Advances in the antitumor mechanisms of tripartite motif-containing protein 3.

The tripartite motif-containing (TRIM) protein family has steadily become a hotspot in tumor-related research. As a member of the E3 ubiquitin ligase family, TRIM is working on many crucial biological processes, including the regulation of tumor cell proliferation, metastasis, apoptosis, and autophagy. Among the diverse TRIM superfamily members, TRIM3 operates via different mechanisms in various types of tumors. This review primarily focuses on the current state of research regarding the antitumor mechanisms of TRIM3 in different cancers. A more in-depth study of TRIM3 may provide new directions for future antitumor treatments. Our review focuses on TRIM3 proteins and cancer. We searched for relevant articles on the mechanisms by which TRIM3 affects tumorigenesis and development from 1997 to 2023 and summarized the latest progress and future directions. Triad-containing motif protein 3 (TRIM3) is an important protein, which plays a key role in the process of tumorigenesis and development. The comprehensive exploration of TRIM3 is anticipated to pave the way for future advancements in antitumor therapy, which is expected to be a new hallmark for cancer detection and a novel target for drug action. TRIM3 is poised to become a significant milestone in cancer detection and a promising focal point for drug intervention. Recent years have witnessed notable progress in research aimed at unraveling the antitumor mechanism of TRIM3, with far-reaching implications for practical tumor diagnosis, treatment protocols, efficacy evaluation, economics, and pharmaceutical utilization.

Safety and Efficacy of Stent-Graft in the Treatment of Aortoiliac Artery Occlusive Disease: A Multicenter Study of Short-Term and Medium-Term Outcomes.

BACKGROUND: To evaluate the short-term and mid-term safety and efficacy of stent-graft compared with bare stents for treatment of aortoiliac occlusive disease (AIOD). METHODS: One hundred eighty three patients diagnosed with AIOD who received stent implantation at 3 vascular centers in north China between January 2019 and December 2021 were enrolled. Patients were divided into those undergoing stent-graft (Group A; n = 67) or bare stent (Group B; n = 116) implantation for retrospective cohort analysis. Efficacy was assessed as surgical success rate and rate of freedom from clinically driven target lesion reintervention at each follow-up time point. Safety was assessed by the rate of perioperative complication, major limb amputation, and aortoiliac artery-related mortality. RESULTS: There were no preoperative baseline differences between the 2 groups (P > 0.05). The surgical success was 91.04% for Group A, significantly higher than that for Group B (79.31%; P < 0.05). Incidence of perioperative complications was 2.98% for Group A, significantly lower than that for Group B (9.48%, P < 0.05), as was the rate of major limb amputation (A: 1.49% vs. B: 5.17%) and aortoiliac artery-related mortality (A: 1.49% vs. B: 4.31%), although these 2 indicators were not significantly different (P > 0.05). Follow-up rates were 91.8% for the total follow-up time of 3 years. Kaplan-Meier survival curve analysis gave significantly higher 1-year and 2-year freedom from clinically driven target lesion reintervention for Group A (98.51% and 95.52%) than for Group B (95.69% and 89.66%, P < 0.05). CONCLUSIONS: Stent-graft is more effective and safer than bare stent in the treatment of AIOD.

Midterm Outcomes of Multicenter Castor Single-Branch Stent Graft Use in the Treatment of Thoracic Aortic Diseases.

