Polysaccharides from Lanzhou Lily Attenuate Induced Nonalcoholic Fatty Liver Disease Modifying the Gut Microbiota and Metabolite Profile.

Nonalcoholic fatty liver disease (NAFLD) is closely related to gut microbiota due to the hepatic portal system, and utilizing natural polysaccharides as prebiotics has become a prospective strategy for treating NAFLD. However, the therapeutic effects and potential molecular mechanisms of Lanzhou Lily polysaccharides (LLP) on NAFLD remains unclear. Therefore, the alleviating effects of LLP on NAFLD induced by high-fat diet (HFD) were investigated. LLP treatment greatly ameliorated NAFLD by significantly reducing lipid accumulation and the levels of liver function markers in HFD-induced NAFLD mice, as evidenced by decreased serum levels of TG, TC, HDL-C and LDL-C. Furthermore, LLP administration reduced hepatic steatosis, as shown by H&E and Oil red O staining. LLP also inhibited the TNF-α and IL-1ß expression, thereby reducing levels of hepatic proinflammatory cytokines. Furthermore, LLP restored gut microbiota dysbiosis, and regulated microbial metabolic pathways such as primary bile acid biosynthesis and amino acid metabolism. In addition, the resultes of Spearman's correlation analysis found that some key metabolites in these metabolic pathways were associated with intestinal microorganisms such as Desulfobacterota, Prevotellaceae-UCG-001, Colidextribacter and Alistipes. Therefore, our study suggests that LLP may has potential applications in the treatment of NAFLD by regulating gut microbiota and its metabolite profile.

Treatment of Parkinson's disease model with human umbilical cord mesenchymal stem cell-derived exosomes loaded with BDNF.

AIMS: Parkinson's disease (PD) is a common neurodegenerative disease that has received widespread attention; however, current clinical treatments can only relieve its symptoms, and do not effectively protect dopaminergic neurons. The purpose of the present study was to investigate the therapeutic effects of human umbilical cord mesenchymal stem cell-derived exosomes loaded with brain-derived neurotrophic factor (BDNF-EXO) on PD models and to explore the underlying mechanisms of these effects. MAIN METHODS: 6-Hydroxydopamine was used to establish in vivo and in vitro PD models. Western blotting, flow cytometry, and immunofluorescence were used to detect the effects of BDNF-EXO on apoptosis and ferroptosis in SH-SY5Y cells. The in vivo biological distribution of BDNF-EXO was detected using a small animal imaging system, and dopaminergic neuron improvements in brain tissue were detected using western blotting, immunofluorescence, immunohistochemistry, and Nissl and Prussian blue staining. KEY FINDINGS: BDNF-EXO effectively suppressed 6-hydroxydopamine-induced apoptosis and ferroptosis in SH-SY5Y cells. Following intravenous administration, BDNF-EXO crossed the blood-brain barrier to reach afflicted brain regions in mice, leading to a notable enhancement in neuronal survival. Furthermore, BDNF-EXO modulated microtubule-associated protein 2 and phosphorylated tau expression, thereby promoting neuronal cytoskeletal stability. Additionally, BDNF-EXO bolstered cellular antioxidant defense mechanisms through the activation of the nuclear factor erythroid 2-related factor 2 signaling pathway, thereby conferring neuroprotection against damage. SIGNIFICANCE: The novel drug delivery system, BDNF-EXO, had substantial therapeutic effects in both in vivo and in vitro PD models, and may represent a new treatment strategy for PD.

NMR-Guided Isolation of Anti-inflammatory Carabranolides from the Fruits of Carpesium abrotanoides L.

