JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

Acute myeloid leukaemia (AML) is a genetically heterogeneous malignancy associated with poor prognosis and limited treatment options. To identify molecular programs conserved across AML subtypes and perturbations, we analysed three RNA sequencing datasets that captured venetoclax treatment under metabolic stress and the knockdown of chromatin regulators (PSPC1, JMJD1C, and RUNX1). Differential expression analysis was performed using DESeq2, followed by functional enrichment and network analyses. An independent AML cell line dataset was used to validate results. We identified a conserved 73-gene transcriptional signature that is consistently dysregulated across perturbations, characterised by the overexpression of CDKN1A, PHGDH, and ALDH1L2, and the downregulation of MYC and E2F targets. Functional analyses implicated cell cycle arrest, metabolic reprogramming, oxidative stress responses, and suppression of proliferative and biosynthetic pathways. PSPC1 emerged as a central hub linking chromatin remodelling to metabolic adaptation. Translational validation in the TCGA-LAML cohort revealed that higher 73-gene enrichment scores were associated with inferior overall survival, and stratification by hub gene expression recapitulated adverse prognostic trends. Collectively, these findings define a stress-adaptive transcriptional program conserved across diverse AML perturbations, providing mechanistic insights into the coupling of metabolism and the cell cycle, and potential therapeutic vulnerabilities. Incorporation of this 73-gene program into patient stratification frameworks may guide biomarker-driven therapies and combination strategies targeting metabolic and apoptotic stress responses.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. In this study, we investigated the neuroprotective and anti-inflammatory potential of Aesculus hippocastanum (horse chestnut extract, HCE) in an in vitro model of PD. Human neuroblastoma SH-SY5Y cells were treated with the neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺) (1 mM) and/or in combination with HCE at the concentrations of 15.6, 31.2 and 62.5 μg/mL for 24 h. After 24 h, several analyses have been performed. Treatment with HCE at the concentrations of 31.2 and 62.5 μg/mL significantly improved cell viability following MPP⁺-induced neurotoxicity. Furthermore, HCE effectively modulated key Parkinsonian markers by restoring tyrosine hydroxylase (TH) and reducing the number of α-syn-positive cells. At the same concentrations, HCE also attenuated NF-κB signalling pathway activation and diminished the release of pro-inflammatory cytokines IL-1β, IL-17, and TNF-α. Notably, HCE promoted the activation of the nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ), known for its neuroprotective properties, and reduced both oxidative and nitrosative stress. Crucially, silencing of PPARγ abolished the beneficial effects of HCE, indicating that its neuroprotective actions are mediated specifically through PPARγ activation. Thus, these findings suggest that HCE confers neuroprotection in vitro by regulating inflammation and oxidative stress primarily via PPARγ modulation.

Familial hypercholesterolemia (FH) is a genetic disorder characterised by elevated plasma LDL-cholesterol, predisposing to premature atherosclerotic cardiovascular disease. Most cases follow an autosomal dominant pattern (ADH) caused by pathogenic variants in LDLR, APOB or PCSK9. In contrast, the rare autosomal recessive form (ARH) results from biallelic mutations in LDLRAP1, leading to defective LDL receptor-mediated endocytosis. Despite the high rate of consanguinity in Tunisia, LDLRAP1 variants have not yet been reported in this population. In this study, Whole Exome Sequencing of two consanguineous Tunisian families, identified distinct pathogenic variants. In the first family (FH-A), a recurrent LDLR splice-site variant (c.1845+1G>A) was detected in both heterozygous and homozygous states, consistent with an autosomal dominant inheritance pattern. In the second family (FH-B), a novel homozygous LDLRAP1 missense variant (c.161G>A; p.Gly54Asp) was identified, confirming autosomal recessive inheritance. In silico analyses using MutationTaster, DynaMut2, MUpro, DDGun, NetSurfP-2.0, ConSurf and PyMOL predicted that the p.Gly54Asp substitution destabilises the PTB domain of LDLRAP1 by disrupting key hydrogen bonds and hydrophobic interactions, thereby likely impairing LDLR internalisation. According to ACMG guidelines, this variant is classified as likely pathogenic. Clinically, ARH patients exhibited early-onset xanthomas and an unusual quadricuspid aortic valve (QAV). Targeted analysis of valvulogenesis genes (NOTCH1, GATA4, NKX2-5, TBX5, AGTR1, BMP2) revealed no co-segregating pathogenic variants, suggesting that QAV may result from embryonic LDL accumulation disrupting Notch1 signalling rather than a monogenic defect. Comparison with other ADH Tunisian families carrying the same LDLR mutation showed phenotypic variability, likely influenced by genetic modifiers, treatment response and environmental factors. These findings provide the first evidence of LDLRAP1-associated ARH in Tunisia and highlight the genetic heterogeneity of FH, emphasising the importance of integrating molecular, structural and functional analyses for accurate diagnosis, personalised management and early prevention.

