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In the era of immunotherapy, lenvatinib (LEN) still holds an important position in the sequential treatment of advanced hepatocellular carcinoma (HCC). However, the sustained therapeutic effect of LEN is not sufficient, and there is a need to address the development of resistance. Neuropilin-1 (NRP1) is known to act as a co-receptor for epidermal growth factor receptor (EGFR), Met, and vascular endothelial growth factor receptor 2 (VEGFR2), which have been reported to be involved in LEN resistance. In this study, we used cell culture and in vivo transplantation models to evaluate the contribution of NRP1 in the acquisition of LEN resistance in HCC as well as the potential of NRP1 as a therapeutic target. LEN resistance increased EGF/EGFR and hepatocyte growth factor (HGF)/Met signaling in liver cancer cells and VEGFA/VEGFR2 and HGF/Met signaling in vascular endothelial cells, thereby promoting cell proliferation, cell migration, and angiogenesis. We found that activation of NRP1 is essential for the enhancement of these signaling. In addition, NRP1 inhibition combined with LEN therapy synergistically improved the antitumor effects against LEN-resistant HCC, indicating that NRP1 is an attractive therapeutic target.
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PURPOSE: To determine if intravitreal injection of antibiotics alone versus early pars plana vitrectomy (PPV) plus injection of intravitreal antibiotics predicted better or worse visual outcomes for patients with endophthalmitis after anti-vascular endothelial growth factor (anti-VEGF) injections. DESIGN: Retrospective cohort study PARTICIPANTS: Patients developing endophthalmitis after receiving an intravitreal anti-VEGF injection from the American Academy of Ophthalmology IRIS® Registry between 2016 and 2020. METHODS: Inclusion criteria were endophthalmitis diagnosis within 1 to 28 days after anti-VEGF injection and a recorded visual acuity (VA) at baseline, on the day of diagnosis, and post-treatment. Patients in the Injection Only group underwent intravitreal injection of antibiotics alone and in the Early Vitrectomy group received PPV with intravitreal antibiotics or intravitreal injection followed by PPV within 2 days of diagnosis. Patients were excluded if they had cataract surgery during the study, intravitreal steroids before endophthalmitis, or intermediate/posterior uveitis or cystoid macular edema. The study created a 1:1 matched cohort using Mahalanobis Distance Matching, accounting for the differences in VA at baseline and diagnosis. MAIN OUTCOME MEASURES: Post-treatment logMAR VA RESULTS: 1,044 patients diagnosed with post-injection endophthalmitis met the inclusion and exclusion criteria. In the unmatched cohort, there were 935 patients in the Injection Only and 109 in the Early Vitrectomy group. In 1:1 matched cohort 218 patients (109 in each group) were included; the median logMAR VAs were 0.32 [20/40-20/50] at baseline, 0.88 [â¼20/150] at diagnosis, and 0.57 [20/70-20/80] post-treatment. There were no statistically significant differences in the visual outcomes between the two matched treatment groups (b = 0.05, p = 0.23); including the subgroup of patients with VA worse than 1.0 logMAR (b = 0.05, p = 0.452). CONCLUSIONS: There was no significant difference in final VA outcomes between patients receiving Injection Only and those treated with Early Vitrectomy for post-injection endophthalmitis. The findings support the use of either treatment strategy.
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OBJECTIVE: In this study, we established a Sprague-Dawley rat model of vulvar squamous intraepithelial lesions and investigated the impact of focused ultrasound on the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and mutant type p53 (mtp53) in the vulvar skin of rats with low-grade squamous intraepithelial lesions (LSIL). MATERIALS AND METHODS: The vulvar skin of 60 rats was treated with dimethylbenzanthracene (DMBA) and mechanical irritation three times a week for 14 weeks. Rats with LSIL were randomly allocated into the experimental group or the control group. The experimental group was treated with focused ultrasound, while the control group received sham treatment. RESULTS: After 14 weeks treatment of DMBA combined with mechanical irritation, LSIL were observed in 44 (73.33%) rats, and high-grade squamous intraepithelial lesions (HSIL) were observed in 14 (23.33%) rats. 90.91% (20/22) of rats showed normal pathology and 9.09% (2/22) of rats exhibited LSIL in the experimental group at four weeks after focused ultrasound treatment. 22.73% (5/22) of rats exhibited LSIL, 77.27% (17/22) of rats progressed to HSIL in the control group. Compared with the control-group rats, the levels of HIF-1α, VEGF and mtp53 were significantly decreased in experimental-group rats (p < 0.05). CONCLUSIONS: These results indicate that DMBA combined with mechanical irritation can induce vulvar squamous intraepithelial lesion in SD rats. Focused ultrasound can treat LSIL safely and effectively, prevent the progression of vulvar lesions, and improve the microenvironment of vulvar tissues by decreasing the localized expression of HIF-1α, VEGF, and mtp53 in rats.