Carabranolides present characteristic NMR resonances for the cyclopropane moiety, which distinctly differ from those of other compounds and were used for an NMR-guided isolation in this study. As a result, 11 undescribed carabranolides (1-11), along with five known ones (12-16), were isolated from the fruits of Carpesium abrotanoides L. Compounds 1-11 are new esters of carabrol at C-4 with different carboxylic acids. Their structures were elucidated by HRESIMS and NMR spectroscopic data analysis. The biological evaluation showed that compounds 2-4, 15, and 16 exhibited significant inhibitory activity against LPS-induced NO release with an IC50 value of 5.6-9.1 µM and dose-dependently decreased iNOS protein expression in RAW264.7 cells.

HucMSC extracellular vesicles increasing SATB 1 to activate the Wnt/ß-catenin pathway in 6-OHDA-induced Parkinson's disease model.

Parkinson's disease (PD) is a degenerative disorder of the nervous system characterized by the loss of dopaminergic neurons and damage of neurons in the substantia nigra (SN) and striatum, resulting in impaired motor functions. This study aims to investigate how extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (HucMSC) regulate Special AT-rich sequence-binding protein-1 (SATB 1) and influence Wnt/ß-catenin pathway and autophagy in PD model. The PD model was induced by damaging SH-SY5Y cells and mice using 6-OHDA. According to the study, administering EVs every other day for 14 days improved the motor behavior of 6-OHDA-induced PD mice and reduced neuronal damage, including dopaminergic neurons. Treatment with EVs for 12 hours increased the viability of 6-OHDA-induced SH-SY5Y cells. The upregulation of SATB 1 expression with EV treatment resulted in the activation of the Wnt/ß-catenin pathway in PD model and led to overexpression of ß-catenin. Meanwhile, the expression of LC3 II was decreased, indicating alterations in autophagy. In conclusion, EVs could mitigate neuronal damage in the 6-OHDA-induced PD model by upregulating SATB 1 and activating Wnt/ß-catenin pathway while also regulating autophagy. Further studies on the potential therapeutic applications of EVs for PD could offer new insights and strategies.

Discovery of Prenyltransferase-Guided Hydroxyphenylacetic Acid Derivatives from Marine Fungus Penicillium sp. W21C371.

Traditional isolation methods often lead to the rediscovery of known natural products. In contrast, genome mining strategies are considered effective for the continual discovery of new natural products. In this study, we discovered a unique prenyltransferase (PT) through genome mining, capable of catalyzing the transfer of a prenyl group to an aromatic nucleus to form C-C or C-O bonds. A pair of new hydroxyphenylacetic acid derivative enantiomers with prenyl units, (±)-peniprenydiol A (1), along with 16 known compounds (2-17), were isolated from a marine fungus, Penicillium sp. W21C371. The separation of 1 using chiral HPLC led to the isolation of the enantiomers 1a and 1b. Their structures were established on the basis of extensive spectroscopic analysis, including 1D, 2D NMR and HRESIMS. The absolute configurations of the new compounds were determined by a modified Mosher method. A plausible biosynthetic pathway for 1 was deduced, facilitated by PT catalysis. In the in vitro assay, 2 and 3 showed promising inhibitory activity against Escherichia coli ß-glucuronidase (EcGUS), with IC50 values of 44.60 ± 0.84 µM and 21.60 ± 0.76 µM, respectively, compared to the positive control, D-saccharic acid 1,4-lactone hydrate (DSL). This study demonstrates the advantages of genome mining in the rational acquisition of new natural products.

Non-Clinical Safety Evaluation of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys.

Purpose: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future. Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection. Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group. Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.

