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In the case of non-independent and identically distributed samples, we propose a new ueMC algorithm based on uniformly ergodic Markov samples, and study the generalization ability, the learning rate and convergence of the algorithm. We develop the ueMC algorithm to generate samples from given datasets, and present the numerical results for benchmark datasets. The numerical simulation shows that the logistic regression model with Markov sampling has better generalization ability on large training samples, and its performance is also better than that of classical machine learning algorithms, such as random forest and Adaboost. [ABSTRACT FROM AUTHOR]

Electrical reverse remodeling of native conduction is associated with better clinical outcome following cardiac resynchronization therapy (CRT). We aimed to describe characteristics, time course and long-term outcome of patients with complete electrical reverse remodeling (CERR) after resynchronization therapies. CRT candidates were treated with bi-ventricular, His bundle or left bundle branch pacing. CERR was defined if native QRS duration post-implantation was narrowed to ≤120 ms. A total of 322 patients met the inclusion criteria. Among them, 66 were super-responders and 12 exhibited CERR. All 12 patients were diagnosed of non-ischemic cardiomyopathy with left bundle branch block (LBBB) meeting the Strauss criteria. The mean native QRS duration when CERR was achieved was 110.8 ± 10.0 ms, significantly shorter than the baseline (175.0 ± 18.8 ms). The occurrence of CERR varied from several days post-implantation to 18-month follow-up. The persistence of CERR also showed great variations. Eleven patients (91.7%, 11/12) showed echocardiographic super-response. Patients with CERR showed similar baseline characteristics compared to those with echocardiographic super-response but without CERR. Two patients with CERR showed different responses after bi-ventricular pacing was turned off. One patient remained stable with narrow QRS complex and great response. The other patient had reappearance of LBBB and decreased cardiac function, but recovered by turning on the device again. Patients with CERR exhibited great response to different resynchronization therapies. The time course of CERR and echocardiographic super-response varied greatly. The variability of native conduction system and accompanied changes of mechanical remodeling suggest the mechanisms of electrical-disorder related cardiomyopathy. • This study described the clinical features and outcome of patients with CERR after different resynchronization therapies. • Patients with CERR showed typical LBBB in the baseline ECGs and great response to the resynchronization therapies. • The time course of occurrence of CERR varied greatly in this population. • Two patients with CERR showed different responses after bi-ventricular pacing was turned off. [ABSTRACT FROM AUTHOR]

Background: Left bundle branch pacing (LBBP) is a new near‐physiological pacing modality. Distinguishing left ventricular septal only pacing (LVSP) from nonselective LBBP still needs clarification. This prospective study sought to establish a differentiation algorithm to confirm LBBP. Methods and Results: LBBP was attempted in consecutive patients. If direct LBB capture (LBBP) could not be confirmed, LVSP was considered to have been achieved. Intracardiac left ventricular (LV) activation sequence and activation time were analyzed using coronary sinus (CS) electrogram mapping. Electrophysiological parameters including S‐CSmax, S‐CSmin, LV lateral wall activation time, ΔLV, and LBB potential were compared between LBBP and LVSP. Stimulated LV activation time (S‐LVAT) and stimulated QRS duration (S‐QRSd) were also compared between the two groups. Multivariate logistic regression analysis was used to develop a prediction algorithm for LBBP. Of the 43 prospectively enrolled patients, 27 underwent LBBP and 16 underwent LVSP. All LBBP patients showed identical LV activation sequences to their intrinsic rhythm while no LVSP patients maintained their intrinsic sequence. S‐CSmax, ΔLV, LV lateral wall activation time, and S‐LVAT during LBBP were significantly shorter than those during LVSP. Combining LBB potential with S‐LVAT had the largest area under the curve (AUC) of 0.985 for confirming LBBP with a sensitivity of 95.2% and a specificity of 93.7%. Conclusions: Compared with LVSP, LBBP preserves a normal LV activation sequence and better electrical synchrony. A combination of LBB potential with S‐LVAT can be an effective and practical model to distinguish LBBP from LVSP during implantation in patients with normal LBB activation. [ABSTRACT FROM AUTHOR]

Background: Chronic right ventricular (RV) pacing is associated with an increased incidence of heart failure and mortality. Left bundle branch (LBB) pacing could produce near‐physiological electrical activation and mechanical synchrony. We aimed to report the effects of upgrading to LBB pacing in heart failure patients after chronic RV pacing. Methods: The indications included pacing‐induced cardiomyopathy (PICM) in Group 1 and heart failure after RV pacing with left ventricular ejection fraction (LVEF) ≥ 50% in Group 2. LBB pacing was achieved by penetrating the pacing lead to the subendocardium of left‐sided interventricular septum through the venous access. Left ventricular activation time (LVAT) was measured from the pacing stimulus to the ascending peak of lead V5 or V6. All patients underwent clinical and echocardiographic evaluations before and after upgrading. Results: Totally 27 patients (13 in Group 1 and 14 in Group 2) were consecutively enrolled. The mean follow‐up time after upgrade was 10.4 ± 6.1 months. Paced QRS duration was significantly shortened from 174.1 ± 15.8 milliseconds to 116.6 ± 11.7 milliseconds (p <.0001). The mean LVAT was 83.2 ± 11.7 milliseconds. LVEF increased from 40.3 ± 5.2% before upgrading to 48.1 ± 9.5% at follow‐up in patients with PICM. Serum N‐terminal probrain natriuretic peptide levels decreased and New York Heart Association classification improved in both groups. No upgrade‐related complications were observed. Conclusions: Upgrading to LBB pacing was feasible and effective with improved cardiac function in heart failure patients with both reduced and preserved LVEF after RV pacing. [ABSTRACT FROM AUTHOR]

In this study, a solution chitosan fibroin emulsion with added Silver Nanoparticles (AgNPs) was freeze-dried to be the scaffold, and an asymmetric coating was formed on one side. PRP was loaded onto the composite scaffold using a secondary lyophilization technology to prepare the tissue engineering dressings. AgNPs were characterized using a transmission electron microscope. The morphologies of the composite dressing were examined under a scanning electron microscope. The silver content of the dressing was measured by inductively coupled plasma mass spectrometry. The asymmetric wettability of the composite dressing was demonstrated by water contact angle measurement. Relatively high porosity, favourable moisture retention capability and appropriate tensile strength were observed by measuring the physical and mechanical properties. Satisfactory antibacterial properties against various bacteria and microbial isolation performance were observed by the antibacterial effect analysis in vitro. The total protein slow-release property was measured using the BCA assay. Good biocompatibility and lower sensitization were examined both in vitro and in vivo. In addition, the healing effciency of the composite dressing on infected wound were examined in mice infected wound models. Analysis of wound healing rates, bacterial cultures of wound exudate, whole blood cell analysis and histological examination all showed satisfactory results. These results are demonstrated to provide a potential and possible pathway to promote wound tissue repair and regeneration. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronization therapy (CRT) is the standard‐of‐care therapy for the patients with heart failure and left ventricular (LV) dyssynchrony. However, approximately 30% of the patients show no response. Recent studies have shown that His bundle pacing (HBP) could be an alternative for the patients with CRT indications. The purpose of this study was to evaluate the efficacy of HBP in patients with heart failure. Methods: We searched PubMed and Embase databases for studies evaluating HBP in patients with heart failure and LV dyssynchrony. The successful rate of implantation, QRS duration, pacing threshold, LV function at baseline and follow‐up, and mortality rates were extracted and summarized. Results: Eleven studies including 494 patients were included in this analysis. The overall successful rate for implantation was 82.4%. The main indications for HBP were CRT candidates and cardiomyopathy with atrial fibrillation undergoing atrioventricular node ablation. Permanent HBP resulted in narrow QRS duration of 116.3 ± 13.9 ms after implantation. LV functions, including echocardiographic parameters and clinical outcomes, significantly improved at follow‐up (P < 0.001). However, there was a trend of increased capture and bundle branch block correction thresholds at follow‐up compared to baseline (P = 0.01 and 0.02, respectively). During a mean follow‐up of 23.7 months, 5.9% of the patients experienced heart failure‐related hospitalization and the mortality rate was 9.1%. Conclusion: Permanent HBP has shown promising results for heart failure patients in small observational studies. Randomized controlled trials are needed to assess the efficacy of HBP in these patients. [ABSTRACT FROM AUTHOR]