PURPOSE: The aim of this study was to evaluate the midterm efficacy and safety of a single-branch Castor stent graft in the treatment of thoracic aortic disease. MATERIALS AND METHODS: Clinical data of 106 patients with thoracic aortic disease treated with Castor single-branch stent graft at 3 centers were collected between May 2018 and June 2023. The indicators included technical success, stent-related complication, reintervention, retrograde dissection, endoleak, distal stent graft-induced entry (dSINE), branch patency, and mortality. The outcomes of the Castor stent graft for multibranch reconstruction above the arch was also analyzed. RESULTS: The technical success was 98.1% (104/106), while the surgical success was 93.4% (99/106). The reintervention was 2.8% (3/106), consisting of a case of retrograde type A dissection, an endoleak, and a dSINE. The retrograde dissection was 1.9% (2/106), while type I endoleak was 1.9% (2/106). The new dSINE was 2.8% (3/106), and the branch patency rate was 100%. The mortality was 1.9% (2/106). The mean follow-up time was 29.1±17.7 months. The 2-year post-surgery cumulative survival rate was 91.0%±3.1%, while the cumulative branch patency rate was 96.2%±2.2%. In addition, the cumulative freedom from stent-related reintervention rate was 93.2%±2.8%. A comparison showed no significant difference in the stent-related complication, branch patency, endoleak, reintervention, and mortality when the proximal end of the Castor stent graft was anchored to zones 1 or 2 of the aorta. CONCLUSION: Castor single-branch stent graft showed favorable early and midterm outcomes in the treatment of thoracic aortic disease. In addition, it was feasible to combine Castor stent graft with other advanced techniques for multibranch aortic arch reconstruction. CLINICAL IMPACT: The Castor single-branch stent graft was approval by the Chinese Food and Drug Administration in 2017. However, there were few studies on the mid-term outcomes for thoracic aortic disease after launching, which mainly focused on small single-center retrospective study. In the study, we assessed the mid-term outcomes of Castor stent graft through multi-center cases, Castor stent graft combined with other advanced techniques (such as fenestration and hybrid) for multi-branch reconstruction of aortic arch were also conducted. We found Castor single-branch stent graft showed favorable early and mid-term outcomes in the treatment of thoracic aortic disease. Additionally, it was feasible to combine Castor stent graft with other advanced technique for multi-branch aortic arch reconstruction. As an off-the-shelf branched stent graft with a wide range of models, it could be also used in most emergent situation. The Castor stent graft was expected to become more widely used in the future.

Hyperhomocysteinemia may aggravate abdominal aortic aneurysm formation by up-regulating RASSF2.

Abdominal aortic aneurysm (AAA) is a fatal cardiovascular disorder with high mortality and morbidity rates. To date, no drug has shown to significantly alleviate the risk of AAA. Previous studies have indicated that hyperhomocysteinemia (HHcy) significantly increases the incidence of AAA by disrupting endothelial cell homeostasis; however, the potential molecular mechanisms require clarification. Herein, we aimed to integrate transcriptomics analysis and molecular biology experiments to explore the potential molecular targets by which HHcy may increase the incidence of AAA. We integrated two AAA data profiles (GSE57691 and GSE7084) based on previously published microarray ribonucleic acid sequencing (RNAseq) data from the GEO database. Additionally, 500 µM homocysteine-treated human aorta endothelium cells microarray dataset (GSE175748) was downloaded and processed. Subsequently, single-cell RNA-seq profiles of the aortic aneurysms (GSE155468) were downloaded, scaled, and processed for further analysis. The microarray profiles analysis demonstrated that the Ras association domain family member 2 (RASSF2) and interleukin (IL)-1ß are potentially the target genes involved in the HHcy-mediated aggravation of AAA formation. Single-cell RNAseq analysis revealed that RASSF2 might impair endothelial cell function by increasing inflammatory cell infiltration to participate in AAA formation. Finally, we conducted reverse transcription quantitative polymerase chain reaction and immunofluorescence analysis to validate the up-regulated mRNA expression of RASSF2 (p = 0.008) and IL-1ß (p = 0.002) in AAA tissue compared to control tissue. Immunofluorescence staining revealed overexpression of RASSF2 protein in AAA tissue sections compared to control tissue (p = 0.037). Co-localization of RASSF2 and the aortic endothelium cell marker, CD31, was observed in tissue sections, indicating the potential involvement of RASSF2 in aortic endothelial cells. To summarise, our preliminary study revealed that HHcy may worsen AAA formation by up-regulating the expression of RASSF2 and IL-1ß in aortic endothelium cells.

Monofunctional dimetallic Ru(η6-arene) complexes inhibit NOTCH1 signaling pathway and synergistically enhance anticancer effect in combination with cisplatin or vitamin C.

