International Journal of Molecular Medicine

Chen, Yongxin; Wang, Zhuanghui; Ma, Qinghong; Sun, Chao

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Various forms of tissue damage can lead to fibrosis, an abnormal reparative reaction. In the industrialized countries, 45% of deaths are attributable to fibrotic disorders. Autophagy is a highly preserved process. Lysosomes break down organelles and cytoplasmic components during autophagy. The cytoplasm is cleared of pathogens and dysfunctional organelles, and its constituent components are recycled. With the growing body of research on autophagy, it is becoming clear that autophagy and its associated mechanisms may have a role in the development of numerous fibrotic disorders. However, a comprehensive understanding of autophagy in fibrosis is still lacking and the progression of fibrotic disease has not yet been thoroughly investigated in relation to autophagy‑associated processes. The present review focused on the latest findings and most comprehensive understanding of macrophage autophagy, endoplasmic reticulum stress‑mediated autophagy and autophagy‑mediated endothelial‑to‑mesenchymal transition in the initiation, progression and treatment of fibrosis. The article also discusses treatment strategies for fibrotic diseases and highlights recent developments in autophagy‑targeted therapies.

Wang, Xiaotong; Sun, Liang; Han, Xudong; Li, Zhanglong; Xing, Yuqing; Chen, Xinyue; Xi, Ruofan; Sun, Yuecong; Wang, Guilong; Zhao, Ping

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Glaucoma is a neurodegenerative disease characterized by progressive and irreversible necrosis and apoptosis of retinal ganglion cells (RGCs). Deformation of the lamina cribrosa (LC) has been identified as a factor leading to damage to the optic nerve and capillaries passing through the LC, ultimately causing visual field defects and glaucoma development. Recent advancements in molecular biology, both domestically and internationally, have enabled a more comprehensive and in‑depth understanding of glaucoma pathogenesis. In the present review, the role of molecular signaling pathways associated with RGCs apoptosis, optic nerve protection and regeneration, and LC damage and remodeling in the development of glaucoma, are summarized and discussed. The insights provided herein may offer new targets and ideas for interventions and treatment strategies for glaucoma.

Chien, Ming-Hsien; Hung, Wen-Yueh; Lai, Tsung-Ching; Tsai, Ching Han; Lee, Kai-Ling; Hsieh, Feng-Koo; Lee, Wei-Jiunn; Chang, Jer-Hwa

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Lung adenocarcinoma (LUAD) is a typical inflammation‑associated cancer, and anti‑inflammatory medications can be valuable in cancer therapy. Loratadine, a histamine receptor H1 (HRH1) antagonist, shows both anti‑inflammatory and anticancer properties. The present study aimed to evaluate impacts of loratadine on LUAD cells as well as in a LUAD xenograft mouse model, and explore underlying mechanisms. Mechanistic investigations were conducted through using western blotting, flow cytometry, immunohistochemistry, acridine orange staining, TUNEL assays, and in silico analyses of loratadine‑modulated genes in LUAD specimens. It was observed that loratadine inhibited LUAD cell proliferation and colony formation by inducing autophagy‑mediated apoptotic cell death independently of HRH1. In a LUAD xenograft model, loratadine decreased tumor proliferation and angiogenesis while enhancing autophagy and apoptosis. Mechanistically, loratadine induced protein phosphatase 2A (PP2A) activation to deactivate c‑Jun N‑terminal kinase (JNK)1/2 and p38 in H23 and PC9 LUAD cells. Additionally, loratadine inhibited signal transducer and activator of transcription 3 (STAT3) activation via a PP2A‑independent pathway. Furthermore, the combination of loratadine with inhibitors for JNK, p38 and STAT3 all enhanced proliferation inhibition of loratadine alone in both cell lines. In the clinic, patients with LUAD expressing high PP2A had favorable prognoses. The present study suggests that loratadine can be used as a PP2A activator for LUAD treatment, and the combination of repurposing loratadine with inhibitors of STAT3, JNK and p38 would be an effectively strategy for inhibiting LUAD growth.