Abstract Rapid neovascularization within scaffolds is critical for the regeneration of thick complex tissues. The surface immobilization of peptides and other active molecules have been explored to improve the vascularization capacity of implants. However, the rapid degradation of these molecules, the reaction conditions and cross-linking usually result in decreased vascularization capability. Here, we introduced a temperate, all-aqueous process to achieve bulk porous silk fibroin (SF) scaffolds. A temperature controlled process was used to induce the water stable structure by SF self-assembly. Arg-Glu-Asp-Val (REDV) peptides were added into SF solution and fixed within SF scaffolds during the self-assembly process. The results showed that the functionalized scaffolds markedly promoted the adhesion of endothelial cells in vitro. Moreover, the in vivo studies indicated enhanced cell infiltration in the bulk functionalized SF scaffolds and impressive vascularization at 4 weeks post-implantation. The functionalized scaffolds demonstrated excellent vascularization capability, providing an exciting biomaterial option for thick tissue regeneration. Highlights • A temperate, all-aqueous process was developed to achieve bulk porous silk fibroin (SF) scaffolds. • REDV peptides were added into SF solution and fixed within SF scaffolds during the self-assembly process. • The functionalized scaffolds markedly promoted the adhesion of endothelial cells in vitro. • Enhanced cell infiltration and impressive vascularization were observed at 4 weeks post-implantation. [ABSTRACT FROM AUTHOR]

Left ventricular noncompaction (LVNC) is an inherited cardiomyopathy involving numerous genes. To identify novel candidate causal mutations, a whole exome sequencing study was performed on a Chinese LVNC family. Exons of the most prevalent pathogenic genes of LVNC (myosin heavy chain 7 and actin, α‑cardiac muscle 1) were sequenced, although no mutations were identified. Following this, Burrows‑Wheeler Aligner, PICARD and Genome Analysis Toolkit (v.2.8) were used to analyze the exome sequencing data. Non‑silent single nucleotide variants (SNVs) that were identified in patients with LVNC, although not in the healthy individual, were investigated further using SNV prioritization via the integration of genomic data (SPRING) based on P‑values. Co‑expressed gene enrichment analysis was performed using Genotype Tissue Expression (GTEx) data in order to investigate the potential roles of the genes containing SNVs in the myocardium. In the Chinese LVNC family, seven novel SNVs were identified that were only present in patients with LVNC and annotated by SPRING with P<0.05. Among these SNVs, hemicentin 1 [c. thymine (T) 9776 cytosine (C)], tolloid like 2 [c. cytosine (C) 2615 thymine (T)], fms related tyrosine kinase 3 [c. guanine (G) 976 adenine (A)] and nucleotide binding protein like [c. guanine (G) 91 thymine (T)] were located in conserved regions and annotated as deleterious by PolyPhen2, LRT and MutationTaster database analyses. Based on GTEx data, it was revealed that NUBPL was co‑expressed with almost all previously established LVNC pathogenic genes. Furthermore, the results of the present study demonstrated that genes co‑expressed with NUBPL were additionally enriched in the Notch signaling pathway. In addition, the results revealed numerous novel mutations that may be causal SNVs for the development of LVNC in the family involved in the present study. [ABSTRACT FROM AUTHOR]

A 90-day in-country feeding trial in Wistar rats was conducted at Tianjin Laboratory in China to assess toxicity of diets containing DAS-44406-6 soybean meal. There were no treatment-related changes observed when compared with the non-GM isoline control groups but histopathologically, 2 of 10 high-dose females were reported to show kidney lesions. However, these findings contrasted with the absence of any treatment-related kidney lesions in 3 separate 90-day toxicity studies previously conducted in Sprague Dawley rats. Strain difference is not expected in the kidney response, and based on the low incidence and contrary evidence from previous studies, it is likely that these lesions were of spontaneous origin, or artefactual. To determine that the lesions observed were not treatment-related in Wistar rats, a specific follow-up confirmatory study was conducted under Good Laboratory Practices (GLP) in the Wistar strain of rats following an identical study design to the Tianjin study. To increase the power of detecting effects, twice the number of animals per group (20/sex/group) were used, and no treatment-related kidney histopathological changes were observed. Based on these results and entire weight of evidence evaluation, it is concluded that the histopathological changes previously noted in the 2 female Wistar rats of Tianjin study were not treatment-related and that DAS-44406-6 soybeans are as safe as conventional non-GM soybeans. [ABSTRACT FROM AUTHOR]

Abstract: Background: The incidence and clinical outcomes of delayed response to cardiac resynchronization therapy (CRT) have not been well clarified. We aimed to observe the incidence and prognosis of delayed response and to identify its possible mechanisms. Methods: A total of 115 CRT patients were retrospectively analyzed in our study. Patients who met the enrollment criteria were divided into two groups: group A, conventional responders who showed response at 1‐year follow‐up, and group B, delayed responders who showed response after 1‐year follow‐up. CRT response was defined as an absolute increase of ≥10% in left ventricular ejection fraction. Results: Fifty‐two patients (61 ± 12 years, 37 male) experienced conventional response to CRT and 17 patients (63 ± 11 years, 10 male) experienced delayed response. The mean follow‐up time was 5.2 ± 2.4 years. The incidence of delayed response was 14.8% (17/115). All‐cause mortality and hospitalization rates for heart failure were similar for delayed and conventional responders. Multivariate logistic regression analysis revealed that scar burden > 35% was an independent predictor of CRT delayed response (odds ratio 8.794, P  =  0.038). Conclusions: A significant proportion of patients demonstrated delayed response to CRT. The delayed responders had a good prognosis that was similar to that of conventional responders. More scar burden might be related to the incidence of delayed response. [ABSTRACT FROM AUTHOR]

