Polystyrene nano-plastics impede skeletal muscle development and induce lipid accumulation via the PPARγ/LXRß pathway in vivo and in vitro in mice.

Nano-plastics (NPs) have emerged as a significant environmental pollutant, widely existing in water environment, and pose a serious threat to health and safety with the intake of animals. Skeletal muscle, a vital organ for complex life activities and functional demands, has received limited attention regarding the effects of NPs. In this study, the effects of polystyrene NPs (PS-NPs) on skeletal muscle development were studied by oral administration of different sizes (1 mg/kg) of PS-NPs in mice. The findings revealed that PS-NPs resulted in skeletal muscle damage and significantly hindered muscle differentiation, exhibiting an inverse correlation with PS-NPs particle size. Morphological analysis demonstrated PS-NPs caused partial disruption of muscle fibers, increased spacing between fibers, and lipid accumulation. RT-qPCR and western blots analyses indicated that PS-NPs exposure downregulated the expression of myogenic differentiation-related factors (Myod, Myog and Myh2), activated PPARγ/LXRß pathway, and upregulated the expressions of lipid differentiation-related factors (SREBP1C, SCD-1, FAS, ACC1, CD36/FAT, ADIPOQ, C/EBPα and UCP-1). In vitro experiments, C2C12 cells were used to confirm cellular penetration of PS-NPs (0, 100, 200, 400 µg/mL) through cell membranes along with activation of PPARγ expression. Furthermore, to verify LXRß as a key signaling molecule, silencing RNA transfection experiments were conducted, resulting in no increase in the expressions of PPARγ, LXRß, SREBP1C, FAS, CD36/FAT, ADIPOQ, C/EBPα and UCP-1 even after exposure to PS-NPs. However, the expressions of SCD-1and ACC1 remained unaffected. The present study evidenced that exposure to PS-NPs induced lipid accumulation via the PPARγ/LXRß pathway thereby influencing skeletal muscle development.

[Anti-myocardial ischemic injury effects and mechanisms of cryptotanshinone in regulating macrophage polarisation through Dectin-1 signalling pathway].

The aim of this study was to investigate the potential mechanism by which cryptotanshinone(CTS) may exert its anti-myo-cardial ischemic effect through the regulation of macrophage polarization via the dendritic cell-associated C-type lectin 1(Dectin-1) signaling pathway. Male C57BL/6 mice, aged six weeks, were utilized to establish myocardial ischemia models and were subsequently divided into five groups: sham, model, CTS low-dose(21 mg·kg~(-1)·d~(-1)), CTS high-dose(84 mg·kg~(-1)·d~(-1)), and dapagliflozin(0.14 mg·kg~(-1)·d~(-1)). The cardiac function, serum enzyme levels, Dectin-1 expression, macrophage polarization, and neutrophil infiltration in the myocardial infarction area were assessed in each group. An in vitro model of M1-type macrophages was constructed using lipopolysaccharide/interfe-ron-γ(LPS/IFN-γ) stimulated RAW264.7 cells to investigate the impact of CTS on macrophage polarization and to examine alterations in key proteins within the Dectin-1 signaling pathway. In the CTS group, compared to the model group mice, there was a significant improvement in the cardiac function and myocardial injury, along with a notable increase in the ratio of M2/M1-type macrophages in the myocardial infarcted area and a decrease in neutrophil infiltration. Additionally, Dectin-1 exhibited low expression. The results of in vitro experiments demonstrated that CTS can decrease the expression of M1-type marker genes and increase the expression of M2-type marker genes. Besides, it can decrease the levels of Dectin-1 and the phosphorylation of its associated proteins, including spleen tyrosine kinase(Syk), protein kinase B(Akt), nuclear factor-kappaB p65(NF-κB p65), and extracellular signal-regulated protein kinases(ERK1/2). Additionally, CTS was found to enhance the phosphorylation of signal transducer and activator of transcription-6(STAT6). The above results suggest that CTS exerts its anti-myocardial ischemic injury effect by regulating macrophage polarization through the Dectin-1 signaling pathway.

Neural mechanisms underlying cognitive impairment in depression and cognitive benefits of exercise intervention.

