International journal of molecular medicine最新文献

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, regarding the Transwell invasion assay experiments shown in Figs. 2D and 5F, the 'Mimic control' panel in Fig. 2D appeared to contain an overlapping section of data with the 'Blank' data panel in Fig. 5F, such that data which were intended to show the results from differently performed experiments had apparently been derived from the same original source. In addition, the control western blot data (GAPDH protein bands) shown in the western blots in Figs. 3C and 5H were apparently the same, although the images had been inserted into these figures as mirror images of each other. In view of the fact that these figures were assembled erroneously, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 1824‑1832, 2019; DOI: 10.3892/ijmm.2019.4328].

Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is characterized by the death of dopaminergic neurons. It has been reported that ceftriaxone (CEF) exerts promising effects on alleviating dopaminergic neuron death in PD models. However, the neuroprotective mechanisms of CEF in PD have not been well understood. In the present study, to investigate the neuroprotective effects of CEF through western blot and immunofluorescence assays, two in vivo models were established, namely the 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP)‑ and lipopolysaccharide (LPS)‑induced models. Additionally, three in vitro models were used to explore the neuroprotective mechanisms of CEF, namely the 1‑methyl‑4‑phenylpyridinium ion (MPP+)‑induced dopaminergic neuron injury, LPS‑induced microglia activation and TNFα‑induced astrocyte activation models, with key insights derived from western blot and qPCR experiments. The in vivo studies demonstrated that CEF exerted neuroprotective effects and reduced glial cell activation. Additionally, CEF reversed the reduction of tyrosine hydroxylase and suppressed the activation of microglia and astrocytes. Furthermore, the in vitro experiments revealed that CEF could display both direct and indirect neuroprotective effects and could directly alleviate MPP+‑induced neuronal toxicity and suppress the activation of microglia and astrocytes. In addition, CEF indirectly reduced neuronal injury caused by conditioned medium from activated microglia and astrocytes. Mechanistic studies revealed that CEF inhibited the ferroptosis pathway via regulating the expression of solute carrier family 7 member 11 and glutathione peroxidase 4 in a non‑cell‑specific manner. Via inhibiting ferroptosis, CEF could directly protect dopaminergic neurons and prevent glial cell activation, and indirectly impair neurons. In conclusion, the results of the current study highlighted the potential research and therapeutic value of CEF in regulating ferroptosis in PD.

Muscarinic acetylcholine (ACh) receptors (also known as M receptors) are widely distributed in all organs and tissues of the body, mainly playing a role in cholinergic nerve conduction. There are five known subtypes of muscarinic ACh receptors, but their pharmacological mechanisms of action on myocardial function have remained to be clearly defined. Functional myocardial diseases and myocardial injuries, such as arrhythmia, myocardial ischemia, myocarditis and myocardial fibrosis, may be affected by muscarinic ACh receptors. This article reviews the research progress of the regulation of myocardial function by muscarinic ACh receptors and related diseases, with the aim of developing better strategies and providing references for further revealing and clarifying the signal transduction and mechanisms of muscarinic ACh receptors in cardiomyocytes, and finding potential myocardial protective drugs that act on muscarinic ACh receptors.

Endometriosis affects ~15% of women of reproductive age worldwide, impacting ~190 million individuals. Despite its high prevalence, the precise pathogenesis of endometriosis remains unclear. Emerging evidence has highlighted oxidative stress as a pivotal factor in the initiation and progression of this disease. The present review comprehensively summarizes the sources of oxidative stress in endometriosis, including redox imbalance characterized by increased oxidative markers and diminished antioxidant defenses, mitochondrial dysfunction leading to excessive production of reactive oxygen species (ROS), and aberrant iron metabolism that further amplifies ROS generation. The accumulation of ROS disrupts cellular redox homeostasis, thereby exacerbating oxidative stress and activating key cell proliferation signaling pathways, such as the Raf/MEK/ERK and mTOR pathways. Activation of these pathways promotes the survival and proliferation of ectopic endometrial cells, contributing to lesion development and disease progression. The present review also discusses how oxidative stress induces epigenetic modifications that may further drive the pathological features of endometriosis. Finally, the recent advances in the application of antioxidants as therapeutic agents for endometriosis are highlighted, underscoring their potential to mitigate oxidative stress and ameliorate disease symptoms. Understanding the intricate relationship between oxidative stress and endometriosis may pave the way for novel diagnostic and therapeutic strategies aimed at improving patient outcomes.