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Ratas Sprague-Dawley , Lesiones Intraepiteliales Escamosas , Animales , Femenino , Ratas , Lesiones Intraepiteliales Escamosas/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neoplasias de la Vulva/patología , Neoplasias de la Vulva/terapia , Terapia por Ultrasonido/métodos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The kidney is the main organ that senses changes in systemic O2 pressure by hypoxia-PHD-HIFa (HPH) signaling, resulting in adaptive target gene activation, including erythropoietin (EPO). The non-essential transition metal cadmium (Cd) is nephrotoxic and disrupts the renal HPH pathway, which may promote Cd-associated chronic renal disease (CKD). A deeper molecular understanding of Cd interference with renal HPH signaling is missing, and no data with renal cell lines are available. In rat kidney NRK-52E cells, which model the proximal tubule, and murine fibroblastoid atypical interstitial kidney (FAIK3-5) cells, which mimic renal EPO-producing cells, the chemical hypoxia mimetic dimethyloxalylglycine (DMOG; 1 mmol/l) or hypoxia (1% O2) activated HPH signaling. Cd2+ (2.5-20 µmol/l for ≤ 24 h) preferentially induced necrosis (trypan blue uptake) of FAIK3-5 cells at high Cd whereas NRK-52E cells specially developed apoptosis (PARP-1 cleavage) at all Cd concentrations. Cd (12.5 µmol/l) abolished HIFa stabilization and prevented upregulation of target genes (quantitative real-time polymerase chain reaction and immunoblotting) induced by DMOG or hypoxia in both cell lines, which was caused by the formation of insoluble HIFa aggregates. Strikingly, hypoxic preconditioning (1% O2 for 18 h) reduced apoptosis of FAIK3-5 and NRK-52E cells at low Cd concentrations and decreased insoluble HIFa proteins. Hence, drugs mimicking hypoxic preconditioning could reduce CKD induced by chronic low Cd exposure.
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Age-related macular degeneration (AMD) is one of the leading causes of visual loss in older patients. No effective drug is available for this pathology, but studies about therapy with stem cells replacing the damaged retinal cells with retinal pigment epithelium (RPE) were described. The documentation of AMD progression and the response to stem cell therapy have been performed by optical coherence tomography, microperimetry, and other diagnostic technologies.This chapter reports a clinical review of the most important clinical trials and protocols regarding the use of stem cells in AMD.
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OBJECTIVE: This study aimed to compare baseline and subsequent vascular endothelial growth factor (VEGF) levels in predicting futile recanalization (FR) in acute ischemic stroke (AIS) patients undergoing endovascular treatment (EVT), and to explore the association between angiogenesis and VEGF. METHODS: 84 participants were recruited, including 46 AIS in the EVT group, 20 AIS in the conventional treatment group, and 18 healthy controls. Plasma VEGF levels were measured at different time points. FR was defined as a modified Rankin scale score of 3-6 at 3 months. Multivariable analysis evaluated whether VEGF levels at different time points independently predicted FR, and receiver operating characteristic (ROC) curves assessed their predictive value. Using intracranial lesion side vascular imaging, the Maas scoring system assessed angiogenesis post-onset, with scores of 4 to 5 indicating angiogenesis. RESULTS: In the conventional treatment group, VEGF levels significantly decreased by day 7, while in the EVT group, reduction was observed as early as day 3. After adjusting for potential confounders, only VEGF levels on day 3 emerged as an independent predictor of FR. The combined model incorporating VEGF levels on day 3 with other factors effectively predicted FR (area under the curve = 0.916; sensitivity = 84.21 %; specificity = 100 %, P<0.0001). Plasma VEGF levels were notably higher in patients with angiogenesis in specific brain regions compared to those without angiogenesis at days 1, 3, 7, and 14 (P<0.05). CONCLUSION: VEGF levels on the 3rd day post-EVT demonstrate superior predictive value for FR. Elevated VEGF levels correlate with angiogenesis, suggesting its potential as a therapeutic target.
