HDAC/H3K27ac-mediated transcription of NDUFA3 exerts protective effects on high glucose-treated human nucleus pulposus cells through improving mitochondrial function.

Diabetes mellitus (DM) is a well-documented risk factor of intervertebral disc degeneration (IVDD). The current study was aimed to clarify the effects and mechanisms of NADH: ubiquinone oxidoreductase subunit A3 (NDUFA3) in human nucleus pulposus cells (HNPCs) exposed to high glucose. NDUFA3 was overexpressed in HNPCs via lenti-virus transduction, which were co-treated with high glucose and rotenone (a mitochondrial complex I inhibitor) for 48 h. Cell activities were assessed for cell viability, cell apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) ratio, oxygen consumption rate (OCR) and mitochondrial complexes I activities. High glucose decreased cell viability, increased apoptotic cells, increased ROS production, decreased MMP levels and OCR values in HNPCs in a dose-dependent manner. Rotenone co-treatment augmented the high glucose-induced injuries on cell viability, apoptosis, ROS production and mitochondrial function. NDUFA3 overexpression counteracted the high glucose-induced injuries in HNPCs. HDAC/H3K27ac mechanism was involved in regulating NDUFA3 transcription. NDUFA3 knockdown decreased cell viability and increased apoptotic cells, which were reversed by ROS scavenger N-acetylcysteine. HDAC/H3K27ac-mediated transcription of NDUFA3 protects HNPCs against high glucose-induced injuries through suppressing cell apoptosis, eliminating ROS, improving mitochondrial function and oxidative phosphorylation. This study sheds light on candidate therapeutic targets and deepens the understanding of molecular mechanisms behind DM-induced IVDD.

Multivariate longitudinal analysis for the association between brain atrophy and cognitive impairment in prodromal Huntington's disease subjects.

Cognitive impairment has been widely accepted as a disease progression measure prior to the onset of Huntington's disease. We propose a sophisticated measurement error correction method that can handle potentially correlated measurement errors in longitudinally collected exposures and multiple outcomes. The asymptotic theory for the proposed method is developed. A simulation study is conducted to demonstrate the satisfactory performance of the proposed two-stage fitting method and shows that the independent working correlation structure outperforms other alternatives. We conduct a comprehensive longitudinal analysis to assess how brain striatal atrophy affects impairment in various cognitive domains for Huntington's disease.

Metastatic Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patient: A Systematic Review.

Patients who are immunosuppressed, such as solid organ transplant recipients (SOTRs), are at a higher risk of developing cutaneous squamous cell carcinoma (cSCC). This population is at a higher risk of metastasis and worse disease-specific survival. The objective of this review is to better characterize the immunosuppressed population with metastatic cSCC. A literature search was conducted to identify reports of lymphatic metastases in immunosuppressed patients with cSCC. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed during creation of a cohort with desired inclusion and exclusion criteria. One hundred and thirty-five articles met the inclusion/exclusion criteria, yielding 1020 total cases. We discovered that the most common forms of immunosuppression within the cohort were solid organ transplantation and hematologic malignancy. White males and cSCC tumors involving the head and neck comprised most cases. Using Brigham and Women's Hospital and Eighth edition of American Joint Committee on Cancer tumor staging criteria, we observed a trend toward higher stage tumors in SOTR than in patients with hematologic malignancy. This review confirms that known clinical risk factors for metastatic cSCC appear to be similar among the immunosuppressed population and the cSCC population at large. Interestingly, our data suggest that current staging systems may not accurately reflect metastatic risk among patients with hematologic malignancy.

Evaluation of Saffron Quality Using Rapid Quantitative Inspection Technology with Near-Infrared Spectroscopy.

