miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells.

JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Revealing spatial distribution and accessibility of cell wall polymers in bamboo through chemical imaging and mild chemical treatments.

Understanding the distribution and accessibility of polymers within plant cell walls is crucial for addressing biomass recalcitrance in lignocellulosic materials. In this work, Imaging Fourier Transform Infrared (FTIR) and Raman spectroscopy, coupled with targeted chemical treatments, were employed to investigate cell wall polymer distribution in two bamboo species at both tissue and cell wall levels. Tissue-level Imaging FTIR revealed significant disparities in the distribution and chemical activity of cell wall polymers between the fibrous sheath and fibrous strand. At the cell wall level, Imaging Raman spectroscopy delineated a distinct difference between the secondary wall and intercellular layer, with the latter containing higher levels of lignin, hydroxycinnamic acid (HCA), and xylan, and lower cellulose. Mild acidified sodium chlorite treatment led to partial removal of lignin, HCA, and xylan from the intercellular layer, albeit to a lesser extent than alkaline treatment, indicating susceptibility of these polymers to chemical treatment. In contrast, lignin in the secondary wall exhibited limited reactivity to acidified sodium chlorite but was slightly removed by alkaline treatment, suggesting stable chemical properties with slight alkaline intolerance. These findings provide valuable insights into the inherent design mechanism of plant cells and their efficient utilization.

ARRB1 inhibits extracellular matrix degradation and apoptosis of nucleus pulposus cells by promoting autophagy and attenuates intervertebral disc degeneration.

OBJECTIVE: Intervertebral disc degeneration (IVDD) is the leading cause of lower back pain (LBP). ß-arrestin 1 (ARRB1) is a multifunctional protein that regulates numerous pathological processes. The aim of this study was to investigate the role of ARRB1 in IVDD. METHODS: The expression of ARRB1 in nucleus pulposus (NP) of rats with IVDD was assayed. Next, rat nucleus pulposus cells (NPCs) were infected with lentiviruses containing shArrb1 (LV-shArrb1) and overexpressing Arrb1 (LV-oeArrb1). The roles of Arrb1 in serum-deprived NPCs were investigated by measuring apoptosis, extracellular matrix degradation, and autophagic flux. For experiments in vivo, LV-oeArrb1 lentivirus was injected into the NP tissues of IVDD rats to evaluate the effects of Arrb1 overexpression on NP. RESULTS: In the NP tissues of IVDD rats, ARRB1 and cleaved caspase-3 expression increased, and the ratio of LC3II/LC3I protein expression was upregulated. Arrb1 knockdown aggravated extracellular matrix degradation, cellular apoptosis, and impairment of autophagic flux in rat NPCs under serum-deprived conditions, whereas Arrb1 overexpression significantly reversed these effects. ARRB1 interacted with Beclin 1, and Arrb1 knockdown suppressed the formation of the Beclin1-PIK3C3 core complex. The autophagy inhibitor 3-methyladenine (3-MA) offset the protective effects of Arrb1 overexpression in serum-deprived NPCs. Furthermore, Arrb1 overexpression inhibited apoptosis and extracellular matrix degradation, promoted autophagy in NP, and delayed the development of IVDD in rats. CONCLUSION: ARRB1 prevents extracellular matrix degradation and apoptosis of NPCs by upregulating autophagy and ameliorating IVDD progression, presenting an innovative strategy for the treatment of IVDD.

Inhibiting the Jahn-Teller Effect of Manganese Hexacyanoferrate via Ni and Cu Co-Doping for Advanced Sodium Ion Batteries.

