Fluorinated BPA derivatives enhanced 10B delivery in tumors.

Boron neutron capture therapy (BNCT) is an emerging approach for treating malignant tumors with binary targeting. However, its clinical application has been hampered by insufficient 10B accumulation in tumors and low 10B concentration ratios of tumor-to-blood (T/B) and tumor-to-normal tissue (T/N). Herein, we developed fluorinated BPA derivatives with different fluorine groups as boron delivery agents for enabling sufficient 10B accumulation in tumors and enhancing T/B and T/N ratios. Our findings demonstrated that fluorinated BPA derivatives had good biological safety. Furthermore, fluorinated BPA derivatives showed improved 10B accumulation in tumors and enhanced T/B and T/N ratios compared to the clinical boron drug fructose-BPA (f-BPA). In particular, in B16-F10 tumor-bearing mice, fluorinated BPA derivatives met the requirements for clinical BNCT even at half of the clinical dose. Thus, fluorinated BPA derivatives are potentially effective boron delivery agents for clinical BNCT in melanoma.

Long-term and short-term cardiovascular disease mortality among patients of 21 non-metastatic cancers.

INTRODUCTION: Previous studies on cardiovascular disease (CVD) death risk in cancer patients mostly focused on overall cancer, age subgroups and single cancers. OBJECTIVES: To assess the CVD death risk in non-metastatic cancer patients at 21 cancer sites. METHODS: A total of 1,672,561 non-metastatic cancer patients from Surveillance, Epidemiology, and End Results (SEER) datebase (1975-2018) were included in this population-based study, with a median follow-up of 12·7 years. The risk of CVD deaths was assessed using proportions, competing-risk regression, absolute excess risks (AERs), and standardized mortality ratios (SMRs). RESULTS: In patients with localized cancers, the proportion of CVD death and cumulative mortality from CVD in the high-competing risk group (14 of 21 unique cancers) surpassed that of primary neoplasm after cancer diagnosis. The SMRs and AERs of CVD were found higher in patients with non-metastatic cancer than the general US population (SMR 1·96 [95 %CI, 1·95-1·97]-19·85[95 %CI, 16·69-23·44]; AER 5·77-210·48), heart disease (SMR 1·94[95 %CI, 1·93-1·95]-19·25[95 %CI, 15·76-23·29]; AER 4·36-159·10) and cerebrovascular disease (SMR 2·05[95 %CI, 2·02-2·08]-24·71[95 %CI, 16·28-35·96]; AER 1·01-37·44) deaths. In the high-competing risk group, CVD-related SMR in patients with localized stage cancer increased with survival time but followed a reverse-dipper pattern in the low-competing risk group (7 of 21 cancers). The high-competing risk group had higher CVD-related death risks than the low-competing risk group. CONCLUSION: The CVD death risk in patients with non-metastatic cancer varied by cancer stage, site and survival time. The risk of CVD mortality is higher in 14 out of 21 localized cancers (high-competing cancers). Targeted strategies for CVD management in non-metastatic cancer patients are needed.

MRI-Guided Tumor Therapy Based on Synergy of Ferroptosis, Immunosuppression Reversal and Disulfidptosis.

Triple negative breast cancer (TNBC) cells have a high demand for oxygen and glucose to fuel their growth and spread, shaping the tumor microenvironment (TME) that can lead to a weakened immune system by hypoxia and increased risk of metastasis. To disrupt this vicious circle and improve cancer therapeutic efficacy, a strategy is proposed with the synergy of ferroptosis, immunosuppression reversal and disulfidptosis. An intelligent nanomedicine GOx-IA@HMON@IO is successfully developed to realize this strategy. The Fe release behaviors indicate the glutathione (GSH)-responsive degradation of HMON. The results of titanium sulfate assay, electron spin resonance (ESR) spectra, 5,5'-Dithiobis-(2-nitrobenzoic acid (DTNB) assay and T1-weighted magnetic resonance imaging (MRI) demonstrate the mechanism of the intelligent iron atom (IA)-based cascade reactions for GOx-IA@HMON@IO, generating robust reactive oxygen species (ROS). The results on cells and mice reinforce the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis triggered by the GOx-IA@HMON@IO with the following steps: 1) GSH peroxidase 4 (GPX4) depletion by disulfidptosis; 2) IA-based cascade reactions; 3) tumor hypoxia reversal; 4) immunosuppression reversal; 5) GPX4 depletion by immunotherapy. Based on the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis, the intelligent nanomedicine GOx-IA@HMON@IO can be used for MRI-guided tumor therapy with excellent biocompatibility and safety.

