Molecular medicine reports最新文献

Diabetes is a metabolic disorder that has notable impacts on human health. Since improving insulin sensitivity and metabolic homeostasis is important for the treatment of diabetes and its complications, there is a need to evaluate therapies that improve insulin resistance. The aim of the present review was to introduce the effects of the insulin receptor substrate (IRS)/PI3K/Akt pathway on insulin resistance by summarizing and evaluating all existing insulin signaling pathway studies as the entry point, and to integrate the processes and mechanisms through which drugs alleviate insulin resistance. Peer‑reviewed studies and reports on diabetes, insulin resistance and drug therapy were retrieved by searching websites such as PubMed (https://pubmed.ncbi.nlm.nih.gov/) and China National Knowledge Infrastructure (CNKI, https://www.cnki.net/), as well as by a manual search. The present review discusses the association between diabetes and the IRS/PI3K/Akt pathway, the treatment of diabetes by regulating this pathway to alleviate insulin resistance, the process and mechanism of combining drugs to alleviate insulin resistance, including natural compounds, Traditional Chinese Medicine and active ingredients, and the latest modern treatment methods. In conclusion, the present review summarizes the potential role of the IRS/PI3K/Akt pathway in the treatment of diabetes through its effect on insulin resistance and elucidates the therapeutic effects of drugs targeting this pathway.

As an important clinical microvascular complication in diabetic patients, diabetic kidney disease (DKD) exhibits cardinal symptoms such as edema, proteinuria and unceasing reduction of renal function, and endoplasmic reticulum (ER) stress (ERS) profoundly affects its pathological course. ERS is triggered by an imbalance of ER homeostasis, which activates the three classical pathways of the unfolded protein response, including the PKR‑like ER kinase, inositol‑requiring enzyme 1α and activating transcription factor 6 pathways, to restore homeostasis. However, sustained ERS leads to apoptosis and inflammatory responses that accelerate kidney injury. Podocyte injury, renal tubular dysfunction and extracellular matrix deposition induced by ERS collectively drive the progression of DKD. The present review offer novel perspectives on potential clinical interventions for patients with DKD.

Liver X receptor (LXR), comprising isoforms LXRα and LXRβ, is a member of the nuclear receptor family, which serves important roles in maintaining cholesterol and lipid metabolism homeostasis by regulating cholesterol excretion and reverse transport. LXR activation also participates in regulating the pathological processes of inflammation and tumor‑related processes, such as proliferation and apoptosis. Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are two common intestinal inflammatory diseases, and the occurrence of CRC is closely associated with the development of chronic inflammation, particularly IBD. To date, the pathogenesis of IBD and CRC remains to be fully elucidated, although research is being conducted in this area. LXR has been suggested to participate in regulating the pathogenesis of both IBD and CRC. Although previous findings illustrate the benefits of LXR activation on intestinal inflammatory response and cancer, there remains a lack of comprehensive understanding of how LXR exerts its properties. The present review provided an overview of the recent advances in understanding the roles of LXR in IBD and CRC, to explore the potential therapeutic strategies and targets mediated by the dual roles of LXR in immune modulation and cholesterol metabolism, and to identify the link between IBD and CRC. The present review highlighted the novel role of LXR in bridging metabolic regulation and immune homeostasis, positioning it as a promising therapeutic target for IBD and CRC.

