Determinants of macaques' space use: A test for the ecological constraints model using GPS collars.

As a central topic in Behavioral Ecology, animal space use involves dynamic responses to social and ecological factors. We collared 22 rhesus macaques (Macaca mulatta) from six groups on Neilingding Island, China, and collected 80,625 hourly fixes over a year. Using this high-resolution location data set, we quantified the macaques' space use at the individual level and tested the ecological constraints model while considering various environmental and human interfering factors. As predicted by the ecological constraints model, macaques in larger groups had longer daily path lengths (DPLs) and larger home ranges. We found an inverted U-shape relationship between mean daily temperatures and DPLs, indicating that macaques traveled farther on mild temperature days, while they decreased DPLs when temperatures were too high or too low. Anthropogenic food subsidies were positively correlated to DPLs, while the effect of rainfall was negative. Macaques decreased their DPLs and core areas when more flowers and less leaves were available, suggesting that macaques shifted their space use patterns to adapt to the seasonal differences in food resources. By applying GPS collars on a large number of individuals living on a small island, we gained valuable insights into within-group exploitation competition in wild rhesus macaques.

Posterior cingulate and medial prefrontal excitation-inhibition balance in euthymic bipolar disorder.

BACKGROUND: Persistent cognitive deficits and functional impairments are associated with bipolar disorder (BD), even during the euthymic phase. The dysfunction of default mode network (DMN) is critical for self-referential and emotional mental processes and is implicated in BD. The current study aims to explore the balance of excitatory and inhibitory neurotransmitters, i.e. glutamate and γ-aminobutyric acid (GABA), in hubs of the DMN during the euthymic patients with BD (euBD). METHOD: Thirty-four euBD and 55 healthy controls (HC) were recruited to the study. Using proton magnetic resonance spectroscopy (1H-MRS), glutamate (with PRESS sequence) and GABA levels (with MEGAPRESS sequence) were measured in the medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC) and the posterior cingulate gyrus (PCC). Measured concentrations of excitatory glutamate/glutamine (Glx) and inhibitory GABA were used to calculate the excitatory/inhibitory (E/I) ratio. Executive and attentional functions were respectively assessed using the Wisconsin card-sorting test and continuous performance test. RESULTS: euBD performed worse on attentional function than controls (p = 0.001). Compared to controls, euBD had higher E/I ratios in the PCC (p = 0.023), mainly driven by a higher Glx level in the PCC of euBD (p = 0.002). Only in the BD group, a marginally significant negative association between the mPFC E/I ratio (Glx/GABA) and executive function was observed (p = 0.068). CONCLUSIONS: Disturbed E/I balance, particularly elevated Glx/GABA ratio in PCC is observed in euBD. The E/I balance in hubs of DMN may serve as potential biomarkers for euBD, which may also contribute to their poorer executive function.

MicroRNA-361-5p Alleviates Leydig Cell Apoptosis and Promotes Cell Growth by Targeting PIAS1 in Late-Onset Hypogonadism.

Late-onset hypogonadism (LOH) is an age-related syndrome characterized by deficiency of serum testosterone produced by Leydig cells. Previous evidence suggested that microRNA (miR)-361-3p can serve as a promising biomarker for LOH. Nonetheless, its detailed function and molecular mechanism in LOH remain unclarified. The 24-month-old male mice were selected as an animal LOH model, and mouse Leydig cell line TM3 was stimulated with H2O2. ELISA was employed for testosterone level evaluation. Hematoxylin-eosin staining was implemented for histologic analysis of mouse testicular tissues. Western blotting and RT-qPCR were utilized for evaluating molecular protein and RNA expression, respectively. Functional experiments were conducted to test miR-361-5p roles. Luciferase reporter assay was for verifying the interaction between miR-361-5p and protein inhibitor of activated STAT 1 (PIAS1). miR-361-5p displayed a decreased level in the testes of LOH mice. Overexpressing miR-361-5p attenuated Leydig cell loss in the testis and elevated serum and intratesticular testosterone levels in LOH mice. H2O2 stimulation impaired TM3 cell viability, proliferation and intracellular testosterone production and enhanced cell apoptosis. miR-361-5p targeted PIAS1 in TM3 cell. PIAS1 upregulation counteracted miR-361-5p overexpression-mediated alleviation of cell apoptosis and elevation of testosterone synthesis in H2O2-stimualetd TM3 cells. miR-361-5p ameliorates LOH progression by increasing testosterone production and alleviate Leydig cell apoptosis via downregulation of PIAS1.

