International journal of molecular medicine最新文献

Despite the established clinical efficacy of oxaliplatin in colorectal cancer (CRC), resistance to this platinum‑based agent continues to pose a significant therapeutic challenge. Increased exportin 1 (XPO1) expression in CRC has been linked to chemoresistance, while KPT‑330, a selective XPO1 inhibitor, has exhibited potential in enhancing platinum drug effectiveness in other cancer types. The present study explored the synergistic effects of KPT‑330 and oxaliplatin in oxaliplatin‑resistant CRC models. Oxaliplatin‑resistant cell lines (HCT116/L‑OHP and HCT8/L‑OHP) were developed, exhibiting elevated XPO1 expression as demonstrated by western blotting. A range of in vitro assays (Cell Counting Kit‑8 assays, ethynyldeoxyuridine assays, crystal violet staining, transmission electron microscopy and flow cytometry) and an in vivo subcutaneous xenograft model in nude mice were used to evaluate the combination therapy. Co‑treatment with KPT‑330 and oxaliplatin induced G2/M phase arrest and mitochondrial dysfunction, thereby triggering apoptosis and ferroptosis. Mechanistically, the combination therapy of KPT‑330 and oxaliplatin promoted the nuclear retention of p53, which in turn upregulated p21 and downregulated solute carrier family 7 member 11. In vivo, the combination therapy significantly enhanced tumor sensitivity to oxaliplatin. These results suggested that KPT‑330 restored oxaliplatin sensitivity in resistant CRC by facilitating p53 nuclear retention, presenting a promising approach to overcome chemoresistance through dual modulation of cell cycle arrest and ferroptosis pathways.

Copper is an important trace element in the human body and plays an essential role in cells, where it is involved in synthesizing copper‑dependent enzymes, including superoxide dismutase, cytochrome c oxidase, tyrosinase, lysyl oxidase, dopamine‑β‑hydroxylase and other related copper‑containing enzymes. Copper overload or deficiency affects cell activity, leading to the development of neurodegenerative diseases or cancer. Neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's disease, as well as cancer, represent significant chronic health burdens. The complexity of their pathophysiological mechanisms, coupled with the limitations of current targeted therapies, complicates the development of effective treatments. This review provides a comprehensive overview of the current understanding of copper's regulatory mechanisms in health and disease, with particular emphasis on its roles in neurodegenerative disorders and cancer. Recent advances in copper‑targeted therapeutic strategies, including copper chelators, ionophores and copper‑based nanoparticles, were highlighted. Furthermore, the clinical potential, key challenges and future prospects of these interventions were assessed. By synthesizing recent preclinical and clinical evidence, this review aims to contribute novel perspectives for improving the treatment of copper‑associated diseases.

Astrocytes, the predominant glial cells within the central nervous system, participate in a variety of processes, including metabolic homeostasis, regulation of blood‑brain barrier function, and the integration of neuronal function and structure. Lipids, which are critical components of astrocyte architecture and functionality, play a pivotal role in energy production, membrane fluidity, and the integration of astrocyte‑neuronal structure and function via lipid droplet storage and lipid metabolism. Research indicates that the proper storage of lipid droplets (LDs) in astrocytes is essential for maintaining normal physiological functions of the CNS. Fatty acids released from astrocyte LDs undergo β‑oxidation within mitochondria and are intricately linked to neuronal inflammatory signaling, oxidative stress and mitochondrial energy production. Furthermore, dysregulated lipid metabolism in astrocytes is strongly linked to the onset and progression of neurological disorders. The alteration of lipid metabolic profiles in astrocytes across various microenvironments, along with the identification and screening of critical lipid metabolites, has emerged as a focal point in current research. Nonetheless, the precise mechanisms through which aberrant lipid metabolism in astrocytes influences the onset and progression of neurodegenerative diseases require further elucidation. This article seeks to synthesize recent advancements in the study of LDs‑key organelles responsible for lipid homeostasis in astrocytes‑to elucidate the response characteristics and underlying mechanisms of lipid metabolism in these cells. Furthermore, it aims to investigate the therapeutic potential of inhibiting abnormal lipid secretion and excessive lipid accumulation in astrocytes in the context of neurodegenerative disease progression.

