Healing with precision: A multi-functional hydrogel-bioactive glass dressing boosts infected wound recovery and enhances neurogenesis in the wound bed.

Chronic skin wounds, especially infected ones, pose a significant clinical challenge due to their increasing incidence and poor outcomes. The deteriorative microenvironment in such wounds, characterized by reduced extracellular matrix, impaired angiogenesis, insufficient neurogenesis, and persistent bacterial infection, has prompted the exploration of novel therapeutic strategies. In this study, we developed an injectable multifunctional hydrogel (GEL/BG@Cu + Mg) incorporating Gelatin-Tannic acid/ N-hydroxysuccinimide functionalized polyethylene glycol and Bioactive glass doped with copper and magnesium ions to accelerate the healing of infected wounds. The GEL/BG@Cu + Mg hydrogel composite demonstrates good biocompatibility, degradability, and rapid formation of a protective barrier to stop bleeding. Synergistic bactericidal effects are achieved through the photothermal properties of BG@Cu + Mg and sustained copper ions release, with the latter further promoting angiogenesis. Furthermore, the hydrogel enhances neurogenesis by stimulating axons and Schwann cells in the wound bed through the beneficial effects of magnesium ions. Our results demonstrate that the designed novel multifunctional hydrogel holds tremendous promise for treating infected wounds and allowing regenerative neurogenesis at the wound site, which provides a viable alternative for further improving clinical outcomes.

MiR-145-5p overexpression rejuvenates aged adipose stem cells and accelerates wound healing.

Adipose-derived stem cells (ADSCs) have been widely applied in translational and regenerative medicine. During aging, there is a recognized functional decline in ADSCs, which compromises their therapeutic effectiveness. Currently, the mechanisms of aging-induced stem cell dysfunction remain unclear, hence there is a need to elucidate these mechanisms and propose strategies for reversing this functional impairment. In this study, we found that ADSCs isolated from old donors (O-ADSCs) presented inferior phenotypes and decreased miR-145-5p levels compared to those from young donors (Y-ADSCs). To interrogate the role of miR-145-5p in ADSCs, gain- and loss-of-function assays were performed. The results indicated that miR-145-5p overexpression in O-ADSCs promoted cellular proliferation and migration, while reducing cell senescence. Further study demonstrated that miR-145-5p could regulate ADSCs function by targeting bone morphogenetic protein binding endothelial cell precursor-derived regulator (BMPER), which is a crucial modulator in angiogenesis. Moreover, in vivo experiments showed that miR-145-5p-overexpressing O-ADSCs accelerated wound healing by promoting wound re-epithelialization and angiogenesis. Collectively, this study indicates that miR-145-5p works as a positive regulator for optimizing O-ADSCs function, and may be a novel therapeutic target for restoring aging-associated impairments in stem cell function.

Genome-wide analysis reveals extensive genetic overlap between childhood phenotypes and later-life type 2 diabetes.

Observational studies have indicated a potential influence of childhood phenotypes on the later development of type 2 diabetes (T2D). However, the underlying biological mechanisms remain unclear. In this study, we conducted a comprehensive genome-wide analysis to investigate the shared genetic architecture and genetic loci between nine childhood phenotypes (N = 4202-620,26) and later-life T2D (N = 80,154) using genetic correlation, mendelian randomization (MR), and conjunctional false discovery rate (conjFDR) statistical frameworks. Our findings demonstrated substantial genetic correlations and pleiotropic enrichment between childhood obesity, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and later-life T2D. Childhood obesity exhibited a significant association with increased later-life T2D risk through 10 mediators, 6 of which were adulthood obesity-related phenotypes. Additionally, we identified 69, 83, 3, 5, 10, 5, 3, and 7 loci shared between childhood obesity, BMI, SBP, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and T2D at conjFDR <0.05, with the majority of these loci being novel discoveries. Overall, our study reveals extensive genetic overlap between childhood obesity-related phenotypes and T2D with concordant effect directions, shedding new light on variants and phenotypes with lifelong effects.

Biomimetic hybrid nanovesicles improve infected diabetic wound via enhanced targeted delivery.