CHD2 Regulates Neuron-glioma Interactions in Pediatric Glioma.

High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler CHD2 regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons.

Population genetic structure of Pomacea canaliculata in China based on the COI and ITS1 genes.

Comprehending the phylogeography of invasive organisms enhances our insight into their distribution dynamics, which is instrumental for the development of effective prevention and management strategies. In China, Pomacea canaliculata and Pomacea maculata are the two most widespread and damaging species of the non-native Pomacea spp.. Given this species' rapid spread throughout country, it is urgent to investigate the genetic diversity and structure of its different geographic populations, a task undertaken in the current study using the COI and ITS1 mitochondrial and ribosomal DNA genes, respectively. The result of this study, based on a nationwide systematic survey, a collection of Pomacea spp., and the identification of cryptic species, showed that there is a degree of genetic diversity and differentiation in P. canaliculata, and that all of its variations are mainly due to differences between individuals within different geographical populations. Indeed, this species contains multiple haplotypes, but none of them form a systematic geographical population structure. Furthermore, the COI gene exhibits higher genetic diversity than the ITS1 gene. Our study further clarifies the invasive pathways and dispersal patterns of P. canaliculata in China to provide a theoretical basis.

Comparison of physicochemical parameters, microbial community composition and flavor substances during mechanical and traditional brewing process of Jiang-flavor baijiu.

Mechanized, automated and intelligent brewing is an important trend of innovation and transition in Jiang-flavor baijiu industry. In this study, physicochemical parameters, microbial community composition and flavor substances during 3rd round heap fermentation between mechanical and traditional workshop were investigated and compared based on traditional culturable methods, high-throughput sequencing technology and gas chromatography analysis. The dominant bacterial and fungal genera were consistent between the two workshops, but mechanized brewing had a significant impact on the composition of fungal communities. Rhodococcus and Monascus were special genera in mechanical workshop. The interaction relationship between physicochemical parameters and dominant microorganisms in mechanized workshop was different from traditional workshop as well. This study provided a scientific basis for further analyzing the mechanism of mechanized brewing of Jiang-flavor baijiu. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01483-y.

Prognostic Impact of Heart Rhythm Shockability Trajectory in Out-of-Hospital Cardiac Arrest: A Multicenter Retrospective Study.

BACKGROUND: This study aimed to investigate the association between the temporal transitions in heart rhythms during cardiopulmonary resuscitation (CPR) and outcomes after out-of-hospital cardiac arrest. METHODS: This was an analysis of the prospectively collected databases in 3 academic hospitals in northern and central Taiwan. Adult patients with out-of-hospital cardiac arrest transported by emergency medical service between 2015 and 2022 were included. Favorable neurological recovery and survival to hospital discharge were the primary and secondary outcomes, respectively. Time-specific heart rhythm shockability was defined as the probability of shockable rhythms at a particular time point during CPR. The temporal changes in the time-specific heart rhythm shockability were calculated by group-based trajectory modeling. Multivariable logistic regression analyses were performed to examine the association between the trajectory group and outcomes. Subgroup analyses examined the effects of extracorporeal CPR in different trajectories. RESULTS: The study comprised 2118 patients. The median patient age was 69.1 years, and 1376 (65.0%) patients were male. Three distinct trajectories were identified: high-shockability (52 patients; 2.5%), intermediate-shockability (262 patients; 12.4%), and low-shockability (1804 patients; 85.2%) trajectories. The median proportion of shockable rhythms over the course of CPR for the 3 trajectories was 81.7% (interquartile range, 73.2%-100.0%), 26.7% (interquartile range, 16.7%-37.5%), and 0% (interquartile range, 0%-0%), respectively. The multivariable analysis indicated both intermediate- and high-shockability trajectories were associated with favorable neurological recovery (intermediate-shockability: adjusted odds ratio [aOR], 4.98 [95% CI, 2.34-10.59]; high-shockability: aOR, 5.40 [95% CI, 2.03-14.32]) and survival (intermediate-shockability: aOR, 2.46 [95% CI, 1.44-4.18]; high-shockability: aOR, 2.76 [95% CI, 1.20-6.38]). The subgroup analysis further indicated extracorporeal CPR was significantly associated with favorable neurological outcomes (aOR, 4.06 [95% CI, 1.11-14.81]) only in the intermediate-shockability trajectory. CONCLUSIONS: Heart rhythm shockability trajectories were associated with out-of-hospital cardiac arrest outcomes, which may be a supplementary factor in guiding the allocation of medical resources, such as extracorporeal CPR.

