Photoinduction of Ferroptosis and cGAS-STING Activation by a H2S-Responsive Iridium(III) Complex for Cancer-Specific Therapy.

Triggering ferroptosis represents a promising anticancer therapeutic strategy, but the development of a selective ferroptosis inducer for cancer-specific therapy remains a great challenge. Herein, a H2S-responsive iridium(III) complex NA-Ir has been well-designed as a ferroptosis inducer. NA-Ir could selectively light up H2S-rich cancer cells, primarily localize in mitochondria, intercalate into mitochondrial DNA (mtDNA), and induce mtDNA damage, exhibiting higher anticancer activity under light irradiation. Mechanistic studies showed that NA-Ir-mediated PDT triggered lipid peroxidation and glutathione peroxidase 4 downregulation through ROS production and GSH depletion, resulting in ferroptosis through multiple pathways. Moreover, the intense mtDNA damage can activate the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway, leading to ferritinophagy and further ferroptosis. RNA-sequencing analysis showed that NA-Ir-mediated PDT mainly affects the expression of genes related to ferroptosis, autophagy, and cancer immunity. This study demonstrates the first cancer-specific example with ferroptosis and cGAS-STING activation, which provides a new strategy for multimodal synergistic therapy.

The role of SIRT1 in kidney diseases.

SIRT1, a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase, exhibits a high level of expression within renal tissues. It has garnered considerable recognition for its pivotal role in modulating signaling pathways intricately linked with the aging process; however, it extends beyond this in the organism. The literature reports that SIRT1 regulates biological processes such as glucose metabolism, lipid metabolism, oxidative stress, inflammation, autophagy, endoplasmic reticulum stress, and apoptosis. Therefore, our study reviews the primary mechanisms by which SIRT1 induces kidney disease and the regulation of related signaling pathways in different models of renal disease. We also discuss commonly studied SIRT1-targeted interventional drugs reported in the literature, including inhibitors (e.g., Ex-527) and activators (e.g., resveratrol). This study aims to provide theoretical foundations and clinical insights for the development and screening of clinical drugs targeting SIRT1, aiming at enhanced scientific approaches for the prevention and treatment of kidney diseases.

Analysis of the Predictive Efficacy of Serum suPAR Combined with APN and IgE Test and the Relationship of Patients with CHF and Cardiac Function.

Background: Chronic heart failure (CHF) is a complex cardiovascular disorder resulting from prolonged heart disease, leading to structural and functional damage, weakened myocardial contraction, and inadequate cardiac output for daily metabolism. The purpose of study is accurate evaluation and early identification of cardiac function and ventricular remodeling through effective biochemical indicators. Methods: This study, conducted from April 2020 to March 2021, included 100 CHF patients meeting the Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2020 from First People's Hospital of Linping District, ascertaining a confirmed diagnosis based on these established guidelines. The objective of detecting these biomarkers is not for early diagnosis, given that the subjects are already diagnosed according to the guidelines. Instead, our focus is on using these biomarkers to assess disease severity, prognosis, or treatment response in the context of diagnosed CHF patients. Classification comprised 42 ischemic and 58 non-ischemic CHF cases, with NYHA cardiac function grading (I, II, III-IV) and left ventricular ejection fraction (LVEF) categorization (≤ 40%, >40%). A control group of 100 healthy volunteers was selected for comparison. SuPAR, APN, and IgE expressions were analyzed among different groups and LVEF categories. Diagnostic efficacy was assessed through ROC curves, and correlations with cardiac function and LVEF were explored. Results: SuPAR, APN, and IgE expressions were significantly higher in CHF patients compared to the control group. Increasing cardiac function grades in CHF patients correlated with a gradual elevation in suPAR, APN, and IgE expressions. Comparing LVEF groups, CHF patients with LVEF ≤ 40% exhibited significantly higher suPAR, APN, and IgE expressions. Combined detection of suPAR, APN, and IgE demonstrated superior diagnostic accuracy (AUC of 0.899) compared to individual markers. Positive correlations were observed between suPAR, APN, IgE, and cardiac function grades, while LVEF showed a significant negative correlation with these biomarkers. Conclusions: SuPAR, APN, and IgE expressions are elevated in CHF patients, and their combined detection serves as a highly efficient auxiliary diagnostic method. The findings offer valuable insights into the diagnosis and treatment of CHF patients.