Background Implantable cardioverter defibrillators (ICDs) have become the standard approach for prevention of sudden cardiac death. Whether ICD therapy is an independent predictor of all-cause mortality is controversial. We made the systematic review and meta-analysis to estimate the impact of ICD therapy on mortality. Methods We searched the PubMed and Embase databases for studies evaluating the effect of ICD shocks or antitachycardia pacing (ATP) on mortality. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using random effects models. Results Thirteen cohort studies were identified. Mean ejection fraction of the population was 23-35%; 68.0% had ischemic etiology, and 74.5% received a primary prevention ICD implantation. Appropriate shocks were an independent predictor of increased mortality compared with no-shock or no-therapy patients (HR 2.07, 2.76, respectively). In contrast, inconsistent results were obtained during inappropriate-shock analyses: when compared with no-shock patients, inappropriate shocks were associated with an increased risk of death (HR 1.54, 95% CI: 1.25-1.89, P < 0.0001); however, when compared to no-therapy patients, there was no relationship between inappropriate shocks and mortality (HR 1.20, 95% CI: 0.90-1.61, P = 0.22). Subgroup analysis in heart failure patients also did not find any difference in mortality between inappropriate-shock and no-therapy patients. No increased risk of mortality was found in the patients who experienced appropriate or inappropriate ATP only. Conclusion Appropriate shocks were associated with an increased mortality in ICD patients. However, whether inappropriate shocks worsened the clinical outcome was controversial, and larger prospective trials are needed to clarify the issue. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, biodegradable aliphatic copolyesters were synthesized from ε-caprolactone, adipic acid, and 1,6-hexanediol by melt-polycondensation method. The chemical structure, and thermal properties of these copolymers were studied in detail. The water absorption behavior and hydrolytic degradation behavior of this copolyester were also studied. This aliphatic copolyester prepolymer would be used to prepare the biodegradable poly(ester urethane), which might have potential application in biomedical field. [Copyright &y& Elsevier]

In this paper, a new kind of aliphatic biodegradable polyesteramide copolymers P(CL/AU)x/y based on &epsiv;-caprolactone and 11-aminoundecanoic acid were synthesized by the melt polycondensation method. Hydrolytic degradation behavior of P(CL/AU) copolymers were studied by using FTIR, 1H-NMR and DSC. Chemical compositions, macromolecular weight, thickness of the test sample, and pH of the degradation medium have great effect on degradation rate. The degradation rate decreased with increase in aminoundecanoic acid content, macromolecular weight, and thickness of the test samples, but increased with incubation temperature and pH of the degradation medium. The degradation mechanism was studied according to the mathematical model developed by professor Go¨pferich. [Copyright &y& Elsevier]

A new kind of aliphatic polyetheresteramide copolymers (PEEAs) based on ∊-caprolactone, 11-aminoundecanoic acid, and poly(ethylene glycol) (PEG) were synthesized by melt polycondensation. The thermal and hydrolytic degradation behaviour of these copolymers was studied using FTIR, 1H-NMR, and TGA. PEG content, thickness of the test sample, and pH of degradation medium have great effect on degradation rate. The degradation rate increased with PEG content and pH, but decreased with thickness of the test sample. [Copyright &y& Elsevier]

Degradable polyesteramide fibres were processed by melt-spinning. Tensile properties of as-spun and hot-drawn fibres were also investigated. After drawing, the overall crystallinity and the melting temperature of the copolymer increased. As a result, the tensile strength of the fibre increased, and the elongation at break decreased. The morphology of the surface and fracture cross section were studied by SEM. During alkaline degradation, the tensile strength and the elongation at break both decreased. [Copyright &y& Elsevier]

Hydrolytically degradable PET/PEG block copolymer was synthesized by the macromolecular transesterification method from PET and PEG. Non-isothermal crystallization behavior of the copolymers was investigated by differential scanning calorimetry (DSC). Water absorption and in vitro degradation behaviour of these copolymers were studied in detail. When hydrophilic PEG was incorporated into the PET chain, water absorption increased. With the increase in PEG concentration, the degradation rate increased accordingly. PEG molecular weight has different effects on PET/PEG copolymers’ degradation rate. [Copyright &y& Elsevier]

A new kind of polyesteramide copolymer based on &epsiv;-caprolactone and 11-aminoundecanoic acid has been synthesized by melt polycondensation. The copolymers were characterized by FTIR, 1H-NMR, DSC, and WAXD. With the increase in aminoundecanoic acid content, the melting temperature, heat of fusion, and Td,50% increased accordingly. The thermal degradation of the P(CL/AU)x/y copolymers was studied using FTIR, and TG During thermal degradation, the ester bond decomposes at lower temperature, then the amide bond decomposes at higher temperature. [Copyright &y& Elsevier]

Camptothecin (CPT) is a highly cytotoxic molecule with excellent antitumor activity against various cancers. However, its clinical application is severely limited by poor water solubility, easy inactivation, and severe toxicity. Structural modifications and nanoformulations represent two crucial avenues for camptothecin's development. However, the potential for further structural modifications is limited, and camptothecin nanoparticles fabricated via physical loading have the drawbacks of low drug loading and leakage. Prodrug‐based CPT nanoformulations have shown unique advantages, including increased drug loading, reduced burst release, improved bioavailability, and minimal toxic side effects. Stimulus‐responsive CPT nano‐prodrugs that respond to various endogenous or exogenous stimuli by introducing various activatable linkers to achieve spatiotemporally responsive drug release at the tumor site. This review comprehensively summarizes the latest research advances in stimulus‐responsive CPT nano‐prodrugs, including preparation strategies, responsive release mechanisms, and their applications in cancer therapy. Special focus is placed on the release mechanisms and characteristics of various stimulus‐responsive CPT nano‐prodrugs and their application in cancer treatment. Furthermore, clinical applications of CPT prodrugs are discussed. Finally, challenges and future research directions for CPT nano‐prodrugs are discussed. This review to be valuable to readers engaged in prodrug research is expected. [ABSTRACT FROM AUTHOR]

AbstractThe mechanisms underlying subclinical hypothyroidism (SCH) remain unclear, making timely and accurate differentiation between hypothyroidism and SCH, as well as severity assessment, challenging. This study aimed to investigate the role of NFE2 like bZIP transcription factor 2 (Nrf2), gp91phox, and interleukin-17 (IL-17) in the pathogenesis of SCH. In this prospective comparative study, 105 SCH patients, 105 hypothyroidism patients, and 105 healthy individuals were enrolled from January 2022 to August 2023. SCH patients were categorized into mild-moderate and severe groups based on thyroid-stimulating hormone (TSH) levels. Levels of TSH, free T4 (FT4), free T3 (FT3), thyroglobulin antibodies (TG-Ab), thyroid peroxidase antibodies (TPO-Ab), cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-ch), and low-density lipoprotein-cholesterol (LDL-ch) were measured. Nrf2, IL-1β, IL-6, IL-17, and gp91phox levels were tested using ELISA. Nrf2, IL-17 and gp91phox were significantly higher in SCH and hypothyroidism patients compared to the healthy controls, with hypothyroidism patients showing the highest levels. Nrf2 levels were negatively correlated with TSH, TG-Ab and IL-17, but not gp91phox. Nrf2, IL-17 and gp91phox could be used for diagnosis of SCH and severe SCH. Only TG-Ab, IL-17 and gp91phox were independent risk factors for severe SCH. This study demonstrates a negative correlation between serum Nrf2 levels and SCH severity. TG-Ab, IL-17, and gp91phox are independent risk factors, and their associations with SCH pathology suggest their potential roles in the disease mechanism. These findings provide insights into SCH pathogenesis and highlight the need for further research to elucidate their diagnostic or prognostic significance. [ABSTRACT FROM AUTHOR]

