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This review presents evidence that the C-X-C motif chemokine receptor 3 (CXCR3) axis and its ligands, CXCL9, CXCL10, and CXCL11, serve as crucial coordinators of immune responses in viral hemorrhagic fever diseases. We delineated the biology of CXCR3 and its expression in Th1, Th17.1, T follicular helper, regulatory T, cytotoxic CD8 T, and natural killer cells. Additionally, we summarized the role of interferon-mediated gradients of CXCL9, CXCL10, and CXCL11 in the recruitment and programming of these effector cells within inflamed tissues. Research involving both human and animal subjects has consistently associated elevated CXCL9/10/11 signaling with disease activity, endothelial dysfunction, and clinical outcomes. Experimental models have further elucidated that these signals can exert both protective and detrimental effects depending on factors such as timing, tissue compartment, and cell type. Proof-of-concept interventions demonstrate the greatest efficacy in dengue disease models, where modulation of this pathway results in reduced viral replication, restoration of type I interferon functions, improvement in hematologic parameters, and limitation of vascular leakage. In various hemorrhagic fevers, convergent transcriptomic and proteomic signatures identify the pathway as a viable target and source of dynamic biomarkers for risk stratification and response monitoring. Collectively, the CXCR3 axis emerged as a unifying mechanism and is a promising intervention for controlling viral hemorrhagic fever.
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The novel coronavirus disease 2019 (COVID-19) pandemic took the world by storm. Saudi Arabia (SA) made significant efforts to limit the impact of the pandemic. As COVID-19 is no longer a pandemic, it is necessary to reflect on the lessons, challenges, and missed opportunities from the Saudi experience with COVID-19. SA implemented extensive measures to mitigate the pandemic's impact. This study analyzed the measures taken on three major fronts: public health, scientific research, and clinical practice. This reflection is structured around three key fronts: public health, scientific research, and clinical practice. It was found that SA adopted progressive public measures that succeeded in curbing the number of cases, along with mass testing and vaccination programs, further facilitated by technology. Nevertheless, vaccine hesitancy and ineffective educational campaigns hindered such efforts. While SA rapidly allocated research funds, the lack of strategic direction limited the applicability of the research outputs. The clinical management of COVID-19 in SA was evidence-based; however, the North American and European guidelines heavily influenced it and did not benefit from the local academic studies, nor were national clinical trials conducted to inform its clinical practice. These lessons, challenges, and missed opportunities should be carefully considered by healthcare policymakers in order to advance Saudi preparedness for future outbreaks.
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The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) represents a continuously evolving pathological process in which renal interstitial fibrosis serves as the central nexus. This review synthesizes current evidence and delineates the major pathogenic axes that drive fibrosis, including amplification of the NOD-like receptor family pyrin domain containing 3 (NLRP3)–Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB)/Signal Transducer and Activator of Transcription 3 (STAT3) inflammatory cascade, sustained activation of the renin–angiotensin system (RAS), maladaptive tubular epithelial repair with G2/M cell-cycle arrest, endothelial injury and microvascular rarefaction leading to hypoxia-inducible factor (HIF) signaling, mitochondrial dysfunction with impaired autophagy, cellular senescence with a senescence-associated secretory phenotype (SASP), multiple programmed cell-death pathways, and epigenetic alterations involving DNA methylation, histone modifications, and miR-21/29/200 networks. A key innovative finding of this review is the identification of temporally defined intervention windows in the AKI–CKD continuum. Early intervention targets inflammation and oxidative stress suppression; the intermediate phase focuses on transforming growth factor-β (TGF-β) and RAS-mediated fibrogenesis, while promoting adaptive repair; the late phase aims to restore tissue homeostasis through anti-senescence and regenerative strategies. This approach shifts from generalized treatment strategies to personalized, stage-specific therapies in renal fibrosis. Representative interventions—including ACE inhibitor (ACEI)/angiotensin receptor blocker (ARB) therapy, Roxadustat, mesenchymal stem cells and extracellular vesicles, and senolytic regimens—are discussed with regard to their mechanisms and optimal timing. Barriers to clinical translation, such as patient heterogeneity, lack of reliable biomarkers for early fibrosis detection, and discrepancies between preclinical models and clinical endpoints, are also highlighted. The integration of predictive modeling, multi-omics, and spatial transcriptomics is essential for refining individualized intervention windows, advancing precision strategies to prevent or attenuate AKI–CKD progression.
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Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT) frequently require red blood cell (RBC) transfusions. Immunomodulation by RBC transfusion is of great interest in the context of alloHSCT, as donor immune cells mediate tumor control, fight pathogens, but also cause graft-versus-host disease (GvHD), a potentially lethal complication of alloHSCT. Data linking RBC transfusion burden with relevant clinical outcome parameters after alloHSCT are scarce.
Methods: In this retrospective study, we examined the association between RBC transfusion burden and clinical outcomes in a cohort of 116 patients who underwent alloHSCT at a single transplant center. Therefore, we analyzed the impact of RBC transfusion burden on the following relevant outcomes after alloHSCT: overall survival, leukocyte engraftment, GvHD incidence, and infection rate.
Results: Reduced transfusion frequencies, both before (p = 0.003) and after (p = 0.002) alloHSCT, are associated with favorable survival rates 100 days after transplantation. In line, those patients showed an earlier leukocyte engraftment (p < 0.001). However, no significant association was found between the transfusion rate and the incidence of grade II–IV acute GvHD (aGvHD) (p = 0.87). Notably, it was not the frequency of pre-transplant RBC transfusions (p = 0.05), but rather an increased post-transplant transfusion rate (p < 0.001), that was significantly associated with a lower infection rate, particularly with infections within the first 21 days following alloHSCT (p < 0.001 for post-transplant transfusions).
