AI-enabled Cardiac Chambers Volumetry and Calcified Plaque Characterization in Coronary Artery Calcium (CAC) Scans (AI-CAC) Significantly Improves on Agatston CAC Score for Predicting All Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis.

Background: Coronary artery calcium (CAC) scans contain valuable information beyond the Agatston Score which is currently reported for predicting coronary heart disease (CHD) only. We examined whether new artificial intelligence (AI) algorithms applied to CAC scans may provide significant improvement in prediction of all cardiovascular disease (CVD) events in addition to CHD, including heart failure, atrial fibrillation, stroke, resuscitated cardiac arrest, and all CVD-related deaths. Methods: We applied AI-enabled automated cardiac chambers volumetry and automated calcified plaque characterization to CAC scans (AI-CAC) of 5830 individuals (52.2% women, age 61.7±10.2 years) without known CVD that were previously obtained for CAC scoring at the baseline examination of the Multi-Ethnic Study of Atherosclerosis (MESA). We used 15-year outcomes data and assessed discrimination using the time-dependent area under the curve (AUC) for AI-CAC versus the Agatston Score. Results: During 15 years of follow-up, 1773 CVD events accrued. The AUC at 1-, 5-, 10-, and 15-year follow up for AI-CAC vs Agatston Score was (0.784 vs 0.701), (0.771 vs. 0.709), (0.789 vs.0.712) and (0.816 vs. 0.729) (p<0.0001 for all), respectively. The category-free Net Reclassification Index of AI-CAC vs. Agatston Score at 1-, 5-, 10-, and 15-year follow up was 0.31, 0.24, 0.29 and 0.29 (p<.0001 for all), respectively. AI-CAC plaque characteristics including number, location, and density of plaque plus number of vessels significantly improved NRI for CAC 1-100 cohort vs. Agatston Score (0.342). Conclusion: In this multi-ethnic longitudinal population study, AI-CAC significantly and consistently improved the prediction of all CVD events over 15 years compared with the Agatston score.

Indomethacin Does Not Reduce Post-ERCP Pancreatitis in High-Risk Patients Receiving Pancreatic Stenting.

BACKGROUND: Rectal indomethacin reduces pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). However, there is insufficient evidence regarding its added benefits in patients already receiving prophylactic pancreatic stenting. Our goal was to evaluate the impact of indomethacin in high-risk patients undergoing pancreatic stenting. METHODS: A cohort study was conducted on all patients who underwent the rescue cannulation technique for challenging bile duct cannulation (selected high-risk patients). Patients were split into two groups based on the prophylaxis method for post-ERCP pancreatitis (PEP): one receiving a combination of indomethacin and pancreatic stenting, while the other received pancreatic stenting alone. Comparative analyses were carried out on PEP, hyperamylasemia, gastrointestinal bleeding, and postoperative hospital stay among post-ERCP pancreatitis patients. RESULTS: Between November 2017 and May 2023, a total of 607 patients with native papillae were enrolled, with 140 grouped into the indomethacin plus stent group and 467 into the stent alone group. The overall PEP rate was 4.4% in the entire cohort, with no statistical differences observed between the groups in terms of PEP rates (P = 0.407), mild PEP (P = 0.340), moderate to severe PEP (P = 1.000), hyperamylasemia (P = 0.543), gastrointestinal bleeding (P = 0.392), and postoperative hospital stay (P = 0.521). Furthermore, sensitivity analysis using multivariable analysis also validated these findings. CONCLUSIONS: Indomethacin did not reduce the incidence or severity of PEP in high-risk patients who routinely received prophylactic pancreatic stent placement. Therefore, the additional administration of rectal indomethacin to further mitigate PEP appears to be not necessary.

Who takes the lead in consumer choices within romantic relationships: the evidence from electroencephalography hyperscanning and granger causality analysis.