Depression is associated with functional brain impairments, although comprehensive studies remain limited. This study reviews neural mechanisms underlying cognitive impairment in depression and identifies associated activation abnormalities in brain regions. The study also explores the underlying neural processes of cognitive benefits of exercise intervention for depression. Executive function impairments, including working memory, inhibitory control and cognitive flexibility are associated with frontal cortex and anterior cingulate areas, especially dorsolateral prefrontal cortex. Depression is associated with certain neural impairments of reward processing, especially orbitofrontal cortex, prefrontal cortex, nucleus accumbens and other striatal regions. Depressed patients exhibit decreased activity in the hippocampus during memory function. Physical exercise has been found to enhance memory function, executive function, and reward processing in depression patients by increasing functional brain regions and the brain-derived neurotrophic factor (BDNF) as a nutritional factor also plays a key role in exercise intervention. The study documents neurophysiological mechanisms behind exercise intervention's improved functions. In summary, the study provides insights into neural mechanisms underlying cognitive impairments in depression and the effectiveness of exercise as a treatment.

Targeted discovery of clerodane diterpenoids from Tinospora sinensis as immunomodulatory agents.

Under the guidance of MS/MS-based molecular networking, five new clerodane diterpenoid glucosides, tinosinesides R-V (1-5), along with 15 known diterpenoids (6-20), were isolated from the stems of Tinospora sinensis. Compound 1 represents the first example of diterpenoid bearing a thio sugar and compound 5 is the first 18,19-dinor-clerodane with cis-fused A/B ring. The structures of the new compounds were elucidated by spectroscopic means, and their absolute configurations were established on the basis of time-dependent density functional theory (TD-DFT) based electronic circular dichroism (ECD) calculation and chemical methods. Selected compounds were evaluated for their immunomodulatory effect and several compounds could enhance the proliferation of B lymphocytes. Preliminary mechanistic studies disclosed that 3 could promote B cell generation and inhibit B cell differentiation.

Green fabrication of modified lignin/zeolite/chitosan-based composite membranes for preservation of perishable foods.

Chitosan, as a kind of naturally occurring green and degradable material for the preservation of perishable foods, was investigated in this study with the objective of enhancing its preservation performances. Herein, lignin was modified using the solvent fractionation method (modified lignin, ML, including ML1-ML3), while natural clinoptilolite zeolite was modified using the alkali modification method (modified clinoptilolite zeolite, MCZ, including MCZ1-MCZ5). After optimizing the conditions, it was discovered that incorporating both ML3 and MCZ3 into pure chitosan-based membranes might be conducive to fabricate chitosan-based composite membranes for the preservation of perishable foods. As-prepared composite membranes possessed better visible light transmittance, antioxidant activity, and carbon dioxide/oxygen selectivity, resulting in improved preservation effects on the model perishable foods such as bananas, cherry tomatoes, and cheeses. These findings might indicate promising applications for chitosan-based composite membranes with modified lignin and zeolite in the field of eco-friendly degradable materials for the preservation of perishable foods.

Pharmacological Inhibition of TXNRD1 by a Small Molecule Flavonoid Butein Overcomes Cisplatin Resistance in Lung Cancer Cells.

Mammalian cytosolic selenoprotein thioredoxin reductase (TXNRD1) is crucial for maintaining the reduced state of cellular thioredoxin 1 (TXN1) and is commonly up-regulated in cancer cells. TXNRD1 has been identified as an effective target in cancer chemotherapy. Discovering novel TXNRD1 inhibitors and elucidating the cellular effects of TXNRD1 inhibition are valuable for developing targeted therapies based on redox regulation strategies. In this study, we demonstrated that butein, a plant-derived small molecule flavonoid, is a novel TXNRD1 inhibitor. We found that butein irreversibly inhibited recombinant TXNRD1 activity in a time-dependent manner. Using TXNRD1 mutant variants and LC-MS, we identified that butein modifies the catalytic cysteine (Cys) residues of TXNRD1. In cellular contexts, butein promoted the accumulation of reactive oxygen species (ROS) and exhibited cytotoxic effects in HeLa cells. Notably, we found that pharmacological inhibition of TXNRD1 by butein overcame the cisplatin resistance of A549 cisplatin-resistant cells, accompanied by increased cellular ROS levels and enhanced expression of p53. Taken together, the results of this study demonstrate that butein is an effective small molecule inhibitor of TXNRD1, highlighting the therapeutic potential of inhibiting TXNRD1 in platinum-resistant cancer cells.

Path analysis of the effect of positive psychological capital on health-promoting lifestyle in patients with COPD after pulmonary rehabilitation: An observational study.