A predictive model utilizing near-infrared spectroscopy was developed to estimate the loss on drying, total contents of crocin I and crocin II, and picrocrocin content of saffron. Initially, the LD values were determined using a moisture-ash analyzer, while HPLC was employed for measuring the total contents of crocin I, crocin II, and picrocrocin. The near-infrared spectra of 928 saffron samples were collected and preprocessed using first derivative, standard normal variable transformation, detrended correction, multivariate scattering correction, Savitzky-Golay smoothing, and mean centering methods. Leveraging the partial least squares method, regression models were constructed, with parameters optimized through a selective combination of the above six preprocessing methods. Subsequently, prediction models for loss on drying, total contents of crocin I and crocin II, and picrocrocin content were established, and the prediction accuracy of the models was verified. The correlation coefficients and root mean square error of loss on drying, total contents of crocin I and crocin II, and picrocrocin content demonstrated high accuracy, with R2 values of 0.8627, 0.8851, and 0.8592 and root mean square error values of 0.0260, 0.0682, and 0.0465. This near-infrared prediction model established in the present study offers a precise and efficient means of assessing loss on drying, total contents of crocin I and crocin II, and picrocrocin content in saffron and is useful for the development of a rapid quality evaluation system.

Universal sulfatase-based chemiluminescence biosensing platform: Validation via AFP detection in clinical blood samples.

Enzyme-catalyzed chemiluminescence has been widely used in the field of biomedicine, especially in the test kit for various biomarkers. However, the currently reported enzyme-catalyzed chemiluminescence systems suffered from the addition of oxidizing substances, short emission wavelength, and susceptibility to interference by autofluorescence. In this paper, a universal sulfatase-based chemiluminescence system with NIR was developed, in which the designed substrate QM-CF could be transformed into 1,2-dioxetane derivate in the presence of sulfatase and oxygen. This system exhibited long emission wavelengths and CL half-time, a high signal-noise ratio, and without other additives. Importantly, the sulfatase-based chemiluminescence enzyme-linked immunoassay platform was successfully constructed and could be generally applied to detect biomarkers. As a proof of concept, the sulfatase-labeled AFP antibody and substate QM-CF were conveniently suitable for commercial AFP test kits, leading to satisfactory detection results of AFP in clinical blood samples.

Causal association between mitochondrial function and psychiatric disorders: Insights from a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Previous observational studies have suggested that there appears to be a close association between mitochondrial function and psychiatric disorders, but whether a causal role exists remains unclear. METHODS: We extracted genetic instruments for 67 mitochondrial-related proteins and 10 psychiatric disorders from publicly available genome-wide association studies, and employed five distinct MR methods and false discovery rate correction to detect causal associations between them. Additionally, we conducted a series of sensitivity tests and additional model analysis to ensure the robustness of the results. For potential causal associations, we further performed reverse MR analyses to assess the impact of reverse causality. RESULTS: We identified a total of 2 significant causal associations and 24 suggestive causal associations. Specifically, Phenylalanine-tRNA ligase was found to increase the risk of Alzheimer's disease, while Mitochondrial glutamate carrier 2 decreased the risk of autism spectrum disorder. Furthermore, there was no evidence of significant pleiotropy, heterogeneity, or reverse causality. LIMITATIONS: This study was limited to individuals of European ancestry, and the conclusions drawn are merely revelatory. CONCLUSION: This study provides novel insights into the relationship between mitochondria and psychiatric disorders, as well as the pathogenesis and treatment strategies for psychiatric disorders.

Facile engineered macrophages-derived exosomes-functionalized PLGA nanocarrier for targeted delivery of dual drug formulation against neuroinflammation by modulation of microglial polarization in a post-stroke depression rat model.