In real-life scenarios, joint consumption is common, particularly influenced by social relationships such as romantic ones. However, how romantic relationships affect consumption decisions and determine dominance remains unclear. This study employs electroencephalography hyperscanning to examine the neural dynamics of couples during joint-consumption decisions. Results show that couples, compared to friends and strangers, prefer healthier foods, while friends have significantly faster reaction times when selecting food. Time-frequency analysis indicates that couples exhibit significantly higher theta power, reflecting deeper emotional and cognitive involvement. Strangers show greater beta1 power, indicating increased cognitive effort and alertness due to unfamiliarity. Friends demonstrate higher alpha2 power when choosing unhealthy foods, suggesting increased cognitive inhibition. Inter-brain phase synchrony analysis reveals that couples display significantly higher inter-brain phase synchrony in the beta1 and theta bands across the frontal-central, parietal, and occipital regions, indicating more coordinated cognitive processing and stronger emotional bonds. Females in couples may be more influenced by emotions during consumption decisions, with detailed sensory information processing, while males exhibit higher cognitive control and spatial integration. Granger-causality analysis shows a pattern of male dominance and female dependence in joint consumption within romantic relationships. This study highlights gender-related neural synchronous patterns during joint consumption among couples, providing insights for further research in consumer decision-making.

CD28 costimulation augments CAR signaling in NK cells via the LCK/CD3Z/ZAP70 signaling axis.

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3Z creates a platform that recruits critical kinases, such as LCK and ZAP70, initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy.

Breaking up the CD8+ T cell: Treg pas de deux.

Checkpoint blockade immunotherapies, such as anti-programmed death-1 (PD-1), unleash anti-tumor CD8+ T cell responses but may also induce immunosuppressive regulatory T cells (Tregs). In this issue of Cancer Cell, Geels et al. uncover that anti-PD-1 leads to Treg expansion via interleukin-2 (IL-2)-producing CD8+ T cells. Combining anti-PD-1 with anti-ICOSL interrupts this crosstalk, thereby enhancing tumor control.

Progress of the study of pericytes and their potential research value in adenomyosis.

Pericytes (PCs) are versatile cells integral to the microcirculation wall, exhibiting specific stem cell traits. They are essential in modulating blood flow, ensuring vascular permeability, maintaining homeostasis, and aiding tissue repair process. Given their involvement in numerous disease-related pathological and physiological processes, the regulation of PCs has emerged as a focal point of research. Adenomyosis is characterized by the presence of active endometrial glands and stroma encased by an enlarged and proliferative myometrial layer, further accompanied by fibrosis and new blood vessel formation. This distinct pathological condition might be intricately linked with PCs. This article comprehensively reviews the markers associated with PCs, their contributions to angiogenesis, blood flow modulation, and fibrotic processes. Moreover, it provides a comprehensive overview of the current research on adenomyosis pathophysiology, emphasizing the potential correlation and future implications regarding PCs and the development of adenomyosis.

Structural biology of terpene synthases.

Structural biology research of terpene synthases (TSs) has provided a useful basis to understand their catalytic mechanisms in producing diverse terpene products with polycyclic ring systems and multiple chiral centers. However, compared to the large numbers of>95,000 terpenoids discovered to date, few structures of TSs have been solved and the understanding of their catalytic mechanisms is lagging. We here (i) introduce the basic catalytic logic, the structural architectures, and the metal-binding conserved motifs of TSs; (ii) provide detailed experimental procedures, in gene cloning and plasmid construction, protein purification, crystallization, X-ray diffraction data collection and structural elucidation, for structural biology research of TSs; and (iii) discuss the prospects of structure-based engineering and de novo design of TSs in generating valuable terpene molecules, which cannot be easily achieved by chemical synthesis.

Gender Differences of Antioxidant System and Thyroid Function in Depressed Adolescents with Non-Suicidal Self-Injury.

Purpose: The aim of our study was to explore the relation between serum levels of non-enzymatic antioxidants, thyroid function with the risk of non-suicidal self-injury (NSSI) in depressed adolescents. Patients and Methods: We retrospected the electronic records of 454 hospitalized patients aged 13-17 years old with a diagnosis of major depressive disorder (239 patients with NSSI and 215 subjects without NSSI), and collected their demographic and clinical information, including serum levels of total bilirubin (Tbil), uric acid (UA), free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH). Results: The incidence of NSSI was 52.6% among depressed adolescents aged 13-17, 57.1% in female and 38.5% in male. After using the propensity scoring method to exclude the influence of age between the two groups, it was found that patients with NSSI showed lower levels of Tbil (P=0.046) and UA (P=0.015) compared with those without NSSI. Logistic regression results showed that serum UA was associated with NSSI behavior in female patients (OR=0.995, 95% CI: 0.991-0.999, P=0.014), and TSH was associated with NSSI in male participants (OR=0.499, 95% CI: 0.267-0.932, P=0.029). Conclusion: Female and male may have different pathological mechanisms of NSSI. NSSI is more likely to be related to antioxidant reaction in female adolescent patients, while more likely to be related to thyroid function in male depressed adolescent patients.