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Nasopharyngeal carcinoma (NPC) is often diagnosed at a very advanced stage due to its location and non-specific initial symptoms. Moreover, no clinically useful serological marker has been established so far for early detection of NPC. In this study, we have investigated the clinical significance of plasma Epstein-Barr virus DNA load along with interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels to evaluate if these three all together can be useful as a strong serological marker for early detection and prediction of treatment response in patients with NPC. Plasma EBV DNA load, IL-6 level, VEGF expressions were measured in 24 patients with NPC at presentation and various time points during and after treatment. There was a positive correlation between high plasma EBV DNA load with higher IL-6 and VEGF expression, which was closely associated with therapeutic response as well. Persistent or recurrent plasma EBV load with higher IL-6 and VEGF levels can potentially predict disease progression and may be useful to select patients for additional therapy and longer follow-up.
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Carcinoma , ADN Viral , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Interleucina-6 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Factor A de Crecimiento Endotelial Vascular , Carga Viral , Humanos , Interleucina-6/sangre , Neoplasias Nasofaríngeas/virología , Neoplasias Nasofaríngeas/sangre , Neoplasias Nasofaríngeas/diagnóstico , Herpesvirus Humano 4/genética , Femenino , Masculino , ADN Viral/sangre , Persona de Mediana Edad , Factor A de Crecimiento Endotelial Vascular/sangre , Carcinoma Nasofaríngeo/sangre , Carcinoma Nasofaríngeo/virología , Carcinoma Nasofaríngeo/diagnóstico , Adulto , Pronóstico , Carcinoma/virología , Carcinoma/sangre , Carcinoma/diagnóstico , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/diagnóstico , Biomarcadores/sangre , Anciano , Plasma/virologíaRESUMEN
Moyamoya disease (MMD) is a rare chronic vasculopathy characterized by progressive stenosis of the internal carotid arteries and the formation of fragile collateral vessels in the brain. Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome is a rare paraneoplastic syndrome with a complex presentation that includes polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. Here, we report a unique case of a 54-year-old male with MMD presenting with recurrent speech loss and mumbling, later diagnosed with POEMS syndrome. Initial imaging revealed Moyamoya vasculopathy, confirmed by computed tomographic angiography (CTA) and magnetic resonance imaging (MRI). Further examination revealed polyneuropathy, organomegaly, and elevated vascular endothelial growth factor (VEGF), meeting the diagnostic criteria for POEMS syndrome. The patient was treated with a cyclophosphamide-bortezomib-dexamethasone regimen, followed by the addition of daratumumab, resulting in clinical improvement. This case highlights the importance of thorough diagnostics and a multidisciplinary treatment approach for patients with complex comorbidities, emphasizing the need for early detection and targeted therapy in managing dual pathologies of MMD and POEMS syndrome.
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Neovascularization of the macula, a common complication of many chorioretinal diseases such as neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, and pathologic myopia results from increased synthesis of vascular endothelial growth factor (VEGF) by the retinal pigment epithelium and/or Müller cells because of localized ischemia and inflammation. The Consensus on Neovascular AMD Nomenclature (CONAN) study group acknowledged that these vessels may originate from either the choriocapillaris or the retinal microvasculature, prompting them to propose the term 'macular neovascularization' (MNV) to include intraretinal, subretinal, and sub-pigment epithelial neovascularization localized to the macula. MNV frequently appears as a grey-green macular lesion with overlying intraretinal thickening and/or subretinal exudation, causing metamorphopsia, reduced central vision, relative central scotoma, decreased reading speed, and problems with color recognition. Multimodal imaging with optical coherence tomography (OCT), OCT angiography, dye-based angiographies, fundus autofluorescence, and multiwavelength photography help establish the diagnosis and aid in selecting an appropriate treatment. The standard of care for MNV is usually intravitreal anti-VEGF injections, though thermal laser photocoagulation, verteporfin photodynamic therapy, and vitreoretinal surgery are occasionally used. This current review discusses the etiology and clinical features of MNV, the role of multimodal imaging in establishing the diagnosis, and the available therapeutic options.