Following the publication of this paper, it was drawn to the Editor's attention by an interested reader that, for the western blot experiments shown in Fig. 7A on p. 405, the Bcl‑2 and PCNA blots for the SO‑Rb50 cell line appeared to be identical, albeit it with possibly slightly different exposure time of the gel and different vertical dimensions. Similarly, the BAX and PCNA blots for the Y79 cell line also appeared to be identical, although the blots were rotated by 180° relative to each other, again with possibly slightly different exposure time of the gel and different vertical dimensions. In addition, for the experiments showing transfection efficiency in Fig. 1 on p. 402, the 'SO‑Rb50/x100/PAX6‑RNAi GFP' and 'Y79/x200/Ctrl GFP' data panels contained overlapping data, and the 'SO‑Rb50/x200/PAX6‑RNAi GFP' and 'Y79/x100/Ctrl GFP' data panels similarly contained overlapping data, suggesting that these pairings of panels had been placed in this figure the wrong way around. Upon contacting the authors about these issues, they realized that Figs. 1 and 7 in this paper had inadvertently been assembled incorrectly. The revised versions of Fig. 1, now featuring the correct data for the PCNA blots for both the SO‑Rb50 and the Y79 cell lines, and Fig. 7, now showing the correctly positioned data panels for the 'SO‑Rb50/x100/PAX6‑RNAi GFP' and 'Y79/x200/Ctrl GFP' experiments, are presented on the next page. The authors wish to emphasize that the errors made in assembling the data in these Figures did not affect the overall conclusions reported in the paper. The authors are grateful to the Editor of International Journal of Molecular Medicine for granting them this opportunity to publish a Corrigendum, and apologize to both the Editor and the readership for any inconvenience caused. [International Journal of Molecular Medicine 34:  399‑408, 2014; DOI: 10.3892/ijmm.2014.1812].

Over the past few years, bariatric surgery has emerged as a potent remedy for obesity and its related metabolic issues, with its effects on peripheral immune cells garnering considerable attention. Obesity, recognized as a chronic metabolic condition, is intricately connected to dysfunctions spanning a range of immune cell types. Among peripheral immune cells, T cells, B cells and monocytes, obesity markedly alters their counts and functions, driving the inflammation and metabolic dysfunction characteristic of the condition. The modifications in these immune cell cohorts are inextricably intertwined with the augmentation of postoperative metabolic functions and have the potential to exert a salutary effect on complications associated with obesity. The present review primarily examined the latent influence of bariatric surgery on the number and function of peripheral immune cells, thereby offering novel perspectives and therapeutic targets for the immunotherapy of obesity.

Tumor necrosis factor‑like weak inducer of apoptosis (TWEAK)/fibroblast growth factor‑inducible 14 (Fn14) signaling represents a critical regulatory axis in tissue repair and the inflammatory response. However, the impact of TWEAK on the characteristics of periodontal ligament stem cells (PDLSCs), which subsequently influence periodontal homeostasis, remains inadequately understood. To address this, PDLSCs were isolated from human periodontitis tissue and cultured to investigate the effects of TWEAK on PDLSC proliferation, migration and osteogenic differentiation using Cell Counting Kit‑8, TUNEL, Transwell and scratch assays, and alizarin red and alkaline phosphatase staining. Transcriptome sequencing and western blot analysis were used to explore the underlying molecular mechanisms. Additionally, the potential of targeting TWEAK in periodontitis treatment was evaluated using inflammatory PDLSCs (iPDLSCs) and a rat periodontitis model. The present study demonstrated that low levels (1, 5 and 20 ng/ml) of TWEAK enhanced the proliferation and osteogenic differentiation of PDLSCs, with 1 and 5 ng/ml further enhancing their ability to promote M2 macrophage polarization. By contrast, elevated levels (100 ng/ml) of TWEAK impaired PDLSC proliferation, migration and osteogenic potential, activated the RANKL/osteoprotegerin (OPG) system, and promoted the M1 polarization of macrophages induced by PDLSCs, with the Fn14/NF‑κB pathway serving a pivotal role in this regulatory process. The expression levels of TWEAK, Fn14 and NF‑κB were significantly higher in iPDLSCs than in healthy donor‑derived PDLSCs, and these iPDLSCs exhibited reduced proliferation, migration and osteogenic potential, along with increased RANKL/OPG activation and M1 macrophage polarization. In iPDLSCs, inhibition of the TWEAK/Fn14/NF‑κB pathway enhanced cell proliferation, migration and osteogenic differentiation potential, and reversed the activation of the RANKL/OPG system and macrophage M1 polarization induced by iPDLSCs. Furthermore, high TWEAK levels were shown to accelerate the progression of rat periodontitis, while inhibition of the TWEAK/Fn14 pathway mitigated periodontitis‑induced periodontal tissue destruction in rats. Collectively, the present findings revealed the role of the TWEAK‑PDLSCs axis in the maintenance and disruption of periodontal homeostasis, and identified targeting of the TWEAK/Fn14/NF‑κB pathway in iPDLSCs during periodontitis as a promising therapeutic strategy.