Wnt5a-mediated autophagy contributes to the epithelial-mesenchymal transition of human bronchial epithelial cells during asthma.

BACKGROUND: The epithelial-mesenchymal transition (EMT) of human bronchial epithelial cells (HBECs) is essential for airway remodeling during asthma. Wnt5a has been implicated in various lung diseases, while its role in the EMT of HBECs during asthma is yet to be determined. This study sought to define whether Wnt5a initiated EMT, leading to airway remodeling through the induction of autophagy in HBECs. METHODS: Microarray analysis was used to investigate the expression change of WNT5A in asthma patients. In parallel, EMT models were induced using 16HBE cells by exposing them to house dust mites (HDM) or interleukin-4 (IL-4), and then the expression of Wnt5a was observed. Using in vitro gain- and loss-of-function approaches via Wnt5a mimic peptide FOXY5 and Wnt5a inhibitor BOX5, the alterations in the expression of the epithelial marker E-cadherin and the mesenchymal marker protein were observed. Mechanistically, the Ca2+/CaMKII signaling pathway and autophagy were evaluated. An autophagy inhibitor 3-MA was used to examine Wnt5a in the regulation of autophagy during EMT. Furthermore, we used a CaMKII inhibitor KN-93 to determine whether Wnt5a induced autophagy overactivation and EMT via the Ca2+/CaMKII signaling pathway. RESULTS: Asthma patients exhibited a significant increase in the gene expression of WNT5A compared to the healthy control. Upon HDM and IL-4 treatments, we observed that Wnt5a gene and protein expression levels were significantly increased in 16HBE cells. Interestingly, Wnt5a mimic peptide FOXY5 significantly inhibited E-cadherin and upregulated α-SMA, Collagen I, and autophagy marker proteins (Beclin1 and LC3-II). Rhodamine-phalloidin staining showed that FOXY5 resulted in a rearrangement of the cytoskeleton and an increase in the quantity of stress fibers in 16HBE cells. Importantly, blocking Wnt5a with BOX5 significantly inhibited autophagy and EMT induced by IL-4 in 16HBE cells. Mechanistically, autophagy inhibitor 3-MA and CaMKII inhibitor KN-93 reduced the EMT of 16HBE cells caused by FOXY5, as well as the increase in stress fibers, cell adhesion, and autophagy. CONCLUSION: This study illustrates a new link in the Wnt5a-Ca2+/CaMKII-autophagy axis to triggering airway remodeling. Our findings may provide novel strategies for the treatment of EMT-related diseases.

Neonatal Exposure to Polystyrene Nanoplastics Impairs Microglia-Mediated Synaptic Pruning and Causes Social Behavioral Defects in Adulthood.

The increasing prevalence and persistence of nanoplastics (NPs) have become critical environmental concerns. These particles have the potential to enter the food chain and accumulate in living organisms, which exerts their adverse effects on human health. The release of nanoparticles from feeding bottles raises concerns about potential health issues, especially for newborns exposed to NPs at the neonatal stage. In this study, we examined the impacts of neonatal exposure to polystyrene nanoplastics (PS-NPs) on neurodevelopment. Our study demonstrates that exposure to PS-NPs in newborn mice impairs microglial autophagic function and energy metabolism, leading to the disruption of microglia-mediated synaptic pruning during early neurodevelopment. These mice subsequently develop social behavioral defects in adulthood, suggesting the long-lasting effects of neonatal PS-NP exposure on brain development and behavior. Together, these data provide insights into the mechanism by which PS-NPs affect early neurodevelopment, thus emphasizing the crucial need to address plastic pollution globally.

Long-term efficacy and safety of levonorgestrel releasing intrauterine system in the treatment of adenomyosis: evidence mapping.