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BACKGROUND: Rickettsial disease has been commonly associated with retinitis, retinal vasculitis, and optic nerve involvement, but the development of retinal neovascularization has been very rarely reported. We herein describe a case of rickettsial retinitis complicated with the development of sea-fan retinal neovascularization documented with multimodal imaging, including fundus photography, SS-OCT, fluorescein angiography, and SS-OCT angiography. CASE PRESENTATION: A 26-year-old female with a history of fever one week earlier presented with sudden decreased vision in the left eye. Best-corrected visual acuity (BCVA) was 20/2000 and the patient was diagnosed with rickettsial retinitis along the superotemporal retinal vascular arcade associated with serous retinal detachment and retinal hard exudates. The indirect immunofluorescence test was positive for Rickettsia conorii, and the patient was treated with oral doxycycline (200 mg/day) and oral prednisone (0.75 mg/kg/day, with gradual tapering). Four weeks after presentation, the retinal infiltrate and associated serous retinal detachment had resolved, but retinal hard exudates had increased. A large sea-fan preretinal fibrovascular neovascularization became apparent along the superotemporal retinal vascular arcade, but there was no associated retinal ischemia on fluorescein angiography. The patient received an adjunctive single intravitreal injection of 1.25 bevacizumab. Sequential follow-up examinations showed shrinking of sea-fan retinal neovascularization, a complete resolution of retinal hard exudates, and the development of a self-limited vitreous hemorrhage. On last follow-up, 30 months after intravitreal bevacizumab injection, BCVA was 20/25. CONCLUSION: Patients with rickettsial retinitis may develop a sea-fan retinal neovascularization, with subsequent vitreous hemorrhage, putatively through inflammatory mechanisms. Multimodal imaging including OCT, fluorescein angiography, and OCT-angiography, is highly useful for accurate diagnosis and reliable monitoring of the evolution of retinitis, retinal neovascularization, and other retinal changes. The use of a combination therapy with oral doxycycline and corticosteroids and intravitreal anti-VEGF can improve outcomes.
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Angiografía con Fluoresceína , Neovascularización Retiniana , Retinitis , Humanos , Femenino , Adulto , Neovascularización Retiniana/diagnóstico , Neovascularización Retiniana/tratamiento farmacológico , Neovascularización Retiniana/etiología , Retinitis/diagnóstico , Retinitis/microbiología , Retinitis/tratamiento farmacológico , Angiografía con Fluoresceína/métodos , Tomografía de Coherencia Óptica/métodos , Infecciones Bacterianas del Ojo/diagnóstico , Infecciones Bacterianas del Ojo/microbiología , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Infecciones por Rickettsia/diagnóstico , Infecciones por Rickettsia/complicaciones , Infecciones por Rickettsia/tratamiento farmacológico , Infecciones por Rickettsia/microbiología , Rickettsia conorii , Fondo de Ojo , Agudeza Visual , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Inyecciones Intravítreas , Doxiciclina/uso terapéutico , Bevacizumab/uso terapéuticoRESUMEN
OBJECTIVE: Pregnancy-induced hypertension (PIH) is a common disease during pregnancy, which arises from maternal placental vascular endothelial cell dysfunction. Growth differentiation factor 15 (GDF-15) has a protective effect on the cardiovascular system. The purpose of this study is to explore the protective effect of GDF-15 against hypoxia-reoxygenation (H/R)-induced damage to human placental vascular endothelial cells (HPVECs) and the regulatory mechanism of SIRT1 in this effect. METHODS: Serum samples from healthy pregnant women and those with PIH were collected, and their GDF-15 and SIRT1 levels were examined. HPVECs were cultured in vitro and induced with H/R and GDF-15 at varying concentrations. The optimal concentration of GDF-15 in protecting HPVECs was determined by measuring cell viability via the CCK-8 assay. In H/R-induced HPVECs treated with GDF-15 and compound C (the AMPK inhibitor), expression levels of SIRT1, p-AMPK, and t-AMPK were detected. Cell apoptosis was examined by flow cytometry. RESULTS: Serum SIRT1 and GDF-15 were significantly higher in healthy pregnant women than in PIH patients. Suppressed viability and activated apoptosis in H/R-induced HPVECs were partially reversed by the treatment of GDF-15 at a concentration of 100 ng/mL. H/R induction significantly downregulated SIRT1 and p-AMPK in HPVECs, which were then upregulated by GDF-15. Moreover, the protective effect of GDF-15 on H/R-induced HPVECs was blocked by inhibiting the AMPK signaling pathway. CONCLUSION: GDF-15 protects against H/R-inhibited cell viability and H/R-stimulated apoptosis in HPVECs by activating the AMPK signaling pathway to upregulate SIRT1.