Mn-based Prussian blue analogues (PBA) are of great interest as a prospective cathode material for sodium-ion batteries (SIBs) due to their high redox potential, easy synthesis and low cost. However, the Jahn-Teller effect and low electrical conductivity of Mn-based PBA causes poor structure stability and unsatisfactory performance during the cycling. Herein, we develop a novel Ni and Cu co-doped K2Mn[Fe(CN)6] cathode via a simple co-precipitation strategy. The doping elements improve the electrical conductivity of Mn-based PBA by reducing the bandgap, as well as suppress the Jahn-Teller effect by stabilizing the framework, as verified by the density functional theory calculations. Simultaneously, the substitution of sodium with potassium in the lattice is beneficial for filling vacancies in the PBA framework, leading to higher average operating voltages and superior structural stability. As a result, the as-prepared Mn-based cathode exhibits excellent reversible capacity (116.0 mAh g-1 at 0.01 A g-1) and superior cycling stability (81.8% capacity retention over 500 cycles at 0.1 A g-1). This work provides a profitable doping strategy to inhibit the Jahn-Teller structural deformation for designing stable cathode material of SIBs. This article is protected by copyright. All rights reserved.

A 32-Month Follow-Up Study of the Effect of APOE ε4 on the Whole Brain Connection in Young Healthy Individuals.

APOE ε4 is risk for cognitive decline even in normal aging, but its effect on the whole-brain functional connectivity (FC) among time in young adults remain elusive. This study aimed to validate the time-by-APOE ε4 interaction on brain FC of this specific population. Longitudinal changes in neuropsychological assessments and resting-state functional magnetic resonance imaging in 26 ε4 carriers and 26 matched non-ε4 carriers were measured for about 3 years. Whole-brain FC was calculated, and a full factorial design was used to compare the difference among groups. Two-sample t test was used for post-hoc analysis. Pearson's correlation analysis was conducted to investigate the relationships between FC and cognitive tests. Of 26 specially appointed ROIs, left superior temporal gyrus (TG) was most sensitive to the effect of time-by-gene interaction. Specifically, the alteration of FC was distributed between the left TG and right TG with GRF correction (voxel-P < 0.001, cluster-P < 0.05), and decreased in ε4 carriers while increased in non-ε4. The main effect of gene showed ε4 carriers has lower FC between left TG and right middle frontal gyrus as compared with non-ε4 both at baseline and follow-up study; ε4 carriers has lower FC between left TG and right supramarginal as compared with non-ε4 at baseline, but no difference in follow-up study. The time-by-APOE ε4 interaction on brain FC was demonstrated at a young age, and left TG was the earliest affected brain regions. The young adult ε4 carriers experience decreased FC among time in the absence overt clinical symptoms.

Molecular distinctions of bronchoalveolar and alveolar organoids under differentiation conditions.

The bronchoalveolar organoid (BAO) model is increasingly acknowledged as an ex-vivo platform that accurately emulates the structural and functional attributes of proximal airway tissue. The transition from bronchoalveolar progenitor cells to alveolar organoids is a common event during the generation of BAOs. However, there is a pressing need for comprehensive analysis to elucidate the molecular distinctions characterizing the pre-differentiated and post-differentiated states within BAO models. This study established a murine BAO model and subsequently triggered its differentiation. Thereafter, a suite of multidimensional analytical procedures was employed, including the morphological recognition and examination of organoids utilizing an established artificial intelligence (AI) image tracking system, quantification of cellular composition, proteomic profiling and immunoblots of selected proteins. Our investigation yielded a detailed evaluation of the morphologic, cellular, and molecular variances demarcating the pre- and post-differentiation phases of the BAO model. We also identified of a potential molecular signature reflective of the observed morphological transformations. The integration of cutting-edge AI-driven image analysis with traditional cellular and molecular investigative methods has illuminated key features of this nascent model.

Promotive effect of skin precursor-derived Schwann cells on brachial plexus neurotomy and motor neuron damage repair through milieu-regulating secretome.