Conclusion: In summary, our data support recent evidence that high RBC transfusion burden is associated with poor survival. GvHD incidence was not linked to RBC transfusion, but we were able to detect a negative association with infectious complications. Larger, multi-center trials are needed to confirm our findings, accompanied by molecular analysis of RBC–immune cell interactions.
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Background: Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome, are life-threatening pulmonary disorders for which effective therapeutic interventions are currently lacking. This study aimed to investigate the role of ferroptosis in LPS-induced ALI and elucidate the synergistic mechanism of metallothionein-1 (MT-1) and galactoxylan polysaccharide (VDPS) in inhibiting ferroptosis, potentially offering novel therapeutic strategies for ALI.
Methods: Using Lipopolysaccharide (LPS)-induced murine models and MLE-12 cell lines, we analyzed ferroptosis-related indicators, including glutathione peroxidase 4 (GPX4), malondialdehyde (MDA), reduced glutathione (GSH), and iron content. Interventions with ferroptosis inhibitor ferrostatin-1 (Fer-1), activator erastin, and VDPS were performed. MT-1 knockdown experiments were conducted to explore its role in oxidative stress, iron metabolism, and inflammatory responses.
Results: LPS stimulation induced characteristic ferroptosis features in both mice and MLE-12 cells, manifested by increased pulmonary iron content, decreased GSH levels, elevated MDA levels, and reduced GPX4 expression (p < 0.05). Fer-1 treatment significantly ameliorated these oxidative stress markers and protected lung function (p < 0.05). LPS markedly upregulated MT-1 expression, while MT-1 knockdown exacerbated oxidative stress, lipid peroxidation, and ferroptosis (p < 0.05). VDPS effectively inhibited LPS-induced ferroptosis, reducing oxidative damage and inflammation (p < 0.05). Combined treatment with Fer-1 notably decreased pulmonary edema, inflammatory infiltration, and fibrosis (p < 0.05). VDPS also regulated iron metabolism, suppressing elevated iron levels in lung tissue and serum (p < 0.05). Importantly, MT-1 enhanced VDPS-mediated GPX4 pathway activation, synergistically inhibiting ferroptosis and attenuating LPS-induced oxidative injury (p < 0.05).
Conclusion: This study reveals the crucial role of ferroptosis in LPS-induced ALI. MT-1 enhances VDPS-mediated ferroptosis inhibition by modulating oxidative stress responses and antioxidant enzyme activities, effectively alleviating lung injury. These findings provide experimental evidence for MT-1 and VDPS as potential therapeutic strategies, highlighting the promising application of anti-ferroptosis therapy in ALI treatment.
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Background: As an important deubiquitinating enzyme, Ubiquitin Carboxyl-terminal Hydrolase L3 (UCHL3) has been considered to play an important role in tumor progression and DNA damage repair. However, its specific function and regulatory mechanism in colorectal cancer remain to be fully elucidated. This study aims to explore the functional role of deubiquitinating enzyme UCHL3 in colorectal cancer, focusing on analyzing its specific mechanism in DNA damage repair and cell cycle regulation by regulating Cell Division Cycle Associated 5 (CDCA5) protein stability, thereby revealing the role of UCHL3 in colorectal cancer and its potential impact on cancer progression.
Methods: The experiment consists of normal colon epithelial cells (FHC) and colorectal cancer cell line (SW480) as research subjects to construct UCHL3 knockdown and overexpression models, respectively. The expression levels of UCHL3 and CDCA5 were evaluated using quantitative real-time PCR (qRT-PCR) and Western blot analyses, respectively. Cell viability was assessed using the CCK-8 assay, apoptosis rate and cell cycle distribution were analyzed using flow cytometry, DNA damage level was assessed via comet assay, and Co-IP was used to verify the relationship between UCHL3 and CDCA5, protein interaction of CDCA5, and its ubiquitination level of CDCA5.
Results: UCHL3 and CDCA5 were significantly upregulated in CRC cells compared with normal controls (p < 0.05). Silencing UCHL3 markedly reduced cell viability (p < 0.05), increased apoptosis (p < 0.05), enhanced DNA damage (p < 0.05), and induced G2/M cell cycle arrest (p < 0.05). Conversely, UCHL3 overexpression significantly promoted cell viability (p < 0.05), decreased apoptosis (p < 0.05), and attenuated DNA damage (p < 0.05). Mechanistically, UCHL3 stabilized CDCA5 protein by suppressing its ubiquitination (p < 0.05), thereby facilitating DNA damage repair and regulating cell cycle progression.
Conclusion: UCHL3 promotes DNA damage repair and inhibits apoptosis by stabilizing CDCA5, thereby driving the progression of colorectal cancer. UCHL3 may become a potential target for treating colorectal cancer.
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Background: Knee osteoarthritis (OA) is a prevalent, age-related form of arthritis, characterized by chronic inflammation. However, quantitative tools to assess inflammatory homeostasis are currently lacking. Thus, this study aimed to develop a tool for quantitatively evaluating inflammatory homeostasis in knee OA.
Methods: We developed the EntroInflame score, a quantitative algorithm integrating single sample gene set enrichment analysis (ssGSEA) scores and Shannon entropy of inflammation-associated genes from single-cell meniscus RNA-seq data (12 samples and 67,681 cells), to evaluate inflammatory homeostasis.
Results: Based on the algorithm, we identified a unique type of inflammation homeostatic cells (with EntroInflame score < 0.5) in meniscus tissue. Through molecular characterization analysis, we found that signaling pathways, such as the phosphoinositide 3 kinase-protein kinase B (PI3K-Akt), mitogen activated protein kinase (MAPK) and longevity-regulating pathway, are closely associated with the functions of inflammation homeostatic cells. In addition, the macrophage migration inhibitory factor-atypical chemokine receptor 3 (MIF-ACKR3) was pinpointed as a vital link between inflammation and non-inflammation homeostatic cells, suggesting its therapeutic potential. Furthermore, we utilized computational biology methods to predict compounds targeting inflammation homeostatic cells and constructed a scoring system based on literature evidence to assess their credibility.