To investigate the effect of positive psychological capital on the health-promoting lifestyle of patients with chronic obstructive pulmonary disease (COPD) and the intermediary effects of life satisfaction and learned helplessness. A total of 482 patients who completed the pulmonary rehabilitation course at the Nantong Sixth People's Hospital of Jiangsu Province were surveyed using a self-designed questionnaire battery, encompassing the positive psychological capital, health-promoting lifestyle, life satisfaction, and learned helplessness scales. A total of 469 of the 482 questionnaires distributed were effectively returned, leading to an effective response rate of 97.3%. The mean scores on the positive psychological capital, life satisfaction, learned helplessness, and health-promoting lifestyle scales were 105.56 ±â€…10.44, 19.89 ±â€…6.33, 50.14 ±â€…5.47, and 104.22 ±â€…10.44, respectively. The structural equation model demonstrated good fit indexes. The path analysis revealed that positive psychological capital had a direct effect of 0.431 on health-promoting lifestyle, while life satisfaction and learned helplessness had a mediating effect on this relationship (both P < .05). Patients with COPD have low levels of positive psychological capital and health-promoting lifestyle. Thus, addressing psychological problems and providing continuous rehabilitation nursing to strengthen the psychological construct are essential in this patient group. Moreover, the positive psychological capital of patients with COPD can directly predict their health-promoting lifestyle and exert an influence via the chain mediating effect of life satisfaction and learned helplessness. Therefore, clinical medical staff should assess the positive psychological capital of patients with COPD and adjust the daily rehabilitation activities according to the patients' mental state. Furthermore, enhancing the patients' life satisfaction by employing diverse strategies to reduce learned helplessness can notably improve the health-promoting lifestyle of those with COPD.

Heteroaryl Group Containing Trisubstituted Alkenes: Synthesis and Anti-tumor Activity.

Pancreatobililary cancers are fatal solid tumors that pose a significant threat to human life. It is imperative to investigate novel small molecule active compounds for controlling these cancers. Heterocyclic compounds (e.g. gemcitabine) and multi-substituted alkenes (e.g. resveratrol) are commonly applied in tumor treatment. Researchers have proposed that the synthesis of new trisubstituted alkenes containing heteroaromatic rings by combining these two scaffolds may be a fresh strategy to develop new active molecules. In this study, we utilized alkenyl bromide and heteroaryl boronic acid as substrates, employing Suzuki coupling to generate a series of triarylethylenes featuring nitrogen, oxygen, and sulfur atoms. Through in vitro experiments, the results indicated that some compounds exhibited remarkable anti-tumor efficacy (e.g. IC50[3be, GBC-SD] = 0.13 µM and IC50[3be, PANC-1] = 0.27 µM). The results further demonstrated that the antitumor efficacy of these compounds was dependent on the heteroatom, π-system, skeleton-bonding site, and substituent type.

Caregiving risk perception characteristics and associated factors among informal caregivers of functionally dependent elderly individuals at home: a qualitative study.

BACKGROUND: This study explored risk perception characteristics and influencing factors among informal caregivers of functionally dependent elderly individuals at home, aiming to improve caregivers' caregiving risk perception and coping abilities and ultimately enhance the quality of life for these individuals. METHODS: We used purposive sampling to select 22 informal caregivers from a community in Zhengzhou City, Henan Province, China, between March and September 2023 and conducted face-to-face semi-structured in-depth interviews. The data were analyzed using Colaizzi's seven-step analysis method. RESULTS: We extracted two themes, caregiving risk perception characteristics and caregiving risk perception associated factors, and eight sub-themes, perceived risk possibility, perceived risk anticipation, perceived severity of consequences, past caregiving experiences, health literacy, psychological status, caregiving burden, and family social support. CONCLUSION: There were differences in how informal caregivers perceived the risks associated with caring for functionally dependent elderly individuals at home, which various factors could influence. It was essential to provide training that covered the knowledge and skills needed for caregiving, improve caregivers' awareness of safety risks, and establish a correct perception of caregiving risks. The government must construct and refine a comprehensive framework for caregiver respite services. Simultaneously, healthcare professionals should proactively undertake health education endeavors to augment the recognition of care safety risks among informal caregivers, thereby cultivating an accurate awareness of care risk perception.

Blastic plasmacytoid dendritic cell neoplasm in Jinhua, China: Two case reports.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic malignancy originating from the precursors of plasmacytoid dendritic cells. BPDCN often involves the skin, lymph nodes, and bone marrow, with rapid clinical progression and a poor prognosis. The BPDCN diagnosis is mainly based on the immunophenotype. CASE SUMMARY: In this paper, we retrospectively analyzed 2 cases of BPDCN. Both patients were elderly males. The lesions manifested as skin masses. Morphological manifestations included diffuse and dense tumor cell infiltration of the dermis and subcutaneous tissues. Immunohistochemistry staining showed that cluster of differentiation CD4, CD56, CD43, and CD123 were positive. CONCLUSION: In this paper, we retrospectively analyzed 2 cases of BPDCN. Both patients were elderly males. The lesions manifested as skin masses. Morphological manifestations included diffuse and dense tumor cell infiltration of the dermis and subcutaneous tissues. Immunohistochemistry staining showed that cluster of differentiation CD4, CD56, CD43, and CD123 were positive.