An Integrated Arterial Remodeling Hydrogel for Preventing Restenosis After Angioplasty.

The high incidence of restenosis after angioplasty has been the leading reason for the recurrence of coronary heart disease, substantially increasing the mortality risk for patients. However, current anti-stenosis drug-eluting stents face challenges due to their limited functions and long-term safety concerns, significantly compromising their therapeutic effect. Herein, a stent-free anti-stenosis drug coating (denoted as Cur-NO-Gel) based on a peptide hydrogel is proposed. This hydrogel is formed by assembling a nitric oxide (NO) donor-peptide conjugate as a hydrogelator and encapsulating curcumin (Cur) during the assembly process. Cur-NO-Gel has the capability to release NO upon ß-galactosidase stimulation and gradually release Cur through hydrogel hydrolysis. The in vitro experiments confirmed that Cur-NO-Gel protects vascular endothelial cells against oxidative stress injury, inhibits cellular activation of vascular smooth muscle cells, and suppresses adventitial fibroblasts. Moreover, periadventitial administration of Cur-NO-Gel in the angioplasty model demonstrate its ability to inhibit vascular stenosis by promoting reendothelialization, suppressing neointima hyperplasia, and preventing constrictive remodeling. Therefore, the study provides proof of concept for designing a new generation of clinical drugs in angioplasty.

Targeted heart repair by Tß4-loaded cardiac-resident macrophage-derived extracellular vesicles modified with monocyte membranes.

Recent studies have demonstrated the critical role of cardiac-resident macrophages (cMacs) in the maintenance of physiological homeostasis. However, recruitment of circulating monocyte-derived macrophages decreases cMac levels post-myocardial infarction (MI). Transplanting cMacs is not an ideal option due to their low survival rates and the risk of immunological rejection. However, extracellular vesicle therapy has the potential to provide a feasible and safe alternative for cardiac repair. In this study, cell membrane-modified extracellular vesicles (MmEVs) were developed for heart repair by modifying cMac-derived extracellular vesicles (mEVs) with monocyte membranes, resulting in immune evasion and sequential targeted localization to damaged regions through expression of CD47 on MmEVs and strong affinity between monocyte membrane proteins and CCL2. Additionally, to fully exploit the potential clinical application of MmEVs and achieve a better curative effect, thymosin ß4 (Tß4) was loaded into the nanoparticles, resulting in Tß4-MmEVs. In vitro experiments indicated that both the MmEVs and Tß4-MmEVs promoted cardiomyocyte proliferation and endothelial cell migration. Animal experiments suggested that MI mice treated with MmEVs and Tß4-MmEVs exhibited reduced myocardial fibrosis and increased vascular density compared to the control group. Thus, we posit that these targeted nanoparticles hold significant potential for MI adjuvant therapy and may open new avenues for cardiac repair and regeneration. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) derived from bioactive parent cell sources involved in pathological and repair processes for cardiovascular disease have emerged as a compelling strategy for regenerative therapy. In this study, we constructed monocyte membrane-modified extracellular vesicles loaded with a drug (Tß4-MmEVs) for heart repair that exhibit extraordinary abilities of immune evasion and sequential localization to damaged regions owing to the presence of CD47 and the strong affinity between monocytes and damaged cardiomyocytes and endothelial cells. The bioactivities of Tß4-MmEVs on enhancing cardiomyocyte and endothelial cell proliferation were validated both in vitro and in vivo. Effective development and implementation of therapeutically membrane-modified nanoparticles from homologous origins can provide a reference for adjuvant therapy in clinical MI management.

Injectable photocurable Janus hydrogel delivering hiPSC cardiomyocyte-derived exosome for post-heart surgery adhesion reduction.

