Systematic genome-wide Mendelian randomization reveals the causal links between miRNAs and Parkinson's disease.

Background: MicroRNAs (miRNAs) have pivotal roles in gene regulation. Circulating miRNAs have been developed as novel candidate non-invasive biomarkers for diagnosis, prognosis, and treatment response for diseases. However, miRNAs that have causal effects on Parkinson's Disease (PD) remain largely unknown. To investigate the causal relationships between miRNAs and PD, here we conduct a Mendelian randomization (MR) study. Methods: This study utilized the summary-level data of respective genome-wide association studies (GWAS) for 2083 miRNAs and seven PD-related outcomes to comprehensively reveal the causal associations between the circulating miRNAs and PD. Two-sample MR design was deployed and the causal effects were estimated with inverse variance weighted, MR-Egger, and weighted median. Comprehensively sensitive analyses were followed, including Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis, to validate the robustness of our results. Finally, we investigated the potential role of the MR significant miRNAs by predicting their target genes and functional enrichment analysis. Results: Inverse variance weighted estimates suggested that two miRNAs, miR-205-5p (ß = -0.46, 95%CI: -0.690 to -0.229, p = 9.3 × 10-5) and miR-6800-5p (ß = -0.389, 95%CI: -0.575 to -0.202, p = 4.32 × 10-5), significantly decreased the rate of cognitive decline among PD patients. In addition, eight miRNAs were nominally associated with more than three PD-related outcomes each. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. Gene Ontology (GO) analysis showed that the targets of these causal miRNAs were significantly enriched in cell cycle, apoptotic, and aging pathways. Conclusion: This MR study identified two miRNAs whose genetically regulated expression might have a causal role in the development of PD dementia. Our findings provided potential miRNA biomarkers to make better and early diagnoses and risk assessments of PD.

Unraveling Stoichiometry Effect in Nickel-Tungsten Alloys for Efficient Hydrogen Oxidation Catalysis in Alkaline Electrolytes.

Anion-exchange membrane fuel cells provide the possibility to use platinum group metal-free catalysts, but the anodic hydrogen oxidation reaction (HOR) suffers from sluggish kinetics and its source is still debated. Here, over nickel-tungsten (Ni-W) alloy catalysts, we show that the Ni:W ratio greatly governs the HOR performance in alkaline electrolyte. Experimental and theoretical studies unravel that alloying with W can tune the unpaired electrons in Ni, tailoring the potential of zero charge and the catalytic surface to favor hydroxyl adsorption (OHad). The OHad species coordinately interact with potassium (K+) ions, which break the K+ solvation sheath to leave free water molecules, yielding an improved connectivity of hydrogen-bond networks. Consequently, the optimal Ni17W3 alloy exhibits alkaline HOR activity superior to the state-of-the-art platinum on carbon (Pt/C) catalyst and operates steadily with negligible decay after 10,000 cycles. Our findings offer new understandings of alloyed HOR catalysts and will guide rational design of next-generation catalysts for fuel cells.

Managing Post-Stroke Fatigue Using a Mobile Health Called iHealth After Intracerebral Hemorrhage.

Background: Post-stroke Fatigue (PSF) after Intracerebral Hemorrhage (ICH) is a long-term symptom in stroke survivors. However, the pathogenesis of PSF remains inadequately understood and sufficient evidence-based treatments are lacking. Mobile health (mHealth) technology offers a promising approach to expanding access to high-quality and culturally tailored evidence-based mental care. Aim: This study examined the role of mHealth called iHealth in the management of PSF after ICH. Methods: A total of 225 patients diagnosed with intracerebral hemorrhage (ICH) were included in the study and randomly assigned to either the Mobile Health Intervention Group (mHI Group) or the non-Mobile Health Intervention Group (non-mHI). The management involved the utilization of a digital healthcare application named iHealth, which incorporated digital questionnaires, fatigue scale tests, and online videos for the purpose of administering the Patient Fatigue Reporting Measurement Information System (PFRMIS) short form as part of the initial patient assessment following ICH. The study was conducted remotely via video conferencing over a 12-week period in mHI Group, with fatigue assessments being conducted 3 months post-ICH onset in two groups. Results: Following the administration of PSF by iHealth, Univariate Logistic analyses indicated a significant association between fatigue and the type of activity, with patients who were sedentary or did nothing experiencing higher levels of fatigue (ß=2.332, p<0.001; ß=2.517, p<0.001). Multivariate Logistic analyses demonstrated a positive association between the intensity of physical activity and decreased emotional well-being and family support, as well as increased fatigue. (p=0.001, p=0.002, p=0.001). The FSS results demonstrated a significantly reduced incidence of PSF in the MHI group in comparison to non-mHI group following the conclusion of the programme. (13.1% vs 40%, p<0.001). Conclusion: This study explored the effectiveness of the iHealth app for PSF following ICH, indicating that iHealth is a clinically valuable tool that warrants further dissemination.