RVG29 Peptide-Modified Exosomes Loaded with Mir-133b Mediate the RhoA-ROCK Pathway to Improve Motor and Neurological Symptoms in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Drug delivery to the brain through the blood-brain barrier (BBB) is a significant challenge in PD treatment. Exosomes, which can efficiently traverse the BBB, which many drugs cannot penetrate, are ideal natural carriers for drug delivery. In this study, the BBB shuttle peptide was modified on the exosome surfaces. Three types of exosomes were constructed, each modified with a distinct peptide (RVG29, TAT, or Ang2) and loaded with miR-133b. The safety and brain-targeting capabilities of these peptide-modified exosomes were then evaluated. Finally, the mechanism by which RVG29-Exo-133b regulates the RhoA-ROCK signaling pathway was investigated. The findings indicate that the three peptide-modified exosomes were adequately tolerated, safe, and effectively assimilated in vivo and ex vivo, with RVG29 exhibiting superior targeting to the brain. Furthermore, RVG29-Exo-133b decreased the phosphorylation level of the Tau protein by targeting the RhoA-ROCK signaling pathway. It also enhanced the motor function in mice with PD, thereby reducing the degree of depression, improving dopaminergic neuron function, and attenuating 6-OHDA-induced nerve damage. In this study, we developed a stable drug delivery mechanism that targets the intracerebral region using exosomes. Furthermore, a novel strategy was developed to manage PD and can potentially serve as a preclinical basis for utilizing exosomes in the diagnosis and treatment of neurodegenerative conditions.

Advancing Guideline-Directed Medical Therapy in Heart Failure: Overcoming Challenges and Maximizing Benefits.

The delayed titration of guideline-directed drug therapy (GDMT) is a complex event influenced by multiple factors that often result in poor prognosis for patients with heart failure (HF). Individualized adjustments in GDMT titration may be necessary based on patient characteristics, and every clinician is responsible for promptly initiating GDMT and titrating it appropriately within the patient's tolerance range. This review examines the current challenges in GDMT implementation and scrutinizes titration considerations within distinct subsets of HF patients, with the overarching goal of enhancing the adoption and effectiveness of GDMT. The authors also underscore the significance of establishing a novel management strategy that integrates cardiologists, nurse practitioners, pharmacists, and patients as a unified team that can contribute to the improved promotion and implementation of GDMT.

Rolling bearing fault diagnosis based on fine-grained multi-scale Kolmogorov entropy and WOA-MSVM.

In allusion to solve the issue of fault diagnosis for bearing and other rotatory machinery, a technique based on fined-grained multi-scale Kolmogorov entropy and whale optimized multi-class support vector machine (abbreviated as FGMKE-WOA-MSVM) is proposed. Firstly, vibration signals are decomposed by fine-grained multi-scale decomposition, and the Kolmogorov entropy of the sub-signals at different analysis scales is calculated as the multi-dimension feature vector, which quantitatively characterize the complexity of the signal at multi-scales. Aiming at the problem of sensitive parameters selection for multi-class support vector machine model (abbreviated as MSVM), the whale optimization algorithm (abbreviated as WOA) is introduced to optimize the penalty factor and kernel function parameter, and constructing optimal WOA-MSVM model. Finally, an instance analysis is carried out with Jiangnan University bearing datasets to verify the effectiveness and superiority of this technique. The results show that compared with different feature vectors and models such as K nearest neighbors (abbreviated as KNN) and Decision Tree (abbreviated as RF), the proposed technique is superior with fast computation speed and high diagnostic efficiency.

Overcoming barriers for left atrial appendage thrombus: a systematic review of left atrial appendage closure.

BACKGROUND: Approximately 90% of intracardial thrombi originate from the left atrial appendage in non-valvular atrial fibrillation patients. Even with anticoagulant therapy, left atrial appendage thrombus (LAAT) still occurs in 8% of patients. While left atrial appendage closure (LAAC) could be a promising alternative, the current consensus considers LAAT a contraindication to LAAC. However, the feasibility and safety of LAAC in patients with LAAT have yet to be determined. METHODS: This systematic review synthesizes published data to explore the feasibility and safety of LAAC for patients with LAAT. RESULTS: This study included a total of 136 patients with LAATs who underwent successful LAAC. The Amulet Amplatzer device was the most frequently utilized device (48.5%). Among these patients, 77 (56.6%) had absolute contraindications to anticoagulation therapy. Cerebral protection devices were utilized by 47 patients (34.6%). Transesophageal echocardiography (TEE) is the primary imaging technique used during the procedure. Warfarin and novel oral anticoagulants were the main anticoagulant medications used prior to the procedure, while dual antiplatelet therapy was primarily used post-procedure. During a mean follow-up period of 13.2 ± 11.5 months, there was 1 case of fatality, 1 case of stroke, 3 major bleeding events, 3 instances of device-related thrombus, and 8 cases of peri-device leakage. CONCLUSIONS: This review highlights the preliminary effectiveness and safety of the LAAC procedure in patients with persistent LAAT. Future large-scale RCTs with varied LAAT characteristics and LAAC device types are essential for evidence-based decision-making in clinical practice.