Brachial plexus injury (BPI) with motor neurons (MNs) damage still remain poor recovery in preclinical research and clinical therapy, while cell-based therapy approaches emerged as novel strategies. Previous work of rat skin precursor-derived Schwann cells (SKP-SCs) provided substantial foundation for repairing peripheral nerve injury (PNI). Given that, our present work focused on exploring the repair efficacy and possible mechanisms of SKP-SCs implantation on rat BPI combined with neurorrhaphy post-neurotomy. Results indicated the significant locomotive and sensory function recovery, with improved morphological remodeling of regenerated nerves and angiogenesis, as well as amelioration of target muscles atrophy and motor endplate degeneration. Besides, MNs could restore from oxygen-glucose-deprivation (OGD) injury upon SKP-SCs-sourced secretome treatment, implying the underlying paracrine mechanisms. Moreover, rat cytokine array assay detected 67 cytokines from SKP-SC-secretome, and bioinformatic analyses of screened 32 cytokines presented multiple functional clusters covering diverse cell types, including inflammatory cells, Schwann cells, vascular endothelial cells (VECs), neurons, and SKP-SCs themselves, relating distinct biological processes to nerve regeneration. Especially, a panel of hypoxia-responsive cytokines (HRCK), can participate into multicellular biological process regulation for permissive regeneration milieu, which underscored the benefits of SKP-SCs and sourced secretome, facilitating the chorus of nerve regenerative microenvironment. Furthermore, platelet-derived growth factor-AA (PDGF-AA) and vascular endothelial growth factor-A (VEGF-A) were outstanding cytokines involved with nerve regenerative microenvironment regulating, with significantly elevated mRNA expression level in hypoxia-responsive SKP-SCs. Altogether, through recapitulating the implanted SKP-SCs and derived secretome as niche sensor and paracrine transmitters respectively, HRCK would be further excavated as molecular underpinning of the neural recuperative mechanizations for efficient cell therapy; meanwhile, the analysis paradigm in this study validated and anticipated the actions and mechanisms of SKP-SCs on traumatic BPI repair, and was beneficial to identify promising bioactive molecule cocktail and signaling targets for cell-free therapy strategy on neural repair and regeneration.

Non-invasive prediction of preeclampsia using the maternal plasma cell-free DNA profile and clinical risk factors.

Background: Preeclampsia (PE) is a pregnancy complication defined by new onset hypertension and proteinuria or other maternal organ damage after 20 weeks of gestation. Although non-invasive prenatal testing (NIPT) has been widely used to detect fetal chromosomal abnormalities during pregnancy, its performance in combination with maternal risk factors to screen for PE has not been extensively validated. Our aim was to develop and validate classifiers that predict early- or late-onset PE using the maternal plasma cell-free DNA (cfDNA) profile and clinical risk factors. Methods: We retrospectively collected and analyzed NIPT data of 2,727 pregnant women aged 24-45 years from four hospitals in China, which had previously been used to screen for fetal aneuploidy at 12 + 0 ~ 22 + 6 weeks of gestation. According to the diagnostic criteria for PE and the time of diagnosis (34 weeks of gestation), a total of 143 early-, 580 late-onset PE samples and 2,004 healthy controls were included. The wilcoxon rank sum test was used to identify the cfDNA profile for PE prediction. The Fisher's exact test and Mann-Whitney U-test were used to compare categorical and continuous variables of clinical risk factors between PE samples and healthy controls, respectively. Machine learning methods were performed to develop and validate PE classifiers based on the cfDNA profile and clinical risk factors. Results: By using NIPT data to analyze cfDNA coverages in promoter regions, we found the cfDNA profile, which was differential cfDNA coverages in gene promoter regions between PE and healthy controls, could be used to predict early- and late-onset PE. Maternal age, body mass index, parity, past medical histories and method of conception were significantly differential between PE and healthy pregnant women. With a false positive rate of 10%, the classifiers based on the combination of the cfDNA profile and clinical risk factors predicted early- and late-onset PE in four datasets with an average accuracy of 89 and 80% and an average sensitivity of 63 and 48%, respectively. Conclusion: Incorporating cfDNA profiles in classifiers might reduce performance variations in PE models based only on clinical risk factors, potentially expanding the application of NIPT in PE screening in the future.

Acupuncture for dyspnea and breathing physiology in chronic respiratory diseases: A systematic review and meta-analysis of randomized controlled trials.

