Journal of Molecular Histology最新文献

Cervical cancer remains a major cause of mortality worldwide, highlighting the need for alternative therapeutic strategies. Lycopene, a dietary carotenoid with known antioxidant properties, has demonstrated anticancer activity in several malignancies; however, its mechanistic effects in cervical cancer remain poorly understood. We hypothesize that lycopene inhibits the growth of cervical cancer cell lines and certain cancer-related processes. Therefore, we performed an in vitro study to investigate lycopene's effects on proliferation, viability, migration, and apoptosis in three cervical cancer cell lines (HeLa, SiHa, and ViBo) using lycopene concentrations ranging from 1.25 to 40 µM, and further evaluated the underlying mechanisms using 2.5 and 40 µM lycopene, and evaluated its effects on non-malignant cardiomyoblasts (H9c2). Lycopene significantly reduced proliferation and cell viability and impaired migration in all cancer cell lines. Flow cytometry revealed increased apoptosis, associated with time-dependent modulation of the Bax/Bcl-2 ratio and caspase-3 activation. Mechanistically, lycopene decreased Akt phosphorylation without affecting total Akt or PI3K levels, indicating the participation of the PI3K/Akt survival pathway. Importantly, pharmacological PI3K inhibition with wortmannin supported this pathway's involvement in mediating lycopene-induced effects. Notably, lycopene at lower concentrations showed minimal cytotoxicity in H9c2 cells, suggesting some selectivity toward cancer cells. Together, these findings show that lycopene decreases proliferation and viability, promotes apoptosis, and suppresses migration in cervical cancer cells; these effects were associated with PI3K/Akt signaling, indicating that this pathway may contribute to its anticancer effects and highlighting lycopene's potential as a therapeutic candidate.

Graphical abstract

Rheumatoid arthritis (RA) is characterized by persistent synovial inflammation and progressive joint destruction, while ferroptosis has emerged as a potential contributor to inflammatory tissue injury. This study investigated whether angiotensin-(1–7) [Ang-(1–7)] attenuates arthritis by regulating ferroptosis and explored the involvement of p53/solute carrier family 7 member 11 (SLC7A11) signaling. Bioinformatic analysis of the GSE55235 dataset was performed to identify ferroptosis-related differentially expressed genes in RA. A collagen-induced arthritis (CIA) mouse model and erastin-treated THP-1-derived macrophages were used to evaluate the effects of Ang-(1–7) in vivo and in vitro. Ferroptosis-related genes in RA were enriched in inflammatory responses, oxidative stress, ferroptosis, and p53 signaling. In CIA mice, Ang-(1–7) reduced paw swelling and arthritis scores, ameliorated synovial inflammation and joint damage, and attenuated iron deposition, lipid peroxidation, and ferroptosis-related molecular alterations. Double-immunofluorescence staining further demonstrated decreased glutathione peroxidase 4 (GPX4) and increased acyl-CoA synthetase long-chain family member 4 (ACSL4) expression in F4/80-positive macrophage areas in CIA joints, both of which were reversed by Ang-(1–7). In erastin-treated THP-1-derived macrophages, Ang-(1–7) improved cell viability, restored glutathione levels, reduced malondialdehyde, reactive oxygen species, lipid reactive oxygen species, and Fe²⁺ accumulation, alleviated mitochondrial injury, and reversed ferroptosis-related molecular abnormalities. Nutlin-3 A-mediated p53 stabilization partially weakened these protective effects, whereas TP53 knockdown diminished the additional protective response to Ang-(1–7). These findings suggest that Ang-(1–7) attenuates ferroptosis-related joint injury in CIA mice and suppresses erastin-induced ferroptosis in THP-1-derived macrophages, with these effects being partially associated with modulation of p53/SLC7A11 signaling.