RICH1 is a novel key suppressor of isoproterenol­ or angiotensin II­induced cardiomyocyte hypertrophy.

Cardiac hypertrophy is one of the key processes in the development of heart failure. Notably, small GTPases and GTPase­activating proteins (GAPs) serve essential roles in cardiac hypertrophy. RhoGAP interacting with CIP4 homologs protein 1 (RICH1) is a RhoGAP that can regulate Cdc42/Rac1 and F­actin dynamics. RICH1 is involved in cell proliferation and adhesion; however, to the best of our knowledge, its role in cardiac hypertrophy remains unknown. In the present study, the role of RICH1 in cardiomyocyte hypertrophy was assessed. Cell viability was analyzed using the Cell Counting Kit­8 assay and cells surface area (CSA) was determined by cell fluorescence staining. Reverse transcription­quantitative PCR and western blotting were used to assess the mRNA expression levels of hypertrophic marker genes, such as Nppa, Nppb and Myh7, and the protein expression levels of RICH1, respectively. RICH1 was shown to be downregulated in isoproterenol (ISO)­ or angiotensin II (Ang II)­treated H9c2 cells. Notably, overexpression of RICH1 attenuated the upregulation of hypertrophy­related markers, such as Nppa, Nppb and Myh7, and the enlargement of CSA induced by ISO and Ang II. By contrast, the knockdown of RICH1 exacerbated these effects. These findings suggested that RICH1 may be a novel suppressor of ISO­ or Ang II­induced cardiomyocyte hypertrophy. The results of the present study will be beneficial to further studies assessing the role of RICH1 and its downstream molecules in inhibiting cardiac hypertrophy.

Effects of the lncRNA MALAT1 gene region rs664589 site mutation on acute myocardial infarction in Chinese Han.

We aimed to study the association between the non-coding region of the lncRNA MALAT1 gene, the non-coding region rs664589 C>G variant, and the risk of acute myocardial infarction (AMI) in the Chinese Han population. 165 NSTEMI and 135 STEMI patients were enrolled in the study. An additional 150 healthy individuals were enrolled as the controls. All subjects were analyzed for the MALAT1 rs664589 locus genotype. The receiver operating curve (ROC) was used to determine the effect of MALAT1 rs664589 single nucleotide polymorphism (SNP) on the diagnosis of AMI by plasma lncRNA MALAT1. The MALAT1 rs664589 site G allele carrier was 1.39 times more likely to have NSTEMI than the C allele carrier (95% CI: 1.16-1.61, P = 0.001) and 1.59 times more likely to have STEMI than the C allele carrier (95% CI: 1.31-1.85, P < 0.001). The MALAT1 rs664589 site C>G mutation resulted in an increase in the area under the ROC curve (AUC) of the plasma lncRNA MALAT1 level for the diagnosis of AMI. The plasma lncRNA MALAT1 levels in AMI patients were negatively correlated with hsa-miR-1972, hsa-miR-194-5p, hsa-miR-4717-5p, hsa-miR-6735-3p, and hsa-miR-3677-5p (r = -0.81, -0.75, -0.66, -0.71, and -0.88). The C>G mutation of MAL6641 rs664589 causes an increased risk of AMI in the Chinese Han population. The SNP at this site affects the value of plasma lncRNA MALAT1 in the diagnosis of AMI. The specific mechanism may indicate that the C>G mutation of the MALAT1 rs664589 changes the regulation of miRNAs expression by lncRNA MALAT1.