Losartan, a widely prescribed antihypertensive agent, has attracted growing interest as a potential adjuvant in cancer therapy due to its affordability, established safety profile and pleiotropic effects. Emerging preclinical evidence demonstrates that losartan can effectively modulate the tumour microenvironment (TME) by inhibiting transforming growth factor-β (TGF-β) signalling, reducing stromal stiffness and improving vascular perfusion. These changes are shown to enhance the delivery and efficacy of chemotherapeutic agents, an effect potentially amplified when combined with nanocarriers by augmenting the enhanced permeability and retention effect. Beyond TME remodelling, losartan has demonstrated anti-tumour activity across various preclinical models, including those of pancreatic, breast and colorectal cancers. Mechanistically, angiotensin II type 1 receptor (AT1R) blockade is reported to modulate key downstream oncogenic pathways, including PI3K/AKT and YAP/TAZ, and to promote vascular normalisation via mechanisms that may include VEGF downregulation, thereby alleviating hypoxia and improving radiotherapy response. Furthermore, evidence suggests losartan remodels the tumour immune landscape by promoting CD8⁺ T and natural killer (NK) cell infiltration, reprogramming tumour-associated macrophages (TAMs) and suppressing immunosuppressive cytokines. It also appears to inhibit epithelial-mesenchymal transition (EMT) and metastasis-related pathways, including CXCR4/SDF-1α and matrix metalloproteinases (MMPs). These multifaceted mechanisms highlight its potential as a therapeutic adjuvant capable of overcoming stromal barriers, mitigating immune evasion and limiting metastatic dissemination. However, the translation of these compelling preclinical findings into clinical practice remains a major challenge. The promising preclinical data are tempered by variable efficacy across cancer types, a nascent clinical evidence base and unresolved questions regarding optimal patient selection and dosing. Clinical validation is still nascent, predominantly limited to early-phase trials and critical parameters such as optimal dosing, treatment sequencing and long-term safety in oncology patients await rigorous definition. This review synthesises the current mechanistic and translational research on losartan in solid tumours, aiming to clarify its anti-cancer properties, explore its synergy with nano- and immune-therapeutics, critically assess the associated challenges and identify key gaps and future directions for clinical application.

Trial Registration: ClinicalTrials.gov identifier: NCT01821729 and NCT03563248

Platinum-based chemotherapy remains a cornerstone of glioma treatment, yet resistance driven by the Fanconi anaemia (FA) DNA repair pathway limits efficacy. Here, we identified betulinic acid (BA) as a potent inhibitor of FA pathway activation. BA pretreatment abrogated cisplatin-induced monoubiquitination of FANCI/FANCD2 and disrupted their nuclear foci formation and interactions with downstream repair proteins (ERCC1, REV1 and BRCA1), leading to persistent DNA interstrand crosslinks without affecting intrastrand lesion repair. Biochemical analyses revealed that BA selectively suppressed UBE2T expression at the transcriptional level, without altering mRNA stability or protein degradation, thereby blocking the FANCL-UBE2T-mediated ID2 monoubiquitination cascade. In vivo, BA significantly enhanced the antitumour efficacy of cisplatin in xenograft models. Mechanistically, BA inhibited MAPK/ERK signalling, and pharmacological reactivation of ERK reversed BA-induced suppression of UBE2T and tumour growth. Collectively, these findings uncover a previously unrecognised MAPK/ERK-UBE2T-FA axis in glioma and highlight BA as a potential adjuvant to overcome cisplatin resistance through transcriptional repression of UBE2T.

Aortic dissection is a life-threatening cardiovascular emergency with limited pharmacological options. This study focuses on elucidating the multi-target and multi-pathway mechanisms through which morusin mitigates aortic dissection progression, integrating network pharmacology, single-cell transcriptomics and experimental validation. Multi-database analysis identified 281 morusin targets and 1741 ad-related genes, with 84 overlaps. Enrichment analyses highlighted IL-17, HIF-1 and MAPK signalling pathways as potential regulatory hubs. Protein–protein interaction network analysis identified seven key targets, all showing high binding affinity to morusin in molecular docking. Single-cell transcriptomics revealed cell-type-specific dysregulation, notably MAPK8 upregulation in fibroblasts and immune cells. In vitro, morusin dose-dependently inhibited AngII-induced vascular smooth muscle cell proliferation and modulated IL-17 pathway gene expression. In vivo, morusin attenuated aortic dilation and reduced morbidity and mortality in a BAPN-induced AD mouse model. These findings suggest that morusin mitigates AD progression by targeting key inflammatory and apoptotic pathways, supporting its potential as a multi-target therapeutic candidate.

