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BACKGROUND: Child and adolescent mental health is a major public health concern worldwide. The development of children's social and emotional skills helps to improve mental health and wellbeing, and prevent anxiety and depression. The school-based social emotional learning (SEL) programmes have proved effective in a number of countries. But in Mainland China, there has been no empirical research of the effectiveness on children's mental health. The study conducted a SEL programme in China during the COVID-19 pandemic and aimed to determine whether: (1) a SEL programme can reduce anxiety and depression, (2) the intervention effect is influenced by sociodemographic characteristics, (3) the programme effects change children's emotion management and communication. METHODS: Participants were 230 children aged 8-12 years in the intervention school and 325 in the control school in two poor villages in central China. The study was a quasi-experimental trial, comprising 16 weekly 90-minute sessions. It used a mixed-methods design, with a quantitative survey administered at baseline, post-intervention, and 5-month follow-up, and qualitative interviews. Linear mixed effects regression modeling was used to analyse the intervention effectiveness, linear models were conducted to examine the moderation effect of sociodemographic variables, and the inductive thematic analysis approach was used for interview data. RESULTS: The intervention had no significant effect on anxiety or depression, except that intervention school children who lived with neither parent (left behind children) reported lower depression scores than control school at post-intervention and 5-month follow-up. Qualitative interviews showed after intervention children were more able to control tempers and better communicated their thoughts and feelings, improving their relationships with family and friends. CONCLUSIONS: The programme was cheap, easy to implement, and warmly welcomed by children, schools and caregivers, suggesting it was feasible and potentially sustainable. More research is needed on the adaptation of the SEL programme in the Chinese context.
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Stroke in China is distinguished by its high rates of morbidity, recurrence, disability, and mortality. The ultra-early administration of rtPA is essential for restoring perfusion in acute ischemic stroke, though it concurrently elevates the risk of hemorrhagic transformation. High-mobility group box 1 (HMGB1) emerges as a pivotal player in neuroinflammation after brain ischemia and ischemia-reperfusion. Released passively by necrotic cells and actively secreted, including direct secretion of HMGB1 into the extracellular space and packaging of HMGB1 into intracellular vesicles by immune cells, glial cells, platelets, and endothelial cells, HMGB1 represents a prototypical damage-associated molecular pattern (DAMP). It is intricately involved in the pathogenesis of atherosclerosis, thromboembolism, and detrimental inflammation during the early phases of ischemic stroke. Moreover, HMGB1 significantly contributes to neurovascular remodeling and functional recovery in later stages. Significantly, HMGB1 mediates hemorrhagic transformation by facilitating neuroinflammation, directly compromising the integrity of the blood-brain barrier, and enhancing MMP9 secretion through its interaction with rtPA. As a systemic inflammatory factor, HMGB1 is also implicated in post-stroke depression and an elevated risk of stroke-associated pneumonia. The role of HMGB1 extends to influencing the pathogenesis of ischemia by polarizing various subtypes of immune and glial cells. This includes mediating excitotoxicity due to excitatory amino acids, autophagy, MMP9 release, NET formation, and autocrine trophic pathways. Given its multifaceted role, HMGB1 is recognized as a crucial therapeutic target and prognostic marker for ischemic stroke and hemorrhagic transformation. In this review, we summarize the structure and redox properties, secretion and pathways, regulation of immune cell activity, the role of pathophysiological mechanisms in stroke, and hemorrhage transformation for HMGB1, which will pave the way for developing new neuroprotective drugs, reduction of post-stroke neuroinflammation, and expansion of thrombolysis time window.
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Previous studies have indicated the neuroprotective effect of olfactory mucosa mesenchymal stem cells (OM-MSCs) on brain injury. Intracerebral hemorrhage (ICH) models were established in rats by injecting autologous blood. SENP1 expression was enhanced in neurons but decreased in astrocytes compared to that in OM-MSCs. Overexpression of SENP1 promoted the proliferation and neuronal differentiation, while inhibiting the astrocytic differentiation of OM-MSCs. Conversely, its knockdown had the opposite effect. Moreover, OM-MSCs reduced neurological dysfunction in rats after ICH, and the neuroprotective effect of OM-MSCs could be further enhanced by SENP1 overexpression. In addition, SENP1 promoted mitophagy, which might be related to SENP1-mediated OPTN deSUMOylation. Furthermore, SENP1 promoted neuronal differentiation of OM-MSCs through mitophagy mediated by OPTN. Similar to SENP1, OPTN transfection further enhanced the remission effect of OM-MSC on ICH rats. SENP1 promoted neuronal differentiation of OM-MSCs through OPTN-mediated mitophagy to improve neurological deficits in ICH rats.