Inflammation‐associated diseases are very common clinically with a high incidence; however, there is still a lack of effective treatments. Cell‐biomimetic nanoplatforms have led to many breakthroughs in the field of biomedicine, significantly improving the efficiency of drug delivery and its therapeutic implications especially for inflammation‐associated diseases. Macrophages are an important component of immune cells and play a critical role in the occurrence and progression of inflammation‐associated diseases while simultaneously maintaining homeostasis and modulating immune responses. Therefore, macrophage‐biomimetic nanoplatforms not only inherit the functions of macrophages including the inflammation tropism effect for targeted delivery of drugs and the neutralization effect of pro‐inflammatory cytokines and toxins via membrane surface receptors or proteins, but also maintain the functions of the inner nanoparticles. Macrophage‐biomimetic nanoplatforms are shown to have remarkable therapeutic efficacy and excellent application potential in inflammation‐associated diseases. In this review, inflammation‐associated diseases, the physiological functions of macrophages, and the classification and construction of macrophage‐biomimetic nanoplatforms are first introduced. Next, the latest applications of different macrophage‐biomimetic nanoplatforms for the treatment of inflammation‐associated diseases are summarized. Finally, challenges and opportunities for future biomedical applications are discussed. It is hoped that the review will provide new ideas for the further development of macrophage‐biomimetic nanoplatforms. [ABSTRACT FROM AUTHOR]

Antibacterial photocatalytic therapy (APCT) is one of the most promising non‐antibiotic treatment strategies for biofilm‐infected wounds and inflammation caused by drug‐resistant bacteria. However, it still faces issues such as inadequate single antibacterial capacity and lack of antioxidant capacity. In this study, a Z‐scheme heterojunction (Bi2S3‐X@PDA) is designed using a polydopamine (PDA) shell firmly anchored to the surface of sulfur vacancy‐rich bismuth sulfide nanorods (Bi2S3‐X NRs). Under near‐infrared light and hydrogen peroxide, Bi2S3‐X@PDA significantly improves the photocatalytic efficiency of reactive oxygen species generation and shows a nearly 100% broad‐spectrum antibacterial effect against multiple bacterial strains and bacterial biofilms in vitro. Interestingly, the antioxidant activity of the PDA shell in Bi2S3‐X@PDA remarkably downregulates the expression of pro‐inflammatory factors and promotes macrophage reprogramming toward the proregenerative M2 phenotype. In a mouse wound model of methicillin‐resistant Staphylococcus aureus biofilm infection, Bi2S3‐X@PDA effectively eliminates drug‐resistant bacterial biofilms through APCT/mild photothermal therapy, while reducing inflammation in normal tissues and regulating the immune microenvironment, thereby promoting rapid wound healing. Overall, this light‐controlled treatment strategy, which provides both antibacterial and anti‐inflammatory functions, is a reliable tool for combating biofilm infection and inflammation caused by drug‐resistant bacteria. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is a critical global health challenge, with current treatments limited by the complex MI microenvironment, particularly the excessive oxidative stress and intense inflammatory responses that exacerbate cardiac dysfunction and MI progression. Herein, a mannan‐based nanomedicine, Que@MOF/Man, is developed to target the inflammatory infarcted heart and deliver the antioxidative and anti‐inflammatory agent quercetin (Que), thereby facilitating a beneficial myocardial microenvironment for cardiac repair. The presence of mannan on the nanoparticle surface enables selective internalization by macrophages rather than cardiomyocytes. Que@MOF/Man effectively neutralizes reactive oxygen species in macrophages to reduce oxidative stress and promote their differentiation into a reparative phenotype, reconciling the inflammatory response and enhancing cardiomyocyte survival through intercellular communication. Owing to the recruitment of macrophages into inflamed myocardium post‐MI, in vivo, administration of Que@MOF/Man in MI rats revealed the specific distribution into the injured myocardium compared to free Que. Furthermore, Que@MOF/Man exhibited favorable results in resolving inflammation and protecting cardiomyocytes, thereby preventing further myocardial remodeling and improving cardiac function in MI rats. These findings collectively validate the rational design of an inflammation‐targeted delivery strategy to mitigate oxidative stress and modulate the inflammation response in the injured heart, presenting a therapeutic avenue for MI treatment. [ABSTRACT FROM AUTHOR]

Methicillin‐resistant Staphylococcus aureus (MRSA) biofilm infection, caused by impaired glucose metabolism in diabetic foot patients, poses a significant obstacle to the healing process and carries a high risk of being life‐threatening. Due to microvascular occlusion and the entrenchment of MRSA biofilms in diabetic foot, controlling and effectively treating MRSA infection remains challenging. Traditional hydrogels suffer from swelling‐related mechanical issues and inadequate drug release control, limiting their applications as biomimetic extracellular matrices for wound healing. Herein, a double‐network hydrogel composed of polyvinyl alcohol, sodium alginate, and gelatin (PSG) loaded with tea polyphenol self‐assembled magnesium nanoparticles (TP‐Mg NPs) with antibacterial and angiogenic properties for treating MRSA‐infected diabetic foot wounds under hyperglycemic conditions is constructed. TP‐Mg@PSG exhibits enhanced mechanical strength and toughness for wound attachment and recovery movement torsion. In the acidic infection microenvironment representative of MRSA‐infected wounds, the TP‐Mg@PSG hydrogel degrades to release TP‐Mg NPs, showing excellent anti‐MRSA biofilm effect and high biocompatibility. Such localized controlled release enhances the inhibition of MRSA infection and reduces the inflammatory response in rats, promoting cell proliferation and rapid wound repair. Therefore, this study presents a multifunctional biomaterial system for managing diabetic foot conditions, highlighting its potential for clinical applications. [ABSTRACT FROM AUTHOR]

Micro/nano drug delivery systems can provide ideal controlled drug release. Microfluidic chip technology plays an important role in the preparation of microspheres. Sodium alginate (SA) has been used to prepare microspheres as drug carriers owing to its good biosafety and easy preparation. However, these microspheres lack antimicrobial activity and drug loading efficiency, which prevent their application for infected wound repair. Although silver nanoparticles (AgNPs) possess broad-spectrum antibiotic activity, liquid mixtures of AgNPs and SA are too unstable to fabricate drug-loaded microspheres using microfluidic chip technology. In this study, AgNPs were coated with silk fibroin (SF) and then dispersed in SA solution to fabricate antibacterial microspheres (denoted SA-SF-Ag) using microfluidic chip technology. SA-SF-Ag effectively inhibited the growth of microorganisms and gradually released AgNPs. Moreover, in vivo results showed that SA-SF-Ag promoted infected wound healing and angiogenesis by killing Pseudomonas aeruginosa on the surface of infected skin wounds of mouse models. This study offers a new method to integrate AgNPs into organic polymeric microspheres for the treatment of infected wounds. [ABSTRACT FROM AUTHOR]

Melanoma, the most aggressive skin cancer type, is challenging to treat due to its high metastatic potential and low response to conventional therapies. Innovative approaches, including combination therapies, are crucial for enhancing treatment efficacy while minimizing side effects. It is developed boronophenylalanine‐containing polydopaine (B‐PDA) nanoparticles by encapsulating boronophenylalanine in polydopamine through nitrogen‐boronate coordination, targeting both boron neutron capture therapy (BNCT) and photothermal therapy (PTT). With stability and biocompatibility under physiological conditions, these nanoparticles utilize the phenylalanine residues in BPA to target the overexpressed neutral amino acid transporter 1 (LAT1) in melanoma cells, resulting in enhanced cell‐specific targeting. B‐PDA nanoparticles demonstrated significant photothermal effects under external stimulation, inducing localized heating and triggering heterogeneous tumor cell death, thereby enhancing sensitivity to BNCT. Combining BNCT and PTT, the B‐PDA nanoparticles offer a promising strategy for melanoma treatment. [ABSTRACT FROM AUTHOR]