Black phosphorus boosts wet-tissue adhesion of composite patches by enhancing water absorption and mechanical properties.

Wet-tissue adhesives have long been attractive materials for realizing complicated biomedical functions. However, the hydration film on wet tissues can generate a boundary, forming hydrogen bonds with the adhesives that weaken adhesive strength. Introducing black phosphorus (BP) is believed to enhance the water absorption capacity of tape-type adhesives and effectively eliminate hydration layers between the tissue and adhesive. This study reports a composite patch integrated with BP nanosheets (CPB) for wet-tissue adhesion. The patch's improved water absorption and mechanical properties ensure its immediate and robust adhesion to wet tissues. Various bioapplications of CPB are demonstrated, such as rapid hemostasis (within ~1-2 seconds), monitoring of physical-activity and prevention of tumour-recurrence, all validated via in vivo studies. Given the good practicability, histocompatibility and biodegradability of CPB, the proposed patches hold significant promise for a wide range of biomedical applications.

Time-Sequential and Multi-Functional 3D Printed MgO2 /PLGA Scaffold Developed as a Novel Biodegradable and Bioactive Bone Substitute for Challenging Postsurgical Osteosarcoma Treatment.

Osteosarcoma (OS) is the most commonly occurring primary bone malignant tumor. The clinical postsurgical OS treatment faces big challenges for the staged therapeutic requirements of early anti-tumor, anti-bacterial, and long-lasting osteogenesis. Herein, multi-functional bioactive scaffolds with time-sequential functions of preventing tumor recurrence, inhibiting bacterial infection, and promoting bone defect repair are designed as a novel strategy. Nanocomposite scaffold magnesium peroxide (MgO2 )/poly (lactide-co-glycolide) is prepared by low-temperature 3D printing for controllable releasing magnesium ions (Mg2+ ) and reactive oxygen species in a time-sequential manner. The scaffold with 20 wt% MgO2 (20MP) is verified with desired mechanical properties, as well as exhibits staged release behavior of bioactive elements with hydrogen peroxide (H2 O2 ) release for the first 3 weeks, and long-lasting Mg2+ release for 12 weeks. The released H2 O2 initiates chemodynamic therapy to induce apoptosis and ferroptosis in tumor cells, along with activating the anticancer immune microenvironment by M1 polarization of macrophages. The released Mg2+ subsequently enhances bone repair by activating the Wnt3a/GSK-3ß/ß-catenin signaling pathway to promote osteogenic differentiation of bone marrow mesenchymal stem cells and create osteopromotive immune microenvironment by M2 polarization of macrophages. In conclusion, the multi-functional 20MP scaffold demonstrates time-sequential therapeutic properties as an innovative strategy for OS-associated bone defect treatment.

Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation.

Atrial fibrillation (AF) is a common critical cause of stroke and cardiac dysfunction worldwide with lifetime risks. Viral infection and inflammatory response with myocardial involvement may lead to an increase in AF-related mortality. To dissect the potential sequelae of viral infection in AF patients, especially the coronavirus disease 2019 (COVID-19), based on AF and COVID-19 databases from Gene Expression Omnibus, weighted gene co-expression network analysis was used to identify key genes in heart tissues and peripheral blood mononuclear cells. Here, HSCT, PSMB9, STAT2, and TNFSF13B were identified as common risk genes of AF and COVID-19 patients. Correlation analysis of these genes with AF and COVID-19 showed a positive disease relevance. silencing of STAT2 by small interfering RNA significantly rescued SARS-CoV-2 XBB1.5 pseudovirus-induced cardiac cell contraction dysfunction in vitro. In conclusion, we identified STAT2 may be a novel biomarker of inflammation-related cardiac dysfunction in AF.

Regulation of Osteoimmune Microenvironment and Osteogenesis by 3D-Printed PLAG/black Phosphorus Scaffolds for Bone Regeneration.