Li, Bo; Yang, Wei-Wei; Yao, Bo-Chen; Chen, Qing-Liang; Zhao, Li-Li; Song, Yan-Qiu; Jiang, Nan; Guo, Zhi-Gang

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Myocardial ischemia‑reperfusion (I/R) injury may lead to dysfunction of signaling pathways related to cell apoptosis, inflammation, oxidative stress, and mitochondrial damage. The present study investigated the defensive effect of liriodendrin, as a natural product isolated from Linaria vulgaris, on reperfusion injury in rats and the underlying mechanisms involved in this process. An in vivo rat model of I/R constructed by ligation of the left anterior descending artery, as well as an in vitro model using H9C2 cells under hypoxic conditions, was established to assess the cardioprotective effects of liriodendrin. The biomarkers of myocardial damage, oxidative stress, and inflammatory response were measured with enzyme‑linked immunosorbent assay (ELISA). Gene and protein expression were detected by reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. Mitochondrial morphology was observed by electron microscopy. The levels of creatine kinase isoenzymes and cardiac troponin T were significantly elevated in the I/R compared with the sham group; liriodendrin mitigated this elevation. The liriodendrin group exhibited a significant reduction in myocardial tissue apoptosis, as indicated by immunohistochemical staining and western blotting. Additionally, ELISA indicated that the I/R group had higher levels of reactive oxygen species (ROS) compared with the liriodendrin group, while the liriodendrin group had higher levels of superoxide dismutase. The in vitro experiments demonstrated that liriodendrin ameliorated hypoxia‑induced injury to mitochondria and suppressed the activation of nuclear factor-B and B-cell lymphoma-2 associated X protein (Bax). Therefore, the present study demonstrated that liriodendrin impeded ROS‑associated metabolic disorders, maintained mitochondrial homeostasis and partially alleviated cardiomyocyte apoptosis by inhibiting the Bax signaling pathway.

Zhang, Jing-Xing; Wang, Rui; Xi, Jin; Shen, Lin; Zhu, An-You; Qi, Qi; Wang, Qi-Yi; Zhang, Lun-Jun; Wang, Feng-Chao; Lü, He-Zuo; Hu, Jian-Guo

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Following the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 2D on p. 606, which showed the results of cellular morphological experiments, two pairs of data panels were overlapping, such that data which were intended to show the results obtained under different experimental conditions may have been derived from the same original sources. The authors examined their original data, and realized that this figure had been assembled incorrectly (they were also able to send the data underlying this figure on to the Editorial Office for our inspection). The revised version of Fig. 2, now showing alternative data from one set of the repeated experiments, is shown on the next page. The authors confirm that the errors associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of International Journal of Molecular Medicine for granting them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 39: 603‑612, 2017; DOI: 10.3892/ijmm.2017.2882]

Liu, Xueru; Shui, Guojing; Wang, Yan; Chen, Tangting; Zhang, Peng; Liu, Li; Li, Chunhong; Li, Tao; Wang, Xiaobin

