Molecular medicine reports最新文献

Steroid‑induced osteonecrosis of the femoral head (SONFH) is a progressive hip condition marked by osteocyte apoptosis from poor blood supply, leading to femoral head collapse and hip joint dysfunction. Examination of the GSE123568 dataset revealed the important role of ubiquitination in the development of SONFH, contributing to processes such as 'apoptosis', 'protein processing in the endoplasmic reticulum', 'lysosome function', 'cell cycle regulation and autophagy'. The present research revealed that the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) is involved in SONFH, showing positive correlations with key genes in the p53 signaling pathway, DNA damage response and cell cycle regulation. This highlights the role of NEDD4 in DNA repair and cell cycle control. Additionally, NEDD4 exhibited varying regulatory effects on integrin, TGF‑β/SMAD, Hippo/yes‑associated protein and Notch signaling pathways, underscoring its multifaceted role in cellular signaling. A NEDD4 overexpression vector was created and found to significantly boost the viability, migration and angiogenesis of bone microvascular endothelial cells (BMECs). Reverse transcription‑quantitative PCR results revealed higher mRNA levels of mTOR, VEGF and VEGFR2 in NEDD4‑overexpressing cells, suggesting that the VEGF signaling pathway was activated. Immunoprecipitation assays showed decreased mTOR ubiquitination levels following NEDD4 overexpression, suggesting NEDD4 may indirectly modulate mTOR ubiquitination rather than directly catalyzing it., Small interfering RNA experiments found that NEDD4 and mTOR cooperated to boost BMEC proliferation and migration, as confirmed by MTT, EdU and wound healing assays. Furthermore, the present research showed that glucocorticoids could suppress NEDD4 expression by increasing promoter methylation levels. These findings highlight the key roles of NEDD4 in angiogenesis, maintaining cell balance, regulating the cell cycle and repairing DNA damage in SONFH. By demonstrating the numerous functions of NEDD4 in steroid‑induced osteonecrosis and angiogenesis, the present study suggested that it may impact vascular growth and bone tissue repair through multiple pathways and mechanisms.

Metabolic‑associated fatty liver disease (MAFLD) is widely recognized as the most common type of chronic liver disease. As a member of the perilipin (PLIN) family, PLIN5 serves an important role in the regulation of lipid metabolism. Ferroptosis is a form of iron‑dependent non‑apoptotic cell death characterized by lipid peroxidation. Notably, knockout of PLIN5 can attenuate high‑fat diet (HFD)‑induced MAFLD; however, the specific underlying mechanism remains unclear. The present study induced PLIN5 overexpression by transfecting AML12 cells with a pcDNA3.1‑PLIN5 plasmid, and PLIN5 knockdown was achieved using short hairpin RNA‑mediated interference. Subsequently, intracellular ferrous iron (Fe²⁺) levels were assessed via immunofluorescence staining. Furthermore, a MAFLD model was established in C57BL/6J mice by feeding them a HFD. To establish an in vitro model of hepatic steatosis, AML12 hepatocytes were treated with palmitic acid and oleic acid to induce intracellular lipid accumulation. To further explore the effects of PLIN5 on ferroptosis, liver single‑cell sequencing was conducted and cellular experiments were performed to assess changes in redox and ferroptosis‑related proteins. The current study investigated the effects of PLIN5 on MAFLD in animal and cellular experiments, including the changes in lipid accumulation, redox and ferroptosis‑related markers. The results revealed that genetic knockdown of PLIN5 significantly attenuated lipid accumulation and intracellular Fe²⁺ levels in AML12 hepatocytes, whereas PLIN5 overexpression markedly exacerbated these parameters. In addition, PLIN5 deficiency substantially reduced malondialdehyde content while enhancing glutathione levels, indicating attenuated oxidative stress. The results of the in vivo studies demonstrated that PLIN5 knockout effectively ameliorated MAFLD progression in mice by suppressing ferroptosis. In conclusion, PLIN5 knockout may delay the progression of MAFLD in mice via ferroptosis inhibition. Therefore, targeting PLIN5 could offer a novel therapeutic strategy to address MAFLD by modulating lipid metabolism and ferroptosis pathways.