Infected diabetic wounds have been raising the global medical burden because of its high occurrence and resulting risk of amputation. Impaired endothelium has been well-documented as one of the most critical reasons for unhealed wounds. Recently, endothelial cell-derived nanovesicles (NVs) were reported to facilitate angiogenesis, whereas their efficacy is limited in infected diabetic wounds because of the complex niche. In this study, extrusion-derived endothelial NVs were manufactured and then hybridized with rhamnolipid liposomes to obtain biomimetic hybrid nanovesicles (HNVs). The HNVs were biocompatible and achieved endothelium-targeted delivery through membrane CXCR4-mediated homologous homing. More importantly, the HNVs exhibited better penetration and antibacterial activity compared with NVs, which further promote the intrinsic endothelium targeting in infected diabetic wounds. Therefore, the present research has established a novel bioactive delivery system-HNV with enhanced targeting, penetration, and antibacterial activity-which might be an encouraging strategy for infected diabetic wound treatment.

LncRNA12097.1 contributes to endometrial cell growth by enhancing YES1 activating ß-catenin via sponging miR-145-5p.

Despite previous investigations elucidating the regulatory mechanisms of long non-coding RNAs (lncRNAs) in endometrial function and reproductive disorders, the precise pathways through which lncRNAs impact endometrial functions and fertility remain unclear. In this study, we performed an expression profile analysis of lncRNAs in the endometrial tissue of Hu sheep with different prolificacy, identifying 13,707 lncRNAs. We discovered a bidirectional lncRNA, designated lncRNA12097.1, exhibiting significant up-regulation exclusively in the endometrium of Hu sheep with high fecundity. Functional analyses revealed lncRNA12097.1 significantly enhanced proliferation and cell cycle progression in both endometrial epithelial cell (EEC) and stromal cells (ESC), while inhibiting apoptosis in these cell types. Mechanistically, we demonstrated a directly interaction between lncRNA12097.1 and miR-145-5p, with YES proto-oncogene 1 (YES1) being identified as a validated target of miR-145-5p. Interference with lncRNA12097.1 resulted in suppressed cell growth through down-regulation of YES1 expression, which could be rescued by miR-145-5p. Furthermore, lncRNA12097.1 functions as a competitive endogenous RNA (ceRNA) for miR-145-5p in ESCs, sequestering miR-145-5p and preventing its binding to the 3'UTR of YES1 mRNA. This interaction led to increased expression of YES1 and subsequent activation of downstream ß-catenin signaling, thereby promoting ESC growth in Hu sheep. These findings provide novel molecular insights into the mechanisms underlying prolificacy in sheep.

Multifunctional ADM hydrogel containing endothelial cell-exosomes for diabetic wound healing.

Non-healing wound, with limited treatment options, remains a prevalent complication of diabetes mellitus. The underlying causes wherein include oxidative stress injury, bacterial infection, cellular dysfunction, and persistent inflammation. Acellular Dermal Matrix (ADM), a wound dressing composed of natural extracellular matrix and abundant bioactive factors, has been successfully developed to treat various wounds, including burns and diabetic ulcers. Protocatechualdehyde (PA) & trivalent iron ion (Fe3+) complex (Fe3+@PA) exhibits potential antioxidant and antibacterial properties. In this study, we developed a dual hydrogel network by combining Fe3+@PA complex-modified ADM with light-cured gelatin (GelMA), supplemented with exosomes derived from human umbilical vein endothelial cells (HUVEC-Exos), to create an ADM composite hydrogel system (ADM-Fe3+@PA-Exos/GelMA) with antioxidant, antibacterial, and cell-promoting functions for diabetic wound treatment. Through in vitro experiments, we investigated the biosafety, antioxidant and antibacterial properties of ADM composite hydrogel. Furthermore, we examined the protective effects of ADM composite hydrogel on diabetic wound. The above experiments collectively demonstrate that our ADM-Fe3+@PA-Exos/GelMA hydrogel promotes diabetic wound healing by eliminating bacterial infection, reduced the reactive oxygen species (ROS) levels, protecting cells against oxidative stress damage, promotingcollagen deposition and angiogenesis, which provides a promising strategy to optimize ADM for diabetic wound treatment.

CREB1 Is Involved in miR-134-5p-Mediated Endometrial Stromal Cell Proliferation, Apoptosis, and Autophagy.