Conclusions: In summary, our study establishes inflammatory homeostasis as a critical regulatory mechanism in OA and provides a framework for precision interventions. Currently, inflammation homeostatic cells are inferred through calculation. In the future, we will further verify them through in vivo and in vitro experiments.
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Background: Methotrexate (MTX) is widely used as a chemotherapeutic and immunosuppressive agent, but is frequently associated with hepatotoxicity. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, is increasingly recognized as a major contributor to drug-induced liver injury. Peroxisome proliferator-activated receptor α (PPARα) serves as a critical regulator of lipid metabolism and antioxidant defense. However, its role in MTX-induced hepatocyte ferroptosis remains unclear. This study aimed to determine whether PPARα modulates MTX-induced liver injury by regulating oxidative stress and ferroptosis in vivo and in vitro.
Methods: A mouse model of MTX-induced liver injury was established, and hepatic histopathology, serum biochemical parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST)), inflammatory cytokines (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6)), oxidative stress markers (4-hydroxynonenal (4-HNE), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH)), and ferroptosis-related proteins (glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), acyl-CoA synthetase long-chain family member 4 (ACSL4), arachidonate 15-lipoxygenase (ALOX15), transferrin receptor 1 (TFR1)) were assessed. PPAR-related signaling molecules (PPARα, PPARγ, and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α)) were analyzed using Western blotting. In vitro, AML-12 hepatocytes were exposed to MTX with or without the PPARα agonist GW7647 to evaluate lipid peroxidation, antioxidant capacity, and ferroptosis markers.
Results: MTX treatment induced significant liver injury, characterized by hepatocellular swelling, vacuolization, elevated ALT/AST (p < 0.05), increased proinflammatory cytokines (p < 0.05), enhanced lipid peroxidation (p < 0.05), and reduced antioxidant capacity (p < 0.05). Ferroptosis-associated markers were significantly altered (decreased GPX4; increased ACSL4, ALOX15, and TFR1; p < 0.05). MTX also disrupted PPAR signaling (reduced PPARα and PGC-1α; increased PPARγ; p < 0.05). Activation of PPARα by GW7647 restored PGC-1α expression, enhanced antioxidant defenses (GPX4, SLC7A11, GSH, SOD; p < 0.05), suppressed ferroptosis-related lipid-remodeling enzymes (p < 0.05), and reduced lipid peroxidation (p < 0.05), thereby alleviating MTX-induced hepatocellular damage in vivo and in vitro.
Conclusion: PPARα activation mitigates MTX-induced liver injury by reprogramming lipid metabolism and enhancing antioxidant defenses, ultimately suppressing ferroptosis. These findings highlight the therapeutic potential of targeting the PPARα-ferroptosis pathway as an innovative strategy to counteract MTX-associated hepatotoxicity.
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Background: Obstructive sleep apnea-hypopnea syndrome (OSAHS) can lead to intermittent hypoxia and systemic inflammatory response, which may influence the progression of lung cancer in patients. This study aims to evaluate the relationship between serum platelet-derived growth factor BB (PDGF-BB) and peripheral oxygen saturation (SpO2), and to explore the diagnostic value of PDGF-BB in distinguishing mild-moderate and severe OSAHS in patients with lung cancer (LC).
Methods: This study is a retrospective study that included 76 patients diagnosed with OSAHS combined with LC from March 2021 to March 2023, as well as a control group comprising 72 healthy adults, 30 cases of OSAHS only, and 29 cases of LC only. All subjects underwent nighttime polysomnography to obtain Apnea Hypopnea Index (AHI), minimum/average SpO2, and T90%. Serum PDGF-BB was measured by ELISA. Patients with OSAHS and concomitant LC were divided into two groups based on AHI: a mild-moderate group (5 ≤ AHI ≤ 30, n = 47) and a severe group (AHI >30, n = 29). Pearson correlation analysis was used to investigate the relationship between PDGF-BB and disease indicators. The efficacy of PDGF-BB in distinguishing the severity of the disease was evaluated by using receiver operating characteristic (ROC) curve.
Results: The OSAHS-with-concomitant-LC group showed significantly elevated PDGF-BB levels (p < 0.05) than the control group. PDGF-BB was significantly elevated in the severe group than in the mild-moderate group (p < 0.001). PDGF-BB was positively linked with AHI (r = 0.888, p < 0.001) and T90% (r = 0.750, p < 0.001), but was negatively linked with Min SpO2 (r = –0.740, p < 0.001) and Mean SpO2 (r = –0.534, p < 0.001). ROC curves demonstrated the AUC of PDGF-BB level for distinguishing the mild-moderate group from the severe group as 0.9912 (95% CI: 0.9770–1.0000, p < 0.0001), optimal cutoff value as 757.7 ng/L, sensitivity as 100.0%, and specificity as 95.74%.
Conclusion: Serum PDGF-BB is significantly elevated in patients with OSAHS and concomitant LC, and is highly correlated with the severity of hypoxia. It has high diagnostic value and can be used as a biomarker to assist in evaluating the severity of OSAHS.
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Background: A previous caesarean scar defect (PCSD), also referred to as a caesarean scar diverticulum, is a highly prevalent condition, resulting in infertility and uterine rupture. Currently, there are no effective treatment options for treating this condition. Evidence indicates that mesenchymal stem cells (MSCs) promote tissue repair and regeneration. Furthermore, studies have demonstrated that the therapeutic effects of MSCs are mediated by exosomes produced through a paracrine mechanism. Therefore, this study aims to explore the potential of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) in repairing post-caesarean uterine scar defects in rat models.
