-
International Immunopharmacology May 2024Emodin, a natural anthraquinone derivative isolated from the roots of Rheum officinale Baill, has many pharmacological effects including anti-inflammatory, antioxidant,...
BACKGROUND
Emodin, a natural anthraquinone derivative isolated from the roots of Rheum officinale Baill, has many pharmacological effects including anti-inflammatory, antioxidant, antiviral, antibacterial and anti-cancer. However, little is known about the effect of emodin on acute radiation proctitis (ARP). The present study was conducted to determine its effects and elucidate its mechanisms involving AKT/MAPK/NF-κB/VEGF pathways in ARP mice.
METHODS
Total 60 C57BL/6 mice were divided randomly into control group, ARP group, AKT inhibitor MK-2206 group, and different doses of emodin groups. ARP mice were induced by 27 Gy of 6 MV X-ray pelvic local irradiation. MK-2206 was given orally for 2 weeks on alternate days. Emodin was administered daily by oral gavage for 2 weeks. Subsequently, all mice were sacrificed on day 15. The rectal tissues were obtained for further tests. The general signs score and the pathological grade were used to evaluate the severity of ARP. The expression of NF-κB, VEGF and AQP1 were determined by immunohistochemistry and western blot. The expression of p-AKT, p-ERK, p-JNK, p-p38, Bcl-2 and Bax were assessed using western blot.
RESULTS
The worse general signs and damaged tissue structure of ARP mice were profoundly ameliorated by emodin. The expression of p-AKT, p-ERK, NF-κB, VEGF and AQP1 were significantly increased, resulting in the inflammation-induced angiogenesis in ARP mice. However, the expression of p-JNK and p-p38 were decreased, leading to the reduction of apoptosis in ARP mice. Excitedly, emodin reversed these changes, not only inhibited inflammation-induced angiogenesis, but also promoted apoptosis. Notably, the effects of emodin were similar to that of AKT inhibitor MK-2206, suggesting the involvement of AKT signaling in the effect of emodin.
CONCLUSION
These results suggest that emodin attenuates ARP in mice, and the underlying mechanism might involve inhibition of the AKT/ERK/NF-κB/VEGF pathways and the induction of apoptosis mediated by JNK and p38.
Topics: Animals; Emodin; NF-kappa B; Proto-Oncogene Proteins c-akt; Mice, Inbred C57BL; Proctitis; Vascular Endothelial Growth Factor A; Mice; Signal Transduction; Radiation Injuries; Male; Anti-Inflammatory Agents; Heterocyclic Compounds, 3-Ring; Radiation Injuries, Experimental; Rectum
PubMed: 38555816
DOI: 10.1016/j.intimp.2024.111945 -
Journal of Cancer Research and... Jan 2024Gallbladder cancer (GBC) is usually diagnosed in advanced stages with poor survival. The molecular mechanisms of GBC still remain unexplored. Several angiogenesis...
AIM
Gallbladder cancer (GBC) is usually diagnosed in advanced stages with poor survival. The molecular mechanisms of GBC still remain unexplored. Several angiogenesis factors play a pivotal role in tumor progression. We aimed to study the expression of VEGF, PDGF-B, and human epidermal growth factor receptor 2 (HER2/neu) and its association with clinicopathological features and survival in GBC.
MATERIALS AND METHODS
VEGF, PDGF-B, and HER2/neu expression was studied by immunohistochemistry (IHC) after histological evaluation in 91 GBC cases. The relationship between these markers and clinicopathological features and survival was explained through the Cox regression model and Kaplan-Meier method.
RESULTS
VEGF, PDGF-B, and HER2/neu overexpressed in 45, 79, and 68% GBC cases, respectively. VEGF was significantly overexpressed in GBC without gall stones (GS) (p = 0.007) and with moderately and poorly differentiated tumors (p = 0.012). HER2/neu was significantly overexpressed in GBC with GS (p = 0.022). Median overall survival (OS) was 39 months (95% CI: 23-55). In univariate analysis, histological type (adenocarcinoma and papillary) vs. others (signet ring/mucinous/adenosquamous) (p = 0.004), depth of tumor infiltration (p = 0.017), distant metastasis (p = 0.012), and adjuvant therapies (chemotherapy/radiotherapy) (p = 0.083) were associated with poor prognosis. Multivariate survival analysis showed histological type (p = 0.004) and distant metastasis (p = 0.032) to be independent prognostic factors for OS. Histological type (p = 0.002), distant metastasis (p = 0.003), and depth of tumor infiltration (T3-T4) (p = 0.012) showed poor median survival. Poor survival was seen in VEGF and HER2/neu positive cases.