ONS donor ligands L1-L4 were utilized in the preparation of monofunctional dimetallic Ru(η6-arene) complexes (C1-C4). These ONS donor ligand based novel tricoordinated Ru(II) complexes bearing η6-arene co-ligand were prepared for the first time. The current methodology resulted in excellent isolated yields and these complexes were characterized in detail by different spectroscopic and spectrometric techniques. The structures of C1-C2 and C4 were characterized in solid state by single crystal X-ray analysis. The in vitro anticancer analyses showed these novel complexes suppressed the growth of breast (MCF-7), liver (HepG2) and lung (A549) cancer cells. C2 suppressed the growth of these cells in dose-dependent manner revealed form the MTT and crystal violet cell viability assays. Moreover, C2 was observed the most potent complex that was used further in detailed mechanistic analyses in cancer cells. C2 showed good cytotoxic activity at 10 µM dose level as compared to cisplatin or oxaliplatin in these cancer cells. We observed morphological changes in cancer cells upon treatment with C2. Moreover, C2 suppressed the invasion and migration ability of cancer cells. C2 induced cellular senescence to retard cell growth and suppressed the formation of cancer stem cells. Importantly, C2 showed synergistic anticancer effect in combination with cisplatin and Vitamin C to further inhibit cell growth which suggested the potential role of C2 in cancer therapy. Mechanistically, C2 inhibited NOTCH1 dependent signaling pathway to suppress cancer cell invasion, migration and cancer stem cells formation. Thus, these data suggested potential role of C2 in cancer therapy by targeting NOTCH1-dependent signaling to suppress tumorigenesis. The results obtained in this study for these novel monofunctional dimetallic Ru(η6-arene) complexes showed their high anticancer potency and this study will pave to further cytotoxicity exploration on this class of complexes.

Fibrin Glue Sac Filling for Preventing Type II Endoleak, Short-Term Outcomes of a Prospective Randomized Controlled Trial.

OBJECTIVE: Type II endoleak (T2EL) worsens the long-term results of endovascular aneurysm repair (EVAR). How to prevent T2ELs remains controversial. This study aimed to evaluate the efficacy and safety of fibrin glue sac filling (FGSF) to prevent T2ELs after EVAR. METHODS: A prospective randomized controlled trial was conducted. Patients were randomly divided into group A (standard EVAR + FGSF) and group B (standard EVAR). The follow-up plans included outpatient or telephone consultation at 1 and 3 months and computed tomography (CT) angiography at 6 months, 1 year, and once a year after EVAR. RESULTS: A total of 64 abdominal aortic aneurysm (AAA) patients were randomized to the 2 groups. All patients were followed up for more than 6 months. The 2 groups showed similar baseline characteristics. The rate of T2ELs on immediate angiography in group A (9.6%) was significantly lower than that in group B (33.3%, p=0.033). Moreover, the sac area change was significantly reduced in group A at 6 months after EVAR (p=0.021). However, T2EL incidence was similar at the 6-month (p=0.055) and 1-year (p=0.057) follow-ups, and AAA diameter change was also similar at 1 year. There were similar operation times, radiation doses, severe adverse events (SAEs), and reinterventions between the 2 groups. CONCLUSION: Fibrin glue sac filling could prevent short-term type II endoleaks and promote AAA shrinkage after 6 months. The FGSF procedure is swift and straightforward; however, patients are at risk of bowel ischemia, especially after previous bowel resections or concomitant superior mesenteric artery (SMA) disease. CLINICAL IMPACT: Standard endovascular aneurysm repair (EVAR) couldn't prevent type II endoleak (T2EL). In this study, we found fibrin glue sac filling (FGSF) could prevent T2EL and promote AAA shrinkage in a short term. And the FGSF procedure is easy, it will be a useful supplement to standard EVAR for clinicians. And FGSF might have potential usefulness on ruptured aneurysms, although without direct evidence.Fibrin glue is often used to hemostasis and tissue adhesion in surgical patients and burn patients, we firstly carry out a randomized controlled study and prove that fibrin glue sac filling could prevent T2EL and promote sac remodeling.

A nomogram risk assessment model to predict the possibility of type II endoleak-related re-intervention after endovascular aneurysm repair (EVAR).

