ, but the quantitative study of the adsorption interactions is unclear. In this study, a carboxylated lignin-based sponge (PLC) was fabricated, and the adsorption contributions of electrostatic attraction (EA), hydrogen bond (HB), and π-π electron donor–acceptor (π-π EDA) interactions were quantitatively investigated. The results showed that PLC exhibited excellent adsorption performance under wide pH range (4.0 < pH < 11.0), with the highest adsorption capacity of 0.165 mmol/g. Inhibitor and molecular probe experiments showed that EA and HB were the main contributors to adsorption at neutral and basic pH ranges, respectively. A linear correlation model of the carboxyl groups of lignin-based sponges with the adsorption capacity of EA, HB, and π-π EDA interactions of HCQ ( R 2 > 0.822) and three molecular probes ( R 2 > 0.749) was established, respectively. The optimal adsorption capacity was achieved by the synergistic combination of the deprotonated carboxyl of PLC with the HB of Ka1 amino, EA of Ka2 amino, and the π-π EDA of the quinoline ring. This study provided a new strategy for the quantitative construction of structure–activity relationships of adsorbents.
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