Ultrathin layer TAFC on BiVO4 with ligand-to-metal charge transfer enhances built-in electric field for boosting photoelectrochemical water oxidation.

To reveal the mechanism of charge transfer between interfaces of BiVO4-based heterogeneous materials in photoelectrochemical water splitting system, the cocatalyst was grown in situ using tannic acid (TA) as a ligand and Fe and Co ions as metal centers (TAFC), and then uniformly and ultra-thinly coated on BiVO4 to form photoanodes. The results show that the BiVO4/TAFC achieves a superior photocurrent density (4.97 mA cm-2 at 1.23 VRHE). The charge separation and charge injection efficiencies were also significantly higher, 82.0 % and 78.9 %, respectively. From XPS, UPS, KPFM, and density functional theory calculations, Ligand-to-metal charge transfer (LMCT) acts as an electron transport highway in TAFC ultrathin layer to promote the concentration of electrons towards metal center, leading to an increase in the work function, which enhances the built-in electric field and further improves the charge transport. This study demonstrated that the LMCT pathway on TA-metal complexes enhances the built-in electric field in BiVO4/TAFC to promote charge transport and thus enhance water oxidation, providing a new understanding of the performance improvement mechanism for the surface-modified composite photoanodes.

A role for the C. elegans Argonaute protein CSR-1 in small nuclear RNA 3' processing.

The Integrator is a multi-subunit protein complex that catalyzes the maturation of snRNA transcripts via 3' cleavage, a step required for snRNA incorporation with snRNP for spliceosome biogenesis. Here we developed a GFP based in vivo snRNA misprocessing reporter as a readout of Integrator function and performed a genome-wide RNAi screen for Integrator regulators. We found that loss of the Argonaute encoding csr-1 gene resulted in widespread 3' misprocessing of snRNA transcripts that is accompanied by a significant increase in alternative splicing. Loss of the csr-1 gene down-regulates the germline expression of Integrator subunits 4 and 6 and is accompanied by a reduced protein translation efficiency of multiple Integrator catalytic and non-catalytic subunits. Through isoform and motif mutant analysis, we determined that CSR-1's effect on snRNA processing is dependent on its catalytic slicer activity but does not involve the CSR-1a isoform. Moreover, mRNA-sequencing revealed high similarity in the transcriptome profile between csr-1 and Integrator subunit knockdown via RNAi. Together, our findings reveal CSR-1 as a new regulator of the Integrator complex and implicate a novel role of this Argonaute protein in snRNA 3' processing.

Receptor Ligand-Free Mesoporous Silica Nanoparticles: A Streamlined Strategy for Targeted Drug Delivery across the Blood-Brain Barrier.

Mesoporous silica nanoparticles (MSNs) represent a promising avenue for targeted brain tumor therapy. However, the blood-brain barrier (BBB) often presents a formidable obstacle to efficient drug delivery. This study introduces a ligand-free PEGylated MSN variant (RMSN25-PEG-TA) with a 25 nm size and a slight positive charge, which exhibits superior BBB penetration. Utilizing two-photon imaging, RMSN25-PEG-TA particles remained in circulation for over 24 h, indicating significant traversal beyond the cerebrovascular realm. Importantly, DOX@RMSN25-PEG-TA, our MSN loaded with doxorubicin (DOX), harnessed the enhanced permeability and retention (EPR) effect to achieve a 6-fold increase in brain accumulation compared to free DOX. In vivo evaluations confirmed the potent inhibition of orthotopic glioma growth by DOX@RMSN25-PEG-TA, extending survival rates in spontaneous brain tumor models by over 28% and offering an improved biosafety profile. Advanced LC-MS/MS investigations unveiled a distinctive protein corona surrounding RMSN25-PEG-TA, suggesting proteins such as apolipoprotein E and albumin could play pivotal roles in enabling its BBB penetration. Our results underscore the potential of ligand-free MSNs in treating brain tumors, which supports the development of future drug-nanoparticle design paradigms.

