Molecular medicine reports最新文献

The nuclear receptor subfamily 4 group A member 1 (NR4A1) gene plays a crucial role in both osteoporosis and adipogenesis. The present study investigated the mechanisms by which NR4A1 influences osteoblastogenesis and adipogenesis in human bone marrow‑derived mesenchymal stem cells (BMD‑MSCs). NR4A1 was overexpressed or knocked down in mouse MC3T3‑E1 osteoblast cells and 3T3‑L1 adipocyte cells, as well as in PCS‑500‑012, a BMD‑MSC line. The alkaline phosphatase (ALP) assay and Alizarin Red S staining were performed using MC3T3‑E1 and BMD‑MSCs to assess ALP activity and mineralization, while Oil Red O staining was used to assess the lipid content in 3T3‑L1 cells and BMD‑MSCs. Total RNA was isolated from control, NR4A1‑overexpressing and NR4A1 small interfering RNA (siRNA; siNR4A1)‑treated BMD‑MSCs. RNA sequencing (RNA‑seq) was performed to identify differentially expressed genes, followed by ingenuity pathway analysis (IPA) to determine the role of NR4A1 in osteoblastogenesis and adipogenesis. NR4A1 or Nr4a1 knockdown tended to increase ALP activity and significantly increased calcification in BMD‑MSCs (P<0.005) and MC3T3‑E1 cells (P<0.005), respectively. By contrast, NR4A1 or Nr4a1 overexpression significantly decreased ALP activity and calcification. NR4A1 or Nr4a1 knockdown and overexpression significantly decreased and increased adipogenesis, respectively, in BMD‑MSCs (P<0.005 and <0.05, respectively) and 3T3‑L1 cells (P<0.005 in both). Treatments of BMD‑MSCs with an NR4A1 antagonist, 1,1‑bis(3'‑indolyl)‑1‑(p‑hydroxyphenyl) methane and siNR4A1 showed similar results. RNA‑seq and IPA in control, NR4A1 knockdown and NR4A1 overexpressing cells indicated that Notch signaling mediated the effects of NR4A1 in osteoblastogenesis and adipogenesis. Expression of mastermind‑like transcriptional coactivator 3 was reduced in the Notch signaling pathway in cells treated with siNR4A1. In conclusion, NR4A1 suppressed osteoblastogenesis and promotes adipogenesis in human BMD‑MSCs. The present study also suggested that NR4A1 plays a role in the progression of osteoporosis and adipogenesis by modulating the Notch signaling cascade.

Baicalein, a flavonoid monomer compound isolated from the dried root of the traditional Chinese herb Scutellaria baicalensis, has several pharmacological activities, such as anti‑inflammatory, anti‑angiogenic, antitumor, antimicrobial and antiviral properties. Acute lung injury (ALI) is characterized by injury of the alveolar epithelium and capillary endothelium, which results in decreased lung volume, decreased lung compliance, ventilation/perfusion mismatch, intrapulmonary edema, alveolar edema and even acute hypoxemic respiratory failure. The present study aimed to investigate the effects of baicalein on lung injury and inflammation. Bioinformatics analysis using network pharmacology predicted that the hypoxia inducible factor‑1α (HIF‑1α) and glycolysis signaling pathways were involved in the mechanism underlying the therapeutic effects of baicalein. Further in vitro and in vivo experiments, such as immunohistochemistry, immunofluorescence and PCR, verified that baicalein could inhibit HIF‑1α signaling, thus suppressing glycolysis, and improving inflammatory responses and ALI. Taken together, the results of the present study suggested that the anti‑inflammatory effects of baicalein on treating ALI were associated with its ability to suppress glycolysis via the HIF‑1α signaling pathway.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the flow cytometric assay data shown in Fig. 2C on p. 5, certain of the fluorescence microscopy data shown in Fig. 4B on p. 7, the FerroOrange‑stained cellular data in Fig. 5B and the C11‑BODIPY581/591‑stained cellular data in Fig. 5C on p. 8, and the cell autophagic data in Fig. 6E and G on p. 9 were strikingly similar to data that had already been submitted for publication in different form in different articles written by different authors at different research institutes (a few of which have now been retracted). Owing to the fact that the contentious data in the above article had already been published, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, 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 satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 27: 76, 2023; DOI: 10.3892/mmr.2023.12963].