Background: Dyspnea, a common symptom of chronic respiratory diseases (CRDs), is closely linked to higher levels of functional impairment and death, leading to significant societal and financial challenges. Despite numerous clinical trials and systematic reviews suggested the potential benefits of acupuncture for chronic obstructive pulmonary disease (COPD) and lung cancer, there is currently insufficient evidence to conclusively prove its effectiveness in alleviating dyspnea in patients with CRDs. Methods: To compile and evaluate the existing data on the effectiveness and safety of acupuncture for managing dyspnea in CRDs. Randomized controlled trials investigating acupuncture for the treatment of dyspnea in patients with CRDs, such as COPD, lung cancer, asthma, bronchiectasis, interstitial lung disease, chronic pulmonary heart disease and bronchitis, were searched and retrieved from five electronic databases in English or Chinese. Results: A total of 23 studies meeting the inclusion criteria were found in databases, covering various CRDs such as COPD, lung cancer, and asthma. A meta-analysis that compared acupuncture to a control group (which included no acupuncture and sham acupuncture) found significant advantages for acupuncture in reducing dyspnea severity (P = 0.0003), increasing 6MWD (P < 0.00001), improving quality of life measured by St. George's Respiratory Questionnaire (P = 0.03) and karnofsky performance status score (P < 0.00001). No significance was found in breathing physiology represented by FEV1 (P = 0.34) and FVC (P = 0.15). There was a comparable incidence of negative outcomes in both groups (P = 0.07). Results were consistent when compared to sham acupuncture. In addition, subgroup analyses were also consistent when different diseases or types of acupuncture were analyzed. Conclusions: Acupuncture may be an effective and safe non-pharmacological complementary intervention to relief dyspnea for patients with CRDs. Nevertheless, research with high quality and large sample sizes is needed for further investigation.

Investigating the L-Glu-NMDA receptor-H2S-NMDA receptor pathway that regulates gastric function in rats' nucleus ambiguus.

Background: In previous investigations, we explored the regulation of gastric function by hydrogen sulfide (H2S) and L-glutamate (L-Glu) injections in the nucleus ambiguus (NA). We also determined that both H2S and L-Glu have roles to play in the physiological activities of the body, and that NA is an important nucleus for receiving visceral sensations. The purpose of this study was to explore the potential pathway link between L-Glu and H2S, resulting in the regulation of gastric function. Methods: Physiological saline (PS), L-glutamate (L-Glu, 2 nmol), NaHS (2 nmol), D-2-amino-5-phopho-novalerate (D-AP5, 2 nmol) + L-Glu (2 nmol), aminooxyacetic acid (AOAA, 2 nmol) + L-Glu (2 nmol), D-AP5 (2 nmol) + NaHS (2 nmol) were injected into the NA. A balloon was inserted into the stomach to observe gastric pressure and for recording the changes of gastric smooth muscle contraction curve. The gastric fluid was collected by esophageal perfusion and for recording the change of gastric pH value. Results: Injecting L-Glu in NA was found to significantly inhibit gastric motility and promote gastric acid secretion in rats (p < 0.01). On the other hand, injecting the PS, pre-injection N-methyl-D-aspartate (NMDA) receptor blocker D-AP5, cystathionine beta-synthase (CBS) inhibitor AOAA and re-injection L-Glu did not result in significant changes (p > 0.05). The same injection NaHS significantly inhibit gastric motility and promote gastric acid secretion in rats (p < 0.01), but is eliminated by injection D-AP5 (p > 0.05). Conclusion: The results indicate that both exogenous L-Glu and H2S injected in NA regulate gastric motility and gastric acid secretion through NMDA receptors. This suggests that NA has an L-Glu-NMDA receptor-CBS-H2S pathway that regulates gastric function.

Conventionality matters in Chinese metaphor but not simile comprehension: evidence from event-related potentials.