The treatment of bone defects remains a significant challenge to be solved clinically. Immunomodulatory properties of orthopedic biomaterials have significance in regulating osteoimmune microenvironment for osteogenesis. A lactic acid-co-glycolic acid (PLGA) scaffold incorporates black phosphorus (BP) fabricated by 3D printing technology to investigate the effect of BP on osteoimmunomodulation and osteogenesis in site. The PLGA/BP scaffold exhibits suitable biocompatibility, biodegradability, and mechanical properties as an excellent microenvironment to support new bone formation. The studies' result also demonstrate that the PLGA/BP scaffolds are able to recruit and stimulate macrophages M2 polarization, inhibit inflammation, and promote human bone marrow mesenchymal stem cells (hBMSCs) proliferation and differentiation, which in turn promotes bone regeneration in the distal femoral defect region of steroid-associated osteonecrosis (SAON) rat model. Moreover, it is screened and demonstrated that PLGA/BP scaffolds can promote osteogenic differentiation by transcriptomic analysis, and PLGA/BP scaffolds promote osteogenic differentiation and mineralization by activating PI3K-AKT signaling pathway in hBMSC cells. In this study, it is shown that the innovative PLGA/BP scaffolds are extremely effective in stimulating bone regeneration by regulating macrophage M2 polarization and a new strategy for the development of biomaterials that can be used to repair bone defects is offered.

Effect of pretreatment with a P2Y12 inhibitor in patients with non-ST-elevation acute coronary syndrome: a systematic review and network meta-analysis.

Background: This study aimed to systematically evaluate the effects of different types and doses of pretreatment with P2Y12 inhibitors in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). Methods: Electronic databases were searched for studies comparing pretreatment with different types and doses of P2Y12 inhibitors or comparison between P2Y12 inhibitor pretreatment and nonpretreatment. Electronic databases included the Cochrane Library, PubMed, EMBASE, and Web of Science. Literature was obtained from the establishment of each database until June 2022. The patients included in the study had pretreatment with P2Y12 inhibitors with long-term oral or loading doses, or conventional aspirin treatment (non-pretreatment). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs) during follow-up within 30 days after PCI, which included determining the composite endpoints of cardiac death, myocardial infarction, ischemia-driven revascularization, and stroke. The safety endpoint was a major bleeding event. Results: A total of 119,014 patients from 21 studies were enrolled, including 13 RCTs and eight observational studies. A total of six types of interventions were included-nonpretreatment (placebo), clopidogrel pretreatment, ticagrelor pretreatment, prasugrel pretreatment, double loading pretreatment (double loading dose of clopidogrel, ticagrelor, prasugrel) and P2Y12 inhibitors pretreatment (the included studies did not distinguish the types of P2Y12 inhibitors, including clopidogrel, ticagrelor, and prasugrel). The network meta-analysis results showed that compared to patients without pretreatment, patients receiving clopidogrel pretreatment (RR = 0.78, 95% CI:0.66, 0.91, P < 0.05) and double-loading pretreatment (RR = 0.62, 95% CI:0.41, 0.95, P < 0.05) had a lower incidence of MACCEs. There was no statistically significant difference in the incidence of major bleeding events among the six pretreatments (P > 0.05). Conclusions: In patients with NSTE-ACS, pretreatment with P2Y12 inhibitors before percutaneous intervention reduced the incidence of recurrent ischemic events without increasing the risk of major bleeding after PCI compared with nonpretreatment. Clopidogrel or double loading dose P2Y12 inhibitors can be considered for the selection of pretreatment drugs.

Overexpression of YEATS2 Remodels the Extracellular Matrix to Promote Hepatocellular Carcinoma Progression via the PI3K/AKT Pathway.