Diabetic osteoporosis (DOP) is on the rise globally, presenting a notable healthcare challenge due to its complex pathogenesis and high fracture risk. Currently, available treatments have limitations, highlighting an urgent need for novel therapeutic approaches. Zinc carnosine (ZnC), a compound formed by the chelation of carnosine with trace‑element zinc ions, has shown potential in inhibiting the accumulation of advanced glycation end products in the bone microenvironment, yet its effects on DOP remain under‑explored. The present study aimed to examine the effects of ZnC on bone loss in a mouse model of DOP. A total of 24 male mice, aged 6 weeks, were assigned to control, type 2 diabetes mellitus (T2DM) and ZnC intervention groups. DOP was induced using a high‑fat diet combined with streptozotocin (STZ). Following 8 weeks of treatment with ZnC at a dosage of 100 mg/kg/day, bone parameters were evaluated using micro‑computed tomography (micro‑CT), histological staining and molecular analyses. The micro‑CT analysis revealed that bone mineral density (BMD), bone volume/tissue volume (BV/TV), number of bone trabeculae (Tb.N), thickness of cortical bone (Ct.Th) and area of cortical bone (Ct.Ar) were significantly lower in the T2DM model group compared with that in the control group (P<0.05). Conversely, bone trabecular separation (Tb.Sp) structural model index (SMI) and porosity of cortical bone (Ct.Po) were significantly higher in the T2DM model group compared with those in the control group (P<0.05). The ZnC intervention group showed significant increases in BMD, BV/TV, Tb.N, Ct.Th and Ct.Ar, and significant decreases in Tb.Sp compared with the T2DM model group. Tartrate‑resistant acid phosphatase staining demonstrated a notable reduction in osteoclast numbers in the ZnC intervention group relative to the T2DM model group. Furthermore, immunohistochemical staining and reverse transcription‑quantitative PCR indicated an upregulation of osteoblastic markers, including type Ⅰ collagen, osteocalcin and osteoprotegerin, alongside a downregulation of the osteoclastic marker receptor activator of nuclear factor‑κB ligand in the ZnC group. In conclusion, ZnC supplementation was shown to mitigate bone loss in DOP by promoting bone formation and reducing bone resorption. This was evidenced by enhancements in bone microstructure, a reduction in osteoclast activity and favorable changes in bone metabolism markers. These findings underscore the potential of ZnC as a therapeutic option for bone diseases associated with diabetes.

Hirschsprung‑associated enterocolitis (HAEC) represents a severe complication of Hirschsprung disease, characterized by intestinal barrier dysfunction and life‑threatening inflammation. The present study systematically reviews the updated molecular mechanisms underlying HAEC pathogenesis, with particular focus on the tight junction (TJ) proteins claudin, occludin and zonula occludens protein 1 (ZO‑1) and their interactions with the actin cytoskeleton. The present review demonstrates that dysregulation of claudin family members, particularly upregulation of pore‑forming claudin‑2 and downregulation of barrier‑forming claudin‑4, disrupts intestinal homeostasis. Occludin undergoes cytokine‑mediated endocytosis through myosin light chain kinase (MLCK)/NF‑κB signaling, while ZO‑1 dysfunction impairs mechanical coupling between TJs and actin filaments. Furthermore, the present review identifies that inflammatory mediators, such as IL‑1β, TNF‑α and IFN‑γ, trigger actin cytoskeleton remodeling via the cofilin phosphorylation cycle and the Rho‑associated protein kinase/MLCK pathway, establishing a cycle of barrier breakdown. Importantly, the present review highlights the lipocalin 10/slingshot homologue 1/cofilin axis and TJ‑cytoskeleton interactions as mechanistic targets for future intervention in HAEC treatment. These findings provide a comprehensive mechanistic framework for understanding HAEC pathogenesis and offer novel targets for clinical intervention.

Mucosa‑associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a scaffold protein and protease that is associated with multiple biological processes, such as immune signaling transduction, inflammation and glucose variation. However, its implication in diabetic nephropathy (DN) is unclear. The present study aimed to investigate the dysregulation of MALT1 and the effect of its inhibition by MI‑2 in high glucose‑treated renal tubular epithelial cells. HK‑2 cells were treated with 15 mM D‑glucose [low‑concentration glucose (LG) group] and 30 mM D‑glucose [high‑concentration glucose (HG)]. The negative control (NC) group consisted of cells cultured only with the standard medium. Subsequently, HK‑2 cells under the HG condition were treated with 0, 1, 2 and 4 µM MI‑2, an inhibitor of MALT1. Cell migration rate, invasive cell count, and the expression levels of vimentin, α‑smooth muscle actin (α‑SMA), fibronectin (FN) and collagen I were increased, whereas E‑cadherin expression was decreased in the HG group compared with that in the NC group (all P<0.01), implying enhanced epithelial‑to‑mesenchymal transition (EMT) and fibrosis in the HG group. Furthermore, MALT1 was upregulated in the HG group compared with that in the NC group (P<0.01). Following MI‑2 treatment in cells under the HG condition, the inhibitory effects of MI‑2 on EMT, fibrosis and the NF‑κB pathway were dose‑dependent. Cell migration rate, invasive cell count and vimentin expression were reduced, whereas E‑cadherin expression was elevated; furthermore, the expression levels of α‑SMA, FN and collagen I were downregulated in the high concentration MI‑2 (HC‑MI‑2) group compared with those in the HG group (all P<0.01). In addition, the NF‑κB pathway was inactivated, as reflected by increased inhibitor of κB α expression and decreased phosphorylated-p65 expression in the HC‑MI‑2 group compared with in the HG group (both P<0.001). In conclusion, MALT1 inhibition by MI‑2 suppresses EMT and fibrosis by inactivating the NF‑κB pathway in HG‑treated HK‑2 cells, indicating its potency as a target for DN.