CONCLUSION
Overexpression of VEGF, PDGF-B, and HER2/neu might be possible prognostic biomarkers in GBC. Poor survival of VEGF and HER2/neu positive cases indicates the possibilities of using their blockers as therapeutic agents.
Topics: Humans; Prognosis; Gallbladder Neoplasms; Vascular Endothelial Growth Factor A; Neoplasm Staging; Lymphatic Metastasis; Receptor, ErbB-2
PubMed: 38554345
DOI: 10.4103/jcrt.jcrt_1473_22 -
Medicine Mar 2024Current study aimed to investigate the clinical characterization, differential diagnosis, and treatment of splenic littoral cell angioma (LCA). (Review)
Review
BACKGROUND
Current study aimed to investigate the clinical characterization, differential diagnosis, and treatment of splenic littoral cell angioma (LCA).
METHODS
A retrospective analysis was performed for 10 LCA cases admitted to Huzhou Central Hospital from 2007 to 2023, for clinical manifestations, hematological tests, imaging features, pathological features, treatment methods, and prognosis along with the relevant literature was also reviewed.
RESULTS
During examinations, no specific clinical manifestations and hematological abnormalities were seen in all 10 cases of LCA. Imaging observations depicted single or even multiple spherical lesions in the spleen. Plains shown by computed tomography (CT) were found somewhat equal or slightly lower in density. On the other hand, magnetic resonance imaging (MRI) plain scans viz. T1 weighted image showed equal low and mixed signals while T2-weighted showed high and low mixed signals. Moreover, punctate low signals could be seen in high signals named "freckle sign" in MRI scans. On contrast-enhanced CT scans, the enhancement of the lesions was not obvious in the arterial phase, and some of the lesions showed edged ring-like enhancements and "filling lake" progressive enhancement during the venous phase and delayed phase. In multiple lesions, the number of enhanced scan lesions showed a variable changing pattern "less-more-less." MRI-enhanced scan showed the characteristics of "fast in and slow out." Microscopic examinations identified tumor tissue actually composed of sinus-like lacunae that anastomosed with each other in the form of a network. Furthermore, cystic expansion and pseudopapillary protrusions were also seen in the dilated sinus cavity which was lined with single-layer endothelial cells having conspicuous cytoplasmic hemosiderin. High immunophenotypic expressions of vascular endothelial cell phenotype (CD31, CD34, FVIII) and tissue cell phenotype (CD68) were also seen. Total and partial splenectomy were performed in 8 and 2 patients, respectively, and follow-up examinations showed survival in all patients with no recurrence.
CONCLUSION
LCA is a rare splenic benign lesion with atypical clinical manifestations. CT and MRI imaging are important tools in preoperative diagnosis based on pathomorphological and immunohistochemical examinations. Splenectomy is a superior therapeutic choice with significant impacts and prognosis.
Topics: Humans; Endothelial Cells; Retrospective Studies; Splenic Neoplasms; Hemangioma
PubMed: 38552075
DOI: 10.1097/MD.0000000000037550 -
The Journal of Biological Chemistry May 2024Impaired cholesterol efflux and/or uptake can influence arterial lipid accumulation leading to atherosclerosis. Here, we report that tripartite motif-containing protein...
Impaired cholesterol efflux and/or uptake can influence arterial lipid accumulation leading to atherosclerosis. Here, we report that tripartite motif-containing protein 13 (TRIM13), a RING-type E3 ubiquitin ligase, plays a role in arterial lipid accumulation leading to atherosclerosis. Using molecular approaches and KO mouse model, we found that TRIM13 expression was induced both in the aorta and peritoneal macrophages (pMφ) of ApoE mice in response to Western diet (WD) in vivo. Furthermore, proatherogenic cytokine interleukin-1β also induced TRIM13 expression both in pMφ and vascular smooth muscle cells. Furthermore, we found that TRIM13 via ubiquitination and degradation of liver X receptor (LXR)α/β downregulates the expression of their target genes ABCA1/G1 and thereby inhibits cholesterol efflux. In addition, TRIM13 by ubiquitinating and degrading suppressor of cytokine signaling 1/3 (SOCS1/3) mediates signal transducer and activator of transcription 1 (STAT1) activation, CD36 expression, and foam cell formation. In line with these observations, genetic deletion of TRIM13 by rescuing cholesterol efflux and inhibiting foam cell formation protects against diet-induced atherosclerosis. We also found that while TRIM13 and CD36 levels were increased, LXRα/β, ABCA1/G1, and SOCS3 levels were decreased both in Mφ and smooth muscle cells of stenotic human coronary arteries as compared to nonstenotic arteries. More intriguingly, the expression levels of TRIM13 and its downstream signaling molecules were correlated with the severity of stenotic lesions. Together, these observations reveal for the first time that TRIM13 plays a crucial role in diet-induced atherosclerosis, and that it could be a potential drug target against this vascular lesion.