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Programmes based on social emotional learning (SEL) have been effective in reducing psychosocial difficulties in a number of countries. In Mainland China, there has been no empirical research on the prevention of children's psychosocial difficulties using the SEL approach. This study aimed to assess whether an adapted version of the SEL programme can reduce psychosocial difficulties of primary school children in rural China. The intervention consisted of 16 weekly 90-min class sessions, conducted among 206 children aged 8-12 years (with 290 controls) in a poor rural area of Central China. Self-report questionnaires were administered at baseline, post-intervention and 5-month follow-up. The results suggested that the programme (1) can reduce children's total difficulties (measured using the Strength and Difficulties Questionnaire) at post-intervention (d = -0.18) and 5-month follow-up (d = -0.19), (2) was more effective among children experiencing verbal abuse (d = -0.21) or physical abuse (d = -0.24) from caregivers and (3) was popular among more than 90% of the participants. The programme is cheap, easy to implement and can be delivered in school hours. Therefore, it has clear potential for replicability and sustainability.
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Emociones , Instituciones Académicas , Niño , Humanos , Cognición , Encuestas y Cuestionarios , AutoinformeRESUMEN
Numerous studies have established that the hypoxic conditions within ovarian follicles induce apoptosis in granulosa cells (GCs), a pivotal hallmark of follicular atresia. Melatonin (N-acetyl-5-methoxytryptamine, MT), a versatile antioxidant naturally present in follicular fluid, acts as a safeguard for maintaining GCs' survival during stress exposure. In this study, we unveil an innovative protective mechanism of melatonin against hypoxia-triggered GC apoptosis by selectively inhibiting mitochondrial ROS (mtROS) generation. Specifically, under hypoxic conditions, a gradual accumulation of mitochondrial ROS occurred, consequently activating the JNK-FOXO1 pathway, and driving GCs toward apoptosis. The blocking of JNK or FOXO1 diminished hypoxia-induced GC apoptosis, but this effect was nullified in the presence of GSH, indicating that mtROS instigates apoptosis through the JNK-FOXO1 pathway. Consistent with this, hypoxic GCs treated with melatonin exhibited decreased levels of mtROS, reduced JNK-FOXO1 activation, and mitigated apoptosis. However, the protective capabilities of melatonin were attenuated upon inhibiting its receptor MTNR1B, accompanied by the decreased expression of antioxidant genes. Notably, SOD2, a key mitochondrial antioxidant gene modulated by the melatonin-MTNR1B axis, effectively inhibited the activation of mtROS-JNK-FOXO1 and subsequent apoptosis, whereas SOD2 knockdown abrogated the protective role of melatonin in hypoxic GCs. In conclusion, our study elucidates that melatonin, through MTNR1B activation, fosters SOD2 expression, effectively quelling mtROS-JNK-FOXO1-mediated apoptosis in follicular GCs under hypoxic stress.
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OBJECTIVE: To determine whether miRNA-128-3p regulates malignant biological behavior of glioma cells by targeting KLHDC8A. METHODS: Dual-luciferase reporter assays, qRT-PCR and Western blotting were used to verify the targeting of miRNA-128-3p to KLHDC8A. Edu assay, flow cytometry, Transwell assay and would healing assay were used to determine the effects of changes in miRNA-128-3p and KLHDC8A expression levels on malignant behavior of glioma cells. Rescue experiment was carried out to verify that miRNA-128-3p regulated glioma cell proliferation, apoptosis, invasion and migration by targeting KLHDC8A. RESULTS: The expression level of KLHDC8A was significantly increased in high-grade glioma tissue and was closely related to a poor survival outcome of the patients. Overexpression of KLHDC8A promoted glioma cell proliferation, migration and invasion, and miRNA-128-3p overexpression inhibited proliferative and metastatic capacities of glioma cells. Mechanistically, KLHDC8A expression was directly modulated by miRNA-128-3p, which, by targeting KLHDC8A, inhibited malignant behavior of glioma cells. CONCLUSION: Upregulation of miRNA-128-3p inhibits uncontrolled growth of glioma cells by negatively regulating KLHDC8A expression and its downstream effectors, suggesting that the miRNA-128-3p-KLHDC8A axis may serve as a potential prognostic indicator and a therapeutic target for developing new strategies for glioma treatment.