Atherosclerosis (AS) is a chronic inflammatory vascular disease in which macrophage polarization plays a pivotal role in plaque progression and stability. Aloin, a major anthraquinone compound isolated from Aloe vera, possesses potent anti-inflammatory activities; however, its therapeutic potential and underlying mechanisms in AS remain insufficiently understood. In the present study, a network pharmacology approach combined with molecular docking, cellular experiments, and animal validation was employed to investigate the protective effects of aloin against AS and elucidate its molecular mechanism. Common targets shared by aloin, macrophage polarization, and AS were identified, followed by protein–protein interaction network construction and GO/KEGG enrichment analyses. Molecular docking demonstrated strong binding affinities of aloin toward key inflammatory targets, particularly NF-κB and STAT3. Experimental validation showed that aloin significantly suppressed nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophages and inhibited M1 macrophage polarization while promoting the M2 phenotype, as evidenced by decreased expression of iNOS and TNF-α and increased expression of Arg-1 and IL-10. In ApoE-/- mice fed a high-fat diet, aloin markedly reduced aortic plaque formation and alleviated vascular pathological injury. Mechanistically, both in vitro and in vivo analyses revealed that aloin significantly attenuated the phosphorylation of NF-κB and STAT3, thereby blocking activation of the NF-κB/STAT3 signaling pathway. Collectively, these findings suggest that aloin may contribute to the amelioration of atherosclerotic lesions by modulating macrophage polarization balance through inhibition of NF-κB/STAT3 signaling, highlighting its potential as a candidate worthy of further investigation for the prevention and treatment of atherosclerosis.

Cervical cancer is a common malignant tumor of the female reproductive system, and patients with advanced and metastatic diseases have poor prognosis. It is urgent to explore novel molecular targets and regulatory mechanisms. As a core circadian rhythm factor, BMAL1 exerts tumor-suppressive or oncogenic effects in various malignancies, while its biological functions, downstream pathways and molecular mechanisms in cervical cancer remain largely unclear. In this study, human cervical cancer cell lines SiHa and HeLa, as well as nude mouse subcutaneous xenograft models were used as research systems. A series of experiments including transcriptome sequencing, protein interaction assay, ubiquitination detection, cellular functional experiments and in vivo animal assays were performed. The results demonstrated that BMAL1 knockdown markedly inhibited the proliferation, colony formation, invasion and migration of cervical cancer cells, and induced G1-phase cell cycle arrest. Transcriptome sequencing and KEGG pathway enrichment analysis identified the ERK signaling pathway as the major downstream pathway of BMAL1, and BMAL1 positively regulated the phosphorylation of key molecules in the ERK pathway. Mechanistically, BMAL1 specifically bound to FAM43B via its transactivation domain (TAD), promoted K63-linked ubiquitination of FAM43B, enhanced the protein stability of FAM43B. As a downstream effector, FAM43B unidirectionally activated the ERK signaling pathway, and no reverse regulatory loop existed between the two proteins. Silencing FAM43B significantly reversed the malignant phenotypes of cervical cancer cells. In vivo xenograft experiments further verified that BMAL1 knockdown suppressed tumor growth, reduced tumor proliferative activity. In summary, BMAL1 regulates the ERK signaling pathway by modulating the ubiquitination of FAM43B, thereby promoting the progression of cervical cancer. This study reveals a novel BMAL1/FAM43B/ERK regulatory axis and its underlying mechanism, providing potential molecular targets and experimental evidence for prognostic evaluation and targeted therapy of cervical cancer.

Vascular calcification (VC) is a common and severe complication in hemodialysis patients, increasing the risk of major adverse cardiovascular events (MACE). This study aimed to explore the clinical value of miR-671-3p in hemodialysis patients and its regulatory role in VC. A total of 163 end-stage renal disease (ESRD) patients undergoing hemodialysis were enrolled, including 107 with VC and 56 without VC. Clinical data were used to evaluate the role of miR-671-3p in the diagnosis (ROC) and risk prediction (logistic regression) of VC and MACE. A high-phosphorus-induced human aortic smooth muscle cells (hASMCs) calcification model was established, and then cell viability (CCK-8), apoptosis rate (flow cytometry), calcium content, alkaline phosphatase (ALP) activity, and the levels of Runx2 and α-SMA were measured. Bioinformatics analysis and a dual-luciferase assay were employed to predict and validate the downstream target genes of miR-671-3p. miR-671-3p was downregulated in VC patients and showed high diagnostic value for VC. Its levels showed significant correlations with disease severity and could effectively predict the risk of MACE in VC patients. Overexpression of miR-671-3p markedly alleviated calcification-induced decreases in cell viability, increases in apoptosis and calcium content, upregulation of ALP and Runx2, and downregulation of α-SMA; however, this protective effect was reversed by overexpression of its downstream target FBXW2. miR-671-3p may serve as a promising candidate biomarker for diagnosing VC and predicting MACE in VC patients. miR-671-3p may attenuate the progression of VC by inhibiting calcification in hASMCs.