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Remimazolam (Rema) is a novel anesthetic that is widely used in anesthesia and sedation in critically ill patients. Notably, Rema exerts effects in patients through activation of the ‑aminobutyric acid (GABA) receptor. GABA may alleviate myocardial ischemia/reperfusion (I/R) injury; however, the impact of Rema and underlying molecular mechanism in myocardial I/R injury remain to be fully understood. Therefore, the present study aimed to investigate the effects of Rema on cardiac I/R injury and to determine the underlying mechanisms. An acute myocardial I/R model was established by ligating the left anterior descending artery in adult male C57BL/6 mice (8‑10 weeks). Cultured Raw264.7 cells treated with lipopolysaccharide (LPS) were also used to investigate the effect of Rema on macrophages. The results of the present study revealed that Rema improved I/R‑induced cardiac dysfunction by increasing the ejection fraction value and reducing the myocardial infarction area. In addition, Rema also alleviated I/R‑induced cardiac inflammatory cell infiltration based on H&E and immunofluorescence staining. Transmission electron microscopy and ROS measurements showed that Rema improved I/R‑induced mitochondrial structural disruption and oxidative stress in cardiomyocytes. Transcriptomics analysis and reverse transcription‑quantitative PCR revealed that Rema alleviated I/R‑induced release of inflammatory factors and cytokines by inhibiting the expression of IL‑1, IL‑6, C‑C chemokine receptor 2 and C‑X‑C motif chemokine ligand 5. Rema also inhibited I/R‑induced CD68+ cell proliferation, IL‑1 release, and NOD‑like receptor thermal protein domain associated protein 3 (NLRP3) and IL‑1 expression. The results of in vitro assays revealed that Rema inhibited LPS‑induced increases in IL‑1, IL‑6 and TNF‑ expression and release in cultured RAW264.7 macrophages. In conclusion, the present study revealed that Rema may alleviate I/R‑induced cardiac dysfunction and myocardial injury by inhibiting oxidative stress and inflammatory responses via the NLRP3/IL‑1 pathway.

Zhao, Yao; Xu, Yunfei; Xu, Qing; He, Nina; Zhao, Jie; Liu, Ying

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Ferroptosis is a type of iron‑dependent regulated cell death that differs from apoptosis, autophagy or necrosis. p23 serves as a co‑chaperone and performs a unique biological function in various diseases by binding to client proteins to modulate their biological functions; however, its effect on ferroptosis remains largely unknown. In the present study, the effects of cerebral ischemia/reperfusion (I/R) injury (CIRI) or oxygen‑glucose deprivation/reoxygenation on the blood‑brain barrier (BBB) and ferroptosis in brain microvascular endothelial cells (BMECs), as well as the expression of p23, were examined. Subsequently, the effects of p23 on CIRI‑induced BBB dysfunction and BMEC ferroptosis were determined. Finally, the role of glutathione peroxidase 4 (GPX4) in the regulatory effects of p23 on ferroptosis was detected. The results revealed that p23 protected against BBB injury caused by CIRI by inhibiting ferroptosis in BMECs. The effect of p23 on ferroptosis was then explored, and it was found that the expression of GPX4, a major regulator of ferroptosis, was promoted by p23. Furthermore, molecular docking and co‑immunoprecipitation experiments revealed that p23 could bind to GPX4 through its N‑terminal domain (1‑90aa), enhance the stability of GPX4 and inhibit the degradation of GPX4 by cycloheximide. Finally, a cerebral I/R animal model was established using GPX4 conditional knockout mice (GPX4 FosCreERT2/+), and it was revealed that the protective effect of p23 overexpression on the BBB in GPX4 FosCreERT2/+ mice was attenuated compared with that in GPX4 FosCreERT2/‑ mice. In conclusion, p23 may serve a protective role against cerebral I/R‑induced BBB injury by inhibiting ferroptosis in BMECs through enhancing the stability of GPX4, providing a potential therapeutic target for ischemic stroke.

Yang, Ying; Song, Lulu; Yu, Liping; Zhang, Jinping; Zhang, Bo

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The aim of the present study was to investigate the neuroprotective effects of semaglutide in diabetes‑associated cognitive decline (DACD), while also exploring the underlying mechanisms targeting anti‑oxidative effects. The present study evaluated the antioxidant properties of semaglutide using a DACD model of inflammation. To investigate the underlying mechanisms, omics technologies were employed. Comprehensive transcriptomic and proteomic analysis of the cells was conducted to identify the pathways responsible for the observed antioxidant effects. Semaglutide demonstrated the potential to enhance learning and memory functions while mitigating hippocampal pathological damage. RNA‑sequencing and data‑independent acquisition proteomics analyses identified 13,511 differentially expressed genes and 588 differentially expressed proteins between the control and type 2 diabetes mellitus (T2DM) groups. In addition, 1,378 genes and 2,394 proteins exhibited a differential expression between the T2DM and semaglutide (10 g/kg) treatment groups. A combined transcriptomic and proteomic analysis unveiled 40 common pathways. Acyl‑CoA oxidase 1 (ACOX1) was observed to be activated during oxidative stress and subsequently suppressed by semaglutide. Of note, the antioxidant and anti‑apoptotic properties of semaglutide in high glucose (HG) conditions were partially reversed upon ACOX1 overexpression. Overall, the present data provided molecular evidence to elucidate the physiological connections between semaglutide and neuronal function, and contribute to clarifying the role of semaglutide in combating oxidative stress and HG‑induced cognitive impairment.

