International journal of molecular medicine最新文献

Placentation is a key process that is tightly regulated that ensures the normal placenta and fetal development. Preeclampsia (PE) is a hypertensive pregnancy‑associated disorder characterized by increased oxidative stress and inflammation. STAT3 signaling plays a key role in modulating important processes such as cell proliferation, differentiation, invasion and apoptosis. The present review aimed to analyse the role of STAT3 signaling in PE pregnancies, discuss the main natural and synthetic compounds involved in modulation of this signaling both in vivo and in vitro and summarize the main cellular modulators of this signaling to identify possible therapeutic targets and treatments to improve the outcome of PE pregnancies.

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 µg/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.

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 γ‑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‑1β, 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‑1β release, and NOD‑like receptor thermal protein domain associated protein 3 (NLRP3) and IL‑1β expression. The results of in vitro assays revealed that Rema inhibited LPS‑induced increases in IL‑1β, IL‑6 and TNF‑α 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‑1β pathway.

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.

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.

The adaptation of cancer cells to hostile environments often necessitates metabolic pathway alterations to sustain proliferation and invasion. Head and neck cancer (HNC) has unfavorable outcomes. Therefore, elucidating the functional effects and molecular mechanisms underlying metabolic changes is key. Ingenuity Pathway Analysis identified 'ethanol degradation pathway II and IV' was consistently downregulated in tumor tissue, with aldehyde dehydrogenase 2 (ALDH2) emerging as a key prognostic gene among the top‑ranked differentially expressed metabolic pathways. Immunohistochemistry (IHC) of HNC specimens revealed significant downregulation of ALDH2 expression in tumor tissue, which was inversely correlated with T classification, overall stage, recurrence rate and independently predicted poor prognosis. Functional assays showed that ALDH2 knockdown enhanced HNC cell migration, invasion and colony formation, while ALDH2 overexpression attenuated these processes. Mechanistically, ALDH2 downregulation and subsequent reactive oxygen species (ROS) production in cells activated NF‑κB, upregulating vascular endothelial growth factor C (VEGFC) expression. ALDH2 overexpression inhibited ROS production and the NF‑κB/VEGFC oncogenic pathway, with pharmacological inhibition of NF‑κB and VEGFC mitigating the enhanced migration and invasion of ALDH2‑knockdown HNC cells. IHC and transcriptome analysis further highlighted an inverse association between ALDH2 and VEGFC, with the ALDH2^high/VEGFC^low profile predicting the most favorable survival outcome. Inhibition of ALDH2 with Daidzin increased VEGFC and phosphorylated NF‑κB levels, restoring the migration and invasion of ALDH2‑overexpressing HNC cells by enhancing the effects of VEGFC. Notably, modulating ALDH2 activity using Alda‑1 ameliorated NF‑kB/VEGFC axis upregulation following acetaldehyde treatment, aligning with the aforementioned alterations in alcohol metabolisms. These findings emphasize the key role of ALDH2 in influencing HNC progression and patient outcome, suggesting that targeting the ALDH2/NF‑κB/VEGFC pathway may represent a potential therapeutic strategy for HNC.

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.

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‑γ (PPAR‑γ), which interacted with 14‑3‑3γ protein, leading to autophagy activation and subsequent cellular protection. However, the protective autophagic effects were attenuated when PPAR‑γ activity was inhibited alongside pAD/14‑3‑3γ‑short hairpin RNA administration. The present findings demonstrate that TQ mitigates cardiac hypertrophy by modulating autophagy via the PPAR‑γ/14‑3‑3γ signaling axis, highlighting its therapeutic potential for cardiac hypertrophy treatment.

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].

The 5‑year survival rate of patients with esophageal squamous cell carcinoma (ESCC) is <20%, highlighting the need for the development of novel therapeutic targets. Neuregulin‑1 (NRG1), a transmembrane protein involved in cell proliferation and survival signaling, has unclear biological functions and clinical value in ESCC. The present study investigated the association between NRG1 expression and ESCC by analyzing data from both patients with ESCC and The Cancer Genome Atlas database. Reverse transcription‑quantitative PCR and immunohistochemistry staining were used to determine the levels of gene and protein in the tissue. The findings revealed that NRG1 gene and protein levels were significantly higher in tumor tissues compared with the normal tissues. Elevated expression of NRG1 was associated with poor outcomes, particularly in patients with advanced ESCC. Silencing NRG1 decreased both its mRNA and protein levels, disrupting key signaling pathways, such as phosphorylated (p‑)AKT and cellular rapidly accelerated fibrosarcoma (p‑cRAF), which led to decreased cancer cell proliferation, migration and tumor sphere formation, along with increased cell death. High expression levels of NRG1 and cRAF were significantly associated with poor prognosis. Additionally, silencing NRG1 promoted autophagosome and autolysosome formation, decreasing LC3B levels. The use of the autophagy inhibitor chloroquine significantly enhanced cell death induced by NRG1 silencing, suggesting that autophagy functions as a survival mechanism in ESCC cells in which NRG1 is silenced. Furthermore, high co‑expression of NRG1 and LC3B was associated with a worse prognosis. On the whole, the present study demonstrated that targeting NRG1 with autophagy inhibitors may serve as a potential therapeutic strategy for ESCC.