Identification of excessive contact pressures under hand orthosis based on finite element analysis.

BACKGROUND: Implicit magnitudes and distribution of excessive contact pressures under hand orthoses hinder clinicians from precisely adjusting them to relieve the pressures. To address this, contact pressure under a hand orthosis were analysed using finite element method. METHODS: This paper proposed a method to numerically predict the relatively high magnitudes and critical distribution of contact pressures under hand orthosis through finite element analysis, to identify excessive contact pressure locations. The finite element model was established consisting of the hand, orthosis and bones. The hand and bones were assumed to be homogeneous and elastic bodies, and the orthosis was considered as an isotropic and elastic shell. Two predictions were conducted by assigning either low (fat) or high (skin) material stiffness to the hand model to attain the range of pressure magnitudes. An experiment was conducted to measure contact pressures at the predicted pressure locations. RESULTS: Identical pressure distributions were obtained from both predictions with relatively high pressure values disseminated at 12 anatomical locations. The highest magnitude was found at the thumb metacarpophalangeal joint with the maximum pressure range from 13 to 78 KPa. The measured values were within the predicted range of pressure magnitudes. Moreover, 6 excessive contact pressure locations were identified. CONCLUSIONS: The proposed method was verified by the measurement results. It renders understanding of interface conditions underneath the orthosis to inform clinicians regarding orthosis design and adjustment. It could also guide the development of 3D printed or sensorised orthosis by indicating optimal locations for perforations or pressure sensors.

Treatment of metastatic hormone-sensitive prostate cancer: from doublet therapy to triplet therapy.

For metastatic prostate cancer, androgen deprivation therapy (ADT) is the key strategy to control the disease. However, after 18-24 months of treatment, most patients will progress from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic castration-resistant prostate cancer (mCRPC) even with ADT. Once patients enter into mCRPC, they face with significant declines in quality of life and a dramatically reduced survival period. Thus, doublet therapy, which combines ADT with new hormone therapy (NHT) or ADT with docetaxel chemotherapy, substitutes ADT alone and has become the "gold standard" for the treatment of mHSPC. In recent years, triplet therapy, which combines ADT with NHT and docetaxel chemotherapy, has also achieved impressive effects in mHSPC. This article provides a comprehensive review of the recent applications of the triplet therapy in the field of mHSPC.

A comprehensive analysis of the oncogenic and prognostic role of TBC1Ds in human hepatocellular carcinoma.

