Molecular medicine reports最新文献

In the present study, pleckstrin homology domain‑containing family A member 4 (PLEKHA4) was identified as being upregulated in renal cell carcinoma, particularly within the kidney renal clear cell carcinoma (KIRC) subtype. The present study conducted bioinformatics analysis, Cell Counting Kit‑8 and cell migration assays, flow cytometry, western blotting and in vivo experiments with the aim of uncovering the role of PLEKHA4 in β‑catenin signaling in KIRC cells. Notably, PLEKHA4 upregulation was revealed to be associated with enhanced cell proliferation, indicating its potential role as an oncogene in KIRC. Mechanistically, knockdown of PLEKHA4 in KIRC cells led to decreased β‑catenin signaling and cyclin D1 expression and the induction of cell cycle arrest at the G1/S phase, suggesting that PLEKHA4 facilitated tumorigenesis through modulation of the Wnt/β‑catenin pathway. PLEKHA4 knockdown also inhibited cell viability, migration and colony formation, further emphasizing its role in cancer progression. Notably, overexpression of PLEKHA4 activated Wnt/β‑catenin signaling, reinforcing its role in promoting β‑catenin nuclear translocation and signaling activity. The present findings suggested that PLEKHA4 could serve as a potential therapeutic target for KIRC; inhibiting PLEKHA4 or modulating Wnt/β‑catenin signaling could provide new avenues for treatment strategies in KIRC.

Lung adenocarcinoma (LUAD) is a leading cause of cancer‑related death due to its aggressive nature and metastatic potential. The present study aimed to explore the expression of phospholipid phosphatase 2 (PPAP2C) in LUAD, and its effect on cell migration and invasion, with a particular focus on its association with the ERK/JNK signaling pathway and epithelial‑mesenchymal transition (EMT). The expression of PPAP2C in LUAD was analyzed using data from The Cancer Genome Atlas database. Pearson's correlation coefficient analysis was used to assess the correlation between PPAP2C and genes such as MAPK1, MAPK3, MAPK8, CDH1, CDH2 and SNAI1. Subsequently, the PPAP2C gene was silenced in A549 and H1299 LUAD cell lines using siRNA vectors, followed by assessments of gene expression, cell migration, invasion and protein interaction using reverse transcription‑quantitative PCR, western blotting, wound healing assay, Transwell invasion assay, molecular docking analysis, co‑immunoprecipitation and immunofluorescence staining. The results showed that PPAP2C was significantly upregulated in LUAD tissues compared with that in normal tissues. In addition, high levels of PPAP2C were significantly correlated with MAPK3, MAPK8, CDH1 and SNAI1. Notably, PPAP2C silencing significantly inhibited cell migration and invasion. Additionally, it reduced the phosphorylation levels of ERK and JNK proteins. PPAP2C showed specific binding sites with ERK1, and co‑precipitated with ERK1 in both A549 and H1299 cells. Furthermore, PPAP2C silencing decreased the expression levels of N‑cadherin and Snail, while increasing E‑cadherin expression, thereby inhibiting EMT. In conclusion, PPAP2C may be highly expressed in LUAD tissues, and could promote cell migration and invasion by activating the ERK/JNK signaling pathway and inducing EMT. These findings provide a novel potential target for the diagnosis and treatment of LUAD.

Alveolar bone defects caused by inflammation, trauma and tumors adversely affect periodontal health, causing tooth loosening or dentition defects, thus affecting denture or implant repair. Advancements in tissue engineering technology and stem cell biology have significantly improved the regenerative reconstruction of alveolar bone defects. The multiple trophic activities of extracellular vesicles (EVs) produced by mesenchymal stem cells play important roles in exerting their therapeutic effects. Several studies have reported the role of dental pulp stem cells (DPSCs) in bone regeneration, but the regenerative effects of DPSC‑EVs on alveolar bone defects are unclear. In the present study, the osteogenic effects of DPSC‑EVs on Hertwig's epithelial root sheath (HERS) cells in vitro and their osteoinductive effects in an alveolar bone defect rat model were investigated. The results showed that DPSC‑EVs significantly promoted the expression of osteogenic genes, such as runt‑related transcription factor 2 and alkaline phosphatase, and increased the osteogenic differentiation capability of HERS. These findings suggested that transforming growth factor β1 inhibition decreased DPSC‑EV‑induced Smad, MAPK and ERK phosphorylation in HERS. In vivo, DPSC‑EV‑loaded hydrogels were transplanted into the alveolar sockets of Sprague‑Dawley rats and observed for eight weeks. The new bone grew concentrically in the DPSC‑EV or DPSC‑EV‑loaded hydrogel group, with greater bone mass than that in the control group, and the bone volume/total volume increased notably. The results confirmed the osteogenic and osteoinductive effects of DPSC‑EVs and DPSC‑Exo‑loaded hydrogels on alveolar bone defects. Due to their low immunogenicity, high stability, good biocompatibility and osteogenic propensity, DPSC‑EV‑loaded hydrogels are a safe cell‑free therapeutic approach for defective alveolar bone regeneration.