Hepatocellular carcinoma (HCC) is one of the most common cancers and the fourth leading cause of death in men. YEATS domain containing 2 (YEATS2) gene encodes a scaffolding subunit of the ATAC complex. We found that YEATS2 was upregulated in HCC tissues and was associated with a poor prognosis. However, the role of YEATS2 in HCC remains unclear. The purpose of this study was to investigate the effect of YEATS2 on the progression of HCC and to elucidate its related mechanisms. We found that overexpression of YEATS2 promoted tumor cell proliferation, migration, and invasion through the PI3K/AKT signaling pathway and regulation of extracellular matrix. These findings help to understand the role of YEATS2 in HCC, and YEATS2 may become a new target for HCC therapy.

Effectiveness of dual antiplatelet de-escalation therapy on the prognosis of patients with ST segment elevation myocardial infarction undergoing percutaneous coronary intervention.

AIM: To investigate the effectiveness of de-escalation of ticagrelor (from ticagrelor 90 mg to clopidogrel 75 mg or ticagrelor 60 mg) on the prognosis of patients with ST segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) after 3 months of oral dual antiplatelet therapy (DAPT). METHODS: From March 2017 to August 2021, 1056 patients with STEMI in a single centre, through retrospective investigation and analysis, were divided into intensive (ticagrelor 90 mg), standard (clopidogrel 75 mg after PCI) and de-escalation groups (clopidogrel 75 mg or ticagrelor 60 mg after 3 months of treatment with 90 mg ticagrelor) based on the type and dose of P2Y12 inhibitor 3 months after PCI, and the patients had a ≥ 12-month history of oral DAPT. The primary end point was major adverse cardiovascular and cerebrovascular events (MACCEs) during the 12-month follow-up period, including composite end points of cardiac death, myocardial infarction, ischaemia-driven revascularization and stroke. The major safety endpoint was bleeding events. RESULTS: The results showed that during the follow-up period, there was no statistically significant difference in the incidence of MACCEs between the intensive and de-escalation groups (P > 0.05). The incidence of MACCEs in the standard treatment group was higher than that in the intensive treatment group (P = 0.014), but the incidence of bleeding events in the de-escalation group was significantly lower than that in the standard group (9.3% vs. 18.4%, χ²=7.191, P = 0.027). The Cox regression analysis showed that increases in haemoglobin (HGB) (HR = 0.986) and estimated glomerular filtration rate (eGFR) (HR = 0.983) could reduce the incidence of MACCEs, while old myocardial infarction (OMI) (P = 0.023) and hypertension (P = 0.013) were independent predictors of MACCEs. CONCLUSION: For STEMI patients undergoing PCI, the de-escalation scheme of ticagrelor to clopidogrel 75 mg or ticagrelor 60 mg at 3 months after PCI was related to the reduction of bleeding events, especially minor bleeding events, without an increase in ischaemic events.

Injectable spontaneous hydrogen-releasing hydrogel for long-lasting alleviation of osteoarthritis.

Excessive production of reactive oxygen species (ROS) amplifies pro-inflammatory pathways and exacerbates immune responses, and is a key factor in the progression of osteoarthritis (OA). Therapeutic hydrogen gas (H2) with antioxidative and anti-inflammatory effects, has a potential for OA alleviation, but the targeted delivery and sustained release of H2 are still challenging. Herein, we develop an injectable calcium boride nanosheets (CBN) loaded hydrogel platform (CBN@GelDA hydrogel) as a high-payload and sustainable H2 precursor for OA treatment. The CBN@GelDA hydrogel could maintain constant physiological pH conditions which further promotes more H2 release than the CBN alone and lasts more than one week. The biocompatibility of this hydrogel with macrophages and chondrocytes is effectively enhanced. The experiments show that the CBN@GelDA hydrogel holds the ROS scavenging ability, reducing the expression of related inflammatory cytokines, lessening M1 macrophages but stimulating M2 phenotype, and thereby decreasing chondrocyte apoptosis, which facilitates to breaking of the vicious circle of OA progression. Furthermore, a single-time injection of the CBN@GelDA hydrogel markedly reduces joint destruction in OA rats. From what has been discussed above, this injectable spontaneous H2-releasing hydrogel is promising for OA treatment. STATEMENT OF SIGNIFICANCE: Oxidative stress and inflammation play the key role in the occurrence and development of osteoarthritis (OA). The system of a hydrogel loaded with H2 precursor calcium boride nanosheet (CBN), which is the first to use as an H2 precursor, integrates superior injectable and biocompatible of hydrogel and the selection of antioxidant properties of H2. This system can improve H2 release behavior and achieve a single injection into the articular cavity to alleviate the progression of OA in rats. This study of the combination of a convenient long-acting injectable hydrogel and a safe therapeutic gas is of great value for improving the quality of life of clinical patients.