Postsurgical pericardial adhesions pose increased risks of sequelae, prolonged reoperation time, and reduced visibility in the surgical field. Here, we introduce an injectable Janus hydrogel, which exhibits asymmetric adhesiveness properties after photocrosslinking, sustained delivering induced pluripotent stem cell-derived cardiomyocyte exosomes (iCM-EXOs) for post-heart surgery adhesion reduction. Our findings reveal that iCM-EXOs effectively attenuate oxidative stress in hydrogen peroxide-treated primary cardiomyocytes by inhibiting the activation of the transcription factor nuclear factor erythroid 2-related factor 2. Notably, in rat cardiac postsurgery models, the Janus hydrogels loaded with iCM-EXOs demonstrate dual functionality, acting as antioxidants and antipericardial adhesion agents. These hydrogels effectively protect iCM-EXOs from GATA6+ cavity macrophage clearance by inhibiting the recruitment of macrophages from the thoracic cavity. These results highlight the promising potential of iCM-EXO-laden Janus hydrogels for clinical safety and efficacy validation in trials involving heart surgery patients, with the ultimate goal of routine administration during open-heart surgeries.

Long-term risks of cardiovascular death in a population-based cohort of 1,141,675 older patients with cancer.

BACKGROUND: previous studies have focused on the risk of cardiovascular disease (CVD)-related death in individual cancers, adolescents or all cancers. OBJECTIVE: to evaluate the risk of CVD-related death in older patients with cancer. METHODS: older patients with cancer (over 65 years) of 16 cancers diagnosed between 1975 and 2018 were screened out from the Surveillance, Epidemiology and End Results program. The proportion of deaths, competing risk regression models, standardized mortality ratios (SMRs) and absolute excess risks (AERs) were used to assess the risk of CVD-related death. RESULTS: this study included 1,141,675 older patients (median follow-up: 13.5 years). Of the 16 individual cancers, the risk of CVD death exceeded primary neoplasm death in older patients with cancers of the breast, endometrium, vulva, prostate gland, penis and melanoma of the skin over time (high competing risk group). Compared to the general older population, older patients with cancer had higher SMR and AER of CVD-related death (SMR: 1.58-4.23; AER: 21.16-365.89), heart disease-related death (SMR: 1.14-4.16; AER: 16.29-301.68) and cerebrovascular disease-related death (SMR: 1.11-4.66; AER: 3.02-72.43), with the SMR trend varying with CVD-related death competing risk classifications. The risk of CVD-related death in the high-competing risk group was higher than in the low-competing risk group. CONCLUSIONS: for older patients with cancer, six of 16 individual cancers, including breast, endometrium, vulva, prostate gland, penis and melanoma of the skin was at high risk of CVD-related death. Management for long-term cardiovascular risk in older patients with cancer is needed.

Laparoscopic vs. open distal gastrectomy for locally advanced gastric cancer: A systematic review and meta-analysis of randomized controlled trials.

Objective: The aim of this systematic review and meta-analysis is to compare the short- and long-term outcomes of laparoscopic distal gastrectomy (LDG) with those of open distal gastrectomy (ODG) for patients with advanced gastric cancer (AGC) who exclusively underwent distal gastrectomy and D2 lymphadenectomy in randomized controlled trials (RCTs). Background: Data in published meta-analyses that included different gastrectomy types and mixed tumor stages prevented an accurate comparison between LDG and ODG. Recently, several RCTs that compared LDG with ODG included AGC patients specifically for distal gastrectomy, with D2 lymphadenectomy being reported and updated with the long-term outcomes. Methods: PubMed, Embase, and Cochrane databases were searched to identify RCTs for comparing LDG with ODG for advanced distal gastric cancer. Short-term surgical outcomes and mortality, morbidity, and long-term survival were compared. The Cochrane tool and GRADE approach were used for evaluating the quality of evidence (Prospero registration ID: CRD42022301155). Results: Five RCTs consisting of a total of 2,746 patients were included. Meta-analyses showed no significant differences in terms of intraoperative complications, overall morbidity, severe postoperative complications, R0 resection, D2 lymphadenectomy, recurrence, 3-year disease-free survival, intraoperative blood transfusion, time to first liquid diet, time to first ambulation, distal margin, reoperation, mortality, or readmission between LDG and ODG. Operative times were significantly longer for LDG [weighted mean difference (WMD) 49.2 min, p < 0.05], whereas harvested lymph nodes, intraoperative blood loss, postoperative hospital stay, time to first flatus, and proximal margin were lower for LDG (WMD -1.3, p < 0.05; WMD -33.6 mL, p < 0.05; WMD -0.7 day, p < 0.05; WMD -0.2 day, p < 0.05; WMD -0.4 mm, p < 0.05). Intra-abdominal fluid collection and bleeding were found to be less after LDG. Certainty of evidence ranged from moderate to very low. Conclusions: Data from five RCTs suggest that LDG with D2 lymphadenectomy for AGC has similar short-term surgical outcomes and long-term survival to ODG when performed by experienced surgeons in hospitals contending with high patient volumes. It can be concluded that RCTs should highlight the potential advantages of LDG for AGC. Systematic Review Registration: PROSPERO, registration number CRD42022301155.