Methods: A rat model of PCSD was established using the combination of mechanical injury and infection. Two weeks post-surgery, hUCMSC-Exos were transplanted into the uterine scar area. At 8 weeks post-transplantation, endometrial thickness, myometrial thickness, and fibrosis were assessed using H&E and Masson's trichrome staining. Immunohistochemistry (IHC) and Western blot analysis were performed to evaluate α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and vascular endothelial growth factor (VEGF) protein levels. The remaining female rats were mated with males, and fertility was examined by euthanizing them at 19 days post-conception.
Results: Excessive collagen deposition and thinning of the endometrium and myometrium were observed in PCSD model rats. Following hUCMSC-Exos transplantation, collagen deposition in the uterine scar decreased (p < 0.001), while endometrium thickness, myometrium thickness, and angiogenesis levels all significantly increased (p < 0.001). Furthermore, TGF-β1 levels decreased (p < 0.01), while α-SMA and VEGF levels increased (p < 0.001) after hUCMSC-Exos treatment. Additionally, pregnancy rates improved, and the number of implanted fetuses within the scar area increased (p < 0.01).
Conclusion: hUCMSC-Exos exerts significant therapeutic effects by improving both the morphology and function in a previous caesarean scar defect model. hUCMSC-Exos offers a novel, cell-free therapeutic option for patients with PCSD.
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Background: Colorectal cancer (CRC) poses a significant global health burden. Cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody, and irinotecan, a topoisomerase I inhibitor, are established therapeutic agents for CRC. Although cetuximab can be administered as monotherapy or in combination with irinotecan, the differences in efficacy and safety between these treatment strategies remain unclear. Therefore, this meta-analysis aimed to comprehensively compare the efficacy and safety between cetuximab alone and cetuximab plus irinotecan for treating patients with CRC.
Methods: Studies about randomized controlled trials on cetuximab monotherapy or combination therapy with irinotecan for treating CRC were retrieved from Cochrane Library, PubMed, and China National Knowledge Infrastructure (CNKI) since inception until 1 April 2024. The subjects were categorized into combination and monotherapy groups. The quality assessment of literature was analyzed using Cochrane risk-of-bias tool. Review Manager Software was utilized for meta-analysis. Progression-free survival (PFS) and grade 3–4 adverse events (AEs) were applied as primary outcome indicators. Overall survival (OS), objective remission rate (ORR) and disease control rate (DCR) were used as secondary outcome indicators.
Results: Six studies and 875 CRC patients were finally included. Meta-analysis results showed that the combination group had a longer PFS than the monotherapy group (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.42–1.16, p = 0.16), while there was no significant difference in OS between the two groups (HR = 0.84, 95% CI: 0.70–1.00, p = 0.05). The incidence of grade 3–4 AEs was higher in the combination group than in the monotherapy group (relative risk [RR] = 1.38, 95% CI: 1.17–1.64, p = 0.0002). In addition, the DCR of the combination group was significantly higher than that of the monotherapy group (RR = 1.45, 95% CI: 1.16–1.81, p = 0.001), while the ORR was not significantly different between the two groups (RR = 1.12, 95% CI: 0.96–1.31, p = 0.13).
Conclusion: Our findings indicate that cetuximab plus irinotecan confers higher anti-tumor protection than the monotherapy, with a compromise in an evidently increased risk of severe adverse events. The trade-off between efficacy and toxicity must be carefully considered in clinical decision-making.
Registration number: CRD420251124881.
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Background: Macrophage polarization to M2 type plays a key role in promoting the progression of oral squamous cell carcinoma (OSCC). Curcumin, as a natural active ingredient, has been proven to have anti-tumor activity, but its regulatory mechanism on macrophage polarization in OSCC remains unclear. This study aims to explore whether curcumin affects the M2 polarization of macrophages by regulating the axis inhibition protein 2 (AXIN2)/β-catenin pathway, and to clarify its effects and molecular mechanisms on the growth and invasion of OSCC cells.
Methods: RAW264.7 cells were selected to be treated with different concentrations (0, 5, 10, 20 μM) of curcumin, and the expression of M2 markers was detected by Real-time fluorescence quantitative PCR (qRT-PCR) and flow cytometry. The expression of AXIN2/β-catenin pathway molecules and downstream genes was detected using Western blotting. The localization and expression intensity of arginase-1 (ARG1) and β-catenin were observed using immunofluorescence staining. The secretion levels of cytokines were detected by enzyme-linked immunosorbent assay (ELISA). The conditioned medium of curcumin-pre-treated macrophages was collected and used to treat OSCC cell lines (HSC3, CAL33). Cell viability, proliferation, apoptosis and invasion ability were evaluated. The role of AXIN2 in curcumin-regulated macrophage polarization and OSCC cell behavior was verified by knockdown of AXIN2 in macrophages.
Results: Curcumin inhibited the polarization of M2 type macrophages in a concentration-dependent manner (p < 0.01). Mechanistically, curcumin upregulated AXIN2 expression in macrophages and inhibited the nuclear translocation of β-catenin and the expression of its downstream target genes (p < 0.01). The conditioned medium from curcumin-pre-treated macrophages significantly inhibited the viability, colony formation ability, and invasion ability of OSCC cells, and promoted cell apoptosis (p < 0.01). Knockdown of AXIN2 partially reversed the inhibitory effect of curcumin on M2 polarization of macrophages and weakened the inhibitory effect of the conditioned medium on the growth and invasion of OSCC cells (p < 0.01).