Pulsed field ablation: A promising approach for ventricular tachycardia ablation.

Radiofrequency ablation (RFA) has been a central therapeutic strategy for ventricular tachycardia (VT). However, concerns about its long-term effectiveness and complications have arisen. Pulsed field ablation (PFA), characterized by its nonthermal, highly tissue-selective ablation technique, has emerged as a promising alternative. This comprehensive review delves into the potential advantages and opportunities presented by PFA in the realm of VT, drawing insights from both animal experimentation and clinical case studies. PFA shows promise in generating superior lesions within scarred myocardial tissue, and its inherent repetition dependency holds the potential to enhance therapeutic outcomes. Clinical cases underscore the promise of PFA for VT ablation. Despite its promising applications, challenges such as catheter maneuverability and proarrhythmic effects require further investigation. Large-scale, long-term studies are essential to establish the suitability of PFA for VT treatment.

Enhanced wound healing and hemostasis with exosome-loaded gelatin sponges from human umbilical cord mesenchymal stem cells.

BACKGROUND: Rapid wound healing remains a pressing clinical challenge, necessitating studies to hasten this process. A promising approach involves the utilization of human umbilical cord mesenchymal stem cells (hUC-MSCs) derived exosomes. The hypothesis of this study was that these exosomes, when loaded onto a gelatin sponge, a common hemostatic material, would enhance hemostasis and accelerate wound healing. AIM: To investigate the hemostatic and wound healing efficacy of gelatin sponges loaded with hUC-MSCs-derived exosomes. METHODS: Ultracentrifugation was used to extract exosomes from hUC-MSCs. Nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and western blot techniques were used to validate the exosomes. In vitro experiments were performed using L929 cells to evaluate the cytotoxicity of the exosomes and their impact on cell growth and survival. New Zealand rabbits were used for skin irritation experiments to assess whether they caused adverse skin reactions. Hemolysis test was conducted using a 2% rabbit red blood cell suspension to detect whether they caused hemolysis. Moreover, in vivo experiments were carried out by implanting a gelatin sponge loaded with exosomes subcutaneously in Sprague-Dawley (SD) rats to perform biocompatibility tests. In addition, coagulation index test was conducted to evaluate their impact on blood coagulation. Meanwhile, SD rat liver defect hemostasis model and full-thickness skin defect model were used to study whether the gelatin sponge loaded with exosomes effectively stopped bleeding and promoted wound healing. RESULTS: The NTA, TEM, and western blot experimental results confirmed that exosomes were successfully isolated from hUC-MSCs. The gelatin sponge loaded with exosomes did not exhibit significant cell toxicity, skin irritation, or hemolysis, and they demonstrated good compatibility in SD rats. Additionally, the effectiveness of the gelatin sponge loaded with exosomes in hemostasis and wound healing was validated. The results of the coagulation index experiment indicated that the gelatin sponge loaded with exosomes had significantly better coagulation effect compared to the regular gelatin sponge, and they showed excellent hemostatic performance in a liver defect hemostasis model. Finally, the full-thickness skin defect healing experiment results showed significant improvement in the healing process of wounds treated with the gelatin sponge loaded with exosomes compared to other groups. CONCLUSION: Collectively, the gelatin sponge loaded with hUC-MSCs-derived exosomes is safe and efficacious for promoting hemostasis and accelerating wound healing, warranting further clinical application.