Post-stroke depression (POSD) is a common difficulty and most predominant emotional syndrome after stroke often consequences in poor outcomes. In the present investigation, we have designed and studied the neurologically active celastrol/minocycline encapsulated with macrophages-derived exosomes functionalized PLGA nanoformulations (CMC-EXPL) to achieve enhanced anti-inflammatory behaviour and anti-depressant like activity in a Rat model of POSD. The animal model of POSD was established through stimulating process with chronic unpredictable mild stress (CUM) stimulations after procedure of middle cerebral artery occlusion (MCAO). Neuronal functions and Anti-inflammation behaviours were observed by histopathological (H&E) examination and Elisa analyses, respectively. The anti-depressive activity of the nanoformulations treated Rat models were evaluated by open-field and sucrose preference test methods. Microglial polarization was evaluated via flow-cytometry and qRT-PCR observations. The observed results exhibited that prepared nanoformulations reduced the POSD-stimulated depressive-like activities in rat models as well alleviated the neuronal damages and inflammatory responses in the cerebral hippocampus. Importantly, prepared CMC-EXPL nanoformulation effectively prevented the M1 pro-inflammatory polarization and indorsed M2 anti-inflammatory polarization, which indicates iNOS and CD86 levels significantly decreased and upsurged Arg-1 and CD206 levels. CMC-EXPL nanoformulation suggestively augmented anti-depressive activities and functional capability and also alleviated brain inflammation in POSD rats, demonstrating its therapeutic potential for POSD therapy.

Exploring Individualized Follow-up of Gastric Cancer After Radical Surgery Based on pTNM Stage: A Retrospective Cohort Study From China.

Background: Patients with gastric cancer (GC) who underwent radical surgery require long-term follow-up (usually 5 years). The purpose of this study was to explore individualized follow-up strategies for patients with GC. Methods: This is a retrospective cohort study that established a clinicopathologic database of patients who underwent gastrectomy from January 2010 to December 2020 at Ningbo No. 2 Hospital. Follow-up was performed until March 2023. The rate of new-onset recurrence of patients with GC was explored annually according to different pTNM stages, defining a recurrence rate of less than 1% as adequate follow-up time. Results: Of the 1606 patients who were eligible, the total number of patients who completed the 5- and 10-year follow-up was 1107 and 586, respectively. A total of 444 cases were diagnosed with recurrence. The recurrence rate for stage IA patients was consistently less than 1% during the follow-up time. The adequate follow-up time (the rate of new-onset recurrence less than 1%) was 5 years for stage IB and IIA patients, and 8 years for stage IIB and IIIA patients, respectively. In contrast, stage IIIB patients were always at risk of recurrence during the follow-up time (>1%). Time to a new recurrence rate for stage IIIC patients was 6 years. Conclusion: Among patients who underwent radical gastrectomy, the rate of new-onset recurrence varied among patients with different pTNM stages. This study suggests that the follow-up of GC can be individualized and refer to pTNM stage.

Promotion of Raf-1/ASK1 complex formation by corylin inhibits cell apoptosis in myocardial ischemia/reperfusion injury.

Effective treatment of myocardial ischemia-reperfusion (MIR) injury remains an unmet clinical need. Cardiomyocyte apoptosis is common at this stage and poses a significant risk. Corylin, a flavonoid compound extracted from Psoralea corylifolia L., has been shown to have anti-inflammatory, anticancer, and antiatherosclerotic properties. However, whether and how corylin affects MIR injury remain unclear. In this study, we explored the mechanism of corylin as a potent therapeutic agent for MI/R injury, using a left anterior descending (LAD) coronary artery ligation and oxygen-glucose deprivation and reperfusion (OGD/R) model in vivo and in vitro. TUNEL, Annexin-V/PI double staining,Ki67 immunohistochemistry, western blot analysis, and immunofluorescence were used to validate cell apoptosis level and Raf-1/ASK1 complex activity. The interaction between corylin and Raf-1/ASK1 complex was detected using molecular docking, corylin-Raf-1 binding assays, and coimmunoprecipitation (Co-IP). Moreover, TTC staining, echocardiography, HE staining, Masson trichrome staining and serological testing were performed to assess the cardioprotective effects of corylin in vivo. These findings showed that corylin reduces MIR injury-induced cardiomyocyte apoptosis and improves cardiac function. Mechanistically, corylin can interact with Raf-1 and promote the formation of the Raf-1/ASK1 complex, thus inhibiting cardiomyocyte apoptosis. In conclusion, our results demonstrate that corylin ameliorated cardiac dysfunction after MIR injury by reducing myocardial apoptosis.