Osteosarcoma, a prevalent primary malignant bone tumor, primarily affects adolescents and young adults. Current treatment strategies involve a combination of surgical intervention and chemotherapy. However, the effectiveness of chemotherapy is constrained by considerable challenges, such as drug resistance and insensitivity. Ferroptosis, a form of programmed cell death that is distinct from apoptosis, presents a promising alternative target for cancer therapy. Ferroptosis is characterized by iron‑dependent lipid peroxidation, producing reactive oxygen species (ROS) and suppressing glutathione peroxidase 4 (GPX4). Notably, ferroptosis circumvents the conventional mechanisms associated with apoptosis. Inducing ferroptosis in cancer cells may help overcome drug resistance and enhance the effectiveness of existing treatments, including chemotherapy, radiotherapy and immunotherapy. Acetylshikonin is a derivative of naphthoquinone that possesses anticancer properties. However, the effects of acetylshikonin on the treatment of osteosarcoma and the mechanisms by which it induces cancer cell death remain unclear. The present study aimed to investigate the potential of acetylshikonin to induce apoptosis in osteosarcoma cells. Using cell viability assays, ROS detection, mitochondrial membrane potential analysis and ferroptosis inhibitor rescue experiments, the results demonstrated that acetylshikonin significantly reduced the viability of osteosarcoma cell lines while exhibiting low toxicity to normal cells. Mechanistically, acetylshikonin induced the production of ROS, disrupted the mitochondrial membrane potential and promoted lipid peroxidation, ultimately leading to ferroptosis. Additionally, treatment with acetylshikonin led to decreased levels of GPX4 and increased intracellular ferrous ion (Fe²+) concentrations, further supporting its role in the induction of ferroptosis. In conclusion, the current study emphasized the potential of acetylshikonin as an effective agent in inducing ferroptosis in osteosarcoma cells. Acetylshikonin reduced osteosarcoma cell viability and selectively promoted ferroptosis by increasing ROS production, disrupting mitochondrial function and enhancing lipid peroxidation. Furthermore, its ability to downregulate GPX4 and increase intracellular Fe2+ levels indicated its role in triggering ferroptosis. These findings suggest that acetylshikonin may be a valuable therapeutic candidate for the treatment of osteosarcoma, potentially improving outcomes and addressing the limitations of current therapies.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that there was a possible duplication of cell‑cycle analysis data shown in Fig. 4A on p. 4977. The authors were contacted by the Editorial Office to offer an explanation for this apparent anomaly in the presentation of the data in this paper; however, up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Molecular Medicine Reports 17: 4973‑4980, 2018; DOI: 10.3892/mmr.2018.8509].

Neuroblastoma (NB), the most common extracranial solid tumor in children, remains challenging to treat due to limited therapeutic efficacy and poor prognosis. Emerging evidence highlights the critical roles of endoplasmic reticulum (ER) stress and autophagy in cancer progression. The present study investigated the therapeutic potential of melatonin in neuroblastoma and its underlying mechanisms. Using Neuro‑2a (N2a) cells, it demonstrated that melatonin alleviated ER stress by upregulating ER chaperones glucose‑regulated protein (GRP)78 and GRP94 and the pro‑apoptotic protein CHOP, while enhancing autophagic activity. Western blotting revealed increased LC3‑II/I ratios, elevated autophagy‑related protein 5 and Beclin1 levels, and reduced p62 expression, indicating autophagy induction. Immunofluorescence and transmission electron microscopy confirmed the dose‑dependent accumulation of autophagosomes. ER stress inhibitor 4‑phenylbutyric acid attenuated melatonin‑induced autophagy, linking ER stress relief to autophagic activation. Mechanistically, melatonin upregulated p21‑activated kinase 2 (Pak2), which suppressed mTOR phosphorylation and activated unc‑51‑like kinase 1, thereby modulating the AMP‑activated protein kinase (AMPK) pathway. Pak2 overexpression amplified melatonin's ER stress‑alleviating effects, whereas Pak2 knockdown or AMPK inhibition diminished its efficacy. These findings established that melatonin suppresses neuroblastoma growth by mitigating Pak2‑mediated ER stress to induce cytotoxic autophagy. The present study provided novel insights into melatonin as a promising therapeutic agent for neuroblastoma, warranting further exploration in preclinical models and clinical trials.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that western blot data appeared to have been assembled incorrectly in Fig. 4A on p. 6709. In this case, there was an apparent inversion of the p‑PI3K bands, and inclusion of one of these bands as a unique band (upside down) for the Control experiment in the p‑Akt row of data, purportedly showing the results of a different set of experiments. The authors were contacted by the Editorial Office to offer an explanation for this apparent anomaly in the presentation of the data in this paper; however, up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [Molecular Medicine Reports 17: 6705-6710, 2018; DOI: 10.3892/mmr.2018.8678].