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Background: The development of benign prostatic hyperplasia (BPH) is closely related to hypoxia in the prostatic stroma, and the hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway has been shown to significantly activate in response to hypoxia. The underlying mechanism for activation of this pathway in the pathogenesis of BPH remains unclear. Materials and methods: We constructed HIF-1α overexpression and knockdown BPH stromal (WPMY-1) and epithelial (BPH-1) cell lines, which were cultured under different oxygen conditions (hypoxia, normoxia, and hypoxia + HIF-1α inhibitor). Quantitative real-time polymerase chain reaction (qPCR) and Western blotting were applied to detect the expression of the HIF-1α/VEGF pathway. Cell proliferation and apoptosis were analyzed by Cell Counting Kit-8 and flow cytometry. We used the miRWalk 2.0 database and Western blotting to predict the potential miRNA that selectively targets the HIF-1α/VEGF pathway, and verified the prediction by qPCR and dual-luciferase assays. Results: In a BPH stromal cell line (WPMY-1), the expression of VEGF was in accordance with HIF-1α levels, elevated in the overexpression cells and decreased in the knockdown cells. Hypoxia-induced HIF-1α overexpression, which could be reversed by a HIF-1α inhibitor. Moreover, the HIF-1α inhibitor significantly depressed cellular proliferation and promoted apoptosis in hypoxic conditions, assessed by Cell Counting Kit-8 and flow cytometry. However, in the BPH epithelial cell line (BPH-1), the expression level of HIF-1α did not influence the expression of VEGF. Finally, a potential miRNA, miR-17-5p, regulating the HIF-1α/VEGF pathway was predicted from the miRWalk 2.0 database and Western blotting, and verified by qPCR and dual-luciferase assay. Conclusions: In hypoxia, activation of the HIF-1α/VEGF pathway plays a crucial role in regulating cell proliferation in a BPH stromal cell line. Regulation by miR-17-5p may be the potential mechanism for the activation of this pathway. Regulation of this pathway may be involved in the pathogenesis of BPH.
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This letter addresses the review titled "Wharton's jelly mesenchymal stem cells: Future regenerative medicine for clinical applications in mitigation of radiation injury". The review highlights the regenerative potential of Wharton's jelly mesenchymal stem cells (WJ-MSCs) and describes why WJ-MSCs will become one of the most probable stem cells for future regenerative medicine. The potential plausible role of WJ-MSCs for diabetic bone regeneration should be noticeable, which will provide a new strategy for improving bone regeneration under diabetic conditions.