This study aimed to develop and validate a novel nomogram risk assessment model to predict the possibility of type II endoleak (T2EL)-related re-intervention. The data of 455 patients with abdominal aortic aneurysms who underwent elective endovascular aneurysm repair (EVAR) procedures between January 2018 and December 2021 at our single center were retrospectively reviewed. Following the implementation of exclusion criteria, 283 patients were finally included and divided into T2EL-related re-intervention (n = 42) and non-T2EL (n = 241) groups. The overall T2EL-related re-intervention rate for 283 patients was 14.8% (42/283). Using multivariate analysis, significant risk factors for re-intervention included age (OR, 1.172; 95% CI, 1.051-1.307; P = 0.004), smoking (OR, 13.418; 95% CI, 2.362-76.215; P = 0.003), diameter of inferior mesenteric artery (IMA) (OR, 21.380; 95% CI, 3.060-149.390; P = 0.002), and number of patent lumbar arteries (OR, 9.736; 95% CI, 3.175-29.857; P < 0.001). The discrimination ability of this risk-predictive model was reasonable (concordance index [C-index] = 0.921; 95% CI, 0.878-0.964). The Hosmer-Lemeshow goodness of fit test was performed on the model, and the chi-square value was 3.210 (P = 0.920), presenting an excellent agreement between the model-predicted and observed values. The receiver operating characteristic (ROC) curve identified that the risk thresholds of re-intervention were a diameter of > 2.77 mm for the diameter of the inferior mesenteric artery and a proportion of < 45.5% for thrombus volume in the aneurysm sac. This novel nomogram risk assessment model for predicting the possibility of patients' T2EL-related re-interventions after EVAR should be helpful in discriminating high-risk patients. Two novel risk thresholds may imply a higher possibility of T2EL-related re-intervention after EVAR.

Midterm outcomes of fenestrated TEVAR using physician-modified endovascular grafts for zone 2.

OBJECTIVES: To summarize the experience and midterm outcomes of physician-modified endovascular grafts for zone 2 thoracic endovascular aortic repair. METHODS: A retrospective analysis was conducted of 51 consecutive patients (mean age 57.6 ± 12.5 years, 39 males) treated with thoracic endovascular aortic repair using physician-modified endovascular grafts for reconstructing the left subclavian artery from November 2015 to December 2019. The primary endpoints during follow-up were the overall mortality, aorta-related mortality, and major complications. The secondary endpoints were reintervention and the patency of the target branches, the demographics and technical details were also described and analyzed. RESULTS: Sixty-three thoracic stent-grafts were deployed in 51 patients and emergency surgery was performed in 10 patients (19.6%). Technical success was 94.1% (48/51). The incidence of perioperative complications was 15.7%, and the 30-day mortality was 0%. At a mean follow-up of 42.0 ± 14.4 months (range, 14-63 months), all the left subclavian arteries remained patent. All-cause mortality was 3.9% (2/51) and not aorta-related deaths. Estimated survival at one and three years was 98.0 ± 1.9% and 96.0 ± 2.8%, respectively. CONCLUSIONS: The physician-modified endovascular grafts is feasible and effective to preserve left subclavian artery in thoracic endovascular aortic repair for aortic arch pathologies with unhealthy proximal landing zone.

Inhibition of SREBP-mediated lipid biosynthesis and activation of multiple anticancer mechanisms by platinum complexes: Ascribe possibilities of new antitumor strategies.

Cancer is one of the most aggressive diseases with poor prognosis and survival rates. Lipids biogenesis play key role in cancer progression, metastasis and tumor development. Suppression of SREBP-mediated lipid biogenesis pathway has been linked with cancer inhibition. Platinum complexes bearing good anticancer effect and multiple genes activation properties are considered important and increase the chances for development of new platinum-based drugs. In this study, we synthesized pyridine co-ligand functionalized cationic complexes and characterized them using multiple spectroscopic and spectrophotometric methods. Two of these complexes were studied in solid state by single crystal X-ray analysis. The stability of these complexes were measured in solution state using 1H NMR methods. These complexes were further investigated for their anticancer activity against human breast, lung and liver cancer cells. MTT assay showed potential cytotoxic activity in dose-dependent manner and decrease survival rates of cancer cells was observed upon treatment with these complexes. Biological assays results revealed higher cytotoxicity as compared to cisplatin and oxaliplatin. Further we studied C2, C6 and C8 in detailed mechanistic anticancer analyses. Clonogenic assay showed decrease survival of MCF-7, HepG2 and A549 cancer cells treated with C2, C6 and C8 as compared to control cells treated with DMSO. TUNEL assay showed more cell death, these complexes suppressed invasion and migration ability of cancer cells and decreased tumor spheroids formation, thus suggesting a potential role in inhibition of cancer metastasis and cancer stem cells formation. Mechanistically, these complexes inhibited sterol regulatory element-binding protein 1 (SREBP-1) expression in cancer cells in dose-dependent manner and thereby reduced lipid biogenesis to suppress cancer progression. Furthermore, expression level was decreased for the key genes LDLR, FASN and HMGCR, those required for sterol biosynthesis. Taken together, these complexes suppressed cancer cell growth, migration, invasion and spheroids formation by inhibiting SREBP-1 mediated lipid biogenesis pathway.