Background. The study was aimed at exploring the electrophysiological characteristics (EPS) of the optimal ablation site and its relationship with electroanatomic voltage mapping (EVM) in idiopathic premature ventricular contractions (PVCs) originating from the right ventricular outflow tract (RVOT). Methods. A total of 28 patients with idiopathic RVOT PVCs underwent successful ablation and EVM using a 3D electroanatomical mapping (CARTO) system. Results. Both bipolar and unipolar EVM showed a similar band-like lower-voltage area (LVA) under the pulmonary valve in all the patients; 21.4% of the targets were located in the band-like LVA. 42.9% of the targets were at the border of the band-like LVA on the bipolar voltage map, but unipolar mapping showed that 53.6% of the targets were located in the band-like LVA, and 35.7% of the targets at the border of the band-like LVA. A significant difference was found in both unipolar and bipolar voltage values between the regions within 0-5 mm above the optimal ablation site and the other regions. A similar difference was observed only in unipolar voltage values below the optimal ablation site. At the ablation site, there were frequent occurrences of a fragmented wave and voltage reversion in the bipolar electrograms, frustrated falling limbs, W bottom, and a QS configuration width > 150 ms in the unipolar electrograms. Conclusions. EVM showed that the band-like LVA was an interesting area for the search of the optimal ablation sites of idiopathic RVOT-PVCs, especially the border area. There was focal microscarring around the ablation targets; some characteristics of EPS proved significant for successful ablation. [ABSTRACT FROM AUTHOR]

Here we describe a cost-effective and simplified cell sorting method using tetrazine bioorthogonal chemistry. We successfully isolated SKOV3 cells from complex mixtures, demonstrating efficacy in separating mouse lymphocytes expressing interferon and HeLa cells expressing virally transduced green fluorescent protein post-infection. [ABSTRACT FROM AUTHOR]

Selenium (Se) and vitamin B2 (VitB2) all play essential roles in participating in hepatic lipid metabolism regulation. In this study, we aimed to identify whether Se combined with VitB2 could meliorate nonalcoholic fatty liver disease (NAFLD) caused by high‐fat (HF) diet in rats. To this end, 50 SD male rats were randomly allotted into five groups equally after receiving a HF diet for 2 weeks. Rats were fed high‐fat diets and gavaged daily with 0.83 or 8.33 µg kg–1 Se combined with 0.70 or 3.50 mg kg–1 VitB2 for 8 weeks. Another 10 rats were given a conventional diet as a control group. The result showed that Se combined with VitB2 decreased NAFLD activity score and liver lipid's levels, relieved hepatic steatosis and lipid deposition and promoted the balance of ApoA1/ApoB ratio. The hepatic 3‐hydroxy‐3‐methyl glutaryl coenzyme A reductase (HMGR) level was declined, and the serum HL level was increased in NAFLD rats through the combined intervention. In addition, Se and VitB2 regulated hepatic metabolism factor's (FAS, ACC, ACAT1, PPARγ, and SREBP‐1c) expression level. Taken together, the combined intervention of Se and VitB2 can alleviate HF‐diet‐induced NAFLD in rats. The molecular mechanism may be related to affecting the activities of lipid metabolic enzymes such as FAS, ACC, HMGR, ACAT1, and HL by inhibiting the expression of PPARγ and SREBP‐1c. Practical Applications: The present study showed that a combination of Se and VitB2 can effectively reduce hepatic lipid accumulations, exert hepatoprotective effects and regulate hepatic lipid metabolism in NAFLD rats caused by a high‐fat diet. The possible molecular mechanism may be related to affecting the activities of lipid metabolic enzymes such as FAS, ACC, HMGR, ACAT1, and HL, and inhibiting the expression of PPARγ and SREBP‐1c. Se and VitB2 cosupplementation may be a potential therapeutic strategy in overcoming hepatic lipid disorders' adverse effects beyond pharmacological interventions to ameliorate NAFLD. [ABSTRACT FROM AUTHOR]

Despite the tremendous progress in cancer treatment in recent decades, cancers often become resistant due to multiple mechanisms, such as intrinsic or acquired multidrug resistance, which leads to unsatisfactory treatment effects or accompanying metastasis and recurrence, ultimately to treatment failure. With a deeper understanding of the molecular mechanisms of tumors, researchers have realized that treatment designs targeting tumor resistance mechanisms would be a promising strategy to break the therapeutic deadlock. Nanodelivery systems have excellent physicochemical properties, including highly efficient tissue‐specific delivery, substantial specific surface area, and controllable surface chemistry, which endow nanodelivery systems with capabilities such as precise targeting, deep penetration, responsive drug release, multidrug codelivery, and multimodal synergy, which are currently widely used in biomedical researches and bring a new dawn for overcoming cancer resistance. Based on the mechanisms of tumor therapeutic resistance, this review summarizes the research progress of nanodelivery systems for overcoming tumor resistance to improve therapeutic efficacy in recent years and offers prospects and challenges of the application of nanodelivery systems for overcoming cancer resistance. [ABSTRACT FROM AUTHOR]

Bone defects in osteoporosis usually present excessive reactive oxygen species (ROS), abnormal inflammation levels, irregular shapes and impaired bone regeneration ability; therefore, osteoporotic bone defects are difficult to repair. In this study, an injectable thermosensitive hydrogel poly (D, L‐lactide)‐poly (ethylene glycol)‐ poly (D, L‐lactide) (PLEL) system containing resveratrol (Res) and dexamethasone (DEX) is designed to create a microenvironment conducive to osteogenesis in osteoporotic bone defects. This PLEL hydrogel is injected and filled irregular defect areas and achieving a rapid sol‐gel transition in situ. Res has a strong anti‐inflammatory effects that can effectively remove excess free radicals at the damaged site, guide macrophage polarization to the M2 phenotype, and regulate immune responses. Additionally, DEX can promote osteogenic differentiation. In vitro experiments showed that the hydrogel effectively promoted osteogenic differentiation of mesenchymal stem cells, removed excess intracellular ROS, and regulated macrophage polarization to reduce inflammatory responses. In vivo experiments showed that the hydrogel promoted osteoporotic bone defect regeneration and modulated immune responses. Overall, this study confirmed that the hydrogel can treat osteoporotic bone defects by synergistically modulating bone damage microenvironment, alleviating inflammatory responses, and promoting osteogenesis; thus, it represents a promising drug delivery strategy to repair osteoporotic bone defects. [ABSTRACT FROM AUTHOR]