In colorectal cancer (CRC), KRAS mutations enhance metachronous metastasis, a condition without prognostic biomarkers or preventive measures. The present study demonstrated that KRAS mutation may be a risk factor for CRC metachronous metastasis through meta‑analysis of public databases. A risk scoring model was constructed using machine learning for predicting metachronous metastasis in KRAS‑mutant CRC. Wound healing and Transwell assay indicated that KRAS inhibitors strongly suppress migration and invasion capabilities of high‑risk CRC cells and these findings were validated through ex vivo organoid and a mouse model of splenic‑liver metastasis. Mechanistically, RNA sequencing, reverse transcription‑quantitative PCR and western blot analyses revealed that KRAS inhibitors suppressed epithelial‑mesenchymal transition (EMT) and transforming growth factor β (TGF‑β) signaling. Notably, addition of TGF‑β1 protein partially reversed the inhibitory effects of KRAS inhibitors on CRC. These results suggested that KRAS inhibitors may prevent CRC metachronous metastasis by downregulating TGF‑β‑mediated EMT, suggesting they can be used prophylactically in high‑risk KRAS‑mutant CRC.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that one of the data panels in Fig. 3A on p. 6, showing how carnosol inhibits RANKL-induced osteoclastogenesis in the early stage of differentiation,  was strikingly similar to data that had already been submitted for publication in another article in the journal Annals of Translational Medicine written by different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been submitted for publication prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [26: 225, 2022; DOI: 10.3892/mmr.2022.12741].

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the  Transwell invasion assay data shown in Fig. 5E on p. 9 were strikingly similar to data that had already been published in different form in another article written by different authors at a different research institute [Zuo K, Zhao Y, Zheng Y, Chen D, Liu X, Du S and Liu Q: Long non‑coding RNA XIST promotes malignant behavior of epithelial ovarian cancer. Onco Targets Ther 12: 7261‑7267, 2019]. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, 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 satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 25: 112, 2022; DOI: 10.3892/mmr.2022.12628].

Peripheral nerve injury exacerbates progression of muscle heterotopic ossification (HO) and induces changes in expression of local cytokines in muscle tissue. The objective of the present study was to assess the impact of peripheral nerve injury on muscle HO development and the mechanism of cytokine modulation. A mouse model of gastrocnemius muscle HO was established and the sciatic nerve cut to simulate peripheral nerve injury. To evaluate the underlying factors contributing to the exacerbation of muscle HO resulting from denervation, fresh muscle tissue was collected and micro‑computed tomography, histochemical staining, RNA‑sequencing, reverse transcription‑quantitative PCR, Western blot, muscle tissue chip array were performed to analyze the molecular mechanisms. Sciatic nerve injury exacerbated HO in the gastrocnemius muscle of mice. Moreover the osteogenic differentiation of nerve‑injured muscle tissue‑derived fibro‑adipogenic progenitors (FAPs) increased in vitro. The expression of neuregulin 3 (NRG3) was demonstrated to be increased after nerve injury by muscle tissue chip array. Subsequent transcriptome sequencing analysis of muscle tissue revealed an enrichment of the PI3K/Akt pathway following nerve injury and an inhibitor of the PI3K/Akt pathway reduced the osteogenic differentiation of FAPs. Mechanistically, in vitro, peripheral nerve injury increased secretion of NRG3, which, following binding to ErbB4 on the cell surface of FAPs, promoted expression of osteogenesis‑associated genes via the PI3K/Akt signaling pathway, thus contributing to osteogenic differentiation of FAPs. In vivo, inhibition of the PI3K/Akt pathway effectively protected against muscle HO induced by peripheral nerve injury in mice. The present study demonstrated that the regulatory roles of NRG3 and the PI3K/Akt pathway in peripheral nerve injury exacerbated muscle HO and highlights a potential therapeutic intervention for treatment of peripheral nerve injury‑induced muscle HO.