Conclusions: Curcumin inhibits the activation of the β-catenin pathway by up-regulating AXIN2 expression, thereby blocking the polarization of macrophages to the M2 type, reducing the secretion of pro-cancer cytokines, and ultimately suppressing the growth and invasion of OSCC cells. This study reveals a new mechanism by which curcumin regulates the polarization of macrophages in the tumor microenvironment, providing experimental evidence for targeted therapy of OSCC.
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Background: The damage caused by pathological angiogenesis to visual function is grievous. Retinol-binding protein 3 (RBP3) demonstrates an inverse relationship with diabetic retinopathy (DR) progress and suppresses pathological retinal angiogenesis under hyperglycemic conditions. However, the impact of externally administered RBP3 in such pathological retinal angiogenesis remains undefined. This research explores how intravitreally delivered RBP3-loaded exosomes (RBP3-Exo) curtail abnormal retinal vessel growth.
Methods: We generated RBP3-Exo with safety and good biocompatibility using plasmid transfection technology. The anti-angiogenic effect of RBP3-Exo was evaluated in vitro through cell proliferation, sprouting assays, and other experiments. Using an oxygen-induced retinopathy (OIR) model, we administered exosomes intravitreally and conducted subsequent staining assays to evaluate angiogenic activity in vivo. RNA-seq was conducted, which revealed that its main target pathway is the DNA replication pathway, and this was verified by Real-time quantitative polymerase chain reaction (qPCR) and Western blot.
Results: Results indicate that RBP3-loaded exosomes markedly restrain endothelial cell proliferation and sprouting in laboratory settings. In OIR mice, they also diminish both avascular retinal zones and pathological neovascular tuft formation. Mechanistically, RBP3-loaded exosomes may achieve these effects by interfering with DNA replication processes.
Conclusion: In conclusion, RBP3-Exo potently suppress pathological retinal angiogenesis, positioning them as a compelling therapeutic candidate for ocular neovascular diseases.
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Background: While programmed death 1 (PD-1) inhibitors have shown remarkable efficacy and survival benefits in lung cancer, their clinical utility is limited when used alone. This study aims to investigate the underlying mechanism by which sodium butyrate (NaB), combined with PD-1 inhibitors, enhances immunotherapeutic efficacy of lung cancer via modulating the signal transducer and activator of transcription 1 (STAT1)/Indoleamine 2, 3-dioxygenase 1 (IDO1)-activated tryptophan (Trp)-kynurenine (Kyn) pathway.
Methods: To assess the effect of combining NaB with a PD-1 inhibitor on lung cancer, we employed a comprehensive array of techniques, including live animal imaging, hematoxylin and eosin (H&E) staining, immunohistochemical analysis, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and various biochemical tests.
Results: Our findings indicated that NaB had the potential to dramatically slow down tumor progression, promote cancer cell death, decrease the ratio of kynurenine to tryptophan, boost the efficacy of PD-1 inhibitors through impeding STAT1/IDO1 pathway (p < 0.05), thereby bolstering the body's anti-cancer response. Meanwhile, co-administration of NaB and PD-1 inhibitor activated CD8+ T cells to trigger apoptosis, inhibited tumor cell proliferation, and reduced the Kyn content in vitro (p < 0.05). Moreover, NaB, coupled with a PD-1 inhibitor, down-regulated p-STAT1, IDO1, and programmed death-ligand 1 (PD-L1) protein expression in CD8+ T cells and Lewis lung carcinoma (LLC) co-cultured system (p < 0.05). However, the occurrence of the above results was abolished by 2-(1, 8-Naphthyridin-2-yl)phenol (2-NP) or 6-Formylindolo[3, 2-b]carbazole (FICZ) (p < 0.05).
Conclusion: Collectively, our findings revealed that NaB ameliorates the immunosuppressive surroundings in lung cancer and enhances the effect of PD-1 inhibitor through STAT1/IDO1-mediated tryptophan and kynurenine metabolism.
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Background: Ulcerative colitis (UC), a chronic subtype within the spectrum of inflammatory bowel diseases, involves repeated episodes of mucosal injury and impairment of the epithelial barrier. Despite evidence suggesting numerous signaling pathways in UC pathogenesis, the underlying molecular mechanisms remain elusive. Herein, we sought to uncover disease-related genes and investigate the role of β-site APP cleaving enzyme 2 (BACE2) in disease progression.
Methods: Differentially expressed genes were screened from the GSE53306 and GSE75214 datasets. BACE2 expression in a murine UC model was examined using quantitative real-time PCR (qRT‒PCR), Western blotting, and immunohistochemistry assays. Functional assays were performed in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages following BACE2 knockdown, including qRT‒PCR, Western blotting, enzyme-linked immunosorbent assay (ELISA), Cell Counting Kit-8 (CCK-8) viability assays, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and flow cytometry. The potential contribution of the MAP kinase phosphatase-1 (MKP1)/nuclear factor kappa-B (NF-κB)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathway was examined. Finally, the effects of BACE2 silencing and MKP1 inhibition on disease progression were evaluated in vivo using a mouse model with UC.
Results: Bioinformatic analysis identified BACE2 as one of the top upregulated genes in UC datasets. In vivo, UC mice exhibited a notable reduction in body mass, an increased disease activity index, a shortened colon length, and increased expression of BACE2 at both transcriptional and protein levels (p < 0.05). Histopathological analysis revealed severe epithelial damage and inflammatory cell infiltration, accompanied by enhanced BACE2 expression in colon tissues. In vitro, BACE2 knockdown reduced LPS-stimulated tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 production (p < 0.05), improved cell viability (p < 0.05), and attenuated apoptosis (p < 0.05). Mechanistically, BACE2 silencing restored MKP1 expression (p < 0.05), suppressed NF-κB activation (p < 0.05), and inhibited NLRP3 inflammasome signaling (p < 0.05). In UC mice, BACE2 knockdown alleviated colonic inflammation, whereas MKP1 inhibition partially reversed these protective effects.