PURPOSE: To summarize evidence on levonorgestrel releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis (AM) and to identify potential research gaps. METHODS: Search was conducted in MEDLINE, The Cochrane Library, EMBASE, CBM, CNKI, and Wanfang. We included studies investigating patients with AM treated with LNG-IUS combined with conservative therapy. RESULTS: Thirty-nine studies compared LNG-IUS with other conservative therapeutic drugs. The most common comparison was GnRH-a + LNG-IUS vs. LNG-IUS alone, followed by LNG-IUS vs. mifepristone, expected treatment, and GnRH-a. GnRH-a + LNG-IUS was more beneficial in reducing the intensity of dysmenorrhea than LNG-IUS alone at the 6-month follow-up in patients with an enlarged uterus and moderate to severe dysmenorrhea. Large and well-designed studies are needed to confirm the efficacy of LNG-IUS and GnRH-a on reducing uterine volume at 6-month follow-up. Thirty-two studies investigated LNG-IUS as the postoperative management. The most common comparison was surgical excision + LNG-IUS vs. surgical excision. Results showed VAS scores were lower in the surgical excision + LNG-IUS group than in the surgical excision group at the 1-year follow-up. Evidence on endometrial thickness, quality of life, adverse events and beneficial effect at 3 and 5 years are needed. CONCLUSIONS: Combined GnRH-a and LNG-IUS treatment was more efficacious than LNG-IUS alone for patients with an enlarged uterus and moderate to severe dysmenorrhea. Moreover, LNG-IUS seemed to show potential long-term benefits in postoperative therapy, warranting further meta-analysis for confirmation.

Association between the triglyceride-glucose index and thyroid disorders: a cross-sectional survey and Mendelian randomization analysis.

BACKGROUND: Metabolic diseases are associated with thyroid disorders. Insulin resistance is the common pathological basis of metabolic diseases. We explored the relationship between the triglyceride-glucose (TyG) index, a simple insulin-resistance marker, and thyroid disorders. METHODS: Eligible TIDE (Thyroid Diseases, Iodine Status and Diabetes Epidemiology) subjects (n = 47,710) were screened with inclusion/exclusion criteria. Thyroid disorder prevalence among different TyG index groups was stratified by sex. Logistic regression evaluated the correlation between the TyG index and thyroid disorders. Multiple linear regression evaluated the association between the TyG index and TSH. Additionally, two-sample Mendelian randomization (MR) using published genome-wide association study data evaluated causality in the association between the TyG index and TSH. RESULTS: Men and women with greater TyG indices had a significantly greater prevalence of thyroid disorders than individuals with the lowest quartile (Q1) of TyG index (p < 0.05). Following adjustment for confounding factors, we observed that a greater TyG index significantly increased the risk of subclinical hypothyroidism in men and women (men: Q2: odds ratio (OR) [95% confidence interval (CI)] = 1.22 [1.07-1.38], p = 0.002; Q3: OR [95% CI] = 1.28 [1.12-1.45], p < 0.001; Q4: OR [95% CI] = 1.29 [1.12-1.50], p = 0.001; women: Q2: OR [95% CI] = 1.25 [1.12-1.39], p < 0.001; Q3: OR [95% CI] = 1.47 [1.31-1.64], p < 0.001; Q4: OR [95% CI] = 1.61 [1.43-1.82], p < 0.001). Only among women was the highest TyG index quartile associated with hypothyroidism (OR [95% CI] = 1.70 [1.15-2.50], p = 0.007). Additionally, in men, the association exists only in the more than adequate iodine intake population. In women, the relationship between the TyG index and thyroid disorders disappears after menopause. Furthermore, the TyG index exhibited a linear positive correlation with TSH levels. The MR analysis results revealed a causal relationship between a genetically determined greater TyG index and increased TSH (inverse-variance weighting (IVW): OR [95% CI] = 1.14 [1.02-1.28], p = 0.020); however, this causal relationship disappeared after adjusting for BMI in multivariable MR (MVMR) analysis (MVMR-IVW: OR 1.03, 95% CI 0.87-1.22, p = 0.739). CONCLUSIONS: A greater TyG index is associated with hypothyroidism and subclinical hypothyroidism and varies by sex and menopausal status. MR analysis demonstrated that the causal relationship between a genetically determined greater TyG index and elevated TSH levels is confounded or mediated by BMI.

High-density genetic map construction and QTL mapping of a zigzag-shaped stem trait in tea plant (Camellia sinensis).

The highly unique zigzag-shaped stem phenotype in tea plants boasts significant ornamental value and is exceptionally rare. To investigate the genetic mechanism behind this trait, we developed BC1 artificial hybrid populations. Our genetic analysis revealed the zigzag-shaped trait as a qualitative trait. Utilizing whole-genome resequencing, we constructed a high-density genetic map from the BC1 population, incorporating 5,250 SNP markers across 15 linkage groups, covering 3,328.51 cM with an average marker interval distance of 0.68 cM. A quantitative trait locus (QTL) for the zigzag-shaped trait was identified on chromosome 4, within a 61.2 to 97.2 Mb range, accounting for a phenotypic variation explained (PVE) value of 13.62%. Within this QTL, six candidate genes were pinpointed. To better understand their roles, we analyzed gene expression in various tissues and individuals with erect and zigzag-shaped stems. The results implicated CsXTH (CSS0035625) and CsCIPK14 (CSS0044366) as potential key contributors to the zigzag-shaped stem formation. These discoveries lay a robust foundation for future functional genetic mapping and tea plant genetic enhancement.