Discovery of 2,5-diketopiperazine alkaloids with quorum sensing inhibitory activity from the marine fungus Penicillium sp. ZJUT-34.

One new 2,5-DKP derivative O-dihydroxycyclopenol (1) and seven known congeners 2-8 were isolated from the marine fungus Penicillium sp. ZJUT-34 cultured on rice medium. The planar structure of 1 was established by extensive spectroscopic analysis, including 1D, 2D NMR and HR-ESI-MS, while the relative configuration of 1 was determined by quantum chemical calculation. In the QS inhibitory assay, 1 significantly inhibited the production of violacein in Chromobacterium violaceum ATCC12472 (20.65%) at a concentration of 6.25 µg/mL without affecting the growth of the strain, as compared with norharmane (22.14%), a quorum sensing inhibitor (QSI) identified in our previous study. It represented the first report on the QS inhibitory activity of the seven-membered 2,5-DKPs. In addition, compounds 1-8 were subjected to antibacterial assay against six pathogenic bacteria Compound 8 exhibited comparable antibacterial activity against Enterococcus faecalis FA2-2 (MIC = 96 µg/mL) with the positive control gentamicin (MIC = 80 µg/mL).

Adenovirus-vectored PDCoV vaccines induce potent humoral and cellular immune responses in mice.

Porcine deltacoronavirus (PDCoV) is a novel swine enteropathogenic coronavirus that causes severe watery diarrhea, vomiting, dehydration and high mortality in piglets, resulting in significant economic losses by the global pig industry. Recently, PDCoV has also shown the potential for cross-species transmission. However, there are currently few vaccine studies and no commercially available vaccines for PDCoV. Hence, here, two novel human adenovirus 5 (Ad5)-vectored vaccines expressing codon-optimized forms of the PDCoV spike (S) glycoprotein (Ad-PD-tPA-Sopt) and S1 glycoprotein (Ad-PD-oriSIP-S1opt) were constructed, and their effects were evaluated via intramuscular (IM) injection in BALB/c mice with different doses and times. Both vaccines elicited robust humoral and cellular immune responses; moreover, Ad-PD-tPA-Sopt-vaccinated mice after two IM injections with 108 infectious units (IFU)/mouse had significantly higher anti-PDCoV-specific neutralizing antibody titers. In contrast, the mice immunized with Ad-PD-tPA-Sopt via oral gavage (OG) did not generate robust systemic and mucosal immunity. Thus, IM Ad-PD-tPA-Sopt administration is a promising strategy against PDCoV and provides useful information for future animal vaccine development.

α-Glucosidase Inhibitors from Two Mangrove-Derived Actinomycetes.

α-Glucosidase (AGS) inhibitors have been regarded as an ideal target for the management of type 2 diabetes mellitus (T2DM) since they can maintain an acceptable blood glucose level by delaying the digestion of carbohydrates and diminishing the absorption of monosaccharides. In the process of our endeavor in mining AGS inhibitors from natural sources, the culture broth of two mangrove-derived actinomycetes Streptomyces sp. WHUA03267 and Streptomyces sp. WHUA03072 exhibited an apparent inhibitory activity against AGS. A subsequent chemical investigation into the two extracts furnished 28 secondary metabolites that were identified by spectroscopic methods as two previously undescribed linear polyketides 1-2, four benzenoid ansamycins 3-6, fourteen cyclodipeptides 7-18, one prenylated indole derivative 19, two fusicoccane-type diterpenoids 20-21, two hydroxamate siderophore 22-23, and five others 24-28. Among all of the isolates, 11 and 24 were obtained from actinomycetes for the first time, while 20-21 had never been reported to occur in a marine-derived microorganism previously. In the in vitro AGS inhibitory assay, compounds 3, 8, 9, 11, 14, 16, and 17 exhibited potent to moderate activity with IC50 values ranging from 35.76 ± 0.40 to 164.5 ± 15.5 µM, as compared with acarbose (IC50 = 422.3 ± 8.4 µM). The AGS inhibitory activity of 3, 9, 14, 16, and 17 was reported for the first time. In particular, autolytimycin (3) represented the first ansamycin derivative reported to possess the AGS inhibitory activity. Kinetics analysis and molecular docking were performed to determine the inhibition types and binding modes of these inhibitors, respectively. In the MTT assay, 3, 8, 9, 11, 14, 16, and 17 exhibited no apparent cytotoxicity to the human normal hepatocyte (LO2) cells, suggesting satisfactory safety of these AGS inhibitors.