Conclusion: BACE2 is aberrantly upregulated in UC and exacerbates disease progression by downregulating MKP1 and activating the NF-κB/NLRP3 pathway. Targeting BACE2 may provide a novel approach to inflammatory bowel disease.
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Background: This study systematically evaluated the expression profile and functional significance of minichromosome maintenance 10 (MCM10) in colorectal cancer (CRC), assessed its association with the tumor immune microenvironment, and investigated its role in regulating cellular proliferation, migration, invasion, and stemness, thereby highlighting its potential as a therapeutic candidate.
Methods: Transcriptomic datasets were accessed from publicly available databases (GEO and TCGA). The data were analyzed to determine MCM10 expression and assess its association with immune cell infiltration. Functional enrichment profiling and molecular network modeling were performed to uncover underlying mechanisms. Furthermore, in vitro validation, including quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation assays, Transwell migration and invasion assays, and tumor sphere formation assays, was conducted to determine the biological effects of MCM10 on CRC cells.
Results: MCM10 was upregulated in CRC tissues and demonstrated a positive association with immune-cell infiltration, particularly helper T cells and T helper 2 (Th2) cells. Notably, MCM10 expression was substantially higher in CRC tissues compared with adjacent normal tissues (p < 0.001), consistent with TCGA and GTEx cohort analyses. Furthermore, MCM10 was enriched in cancer-related signaling pathways and immune regulatory processes. Functional assays demonstrated that MCM10 overexpression promoted CRC cell proliferation, migration, invasion, and stemness, while its knockdown produced the opposite effects.
Conclusion: Our findings confirm a pivotal role of MCM10 in CRC, suggesting its potential as a diagnostic biomarker and therapeutic target. The findings offer promising insights into the molecular biology of CRC and provide a foundation for the development of precision treatment strategies.
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Background: Osteogenic-angiogenic coupling is essential for skeletal homeostasis, and its dysregulation constitutes a pathological basis for osteoporosis. This study investigates whether the E3 ubiquitin ligase Mind bomb 2 (MIB2) plays a critical role in this coupling by regulating the deubiquitinase cylindromatosis (CYLD) and oxidative stress.
Methods: Key regulatory factors were identified using integrated bioinformatics analysis. Gain-of-function studies were performed on MC3T3-E1 osteoprogenitors and bEnd.3 endothelial cells through lentiviral transduction. Protein interactions and ubiquitination were assessed using co-immunoprecipitation and ubiquitination assays. Osteogenic differentiation and angiogenic capacity were evaluated by alkaline phosphatase activity assay, Alizarin Red S staining, scratch wound, and tube formation assays. Oxidative stress markers, including reactive oxygen species, malondialdehyde, and glutathione, were measured. Cellular crosstalk was examined using a Transwell co-culture system.
Results: CYLD was identified as a key node regulating both osteogenic and angiogenic processes. Functional studies demonstrated that CYLD overexpression enhanced osteogenic differentiation and angiogenesis while attenuating oxidative stress in both cell types. Mechanistically, MIB2 was identified as an E3 ubiquitin ligase for CYLD, binding CYLD and promoting its ubiquitination and degradation. Rescue experiments confirmed that MIB2 overexpression suppressed osteogenesis and induced oxidative stress (reactive oxygen species (ROS), reduced glutathione (GSH), and malondialdehyde (MDA)) by downregulating CYLD. Co-culture experiments further revealed that disruption of the MIB2–CYLD axis in osteoblasts significantly suppressed endothelial expression of key angiogenic markers (PECAM1, EMCN, and HIF-1α), elevated intracellular ROS, and altered oxidative stress markers in the conditioned medium (GSH and MDA), thereby demonstrating that osteoblast-derived oxidative stress signals impair endothelial function and compromise osteogenic-angiogenic coupling.
Conclusion: MIB2 impairs osteogenic-angiogenic coupling through the ubiquitin-mediated degradation of CYLD, exacerbating oxidative stress and simultaneously suppressing osteogenesis and angiogenesis. These findings provide new insights into the pathogenesis of skeletal disorders and highlight the MIB2-CYLD axis as a potential therapeutic target.
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Background: Tendon–bone healing after anterior cruciate ligament reconstruction (ACLR) remains limited by insufficient bone formation and an unfavorable inflammatory microenvironment. Although bone marrow–derived mesenchymal stem cells (BMSCs) have therapeutic potential, their osteogenic and immunomodulatory effects are suboptimal. Additionally, the role of R-spondin 2 (RSPO2) in enhancing BMSC-mediated tendon–bone healing remains unclear. This study aims to investigate the role of RSPO2 in promoting the osteogenic differentiation of BMSCs and its effect on M2 macrophage polarization, as well as the potential of RSPO2 combined with BMSCs to accelerate tendon-bone healing after ACLR.
Methods: During the osteogenic induction of BMSCs, low, medium, and high concentrations of RSPO2 recombinant protein (10, 20, 40 nmol/L) were added, respectively, followed by alkaline phosphatase (ALP) staining and the measurement of osteogenesis-related protein expression. RAW264.7 cells were differentiated into macrophages using PMA, and the effects of BMSCs and/or RSPO2 on M1/M2 macrophage polarization were analyzed using qRT-PCR. A rat ACLR model was established, and the rats were divided into four groups: Control, BMSCs, BMSCs+Low RSPO2 (co-injection), and BMSCs+Medium RSPO2 (co-injection). Micro-CT imaging was performed to analyze bone tunnel area and mineralized tissue formation at 4 and 8 weeks post-ACLR. Histological analysis, including HE staining, Safranin O-Fast Green staining, and COL2α1 immunohistochemistry, was used to evaluate tendon-bone healing. Immunofluorescence staining was conducted to detect the expression of M1 (iNOS) and M2 (CD163) macrophage markers at the tendon-bone interface.