Intrahepatic cholangiocarcinoma (ICC) is characterized by high postoperative recurrence and limited benefit from conventional adjuvant therapy. Qinghao Biejia Decoction (QHBJD), a classical traditional Chinese medicine formula, has demonstrated potential anticancer effects. This study investigated the molecular mechanisms of QHBJD in ICC and evaluated its impact on postoperative survival, with a focus on AKT1 expression. In this retrospective study of 60 patients with intrahepatic cholangiocarcinoma (ICC), network pharmacology and bioinformatics analyses were used to identify candidate targets of QHBJD. AKT1 expression was validated by immunohistochemistry in tissue microarrays, and associations between AKT1 expression, treatment strategies, and survival outcomes were assessed using Kaplan–Meier and Cox regression analyses. AKT1 was identified as a key target of QHBJD. In ICC tissues, AKT1 showed predominant nuclear localization, and high nuclear expression was associated with significantly shorter overall survival (OS) (18.4 vs. 25.1 months, p = 0.046). Postoperative adjuvant therapy alone did not significantly improve survival. In contrast, QHBJD-based integrative therapy significantly prolonged OS compared with no treatment (28.8 vs. 14.2 months, p = 0.041) and conventional therapy alone (28.8 vs. 11.2 months, p = 0.001). Among patients with high nuclear AKT1 expression, QHBJD significantly improved both disease-free survival (DFS) (5.95 vs. 2.0 months, p = 0.001) and OS (23.9 vs. 8.0 months, p < 0.001). Multivariate analysis confirmed QHBJD-based therapy as an independent protective factor for OS (HR 0.47, p < 0.05). QHBJD-based integrative therapy significantly improves survival in ICC, particularly in patients with high nuclear AKT1 expression, highlighting AKT1 as a potential therapeutic target and candidate prognostic biomarker that warrants further validation.

Graphical abstract

Schematic illustration of the therapeutic mechanism of QHBJD in ICC based on TCM theory. The figure depicts the pathogenesis of ICC as “toxic accumulation and Qi deficiency” and illustrates how QHBJD regulates liver–kidney balance, reduces toxic accumulation, and improves systemic homeostasis. (QHBJD; Qinghao Biejia Decoction, ICC; intrahepatic cholangiocarcinoma, TCM; Traditional Chinese Medicine)

This study investigated whether Retatrutide, a triple incretin agonist, attenuates early diabetes-associated renal injury in a streptozotocin-induced rat model, and whether any protective effect is mediated through modulation of inflammatory cytokines (IL-1β, TNF-α) and HIF-1α gene expression in kidney tissue. Male Sprague-Dawley rats were divided into four groups: control, STZ-induced diabetic, STZ plus Retatrutide, and Retatrutide alone. Diabetes was induced via a single intraperitoneal STZ injection; Retatrutide was administered subcutaneously for 21 days at a dose adapted from prior metabolic studies. Renal tissue underwent ELISA for interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), quantitative real-time PCR for HIF-1α expression, and semi-quantitative histopathological scoring of cortical and medullary parameters including haemorrhage, tubular dilatation, inflammatory cell infiltration, tubular vacuolisation, interstitial fibrosis, and intraluminal debris. STZ-induced rats exhibited significantly elevated cortical and medullary histopathological scores and increased renal IL-1β levels relative to controls, confirming successful early injury induction. Retatrutide did not produce statistically significant histopathological protection, although STZ plus Retatrutide animals showed consistently lower damage scores than STZ-only animals, corresponding to large standardised effects (Cliff’s δ = 0.90 in the cortex and 0.85 in the medulla) that could not be confirmed under family-wise error correction. HIF-1α expression was highest in the untreated diabetic group and was significantly lower in Retatrutide-treated diabetic animals (S vs. SR, p = 0.020), whereas Retatrutide alone did not alter expression relative to controls. TNF-α did not differ significantly in any pairwise comparison; levels in Retatrutide-treated diabetic animals were nonetheless comparable to controls (g* = 0.03). Retatrutide selectively modulated HIF-1α transcriptional levels in the acute STZ model without statistically confirmed histopathological renoprotection, and without evidence of intrinsic renal toxicity. Because the acute STZ model reflects insulin-deficient rather than T2DM-like disease, the model itself is a critical limitation; chronic type 2 diabetes models, together with longer treatment durations and refined dosing regimens, are required to determine whether the observed early molecular effects translate into structural renal benefit.