Gastric cancer stem cells (GCSCs) contribute to the challenging aspects of gastric cancer, such as progression, metastasis, treatment resistance and recurrence. Inhibitors targeting cyclophilin A (CypA) have shown potential in curtailing GCSC growth. Building upon this, the current study delved deeper into understanding the functional role of CypA in controlling the proliferation and metastatic capabilities of GCSCs, employing CypA‑specific small interfering RNA. The results revealed that knockdown of CypA led to significant suppression of the growth and tumorsphere‑forming capacity of GCSCs derived from AGS cells. This effect was mediated by arresting the cell cycle at the G₀/G₁ and S phases, and promoting apoptosis. Furthermore, silencing of CypA exerted inhibitory effects on the migration and invasion of AGS GCSCs by modulating the process of epithelial‑mesenchymal transition. Notably, the observed antiproliferative and antimetastatic effects of CypA knockdown were associated with the downregulation of critical regulators of gastric cancer stemness, such as CD44, CD133, aldehyde dehydrogenase 1 family member A1, NANOG, OCT4 and SOX2. This regulation occurred through inactivation of the CD147/STAT3/AKT/ERK signaling pathway. Additionally, CypA knockdown effectively curbed in vivo tumor growth of AGS GCSCs in a chorioallantoic membrane assay using chick embryos. These findings underscore the critical role of CypA in promoting the proliferation and metastasis of GCSCs, highlighting its potential as an effective therapeutic target for eradicating GCSCs and improving gastric cancer treatment outcomes.

Lung cancer is responsible for the highest number of tumor‑related deaths worldwide. A flavonoid extracted from the heartwood of Dalbergia sissoo Roxb., 4‑methoxydalbergione (4‑MD), exhibits potent anticancer activity in multiple malignancies; however, the potential anticancer activity of 4‑MD in lung cancer has not yet been elucidated. In the present study, A549 cells were treated with increasing concentrations of 4‑MD, and cell viability was assessed using a Cell Counting Kit‑8 assay. In addition, colony formation, 5‑ethynyl‑2'‑deoxyuridine, wound healing and Transwell assays were conducted to evaluate cell proliferation, migration and invasion, respectively. Cell morphology was observed using transmission electron microscopy, and ferroptosis was determined using thiobarbituric acid reactive substance, lipid reactive oxygen species (ROS) and iron assays. Moreover, molecular docking was used to verify the potential interaction between 4‑MD and DNA methyltransferase 1 (DNMT1). Tumor‑bearing mice were established and treated with 10 or 30 mg/kg 4‑MD, and tumor volume and weight were recorded. Immunohistochemistry and Prussian blue staining were conducted to examine Ki‑67 expression and iron deposition in tumor tissues, and protein expression was further explored using western blot analysis. The results of the present study revealed that 4‑MD significantly inhibited cell proliferation, migration, invasion and epithelial‑mesenchymal transition in a concentration‑dependent manner. Notably, 4‑MD induced ferroptosis via increased lipid peroxidation, lipid ROS and Fe2+ levels. In addition, it was revealed that 4‑MD can directly bind to DNMT1 to inhibit expression, and inhibit solute carrier family 7 member 11 (SLC7A11; also known as cystine‑glutamate antiporter) and glutathione peroxidase 4 expression. Following DNMT1 overexpression, the observed antitumor activity and ferroptosis‑promoting effects of 4‑MD were partially reversed. Furthermore, 4‑MD significantly inhibited tumor growth in vivo, and reduced tumor volume and weight. In addition, Ki‑67 expression was reduced while iron deposition was increased in the tumor tissues of mice following treatment with 4‑MD. In conclusion, 4‑MD may exhibit anticancer activity through the promotion of DNMT1‑mediated cell ferroptosis. Thus, 4‑MD may have potential as a novel therapeutic agent in the treatment of lung cancer.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the Transwell cell invasion data shown in Fig. 4D were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had already been published elsewhere prior to the submission of this paper to Molecular Medicine Reports (one of which has been retracted). In view of the fact that certain of the abovementioned data had already apparently been published previously, the Editor of Molecular Medicine Reports 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. [Molecular Medicine Reports 21: 1509‑1516, 2020; DOI: 10.3892/mmr.2020.10944].