Previous studies have reported that a strong correlation between the estimated cumulative thermal exposure in the crystalline lens and the incidence of nuclear cataracts; however, the precise relationship between temperature and cataracts remains to be fully elucidated. In the present study, the shotgun liquid chromatography/mass spectroscopy‑based global proteomic approach was applied to investigate cataract‑inducing factors in lens cultured at normal (35.0˚C) and slightly warmer (37.5˚C) conditions. In the rat lens, 190 proteins (total) were identified. Of these, 48 proteins (25.3%) were found in lenses cultured at both 35.0˚C and 37.5˚C. Moreover, 85 proteins (44.7%) were unique to lenses cultured at 35.0˚C, while 57 proteins (30.0%) were unique to lenses cultured at 37.5˚C. Protein expression changes in rat lenses cultured at 37.5˚C were examined using a label‑free semiquantitative approach that uses spectral counting and Gene Ontology analysis. Filensin and vimentin protein expression, key factors in maintaining lens structure, were decreased. These findings may serve as a valuable indicator for elucidating the relationship between temperature and the onset of nuclear cataracts.

Aseptic loosening is a major complication of joint replacement surgery, characterized by periprosthetic osteolysis and chronic inflammation at the bone‑implant interface. Cells release chemokines, cytokines and other pro‑inflammatory substances that perpetuate inflammation reactions, while other particle‑stimulated macrophages promote osteoclastic bone resorption and impair bone formation. The present study investigated integrin and inflammatory cytokine expression patterns in RAW 264.7 cells treated with titanium (Ti) particles to elucidate the role of integrins in Ti particle‑mediated inflammatory osteolysis. Assessment was performed by reverse transcription‑quantitative PCR, western blotting, confocal immunofluorescence, flow cytometry and enzyme‑linked immunosorbent assays. Cell migration was evaluated by wound healing assay. It was found that Ti particles significantly induced integrin expression in RAW 264.7 cells, including upregulation of integrins β2 (CD18), aL (CD11a), aM (CD11b) and aX (CD11c). Ti particles also enhanced the expression of Toll‑like receptors (TLRs; TLR1, TLR2, TLR3 and TLR4) and triggered the release of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)‑1β, IL‑8 and IL‑12. Proteomics showed higher expression and activity levels of TLR2 and TLR4, along with their downstream signaling adaptors myeloid differentiation primary response protein 88 (MyD88) and Mal/TIR‑domain‑containing adapter protein (TIRAP), following Ti treatment. Additionally, Ti treatment significantly enhanced the migration rate of RAW 264.7 cells. The present findings indicated that Ti particles regulate the inflammatory response of RAW 264.7 cells in an in vitro aseptic loosening model by activating the TLR/TIRAP/MyD88 signaling pathway.

The present review aimed to provide an update on the scientific progress of the role of epigenetic modifications on diabetic peripheral neuropathic pain (DPNP). DPNP is a devastating and troublesome complication of diabetes mellitus (DM), which affects one third of patients with DM and causes severe hyperalgesia and allodynia, leading to challenges in the treatment of these patients. The pathophysiology of DPNP is multifactorial and is not yet fully understood and treatment options for this disease are currently unsatisfactory. The underlying mechanisms and pathophysiology of DPNP have largely been explored in animal models and a mechanism‑derived approach might offer a potential therapeutic‑target for attenuating certain phenotypes of DPNP. Altered gene expression levels within the peripheral or central nervous systems (CNS) are a crucial mechanism of DPNP, however, the transcriptional mechanisms of these genes have not been fully elucidated. Epigenetic modifications, such as DNA methylation and histone modifications (methylation, acetylation, or phosphorylation), can alter gene expression levels via chromatin remodeling. Moreover, it has been reported that altering gene expression via epigenetic modifications within the peripheral or CNS, contributes to the changes in both pain sensitivity and pharmacological efficacy in DPNP. Therefore, the present review summarized the findings of relevant literature on the epigenetic alterations in DPNP and the therapeutic potential for targeting these alterations in the future treatment of this disease.