This study assessed the anticancer activity of boron-containing and structurally diverse small molecules in 4T1 breast cancer and Caco-2 colon adenocarcinoma cells. Initial screening showed that five boronic acids lacked significant cytotoxicity, underscoring the structural specificity required for boron-mediated bioactivity. Similarly, reference compounds, including fumaric acid, caffeic acid, ferulic acid, dimethyl malonate and N-(tert-butoxycarbonyl)-L-alanine, showed no cytotoxic effect under identical conditions. Among the tested agents, 1-acetyl-4-(4-hydroxyphenyl)piperazine (1A4HP) displayed the most potent cytotoxicity, with IC₅₀ values of 149.7 μM in 4T1 and 825 μM in Caco-2 cells. For comparison, the clinically investigated antimetastatic agent tasquinimod showed moderate activity in 4T1 cells (IC₅₀ = 180.7 μM), serving as a pharmacological benchmark. Mechanistic assays revealed that 1A4HP induced apoptosis and significantly impaired 4T1 cell migration, suggesting combined antiproliferative and antimetastatic effects. Computational analyses further supported 1A4HP's drug-like potential by predicting favourable physicochemical properties, including balanced lipophilicity and high solubility. Molecular docking studies indicated a strong binding affinity to oestrogen receptor alpha (ERα), surpassing that of tamoxifen. Notably, despite 4T1's ER-negative status, 1A4HP suppressed cell growth, suggesting possible ER-independent or off-target mechanisms, similar to tamoxifen's secondary effects. Collectively, these results identify 1A4HP as a promising lead compound for further exploration in breast cancers.

Knee osteoarthritis (KOA), a common degenerative joint disease marked by pain, inflammation and cartilage degradation, has been increasingly associated with dysregulated innate immune signalling. Among the implicated molecular pathways, cGAS/STING has emerged as a key modulator in both disease pathogenesis and therapeutic intervention. Quercetin, a naturally derived bioflavonoid with well-documented antitumour and antioxidant activities, also exerts notable anti-inflammatory and analgesic effects. This study investigated the mechanistic interaction between quercetin and the cGAS/STING pathway in the context of pain regulation throughout KOA development. Forty-eight male C57BL/6J mice were randomly allocated into six groups: Sham, KOA, high-dose quercetin (Que-H), low-dose quercetin (Que-L), STING inhibitor (H-151) and STING activator (SR-717). Histological evaluations of entire knee joints were performed using haematoxylin and eosin (H&E) and Safranin O/Fast Green (SO&FG) staining protocols. Serum concentrations of interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) were measured via ELISA. The viability of dorsal root ganglion (DRG) neurons subjected to PGE2 and quercetin was determined through the CCK-8 assay. Expression levels of inflammatory and nociceptive markers were assessed using Western blotting, quantitative PCR, immunofluorescence and immunohistochemistry across both in vivo and in vitro models. Quercetin administration led to a statistically significant reduction in peripheral inflammatory and nociceptive markers (p < 0.05), diminished pain hypersensitivity and preserved cartilage morphology in KOA mice. These outcomes correlated with the inhibition of cGAS/STING signalling and a concomitant decrease in VEGFA, VEGFR1 and phosphorylated VEGFR1 levels (p < 0.05). By inhibiting the cGAS/STING signalling pathway, quercetin mitigates KOA-related nociception through the downregulation of VEGFA, VEGFR1 and its phosphorylated form.

RETRACTION: S.-H. Dai, Q.-C. Wu, R.-R. Zhu, X.-M. Wan and X.-L. Zhou, “ Notch1 Protects Against Myocardial Ischaemia-Reperfusion Injury via Regulating Mitochondrial Fusion and Function,” Journal of Cellular and Molecular Medicine 24, no. 5 (2020): 3183–3191, https://doi.org/10.1111/jcmm.14992.

The above article, published online on 23 January 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Stefan N. Constantinescu; the Foundation for Cellular and Molecular Medicine; and John Wiley & Sons Ltd. The retraction has been agreed upon following concerns raised by a third party. An investigation determined that Figures 4C, 4D, and elements of Figure 6B, duplicate figures previously published in other articles by a different author group. Due to errors in image management leading to unreliable data, the authors have voluntarily requested retraction. The editors consider the results and conclusions compromised.

During intervertebral disc degeneration (IDD), cartilage endplate (CEP) cells undergo calcification and ossification, relying primarily on glycolysis for energy metabolism. Leptin (LEP) initiates the IDD, while its underlying mechanism related to glycolysis remains elusive in CEP cells. To investigate the underlying mechanism of LEP on IDD, an IDD rat model was established and LEP-added CEP cells were adopted, with a glycolysis inhibitor (2-DG) and sh-HIF-1α. A rat IDD model was successfully established, with the model group exhibiting endplate calcification, ossification, and increased LEP levels. In vitro experiments confirmed that LEP dose-dependently promotes calcification and ossification in CEP cells. LEP also upregulated calcification-related indicators (BMP-2, Sox9) and osteogenesis-related genes (OCN, Runx2), inducing the formation of calcified nodules and increased ALP activity. Mechanistic studies revealed that glycolysis-related proteins and lactic acid content in both IDD rat and LEP-added CEP cells were elevated. This process could be reversed using the glycolysis inhibitor 2-DG. Further experiments demonstrated that LEP promoted glycolysis by upregulating the OCN/HIF-1α axis; knockdown of either OCN or HIF-1α blocked LEP-induced calcification and ossification. LEP is elevated in IDD, and LEP accelerates the calcification and ossification through stimulating glycolysis by the OCN/HIF-1α axis.