Results: RSPO2 significantly promoted the osteogenic differentiation of BMSCs, with the medium concentration of RSPO2 showing the most pronounced effect. RSPO2 and BMSCs also promoted M2 macrophage polarization and inhibited M1 polarization, with the medium concentration of RSPO2 demonstrating the most significant impact. Micro-CT results indicated that RSPO2 and BMSCs treatment significantly reduced the bone tunnel area and increased the formation of mineralized tissue compared to the control group. Histological analysis revealed that RSPO2 and BMSCs treatment improved tendon-bone interface healing, characterized by more orderly fiber tissue arrangement and an increase in chondrocytes and fibrocartilaginous tissue. Immunofluorescence staining results showed that RSPO2 and BMSCs promoted M2 macrophage polarization at the tendon-bone interface.
Conclusions: RSPO2 enhances BMSC-induced osteogenic differentiation and promotes M2 macrophage polarization, thereby improving tendon–bone healing after ACLR surgery in a small-animal model. The combined treatment of RSPO2 and BMSCs demonstrates promising preclinical potential in accelerating bone formation and tendon–bone interface repair, with the medium concentration of RSPO2 showing the most notable effect. However, these findings are based solely on a small-animal model, and further validation in large-animal models and clinical studies is required before potential clinical translation.
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Background: Skin flap ischemia/reperfusion (IR) injury contributes to reducing the survival rate in flaps after grafting. Lysine demethylase 5B (KDM5B) plays a crucial role in epigenetic regulation both during normal development and carcinogenesis. Therefore, this study aims to investigate the precise role and underlying mechanism of KDM5B in the skin flap after IR injury.
Methods: An in vitro skin flap model was developed in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated human umbilical vein endothelial cells (HUVECs), and the expression levels of KDM5B, AMP-activated protein kinase (AMPK), and Kruppel-like factor 2 (KLF2) were assessed using western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses. Furthermore, cellular apoptosis rate, scratch wound healing, migration, and tube formation were assessed in treated HUVECs using flow cytometry, Transwell, and tube formation assays, respectively.
Results: KDM5B was downregulated in the skin flap after IR injury in vivo (p < 0.05). In vitro, KDM5B overexpression alleviated OGD/R-induced injury in HUVECs, as verified by the rescued cell viability (p < 0.05), reduced Lactate dehydrogenase (LDH) release (p < 0.05) and restored mitochondrial membrane potential (p < 0.05). Additionally, overexpression of KDM5B suppressed OGD/R-induced apoptosis (p < 0.05), enhanced cell migration (p < 0.05), and promoted tube formation (p < 0.05) in HUVECs. Mechanistically, KDM5B overexpression activated the AMPK/KLF2 signaling pathway, which was inhibited by OGD/R treatment (p < 0.05). The protective effects of KDM5B on apoptosis, migration, and tube formation were abolished by the AMPK inhibitor Compound C (p < 0.05). The in vivo experiments confirmed that KDM5B overexpression promoted skin flap survival (p < 0.05), reduced apoptosis (p < 0.05), and enhanced angiogenesis (p < 0.05).
Conclusion: This study is the first to demonstrate that KDM5B suppresses apoptosis and enhances migration and angiogenesis in the skin flap after IR injury through activation of the AMPK/KLF2 signaling pathway.
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Background: Cu/Zn-SOD plays a crucial role in uremia combined with cerebral hemorrhage (UCH). However, its specific role and underlying mechanisms in this condition have not been fully elucidated. This study aims to investigate the effects of Cu/Zn-SOD on uremia-associated cerebral hemorrhage and whether the NF-κB pathway is involved.
Methods: Samples were collected from healthy adult subjects and age-matched patients with uremic cerebral hemorrhage, and a UCH mouse model was established. Western blot and RT-qPCR analyses were used to evaluate the levels of Cu/Zn-SOD, apoptosis-related proteins, inflammatory cytokines, oxidative stress markers, and proteins involved in the NF-κB pathway in UCH patients. The brain water content measurement, ELISA, TUNEL, immunofluorescence, and DCFH-DA assays were also performed to assess brain edema, apoptosis, inflammation, and oxidative stress in UCH brain tissue.
Results: Cu/Zn-SOD expression was significantly downregulated in the human serum of UCH patients (p < 0.001). Overexpression (OE) of Cu/Zn-SOD alleviated brain edema and inhibited cellular apoptosis in mice (p < 0.05), which was reversed by RNAi (p < 0.05). Furthermore, OE reduced inflammation and oxidative stress levels in UCH mice (p < 0.05), which was reversed by RNAi (p < 0.05). Notably, OE suppressed the expression of NF-κB pathway proteins (p < 0.001), while the NF-κB agonist reversed the inhibitory effect of OE on NF-κB (p < 0.001).
Conclusions: Overexpression of Cu/Zn-SOD alleviates the occurrence of UCH by inhibiting the NF-κB pathway, thereby providing a theoretical reference for Cu/Zn-SOD as a potential target for the prevention and treatment of UCH.
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Background: Chronic kidney disease (CKD) attributable to hypertension represents a significant global health concern. Nonetheless data on the burden and trend of this condition remain scarce. This study aimed to evaluate the trend in the burden of hypertension-induced CKD across various age groups from 1992 to 2021 at a global, regional, and national level.