Topics: Animals; Humans; Male; Mice; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; Cholesterol; Diet, Western; DNA-Binding Proteins; Foam Cells; Lipoproteins, LDL; Liver X Receptors; Mice, Knockout, ApoE; RAW 264.7 Cells; STAT1 Transcription Factor; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 38537695
DOI: 10.1016/j.jbc.2024.107224 -
Multimedia Manual of Cardiothoracic... Mar 2024Micro-invasive totally endoscopic aortic valve replacement surgery is a minimally invasive cardiac procedure that can be performed with the help of several techniques...
Micro-invasive totally endoscopic aortic valve replacement surgery is a minimally invasive cardiac procedure that can be performed with the help of several techniques and technologies that employ the latest innovations in instrumentation and technological advances in the field, thereby greatly limiting the overall invasiveness of the procedure. With the help of a 3-dimensional camera, long instruments, a very small thoracotomy and a soft-tissue retractor without any rib retractor, the aortic valve can be easily and safely accessed for replacement. The other main features of these techniques are extracorporeal circulation that is achieved through peripheral percutaneous cannulation of the femoral vessels, antegrade cardioplegia, the use of automated devices for suturing the valvular ring and the prosthetic suture cuff, namely the RAM device, the Sew-Easy device and the Cor-Knot Mini device. Additionally, an automated vascular closure device such as the MANTA device is later used to close the femoral artery following decannulation.
Topics: Humans; Aortic Valve; Catheters; Endoscopy; Femoral Artery; Lower Extremity
PubMed: 38530245
DOI: 10.1510/mmcts.2023.094 -
Alzheimer's Research & Therapy Mar 2024Posterior cortical atrophy (PCA) is a form of dementia that frequently displays significant visual dysfunction and relatively preserved cognitive and executive...
Potential ocular indicators to distinguish posterior cortical atrophy and typical Alzheimer's disease: a cross-section study using optical coherence tomography angiography.
BACKGROUND
Posterior cortical atrophy (PCA) is a form of dementia that frequently displays significant visual dysfunction and relatively preserved cognitive and executive functions, thus hindering early diagnosis and treatment. This study aimed to investigate possible fundus markers in PCA patients and compare them with those of typical Alzheimer's disease (AD) patients to seek potential diagnostic patterns.
METHODS
Age-matched PCA and AD patients and healthy controls (HC) completed optometry, intraocular pressure measurement, neuropsychologic assessments, optical coherence tomography (OCT), and optical coherence tomography angiography (OCTA) examination in one visit. Overall, six outcomes of thicknesses of various retinal layers and seven outcomes of the retinal microvascular network were calculated. After adjusting for age, sex, and years of education, the OCT and OCTA results were analyzed using analysis of covariance and generalized linear models. Correlation analyses were performed using Spearman correlation, and ROC curves were plotted.
RESULTS
Twelve PCA patients, nineteen AD patients, and thirty HC, aged 45-80 years were included. Fifty HC, thirty AD, and twenty PCA eyes were available for foveal avascular zone (FAZ) area analysis; forty-nine HC, thirty-four AD, and eighteen PCA eyes were available for OCT and OCTA assessments. PCA patients had thinner retinal nerve fiber layer and ganglion cell layer + inner plexiform layer than HC in the 0-3 mm circle and 1-3 mm ring. Few structural differences were observed between the AD group and the other two groups. The flow area of the superficial capillary plexus and the intermediate capillary plexus was smaller in the PCA group than in the HC group in the 0-1 mm circle, 0-3 mm circle. MMSE performed better than any combination of optical parameters in identifying AD and PCA from HC (AUC = 1), while the combination of MoCA, retinal thickness and vascular density of ICP in the 1-3 mm ring, with flow area of ICP in the 0-1 mm circle showed the strongest ability to distinguish PCA from AD (AUC = 0.944).
CONCLUSIONS
PCA patients exhibited similar impairment patterns to AD patients in the fundus structure and microvascular network. OCTA may aid in the non-invasive detection of AD and PCA, but still remains to be substantiated.
Topics: Humans; Alzheimer Disease; Tomography, Optical Coherence; Retinal Vessels; Fluorescein Angiography; Atrophy
PubMed: 38528626
DOI: 10.1186/s13195-024-01431-w -
CASE (Philadelphia, Pa.) Mar 2024• Thoracic vascular rings are congenital anomalies with varied symptomatology. • Suspect and rule out vascular ring in unexplained upper airway/esophageal...