Metaphor and simile, two prevalent forms of figurative language widely employed in daily communication, serve as significant research subjects in linguistics. The Career of Metaphor Theory in cognitive linguistics posits that as conventionality increases, the cognitive mechanisms of metaphor comprehension shift from "comparison" to "categorization." In line with this notion, prior electrophysiological investigations have revealed that novel metaphors elicit a stronger N400 brain response compared to conventional metaphors. However, the observed N400 difference between conventional and novel metaphors may merely stem from the familiarity contrast between them, as conventional metaphors are typically more familiar than novel ones. To address this dichotomy, the present study not only compared the N400 responses between conventional and novel metaphors but also between conventional and novel similes. While conventional and novel similes differ in familiarity, similar to conventional and novel metaphors, both are processed via "comparison" mechanisms. The results revealed that novel metaphors elicited larger N400 amplitudes compared to conventional metaphors, aligning with previous findings. In contrast, no significant N400 differences were observed between conventional and novel similes, suggesting that familiarity disparity is unlikely to account for N400 distinctions. Our findings imply that conventional and novel metaphors undergo distinct cognitive processing mechanisms ("comparison" versus "categorization"), thereby providing further empirical validation for the Career of Metaphor Theory.

The impact of Yoga on patients with knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The objective of this review is to conduct a comprehensive and systematic assessment of the efficacy of Yoga as an intervention for knee osteoarthritis (KOA). METHODS: We searched PubMed, Cochrane Library, Embase, Web of Science, and PEDro as of January 3, 2024. Retrieved a total of 200 articles. Standardised mean differences (SMDs) and 95% confidence intervals (CI) were calculated. RESULTS: The study included a total of 8 trials and involved 756 KOA patients. The results indicated that compared to the control group, Yoga exercise showed significant improvements in alleviating pain (SMD = -0.92; 95% CI = -1.64 ~ - 0.20; P = 0.01, I2 = 94%), stiffness (SMD = -0.51; 95% CI = -0.91 ~ -0.12; P = 0.01; I2 = 66%) and physical function (SMD = -0.53; 95% CI = -0.89 ~ -0.17; P = 0.004; I2 = 59%) among KOA patients. However, there was no significant improvement observed in terms of activities of activity of daily living (ADL) (SMD = 1.03; 95% CI = -0.01 ~ 2.07; P = 0.05; I2 = 84%), and quality of life (QOL) (SMD = 0.21; 95% CI = -0.33 ~ 0.74; P = 0.44; I2 = 83%) with the practice of Yoga. CONCLUSIONS: In general, Yoga has been found to be effective in reducing pain and stiffness in KOA patients, it can also improve the physical function of patients. However, there is limited evidence to suggest significant improvements in terms of ADL and QOL.

Multiomics and biotechnologies for understanding and influencing cadmium accumulation and stress response in plants.

Cadmium (Cd) is one of the most toxic heavy metals faced by plants and, additionally, via the food chain, threatens human health. It is principally dispersed through agro-ecosystems via anthropogenic activities and geogenic sources. Given its high mobility and persistence, Cd, although not required, can be readily assimilated by plants thereby posing a threat to plant growth and productivity as well as animal and human health. Thus, breeding crop plants in which the edible parts contain low to zero Cd as safe food stuffs and harvesting shoots of high Cd-containing plants as a route for decontaminating soils are vital strategies to cope with this problem. Recently, multiomics approaches have been employed to considerably enhance our understanding of the mechanisms underlying (i) Cd toxicity, (ii) Cd accumulation, (iii) Cd detoxification and (iv) Cd acquisition tolerance in plants. This information can be deployed in the development of the biotechnological tools for developing plants with modulated Cd tolerance and detoxification to safeguard cellular and genetic integrity as well as to minimize food chain contamination. The aim of this review is to provide a current update about the mechanisms involved in Cd uptake by plants and the recent developments in the area of multiomics approach in terms of Cd stress responses, as well as in the development of Cd tolerant and low Cd accumulating crops.

Flexible and Free-Standing Metal-Organic Framework Nanowire Paper.