Methods: We extracted data on the population burden of CKD attributable to hypertension from the Global Burden of Disease 2021 study. Using age-period-cohort (APC) modeling, we assessed trends in disability-adjusted life years (DALYs), mortality, prevalence, and incidence. We further quantified several indicators describing temporal dynamics, including the overall yearly rate of change (net drift), age-specific temporal slopes (local drift), the modeled age profiles over time, and the relative risks associated with period and cohort effects.
Results: From 1992 to 2021, the global burden of CKD attributable to hypertension steadily increased, with significant variations across different Socio-Demographic Index (SDI) regions. The most substantial increase in DALYs (+60.0%) and mortality (+75.5%) were observed in high-SDI regions. The incidence of CKD showed a significant rise in medium-SDI regions (+36.6%) and low-middle SDI regions (+28.5%), while global prevalence slightly declined (–4.7%). The burden of CKD increased significantly with age, with DALYs, mortality, and prevalence rising across all SDI regions as age increased. Incidence peaked at 80–84 years. Cohort relative risks (RRs) for hypertension-related CKD exhibited a downward trend in both incidence and mortality, particularly in high-SDI regions.
Conclusion: Following long-term hypertension management, high-SDI regions have shown some improvement in mortality and DALYs. Nonetheless the persistent rise in incidence and the high burden in medium- and low-SDI regions remain prominent issues. Future efforts to alleviate the burden of CKD attributable to hypertension should prioritize addressing the adverse trends in these regions, particularly targeting elderly populations and areas with high incidence. More targeted preventive and intervention strategies are needed to mitigate this growing burden.
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Background: Coronary artery disease (CAD) remains a leading cause of mortality and disability globally, and percutaneous coronary intervention (PCI) is a key revascularization procedure. However, patients often face residual risks, including dyslipidemia and persistent inflammation post-PCI. This meta-analysis aimed to systematically evaluate the effects of Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on lipid profiles and inflammatory biomarkers in CAD patients after PCI.
Methods: We conducted a systematic literature search of PubMed, Web of Science, and Embase databases, with a cutoff date of September 2025. Only randomized controlled trials (RCTs) were included in the analysis. The methodological quality in the selected studies was assessed using the Cochrane Risk of Bias tool, and the meta-analysis was performed using RevMan software. For continuous outcome, results were expressed as the mean difference (MD) with a 95% confidence interval (CI). Fixed-effect or random-effects models were selected for analysis based on the degree of heterogeneity, as quantified by the I2 statistic.
Results: A total of 8 RCTs involving 1043 participants were included. The overall quality of evidence was moderate. PCSK9 inhibitors significantly reduced levels of triglycerides (MD = –0.52, 95% CI: –0.92– –0.12; I2 = 76%), total cholesterol (MD = –0.61, 95% CI: –0.91– –0.32; I2 = 66%), and low-density lipoprotein cholesterol (LDL-C) (MD = –1.37, 95% CI: –2.24– –0.50; I2 = 99%). Regarding inflammatory biomarkers, tumor necrosis factor-α (TNF-α) was significantly reduced (MD = –23.65, 95% CI: –28.68– –18.62; I2 = 67%), while no statistically significant differences were found for high-sensitivity C-reactive protein (hs-CRP) (MD = –1.49, 95% CI: –3.44– 0.46; I2 = 97%) or interleukin-6 (IL-6) (MD = –6.84, 95% CI: –15.15–1.46; I2 = 98%).
Conclusion: PCSK9 inhibitors significantly improve lipid parameters and certain inflammatory markers in CAD patients after PCI, suggesting benefits beyond lipid-lowering. Further high-quality trials are needed to confirm these findings and evaluate clinical outcomes.
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Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent malignancies in the head and neck region, with a high morbidity rate and a poor prognosis. As a result, the search for effective biomarkers to assess OSCC's prognosis has become a research hotspot. Given that the impact of Forkhead box protein P3 (FOXP3) as a significant marker of regulatory T cells (Tregs) on OSCC's prognosis remains a subject of debate, the current study was carried out to elucidate FOXP3 importance in the prognostic assessment of OSCC patients.
Methods: Four major databases, i.e., Web of Science, Embase, Cochrane Library, and PubMed, were searched for relevant articles up to 10 February 2025. The 95% confidence intervals (95% CIs) and hazard ratios (HRs) reported in the selected articles were extracted and combined for analysis. The primary outcome was overall survival (OS), while the secondary outcomes encompassed recurrence-free survival (RFS), disease-specific survival (DSS), and disease-free survival (DFS). These outcomes were pooled and analyzed using Stata 15.
Results: 19 articles were included, comprising a total of 2136 patients. The findings revealed that high FOXP3 did not have a significant association with OS under the random-effects model analysis (HR = 0.96, 95% CI = 0.60–1.54, p = 0.88) but had a significant association with DSS under the fixed-effects model analysis (HR = 0.55, 95% CI = 0.44–0.67, p < 0.001). The heterogeneity was within an acceptable range (I2 = 29.3%, p = 0.175). High FOXP3 was not significantly correlated with either DFS or RFS.
Conclusions: High expression of FOXP3 is significantly associated with improved DSS in OSCC. However, due to inconsistent relationships with other survival outcomes, its clinical application potential requires further validation.
Systematic Review Registration PROSPERO (CRD420250651264).
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Vitamin D (VD) plays a significant immunomodulatory role in various autoimmune diseases, including systemic vasculitides. This short review evaluates the existing literature on VD supplementation (VDS) in systemic vasculitis. A systematic search identified two studies focusing on Kawasaki disease (KD) and Henoch-Schönlein purpura (HSP). Both studies suggest potential benefits of VDS in reducing disease onset and recurrence, as well as modulating immune responses. Although current evidence is limited, findings support further investigation into VD as an adjunctive therapeutic strategy in vasculitis.