The successful establishment of endometrial receptivity is a key factor in ensuring the fertility of ewes and their economic benefits. Hu sheep have attracted attention due to their high fecundity and year-round estrus. In this study, we found that in the luteal phase, the uterine gland density, uterine coefficient, and number of uterine caruncles of high-fertility Hu sheep were higher than those of low-fertility Hu sheep. Thousands of differentially expressed genes were identified in the endometrium of Hu sheep with different fertility potential using RNA sequencing (RNA-Seq). Several genes involved in endometrial receptivity were screened using bioinformatics analysis. The qRT-PCR analysis further revealed the differential expression of cAMP reactive element binding protein-1 (CREB1) in the Hu sheep endometrium during the estrous cycle. Functionally, our results suggested that CREB1 significantly affected the expression level of endometrial receptivity marker genes, promoted cell proliferation by facilitating the transition from the G1 phase to the S phase, and inhibited cell apoptosis and autophagy. Moreover, we observed a negative linear correlation between miR-134-5p and CREB1 in the endometrium. In addition, CREB1 overexpression prevented the negative effect of miR-134-5p on endometrial stromal cell (ESC) growth. Taken together, these data indicated that CREB1 was regulated by miR-134-5p and may promote the establishment of uterine receptivity by regulating the function of ESCs. Moreover, this study provides new theoretical references for identifying candidate genes associated with fertility.

Ultra high b-value diffusion weighted imaging enables better molecular grading stratification over histological grading in adult-type diffuse glioma.

PURPOSE: Accurate preoperative radiological staging of adult-type diffuse glioma is crucial for effective prognostic stratification and selection of appropriate therapeutic interventions. The purpose of this study was to compare the effectiveness of apparent diffusion coefficient (ADC) maps generated from ultrahigh b-value diffusion-weighted imaging (DWI) for molecular grading with that for histological grading of adult-type diffuse glioma, and to evaluate the correlation between these ADC maps and molecular and histological biomarkers. METHODS: This study retrospectively enrolled forty adult-type diffuse glioma patients, diagnosed using the 2021 WHO classification criteria. Preoperative imaging data, including multiple b-value DWI and conventional magnetic resonance imaging, were collected. Tumors were graded using both histological and molecular criteria. Histogram analysis was conducted to generate 14 parameters for each tumor. Receiver operating characteristic curves and the area under the curve (AUC) were used to evaluate tumor grading and molecular status differentiation. Analysis of histological biomarkers was performed by calculating the Pearson and Spearman correlation coefficients of continuous and hierarchical variables, respectively. RESULTS: The intensity-related parameters for molecular grading were found to be superior to those for histological grading for the identification of WHO grade 4 (WHO4) adult-type diffuse glioma. The AUC of both grading systems increased with increasing b-values, with ADC8000-based histogram parameters showing the best results (molecular grading, square root: AUC = 0.897; histological grading, median: AUC = 0.737). The intensity-related parameters could also differentiate molecular WHO4 gliomas from histologically lower-grade gliomas (ADC8000-based square root: AUC = 0.919), and different ADC8000-based kurtosis was observed between molecular and histological WHO4 gliomas (AUC = 0.833). Significant correlations between the Ki-67 index and molecular status prediction for IDH, CDKN2A, and EGFR were also demonstrated. CONCLUSION: The histogram parameters derived from high b-value ADC maps were found to be more effective for differentiating molecular grades of WHO4 adult-type diffuse glioma than for differentiating histological grades.

Knockdown of long noncoding RNA SAN rejuvenates aged adipose-derived stem cells via miR-143-3p/ADD3 axis.

BACKGROUND: Senescent adipose-derived stem cells (ASCs) exhibit reduced therapeutic efficacy during wound healing. Transcriptional regulation factors including long noncoding RNAs (lncRNAs) reportedly have essential roles in stem cell aging. However, the mechanisms of which lncRNAs influence mesenchymal stem cell aging and how it works need further investigation. METHODS: The expression patterns of lncRNA senescence-associated noncoding RNA (SAN) and miR-143-3p in ASCs obtained from old and young volunteer donors were detected by quantitative polymerase chain reaction. ASCs with overexpression or knockdown of SAN and γ-adducin (ADD3) were constructed by lentiviral transduction. Mimic and inhibitor were used to manipulate the cellular level of miR-143-3p in ASCs. The effects of these RNAs on ASCs proliferation, migration and cellular senescence were examined by EdU, transwell and senescence-activated ß-galactosidase (SA-ß-gal) staining assays. Wound scratch and tube formation assays were conducted to evaluate the capacities of ASCs in promoting fibroblasts migration and endothelial cells angiogenesis. Furthermore, dual-luciferase assays and rescue experiments were performed to identify the RNA interactions. Finally, the therapeutic effects of SAN-depleted aged ASCs were evaluated in a skin injury model. RESULTS: The lncRNA SAN (NONHSAT035482.2) was upregulated in aged ASCs; it controlled cellular senescence in ASCs. lncRNA SAN knockdown in ASCs led to ASC functional enhancement and the inhibition of cellular senescence; it also promoted the effects of conditioned medium (CM) on endothelial cell tube formation and fibroblast migration. Mechanistic analysis showed that SAN serves as a sponge for miR-143-3p, thereby regulating the expression of ADD3. The application of SAN-depleted aged ASCs increased re-epithelialization, collagen deposition, neovascularization and led to accelerated skin wound closure, compared with transplantation of aged ASCs. CONCLUSION: The lncRNA SAN mediates ASC senescence by regulating the miR-143-3p/ADD3 pathway, providing a potential target for rejuvenation of senescent ASCs and enhancement of wound repair.