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Glioma , MicroARNs , Humanos , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/patología , MicroARNs/genética , MicroARNs/metabolismo , Regulación hacia ArribaRESUMEN
Cyclic GMP-AMP synthase (cGAS) plays an important role in the inflammatory response. It has been reported that aberrant activation of cGAS is associated with a variety of immune-mediated inflammatory disorders. The development of small molecule inhibitors of cGAS has been considered as a promising therapeutic strategy for the diseases. Flavonoids, a typical class of natural products, are known for their anti-inflammatory activities. Although cGAS is closely associated with inflammation, the potential effects of natural flavonoid compounds on cGAS have been rarely studied. Therefore, we screened an in-house natural flavonoid library by pyrophosphatase (PPiase) coupling assay and identified novel cGAS inhibitors baicalein and baicalin. Subsequently, crystal structures of the two natural flavonoids in complex with human cGAS were determined, which provide mechanistic insight into the anti-inflammatory activities of baicalein and baicalin at the molecular level. After that, a virtual screening based on the crystal structures of baicalein and baicalin in complex with human cGAS was performed. As a result, compound C20 was identified to inhibit both human and mouse cGAS with IC50 values of 2.28 and 1.44 µM, respectively, and its detailed interactions with human cGAS were further revealed by the X-ray crystal structure determination. These results demonstrate the potential of natural products used as hits in drug discovery and provide valuable hints for further development of cGAS inhibitors.
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Productos Biológicos , Flavonoides , Nucleotidiltransferasas , Animales , Humanos , Ratones , Productos Biológicos/química , Productos Biológicos/farmacología , Descubrimiento de Drogas , Flavonoides/química , Flavonoides/farmacología , Nucleotidiltransferasas/antagonistas & inhibidoresRESUMEN
Magnetic resonance imaging (MRI)-safe implantable wireless energy harvester offers substantial benefits to patients suffering from brain disorders, hearing impairment, and arrhythmias. However, rigid magnets in cutting-edge systems with limited numbers of rotation axis impose high risk of device dislodgement and magnet failure. Here, a flexible omnidirectional rotating magnetic array (FORMA) and a flexible MRI-safe implantable wireless energy-harvesting system have been developed. Miniaturized flexible magnetic balls 1 millimeter in diameter achieved by molding three-dimensional printed templates can rotate freely in elastomer cavities and supply a magnetic force of 2.14 Newtons at a distance of 1 millimeter between an implantable receiver and a wearable transceiver. The system can work stably under an acceleration of 9g and obtain a power output of 15.62 decibel milliwatts at a transmission frequency of 8 megahertz. The development of the FORMA may lead to life-long flexible and batteryless implantable systems and offers the potential to promote techniques for monitoring and treating acute and chronic diseases.
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Electrónica , Prótesis e Implantes , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Real-time glucose monitoring conventionally involves non-bioresorbable semi-implantable glucose sensors, causing infection and pain during removal. Despite bioresorbable electronics serves as excellent alternatives, the bioresorbable sensor dissolves in aqueous environments with interferential biomolecules. Here, the theories to achieve stable electrode potential and accurate electrochemical detection using bioresorbable materials have been proposed, resulting in a fully printed bioresorbable electrochemical device. The adverse effect caused by material degradation has been overcome by a molybdenum-tungsten reference electrode that offers stable potential through galvanic-coupling and self-compensation modules. In vitro and in vivo glucose monitoring has been conducted for 7 and 5 days, respectively, followed by full degradation within 2 months. The device offers a glucose detection range of 0 to 25 millimolars and a sensitivity of 0.2458 microamperes per millimolar with anti-interference capability and biocompatibility, indicating the possibility of mass manufacturing high-performance bioresorbable electrochemical devices using printing and low-temperature water-sintering techniques. The mechanisms may be implemented developing more comprehensive bioresorbable sensors for chronic diseases.