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.

Several studies have revealed that an imbalance of the intestinal microbiota is involved in intestinal inflammation associated with ulcerative colitis (UC). Therefore, regulating the homeostasis of gut microbiota is critical for treating UC. Dracocephalum moldavica L. (DML) extract, a common traditional Chinese medicine, has been demonstrated to possess numerous pharmacological effects, such as antioxidative, anti‑inflammatory, and antibacterial properties. The aim of the present study was to evaluate the beneficial effects of DML extract and the probable mechanism of action in a dextran sulfate sodium‑induced chronic colitis model. It was found that DML extract ameliorated UC by improving disease activity index, weight loss, colon length, and histological scoring. DML extract administration also enhanced the count of Lactobacillus and reduced the count of Romboutsia. Furthermore, the results of network pharmacology analysis revealed that the active ingredients (including luteolin, rosmarinic acid, oleanolic acid, ursolic acid, apigenin, acacetin, kaempferol, and isorhamnetin) in the DML extract were closely associated with anti‑inflammatory activity via various signaling pathways, including the NF‑κB, IL‑17, TNF, and Toll‑like receptor (TLR) signaling pathways. Western blot analysis further indicated that DML extract downregulated the expression of members of the TLR4/NF‑κB signaling pathway, which was associated with colitis. Thus, it was hypothesized that DML extract exerted its anti‑colitis effects by modulating the gut microbiota and inflammatory pathways.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that, for the Transwell cell migration and invasion assay experiments shown in Fig. 3 on p. 1650, there were several panels showing overlapping sections of data; moreover, certain of the data shown in this Figure were also strikingly similar to data appearing in different form in Fig. 4 in another article written by different authors at a different research institute [Liu J and Duan X: PA‑MSHA induces apoptosis and suppresses metastasis by tumor associated macrophages in bladder cancer cells. Cancer Cell Int 17: 76, 2017].  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 reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 19: 1645‑1653, 2019; DOI: 10.3892/mmr.2018.9796].

Intraoperative radiotherapy (IORT) is a precise, single high‑dose irradiation directly targeting the tumor bed during surgery. In comparison with traditional external beam RT, it minimizes damage to other normal tissues, ensures an adequate dose to the tumor bed and results in improved cosmetic outcomes and quality of life. Furthermore, IORT offers a shorter treatment duration, lower economic costs and therapeutic efficacy comparable with traditional RT. However, its relatively higher local recurrence rate limits its further clinical applications. Identifying effective radiosensitizing drugs and rational RT protocols will improve its advantages. Furthermore, IORT may not only damage DNA to directly kill breast tumor cells but also alter the tumor microenvironment (TME) to exert a sustained antitumor effect. Specific doses of IORT may exert anti‑angiogenic effects, and consequently antitumor effects, by impacting post‑radiation peripheral blood levels of vascular endothelial growth factor and delta‑like 4. IORT may also modify the postoperative wound fluid composition to continuously inhibit tumor growth, e.g. by reducing components such as microRNA (miR)‑21, miR‑221, miR‑115, oncostatin M, TNF‑β, IL‑6 and IL‑8, and by elevating levels of components such as miR‑223, to inhibit the ability of postoperative wound fluid to induce proliferation, invasion and migration of residual cancer cells. IORT can also modify cancer cell glucose metabolism to inhibit the proliferation of residual tumor cells. In addition, IORT can induce a bystander effect, eliminating the postoperative wound fluid‑induced epithelial‑mesenchymal transition and tumor stem cell phenotype. Insights gained at the molecular level may provide new directions for identifying novel therapeutic targets and approaches. A more comprehensive understanding of the effects of IORT on the breast cancer (BC) TME may further its clinical application. Hence, the present article reviews the primary effects of IORT on BC and its impact on the TME, aiming to offer fresh research perspectives for relevant professionals.