Backgrounds: TBC1D family members (TBC1Ds) are a group of proteins that contain the Tre2-Bub2-Cdc16 (TBC) domain. Recent studies have shown that TBC1Ds are involved in tumor growth, but no analysis has been done of expression patterns and prognostic values of TBC1Ds in hepatocellular carcinoma (HCC). Methods: The expression levels of TBC1Ds were evaluated in HCC using the TIMER, UALCN and Protein Atlas databases. The correlation between the mRNA levels of TBC1Ds and the prognosis of patients with HCC in the GEPIA database was then analyzed. An enrichment analysis then revealed genes that potentially interact with TBC1Ds. The correlation between levels of TBC1Ds and tumor-infiltrating immune cells (TIICs) in HCC were studied using the TIMER 2.0 database. Finally, a series of in vitro assays verified the role of TBC1Ds in HCC progression. Results: This study revealed the upregulated expression of TBC1Ds in HCC and the strong positive correlation between the mRNA levels of TBC1Ds and poor prognosis of patients with HCC. The functions of TBC1Ds were mainly related to autophagy and the AMPK pathway. There was also a significant correlation between level of TBC1Ds and tumor-infiltrating immune cells (TIICs) in HCC. The promoting role of TBC1Ds in HCC progression was verified in vitro assays. Conclusion: The results of this analysis indicate that TBC1Ds may serve as new biomarkers for early diagnosis and treatment of HCC.

Circular RNA circHIPK2 inhibits colon cancer cells through miR-373-3p/RGMA axis.

Circular RNAs (circRNAs) have been implicated in cancer development. However, their regulation, function, and underlying mechanisms of action remain unclear. We found that circHIPK2 was downregulated in colon cancer, and low expression levels of circHIPK2 were associated with high tumor grade and poor patient survival. The expression of circHIPK2 was observed to be regulated by the transcription factor HOXD10, which was downregulated in colon cancer. Consequently, low circHIPK2 expression promoted colon cancer cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, circHIPK2 sponges miR-373-3p to upregulate the expression of the tumor suppressor RGMA, leading to the activation of BMP/Smad signaling and, ultimately, the inhibition of colon cancer cells, indicating that circHIPK2 inhibits colon cancer cells through the miR-373-3p/RGMA/BMP pathway. These findings revealed a previously unknown regulation, function, and underlying mechanism of circHIPK2 in cancer cells. Hence, circHIPK2 may have a prognostic value and serve as a potential target for colon cancer treatment.

The relationship between intraoperative hypothermia and postoperative delirium: The PNDRFAP study.

OBJECTIVE: Our study aimed to investigate the correlation between intraoperative hypothermia and postoperative delirium (POD) in patients undergoing general anesthesia for gastrointestinal surgery. METHODS: The study comprised 750 participants from the Perioperative Neurocognitive Disorder Risk Factor and Prognosis (PNDRFAP) study database, which ultimately screened 510 individuals in the final analysis. Preoperative cognitive function was evaluated using the Mini-Mental State Examination (MMSE). The occurrence of POD was determined using the Confusion Assessment Method, and the severity of POD was evaluated using the Memorial Delirium Assessment Scale. Logistic regression was employed to scrutinize the association between intraoperative hypothermia and the incidence of POD, and the sensitivity analysis was conducted by introducing adjusted confounding variables. Decision curves and a nomogram model were utilized to assess the predictive efficacy of intraoperative hypothermia for POD. Mediation analysis involving 10,000 bootstrapped iterations was employed to appraise the suggested mediating effect of numeric rating scale (NRS) scores at 24 and 48 h post-surgeries. The receiver-operating characteristic (ROC) was utilized to evaluate the effectiveness of intraoperative hypothermia in predicting POD. RESULTS: In the PNDRFAP study, the occurrence of POD was notably higher in the intraoperative hypothermia group (62.2%) compared to the intraoperative normal body temperature group (9.8%), with an overall POD incidence of 17.6%. Logistic regression analysis, adjusted for various confounding factors (age [40-90], gender, education, MMSE, smoking history, drinking history, hypertension, diabetes, and the presence of cardiovascular heart disease), demonstrated that intraoperative hypothermia significantly increased the risk of POD (OR = 4.879, 95% CI = 3.020-7.882, p < .001). Mediation analyses revealed that the relationship between intraoperative hypothermia and POD was partially mediated by NRS 24 h after surgery, accounting for 14.09% of the association (p = .002). The area under the curve of the ROC curve was 0.685, which confirmed that intraoperative hypothermia could predict POD occurrence to a certain extent. Decision curve and nomogram analyses, conducted using the R package, further substantiated the predictive efficacy of intraoperative hypothermia on POD. CONCLUSION: Intraoperative hypothermia may increase the risk of POD, and this association may be partially mediated by NRS scores 24 h after surgery.