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Automonitorización de la Glucosa Sanguínea , Glucemia , Electrónica/métodos , Electrodos , Implantes Absorbibles , Técnicas ElectroquímicasRESUMEN
Rationale: Sepsis is a severe clinical syndrome featured through organ dysfunction due to infection, while the accompanying acute kidney injury (AKI) is linked to significant incidence of morbidity as well as mortality. Recently, emerging evidence has revealed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is implicated in various renal diseases, while its role and modulation in septic acute kidney injury (S-AKI) remains largely unknown. Methods: In vivo, S-AKI in wild-type and renal tubular epithelial cell (RTEC)-specific NOX4 knockout mice was induced by lipopolysaccharides (LPS) injection or cecal ligation and puncture (CLP). In vitro, TCMK-1 (mouse kidney tubular epithelium cell line) cells were treated with LPS. Serum and supernatant biochemical, mitochondrial dysfunctional, inflammatory and apoptotic parameters were measured and compared across groups. The activation of reactive oxygen species (ROS) and NF-κB signaling was also assessed. Results: NOX4 was predominantly upregulated in RTECs of S-AKI mouse model induced by LPS/CLP and cultured TCMK-1 cells exposed to LPS. RTEC-specific deletion of NOX4 or pharmacological inhibition of NOX4 by GKT137831 both alleviated LPS/CLP-injured renal function and pathology in mice. Furthermore, NOX4 inhibition alleviated mitochondrial dysfunction supported by ultrastructural damage, reduction of ATP production and mitochondrial dynamics imbalance, together with inflammation and apoptosis in kidney injured by LPS/CLP and TCMK-1 cells injured by LPS, while NOX4 overexpression aggravated the above-mentioned indices in TCMK-1 cells with LPS stimulation. Mechanism-wise, the raised NOX4 in RTECs may induce ROS and NF-κB signaling activation in S-AKI. Conclusions: Collectively, genetic or pharmacological inhibition of NOX4 protects from S-AKI by reducing generation of ROS and activation of NF-κB signal, which suppress mitochondrial dysfunction, inflammation together with apoptosis. NOX4 may act as a novel target for the S-AKI therapy.
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Lesión Renal Aguda , Sepsis , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Sepsis/metabolismo , Apoptosis , Mitocondrias/metabolismo , Ratones Endogámicos C57BL , Inflamación/metabolismoRESUMEN
Papain-like protease (PLpro) is a promising therapeutic target against SARS-CoV-2, but its restricted S1/S2 subsites pose an obstacle in developing active site-directed inhibitors. We have recently identified C270 as a novel covalent allosteric site for SARS-CoV-2 PLpro inhibitors. Here we present a theoretical investigation of the proteolysis reaction catalyzed by the wild-type SARS-CoV-2 PLpro as well as the C270R mutant. Enhanced sampling MD simulations were first performed to explore the influence of C270R mutation on the protease dynamics, and sampled thermodynamically favorable conformations were then submitted to MM/PBSA and QM/MM MD simulations for thorough characterization of the protease-substrate binding and covalent reactions. The disclosed proteolysis mechanism of PLpro, as characterized by the occurrence of proton transfer from the catalytic C111 to H272 prior to the substrate binding and with deacylation being the rate-determining step of the whole proteolysis process, is not completely identical to that of the 3C-like protease, another key cysteine protease of coronaviruses. The C270R mutation alters the structural dynamics of the BL2 loop that indirectly impairs the catalytic function of H272 and reduces the binding of the substrate with the protease, ultimately showing an inhibitory effect on PLpro. Together, these results provide a comprehensive understanding at the atomic level of the key aspects of SARS-CoV-2 PLpro proteolysis, including the catalytic activity allosterically regulated by C270 modification, which is crucial to the follow-up inhibitor design and development.
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The papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we report the structure-guide design of novel peptidomimetic inhibitors covalently targeting SARS-CoV-2 PLpro. The resulting inhibitors demonstrate submicromolar potency in the enzymatic assay (IC50 = 0.23 µM) and significant inhibition of SARS-CoV-2 PLpro in the HEK293T cells using a cell-based protease assay (EC50 = 3.61 µM). Moreover, an X-ray crystal structure of SARS-CoV-2 PLpro in complex with compound 2 confirms the covalent binding of the inhibitor to the catalytic residue cysteine 111 (C111) and emphasizes the importance of interactions with tyrosine 268 (Y268). Together, our findings reveal a new scaffold of SARS-CoV-2 PLpro inhibitors and provide an attractive starting point for further optimization.