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Purpose: In this study, we aimed to evaluate and compare the effects of intravitreal aflibercept (IVA) and intravitreal faricimab (IVF) injections on the blood flow of retinal vessels in the peripapillary region and optic nerve head (ONH) in eyes with diabetic macular edema (DME) using laser speckle flowgraphy (LSFG). Patients and Methods: This study included 20 eyes of 18 patients treated with IVA and 15 eyes of 11 patients treated with IVF for DME. The mean blur rate (MBR) of the ONH and retinal artery and vein of the peripapillary region were measured using LSFG at baseline and 1 month after injection. Central retinal thickness (CRT) and best-corrected visual acuity (BCVA) were measured for all patients. Results: CRT decreased significantly in both IVA-treated (p = 0.0003) and IVF-treated groups (p = 0.0004). Some of the MBR-related parameters of the ONH, such as MBR of all areas (MA), MBR of vascular areas (MV), and MBR of tissue areas (MT), decreased significantly 1 month after IVA and IVF compared to baseline values (MA of IVA, p < 0.0001; MT of IVA, p = 0.0220; MA of IVF, p = 0.0002; MT of IVF, p = 0.0461). MBR of the retinal artery (MBR-A) and vein (MBR-V) also decreased significantly 1 month after IVA and IVF compared with baseline values (MBR-A of IVA, p = 0.0002; MBR-V of IVA, p = 0.0010; MBR-A of IVF, p = 0.0368). No significant difference in ocular perfusion was observed between the IVA-treated and IVF-treated groups. Conclusion: Intravitreal injection led to a reduction in ocular blood flow in both retinal peripapillary vessels and the ONH in both IVA-treated and IVF-treated groups. No significant difference was observed in MBR reduction between the IVA-treated and IVF-treated groups. Our findings warrant further long-term investigations to reveal differences between aflibercept and faricimab.
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BACKGROUND: Almost half of severe hemophilia A (HA) cases are caused by an intron-22 inversion mutation (Int22Inv), which truncates the 26-exon F8 mRNA after exon 22. Another F8 transcript, F8B, is initiated from within F8-intron-22. F8B mRNA consists of a short exon spliced to exons 23-26 and is expressed in multiple human cell types. It has been hypothesized that Int22Inv patients have self-tolerance to partial FVIII proteins expressed from these two transcripts. FVIII is expressed in endothelial cells, primarily in liver and lung. Several studies have reported FVIII expression in other cell types, although this has been controversial. OBJECTIVES: To determine if partial FVIII proteins are expressed from intron 22-inverted and/or F8B mRNA and if FVIII is expressed in non-endothelial cells. METHODS: A panel of FVIII-specific antibodies was validated and employed to label FVIII in cells and tissues, and for immunoprecipitation followed by western blots and mass spectrometry-proteomics analysis. RESULTS: Immunofluorescent (IF) staining localized FVIII to endothelial cells in liver sections from non-HA but not HA-Int22Inv dogs. Neither FVIII nor FVIIIB was detected in human PBMCs, B-cell or T-cell lines, or in cell lines expanded from PBMCs, whereas FVIII antigen and activity were readily detected in primary non-hemophilic liver sinusoidal endothelial cells. CONCLUSIONS: If FVIII is expressed in non-endothelial cells, or if partial FVIII proteins are expressed in HA-Int22Inv, the concentrations are below the detection limits of these sensitive assays. Our results argue against promotion of immune tolerance through expression of partial FVIII proteins in Int-22Inv patients.
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Vascular endothelial inflammation is crucial in hepatic ischemia-reperfusion injury (IRI). Our previous research has shown that connective tissue growth factor (CTGF), secreted by endothelial cells, protects against acute liver injury, but its upstream mechanism is unclear. We aimed to clarify the protective role of CTGF in endothelial cell inflammation during IRI and reveal the regulation between endoplasmic reticulum stress-induced activating transcription factor 6 (ATF6) and CTGF. Hypoxia/reoxygenation in endothelial cells, hepatic IRI in mice and clinical specimens were used to examine the relationships between CTGF and inflammatory factors and determine how ATF6 regulates CTGF and reduces damage. We found that activating ATF6 promoted CTGF expression and reduced liver damage in hepatic IRI. In vitro, activated ATF6 upregulated CTGF and downregulated inflammation, while ATF6 inhibition had the opposite effect. Dual-luciferase assays and chromatin immunoprecipitation confirmed that activated ATF6 binds to the CTGF promoter, enhancing its expression. Activated ATF6 increases CTGF and reduces extracellular regulated protein kinase 1/2 (ERK1/2) phosphorylation, decreasing inflammatory factors. Conversely, inhibiting ATF6 decreases CTGF and increases the phosphorylation of ERK1/2, increasing inflammatory factor levels. ERK1/2 inhibition reverses this effect. Clinical samples have shown that CTGF increases after IRI, inversely correlating with inflammatory cytokines. Therefore, ATF6 activation during liver IRI enhances CTGF expression and reduces endothelial inflammation via ERK1/2 inhibition, providing a novel target for diagnosing and treating liver IRI.