Resolvin D1 Programs Inflammation Resolution by Increasing TGF-ß Expression Induced by Dying Cell Clearance in Experimental Autoimmune Neuritis.

UNLABELLED: Experimental autoimmune neuritis (EAN) is the animal model of human acute inflammatory demyelinating polyradiculoneuropathies (AIDP), an auto-immune inflammatory demyelination disease of the peripheral nervous system (PNS) and the world's leading cause of acute autoimmune neuromuscular paralysis. EAN and AIDP are characterized by self-limitation with spontaneous recovery; however, endogenous pathways that regulate inflammation resolution in EAN and AIDP remain elusive. A pathway of endogenous mediators, especially resolvins and clearance of apoptotic cells, may be involved. Here, we determined that resolvin D1 (RvD1), its synthetic enzyme, and its receptor were greatly increased in PNS during the recovery stage of EAN. Both endogenous and exogenous RvD1 increased regulatory T (Treg) cell and anti-inflammatory macrophage counts in PNS, enhanced inflammation resolution, and promoted disease recovery in EAN rats. Moreover, RvD1 upregulated the transforming growth factor-ß (TGF-ß) level and pharmacologic inhibition of TGF-ß signaling suppressed RvD1-induced Treg cell counts, but not anti-inflammatory macrophage counts, and RvD1-improved inflammation resolution and disease recovery in EAN rats. Mechanistically, the RvD1-enhanced macrophage phagocytosis of apoptotic T cells leading to reduced apoptotic T-cell accumulation in PNS induced TGF-ß production and caused Treg cells to promote inflammation resolution and disease recovery in EAN. Therefore, these data highlight the crucial role of RvD1 as an important pro-resolving molecule in EAN and suggest its potential as a therapeutic target in human neuropathies. SIGNIFICANCE STATEMENT: Experimental autoimmune neuritis (EAN) is the animal model of human acute inflammatory demyelinating polyradiculoneuropathies, an auto-immune inflammatory demyelination disease of the peripheral nervous system (PNS) and the world's leading cause of acute autoimmune neuromuscular paralysis. Here, we demonstrated that resolvin D1 (RvD1) promoted macrophage phagocytosis of apoptotic T cells in PNS, thereby upregulating transforming growth factor-ß by macrophages, increased local Treg cell counts, and finally promoted inflammation resolution and disease recovery in EAN. These data highlight the crucial role of RvD1 as an important pro-resolving molecule in EAN and suggest that it has potential as a therapeutic target in human neuritis.

Phagocyte respiratory burst activates macrophage erythropoietin signalling to promote acute inflammation resolution.

Inflammation resolution is an active process, the failure of which causes uncontrolled inflammation which underlies many chronic diseases. Therefore, endogenous pathways that regulate inflammation resolution are fundamental and of wide interest. Here, we demonstrate that phagocyte respiratory burst-induced hypoxia activates macrophage erythropoietin signalling to promote acute inflammation resolution. This signalling is activated following acute but not chronic inflammation. Pharmacological or genetical inhibition of the respiratory burst suppresses hypoxia and macrophage erythropoietin signalling. Macrophage-specific erythropoietin receptor-deficient mice and chronic granulomatous disease (CGD) mice, which lack the capacity for respiratory burst, display impaired inflammation resolution, and exogenous erythropoietin enhances this resolution in WT and CGD mice. Mechanistically, erythropoietin increases macrophage engulfment of apoptotic neutrophils via PPARγ, promotes macrophage removal of debris and enhances macrophage migration to draining lymph nodes. Together, our results provide evidences of an endogenous pathway that regulates inflammation resolution, with important implications for treating inflammatory conditions.