Myeloid CCN3 protects against aortic valve calcification.

BACKGROUND: Cellular communication network factor 3 (CCN3) has been implicated in the regulation of osteoblast differentiation. However, it is not known if CCN3 can regulate valvular calcification. While macrophages have been shown to regulate valvular calcification, the molecular and cellular mechanisms of this process remain poorly understood. In the present study, we investigated the role of macrophage-derived CCN3 in the progression of calcific aortic valve disease. METHODS: Myeloid-specific knockout of CCN3 (Mye-CCN3-KO) and control mice were subjected to a single tail intravenous injection of AAV encoding mutant mPCSK9 (rAAV8/D377Y-mPCSK9) to induce hyperlipidemia. AAV-injected mice were then fed a high fat diet for 40 weeks. At the conclusion of high fat diet feeding, tissues were harvested and subjected to histologic and pathologic analyses. In vitro, bone marrow-derived macrophages (BMDM) were obtained from Mye-CCN3-KO and control mice and the expression of bone morphogenic protein signaling related gene were verified via quantitative real-time PCR and Western blotting. The BMDM conditioned medium was cocultured with human valvular intersititial cells which was artificially induced calcification to test the effect of the conditioned medium via Western blotting and Alizarin red staining. RESULTS: Echocardiography revealed that both male and female Mye-CCN3-KO mice displayed compromised aortic valvular function accompanied by exacerbated valve thickness and cardiac dysfunction. Histologically, Alizarin-Red staining revealed a marked increase in aortic valve calcification in Mye-CCN3-KO mice when compared to the controls. In vitro, CCN3 deficiency augmented BMP2 production and secretion from bone marrow-derived macrophages. In addition, human valvular interstitial cells cultured with conditioned media from CCN3-deficient BMDMs resulted in exaggerated pro-calcifying gene expression and the consequent calcification. CONCLUSION: Our data uncovered a novel role of myeloid CCN3 in the regulation of aortic valve calcification. Modulation of BMP2 production and secretion in macrophages might serve as a key mechanism for macrophage-derived CCN3's anti-calcification function in the development of CAVD. Video Abstract.

Metastatic patterns and prognosis of patients with primary malignant cardiac tumor.

Background: Distant metastases are independent negative prognostic factors for patients with primary malignant cardiac tumors (PMCT). This study aims to further investigate metastatic patterns and their prognostic effects in patients with PMCT. Materials and methods: This multicenter retrospective study included 218 patients with PMCT diagnosed between 2010 and 2017 from Surveillance, Epidemiology, and End Results (SEER) database. Logistic regression was utilized to identify metastatic risk factors. A Chi-square test was performed to assess the metastatic rate. Kaplan-Meier methods and Cox regression analysis were used to analyze the prognostic effects of metastatic patterns. Results: Sarcoma (p = 0.002) and tumor size¿4 cm (p = 0.006) were independent risk factors of distant metastases in patients with PMCT. Single lung metastasis (about 34%) was the most common of all metastatic patterns, and lung metastases occurred more frequently (17.9%) than bone, liver, and brain. Brain metastases had worst overall survival (OS) and cancer-specific survival (CSS) among other metastases, like lung, bone, liver, and brain (OS: HR = 3.20, 95% CI: 1.02-10.00, p = 0.046; CSS: HR = 3.53, 95% CI: 1.09-11.47, p = 0.036). Conclusion: Patients with PMCT who had sarcoma or a tumor larger than 4 cm had a higher risk of distant metastases. Lung was the most common metastatic site, and brain metastases had worst survival among others, such as lung, bone, liver, and brain. The results of this study provide insight for early detection, diagnosis, and treatment of distant metastases associated with PMCT.