Distribution of Nerve Fibers in Abdominal Wall Endometriosis and Their Clinical Significance.

Objective: This study aimed to explore the distribution of nerve fibers in abdominal wall endometriosis (AWE) and discern their association with pain. Methods: A retrospective case-control study was conducted. The cases comprised 30 patients diagnosed with AWE, while the control group consisted of 17 patients who had undergone laparotomy without any history of endometriosis. We analyzed clinical characteristics and examined the innervation patterns in samples using stains for S-100, neuron-specific enolase (NSE), protein gene product 9.5 (PGP9.5), neurofilament (NF), and substance P (SP) antibodies. Results: There was a notable increase in the density of S-100, NSE and PGP9.5 immunoreactive nerve fibers and a higher proportion of SP positivity in AWE lesions compared to standard abdominal wall scars (p < 0.05). However, there were no significant differences in the density or proportion of NF-immunoreactive nerve fibers between the cases and the controls. Moreover, no statistically significant correlation was observed between the density of S-100, NSE, PGP9.5, NF, or SP-positive nerve fibers and pain scores. Conclusion: This study demonstrated an increased immunoreactive nerve fiber density located in AWE lesions compared to normal abdominal wall scars. Further high-quality studies are needed to investigate the mechanisms responsible for pain in women with endometriosis.

PD-1/PD-L1 inhibitors for early and middle stage microsatellite high-instability and stable colorectal cancer: a review.

BACKGROUND: Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important immune checkpoint molecules that contribute to tumor immune evasion. However, the main treatment modalities for patients with early and intermediate stage colorectal cancer (CRC) are surgery, and the role of PD-1/PD-L1 inhibitors in these patients is not yet clear. Therefore, this study aims to review the treatment progress of PD-1/PD-L1 inhibitors for early- and intermediate-stage microsatellite high-instability (MSI-H) and stable (MSS) colorectal cancer, in order to provide more options for patients with early- and intermediate-stage colorectal cancer. MATERIALS AND METHODS: A scoping review of clinical trial registries ( Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on PD-1/PD-L1 Inhibitors for early and middle-stage MSI-H and MSS CRC was done up to March 2024. RESULTS: A total of 19 trials related to early to mid-stage MSH-I or MSS CRC were included. Among them, 6 trials are in recruiting status, 3 trials are in active, not recruiting status, 3 trials are completed, 1 trial is terminated, and 1 trial is unknown. Of these, 9 trials involve MSI-H type CRC, and 10 trials involve MSS type CRC. Preclinical phase I/II trials are predominant, with only 3 clinical phase III trials. In trials related to MSI-H type CRC, 4 studies involve PD-1/PD-L1 inhibitors combined with neoadjuvant therapy, and 5 studies involve combination therapy. In trials related to MSS type CRC, 3 studies involve PD-1/PD-L1 inhibitors combined with targeted therapy, 2 studies involve PD-1/PD-L1 inhibitors combined with chemotherapy, 1 study involves PD-1/PD-L1 inhibitor combined immunotherapy, 1 study involves PD-1/PD-L1 inhibitors combined with bacterial therapy, and 3 studies involve PD-1/PD-L1 inhibitors combined with comprehensive therapy. As for primary outcome measures, 4 trials select pathological complete response rates, 3 trials select progression-free survival rate, 3 trials select objective response rate, 3 trials select overall survival rate, 4 trials select disease-free survival rate, 1 trial selects clinical complete response rate, and 1 trial selects percentage of participants with a dose-limiting toxicity. CONCLUSION: For early- and middle-stage MSI-H and MSS CRC, PD-1/PD-L1 inhibitors have shown some therapeutic efficacy, as evidenced by phase I/II studies. However, contemporary trial designs exhibit heterogeneity, with relatively few inclusion criteria, the use of various drug combinations and regimens, and significant variations in reported endpoints. Nevertheless, more double-arm, multicenter, randomized controlled trials are still needed to confirm the efficacy of immunotherapy.