Diffusion tensor imaging versus intraoperative subcortical mapping for glioma resection: a systematic review and meta-analysis.

Maintaining the integrity of crucial fiber tracts allows functional preservation and improved recovery in patients with glioma resection. Diffusion tensor imaging (DTI) and intraoperative subcortical mapping (ISM) are commonly required for pre- and intraoperative assessment of white matter fibers. This study investigated differences of clinical outcomes in glioma resection aided by DTI or ISM. A comprehensive literature retrieval of the PubMed and Embase databases identified several DTI or ISM studies in 2000-2022. Clinical data, including extent of resection (EOR) and postoperative neurological deficits, was collected and statistically analyzed. Heterogeneity was regressed by a random effect model and the Mann-Whitney U test was used to test statistical significance. Publication bias was assessed by Egger test. A total of 14 studies with a pooled cohort of 1837 patients were included. Patients undergoing DTI-navigated glioma surgery showed a higher rate of gross total resection (GTR) than ISM-assisted surgical resection (67.88%, [95% CI 0.55-0.79] vs. 45.73%, [95% CI 0.29-0.63], P = 0.032). The occurrence of early postoperative functional deficit (35.45%, [95% CI 0.13-0.61] vs. 35.60% [95% CI 0.20-0.53], P = 1.000), late postoperative functional deficit (6.00%, [95% CI 0.02-0.11] vs. 4.91% [95% CI 0.03-0.08], P = 1.000) and severe postoperative functional deficit (2.21%, [95% CI 0-0.08] vs. 5.93% [95% CI 0.01-0.16], P = 0.393) were similar between the DTI and ISM group, respectively. While DTI-navigation resulted in a higher rate of GTR, the occurrence of postoperative neurological deficits between DTI and ISM groups was comparable. Together, these data indicate that both techniques could safely facilitate glioma resection.

Exosomal miR-125b-5p derived from adipose-derived mesenchymal stem cells enhance diabetic hindlimb ischemia repair via targeting alkaline ceramidase 2.

INTRODUCTION: Ischemic diseases caused by diabetes continue to pose a major health challenge and effective treatments are in high demand. Mesenchymal stem cells (MSCs) derived exosomes have aroused broad attention as a cell-free treatment for ischemic diseases. However, the efficacy of exosomes from adipose-derived mesenchymal stem cells (ADSC-Exos) in treating diabetic lower limb ischemic injury remains unclear. METHODS: Exosomes were isolated from ADSCs culture supernatants by differential ultracentrifugation and their effect on C2C12 cells and HUVECs was assessed by EdU, Transwell, and in vitro tube formation assays separately. The recovery of limb function after ADSC-Exos treatment was evaluated by Laser-Doppler perfusion imaging, limb function score, and histological analysis. Subsequently, miRNA sequencing and rescue experiments were performed to figure out the responsible miRNA for the protective role of ADSC-Exos on diabetic hindlimb ischemic injury. Finally, the direct target of miRNA in C2C12 cells was confirmed by bioinformatic analysis and dual-luciferase report gene assay. RESULTS: ADSC-Exos have the potential to promote proliferation and migration of C2C12 cells and to promote HUVECs angiogenesis. In vivo experiments have shown that ADSC-Exos can protect ischemic skeletal muscle, promote the repair of muscle injury, and accelerate vascular regeneration. Combined with bioinformatics analysis, miR-125b-5p may be a key molecule in this process. Transfer of miR-125b-5p into C2C12 cells was able to promote cell proliferation and migration by suppressing ACER2 overexpression. CONCLUSION: The findings revealed that miR-125b-5p derived from ADSC-Exos may play a critical role in ischemic muscle reparation by targeting ACER2. In conclusion, our study may provide new insights into the potential of ADSC-Exos as a treatment option for diabetic lower limb ischemia.