Synthetic, structural and reactivity studies of a boryl-ethynyl Silylene.

The salt metathesis of a boryl-ethynyl lithium salt {[(HCDipN)2]B-CC-Li} with a monochlorosilylene [LSi(:)Cl; L = PhC(NtBu)2] produced an isolable boryl-ethynyl silylene {1; [(HCDipN)2]B-CC-Si(L)}. The Si(II) center in 1 possesses a nonbonding lone pair and forms a covalent bond with the ethynyl group. The characterization of 1 was carried out by multinuclear NMR spectroscopy, single-crystal X-ray structure analysis and DFT calculations. Additionally, a reactivity study of 1 was conducted towards oxygen-containing and aryl C-F substrates.

The interactive effect between economic uncertainty and life history strategy on corrupt intentions: a life history theory approach.

Introduction: Why do some people show more corruption when facing uncertain environment? The present study aimed to give a plausible answer from an evolutionary perspective: this might be rooted in people's different life history strategies (slow vs. fast). Methods: The present study measured the participants' corrupt intentions by a hypothetical scenario and primed the feeling of economic environmental uncertainty by requiring the participants to read economic uncertainty (vs. neutral) materials. Results: It is revealed that the participants with fast life history strategies had stronger corrupt intentions after reading materials about economic uncertainty than reading neutral materials. In addition, the desire for power mediated the interactive effect between life history strategy and economic uncertainty on corrupt intentions for fast life history strategists. Discussion: This finding was discussed for its theoretical and practical implications from the perspective of life history theory.

Study on immune persistence of the CTN-1V strain rabies vaccine in humans.

This study is a single-arm, single-center phase IV clinical trial on a rabies vaccine that has been marketed in China. The Vero cells and CTN-1V strain are used in the rabies vaccine product. The purpose of this study was to investigate the safety, immunogenicity and immune persistence of this product. One hundred and forty-nine participants were enrolled to the study, all of whom were included in the safety analysis set (SS), among which 116 participants were included in the protocol analysis set (PPS), One hundred and fifteen participants were included in the 6-month immune persistence analysis set (IPS6) and 111 in the 12-month immune persistence analysis set IPS12. Results showed that: 1) In the SS analysis set, adverse reactions were mainly pyrexia and pain at the vaccination site, the severity of which were mostly grade 1, and concentrated in 0-3 days after vaccination. No grade 3 or above adverse events and serious adverse events (SAE) related to the experimental vaccine were observed. 2) In the PPS analysis set, the antibody positive conversion rate reached 100% at 14 days after full immunization of the pre-immunized negative population; The antibody geometric mean titer (GMT) (95% CI) was 14.82 (13.00, 16.90). 3) The positive rate of serum neutralizing antibody was 93.91 % and the GMT at 1.58 IU/ml at 6 months after full immunization. The positive rate of neutralizing antibody was 85.59 % and GMT at 1.30 IU/ml at 12 months after immunization. Our results show that the human rabies vaccine with the CTN-1V strain and Vero cells as matrix had good safety, immunogenicity and immune persistence in our study.

Incorporating Network Pharmacology and Experimental Validation to Identify Bioactive Compounds and Potential Mechanisms of Digitalis in Treating Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is one of the most lethal malignant tumors for which there is no effective treatment. There are an increasing number of studies on herbal medicine for treating malignant tumors, and the classic botanical medicine Digitalis and its active ingredients for treating heart failure and arrhythmias have been revealed to have significant antitumor efficacy against a wide range of malignant tumors. However, the main components of Digitalis and the molecular mechanisms of its anti-ATC effects have not been extensively studied. Here, we screened the main components and core targets of Digitalis and verified the relationship between the active components and targets through network pharmacology, molecular docking, and experimental validation. These experiments showed that the active ingredients of Digitalis inhibit ATC cell activity and lead to ATC cell death through the apoptotic pathway.