Transpancreatic Sphincterotomy After Double Guidewire Technique Was Noninferior to Primary Transpancreatic Sphincterotomy in Difficult Biliary Cannulation.

BACKGROUND: When unintentional pancreatic duct access occurs during difficult biliary cannulation, the double guidewire (DGW) or transpancreatic sphincterotomy (TPS) may be utilized. DGW can be easily switched to TPS due to the existing guidewire in the pancreatic duct. However, the efficacy of TPS after DGW, named sequential DGW-TPS technique, versus primary TPS has not been assessed. AIMS: Our aim was to compare the benefits and adverse events of sequential DGW-TPS technique and primary TPS. METHODS: We performed a comparative retrospective cohort study that enrolled a total of 117 patients with native papillae. The patients were divided into one of 2 groups according to the primary bile duct access technique (sequential DGW-TPS or primary TPS), both with pancreatic stenting. RESULTS: Between November 2017 and May 2023, a total of 84 patients were grouped into sequential DGW-TPS and 33 into primary TPS. The overall post-ERCP pancreatitis (PEP) rate was 4.3% in the entire cohort, with no statistical differences were observed between the groups in terms of PEP rates (P = 0.927), PEP severity (P = 1.000), first biliary cannulation success (P = 0.621), overall cannulation success (P = 1.000), hyperamylasemia incidence (P = 0.241), elevated amylase levels (P = 0.881), and postoperative hospital stay (P = 0.185). Furthermore, these results remained consistent in multivariable regression analysis. CONCLUSIONS: The sequential DGW-TPS technique showed a comparable safety and biliary cannulation success rate to primary TPS in difficult biliary cannulation. Given the potential long-term complications associated with TPS, DGW should be first if inadvertent pancreatic access occurs, with TPS serving as second only if DGW fails.

Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism.

Recent investigations into heterochronic parabiosis have unveiled robust rejuvenating effects of young blood on aged tissues. However, the specific rejuvenating mechanisms remain incompletely elucidated. Here we demonstrate that small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels. Intravenous injection of young sEVs into aged mice extends their lifespan, mitigates senescent phenotypes and ameliorates age-associated functional declines in multiple tissues. Quantitative proteomic analyses identified substantial alterations in the proteomes of aged tissues after young sEV treatment, and these changes are closely associated with metabolic processes. Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their miRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.

A one-two punch strategy for diabetic wound management based on an antibiotic-hybrid biomineralized iron sulfide nanoparticle.

Bacterial infection and immune imbalance are the primary culprits behind chronic wounds in individuals with diabetes, impeding the progression of damaged tissues towards normal healing. To achieve a harmonious balance between pro- and anti-inflammation within these infected areas, herein, we propose a one-two punch strategy for on-demand therapy of diabetes-infected wounds, utilizing an azithromycin (AZM)-hybrid nanocomposite termed GOx@FexSy/AZM. During the infective stage, the nanocomposite facilitates the production of ROS, coupled with the burst release of AZM and H2S gas, effectively dismantling biofilms and achieving rapid sterilization. Subsequently, the hyperinflammatory response induced by antibiosis is significantly mitigated through the synergistic action of tissue H2S and the prolonged half-life of AZM. These components inhibit the activity of pro-inflammatory transcription factors (AP-1 and NF-κB) within macrophages, thereby promoting the polarization of macrophages towards a reparative M2 phenotype and facilitating tissue remodeling. By catering to the diverse requirements of wound healing at different stages, this nanocomposite accelerates a sensible transition from inflammation to the reparative phase. In summary, this one-two punch strategy gives an instructive instance for procedural treatment of diabetes wound infection. STATEMENT OF SIGNIFICANCE: The treatment of diabetic wound infection presents two major challenges: the diminished antibacterial efficacy arising from biofilm formation and bacterial resistance, as well as the inadequate transition of the wound microenvironment from pro-inflammatory to anti-inflammatory states after bacterial clearance. In this work, a biomineralized iron sulfide nanocomposite was prepared to mediate cascade catalytic (ROS storm) / antibiotic (AZM) / gas (H2S) triple-synergetic antibacterial therapy during the initial stage of bacterial infection, achieving the goal of rapid bactericidal effect; Subsequently, the residual H2S and long half-life AZM would inhibit the key pro-inflammatory transcription factors and promote the macrophages polarization to reparative M2, which effectively mediated tissue repair after hyperinflammatory reactions, leading to orderly treatment of hyperglycemic infected wounds.