Exosomes derived from oral squamous cell carcinoma tissue accelerate diabetic wound healing.

It is a widespread and difficult problem that refractory diabetic wounds have a poor local environment and prolonged inflammatory irritation. Tumor cell-derived exosomes play an important role in the development of tumors, as they can promote tumor cell proliferation, migration, and invasion and enhance tumor cell activity. However, tumor tissue-derived exosomes (Ti-Exos) have been less studied, and it is unclear how they affect wound healing. In this study, we extracted Ti-Exos from human oral squamous carcinoma and paracancerous tissue by ultracentrifugation, size exclusion chromatography, and ultrafiltration and performed exosome characterization. In vitro, the oral squamous cell carcinoma tissue-derived exosomes (OSCC Ti-Exos) promoted the proliferation and migration of endothelial cells, keratinocytes, and fibroblasts. In addition, in vivo experiments showed that the OSCC Ti-Exos accelerated the healing of diabetic wounds and were safe in mice. In contrast, there was no promoting effect of paracancerous tissue-derived exosomes either in vivo or in vitro. In conclusion, OSCC Ti-Exos promoted the healing of diabetic wounds, demonstrated preliminary biosafety in mice, and have promise as therapeutic applications.NEW & NOTEWORTHY Diabetic wound healing has become a public health issue that lacks effective treatment. We collected oral squamous cell carcinoma samples and paracancerous tissue and extracted Ti-Exos for verification. In vitro assays revealed that OSCC Ti-EVs could enhance the proliferation and migration of endothelial cells, keratinocytes, and fibroblasts in diabetic cell model. In vivo assays also verified that OSCC Ti-Exos could promote diabetic wound healing, demonstrated preliminary biosafety in mice, and have promise as therapeutic applications.

Tumor tissue derived extracellular vesicles promote diabetic wound healing.

The diabetic wound nowadays remains a major public health challenge, which is characterized by overproduced reactive oxygen species (ROS). However, the current therapy for diabetic wounds is limited for reliable data in the general application. The growth of tumors has been revealed to share parallels with wound healing. Extracellular vesicles (EVs) derived from breast cancer have been reported to promote cell proliferation, migration and angiogenesis. The tumor tissue-derived EVs (tTi-EVs) of breast cancer performance a feature inheritance from original tissue and might accelerate the diabetic wound healing. We wonder whether the tumor-derived EVs are able to accelerate diabetic wound healing. In this study, tTi-EVs were extracted from breast cancer tissue via ultracentrifugation and size exclusion. Subsequently, tTi-EVs reversed the H2O2-induced inhibition of fibroblast proliferation and migration. Moreover, tTi-EVs significantly accelerated wound closure, collagen deposition and neovascularization, and finally promoted wound healing in diabetic mice. The tTi-EVs also reduced the level of oxidative stress in vitro and in vivo. Besides, the biosafety of tTi-EVs were preliminarily confirmed by blood tests and morphological analysis of major organs. Collectively, the present study proves that tTi-EVs can suppress oxidative stress and facilitate diabetic wound healing, which puts forward a novel function of tTi-EVs and provides potential treatment for diabetic wounds.

Milk-derived exosomes carrying siRNA-KEAP1 promote diabetic wound healing by improving oxidative stress.