Long-Term Cardiovascular Mortality among 80,042 Older Patients with Bladder Cancer.

BACKGROUND: To identify the risk of death from cardiovascular disease (CVD) in older patients with bladder cancer (BC). METHODS: This population-based study included 80,042 older BC patients (≥65 years) diagnosed between 1975 and 2018, with a mean follow-up of 17.2 years. The proportion of deaths, competing risk models, standardized mortality ratio (SMR), and absolute excess risk (AER) per 10,000 person-years were applied to identify the risk of CVD-related deaths among older BC patients. RESULTS: For older patients with BC, CVD-related death was the chief cause of death, and cumulative CVD-related mortality also exceeded primary BC as the leading cause of death mostly 5-10 years after BC diagnosis, especially in localized-stage and low-grade subgroups. The risk of short- and long-term CVD-related death in older BC patients was higher than in the general older adult population (SMR = 1.30, 95% CI 1.28-1.32; AER = 105.68). The risk of sex-specific CVD-related deaths also increased compared to the general population of older adults, including heart disease, cerebrovascular diseases, hypertension without heart disease, atherosclerosis, aortic aneurysm and dissection, and other diseases of the arteries, arterioles, and capillaries. CONCLUSIONS: CVD-related death is an important competing risk among older BC patients and has surpassed primary BC as the chief cause of death, mainly 5-10 years after BC diagnosis. The risk of CVD-related death in older patients with BC was greater than in the general population. The management of older patients with BC should focus not only on the primary cancer but also on CVD-related death.

Curcumin attenuates cadmium-induced atherosclerosis by regulating trimethylamine-N-oxide synthesis and macrophage polarization through remodeling the gut microbiota.

BACKGROUND: Studies have shown that cadmium (Cd) exposure primarily occurs through diet, and Cd ingestion is a risk factor for atherosclerosis (AS). However, the underlying mechanism remains unclear. As a target organ, the gastrointestinal tract may play a key role in Cd-induced AS. Additionally, as curcumin is insoluble in water but stable in the stomach of acidic pH, it may play regulative roles in the gut. OBJECTIVES: We assess the effect of Cd exposure on gut flora, trimethylamine-N-oxide (TMAO) metabolism and macrophage polarization, further investigate whether curcumin protects against Cd-induced AS by remodeling gut microbiota. METHODS AND RESULTS: The results of 16 S rRNA sequencing show that Cd exposure causes diversity reduction and compositional alteration of the microbial community, resulting in the increasing TMAO synthesis, the imbalance of lipid metabolism, and the M1-type macrophage polarization in the mouse model (ApoE-/-) of AS. As a result, the plaque area is increased with Cd exposure, shown by oil red O staining. TMAO synthesis is positively correlated with the concentration of blood Cd, and the dynamics of specific bacteria in this process were revealed at the phylum to genus levels. Moreover, the effects of intestinal flora and TMAO on Cd-induced AS are further confirmed via microbial transplantation from a mouse model not exposed to Cd, as the transplantation decreases plaque area. Finally, the gavage with curcumin reverses the Cd-induced pathological progression via gut flora restoration. CONCLUSIONS: We first demonstrate that Cd exposure worsens the progression of AS via intestinal flora imbalance and increased TMAO synthesis. Curcumin was verified as a potential novel intervention for preventing Cd-induced AS via remodeling gut microbiota. This study elucidates a new approach for treating AS in regions with significant Cd exposure.

Decoy Exosomes Offer Protection Against Chemotherapy-Induced Toxicity.