Ventricular arrhythmias originating from different portions of the communicating vein of the left ventricular summit: electrocardiographic characteristics and catheter ablation.

BACKGROUND: Idiopathic ventricular arrhythmias (IVAs) arising from different portions of the communicating vein of the left ventricular summit (summit-CV) are not a rare phenomenon. Whereas its electrocardiographic (ECG) and electrophysiological characteristics are not fully investigated. OBJECTIVE: This study aimed to identify distinct ECG and electrophysiological features of IVAs originating from different portions of summit-CV. METHODS: Nineteen patients confirmed arising from summit-CV were included in this study. RESULTS: The 19 patients were divided into proximal and distal portion groups based on their target sites in summit-CV. In the proximal portion group, 100% (11/11) VAs showed dominant negative (rs or QS) waves in lead I, while in the distal portion group, 87.5% (7/8) showed dominant positive waves (R, Rs or r) (p < 0.000). In lead V1, 100% (11/11) of the proximal portion group showed dominant positive waves (R or Rs), while 62.50% (5/8) of the distal portion group showed positive and negative bidirectional or negative waves (RS or rS) (p < 0.005). RI>4mV, SI<3.5mV, RV1<13mV, SV1>3.5mV, RI/SI>0.83, and RV1/SV1< 2.6 indicated a distal portion of summit-CV with the predictive value of 0.909, 1.000, 0.653, 0.972, 0.903, 0.966, respectively. A more positive wave in lead I and a more negative wave in lead V1 indicated more distal origin in summit-CV. Target sites in proximal and distal summit-CV groups showed similar electrophysiological characteristics during mapping. CONCLUSIONS: There were significant differences in ECG characteristics of VAs at different portions of summit-CV, which could aid pre-procedure planning and facilitate radiofrequency catheter ablation (RFCA) procedures.

Strategies for enhancing non-small cell lung cancer treatment: Integrating Chinese herbal medicines with epidermal growth factor receptor-tyrosine kinase inhibitors therapy.

Non-small cell lung cancer (NSCLC) poses a global health threat, and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib, afatinib, and osimertinib have achieved significant success in clinical treatment. However, the emergence of resistance limits the long-term efficacy of these treatments, necessitating urgent exploration of novel EGFR-TKIs. This review provides an in-depth summary and exploration of the resistance mechanisms associated with EGFR-TKIs, with a specific focus on representative drugs like gefitinib, afatinib, and osimertinib. Additionally, the review introduces a therapeutic strategy involving the combination of Chinese herbal medicines (CHMs) and chemotherapy drugs, highlighting the potential role of CHMs in overcoming NSCLC resistance. Through systematic analysis, we elucidate the primary resistance mechanisms of EGFR-TKIs in NSCLC treatment, emphasizing CHMs as potential treatment medicines and providing a fresh perspective for the development of next-generation EGFR-TKIs. This comprehensive review aims to guide the application of CHMs in combination therapy for NSCLC management, fostering the development of more effective and comprehensive treatment modalities to ultimately enhance patient outcomes.

Metabolite Predictors of Breast and Colorectal Cancer Risk in the Women's Health Initiative.

Metabolomics has been used extensively to capture the exposome. We investigated whether prospectively measured metabolites provided predictive power beyond well-established risk factors among 758 women with adjudicated cancers [n = 577 breast (BC) and n = 181 colorectal (CRC)] and n = 758 controls with available specimens (collected mean 7.2 years prior to diagnosis) in the Women's Health Initiative Bone Mineral Density subcohort. Fasting samples were analyzed by LC-MS/MS and lipidomics in serum, plus GC-MS and NMR in 24 h urine. For feature selection, we applied LASSO regression and Super Learner algorithms. Prediction models were subsequently derived using logistic regression and Super Learner procedures, with performance assessed using cross-validation (CV). For BC, metabolites did not increase predictive performance over established risk factors (CV-AUCs~0.57). For CRC, prediction increased with the addition of metabolites (median CV-AUC across platforms increased from ~0.54 to ~0.60). Metabolites related to energy metabolism: adenosine, 2-hydroxyglutarate, N-acetyl-glycine, taurine, threonine, LPC (FA20:3), acetate, and glycerate; protein metabolism: histidine, leucic acid, isoleucine, N-acetyl-glutamate, allantoin, N-acetyl-neuraminate, hydroxyproline, and uracil; and dietary/microbial metabolites: myo-inositol, trimethylamine-N-oxide, and 7-methylguanine, consistently contributed to CRC prediction. Energy metabolism may play a key role in the development of CRC and may be evident prior to disease development.