Deciphering the Enhancing Impact of Exogenous Brassinolide on Physiological Indices of Melon Plants under Downy Mildew-Induced Stress.

Melon (Cucumis melo L.) is a valuable horticultural crop of the Cucurbitaceae family. Downy mildew (DM), caused by Pseudoperonospora cubensis, is a significant inhibitor of the production and quality of melon. Brassinolide (BR) is a new type of phytohormone widely used in cultivation for its broad spectrum of resistance- and defense-mechanism-improving activity. In this study, we applied various exogenous treatments (0.5, 1.0, and 2.0 mg·L-1) of BR at four distinct time periods (6 h, 12 h, 24 h, and 48 h) and explored the impact of BR on physiological indices and the genetic regulation of melon seedling leaves infected by downy-mildew-induced stress. It was mainly observed that a 2.0 mg·L-1 BR concentration effectively promoted the enhanced photosynthetic activity of seedling leaves, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis similarly exhibited an upregulated expression of the predicted regulatory genes of photosystem II (PSII) CmHCF136 (MELO3C023596.2) and CmPsbY (MELO3C010708.2), thus indicating the stability of the PSII reaction center. Furthermore, 2.0 mg·L-1 BR resulted in more photosynthetic pigments (nearly three times more than the chlorophyll contents (264.52%)) as compared to the control and other treatment groups and similarly upregulated the expression trend of the predicted key enzyme genes CmLHCP (MELO3C004214.2) and CmCHLP (MELO3C017176.2) involved in chlorophyll biosynthesis. Meanwhile, the maximum contents of soluble sugars and starch (186.95% and 164.28%) were also maintained, which were similarly triggered by the upregulated expression of the predicted genes CmGlgC (MELO3C006552.2), CmSPS (MELO3C020357.2), and CmPEPC (MELO3C018724.2), thereby maintaining osmotic adjustment and efficiency in eliminating reactive oxygen species. Overall, the exogenous 2.0 mg·L-1 BR exhibited maintained antioxidant activities, plastid membranal stability, and malondialdehyde (MDA) content. The chlorophyll fluorescence parameter values of F0 (42.23%) and Fv/Fm (36.67%) were also noticed to be higher; however, nearly three times higher levels of NPQ (375.86%) and Y (NPQ) (287.10%) were observed at 48 h of treatment as compared to all other group treatments. Increased Rubisco activity was also observed (62.89%), which suggested a significant role for elevated carbon fixation and assimilation and the upregulated expression of regulatory genes linked with Rubisco activity and the PSII reaction process. In short, we deduced that the 2.0 mg·L-1 BR application has an enhancing effect on the genetic modulation of physiological indices of melon plants against downy mildew disease stress.

Single Layer Silk and Cotton Woven Fabrics for Acoustic Emission and Active Sound Suppression.

Whether intentionally generating acoustic waves or attempting to mitigate unwanted noise, sound control is an area of challenge and opportunity. This study investigates traditional fabrics as emitters and suppressors of sound. When attached to a single strand of a piezoelectric fiber actuator, a silk fabric emits up to 70 dB of sound. Despite the complex fabric structure, vibrometer measurements reveal behavior reminiscent of a classical thin plate. Fabric pore size relative to the viscous boundary layer thickness is found-through comparative fabric analysis-to influence acoustic-emission efficiency. Sound suppression is demonstrated using two distinct mechanisms. In the first, direct acoustic interference is shown to reduce sound by up to 37 dB. The second relies on pacifying the fabric vibrations by the piezoelectric fiber, reducing the amplitude of vibration waves by 95% and attenuating the transmitted sound by up to 75%. Interestingly, this vibration-mediated suppression in principle reduces sound in an unlimited volume. It also allows the acoustic reflectivity of the fabric to be dynamically controlled, increasing by up to 68%. The sound emission and suppression efficiency of a 130 µm silk fabric presents opportunities for sound control in a variety of applications ranging from apparel to transportation to architecture.

The CBS/H2S signalling pathway regulated by the carbon repressor CreA promotes cellulose utilization in Ganoderma lucidum.