Background: Left bundle branch area pacing (LBBAP) was reported to improve cardiac function by correcting complete left bundle branch block (CLBBB). Our study aimed to compare the efficacy of LBBAP and biventricular pacing (BIVP) in heart failure patients with CLBBB. Methods: Ten patients prospectively underwent LBBAP (LBB‐CRT group) and 30 patients received BIVP (BIV‐CRT group) were matched using propensity score matching. LBBAP was achieved by the trans‐interventricular septum method. Echocardiography, electrocardiogram, NYHA classification, and blood B‐type natriuretic peptide concentration were evaluated at preimplantation and at 6‐month follow up. CRT response was defined as at least 15% decrease in left ventricular end‐systolic volume. Results: In the LBB‐CRT group, CLBBB were successfully corrected by LBBAP with no complications. QRS duration (QRSd) significantly decreased after implantation in both groups, and the decrease of QRSd in the LBB‐CRT group was significantly greater than that in the BIV‐CRT group (60.80 ± 20.09 vs. 33.00 ± 21.48 ms, p =.0009). The echocardiographic measurements including left ventricular end‐diastolic diameter, left ventricular end‐systolic diameter, and left ventricular ejection fraction significantly improved after 6 months in both groups. The response rate was significantly higher in LBB‐CRT group than BIV‐CRT group (100.00% vs. 63.33%, p =.038). The percentage of patients in New York Heart Association classification Grades I and II was significantly higher in the LBB‐CRT group compared with that in the BIV‐CRT group (median 1.5 vs. 2.0, p =.029) at 6‐month follow‐up. Conclusions: It is effective and safe to correct CLBBB with LBBAP in heart failure patients. Compared with BIVP, LBBAP can better optimize electrical synchrony and improve cardiac function. [ABSTRACT FROM AUTHOR]

Patients with colorectal cancer (CRC) and diffuse peritoneal metastasis (PM) are not eligible for surgical intervention. Thus, palliative treatment remains the standard of care in clinical practice. Systemic chemotherapy fails to cause drug accumulation at the lesion sites, while intraperitoneal chemotherapy (IPC) is limited by high clearance rates and associated complications. Given the poor prognosis, a customized OxP/R848@PLEL hydrogel delivery system has been devised to improve the clinical benefit of advanced CRC with diffuse PM. This system is distinguished by its simplicity, security, and efficiency. Specifically, the PLEL hydrogel exhibits excellent injectability and thermosensitivity, enabling the formation of drug depots within the abdominal cavity, rendering it an optimal carrier for IPC. Oxaliplatin (OxP), a first‐line drug for advanced CRC, is cytotoxic and enhances the immunogenicity of tumors by inducing immunogenic cell death. Furthermore, OxP and resiquimod (R848) synergistically enhance the maturation of dendritic cells, promote the expansion of cytotoxic T lymphocytes, and induce the formation of central memory T cells. Moreover, R848 domesticates macrophages to an anti‐tumor phenotype. OxP/R848@PLEL effectively eradicates peritoneal metastases, completely inhibits ascites production, and significantly prolongs mice lifespan. As such, it provides a promising approach to managing diffuse PM in patients with CRC without surgical indications. [ABSTRACT FROM AUTHOR]

The hypoxic tumor microenvironment (TME) significantly affects cancer treatment. Conventional chemotherapeutic agents cannot effectively target hypoxic tumor tissue, which decreases efficacy and results in severe toxic side effects. To alleviate this problem, a self‐driving biomotor is developed by functionalizing MCDP nanoparticles containing calcium peroxide and doxorubicin (DOX) loaded onto polydopamine‐coated metal–organic frameworks（MOF）, with the anaerobic Bifidobacterium infantis (Bif) for synergistic chemotherapy and chemodynamic therapy (CDT) against breast cancer. The materials of institute Lavoisier (MIL) frameworks + CaO2 + DOX + polydopamine (MCDP)@Bif biohybrid actively targets hypoxic regions of solid tumors via the inherent targeting ability of Bif. Once it has accumulated in the tumor tissue, MCDP generates hydroxyl radicals through the enhanced Fenton‐type reactions between Fe2+ and self‐generated hydrogen peroxide in the acidic TME. The disruption of Ca2+ homeostasis and resulting mitochondrial Ca2+ overload triggers apoptosis and enhances oxidative stress, promoting tumor cell death. The results found that the DOX concentration in MCDP@Bif‐treated tumors is 3.8 times higher than that in free‐DOX‐treated tumors, which significantly prolongs the median survival of the tumor‐bearing mice to 69 days and reduces the toxic side effects of DOX. Therefore, the novel bacteria‐driven drug delivery system is highly effective in achieving synergistic chemotherapy and CDT against solid tumors. [ABSTRACT FROM AUTHOR]

The brain has high energy demand making it sensitive to changes in energy fuel supply. Aging shrinks brain volume, decreases glucose uptake availability of the brain, and finally, causes cognitive dysfunction. Folic acid supplementation delayed cognitive decline and neurodegeneration. However, whether folic acid affects brain energy metabolism and structural changes is unclear. The study aimed to determine if long-term dietary folic acid supplementation could alleviate age-related cognitive decline by attenuating hippocampus atrophy and promoting brain glucose uptake in Sprague-Dawley (SD) rats. According to folic acid levels in diet, 3-months old male SD rats were randomly divided into four intervention groups for 22 months in equal numbers: folic acid-deficient diet (FA-D) group, folic acid-normal diet (FA-N) group, low folic acid-supplemented diet (FA-L) group, and high folic acid-supplemented diet (FA-H) group. The results showed that serum folate concentrations decreased and serum homocysteine (Hcy) concentrations increased with age, and dietary folic acid supplementation increased serum folate concentrations and decreased Hcy concentrations at 11, 18, and 22 months of intervention. Dietary folic acid supplementation attenuated aging-induced hippocampus atrophy, which was showed by higher fractional anisotropy and lower mean diffusivity in the hippocampus, increased brain 18F-Fluorodeoxyglucose (18F-FDG) uptake, then stimulated neuronal survival, and alleviated age-related cognitive decline in SD rats. In conclusion, long-term dietary folic acid supplementation alleviated age-related cognitive decline by attenuating hippocampus atrophy and promoting brain glucose uptake in SD rats. [ABSTRACT FROM AUTHOR]

The evolved resistance of antibiotics exhibited by some dreaded clinical pathogens and formation of biofilms has caused life-threatening problems for patients with burns and other wounds. Here, in order to avoid antibiotic overuse, and thus decreasing the occurrence of antimicrobial-resistant bacteria, a theranostic wound dressing, composed of biocompatible UV-photocrosslinkable methacrylated gelatin (GelMA) encapsulating both antimicrobial and fluorescent vesicles, has been developed. The system can respond to the microbiological environment of the wound via a simple color change and antimicrobials release only when require and this is in essence passive as they do not respond to their local environments and benign bacteria, and only operates when pathogenic bacteria exist. Both in Vitro and i n Vivo study demonstrated that the proposed wound dressing was able to kill/inhibit the growth of methicillin-resistant S. aureus and P. aeruginosa , whilst providing a visual warning of infection, due to vesicle bilayer membrane lysed by toxins secreted by the two strains of pathogens but not by a non-pathogenic Escherichia coli species. The strategy of microbiologically responsive wound dressing proposed here could also be used as a general methodology for the design and fabrication of bacterial responsive functional biomaterials that offer opportunities to combat drug-resistant bacterial infections. [ABSTRACT FROM AUTHOR]