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COVID-19 , Peptidomiméticos , Humanos , Peptidomiméticos/farmacología , Células HEK293 , SARS-CoV-2 , Péptido Hidrolasas , Inhibidores de Proteasas/farmacología , Antivirales/farmacología , Antivirales/químicaRESUMEN
In situ fabrication of wearable devices through coating approaches is a promising solution for the fast deployment of wearable devices and more adaptable devices for different sensing demands. However, heat, solvent, and mechanical sensitivity of biological tissues, along with personal compliance, pose strict requirements for coating materials and methods. To address this, a biocompatible and biodegradable light-curable conductive ink and an all-in-one flexible system that conducts in situ injection and photonic curing of the ink as well as monitoring of biophysiological information have been developed. The ink can be solidified through spontaneous phase changes and photonic cured to achieve a high mechanical strength of 7.48 MPa and an excellent electrical conductivity of 3.57 × 105 S/m. The flexible system contains elastic injection chambers embedded with specially designed optical waveguides to uniformly dissipate visible LED light throughout the chambers and rapidly cure the ink in 5 min. The resulting conductive electrodes offer intimate skin contact even with the existence of hair and work stably even under an acceleration of 8 g, leading to a robust wearable system capable of working under intense motion, heavy sweating, and varied surface morphology. Similar concepts may lead to various rapidly deployable wearable systems that offer excellent adaptability to different monitoring demands for the health tracking of large populations.
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Tinta , Dispositivos Electrónicos Vestibles , Electrodos , Conductividad EléctricaRESUMEN
BACKGROUND: Jasminoidin (JA) and ursodeoxycholic acid (UA) were shown to act synergistically against ischemic stroke (IS) in our previous studies. PURPOSE: To investigate the holistic synergistic mechanism of JA and UA on cerebral ischemia. METHODS: Middle cerebral artery obstruction reperfusion (MCAO/R) mice were used to evaluate the efficacy of JA, UA, and JA combined with UA (JU) using neurological function testing and infarct volume examination. High-throughput RNA-seq combined with computational prediction and function-integrated analysis was conducted to gain insight into the comprehensive mechanism of synergy. The core mechanism was validated using western blotting. RESULTS: JA and UA synergistically reduced cerebral infarct volume and alleviated neurological deficits and pathological changes in MCAO/R mice. A total of 1437, 396, 1080, and 987 differentially expressed genes were identified in the vehicle, JA, UA, and JU groups, respectively. A strong synergistic effect between JA and UA was predicted using chemical similarity analysis, target profile comparison, and semantic similarity analysis. As the 'long-tail' drugs, the top 20 gene ontology (GO) biological processes of JA, UA, and JU groups primarily reflected inflammatory response and regulation of cytokine production, with specific GO terms of JU revealing enhanced regulation on immune response and tumor necrosis factor superfamily cytokine production. Comparably, the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling of common targets of JA, UA, and JU focused on extracellular matrix organization and signaling by interleukins, immune system, phagosomes, and lysosomes, which interlock and interweave to produce the synergistic effects of JU. The characteristic signaling pathway identified for JU highlighted the crosstalk between autophagy activation and inflammatory pathways, especially the Dectin-1-induced NF-κB activation pathway, which was validated by in vivo experiments. CONCLUSIONS: JA and UA can synergistically protect cerebral ischemia-reperfusion injury by attenuating Dectin-1-induced NF-κB activation. The strategy integrating high throughput data with computational models enables ever-finer mapping of 'long-tail' drugs to dynamic variations in condition-specific omics to clarify synergistic mechanisms.
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Isquemia Encefálica , Daño por Reperfusión , Ratones , Animales , FN-kappa B/metabolismo , Ácido Ursodesoxicólico/farmacología , Transducción de Señal , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Daño por Reperfusión/metabolismo , CitocinasRESUMEN
Cellular behaviors and functions can be regulated by mechanical cues from microenvironments, which are transmitted to nucleus through the physical connections of cytoskeletons in the cells. How these physical connections determine transcriptional activity were not clearly known. The actomyosin, which generates intracellular traction force, has been recognized to control the nuclear morphology. Here, we have revealed that microtubule, the stiffest cytoskeleton, is also involved in the process of nuclear morphology alteration. The microtubule negatively regulates the actomyosin-induced nuclear invaginations but not the nuclear wrinkles. Moreover, these nuclear shape changes are proven to mediate the chromatin remodeling, which essentially mediates cell gene expression and phenotype determination. The actomyosin disruption leads to the loss of chromatin accessibility, which can be partly recovered by microtubule interference through nuclear shape control. This finding answers the question of how mechanical cues regulate chromatin accessibility and cell behaviors. It also provides new insights into cell mechanotransduction and nuclear mechanics.