Beyond traditional paper, multifunctional nanopaper has received much attention in recent years. Currently, many nanomaterials have been successfully used as building units of nanopaper. However, it remains a great challenge to prepare flexible and freestanding metal-organic framework (MOF) nanopaper owing to the low aspect ratio and brittleness of MOF nanocrystals. Herein, this work develops a flexible and free-standing MOF nanopaper with MOF nanowires as building units. The manganese-based MOF (Mn-MOF) nanowires with lengths up to 100 µm are synthesized by a facile solvothermal method. Through a paper-making technique, the Mn-MOF nanowires interweave with each other to form a three-dimensional architecture, thus creating a flexible and free-standing Mn-MOF nanowire paper. Furthermore, the surface properties can be engineered to obtain high hydrophobicity by modifying polydimethylsiloxane (PDMS) on the surfaces of the Mn-MOF nanowire paper. The water contact angle reaches 130°. As a proof of concept, this work presents two potential applications of the Mn-MOF/PDMS nanowire paper: (i) The as-prepared Mn-MOF/PDMS nanowire paper is compatible with a commercial printer. The as-printed colorful patterns are of high quality, and (ii) benefiting from the highly hydrophobic surfaces, the Mn-MOF/PDMS nanowire paper is able to efficiently separate oil from water.

Andrographolide Attenuates NLRP3 Inflammasome Activation and Airway Inflammation in Exacerbation of Chronic Obstructive Pulmonary Disease.

Purpose: The aim of this study is to uncover the anti-inflammatory propertity of andrographolide (AGP) in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and the underlying mechanisms related to the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway. Methods: An in vivo experiment was conducted on murine model of AECOPD through endotracheal atomization of elastase and lipopolysaccharide (LPS). Intraperitoneal AGP was administered four times. NLRP3 inflammasome pathway molecules were examined using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. By using enzyme-linked immunosorbent assay (ELISA), we tested interleukin (IL)-1ß levels in bronchoalveolar lavage fluid. An in vitro study was conducted to determine how AGP impacts the NLRP3 inflammasome in THP-1 derived macrophages. The levels of molecules involved in the pathway were measured. Furthermore, molecular docking analyses were carried out to investigate the interactions between AGP and pathway targets. Results: In the in vivo study, NLRP3 inflammasome activation was observed in mice experiencing AECOPD. The administration of high-dose AGP demonstrated a mitigating effect on inflammatory cells infiltration in the lungs. Moreover, AGP administration effectively suppressed the expression of NLRP3, apoptosis associated speck-like protein that contains a CARD (PYCARD), cysteinyl aspartate-specific protease-1 (Caspase-1), IL-1ß, and IL-18 at both the genetic and protein levels. In the in vitro experiment, IL-1ß levels were significantly elevated in THP-1 derived macrophages with activated inflammasome compared to the control group. Furthermore, the downregulation of NLRP3, CASP1, and IL1B genes was observed upon the inhibition of NLRP3 expression through small interfering RNA (siRNA). AGP demonstrated inhibitory effects on the gene expression and protein levels of NLRP3, Caspase-1, and IL-1ß. Additionally, molecular docking analysis confirmed that AGP exhibited a favorable binding affinity with all five targets of the pathway. Conclusion: AGP effectively inhibited NLRP3 inflammasome activation and mitigated the inflammatory reaction of AECOPD both in animal models and in vitro experiments, highlighting the potential of AGP as a treatment for AECOPD with anti-inflammatory properties.

Abnormal expression of serum miR-4746-5p in liver cancer patients after interventional chemotherapy and its possible mechanism.

Interventional chemotherapy is a common operation in the clinical treatment of liver cancer. The aim of this study was to investigate the expression and molecular mechanism of serum miR-4746-5p in liver cancer patients before and after interventional chemotherapy. The levels of miR-4746-5p and CDKN1C in serum samples from liver cancer patients were detected using real-time fluorescence quantitative polymerase chain reaction. Receiver operating characteristic curves revealed the diagnostic value of miR-4746-5p in tumors. Differences in clinical indicators between liver cancer patients and healthy controls were assessed using Pearson correlation analysis. Luciferase reporter gene assays confirmed the targeted interaction between miR-4746-5p and CDKN1C. In vitro cellular assays were validated by Cell Counting Kit-8, Transwell assay, and chemoresistance assay. Serum miR-4746-5p levels were increased in liver cancer patients but were downregulated after chemotherapy intervention. CDKN1C expression showed the opposite trend. Low levels of miR-4746-5p mediated cell growth and metastasis by targeting and negatively regulating CDKN1C expression, while silencing CDKN1C restored cell activity. Inhibition of miR-4746-5p reduced chemoresistance, while downregulation of CDKN1C affected cell sensitivity. miR-4746-5p may be a potential therapeutic factor for liver cancer diagnosis and interventional chemotherapy.