Subcutaneous long-acting release (LAR) formulations have been extensively developed in the clinic to increase patient compliance and reduce treatment cost. Despite preliminary success for some LAR systems, a major obstacle limiting the therapeutic effect remains on their interaction with surrounding tissues. In this review, we summarize how living bodies respond to injected or implanted materials, and highlight some typical strategies based on smart material design, which may significantly improve long-term subcutaneous drug delivery. Moreover, possible strategies to achieve ultra-long (months, years) subcutaneous drug delivery systems are proposed. Based on these discussions, we believe the well-designed subcutaneous long-acting formulations will hold great promise to improve patient quality of life in the clinic. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a promising therapy for refractory cancer based on the cytotoxic reaction of 10B (n, α) 7Li. Although two BNCT agents are clinically available, they are quickly metabolized and show modest enrichment in tumor sites, partially limiting BNCT widespread application. Consequently, novel agents that perform active targeting and show good biocompatibility have to be developed. Herein, boronophenylalanine‐containing polydopamine (B‐PDA) nanoparticles are easily fabricated by encapsulating boronophenylalanine (BPA) in polydopamine via nitrogen‐boronate coordination. In this study, B‐PDA achieves increased tumor accumulation and prolonged retention effects in the tumor site and superior antitumor activity post neutron irradiation in the orthotopic xenograft glioma model. In brief, this study offers a novel strategy for BPA delivery and may broaden the perspective on nanomedicine design for BNCT. [ABSTRACT FROM AUTHOR]

Synergistic photothermal immunotherapy has emerged as a favorable therapeutic approach to fight cancer. However, design of an effective photothermal immunotherapy system to suppress tumor growth and simultaneously inhibit tumor metastases continues to be a challenge. Here a dual toll‐like receptor agonists delivery system CPG@Au NRs/m‐R848 for combined photothermal immunotherapy of melanoma is developed. CPG@Au NRs/m‐R848 displays strong antitumor effects by promoting maturation of dendritic cells (DCs) and reprogramming of M2 macrophages into M1 phenotype. Moreover, immunogenic cell death (ICD) induced by photothermal ablation of Au NRs could synergistically produce in situ vaccination effect with CPG ODN and R848, generating systemic and lasting antitumor immunity. It is further proved that CPG@Au NRs/m‐R848 treatment inhibits tumor growth in bilateral B16F10 tumors model by eliciting CD8+ T cell response. Overall, this work suggests that this strategy hold great potential in tumor immunotherapy by regulating tumor‐associated macrophage polarization, triggering DCs maturation and inducing ICD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the aging population. Particularly, long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in PD, while the role of lncRNA SNHG8 in PD remains to be further explored. C57BL/6 mice were induced by rotenone to establish a PD model in vivo, and then the dopaminergic (DA) neuronal damage and locomotor dysfunction in rotenone-treated mice were evaluated. Murine DA cell line MN9D was treated with rotenone to establish a cellular PD model in vitro. Then, the viability, apoptosis, mitochondrial dysfunction, endoplasmic reticulum stress, and autophagy in rotenone-treated MN9D cells were assessed. Expression levels of SNHG8, microRNA-421-3p (miR-421-3p), and sorting nexin 8 (SNX8) in the substantia nigra (SN) of PD mice and rotenone-treated MN9D cells were detected. The interaction between SNHG8 and miR-421-3p, and the targeting relationship between SNX8 and miR-421-3p were confirmed. SNHG8 and SNX8 expression levels were decreased while miR-421-3p expression level was increased in the SN of PD mice and rotenone-treated MN9D cells. Upregulated SNHG8 ameliorated dopaminergic neuron damage and locomotor dysfunction in PD mice. Meanwhile, upregulated SNHG8 enhanced viability, diminished apoptosis, and alleviated mitochondrial dysfunction, endoplasmic reticulum stress, and autophagy in rotenone-treated MN9D cells. Mechanistically, SNHG8 bound to miR-421-3p, and miR-421-3p targeted SNX8. Overexpressed SNHG8 downregulates miR-421-3p to alleviate rotenone-induced dopaminergic neuron injury in PD via upregulating SNX8. [ABSTRACT FROM AUTHOR]

Bromodomain-Containing Protein 4 (BRD4) is a member of the BET family of bromodomains, which participates in gene transcription process and is closely related to tumor progression. We observed the up-regulated expression of BRD4 in colorectal cancer (CRC) after doxorubicin (DOX) treatment, which might be a potential mechanism for DOX resistance. This study constructed the tumor-targeting (cyclo (Arg-Gly-Asp-D-Phe-Lys)-poly(ethylene glycol)-poly(ε-caprolactone)) (cRGD-PEG-PCL) copolymer for co-delivery of DOX and BRD4 PROTAC degrader ARV-825 (ARV-DOX/cRGD-P) for CRC treatment. The ARV-DOX/cRGD-P complexes elicited synergistic anti-tumor effect via cell cycle arrest and the increased cell apoptosis, and mechanism studies implicated the regulation of proliferation- and apoptosis-related pathways in vitro. Moreover, the administration of ARV-DOX/cRGD-P significantly improved anti-tumor activity in subcutaneous colorectal tumors and colorectal intraperitoneal disseminated tumor models in mice by promoting tumor apoptosis, suppressing tumor proliferation and angiogenesis. Taken together, these data reveal that ARV-825 can heighten DOX sensitivity in CRC treatment and BRD4 is a potential therapeutic target for DOX-resistant CRC. The ARV-DOX/cRGD-P preparations have outstanding anti-cancer effects and may be used for clinical treatment of colorectal cancer in the future. Schematic illustration of the structure model about co-encapsulation of DOX and ARV-825 by cRGD-decorated nanoparticles (cRGD-P), and the processes of drug delivery in colorectal cancer-bearing mice. [Display omitted] • DOX induced upregulated expression of BRD4 in colorectal cancer cells. • The ARV-DOX/cRGD-P complexes inhibited tumor growth by blocking cell cycle and promoting cells apoptosis in vitro. • BRD4 degrading ARV sensitized anti-tumor effect of DOX. • cRGDfk peptides-modified nanoparticle improved anti-cancer effect in vivo. [ABSTRACT FROM AUTHOR]

Previously, our group found that the dietary trace mineral element selenium and vitamin B 6 (VitB 6) alone was involved in lipid metabolism. However, the effects of selenium combined with VitB 6 on hyperlipidemia and lipid metabolism have not been reported until now. We hypothesized that selenium and VitB 6 cosupplementation would alleviate the hyperlipidemic and hepatic dysfunction and with minimum side effects in a Sprague-Dawley rat model of hyperlipidemia induced by a high-fat diet. Our results showed that selenium combined with VitB 6 could improve dyslipidemia and displayed better in vivo hypocholesterolemic abilities at early intervention. Moreover, cosupplementation reduced atherogenic indexes (atherogenic index and atherogenic index of plasm) and the ratio of ApoB/ApoA1. The liver function index aspartate aminotransferase in serum was reduced, as was and total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol in liver. The intervention also increased the levels of ApoA1 in serum and high-density lipoprotein cholesterol of liver. In addition, the combination of selenium and VitB 6 decreased liver lipid deposition and alleviated steatosis, reduced adipocyte size of white adipose tissue, increased the activities of hepatic lipase and total lipase and the hepatic 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) level, decreased the hepatic mRNA transcription of lipogenic and regulatory genes including Srebf1 and downstream fat synthesis-related enzymes (Acc and Fasn) and cholesterol synthesis speed limiting enzyme Hmgr, increased the mRNA abundance of Lcat and Cyp7a1 , increased the protein expression of SIRT1 and PPARα, and up-regulated the protein expression of sterol regulatory element–binding protein 1c in the livers of hyperlipidemia rats. We first demonstrated that oral selenium and VitB 6 cosupplementation exerted synergism in lowering blood and liver lipid profiles and antiatherosclerotic effects in hyperlipidemic rats by reducing endogenous cholesterol and lipid synthesis, enhancing the transport of cholesterol to hepatocytes and promoting fatty acid beta oxidation. Selenium (Se) combined with vitamin B 6 (VitB 6) modulates blood lipids and fatty liver by increasing hepatic lipase, silent information regulating factor 1 (SIRT1), and peroxisome proliferator–activated receptor α (PPARα) related to fat decomposition, inhibiting the lipogenesis pathway by lowering sterol regulatory element–binding protein 1c (SREBP-1c) and its downstream acetyl-coenzyme A (CoA) carboxylase (ACC) and fatty acid synthase (FAS). Cholesterol-lowering effects may be achieved by down-regulation of 3-hydroxy-3-methyl glutaryl CoA reductase (HMGR) and up-regulation of lecithin cholesterol acyltransferase (LCAT) and cholesterol 7a-hydroxylase (CYP7A1). [Display omitted] [ABSTRACT FROM AUTHOR]

Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA, C n-3, 22:6) are essential in improving cognitive function and protecting neurocytes. This study explored the effects of the combined intervention of MCTs and DHA on inhibiting neurocyte apoptosis of the brain and improving cognitive function in senescence-accelerated mouse-prone 8 (SAMP8). Four-month-old male SAMP8 mice were randomly divided into four treatment groups (12 mice/group): DHA, MCT, DHA + MCT, and control groups, which intervened for seven months. Twelve age-matched male senescence-accelerated mouse resistant 1 (SAMR1) was used as the natural aging group. TUNEL assay and HE staining were used to assess neurocyte apoptosis and damage in the brain of mice. Moreover, the cognitive function was analyzed using the Morris water maze (MWM) and open field (OF) tests. The results showed that the cognitive function of 11-month-old SAMP8 mice decreased with age, and further pathological examination revealed the damaged neurocyte structure, karyopyknosis, cell atrophy, and even apoptosis. MCTs combined with DHA supplementation could increase octanoic acid (C8:0), decanoic acid (C10:0), and DHA levels in the serum, inhibit neurocyte apoptosis, improve neurocyte damage, moreover delay age-related cognitive decline after seven-month treatment. Furthermore, combining MCTs and DHA was significantly more beneficial than MCTs or DHA alone. In conclusion, MCTs combined with DHA could delay cognitive decline by inhibiting neurocyte apoptosis of the brain in SAMP8 mice. • MCTs combined with DHA delayed cognitive decline of SAMP8 mice. • MCTs combined with DHA inhibited neurocyte apoptosis of the brain in SAMP8 mice. • The combination of MCTs and DHA was more beneficial than alone MCTs or DHA. [ABSTRACT FROM AUTHOR]

Background: Left bundle branch pacing (LBBP) is the most rapidly growing conduction system pacing technique that is capable of correcting intrinsic left bundle branch block (LBBB). As such, it is potentially an optimal alternative to cardiac resynchronization therapy (CRT) with biventricular pacing (BiVP).Objectives: The authors sought to compare the efficacy of LBBP-CRT with BiVP-CRT in patients with heart failure and reduced left ventricular ejection fraction (LVEF).Methods: This is a prospective, randomized trial of patients with nonischemic cardiomyopathy and LBBB with 6-month preplanned follow-up. Crossovers were allowed if LBBP or BiVP were unsuccessful. The primary endpoint was the difference in LVEF improvement between 2 groups. The secondary endpoints included changes in echocardiographic measurements, N-terminal pro-B-type natriuretic peptide (NT-proBNP), New York Heart Association functional class, 6-minute walk distance, QRS duration, and CRT response.Results: The study included 40 consecutive patients (20 males, mean age 63.7 years, LVEF 29.7% ± 5.6%). Crossovers occurred in 10% of LBBP-CRT and 20% of BiVP-CRT. All patients completed follow-up. Intention-to-treat analysis showed significantly higher LVEF improvement at 6 months after LBBP-CRT than BiVP-CRT (mean difference: 5.6%; 95% CI: 0.3-10.9; P = 0.039). LBBP-CRT also appeared to have greater reductions in left ventricular end-systolic volume (-24.97 mL; 95% CI: -49.58 to -0.36 mL) and NT-proBNP (-1,071.80 pg/mL; 95% CI: -2,099.40 to -44.20 pg/mL), and comparable changes in New York Heart Association functional class, 6-minute walk distance, QRS duration, and rates of CRT response compared with BiVP-CRT.Conclusions: LBBP-CRT demonstrated greater LVEF improvement than BiVP-CRT in heart failure patients with nonischemic cardiomyopathy and LBBB. (Left Bundle Branch Pacing Versus Biventricular Pacing for Cardiac Resynchronization Therapy [LBBP-RESYNC]; NCT04110431). [ABSTRACT FROM AUTHOR]

Metastasis is deadly and also tough to treat as it is much more complicated than the primary tumour. Anti-metastasis approaches available so far are far from being optimal. A variety of nanomedicine formulae provide a plethora of opportunities for developing new strategies and means for tackling metastasis. It should be noted that individualized anti-metastatic nanomedicines are different from common anti-cancer nanomedicines as they specifically target different populations of malignant cells. This review briefly introduces the features of the metastatic cascade, and proposes a series of nanomedicine-based anti-metastasis strategies aiming to block each metastatic step. Moreover, we also concisely introduce the advantages of several promising nanoparticle platforms and their potential for constructing state-of-the-art individualized anti-metastatic nanomedicines. [ABSTRACT FROM AUTHOR]

Peptide‐drug conjugates (PDCs) are an important class of therapeutic agents that combine one or more active molecules with a short peptide via a biodegradable spacer to generate prodrugs. Here an antioxidant (i.e., 3,5‐dihydroxybenzoic acid), a non‐steroidal anti‐inflammatory drug (i.e., ibuprofen, IPF), and a self‐assembled peptide motif (i.e., Gly‐Phe‐Phe‐Tyr‐Asp, GFFYD) are integrated to produce a peptide‐drug amphiphile, which self‐assembles to form hydrogel and further exerts the synergistic effects, and consequently emerges high therapeutic efficacy. In the in vitro study toward lipopolysaccharide‐activated RAW264.7 macrophages, the resulting hydrogel significantly reduces the production of cytokines (e.g., IL‐1β, IL‐6 and tumor necrosis factor‐α (i.e., TNF‐α)) compared with that of native IPF via the inhibition of nuclear factor‐κB (i.e., NF‐κB), janus kinase‐signal transducer and activator of transcription (i.e., JAK‐STAT) signals and NLR family pyrin domain containing 3 (i.e., NLRP3) inflammasome activation. Moreover, a rabbit model of endotoxin induced uveitis evidences the superior therapeutic efficacy of the resulting hydrogel over that of clinically used 0.1 wt% diclofenac sodium eyedrop. Overall, this work offers new insights into the anti‐inflammatory mechanism of PDCs hydrogel and presents the therapeutic values in the treatment of ocular disorders, and ultimately fulfils the potential clinical benefits of PDCs. [ABSTRACT FROM AUTHOR]