Expression levels of ATP‑binding cassette (ABC) transporters are known to be increased in various tumor cells, including in breast cancer, and they are responsible for mediating drug resistance, leading to treatment failure. In the present study, gene expression array analysis revealed that among ABC transporter subtypes, ABC subfamily G member 8 (ABCG8) was one of the most increased in radiotherapy‑resistant triple‑negative breast cancer (RT‑R‑TNBC) cells compared with in TNBC cells. ABCG8 is involved in sterol efflux; however, its role in cancer is not well known. Therefore, the present study investigated the effect of ABCG8 on tumor progression in RT‑R‑TNBC cells. Gene expression profiling was conducted using the QuantiSeq 3' mRNA‑Seq Service, followed by western blotting to confirm protein levels. Loss‑of‑function assays using small interfering RNA (si) transfection were performed to assess the roles of ABCG8 and its regulatory signaling pathways. RT‑R‑MDA‑MB‑231 cells exhibited increased cholesterol levels in both cells and the surrounding media via induction of sterol regulatory element binding protein 1 (mature form) and fatty acid synthase. siABCG8 transfection increased intracellular cholesterol levels but decreased cholesterol levels in the media, indicating an accumulation of cholesterol inside cells. Additionally, RT‑R‑MDA‑MB‑231 cells exhibited increased levels of β‑catenin compared with MDA‑MB‑231 cells, which was significantly reduced by ABCG8 knockdown. Furthermore, ABCG8 knockdown led to cell cycle arrest in the G2/M phase in RT‑R‑MDA‑MB‑231 cells by reducing Polo‑like kinase 1 (PLK1) and Cyclin B1 expression. RT‑R‑MDA‑MB‑231 cells also exhibited increased phosphorylated‑low‑density lipoprotein (LDL) receptor‑related protein 6 (LRP6) levels compared with MDA‑MB‑231 cells, and these were decreased by siABCG8 transfection. LRP6 siRNA transfection decreased β‑catenin, PLK1 and Cyclin B1 expression. In addition, feedback mechanisms such as liver X receptor and inducible degrader of LDL were decreased in RT‑R‑MDA‑MB‑231 cells under normal conditions compared with in MDA‑MB‑231 cells. To the best of our knowledge, the present study was the first to suggest that the cholesterol exported by ABCG8, not inside the cells, may affect cancer progression via the LRP6/Wnt/β‑catenin signaling pathway in RT‑R‑TNBC. The regulation of this pathway may offer a potential therapeutic strategy for the treatment of RT‑R‑TNBC.

Hesperetin (HST), a natural flavonoid, has potent antitumor effects on lung adenocarcinoma; however, its effects on lung squamous cell carcinoma (LUSC) are currently unknown. The present study aimed to investigate the anticancer effects of HST on LUSC cells. The influence of 37.5, 75 and 150 µM HST on the H1703 cell line, and of 75, 150 and 300 µM HST on the H226 cell line was determined using the Cell Counting Kit‑8 method, cell cycle assay, JC‑1 mitochondrial membrane potential assay and Annexin V‑FITC/PI staining. DMSO‑treated cells were used as the control group. Western blotting was performed to detect the protein expression levels of cyclin B1, CDK1, Bcl‑2, Bax, caspase‑3, cleaved caspase‑3, phosphorylated‑eIF2α, eIF2α, glucose‑regulated protein 78, CHOP, Notch1 and Hes‑1. The relationship between endoplasmic reticulum stress (ERS), Notch1 signaling and apoptosis was examined using the ERS‑inhibitor 4‑phenylbutyric acid (4‑PBA; 500 µM) and the Notch1 signaling activator Jagged‑1 (4 µM). In vivo, mice were divided into control, HST (30, 60 and 90 mg/kg/q2d) and cisplatin (2 mg/kg/q2d) groups to evaluate the anti‑LUSC effects of HST. The results revealed that HST inhibited the viability of H226 and H1703 cells, leading to cell cycle arrest at the G₂/M phase and the induction of cell apoptosis. In addition, HST downregulated the Notch1 signaling pathway and increased ERS. In H1703 cells, 4‑PBA and Jagged‑1 reduced the expression of apoptosis‑related proteins, and Jagged‑1 also reduced the expression of ERS‑related proteins. In vivo, HST reduced tumor growth without any apparent toxic side effects. In conclusion, HST may exert its antitumor effects by inducing G₂/M cell cycle arrest and inhibiting the Notch1 signaling pathway to activate ERS‑induced apoptosis, making it a promising agent for treating LUSC.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the JNK and phosphorylated (pho)‑JNK western blotting data shown in Fig. 8 on p. 7 were strikingly similar to data featured in a pair of other articles written by different authors at different research institutes, one of which (submitted to the journal Molecular Medicine Reports) has been subsequently retracted, whereas the other (submitted to the journal Renal Failure) was received at that journal prior to the receipt of the above article at International Journal of Molecular Medicine. In view of the fact that the abovementioned data had already apparently been submitted elsewhere prior to the receipt of this paper at International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 47: 103, 2021; DOI: 10.3892/ijmm.2021.4936].