Cellulose is an important abundant renewable resource on Earth, and the microbial cellulose utilization mechanism has attracted extensive attention. Recently, some signalling molecules have been found to regulate cellulose utilization and the discovery of underlying signals has recently attracted extensive attention. In this paper, we found that the hydrogen sulfide (H2S) concentration under cellulose culture condition increased to approximately 2.3-fold compared with that under glucose culture condition in Ganoderma lucidum. Further evidence shown that cellulase activities of G. lucidum were improved by 18.2-27.6% through increasing H2S concentration. Then, we observed that the carbon repressor CreA inhibited H2S biosynthesis in G. lucidum by binding to the promoter of cbs, a key gene for H2S biosynthesis, at "CTGGGG". In our study, we reported for the first time that H2S increased the cellulose utilization in G. lucidum, and analyzed the mechanism of H2S biosynthesis induced by cellulose. This study not only enriches the understanding of the microbial cellulose utilization mechanism but also provides a reference for the analysis of the physiological function of H2S signals.

Structural determinants for membrane binding of the EGFR juxtamembrane domain.

Overactivation of the epidermal growth factor receptor (EGFR) is critical for the development of multiple cancers. Previous studies have shown that the cell membrane is a key regulator of EGFR kinase activity through its interaction with the EGFR juxtamembrane domain (JM). However, the lipid recognition specificity of EGFR-JM and its interaction details remain unclear. Using lipid strip and liposome pulldown assays, we showed that EGFR-JM could specifically interact with PI(4,5)P2-or phosphatidylserine-containing membranes. We further characterized the JM-membrane interaction using NMR-titration-based chemical shift perturbation and paramagnetic relaxation enhancement analyses, and found that residues I649 - L659 comprised the membrane-binding site. Furthermore, the membrane-binding region contains the predicted dimerization motif of JM, 655LRRLL659, suggesting that membrane binding may affect JM dimerization and, therefore, regulate kinase activation.

Hybridizing carbonate and ether at molecular scales for high-energy and high-safety lithium metal batteries.

Commonly-used ether and carbonate electrolytes show distinct advantages in active lithium-metal anode and high-voltage cathode, respectively. While these complementary characteristics hold promise for energy-dense lithium metal batteries, such synergy cannot be realized solely through physical blending. Herein, a linear functionalized solvent, bis(2-methoxyethyl) carbonate (BMC), is conceived by intramolecularly hybridizing ethers and carbonates. The integration of the electron-donating ether group with the electron-withdrawing carbonate group can rationalizes the charge distribution, imparting BMC with notable oxidative/reductive stability and relatively weak solvation ability. Furthermore, BMC also offers advantages including the ability to slightly dissolve LiNO3, excellent thermostability and nonflammability. Consequently, the optimized BMC-based electrolyte, even with typical concentrations in the single solvent, demonstrates high-voltage tolerance (4.4 V) and impressive Li plating/stripping Coulombic efficiency (99.4%). Moreover, it fulfills practical lithium metal batteries with satisfactory cycling performance and exceptional tolerance towards thermal/mechanical abuse, showcasing its suitability for safe high-energy lithium metal batteries.

Circ_0044235 regulates the development of osteoarthritis by the modulation of miR-375/PIK3R3 axis.