Cancer patients often face severe organ toxicity caused by chemotherapy. Among these, chemotherapy-induced hepatotoxicity and cardiotoxicity are the main causes of death of cancer patients. Chemotherapy-induced cardiotoxicity even creates a new discipline termed "cardio-oncology". Therefore, relieving toxicities induced by chemotherapy has become a key issue for improving the survival and quality of life in cancer patients. In this work, mesenchymal stem cell exosomes with the "G-C" abundant tetrahedral DNA nanostructure (TDN) are modified to form a decoy exosome (Exo-TDN). Exo-TDN reduces DOX-induced hepatotoxicity as the "G-C" base pairs scavenge DOX. Furthermore, Exo-TDN with cardiomyopathic peptide (Exo-TDN-PCM) is engineered for specific targeting to cardiomyocytes. Injection of Exo-TDN-PCM significantly reduces DOX-induced cardiotoxicity. Interestingly, Exo-TDN-PCM can also promote macrophage polarization into the M2 type for tissue repair. In addition, those decoy exosomes do not affect the anticancer effects of DOX. This decoy exosome strategy serves as a promising therapy to reduce chemo-induced toxicity.

Islet-1 Mesenchymal Stem Cells-Derived Exosome-Incorporated Angiogenin-1 Hydrogel for Enhanced Acute Myocardial Infarction Therapy.

Although stem cell-derived exosomes have been recognized as new candidates for cell-free treatment in myocardial infarction (MI), the challenge to improve the exosome retention in ischemic tissue remains. Our previous research indicated that islet-1(ISL1) overexpression enhances the paracrine function of mesenchymal stem cells (MSCs) and promotes angiogenesis in a model of MI. In this study, genetically engineered ISL1-MSC-derived exosomes (ISL1-MSCs-Exo) were collected, and the contents were analyzed by exosomal RNA sequencing. Next, we investigated if ISL1-MSCs-Exo could exert therapeutic effects and their incorporation into a new angiogenin-1 hydrogel (Ang-1 gel) could boost the retention of exosomes and further enhance their protective effects. Our results demonstrated that ISL1-MSCs-Exo could play a therapeutic role in vitro and in vivo, which might be due to changed exosomal contents. Ang-1 gel increased the retention and enhanced the anti-apoptosis, proliferation, and angiogenic capacity of ISL1-MSCs-Exo in endothelial cells. Echocardiography revealed that Ang-1 gel significantly augment the therapeutic effects of ISL1-MSCs-Exo for MI. The main mechanism might result from increased retention of ISL1-MSCs-Exo, herein enhanced pro-angiogenetic effects in an ischemic heart. Taken together, our findings indicated that ISL1-MSCs-Exo had endothelium-protective and pro-angiogenic abilities alone and Ang-1 gel could notably retain ISL1-MSCs-Exo at ischemic sites, which improved the survival and angiogenesis of endothelial cells and accelerated the recovery of MI. These results not only shed light on the therapeutic mechanism of ISL1-MSCs-Exo incorporated with Ang-1 gel but also offer a promising therapeutic option for ischemic disease.

Long-term risk of cardiovascular disease mortality among classic Hodgkin lymphoma survivors.

BACKGROUND: The temporal trend of cardiovascular disease (CVD) mortality in patients with classic Hodgkin lymphoma (cHL) throughout follow-up remains unclear. This study aimed to assess this temporal trend in patients with cHL. METHODS: This multicenter cohort included 15,889 patients with cHL diagnosed between 1983 and 2015, covering all ages. The proportional mortality ratio, cumulative incidence of cause-specific mortality accounting for competing risk, standard mortality ratio, and absolute excess risk were analyzed. RESULTS: Among patients in stage I and stage II cHL, the proportional mortality ratio for CVD exceeded that for cHL, after approximately 60 or 120 months of follow-up, respectively. For almost all the patients with stage I or stage II disease, the cumulative incidence of CVD mortality exceeded that of cHL and other neoplasms over time. In recent decades, the risk of cHL mortality declined sharply, but the risk of CVD mortality among patients with cHL declined quite slowly or even remained unchanged among some populations. Patients with stage I or stage II disease experienced a higher risk of CVD mortality than the general population in almost all follow-up intervals. The absolute excess CVD risk among patients in stage I reached 48.5. CONCLUSIONS: The risk of CVD mortality exceeded that of cHL and other neoplasms and became the leading cause of death over time, among patients with stage I or stage II disease. More effective measures should be taken to reduce the risk of CVD mortality. LAY SUMMARY: Among patients with stage I and stage II classic Hodgkin lymphoma (cHL), the proportional mortality ratio of cardiovascular disease (CVD) exceeded that of cHL after approximately 60 or 120 months of follow-up, respectively. For almost all the patients with stage I or stage II disease, the cumulative incidence of CVD mortality exceeded that of cHL and other neoplasms over time. In the past several decades, the risk of cHL mortality declined sharply, but the risk of CVD mortality among patients with cHL declined quite slowly or even unchanged among some populations. CVD exceeded cHL and has become the leading cause of death over time.