Platelets are involved in hemostasis and immune regulation, but little is currently known regarding their role in inflammatory bowel disease. In the present study, the mechanism by which platelet activation affects macrophage C‑X‑C motif chemokine receptor 3 (CXCR3) by releasing platelet factor 4 (PF4), thus aggravating ulcerative colitis (UC) disease progression, was investigated. A dextran sulfate sodium‑induced mouse model showed co‑localization of the platelet marker PF4 with the macrophage M1 marker inducible nitric oxide synthase. Furthermore, co‑culturing platelets with monocytes (THP‑1) in vitro led to the transformation of monocytes into macrophages, as well as the activation of macrophages exhibiting proinflammatory properties. Meanwhile, reverse transcription‑quantitative PCR (RT‑qPCR) showed that inflammatory factors, such as IL‑1β, IL‑6 and TNF‑α were significantly increased in macrophages after platelet co‑culture. It was therefore hypothesized that the PF4/CXCR3 pathway may serve an important role in cell‑to‑cell communication. Furthermore, intervention with PF4 in THP‑1 cells induced the M1 macrophage phenotype and inflammatory cytokine expression, which was consistent with co‑culturing, whereas inhibition of CXCR3 (AMG487) reversed the effects of PF4. In addition, following treatment with PF4, THP‑1 cells were found to be under oxidative stress and apoptosis was enhanced, as determined by detecting reactive oxygen species, mitochondrial membrane potential and Annexin‑V, as well as the classical apoptotic proteins Bcl‑2/Bax/caspase‑3 through western blotting. In addition, changes in MAPK and NF‑κB, two classic inflammatory signaling pathways, were detected. Furthermore, mice were treated with an anti‑platelet medication or CXCR3 inhibitor to observe in vivo inflammatory changes; through phenotypic assessment, immunofluorescence staining, RT‑qPCR and TUNEL assay, it was demonstrated that the PF4/CXCR3 pathway may aggravate inflammation in mice with UC. In conclusion, platelets and macrophages may interact in UC through the PF4/CXCR3 pathway to exacerbate inflammation, providing novel options for the treatment of UC.

Bone fractures, as a global public health issue, lead to disability and reduce the quality of life for patients. Chinese patent drug Osteoking has efficacy in bone fracture therapy. However, its therapeutic properties and underlying mechanisms remain unclear. In the present study, a rat model of bone fracture was established to evaluate the pharmacological effects of Osteoking by behavioral feature detection including mechanical pain threshold measurement, inclined plate and hindlimb weight‑bearing test and CatWalk XT gait analysis, as well as X‑ray scanning and micro‑computed tomography 3D reconstruction. Transcriptomics profiling, network analysis and in vivo western blotting, immunohistochemistry and immunofluorescence assessment were performed to determine the potential targets of Osteoking in promoting bone fracture healing. Osteoking effectively shortened the fracture healing time primarily by accelerating the process of endochondral ossification, decreasing the number of osteoclasts, increasing the levels of bone growth factors and bone formation biomarkers, and decreasing the level of bone resorption biomarkers. Following construction and analysis of the disease gene‑drug target network, it was hypothesized that EGF‑EGFR‑histone deacetylase 1 (HDAC1)‑Wnt/β‑catenin axis‑mediated adipogenesis‑angiogenesis‑osteogenesis crosstalk may be a candidate target of Osteoking in bone fracture. Osteoking significantly decreased expression levels of EGF, phosphorylated‑EGFR and HDAC1 protein and activated Wnt/β‑catenin signaling, which subsequently elevated the expression of VEGFA, Osterix (OSX) and CD31 proteins, increased the RUNX2/PPARγ ratio, decreased the receptor activator of nuclear factor κB ligand/osteoprotegerin ratio and reduced the serum levels of total cholesterol (TC), low‑density lipoprotein cholesterol (LDL‑C) and high‑density lipoprotein cholesterol (HDL‑C). There was a negative association between VEGFA, OSX, TC and LDL‑C levels. In conclusion, Osteoking may effectively reverse the disturbance of adipogenesis‑angiogenesis‑osteogenesis homeostasis and promote the fracture healing by regulating the EGF‑EGFR‑HDAC1‑Wnt/β‑catenin axis. These findings may offer guidance for the clinical application of Osteoking in bone fracture therapy.

Subsequently to the publication of this article, the authors have contacted the Editorial Office to inform us that Fig. 6 on p. 3454 was inadvertently assembled incorrectly; essentially, the wrong immunofluorescence data were featured for the 'Control' experiment in Fig. 6A. The revised version of Fig. 6, now showing the correct data for the Control experiment in Fig. 6A, is shown on the next page. Note that this error did not affect either the results or the conclusions reported in this paper. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum, and apologize both to the Editor and to readership for any inconvenience caused. [International Journal of Molecular Medicine 41: 3448‑3456, 2018; DOI: 10.3892/ijmm.2018.3539].