Orphan receptor GPR50 attenuates inflammation and insulin signaling in 3T3-L1 preadipocytes.

Type 2 diabetes (T2DM) is characterized by insulin secretion deficiencies and systemic insulin resistance (IR) in adipose tissue, skeletal muscle, and the liver. Although the mechanism of T2DM is not yet fully known, inflammation and insulin resistance play a central role in the pathogenesis of T2DM. G protein-coupled receptors (GPCRs) are involved in endocrine and metabolic processes as well as many other physiological processes. GPR50 (G protein-coupled receptor 50) is an orphan GPCR that shares the highest sequence homology with melatonin receptors. The aim of this study was to investigate the effect of GPR50 on inflammation and insulin resistance in 3T3-L1 preadipocytes. GPR50 expression was observed to be significantly increased in the adipose tissue of obese T2DM mice, while GPR50 deficiency increased inflammation in 3T3-L1 cells and induced the phosphorylation of AKT and insulin receptor substrate (IRS) 1. Furthermore, GPR50 knockout in the 3T3-L1 cell line suppressed PPAR-γ expression. These data suggest that GPR50 can attenuate inflammatory levels and regulate insulin signaling in adipocytes. Furthermore, the effects are mediated through the regulation of the IRS1/AKT signaling pathway and PPAR-γ expression.

Metformin Inhibits Autophagy, Mitophagy and Antagonizes Doxorubicin-Induced Cardiomyocyte Death.

The antidiabetic drug metformin has been shown to reduce cardiac injury under various pathological conditions, including anticancer drug doxorubicin (DOX)-induced cardiotoxicity, which makes metformin a prime candidate for repurposing. However, the mechanisms that mediate the cardioprotective effects of metformin remain highly controversial. In this study, we tested a prevailing hypothesis that metformin activates autophagy/mitophagy to reduce DOX cardiotoxicity. FVB/N mice and H9C2 cardiac myoblasts were treated with metformin, respectively. Autophagy/mitophagy was determined by Western blot analysis of microtubule-associated protein light chain 3, form-II (LC3-II), a well-established marker of autophagic vesicles. Although metformin had minimal effects on basal LC3-II levels, it significantly inhibited the accumulation of LC3-II levels by the lysosomal protease inhibitors pepstatin A and E64d in both total cell lysates and mitochondrial fractions. Also, dual fluorescent autophagy/mitophagy reporters demonstrated that metformin slowed the degradation rate of autophagic cargos or mitochondrial fragments in the lysosomes. These surprising results suggest that metformin inhibits rather than stimulates autophagy/mitophagy, sharply contrasting the popular belief. In addition, metformin diminished DOX-induced autophagy/mitophagy as well as cardiomyocyte death. Together, these results suggest that the cardioprotective effects of metformin against DOX cardiotoxicity may be mediated by its ability to inhibit autophagy and mitophagy, although the underlying molecular mechanisms remain to be determined.

Systematic Review and Meta-Analysis on the Rehabilitation Effect of Different Intensity Exercise on the Patients with Cardiovascular Diseases.