m6A Methyltransferase, WTAP, Promotes Cancer Progression in Laryngeal Squamous Cell Carcinoma by Regulating PLAU Stability.

OBJECTIVE: Laryngeal squamous cell carcinoma (LSCC) is a malignancy originating from laryngeal squamous cell lesions. Wilm's tumor 1-associated protein (WTAP)-mediated N6-methyladenosine (m6A) modification has been verified to stimulate the progression of numerous cancers, except for LSCC. This study was aimed at exploring the role of WTAP and its mechanism of action in LSCC. METHODS: The expression of WTAP and plasminogen activator urokinase (PLAU) mRNAs in LSCC tissues and cells was quantified using qRT-PCR. Western blotting was performed to estimate PLAU levels in LSCC cells. The relationship between WTAP and PLAU was ascertained using luciferase reporter and methylated-RNA immunoprecipitation (Me-RIP) assays. Functionally, the interaction of WTAP with PLAU in LSCC cells was investigated using CCK-8, EdU, and Transwell assays. RESULTS: The expression of WTAP and PLAU was increased in LSCC, and was positively correlated. WTAP regulated PLAU stability in an m6A-dependent manner. WTAP deficiency suppressed the migration, invasion, and proliferation of LSCC cells. Overexpression of PLAU rescued the phenotype induced by WTAP knockdown in vitro. CONCLUSIONS: These results indicate that WTAP mediates the m6A modification of PLAU to accelerate the growth, migration, and invasion of cells in LSCC. To our knowledge, this is the first report to clarify the functions of WTAP in LSCC and the underlying mechanisms in detail. Based on these findings, we suggest that WTAP may serve as a therapeutic target for LSCC.

Observer-based model predictive control for uncertain NCS subject to hybrid attacks via interval type-2 T-S fuzzy model.

In this study, an observer-based model predictive control (MPC) algorithm is addressed for an uncertain discrete-time nonlinear networked control system (NCS) subject to hybrid malicious attacks by using interval type-2 Takagi-Sugeno (IT2 T-S) fuzzy theory. Hybrid malicious attacks, including two typical attacks, i.e., denial-of-service (DoS) attacks and false data injection (FDI) attacks, are considered in the communication networks. Under DoS attacks, the control signals will be interfered, which cause the degradation of signal-to-interference-plus-noise ratio, then lead to packets loss. Under FDI attacks, the false signals are injected and output signals are modified so that the system performance is deteriorated. For the NCS subject to hybrid attacks, a secure observer that can resist FDI attacks is devised and a fuzzy MPC algorithm that can solve the controller gains is proposed. Besides, by updating the bound of augmented estimation error, the recursive feasibility can be guaranteed. Finally, illustrative examples are given to show the effectiveness of proposed scheme.

Inflammatory stimulation of astrocytes affects the expression of miRNA-22-3p within NSCs-EVs regulating remyelination by targeting KDM3A.