Method for Testing Etiologic Heterogeneity Among Noncompeting Diagnoses, Applied to Impact of Perinatal Exposures on Autism and Attention Deficit Hyperactivity Disorder.

BACKGROUND: Testing etiologic heterogeneity, whether a disorder subtype is more or less impacted by a risk factor, is important for understanding causal pathways and optimizing statistical power. The study of mental health disorders especially benefits from strategic subcategorization because these disorders are heterogeneous and frequently co-occur. Existing methods to quantify etiologic heterogeneity are not appropriate for noncompeting events in an open cohort of variable-length follow-up. Thus, we developed a new method. METHODS: We estimated risks from urban residence, maternal smoking during pregnancy, and parental psychiatric history, with subtypes defined by the presence or absence of a codiagnosis: autism alone, attention deficit hyperactivity disorder (ADHD) alone, and joint diagnoses of autism + ADHD. To calculate the risk of a single diagnosis (e.g., autism alone), we subtracted the risk for autism + ADHD from the risk for autism overall. We tested the equivalency of average risk ratios over time, using a Wald-type test and bootstrapped standard errors. RESULTS: Urban residence was most strongly linked with autism + ADHD and least with ADHD only; maternal smoking was associated with ADHD only but not autism only; and parental psychiatric history exhibited similar associations with all subgroups. CONCLUSION: Our method allowed the calculation of appropriate P values to test the strength of association, informing etiologic heterogeneity wherein two of these three risk factors exhibited different impacts across diagnostic subtypes. The method used all available data, avoided neurodevelopmental outcome misclassification, exhibited robust statistical precision, and is applicable to similar heterogeneous complex conditions using common diagnostic data with variable follow-up.

Ultra-Long Carrier Lifetime of Spiral Perovskite Nanowires Realized through Cooperative Strategy of Selective Etching and Passivation.

Spiral inorganic perovskite nanowires (NWs) possess unique morphologies and properties that allow them highly attractive for applications in optoelectronic and catalytic fields. In popular solution-based synthesis methodology, however, challenges persist in simultaneously achieving precise and facile control over morphological twisting and fantastic carrier lifetimes. Here, a cooperative strategy of concurrently employing selective etching and ligand engineering is applied to facilitate the formation of spiral CsPbBr3 perovskite NWs with an ultralong carrier lifetime of ≈2 µs. Specifically, a novel amine of 1-(p-tolyl)ethanamine is introduced to functionalize as both a selective etchant and the source of forming an effective ligand to passivate the exposed facets, favoring the structural twisting and the enhancement of carrier lifetimes. The twisting behaviors are dependent on the etch ratios, which are essentially associated with the densities of grain boundaries and dislocations in the NWs. The ultralong carrier lifetime and long-term stability of the spiral NWs open up new possibilities for all-inorganic perovskites in optoelectronic and photocatalytic fields, while the cooperative synthesis strategy paves the way for exploring complex spiral structures with tunable morphology and functionality.

Tannic acid coating gauze immobilized with thrombin with ultra-high coagulation activity and antimicrobial property for uncontrollable hemorrhage.