Diabetic wounds are a serious complication of diabetes mellitus (DM) that can lead to persistent infection, amputation, and even death. Prolonged oxidative stress has been widely recognized as a major instigator in the development of diabetic wounds; therefore, oxidative stress is considered a promising therapeutic target. In the present study, Keap1/Nrf2 signaling was confirmed to be activated in streptozotocin (STZ)-induced diabetic mice and methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). Knockdown of Keap1 by siRNA reversed the increase in Keap1 levels, promoted the nuclear translocation of Nrf2, and increased the expression of HO-1, an antioxidant protein. To explore therapeutic delivery strategies, milk-derived exosomes (mEXOs) were developed as a novel, efficient, and non-toxic siRNA carrier. SiRNA-Keap1 (siKeap1) was loaded into mEXOs by sonication, and the obtained mEXOs-siKeap1 were found to promote HUVEC proliferation and migration while relieving oxidative stress in MGO-treated HUVECs. Meanwhile, in a mouse model of diabetic wounds, injection of mEXOs-siKeap1 significantly accelerated diabetic wound healing with enhanced collagen formation and neovascularization. Taken together, these data support the development of Keap1 knockdown as a potential therapeutic strategy for diabetic wounds and demonstrated the feasibility of mEXOs as a scalable, biocompatible, and cost-effective siRNA delivery system. The therapeutic effect of siKeap1-loaded mEXOs on diabetic wound healing was assessed. First, we found that the expression of Keap1 was upregulated in the wounds of diabetic mice and in human umbilical vein endothelial cells (HUVECs) pretreated with methylglyoxal (MGO). Next, we extracted exosomes from raw milk by differential centrifugation and loaded siKeap1 into milk-derived exosomes by sonication. The in vitro application of the synthetic complex (mEXOs-siKeap1) was found to increase the nuclear localization of Nrf2 and the expression of the antioxidant protein HO-1, thus reversing oxidative stress. Furthermore, in vivo mEXOs-siKeap1 administration significantly accelerated the healing rate of diabetic wounds (Scheme 1). Scheme 1 Schematic diagram. A Synthesis of mEXOs-siKeap1 complex. B Mechanism of mEXOs-siKeap1 in vitro. C The treatment effect of mEXOs-siKeap1 on an in vivo mouse model of diabetic wounds.

Redox- and pH-Responsive Water-Soluble Flexible Organic Frameworks Realize Synergistic Tumor Photodynamic and Chemotherapeutic Therapy.

Water-soluble 3D polymers with inherent nanoscale pores have been shown to be ideal platforms for the inclusion and delivery of drugs and hold a great promise as biocompatible materials for diagnostic and therapeutic purposes. Herein, a low cytotoxic water-soluble flexible organic framework FOF-S6 with a hydrodynamic diameter of about 127.5 nm is synthesized through the formation of a hydrazone bond from a semirigid tetraaldehyde and a flexible biacylhydrazines which contains a disulfide bond (1:2). FOF-S6 has the ability to dissociate and release inclusion complexes in response to weakly acidic media and glutathione (GSH) overexpressed in tumor cells. More importantly, a facile strategy is developed to contain and deliver aggregation-induced emission photosensitizers (AIE PS, TBD-DQA-540) and chemotherapeutic drugs (Doxorubicin hydrochloride, DOX). DOX-PS@FOF-S6 is synthesized by a one-pot method, which can realize efficient photo-chemotherapy under the guidance of fluorescence imaging, thereby improving the multidrug resistance of tumor cells and the instability of photosensitizers, so as to improve the tumor treatment efficacy.

Melatonin Maintains Homeostasis and Potentiates the Anti-inflammatory Response in Staphylococcus aureus-Induced Mastitis through microRNA-16b/YAP1.

Staphylococcus aureus is a highly infectious pathogen and is a considerable threat to food hygiene and safety. Although melatonin is thought to exert an ameliorative effect on bovine mastitis, the regulatory mechanisms are unclear. In this study, we first verified the therapeutic effect of melatonin against S. aureus in vitro and in vivo, a screening of differentially expressed miRNAs and mRNAs among the blank, and S. aureus and melatonin + S. aureus groups by high-throughput sequencing identified miR-16b and YAP1, which exhibited 1.95-fold upregulated and 1.05-fold downregulated expression, respectively. Moreover, epigenetic studies showed that S. aureus inhibited miR-16b expression by methylation (increased DNMT1 expression). Additionally, the DNMT1 expression level was significantly decreased by melatonin treatment, which might indicate that the inhibition of DNMT1 by melatonin reduces the effect of S. aureus on miR-16b. The flow cytometry, scanning and transmission electron microscopy, EdU assay, and cell morphology results indicated that miR-16b in bovine mammary epithelial cells (in vitro) and in mice (in vivo) can modulate the maintenance of homeostasis and potentiate the anti-inflammatory response. In addition, YAP1 was demonstrated to be the target gene of miR-16b through quantitative real-time polymerase chain reaction, western blot, RNA immunoprecipitation, and functional assays. This study indicates that melatonin inhibits S. aureus-induced inflammation via microRNA-16b/YAP1-mediated regulation, and these findings might provide a new strategy for the prevention of bovine mastitis, facilitating further studies good of zoonotic diseases caused by S. aureus infection.