A dual-targeting peptide facilitates targeting anti-inflammation to attenuate atherosclerosis in ApoE-/- mice.

We report a peptidic dual-targeting drug delivery platform (integrins targeting and self-assembly instructed by matrix metalloproteinases) towards inflamed endothelial cells, which improved the anti-inflammatory ability of the loaded drug (i.e., puerarin) in vitro and thus improved the antiatherogenic effect of the loaded drug (i.e., puerarin) in vivo.

Fabrication of Tß4-Exosome-releasing artificial stem cells for myocardial infarction therapy by improving coronary collateralization.

Currently, stem cell transplantations in cardiac repair are limited owing to disadvantages, such as immunological rejection and poor cell viability. Although direct injection of exosomes can have a curative effect similar to that of stem cell transplantation, high clearance hinders its application in clinical practice. Previous reports suggested that induction of coronary collateralization can be a desired method of adjunctive therapy for someone who had missed the optimal operation time to attenuate myocardial ischemia. In this study, to mimic the paracrine and biological activity of stem cells, we developed artificial stem cells that can continuously release Tß4-exosomes (Tß4-ASCs) by encapsulating specific exosomes within microspheres using microfluidics technology. The results show that Tß4-ASCs can greatly promote coronary collateralization in the periphery of the myocardial infarcted area, and its therapeutic effect is superior to that of directly injecting the exosomes. In addition, to better understand how it works, we demonstrated that the Tß4-ASC-derived exosomes can enhance the angiogenic capacity of coronary endothelial cells (CAECs) via the miR-17-5p/PHD3/Hif-1α pathway. In brief, as artificial stem cells, Tß4-ASCs can constantly release functional exosomes and stimulate the formation of collateral circulation after myocardial infarction, providing a feasible and alternative method for clinical revascularization.

Association of Chronic Respiratory Symptoms With Incident Cardiovascular Disease and All-Cause Mortality: Findings From the Coronary Artery Risk Development in Young Adults Study.

BACKGROUND: Respiratory and cardiovascular diseases (CVDs) frequently coexist; however, there is limited evidence on the relationship between chronic respiratory symptoms in young adulthood and late-onset CVD. RESEARCH QUESTION: Are chronic respiratory symptoms in young adulthood associated with CVD and all-cause mortality in later life? STUDY DESIGN AND METHODS: A total of 4,621 participants from the Coronary Artery Risk Development in Young Adults Study (CARDIA) cohort study aged 18 to 30 years were included. Chronic respiratory symptoms were identified through respiratory symptom questionnaires in two consecutive examinations. Incident CVD and all-cause mortality were adjudicated over 30-year follow-up. Multivariable Cox proportional hazards models were used to explore the association of chronic respiratory symptoms with incident CVD and all-cause mortality. RESULTS: During a median follow-up of 30.9 years, 284 CVD events (6.15%) and 378 deaths (8.18%) occurred. Following multivariable adjustment for demographic characteristics, cardiovascular risk factors, smoking, and lung function, the hazard ratios (95% CIs) for CVD events were 1.51 (1.18-1.93) for any respiratory symptom, 1.57 (1.18-2.09) for cough or phlegm, 1.31 (1.01-1.68) for wheeze, 1.73 (1.25-2.41) for shortness of breath, and 1.32 (1.01-1.71) for chest illnesses. Similar findings were also observed in all-cause mortality. Comparing zero vs three to four respiratory symptoms, the hazard ratios (95% CIs) were 1.97 (1.34-2.91) for CVD and 1.75 (1.23-2.47) for all-cause mortality. Similar results were observed in various sensitivity analyses. INTERPRETATION: Chronic respiratory symptoms in young adulthood are associated with an increased risk of CVD and all-cause mortality in midlife independent of established cardiovascular risk factors, smoking, and lung function. Identifying chronic respiratory symptoms in young adulthood may help provide prognostic information regarding future cardiovascular health. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT00005130; URL: https://www. CLINICALTRIALS: gov.

Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis.

Chronic cadmium (Cd) exposure contributes to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but the underlying mechanism is unclear. Since mitochondrial homeostasis is emerging as a core player in the development of CVD, it might serve as a potential mechanism linking Cd exposure and AS. In this study, we aimed to investigate Cd-mediated AS through macrophage polarization and know the mechanisms of Cd-caused mitochondrial homeostasis imbalance. In vitro, flow cytometry shows that Cd exposure promotes M1-type polarization of macrophages, manifested as the increasing expressions of nuclear Factor kappa-light-chain-enhancer of activated B (NF-kB) and NLR family pyrin domain containing 3 (NLRP3). Mitochondrial homeostasis tests revealed that decreasing mitochondrial membrane potential and mitophage, increasing the mitochondrial superoxide (mROS), and mitochondrial fission are involved in the Cd-induced macrophage polarization. The upregulated expressions of receptor-interacting protein kinase 3 (RIPK3) and pseudokinase-mixed lineage kinase domain-like protein (p-MLKL) were observed. Knocking out RIPK3, followed by decreasing the expression of p-MLKL, improves the mitochondrial homeostasis imbalance which effectively reverses macrophage polarization. In vivo, the oil red O staining showed that Cd with higher blood significantly aggravates AS. Besides, M1-type polarization of macrophages and mitochondrial homeostasis imbalance were observed in the aortic roots of the mice through immunofluorescence and western blot. Knocking out RIPK3 restored the changes above. Finally, the administered N-acetyl cysteine (NAC) or mitochondrial division inhibitor-1 (Mdivi-1), which decreased the mROS or mitochondrial fission, inhibited the expressions of RIPK3 and p-MLKL, attenuating AS and macrophage M1-type polarization in the Cd-treated group. Consequently, the Cd exposure activated the RIPK3 pathway and impaired the mitochondrial homeostasis, resulting in pro-inflammatory macrophage polarization and subsequent AS. Knocking out RIPK3 provided a potential therapeutic target for Cd-caused macrophage polarization and subsequent AS.

Dihydromyricetin ameliorates vascular calcification in chronic kidney disease by targeting AKT signaling.

Vascular calcification is highly prevalent in chronic kidney disease (CKD), and is characterized by transdifferentiation from contractile vascular smooth muscle cells (VSMCs) into an osteogenic phenotype. However, no effective and therapeutic option to prevent vascular calcification is yet available. Dihydromyricetin (DMY), a bioactive flavonoid isolated from Ampelopsis grossedentata, has been found to inhibit VSMCs proliferation and the injury-induced neointimal formation. However, whether DMY has an effect on osteogenic differentiation of VSMCs and vascular calcification is still unclear. In the present study, we sought to investigate the effect of DMY on vascular calcification in CKD and the underlying mechanism. DMY treatment significantly attenuated calcium/phosphate-induced calcification of rat and human VSMCs in a dose-dependent manner, as shown by Alizarin Red S staining and calcium content assay, associated with down-regulation of osteogenic markers including type I collagen (COL I), Runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2) and osteocalcin (OCN). These results were further confirmed in aortic rings ex vivo. Moreover, DMY ameliorated vascular calcification in rats with CKD. Additionally, we found that AKT signaling was activated during vascular calcification, whereas significantly inhibited by DMY administration. DMY treatment significantly reversed AKT activator-induced vascular calcification. Furthermore, inhibition of AKT signaling efficiently attenuated calcification, which was similar to that after treatment with DMY alone, and DMY had a better inhibitory effect on calcification as compared with AKT inhibitor. The present study demonstrated that DMY has a potent inhibitory role in vascular calcification partially by inhibiting AKT activation, suggesting that DMY may act as a promising therapeutic candidate for patients suffering from vascular calcification.