Rapid and safe hemostasis is crucial for the survival of bleeding patients in prehospital care. It is urgent to develop high performance hemostatic material to control the massive hemorrhage in the military field and accidental trauma. In this work, an efficient protein hemostat of thrombin was immobilized onto commercial gauze, which was mediated by self-polymerization and anchoring of tannic acid (TA). Through TA treatment, the efficient immobilization of thrombin was achieved, preserving both the biological activity of thrombin and the physical properties of the dressing, including absorbency, breathability, and mechanical performance. Moreover, in the presence of TA coating and thrombin, Gau@TA/Thr could obviously shortened clotting time and enriched blood components such as plasma proteins, platelets, and red blood cells, thereby exhibiting an enhanced in vitro coagulation effect. In SD rat liver volume defect and artery transection hemorrhage models, Gau@TA/Thr still had outstanding hemostatic performance. Besides, the Gau@TA/Thr gauze had inherent antibacterial property and demonstrated excellent biocompatibility. All results suggested that Gau@TA/Thr would be a potential candidate for treating uncontrollable hemorrhage in prehospital care.

Quantum Criticality with Emergent Symmetry in the Extended Shastry-Sutherland Model.

Motivated by the novel phenomena observed in the layered material SrCu_{2}(BO_{3})_{2}, the Shastry-Sutherland model (SSM) has been extensively studied as the minimal model for SrCu_{2}(BO_{3})_{2}. However, the nature of its quantum phase transition from the plaquette valence-bond solid to antiferromagnetic phase is under fierce debate, posing a challenge to understand the underlying quantum criticality. Via the state-of-the-art tensor network simulations, we study the ground state of the SSM on large-scale size up to 20×20 sites. We identify the continuous transition nature accompanied by an emergent O(4) symmetry between the plaquette valence-bond solid and antiferromagnetic phase, which strongly suggests a deconfined quantum critical point (DQCP). Furthermore, we map out the phase diagram of an extended SSM that can be continuously tuned to the SSM, which demonstrates the same DQCP phenomena along a whole critical line. Our results indicate a compelling scenario for understanding the origin of the proposed proximate DQCP in recent experiments of SrCu_{2}(BO_{3})_{2}.

Evidence that spatial scale and environment factors explain grassland community assembly in woodland-grassland ecotones.

How communities of living organisms assemble has long been a central question in ecology. The impact of habitat filtering and limiting similarity on plant community structures is well known, as both processes are influenced by individual responses to environmental fluctuations. Yet, the precise identifications and quantifications of the potential abiotic and biotic factors that shape community structures at a fine scale remains a challenge. Here, we applied null model approaches to assess the importance of habitat filtering and limiting similarity at two spatial scales. We used 63 natural vegetation plots, each measuring 5 × 5 m, with three nested subplots measuring 1 × 1 m, from the 2021 field survey, to examine the alpha diversity as well as beta diversity of plots and subplots. Linear mixed-effects models were employed to determine the impact of environmental variables on assembly rules. Our results demonstrate that habitat filtering is the dominant assembly rules at both the plot and subplot levels, although limiting similarity assumes stronger at the subplot level. Plot-level limiting similarity exhibited a positive association with fine-scale partitioning, suggesting that trait divergence originated from a combination of limiting similarity and spatial partitioning. Our findings also reveal that the community assembly varies more strongly with the mean annual temperature gradient than the mean annual precipitation. This investigation provides a pertinent illustration of non-random assembly rules from spatial scale and environmental factors in plant communities in the loess hilly region. It underscores the critical influence of spatial and environmental constraints in understanding the assembly of plant communities.

Clinical features and risk factors for mortality in patients with Klebsiella pneumoniae bloodstream infections.