Background: Cardiovascular disease is a common disease with high prevalence, disability, and mortality. Exercise therapy can improve cardiac functional reserve and life quality of patients, but the benefits of different exercise intensities for cardiovascular patients are still controversial. In this study, literature search and meta-analysis were used to explore the effect of 2 intensities of exercise on the rehabilitation effect of cardiovascular patients. Methods: We searched Embase, Wiley online library, PubMed, Science Direct, and Clinicaltrials to look for randomized controlled trial (RCT) studies of high-intensity interval training (HIIT) versus moderate continuous training (MCT). After screening the inclusion criteria for the literature and assessing the risk of bias, a software analysis was performed using the R language toolkit to obtain forest plots and funnel maps. Results: 10 articles were included in this study into the quantitative analysis, and 520 patients participated in the study; meta-analysis results showed that after HIIT intervention, the VO2 peak index of patients was higher than that of the MCT group (MD = 1.39, 95% CI (0.10, 2.68), Z = 2.12, P = 0.0344), the peak heart rate HR peak was higher than that of the MCT training (MD = 7.71, 95% CI (5.12, 10.30), Z = 5.84, P < 0.0001), the respiratory exchange rate (maximum RER) was higher than that of the MCT training (MD = 0.02, 95% CI (0.00, 0.04), Z = 2.36, P = 0.0184), and the quality of life was higher than that of the MCT training (MD = 0.39, 95% CI (0.07, 0.71), Z = 2.40, P = 0.0165). Discussion. Compared with moderate continuous training, high intensity interval training is more conducive to improve the cardiopulmonary function of cardiovascular patients and improve their physical life quality.

Cariporide Attenuates Doxorubicin-Induced Cardiotoxicity in Rats by Inhibiting Oxidative Stress, Inflammation and Apoptosis Partly Through Regulation of Akt/GSK-3ß and Sirt1 Signaling Pathway.

Background: Doxorubicin (DOX) is a potent chemotherapeutic agent with limited usage due to its cumulative cardiotoxicity. The Na+/H+ exchanger isoform 1 (NHE1) is a known regulator of oxidative stress, inflammation, and apoptosis. The present study was designed to investigate the possible protective effect of cariporide (CAR), a selective inhibitor of NHE1, against DOX-induced cardiotoxicity in rats. Methods: Male Sprague-Dawley rats were intraperitoneally injected with DOX to induce cardiac toxicity and CAR was given orally for treatment. The injured H9c2 cell model was established by incubation with DOX in vitro. Echocardiography, as well as morphological and ultra-structural examination were performed to evaluate cardiac function and histopathological changes. The biochemical parameters were determined according to the manufacturer's guideline of kits. ROS were assessed by using an immunofluorescence assay. The serum levels and mRNA expressions of inflammatory cytokines were measured by using ELISA or qRT-PCR. Cardiac cell apoptosis and H9c2 cell viability were tested by TUNEL or MTT method respectively. The protein expressions of Cleaved-Caspase-3, Bcl-2, Bax, Akt, GSK-3ß, and Sirt1 were detected by western blot. Results: Treatment with CAR protected against DOX-induced body weight changes, impairment of heart function, leakage of cardiac enzymes, and heart histopathological damage. In addition, CAR significantly attenuated oxidative stress and inhibited the levels and mRNA expressions of inflammatory cytokines (TNF-α, IL-6, IL-18, and IL-1ß), which were increased by DOX treatment. Moreover, CAR significantly suppressed myocardial apoptosis and Cleaved-Caspase-3 protein expression induced by DOX, which was in agreement with the increased Bcl-2/Bax ratio. Also, DOX suppressed phosphorylation of Akt and GSK-3ß, which was significantly reversed by administration of CAR. Furthermore, CAR treatment prevented DOX-induced down-regulation of Sirt1 at the protein level in vitro and in vivo. Finally, Sirt1 inhibitor reversed the protective effects of CAR, as evidenced by reduced cell viability and Sirt1 protein expression in vitro. Conclusion: Taken together, we provide evidence for the first time in the current study that CAR exerts potent protective effects against DOX-induced cardiotoxicity in rats. This cardio-protective effect is attributed to suppressing oxidative stress, inflammation, and apoptosis, at least in part, through regulation of Akt/GSK-3ß and Sirt1 signaling pathway, which has not been reported to date.