The thioredoxin (Trx) system comprises four core components: Trx‑interacting protein (TXNIP), Trx, Trx reductase (TrxR) and NADPH. TrxR utilizes NADPH to reduce Trx, reducing target proteins through its conserved thiol groups, thereby maintaining cellular redox balance. TXNIP inhibits Trx activity by forming a disulfide exchange reaction with Trx. Beyond its role in redox regulation, the Trx system interacts with various cellular regulators and participates in intracellular signaling networks. The Trx system exhibits dual regulatory roles in autophagy, with Trx primarily exerting an inhibitory effect on ferroptosis and apoptosis, whereas TXNIP promotes these processes. Multiple molecular mechanisms are implicated in these regulatory functions. Furthermore, the Trx system mediates cross‑regulation between autophagy and ferroptosis, as well as autophagy and apoptosis, thereby influencing cellular responses to stress conditions. The present review examines the structural components of the Trx system and the cellular translocation of TXNIP. Additionally, it explores the involvement of the Trx system in various diseases, including neurodegenerative disorders, cardiovascular diseases and cancer, highlighting its potential as a therapeutic target. By analyzing the molecular mechanisms through which the Trx system modulates cell death pathways, including ferroptosis, autophagy and apoptosis, the present review may provide novel research perspectives and theoretical foundations for developing disease treatment strategies.

A frequently occurring surgical emergency in gynecology is ovarian torsion, which occurs when the ovary twists on its ligamentous supports, which obstructs blood flow. The aim of the present study was to evaluate the protective effects of hyperbaric oxygen therapy (HBOT) and tadalafil against ischemia‑reperfusion (IR) injury in a rat model of ovarian torsion. Female Wistar albino rats were randomly assigned to five groups (n=8/group): Control, IR, IR + tadalafil, IR + HBOT and IR + tadalafil + HBOT. Ovarian torsion was induced under anesthesia for 2 h, followed by daily post‑operative treatments with tadalafil (10 mg/kg) and/or HBOT (2.4 atmospheres absolute for 1 h) for 7 days. Blood and ovarian tissue specimens were collected for analysis at the end of the treatment period. IR‑induced ovarian tissue injury significantly decreased the counts of primordial, primary and preantral follicles compared with those in the control group. In addition, serum ELISA and immunohistochemical analysis revealed that IR injury reduced anti‑Müllerian hormone (AMH) levels in serum and the granulosa cells of primary, preantral and secondary follicles. HBOT alone resulted in a significant increase in the counts of primordial, primary and preantral cells, as did the combination of HBOT with tadalafil. In addition, AMH immunoreactivity significantly increased in primary, preantral and secondary follicles following treatment with HBOT and tadalafil. Furthermore, all therapeutic interventions elevated serum AMH levels in the IR model rats. These findings suggest that tadalafil treatment combined with HBOT may help protect ovarian reserve and mitigate IR‑induced tissue damage in rat ovaries.

Renal cell carcinoma (RCC) is a malignant tumor originating from the epithelial cells of the renal tubules. RCC has a high propensity for distant metastasis, complicating clinical management due to the paucity of effective post‑metastatic therapeutic strategies and the associated poor prognosis. Epithelial‑mesenchymal transition (EMT) is a biological process in which cells switch from epithelial to mesenchymal characteristics. RCC cells undergoing EMT exhibit a higher grade of malignancy with enhanced invasiveness and metastatic capabilities, thereby markedly promoting the tendency for distant metastasis. Non‑coding RNAs (ncRNAs) are a group of functional RNAs that are not translated into proteins. ncRNAs serve key roles in RCC progression and one of the key mechanisms involved is through regulating the EMT process. The present study reviews the research on ncRNAs regulating EMT in RCC and their future clinical applications, highlighting their notable potential as novel diagnostic biomarkers and therapeutic targets to combat metastatic RCC in the future.

Cardiovascular diseases (CVDs) are among the main factors impacting negatively human health on a global scale. Every year, there is an increase in the prevalence of CVDs despite advancements in therapy for managing traditional risk factors. Research on exosomes is has garnered great interest due to their role in regulating intercellular communication. Exosome‑mediated epigenetic regulation is involved in the interaction between circulating cells and blood arteries, as well as in intercellular communication processes, and exosomes serve as biomarkers of cell activation. The present study aimed to summarize the recent research on exosome‑mediated epigenetic regulation mechanisms, as well as the roles of exosomes in the pathology and diagnosis of CVDs, which may increase the current understanding of the precise functions that exosomes play in the development of CVDs.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that a pair of the p‑AMPK western blots shown in Fig. 3B were strikingly similar to AMPK blots shown in Fig. 5A; in addition, the AMPK blots shown in Fig. 4A were similar to the GAPDH blots shown in Fig. 5A, albeit the dimensions and intensities of the bands differed slightly comparing the two figure parts. Upon re‑examining their original data, the authors realized that inadvertent errors had been made in terms of the assembly of Figs. 3 and 4. The revised versions of Figs. 3 and 4, now showing the correct p‑AMPK western blots in Fig. 3B and the AMPK blots in Fig. 4A, are shown on the next page. The authors wish to emphasize that these errors did not affect the results or the main conclusions reported in the study. All the authors approve of the publication of this corrigendum, and the authors are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this. The authors regret their oversight in allowing these errors to be included in the paper, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 24: 712, 2021; DOI: 10.3892/mmr.2021.12351].