Erythropoeitin Signaling in Macrophages Promotes Dying Cell Clearance and Immune Tolerance.

The failure of apoptotic cell clearance is linked to autoimmune diseases, nonresolving inflammation, and developmental abnormalities; however, pathways that regulate phagocytes for efficient apoptotic cell clearance remain poorly known. Apoptotic cells release find-me signals to recruit phagocytes to initiate their clearance. Here we found that find-me signal sphingosine 1-phosphate (S1P) activated macrophage erythropoietin (EPO) signaling promoted apoptotic cell clearance and immune tolerance. Dying cell-released S1P activated macrophage EPO signaling. Erythropoietin receptor (EPOR)-deficient macrophages exhibited impaired apoptotic cell phagocytosis. EPO enhanced apoptotic cell clearance through peroxisome proliferator activated receptor-γ (PPARγ). Moreover, macrophage-specific Epor(-/-) mice developed lupus-like symptoms, and interference in EPO signaling ameliorated the disease progression in lupus-like mice. Thus, we have identified a pathway that regulates macrophages to clear dying cells, uncovered the priming function of find-me signal S1P, and found a role of the erythropoiesis regulator EPO in apoptotic cell disposal, with implications for harnessing dying cell clearance.

Nonerythropoietic Erythropoietin-Derived Peptide Suppresses Adipogenesis, Inflammation, Obesity and Insulin Resistance.

Erythropoietin (EPO) has been identified as being crucial for obesity modulation; however, its erythropoietic activity may limit its clinical application. EPO-derived Helix B-surface peptide (pHBSP) is nonerythrogenic but has been reported to retain other functions of EPO. The current study aimed to evaluate the effects and potential mechanisms of pHBSP in obesity modulation. We found that pHBSP suppressed adipogenesis, adipokine expression and peroxisome proliferator-activated receptor γ (PPARγ) levels during 3T3-L1 preadipocyte maturation through the EPO receptor (EPOR). In addition, also through EPOR, pHBSP attenuated macrophage inflammatory activation and promoted PPARγ expression. Furthermore, PPARγ deficiency partly ablated the anti-inflammatory activity of pHBSP in macrophages. Correspondingly, pHBSP administration to high-fat diet (HFD)-fed mice significantly improved obesity, insulin resistance (IR) and adipose tissue inflammation without stimulating hematopoiesis. Therefore, pHBSP can significantly protect against obesity and IR partly by inhibiting adipogenesis and inflammation. These findings have therapeutic implications for metabolic disorders, such as obesity and diabetes.

Therapeutic effects of nonerythropoietic erythropoietin analog ARA290 in experimental autoimmune encephalomyelitis rat.

ARA290 is a nonerythropoietic analog of erythropoietin (EPO) containing 11 amino acids which provides the anti-inflammatory and neuroprotective effects of EPO without stimulating hematopoiesis. Here we studied the therapeutic effects of ARA290 in experimental autoimmune encephalomyelitis (EAE) Lewis rats. Therapeutic (from Day 7 to Day 18 or from Day 9 to Day 19) administration of ARA290 (35, 70 µg/kg, intra-peritoneal) to EAE rats once daily significantly reduced the severity and shortened the duration of clinical score, reduced the accumulation of inflammatory cells in EAE spinal cords and suppressed mRNA levels of interleukin-1ß (IL-1ß), IL-17, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), inducible nitric oxide synthase (iNOS), matrix metalloproteinase 9 (MMP9) and transcription factor T-bet in spinal cords of EAE rats. Furthermore, ARA290 treatment reduced the helper T cell number in lymph nodes and circulation in EAE. In vitro study showed that ARA290 dose-dependently inhibited antigen specific- and antigen non-specific-lymphocyte proliferation as well. In addition, ARA290 altered the cytokine milieu to favor the polarization of Th2 and regulatory T (Treg) cells but suppressed the polarization of Th1 and Th17 cells in EAE lymph nodes. In summary, our study here showed that ARA290 could alter T cell function to suppress inflammation to ameliorate EAE, suggesting that ARA290 may be a new therapeutic candidate for multiple sclerosis.