Type 2 diabetes mellitus (T2DM) is a major metabolic disease that poses a threat to human health; therefore, the development of new pharmaceutical therapies for the treatment of T2DM is of great importance. β‑hydroxybutyric acid (β‑HB) is the primary ketone body present in the human body. β‑HB not only serves as an energy substrate to maintain the metabolic homeostasis of the body but also acts as a signaling molecule, exerting multiple biological functions both inside and outside cells. The present review summarizes the research progress and latest findings of β‑HB in T2DM models from the perspective of metabolism, physiological effects and potential as a therapeutic agent. Research indicates that β‑HB exerts protective effects against T2DM by regulating glucose and lipid metabolism, preserving the integrity of pancreatic β‑cells and improving insulin resistance (IR). Additionally, β‑HB can alleviate the core pathological conditions of T2DM and related complications by enhancing the stability of cellular proteins, reducing oxidative stress and controlling inflammatory responses and endoplasmic reticulum stress (ERS), while regulating mitochondrial biogenesis, autophagy and apoptosis. Furthermore, the present review also describes the application of β‑HB in clinical research on T2DM. Research indicates that regulating β‑HB levels through endogenous and exogenous ketogenesis approaches can influence body weight, fasting blood glucose levels, IR and memory ability in T2DM patients. These results suggest that β‑HB is a potential metabolite for T2DM treatment.

Histone lactylation, a novel epigenetic modification, has emerged as a critical mediator of various physiological and pathological processes. The present review elucidates the molecular mechanisms of lysine lactylation (Kla) and its influence on gene expression modulation. In addition, previous findings regarding the mechanisms of Kla and its impact on metabolic regulation, inflammation and tumorigenesis are summarized. Histone lactylation influences macrophage polarization, promotes tumor immune evasion, and affects osteoblast differentiation and embryonic development. While promising as a therapeutic target, research progress is currently hindered by methodological limitations in terms of lactylation quantification and manipulation. The current review not only summarizes fundamental insights into Kla‑mediated disease pathogenesis but also critically addresses existing knowledge gaps. By highlighting the dynamic interplay between lactylation and metabolic regulation, novel perspectives are provided on the biological importance of this posttranslational modification. Ultimately, the aim of this review is to identify innovative approaches for targeting lactylation‑mediated pathways in disease treatment.

Protein homeostasis, or proteostasis, refers to the integrated quality control systems that regulate protein synthesis, folding, post‑translational modification, trafficking and degradation to maintain proteome stability and function. Disruption of these processes, including abnormal synthesis, misfolding or impaired degradation, results in proteostasis collapse and underlies the pathogenesis of cancer, neurodegeneration, cardiovascular disease and metabolic syndromes. Recent studies have highlighted FK506‑binding proteins (FKBPs), a family of immunophilins defined by a conserved peptidyl‑prolyl cis‑trans isomerase domain, as pivotal modulators of proteostasis. By modulating protein folding, stabilizing complexes, regulating endoplasmic reticulum stress and directing selective degradation, FKBPs establish direct links between proteostasis regulation and disease progression. This review presents the first comprehensive synthesis of FKBP‑mediated control of proteostasis across diverse clinical contexts. It analyzed how their structural features confer regulatory potential and elucidate their roles in proteome remodeling in cancer, pathogenic protein aggregation in neurodegenerative disorders, ion channel stabilization in cardiovascular dysfunction and kinase phosphorylation in metabolic regulation. By integrating these diverse actions within a unified proteostasis framework, FKBPs are proposed as versatile regulators and promising therapeutic targets, providing new perspectives on the proteostasis‑disease axis and opportunities for precision intervention across multiple organ systems.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the data panels (namely, three of the six panels) in Fig. 3 showing the results of migration assay experiments were strikingly similar to data in a paper which was submitted for publication at around the same time by the same research group to the journal Stem Cells International, where the results were described differently. Upon performing an independent analysis of the data in this paper in the Editorial Office, it came to light that data included in Figs. 1C, 6D and 7B‑D were also strikingly similar to data appearing in a few other articles written by the same research group, one of which had already been published and one of which was submitted for publication at around the same time as the above paper. Moreover, two pairs of data panels in Fig. 3 also contained overlapping sections of data, such that data which were intended to show the results of differently performed experiments had apparently been derived from a smaller number of original sources. Given the apparent re‑use of a large number of the data featured in the above paper in other articles by the same research group, and in view of the overlapping data identified in Fig. 3, 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 42: 2538‑2550, 2018; DOI: 10.3892/ijmm.2018.3810].