Preparation and characterization of photocurable composite extracellular matrix-methacrylated hyaluronic acid bioink.

Producing a bioink that fulfills the physicochemical requirements of printing and provides a desirable environment for encapsulated cells is a major challenge in three-dimensional (3D) bioprinting. Thus, we have developed a biocompatible bioink (ECM@MeHA bioink) with suitable mechanical support and visible light printable properties. In this bioink system, the thermosensitive extracellular matrix (ECM) was prepared and can be crosslinked at 37 °C. And the prepared methacrylated hyaluronic acid (MeHA) can be crosslinked under visible light using the biosafe initiators (Eosin Y, TEOA, and NVP). Thus, the ECM@MeHA bioink consisted of a mix solution of ECM and MeHA containing visible light initiators can cure at 515 nm visible light for 30 s and then further crosslinked at 37 °C to form a double network hydrogel. Then, the mechanical properties and biocompatibility of ECM@MeHA hydrogel, and the printability and the cell viability of the ECM@MeHA bioink were systemically evaluated. The results showed that the mechanical property of the MeHA hydrogel is significantly improved following the addition of 10 mg mL-1 of ECM (10ECM@MeHA). The compressive strength and modulus of 10ECM@MeHA hydrogel were 102.38 ± 5.27 kPa and 782 ± 20.36 kPa, which were 2.7 times and 3.1 times higher than those of MeHA, respectively. After encapsulating MC3T3-E1 cells in the 10ECM@MeHA hydrogel for 7 days, the culture showed excellent biocompatibility. The 10ECM@MeHA bioink and cell-laden 10ECM@MeHA bioink were printed, and the cells were successfully encapsulated by the extrusion-based bioprinting and digital light processing (DLP) -based bioprinting. The cell-laden 10ECM@MeHA scaffold showed 94.27 ± 3.00% cell viability after 7 days of the 3D culture. In conclusion, 10ECM@MeHA bioink may provide a new strategy for constructing disease models or drug screening models in vitro and is expected to be widely used in the field of tissue engineering scaffolds.

3D-printed NIR-responsive shape memory polyurethane/magnesium scaffolds with tight-contact for robust bone regeneration.

Patients with bone defects suffer from a high rate of disability and deformity. Poor contact of grafts with defective bones and insufficient osteogenic activities lead to increased loose risks and unsatisfied repair efficacy. Although self-expanding scaffolds were developed to enhance bone integration, the limitations on the high transition temperature and the unsatisfied bioactivity hindered greatly their clinical application. Herein, we report a near-infrared-responsive and tight-contacting scaffold that comprises of shape memory polyurethane (SMPU) as the thermal-responsive matrix and magnesium (Mg) as the photothermal and bioactive component, which fabricated by the low temperature rapid prototyping (LT-RP) 3D printing technology. As designed, due to synergistic effects of the components and the fabrication approach, the composite scaffold possesses a homogeneously porous structure, significantly improved mechanical properties and stable photothermal effects. The programmed scaffold can be heated to recover under near infrared irradiation in 60s. With 4 wt% Mg, the scaffold has the balanced shape fixity ratio of 93.6% and shape recovery ratio of 95.4%. The compressed composite scaffold could lift a 100 g weight under NIR light, which was more than 1700 times of its own weight. The results of the push-out tests and the finite element analysis (FEA) confirmed the tight-contacting ability of the SMPU/4 wt%Mg scaffold, which had a signficant enhancement compared to the scaffold without shape memory effects. Furthermore, The osteopromotive function of the scaffold has been demonstrated through a series of in vitro and in vivo studies. We envision this scaffold can be a clinically effective strategy for robust bone regeneration.