Dual-state emission and two-wavelength amplified spontaneous emission behaviors observed from symmetric dyes based on functionalized fluorene and benzotriazole units.

Structurally symmetric dyes using functionalized fluorenes and benzotriazole as the main building moieties have been synthesized and found to exhibit efficient dual-state emission (DSE) and interesting two-wavelength or dual amplified spontaneous emission (dual-ASE) behaviors in the solution phase, which may benefit the development of organic gain materials with dual-wavelength amplification.

The FAcilitates Chromatin Transcription complex regulates the ratio of glycolysis to oxidative phosphorylation in neural stem cells.

Defects in the FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone composed of SSRP1 and SUPT16H, are implicated in intellectual disability. Here, we reveal that the FACT complex promotes glycolysis and sustains the correct cell fate of neural stem cells/neuroblasts in the Drosophila 3rd instar larval central brain. We show that the FACT complex binds to the promoter region of the estrogen-related receptor (ERR) gene and positively regulates ERR expression. ERR is known to act as an aerobic glycolytic switch by upregulating the enzymes required for glycolysis. Dysfunction of the FACT complex leads to the downregulation of ERR transcription, resulting in a decreased ratio of glycolysis to oxidative phosphorylation (G/O) in neuroblasts. Consequently, neuroblasts exhibit smaller cell sizes, lower proliferation potential, and altered cell fates. Overexpression of ERR or suppression of mitochondrial oxidative phosphorylation in neuroblasts increases the relative G/O ratio and rescues defective phenotypes caused by dysfunction of the FACT complex. Thus, the G/O ratio, mediated by the FACT complex, plays a crucial role in neuroblast cell fate maintenance. Our study may shed light on the mechanism by which mutations in the FACT complex lead to intellectual disability in humans.

Signal-averaged electrocardiography as a noninvasive tool for evaluating the ventricular substrate in patients with nonischemic cardiomyopathy: reassessment of an old tool.

Introduction: Signal-averaged electrocardiography (SAECG) provides diagnostic and prognostic information regarding cardiac diseases. However, its value in other nonischemic cardiomyopathies (NICMs) remains unclear. This study aimed to investigate the role of SAECG in patients with NICM. Methods and results: This retrospective study included consecutive patients with NICM who underwent SAECG, biventricular substrate mapping, and ablation for ventricular arrhythmia (VA). Patients with baseline ventricular conduction disturbances were excluded. Patients who fulfilled at least one SAECG criterion were categorized into Group 1, and the other patients were categorized into Group 2. Baseline and ventricular substrate characteristics were compared between the two groups. The study included 58 patients (39 men, mean age 50.4 ± 15.5 years), with 34 and 24 patients in Groups 1 and 2, respectively. Epicardial mapping was performed in eight (23.5%) and six patients (25.0%) in Groups 1 and 2 (p = 0.897), respectively. Patients in Group 1 had a more extensive right ventricular (RV) low-voltage zone (LVZ) and scar area than those in Group 2. Group 1 had a larger epicardial LVZ than Group 2. Epicardial late potentials were more frequent in Group 1 than in Group 2. There were more arrhythmogenic foci within the RV outflow tract in Group 1 than in Group 2. There was no significant difference in long-term VA recurrence. Conclusion: In our NICM population, a positive SAECG was associated with a larger RV endocardial scar, epicardial scar/late potentials, and a higher incidence of arrhythmogenic foci in the RV outflow tract.

The role of focused ultrasound for pediatric brain tumors: current insights and future implications on treatment strategies.

INTRODUCTION: Focused ultrasound (FUS) is an innovative and emerging technology for the treatment of adult and pediatric brain tumors and illustrates the intersection of various specialized fields, including neurosurgery, neuro-oncology, radiation oncology, and biomedical engineering. OBJECTIVE: The authors provide a comprehensive overview of the application and implications of FUS in treating pediatric brain tumors, with a special focus on pediatric low-grade gliomas (pLGGs) and the evolving landscape of this technology and its clinical utility. METHODS: The fundamental principles of FUS include its ability to induce thermal ablation or enhance drug delivery through transient blood-brain barrier (BBB) disruption, emphasizing the adaptability of high-intensity focused ultrasound (HIFU) and low-intensity focused ultrasound (LIFU) applications. RESULTS: Several ongoing clinical trials explore the potential of FUS in offering alternative therapeutic strategies for pathologies where conventional treatments fall short, specifically centrally-located benign CNS tumors and diffuse intrinsic pontine glioma (DIPG). A case illustration involving the use of HIFU for pilocytic astrocytoma is presented. CONCLUSION: Discussions regarding future applications of FUS for the treatment of gliomas include improved drug delivery, immunomodulation, radiosensitization, and other technological advancements.