INTRODUCTION: Concern about Klebsiella pneumoniae (K. pneumoniae) bloodstream infections (KP-BSIs) is widespread because of their high incidence and lethality. The aim of this study was to investigate the clinical features of, and risk factors for mortality caused by KP-BSIs. METHODOLOGY: This was a single-center retrospective observational study performed between 1 January 2019 and 31 December 2021, at a tertiary hospital. All patients with KP-BSIs were enrolled and their clinical data were retrieved from electronic medical records. RESULTS: A total of 145 patients were included (121 in the survival group and 24 in the non-survival group). There was a higher proportion of lower respiratory tract infections in the non-survival group than in the survival group (33.3% vs. 12.4%) (p < 0.05). There was a higher proportion of multi drug resistant (MDR) strains of K. pneumoniae in the non-survival group than in the survival group (41.7% vs. 16.5%) (p < 0.05). Multivariate analysis revealed that sequential organ failure assessment (SOFA) score > 6.5 (OR, 13.71; 95% CI, 1.05-179.84), admission to the intensive care unit (ICU) (OR, 2.27; 95% CI, 0.26-19.61) and gastrointestinal bleeding (OR, 19.97; 95% CI, 1.11-361.02) were independent risk factors for death in patients with KP-BSIs. CONCLUSIONS: Among all KP-BSIs, a high proportion of K. pneumoniae originated from lower respiratory tract infections, and a high proportion of K. pneumoniae were MDR; however, mortality was not influenced. SOFA score > 6.5, admission to the ICU, and gastrointestinal bleeding were independent risk factors for death in patients with KP-BSI.

Exogenous APN protects normal tissues from radiation-induced oxidative damage and fibrosis in mice and prostate cancer patients with higher levels of APN have less radiation-induced toxicities.

Radiation causes damage to normal tissues that leads to increased oxidative stress, inflammation, and fibrosis, highlighting the need for the selective radioprotection of healthy tissues without hindering radiotherapy effectiveness in cancer. This study shows that adiponectin, an adipokine secreted by adipocytes, protects normal tissues from radiation damage invitro and invivo. Specifically, adiponectin (APN) reduces chronic oxidative stress and fibrosis in irradiated mice. Importantly, APN also conferred no protection from radiation to prostate cancer cells. Adipose tissue is the primary source of circulating endogenous adiponectin. However, this study shows that adipose tissue is sensitive to radiation exposure exhibiting morphological changes and persistent oxidative damage. In addition, radiation results in a significant and chronic reduction in blood APN levels from adipose tissue in mice and human prostate cancer patients exposed to pelvic irradiation. APN levels negatively correlated with bowel toxicity and overall toxicities associated with radiotherapy in prostate cancer patients. Thus, protecting, or modulating APN signaling may improve outcomes for prostate cancer patients undergoing radiotherapy.

Mitigating Critical Peripheral Nerve Deficit Therapy with Reactive Oxygen Species/Ca2+-Responsive Dynamic Hydrogel-Mediated mRNA Delivery.

Critical peripheral nerve deficiencies present as one of the most formidable conundrums in the realm of clinical medicine, frequently culminating in structural degradation and derangement of the neuromuscular apparatus. Engineered extracellular vesicles (EVs) exhibit the potential to ameliorate nerve impairments. However, the advent of Wallerian degeneration (WD), an inexorable phenomenon that ensues post peripheral nerve injury, serves as an insurmountable impediment to the direct therapeutic efficacy of EVs. In this investigation, we have fashioned a dynamic network for the conveyance of PTEN-induced kinase 1 (PINK1) mRNA (E-EV-P@HPCEP) using an adaptive hydrogel with reactive oxygen species (ROS)/Ca2+ responsive ability as the vehicle, bearing dual-targeted, engineered EVs. This intricate system is to precisely deliver PINK1 to senescent Schwann cells (SCs) while concurrently orchestrating a transformation in the inflammatory-senescent milieu following injury, thereby stymying the progression of WD in peripheral nerve fibers through the stimulation of autophagy within the mitochondria of the injured cells and the maintenance of mitochondrial mass equilibrium. WD, conventionally regarded as an inexorable process, E-EV-P@HPCEP achieved functionalized EV targeting, orchestrating a dual-response dynamic release mechanism via boronate ester bonds and calcium chelation, effectuating an enhancement in the inflammatory-senescent microenvironment, which expedites the therapeutic management of nerve deficiencies and augments the overall reparative outcome.