BACKGROUND: Circular RNAs (circRNAs) play an important role in osteoarthritis (OA). However, the role of circRNA in OA is still unclear. Here, we explored the role and mechanism of circ_0044235 in OA. METHODS: CHON-001 cells were treated with IL-1ß to establish OA model in vitro. The levels of circ_0044235, miR-375 and phosphoinositide 3-kinase (PI3K) regulatory subunit 3 (PIK3R3) were detected by quantitative real-time PCR. Cell count kit-8 assay and flow cytometry assay were used to detect cell viability and apoptosis. The concentrations of inflammation factors were determined by enzyme-linked immunosorbent assay. Western blot was used to detect protein levels. The interaction between miR-375 and circ_0044235 or PIK3R3 was analyzed by dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: Circ_0044235 was significantly decreased in OA cartilage tissue and IL-1ß-treated CHON-001 cells. Overexpression of circ_0044235 promoted IL-1ß-stimulated CHON-001 cell viability and inhibited apoptosis, inflammation, and extracellular matrix (ECM) degradation. In mechanism analysis, circ_0044235 could act as a sponge for miR-375 and positively regulate PIK3R3 expression. In addition, miR-375 ameliorated the effect of circ_0044235 overexpression on IL-1ß-mediated CHON-001 cells injury. In addition, miR-375 inhibition mitigated IL-1ß-induced CHON-001 cell injury, while PIK3R3 silencing restored the effect. CONCLUSION: Circ_0044235 knockdown alleviated IL-1ß-induced chondrocytes injury by regulating miR-375/PIK3R3 axis, confirming that circ_0044235 might be a potential target for OA treatment.

Enhanced burn wound healing by controlled-release 3D ADMSC-derived exosome-loaded hyaluronan hydrogel.

Adipose mesenchymal stem cell (ADMSC)-derived exosomes (ADMSC-Exos) have shown great potential in regenerative medicine and been evidenced benefiting wound repair such as burns. However, the low yield, easy loss after direct coating, and no suitable loading system to improve their availability and efficacy hinder their clinical application for wound healing. And few studies focused on the comparison of biological functions between exosomes derived from different culture techniques, especially in exosome-releasing hydrogel system. Therefore, we designed a high-performance exosome controllable releasing hydrogel system for burn wound healing, namely loading 3D-printed microfiber culture-derived exosomes in a highly biocompatible hyaluronic acid (HA). In this project, we compared the biological functions in vitro and in a burn model among exosomes derived from the conventional two-dimensional (2D) plate culture (2D-Exos), microcarrier culture (2.5D-Exos), and 3D-printed microfiber culture (3D-Exos). Results showed that compared with 2D-Exos and 2.5D-Exos, 3D-Exos promoted HACATs and HUVECs cell proliferation and migration more significantly. Additionally, 3D-Exos had stronger angiogenesis-promoting effects in tube formation of (HUVECs) cells. Moreover, we found HA-loaded 3D-Exos showed better burn wound healing promotion compared to 2D-Exos and 2.5D-Exos, including accelerated burn wound healing rate and better collagen remodeling. The study findings reveal that the HA-loaded, controllable-release 3D-Exos repair system distinctly augments therapeutic efficacy in terms of wound healing, while concurrently introducing a facile application approach. This system markedly bolsters the exosomal loading efficiency, provides a robust protective milieu, and potentiates the inherent biological functionalities of the exosomes. Our findings provide a rationale for more efficient utilization of high-quality and high-yield 3D exosomes in the future, and a novel strategy for healing severe burns.

Apoptotic Vesicles Derived from Dental Pulp Stem Cells Promote Bone Formation through the ERK1/2 Signaling Pathway.

Osteoporosis is a common degenerative bone disease. The treatment of osteoporosis remains a clinical challenge in light of the increasing aging population. Human dental pulp stem cells (DPSCs), a type of mesenchymal stem cells (MSCs), are easy to obtain and have a high proliferation ability, playing an important role in the treatment of osteoporosis. However, MSCs undergo apoptosis within a short time when used in vivo; therefore, apoptotic vesicles (apoVs) have attracted increasing attention. Currently, the osteogenic effect of DPSC-derived apoVs is unknown; therefore, this study aimed to determine the role of DPSC-derived apoVs and their potential mechanisms in bone regeneration. We found that MSCs could take up DPSC-derived apoVs, which then promoted MSC osteogenesis in vitro. Moreover, apoVs could increase the trabecular bone count and bone mineral density in the mouse osteoporosis model and could promote bone formation in rat cranial defects in vivo. Mechanistically, apoVs promoted MSC osteogenesis by activating the extracellular regulated kinase (ERK)1/2 signaling pathway. Consequently, we propose a novel therapy comprising DPSC-derived apoVs, representing a promising approach to treat bone loss and bone defects.