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Factor de Transcripción Activador 6 , Factor de Crecimiento del Tejido Conjuntivo , Hígado , Daño por Reperfusión , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Animales , Factor de Transcripción Activador 6/metabolismo , Factor de Transcripción Activador 6/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Humanos , Ratones , Masculino , Hígado/metabolismo , Hígado/patología , Inflamación/metabolismo , Inflamación/patología , Ratones Endogámicos C57BL , Estrés del Retículo Endoplásmico/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacosRESUMEN
Background: The development of prognostic models for the identification of high-risk myocardial infarction (MI) patients is a crucial step toward personalized medicine. Genetic factors are known to be associated with an increased risk of cardiovascular diseases; however, little is known about whether they can be used to predict major adverse cardiac events (MACEs) for MI patients. This study aimed to build a machine learning (ML) model to predict MACEs in MI patients based on clinical, imaging, laboratory, and genetic features and to assess the influence of genetics on the prognostic power of the model. Methods: We analyzed the data from 218 MI patients admitted to the emergency department at the Surgut District Center for Diagnostics and Cardiovascular Surgery, Russia. Upon admission, standard clinical measurements and imaging data were collected for each patient. Additionally, patients were genotyped for VEGFR-2 variation rs2305948 (C/C, C/T, T/T genotypes with T being the minor risk allele). The study included a 9-year follow-up period during which major ischemic events were recorded. We trained and evaluated various ML models, including Gradient Boosting, Random Forest, Logistic Regression, and AutoML. For feature importance analysis, we applied the sequential feature selection (SFS) and Shapley's scheme of additive explanation (SHAP) methods. Results: The CatBoost algorithm, with features selected using the SFS method, showed the best performance on the test cohort, achieving a ROC AUC of 0.813. Feature importance analysis identified the dose of statins as the most important factor, with the VEGFR-2 genotype among the top 5. The other important features are coronary artery lesions (coronary artery stenoses ≥70%), left ventricular (LV) parameters such as lateral LV wall and LV mass, diabetes, type of revascularization (CABG or PCI), and age. We also showed that contributions are additive and that high risk can be determined by cumulative negative effects from different prognostic factors. Conclusion: Our ML-based approach demonstrated that the VEGFR-2 genotype is associated with an increased risk of MACEs in MI patients. However, the risk can be significantly reduced by high-dose statins and positive factors such as the absence of coronary artery lesions, absence of diabetes, and younger age.
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Our prior research has effectively developed tissue-engineered vascularized oral mucosa equivalents (VOME); however, challenges such as low repeatability and stability, as well as the inability to accurately replicate the complexity of real blood vessels, were encountered. Therefore, this study aimed to screen the VOME and native oral mucosa vascular homeostasis phenotypes by tandem mass tag-tagged proteomics associated with laser capture microdissection and human angiogenesis antibody array technology. Then, lentiviruses were constructed and stably transfected with vascular endothelial-like cells (VELCs) to detect angiogenic capacity. HE, EdU Apollo tracer staining, immunofluorescence staining, scanning electron microscopy, biomechanical testing, and a small animal ultrasound imaging system were used to analyze the characteristics of vascularization homeostasis and monitor functional regeneration of the vascularized homeostatic phenotypic oral mucosal equivalents (VHPOME). The results showed that PGAM1, COL5A1, ANG, and RNH1 are potential specific angiogenesis phenotypes. High expression of PGAM1, COL5A1, and ANG and/or low expression of RNH1 can promote the angiogenesis of VOME. ANG/shRNH1 has the most significant tube-like structure-formation ability. The expression of PGAM1, COL5A1, and ANG in the VHPOME group was higher than that of the control group, and the expression of RNH1 was lower than that of the control group. COL5A1/ANG can significantly improve the mechanical properties. The blood flow signal was most significant in the ANG/shRNH1 group. PGAM1, COL5A1, ANG, shRNH1, PGAM1/ANG, COL5A1/ANG, PGAM1/shRNH1, PGAM1/shRNH1, COL5A1/shRNH1, and ANG/shRNH1 may be the targets for establishing vascularization homeostasis and functional regeneration of oral mucosal equivalent genes (groups), and ANG/shRNH1 has the most significant effect.