Wogonin ameliorates ER stress-associated inflammatory response, apoptotic death and renal fibrosis in a unilateral ureteral obstruction mouse model.

Wogonin, a vital bioactive compound extracted from the medicinal plant, Scutellaria baicalensis, has been wildly used for its potential in mitigating the progression of chronic diseases. Chronic kidney disease (CKD) represents a significant global health challenge due to its high prevalence, morbidity and mortality rates, and associated complications. This study aimed to assess the potential of wogonin in attenuating renal fibrosis and to elucidate the underlying molecular mechanisms using a unilateral ureteral obstruction (UUO) mouse model as a CKD mimic. Male mice, 8 weeks old, underwent orally administrated of either 50 mg/kg/day of wogonin or positive control of 5 mg/kg/day candesartan following UUO surgery. NRK52E cells were exposed to tumor growth factors-beta (TGF-ß) to evaluate the anti-fibrotic effects of wogonin. The results demonstrated that wogonin treatment effectively attenuated TGF-ß-induced fibrosis markers in NRK-52E cells. Additionally, administration of wogonin significantly improved histopathological alterations and downregulated the expression of pro-fibrotic factors (Fibronectin, α-smooth muscle actin, Collagen IV, E-cadherin, and TGF-ß), oxidative stress markers (Catalase, superoxide dismutase 2, NADPH oxidase 4, and thioredoxin reductase 1), inflammatory molecules (Cyclooxygenase-2 and TNF-α), and the infiltration of neutrophils and macrophages in UUO mice. Furthermore, wogonin treatment mitigated endoplasmic reticulum (ER) stress-associated molecular markers (GRP78, GRP94, ATF4, CHOP, and the caspase cascade) and suppressed apoptosis. The findings indicate that wogonin treatment ameliorates key fibrotic aspects of CKD by attenuating ER stress-related apoptosis, inflammation, and oxidative stress, suggesting its potential as a future therapeutic target.

Chemical Genetics in C. elegans Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response.

C. elegans numr-1/2 (nuclear-localized metal-responsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts for numr-1p::GFP activation. The most potent activator was chaetocin, a fungal 3,6-epidithiodiketopiperazine (ETP) with promising anticancer activity. Chaetocin activates numr-1/2 strongly in the alimentary canal but is distinct from metal exposure, because it represses canonical cadmium-responsive metallothionine genes. Chaetocin has diverse targets in cancer cells including thioredoxin reductase, histone lysine methyltransferase, and acetyltransferase p300/CBP; further work is needed to identify the mechanism in C. elegans as genetic disruption and RNAi screening of homologues did not induce numr-1/2 in the alimentary canal and chaetocin did not affect markers of integrator dysfunction. We demonstrate that disulfides in chaetocin and chetomin, a dimeric ETP analog, are required to induce numr-1/2. ETP monomer gliotoxin, despite possessing a disulfide linkage, had almost no effect on numr-1/2, suggesting a dimer requirement. Chetomin inhibits C. elegans growth at low micromolar levels, and loss of numr-1/2 increases sensitivity; C. elegans and Chaetomiaceae fungi inhabit similar environments raising the possibility that numr-1/2 functions as a defense mechanism. There is no direct orthologue of numr-1/2 in humans, but RNaseq suggests that chaetocin affects expression of cellular processes linked to stress response and metal homeostasis in colorectal cancer cells. Our results reveal interactions between metal response gene regulation and ETPs and identify a potential mechanism of resistance to this versatile class of preclinical compounds.

Ultrasound-Guided Sciatic Nerve Hydrodissection Can Improve the Clinical Outcomes of Patients with Deep Gluteal Syndrome: A Case-Series Study.