BACKGROUND: Endogenous neural stem cells (NSCs) are critical for the remyelination of axons following spinal cord injury (SCI). Cell-cell communication plays a key role in the regulation of the differentiation of NSCs. Astrocytes act as immune cells that encounter early inflammation, forming a glial barrier to prevent the spread of destructive inflammation following SCI. In addition, the cytokines released from astrocytes participate in the regulation of the differentiation of NSCs. The aim of this study was to investigate the effects of cytokines released from inflammation-stimulated astrocytes on the differentiation of NSCs following SCI and to explore the influence of these cytokines on NSC-NSC communication. RESULTS: Lipopolysaccharide stimulation of astrocytes increased bone morphogenetic protein 2 (BMP2) release, which not only promoted the differentiation of NSCs into astrocytes and inhibited axon remyelination in SCI lesions but also enriched miRNA-22-3p within extracellular vesicles derived from NSCs. These miRNA-22 molecules function as a feedback loop to promote NSC differentiation into oligodendrocytes and the remyelination of axons following SCI by targeting KDM3A. CONCLUSIONS: This study revealed that by releasing BMP2, astrocytes were able to regulate the differentiation of NSCs and NSC-NSC communication by enriching miRNA-22 within NSC-EVs, which in turn promoted the regeneration and remyelination of axons by targeting the KDM3A/TGF-beta axis and the recovery of neurological outcomes following SCI.

VitroGel-loaded human MenSCs promote endometrial regeneration and fertility restoration.

Introduction: Intrauterine adhesions (IUA), also known as Asherman's syndrome, is caused by trauma to the pregnant or non-pregnant uterus, which leads to damaged endometrial basal lining and partial or total occlusion of the uterine chambers, resulting in abnormal menstruation, infertility, or recurrent miscarriage. The essence of this syndrome is endometrial fibrosis. And there is no effective treatment for IUA to stimulate endometrial regeneration currently. Recently, menstrual blood-derived stem cells (MenSCs) have been proved to hold therapeutic promise in various diseases, such as myocardial infarction, stroke, diabetes, and liver cirrhosis. Methods: In this study, we examined the effects of MenSCs on the repair of uterine adhesions in a rat model, and more importantly, promoted such therapeutic effects via a xeno-free VitroGel MMP carrier. Results: This combined treatment reduced the expression of inflammatory factors, increased the expression of anti-inflammatory factors, restricted the area of endometrial fibrosis, diminished uterine adhesions, and partially restored fertility, showing stronger effectiveness than each component alone and almost resembling the sham group. Discussion: Our findings suggest a highly promising strategy for IUA treatment.

Semaphorin 3F induces colorectal cancer cell chemosensitivity by promoting P27 nuclear export.

Colorectal adenocarcinoma (CRC) is the third most common malignancy worldwide. Metastatic CRC has a poor prognosis because of chemotherapy resistance. Our previous study demonstrated that semaphorin 3F (SEMA3F) signaling may contribute to reversing chemotherapy resistance in CRC cells by reducing E-cadherin and integrin αvß3 expression levels. Another study showed that upregulation of p27 significantly increase the expression of E-cadherin and integrin. This study aimed to evaluate the effect of SEMA3F on P27 and whether it can reverse resistance in CRC cells. We compared the chemosensitivity of human colorectal cancer cell lines with different SEMA3F expression levels to 5-Fu through cell experiment and animal experiment. Then the interaction between SEMA3F and p27 and its possible mechanism were explored by Western Blot, immunofluorescence and immunocoprecipitation. We also compared the disease-free survival of 118 CRC patients with high or low expression of SEMA3F.The results showed that overexpresstion of SEMA3F enhanced the chemotherapy sensitivity and apoptosis of CRC cells in vitro and in vivo. Among 118 postoperative CRC specimens, the disease-free survival of patients with positive SEMA3F expression was significantly longer than that with negative SEMA3F expression after adjuvant treatment. Upregulation of SEMA3F in multicellular spheroid culture (MSC) could increase p27 phosphorylation at serine 10 (Ser10), subsequently promote the cytosolic translocation of P27. Overall, our results reveal a novel molecular mechanism: SEMA3F mediates the degradation of p27 and regulates its subcellular localization to enhance chemosensitivity to 5-Fu in CRC cells, rather than inhibits p27 expression.