Exosomes from Adipose Stem Cells Promote Diabetic Wound Healing through the eHSP90/LRP1/AKT Axis.

Oxidative damage is a critical cause of diabetic wounds. Exosomes from various stem cells could promote wound repair. Here, we investigated the potential mechanism by which exosomes from adipose-derived stem cells (ADSC-EXOs) promote diabetic wound healing through the modulation of oxidative stress. We found that ADSC-EXOs could promote proliferation, migration, and angiogenesis in keratinocytes, fibroblasts, and endothelial cells. Furthermore, ADSC-EXOs reduced the reactive oxygen species (ROS) levels in these cells and protected them against hypoxic and oxidative stress damage. Finally, the local injection of ADSC-EXOs at wound sites significantly increased collagen deposition and neovascularization while reducing ROS levels and cell death; thus, it led to accelerated diabetic wound closure. The mechanism underlying ADSC-EXO functions involved heat-shock protein 90 (HSP90) expressed on the cell surface; these functions could be inhibited by an anti-HSP90 antibody. Exosomal HSP90 could bind to the low-density lipoprotein receptor-related protein 1 (LRP1) receptor on the recipient cell membrane, leading to activation of the downstream AKT signaling pathway. Knockdown of LRP1 and inhibition of the AKT signaling pathway by LY294002 in fibroblasts was sufficient to impair the beneficial effect of ADSC-EXOs. In summary, ADSC-EXOs significantly accelerated diabetic wound closure through an exosomal HSP90/LRP1/AKT signaling pathway.

Accelerated Bone Regeneration by an Astaxanthin-Modified Antioxidant Aerogel through Relieving Oxidative Stress via the NRF2 Signaling Pathway.

Bone regeneration of critical-sized bone defects (CSBDs) with biomimetic collagen-based aerogels remains a significant challenge due to the oxidative stress on the microenvironment. The excessive oxidative stress could induce apoptosis and dysfunction of host-derived cells. Astaxanthin (ATX) exhibits excellent antioxidant ability to block free radical chain reactions. In the present study, hybrid antioxidant collagen-derived aerogels (ATX-Col aerogels) were fabricated by a simple one-step method through the covalent cross-linking of Col and ATX. The resulting ATX-Col aerogels show porous and interconnected structures due to freeze-drying strategies. The ATX-Col aerogels exhibited excellent biocompatibility and biosafety. Furthermore, ATX-Col aerogels demonstrated favorable antioxidant capacity by eliminating intracellular ROS by activating the NRF2 signaling pathway. Finally, excellent reparative effects in repairing rat cranial defects were observed in ATX-Col aerogels. Taken together, ATX-Col aerogels can accelerate bone regeneration by relieving oxidative stress via the NRF2 signaling pathway and act as a potential bone graft for CSBD. This study provides a simple method of developing antioxidant aerogels for bone regeneration.

LncRNA-412.25 activates the LIF/STAT3 signaling pathway in ovarian granulosa cells of Hu sheep by sponging miR-346.

Although long non-coding RNAs (lncRNAs) are reported to regulate follicular development and reproductive disease pathogenesis, the underlying mechanisms have not been elucidated. In this study, lncRNA expression profiling of different-sized healthy follicles from Hu sheep with different prolificacy revealed 50 613 lncRNAs. Numerous lncRNAs were differentially expressed among different comparison groups. This study characterized one novel transcript, lncRNA-412.25 (from healthy follicles with a diameter of >5 mm), which was predominantly expressed in the high prolificacy group and localized to the cytoplasm of granulosa cells (GCs). LncRNA-412.25 knockdown promoted and inhibited Hu sheep GC apoptosis and proliferation, respectively. Interestingly, lncRNA-412.25 could directly bind to miR-346, which can target the gene of leukemia inhibitory factor (LIF). Knockdown of lncRNA-412.25 promoted GC apoptosis by downregulating LIF expression, where this effect was attenuated by miR-346. Moreover, the miR-346 inhibitor mitigated the lncRNA-412.25 knockdown-induced downregulation of phosphorylated protein of signal transducer and activator of transcription 3 (STAT3), which was validated using immunofluorescence analysis. Our results demonstrated that lncRNA-412.25 regulates GC proliferation and apoptosis in Hu sheep by binding to miR-346 and then activating the LIF/STAT3 pathway. These findings provide novel insights into the mechanisms underlying prolificacy in sheep.