• Thoracic vascular rings are congenital anomalies with varied symptomatology. • Suspect and rule out vascular ring in unexplained upper airway/esophageal obstruction. • Include additional AA and pulmonary branch views in ACHD echo protocol. • Cross-sectional cardiac imaging helps in unambiguous surgical planning.
PubMed: 38524979
DOI: 10.1016/j.case.2023.12.014 -
Cell Reports Apr 2024Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator that mediates cellular adaptation to decreased oxygen availability. HIF-1 recruits chromatin-modifying...
Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator that mediates cellular adaptation to decreased oxygen availability. HIF-1 recruits chromatin-modifying enzymes leading to changes in histone acetylation, citrullination, and methylation at target genes. Here, we demonstrate that hypoxia-inducible gene expression in estrogen receptor (ER)-positive MCF7 and ER-negative SUM159 human breast cancer cells requires the histone H2A/H2B chaperone facilitates chromatin transcription (FACT) and the H2B ubiquitin ligase RING finger protein 20/40 (RNF20/40). Knockdown of FACT or RNF20/40 expression leads to decreased transcription initiation and elongation at HIF-1 target genes. Mechanistically, FACT and RNF20/40 are recruited to hypoxia response elements (HREs) by HIF-1 and stabilize binding of HIF-1 (and each other) at HREs. Hypoxia induces the monoubiquitination of histone H2B at lysine 120 at HIF-1 target genes in an HIF-1-dependent manner. Together, these findings delineate a cooperative molecular mechanism by which FACT and RNF20/40 stabilize multiprotein complex formation at HREs and mediate histone ubiquitination to facilitate HIF-1 transcriptional activity.
Topics: Humans; Cell Hypoxia; Cell Line, Tumor; DNA-Binding Proteins; Histones; Hypoxia-Inducible Factor 1; MCF-7 Cells; Protein Binding; Response Elements; Transcription Factors; Transcriptional Activation; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 38517892
DOI: 10.1016/j.celrep.2024.113972 -
Cells Feb 2024Diabetic foot ulcers (DFU) pose a significant health risk in diabetic patients, with insufficient revascularization during wound healing being the primary cause. This...
The Combination of Vascular Endothelial Growth Factor A (VEGF-A) and Fibroblast Growth Factor 1 (FGF1) Modified mRNA Improves Wound Healing in Diabetic Mice: An Ex Vivo and In Vivo Investigation.
BACKGROUND
Diabetic foot ulcers (DFU) pose a significant health risk in diabetic patients, with insufficient revascularization during wound healing being the primary cause. This study aimed to assess microvessel sprouting and wound healing capabilities using vascular endothelial growth factor (VEGF-A) and a modified fibroblast growth factor (FGF1).
METHODS
An ex vivo aortic ring rodent model and an in vivo wound healing model in diabetic mice were employed to evaluate the microvessel sprouting and wound healing capabilities of VEGF-A and a modified FGF1 both as monotherapies and in combination.
RESULTS
The combination of VEGF-A and FGF1 demonstrated increased vascular sprouting in the ex vivo mouse aortic ring model, and topical administration of a combination of VEGF-A and FGF1 mRNAs formulated in lipid nanoparticles (LNPs) in mouse skin wounds promoted faster wound closure and increased neovascularization seven days post-surgical wound creation. RNA-sequencing analysis of skin samples at day three post-wound creation revealed a strong transcriptional response of the wound healing process, with the combined treatment showing significant enrichment of genes linked to skin growth.
CONCLUSION
f-LNPs encapsulating VEGF-A and FGF1 mRNAs present a promising approach to improving the scarring process in DFU.
Topics: Humans; Mice; Animals; Vascular Endothelial Growth Factor A; Fibroblast Growth Factor 1; Diabetes Mellitus, Experimental; Neovascularization, Physiologic; Wound Healing; Diabetic Foot; Disease Models, Animal
PubMed: 38474378
DOI: 10.3390/cells13050414 -
Biochimica Et Biophysica Acta.... Apr 2024Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and...
AIMS
Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive.
MAIN METHODS
We employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice.
KEY FINDINGS
Inhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway.
CONCLUSIONS
Our findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.
Topics: Animals; Chick Embryo; Humans; Mice; Rats; Endothelial Cells; Guanine Nucleotide Exchange Factors; Phosphatidylinositol 3-Kinases; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A; Neovascularization, Pathologic
PubMed: 38447883
DOI: 10.1016/j.bbadis.2024.167114