Fu, Rong; Wang, Chunbin; Yin, Tongjin; Zhang, Xuyao; Xu, Ying; Shi, Yue; Xu, Jing; Zhang, Wei; Ding, Zhe

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Antibody‑drug conjugates (ADCs) are rapidly advancing the treatment of solid tumors, and Nectin‑4‑targeted ADCs have been approved by the FDA to treat certain cancers. Although Nectin‑4 is overexpressed in the tissues of patients with pancreatic cancer, whether Nectin‑4‑targeted ADCs can effectively treat pancreatic cancer remains unclear. The present study evaluated the therapeutic effects and mechanisms of Nectin‑4‑targeted ADCs in pancreatic cancer. A Nectin‑4‑directed ADC was chosen, Nectin‑4‑MMAE, which triggered apoptosis and induced cell death in the Nectin‑4‑positive pancreatic cancer cell lines BxPC‑3 and YAPC. Nectin‑4‑MMAE also induced autophagy in BxPC‑3 and YAPC cells by inactivating the AKT/mTOR pathway. The entire autophagy process was observed by electron microscopy and laser confocal microscopy. The autophagy inhibitors LY294002 and chloroquine significantly increased the lethal effects of Nectin‑4‑MMAE on BxPC‑3 and YAPC cells by inducing apoptosis. In the xenograft tumor model, Nectin‑4‑MMAE alone elicited potent antitumor effects. When Nectin‑4‑MMAE was combined with autophagy inhibitors, the tumor burden of mice was decreased compared with treatment with either drug alone. The present study confirmed the potent therapeutic effects of Nectin‑4‑MMAE against pancreatic cancer, and its unique antitumor mechanism provides new approaches to treatment.

Qiu, Rong-Bin; Zhao, Shi-Tao; Xu, Zhi-Qiang; Hu, Li-Juan; Zeng, Rui-Yuan; Qiu, Zhi-Cong; Peng, Han-Zhi; Zhou, Lian-Fen; Cao, Yuan-Ping; Wan, Li

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Thymoquinone (TQ), the principal active compound derived from the black seed plant, has been extensively utilized in traditional medicine for treating various ailments. Despite its widespread use, its therapeutic mechanisms in the context of cardiac hypertrophy remain insufficiently understood. The present study focused on assessing the efficacy of TQ in mitigating cardiac hypertrophy while identifying its specific protective pathways. Through a combination of in vivo experiments utilizing a mouse model of transverse aortic constriction (TAC) and in vitro studies utilizing an angiotensin II (AngII)‑induced hypertrophy model in H9C2 cells, the protective actions of TQ were comprehensively evaluated. The results revealed that TQ significantly attenuated TAC‑induced cardiac hypertrophy and improved overall cardiac function. In AngII‑induced H9C2 cells, pretreatment with TQ significantly reduced both cell hypertrophy and reactive oxygen species levels, while simultaneously promoting autophagy and limiting fibrosis. TQ was also found to increase the transcriptional activity of peroxisome proliferator‑activated receptor‑ (PPAR‑), which interacted with 14‑3‑3 protein, leading to autophagy activation and subsequent cellular protection. However, the protective autophagic effects were attenuated when PPAR‑ activity was inhibited alongside pAD/14‑3‑3‑short hairpin RNA administration. The present findings demonstrate that TQ mitigates cardiac hypertrophy by modulating autophagy via the PPAR‑/14‑3‑3 signaling axis, highlighting its therapeutic potential for cardiac hypertrophy treatment.