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Background/aim: In ulcerative colitis (UC), serum vascular endothelial growth factor (sVEGF) concentrations are elevated and there are conflicting results about serum calprotectin (SCP) and sVEGF as biomarkers. We aimed to evaluate the relationship between sVEGF and SCP levels in UC patients and the associations of these molecules with the phenotypes of UC. Materials and methods: This prospective case-control study included 60 UC patients and 30 healthy controls. The Mayo Clinical Score (MCS) was used to evaluate patients' clinical features and the Mayo Endoscopic Score (MES) was used to evaluate endoscopic features of the cases. The method proposed by Truelove and Richards was applied in calculating the histology activity index (HAI). Human sVEGF (Cat.E0080Hu) and human calprotectin (Cat.E4010Hu) kits were used for the enzyme-linked immunosorbent assay (ELISA) measurements of sVEGF and SCP levels. Results: The median sVEGF and SCP levels were higher in the patient group compared to the healthy control group [2139 ng/L (126-5783) vs. 888 ng/L (715-5270), p = 0.002 and 932 ng/L (99-2648) vs. 80 ng/L (56-920), p < 0.001, respectively]. There was a strong correlation between SCP and sVEGF values (rho = 0.819, p < 0.001). The MCS, MES, and HAI values were positively correlated with sVEGF and SCP concentrations. Conclusion: sVEGF and SCP may be valuable auxiliary biomarkers for UC.
Asunto(s)
Biomarcadores , Colitis Ulcerosa , Complejo de Antígeno L1 de Leucocito , Factor A de Crecimiento Endotelial Vascular , Humanos , Colitis Ulcerosa/sangre , Colitis Ulcerosa/diagnóstico , Femenino , Masculino , Factor A de Crecimiento Endotelial Vascular/sangre , Estudios de Casos y Controles , Adulto , Estudios Prospectivos , Biomarcadores/sangre , Complejo de Antígeno L1 de Leucocito/sangre , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Astragaloside IV(AS-IV), the main active ingredient of Astragalus, has been used as a treatment for heart failure with favorable effects, but its molecular mechanism has not been fully elucidated. Network pharmacological analysis and molecular docking revealed that Heat shock transcription factor 1 (HSF1) is a potential target of AS-IV. We designed cellular and animal experiments to investigate the role and intrinsic molecular mechanisms of AS-IV in ameliorating pressure overload-induced heart failure. In cellular experiments, Myocardial microvascular endothelial cells (MMVECs) were cultured in isolation and stimulated by adding high and low concentrations of AS-IV, and a cell model with down-regulation of HSF1 expression was constructed by using siRNA technology. Changes in the expression of key molecules of HSF1/VEGF signaling pathway and differences in tube-forming ability were detected in different groups of cells using PCR, WB and tube-forming assay. In animal experiments, TAC technology was applied to establish a pressure overload-induced heart failure model in C57 mice, postoperative mice were ingested AS-IV by gavage, and adenoviral transfection technology was applied to construct a mouse model with down-regulation of HSF1 expression.Small animal ultrasound for cardiac function assessment, MASSON staining, CD31 immunohistochemistry, and Western blotting (WB) were performed on the mice. The results showed that AS-IV could promote the expression of key molecules of HSF1/VEGF signaling pathway, enhance the tube-forming ability of MMVECs, increase the density of myocardial capillaries, reduce myocardial fibrosis, and improve the cardiac function of mice with TAC.AS-IV could modulate the HSF1/VEGF signaling pathway to promote the angiogenesis and improve the pressure overload-induced heart failure.