A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

[Determination of nine components of fried Ziziphi Spinosae Semen extract in beagle dog plasma by UPLC-MS/MS and its application in pharmacokinetic research].

This study established a convenient, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, swertisin, N-nornuciferine, 6-feruloylspinosin, and jujuboside B in beagle dog plasma after oral administration of fried Ziziphi Spinosae Semen(FZSS) extract. The Waters HSS-T3 C_(18) column(2.1 mm×100 mm, 1.8 µm) was used. The methanol-aqueous solution(containing 0.01% formic acid) was adopted as the mobile phase for gradient elution. The nine components and two internal standards were completely separated within 8 min. The mass spectrometry detection was performed in multiple reaction monitoring(MRM) mode by positive and negative ion switching of electrospray ionization. The analytical method was validated in terms of specificity, selectivity, linear range, accuracy, precision, recovery, matrix effect, and stability. It could meet the requirement of pharmacokinetic research after oral administration of FZSS extract to beagle dogs. The results showed that the time to reach the peak concentration(T_(max)) of magnoflorine,(R)-coclaurine, vicenin Ⅱ, isospinosin, spinosin, 6-feruloylspinosin, and jujuboside B was 2.40-3.20 h, and the elimination halflife(t_(1/2)) was 2.08-6.79 h after a single-dose oral administration of FZSS to beagle dogs. The exposure of magnoflorine and spinosin was high, with a peak concentration(C_(max)) of 76.7 and 31.5 ng·mL~(-1) and an area under the curve(AUC_(0-∞)) of 581 and 315 ng·h·mL~(-1), respectively. The exposure of the remaining five compounds was lower, with a C_(max) of 0.81-13.0 ng·mL~(-1) and an AUC_(0-∞) of 6.00-106 ng·h·mL~(-1). This study provides a reference for the follow-up research of FZSS.

Multifunctional Hierarchical Nanoplatform with Anisotropic Bimodal Mesopores for Effective Neural Circuit Reconstruction after Spinal Cord Injury.

A persistent inflammatory response, intrinsic limitations in axonal regenerative capacity, and widespread presence of extrinsic axonal inhibitors impede the restoration of motor function after a spinal cord injury (SCI). A versatile treatment platform is urgently needed to address diverse clinical manifestations of SCI. Herein, we present a multifunctional nanoplatform with anisotropic bimodal mesopores for effective neural circuit reconstruction after SCI. The hierarchical nanoplatform features of a Janus structure consist of dual compartments of hydrophilic mesoporous silica (mSiO2) and hydrophobic periodic mesoporous organosilica (PMO), each possessing distinct pore sizes of 12 and 3 nm, respectively. Unlike traditional hierarchical mesoporous nanomaterials with dual-mesopores interlaced with each other, the two sets of mesopores in this Janus nanoplatform are spatially independent and possess completely distinct chemical properties. The Janus mesopores facilitate controllable codelivery of dual drugs with distinct properties: the hydrophilic macromolecular enoxaparin (ENO) and the hydrophobic small molecular paclitaxel (PTX). Anchoring with CeO2, the resulting mSiO2&PMO-CeO2-PTX&ENO nanoformulation not only effectively alleviates ROS-induced neuronal apoptosis but also enhances microtubule stability to promote intrinsic axonal regeneration and facilitates axonal extension by diminishing the inhibitory effect of extracellular chondroitin sulfate proteoglycans. We believe that this functional dual-mesoporous nanoplatform holds significant potential for combination therapy in treating severe multifaceted diseases.