Myocardial ischemia/reperfusion injury (MIRI) is a challenging cardiovascular disease. Mepivacaine, a common local anesthetic, exacerbates myocardial injury during ischemia‑reperfusion (IR). Understanding the underlying mechanisms of MIRI and potential therapeutic targets is important to treat this disease. In the present study, differentially expressed genes (DEGs) from the GSE19339 dataset were identified and analyzed. The expression of calcium voltage‑gated channel auxiliary subunit β1 (CACNB1) was measured in myocardial infarction samples and the effects of different doses of mepivacaine on cell cycle progression, apoptosis, cell viability, inflammatory response and oxidative stress were evaluated in H9c2 cells. Hypoxia‑reoxygenation (H/R) treatment simulated MIRI, highlighting the role of CACNB1 in mepivacaine‑induced cellular inflammation and injury. The present study identified 2,396 upregulated and 1,230 downregulated DEGs enriched in pathways such as inflammatory response and chemokine signaling. Mepivacaine induced apoptosis, G₁ phase arrest and increased oxidative stress markers, including elevated ROS and MDA levels together with decreased SOD activity, as well as inflammatory cytokines (TNF‑α, IL‑1β and IL‑6), in a dose‑dependent manner in H9c2 cells. CACNB1 knockdown reduced mepivacaine‑ and H/R‑induced damage, inhibiting inflammation and apoptosis via the CACNB1/NOD‑like receptor protein 3 (NLRP3)/Nuclear factor erythroid 2‑related factor 2 (Nrf2) axis. Furthermore, CACNB1 knockdown enhanced Nrf2 nuclear translocation, indicating a stress response mechanism. Mepivacaine exacerbated MIRI by inducing apoptosis, G₁ phase arrest, oxidative stress and inflammation in H9c2 cells. CACNB1 knockdown reduced these effects. Targeting the CACNB1/NLRP3/Nrf2 axis may be a potential strategy for mitigating myocardial injury caused by mepivacaine and IR.

Aberrant expression of microRNAs (miRNAs) has been closely linked to the progression of rheumatoid arthritis (RA). The present study explored the potential role of miR‑369‑3p in regulating immune‑driven inflammation and bone degradation in RA through the spectrin β, non‑erythrocytic 1 (SPTBN1)/Wnt/β‑catenin signaling cascade. To test this, synthetic mimics and inhibitors of miR‑369‑3p were generated and transfected into RA fibroblast‑like synoviocytes (RA‑FLSs). A pathological model was established by co‑culturing RA‑FLSs with peripheral blood mononuclear cells (PBMCs). The influence of miR‑369‑3p overexpression or suppression on RA‑FLS behavior was assessed in terms of cell survival, cell cycle distribution, proliferation and migratory capacity. Bioinformatics predictions together with luciferase reporter assays confirmed the direct interaction between miR‑369‑3p and SPTBN1. Expression levels of inflammatory cytokines, bone metabolism markers and matrix metalloproteinases were measured by ELISA, while reverse transcription‑quantitative PCR and western blotting were employed to evaluate alterations in the miR‑369‑3p/SPTBN1/Wnt/β‑catenin pathway. The results showed that miR‑369‑3p expression was markedly reduced in the PBMC‑induced RA‑FLS model. Transfection with miR‑369‑3p mimics suppressed the viability and proliferation of RA‑FLS and decreased the expression of SPTBN1, Wnt ligands and β‑catenin mRNA. By comparison, inhibition of miR‑369‑3p produced opposite effects. ELISA findings demonstrated that the miR‑369‑3p/SPTBN1 pathway modulated critical inflammatory and bone‑related markers, which were consistently confirmed across replicate experiments. These results suggested that miR‑369‑3p regulates RA pathology by targeting the SPTBN1/Wnt/β‑catenin pathway, attenuating inflammatory responses and limiting bone destruction in RA.

Myocardial hypertrophy (MH) represents an early pathological manifestation that progresses to severe cardiovascular disease (CVD), and its reversal is important for preventing and treating heart failure. Dysregulated expression of ATP‑binding cassette subfamily C member 9 (ABCC9) has been associated with complex CVD pathogenesis, although its precise mechanistic role remains ambiguous. The present study was designed to investigate the protective effects of ABCC9 knockdown against isoproterenol (ISO)‑induced MH and elucidate its underlying molecular mechanisms. AC16 cardiomyocytes were treated with ISO to establish an MH model, in which ABCC9 protein expression was significantly elevated. Fluorescence staining of cardiomyocyte surface area and quantification of MH‑related biomarkers, including atrial natriuretic peptide, brain natriuretic peptide and β‑myosin heavy chain, demonstrated that ABCC9 knockdown effectively attenuated MH and improved cardiac function. Furthermore, western blot analysis and flow cytometry revealed that ABCC9 knockdown not only decreased cardiomyocyte apoptosis but also reduced oxidative stress, as indicated by lower reactive oxygen species levels. Mechanistically, western blotting and mitochondrial membrane potential assays showed that ABCC9 knockdown inhibited the phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway and improved mitochondrial function. Notably, these protective effects were diminished by treatment with the PI3K/AKT activator 740Y‑P. These findings collectively suggest that ABCC9 knockdown protects against MH by inhibiting the PI3K/AKT signaling pathway, thereby alleviating mitochondrial dysfunction and reducing apoptosis and oxidative stress, positioning ABCC9 as a potential therapeutic target for MH treatment.