Deep gluteal syndrome (DGS) is caused by sciatic nerve entrapment. Because fascial entrapment neuropathies may occur in multiple locations, ultrasound-guided nerve hydrodissection is a key component of DGS treatment. In this study, we examined the clinical outcomes of patients with DGS undergoing ultrasound-guided sciatic nerve hydrodissection. A 10 mL mixture consisting of 5% dextrose, 0.2% lidocaine (Xylocaine), and 4 mg betamethasone (Rinderon) was used for nerve hydrodissection. Clinical outcomes were evaluated using Numeric Rating Scale (NRS) scores of pain, the proportion of patients with favorable outcomes (reduction of ≥50% in pain), the duration for which patients exhibited favorable outcomes (percentage of follow-up duration), and the occurrence of major complications and minor side effects. A total of 53 patients were consecutively included and followed up for 3 to 19 months. After the initial injection, the NRS scores significantly improved at 1 week, 1 month, 3 months, and the final follow-up. Specifically, 73.6%, 71.7%, 64.2%, and 62.3% of the patients exhibited favorable outcomes at 1 week, 1 month, 3 months, and the final follow-up, respectively. The median duration for which the patients exhibited favorable outcomes was 84.7% of the follow-up period. Three patients (5.7%) experienced transient dizziness and vomiting, which resolved without further treatment. No vessel or nerve puncture was observed. Overall, ultrasound-guided sciatic nerve hydrodissection is a safe procedure that mitigates the pain associated with DGS. To achieve favorable outcomes, three consecutive injections 3 weeks apart are required.

Single particle mass spectral signatures from on-road and non-road vehicle exhaust particles and their application in refined source apportionment using deep learning.

With advances in vehicle emission control technology, updating source profiles to meet the current requirements of source apportionment has become increasingly crucial. In this study, on-road and non-road vehicle particles were collected, and then the chemical compositions of individual particles were analyzed using single particle aerosol mass spectrometry. The data were grouped using an adaptive resonance theory neural network to identify signatures and establish a mass spectral database of mobile sources. In addition, a deep learning-based model (DeepAerosolClassifier) for classifying aerosol particles was established. The objective of this model was to accomplish source apportionment. During the training process, the model achieved an accuracy of 98.49 % for the validation set and an accuracy of 93.36 % for the testing set. Regarding the model interpretation, ideal spectra were generated using the model, verifying its accurate recognition of the characteristic patterns in the mass spectra. In a practical application, the model performed hourly source apportionment at three specific field monitoring sites. The effectiveness of the model in field measurement was validated by combining traffic flow and spatial information with the model results. Compared with other machine learning methods, our model achieved highly automated source apportionment while eliminating the need for feature selection, and it enables end-to-end operation. Thus, in the future, it can be applied in refined and online source apportionment of particulate matter.

BMSC-Derived Exosomes Attenuate Rat Osteoarthritis by Regulating Macrophage Polarization through PINK1/Parkin Signaling Pathway.

OBJECTIVE: Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may modulate the M1/M2 polarization of macrophages during osteoarthritis (OA). However, the underlying mechanisms of BMSC-Exos in this process still need to be elucidated. In this study, we explored the role of BMSC-Exos in the polarization of macrophages in vitro and the OA rats in vivo. METHODS: The effects of BMSC-Exos on RAW264.7 cells were determined, including the production of reactive oxygen species (ROS) and the protein expression of Akt, PINK1, and Parkin. We prepared an OA model by resecting the anterior cruciate ligament and medial meniscus of Sprague-Dawley (SD) rats. Hematoxylin-eosin (H&E) and safranin O-fast green staining, immunohistochemistry and immunofluorescence analyses, and the examination of interleukin 6 (IL-6), interleukin 1ß (IL-1ß), tumor necrosis factor alpha (TNF-α), and interleukin 10 (IL-10) were performed to assess changes in cartilage and synovium. RESULTS: BMSC-Exos inhibited mitochondrial membrane damage, ROS production, and the protein expression of PINK1 and Parkin. Akt phosphorylation was downregulated under lipopolysaccharide (LPS) induction but significantly recovered after treatment with BMSC-Exos. BMSC-Exos alleviated cartilage damage, inhibited M1 polarization, and promoted M2 polarization in the synovium in OA rats. The expression of PINK1 and Parkin in the synovium and the levels of IL-6, IL-1ß, and TNF-α in the serum decreased, but the level of IL-10 increased when BMSC-Exos were used in OA rats. CONCLUSION: BMSC-Exos ameliorate OA development by regulating synovial macrophage polarization, and one of the underlying mechanisms may be through inhibiting PINK1/Parkin signaling.