Sepsis, a systemic inflammatory response disorder triggered by infection, often leads to multiple organ dysfunction syndrome. Sepsis-induced acute lung injury (SI-ALI) is among the most common complications. Heparin-binding protein (HBP), a major inflammatory mediator, has been demonstrated to induce vascular permeability and inflammation. Nevertheless, the mechanism by which HBP functions in sepsis-induced lung injury remains unclear. This study aimed to explore the role of HBP in sepsis-induced lung injury. A sepsis mouse model was established via cecal ligation and puncture (CLP), followed by HBP blockade using heparin. Serum inflammatory cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). Neutrophil infiltration was assessed by myeloperoxidase (MPO) activity. Lung tissue pathology was evaluated using hematoxylin-eosin (H&E) and Masson staining. Levels of ferrous iron (Fe²⁺), malondialdehyde (MDA), glutathione (GSH), and glutathione peroxidase 4 (GPX4) in lung tissue lysates were quantified using commercial assay kits. Acyl-CoA synthetase long-chain family member 4 (ACSL4) expression was examined by immunohistochemistry. Reactive oxygen species (ROS) levels in lung tissues were measured using dihydroethidium (DHE) fluorescence probes. Western blot was performed to analyze the protein kinase R-like endoplasmic reticulum kinase-nuclear factor erythroid 2-related factor 2-heme oxygenase-1 (PERK-Nrf2-HO-1) signaling pathway. Additionally, an in vitro sepsis cell model was established by treating murine lung epithelial (MLE-12) cells with lipopolysaccharide (LPS) to further validate HBP’s role. HBP expression was significantly upregulated in the lung tissues of CLP mice. Pharmacological blockade of HBP reduced serum inflammatory cytokine levels, alleviated neutrophil infiltration and lung pathological injury, and attenuated ferroptosis-related alterations in septic lung tissues. HBP blockade was associated with enhanced activation of the PERK-Nrf2-HO-1 signaling pathway. Knockdown of PERK, Nrf2 or HO-1 partially abrogated the protective effects of HBP blockade against SI-ALI and ferroptosis phenotypes. Furthermore, in vitro experiments showed that HO-1 overexpression attenuated the exacerbating effect of HBP on LPS-induced ferroptosis in MLE-12 cells. The findings suggest that HBP may contribute to the progression of sepsis-induced lung injury, at least in part, by promoting ferroptosis through inhibiting the activation of the PERK-Nrf2-HO-1 signaling pathway.

Hypercholesterolemia (HCT) is a major risk factor for cardiovascular diseases and promotes myocardial and vascular injury primarily through oxidative stress (OS)-mediated mechanisms. Ebselen (EBS), a glutathione peroxidase-mimetic antioxidant, has been associated with attenuation of tissue injury in several experimental OS-related models; however, its short-term effects on selected outcomes in HCT-associated cardiovascular damage remain unclear. Twenty-four male Wistar albino rats were randomly assigned to three groups: Control, cholesterol/cholic-acid diet (HCT), and the same diet treated with EBS (HCT+EBS). Rats in the HCT-designated groups received a diet containing 2% cholesterol and 0.5% cholic acid for six weeks; serum lipids were not measured. EBS (10 mg/kg/day, intraperitoneal) was administered during the final week. Hemodynamic and electrocardiographic parameters, serum injury biomarkers, myocardial oxidative-stress parameters, and cardiac and descending-aortic histopathology were assessed. Relative to Control, the cholesterol/cholic-acid diet group designated HCT showed higher myocardial lipid peroxidation, lower superoxide dismutase (SOD) activity, higher serum myoglobin and lactate dehydrogenase, and more severe cardiac and aortic histopathological alterations. Compared directly with HCT, HCT+EBS showed lower myocardial malondialdehyde, higher SOD activity, lower injury biomarkers, and less severe histopathological alterations. Because serum lipids were not measured, these differences cannot be separated from a possible EBS-associated difference in lipid profile. EBS administration also induced a marked hypotensive response: systolic blood pressure was significantly lower in HCT+EBS than in both HCT and Control. Short-term EBS administration was associated with selected biochemical and histopathological differences in rats exposed to a cholesterol/cholic-acid diet. However, the lipid phenotype was not confirmed, and a possible EBS-associated difference in serum lipids cannot be excluded. Together with the absence of an EBS-only control group, this prevents attribution of the findings specifically to direct antioxidant actions of EBS or interpretation as therapeutic efficacy.