Characterization and identification of the wide-polarity multicomponents from Prunella vulgaris by offline two-dimensional liquid chromatography and hydrophilic interaction chromatography coupled to ion mobility-quadrupole time-of-flight mass spectrometry.

Metabolites identification is crucial to develop functional foods or perform quality control. Prunella vulgaris (Xia-Ku-Cao) is a medicinal and edible plant used as the herbal medicine or main additive in functional beverage. However, current analytical strategies can only on-line characterize tens of compounds, restricted by insufficient chromatographic resolution and low coverage of the mass spectrometric scan methods. This work was designed to characterize the wide-polarity components from the ear of P. vulgaris. The total extract was fractionated by semi-preparative high-performance liquid chromatography into the retained medium-polarity fraction and unretained polar fraction, which were further analyzed by offline two-dimensional liquid chromatography (2D-LC) and hydrophilic interaction chromatography, respectively. Data-independent high-definition MSE of the Vion™ ion mobility time-of-flight mass spectrometer was utilized enabling the high-coverage acquisition of collision-induced dissociation-MS2 data. The offline 2D-LC, configuring the XBridge Amide and HSS T3 columns, gave high orthogonality (0.81) and effective peak capacity (1555). Automatic peak annotation facilitated by the UNIFI™ bioinformatics platform and comparison with 62 reference compounds achieved the efficient and more reliable structural elucidation. We could characterize 255 compounds from P. vulgaris, with numerous phenylpropanoid phenolic acids and triterpenoid O-glycosides newly reported. Especially, collision cross section (CCS) prediction and targeted isolation of three compounds assisted in the identification of 39 groups of isomers. Additionally, 17 hydrophilic compounds, involving oligosaccharides and organic acids, were characterized from the unretained polar fraction. Conclusively, the in-depth metabolites identification of P. vulgaris was accomplished, and the results can benefit the development and better quality control of this valuable plant.

Chemoarchitectural signatures of subcortical shape alterations in generalized epilepsy.

Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α4ß2) profiles, but a distinct association was seen in the muscarinic Ach receptor (M1). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE.

Inhalable Polymeric Microparticles for Phage and Photothermal Synergistic Therapy of Methicillin-Resistant Staphylococcus aureus Pneumonia.

Acute methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is a common and serious lung infection with high morbidity and mortality rates. Due to the increasing antibiotic resistance, toxicity, and pathogenicity of MRSA, there is an urgent need to explore effective antibacterial strategies. In this study, we developed a dry powder inhalable formulation which is composed of porous microspheres prepared from poly(lactic-co-glycolic acid) (PLGA), internally loaded with indocyanine green (ICG)-modified, heat-resistant phages that we screened for their high efficacy against MRSA. This formulation can deliver therapeutic doses of ICG-modified active phages to the deep lung tissue infection sites, avoiding rapid clearance by alveolar macrophages. Combined with the synergistic treatment of phage therapy and photothermal therapy, the formulation demonstrates potent bactericidal effects in acute MRSA pneumonia. With its long-term stability at room temperature and inhalable characteristics, this formulation has the potential to be a promising drug for the clinical treatment of MRSA pneumonia.

Arthroscopic M-shaped suture fixation for tibia avulsion fracture of posterior cruciate ligament: A modified technique and case series.

BACKGROUND: Tibial avulsion fractures of the posterior cruciate ligament (PCL) are challenging to treat and compromise knee stability and function. Traditional open surgery often requires extensive soft tissue dissection, which may increase the risk of morbidity. In response to these concerns, arthroscopic techniques have been evolving. The aim of this study was to introduce a modified arthroscopic technique utilizing an M-shaped suture fixation method for the treatment of tibial avulsion fractures of the PCL and to evaluate its outcomes through a case series. AIM: To evaluate the effects of arthroscopic M-shaped suture fixation on treating tibia avulsion fractures of the PCL. METHODS: We developed a modified arthroscopic M-shaped suture fixation technique for tibia avulsion fractures of the PCL. This case series included 18 patients who underwent the procedure between January 2021 and December 2022. The patients were assessed for range of motion (ROM), Lysholm score and International knee documentation committee (IKDC) score. Postoperative complications were also recorded. RESULTS: The patients were followed for a mean of 13.83 ± 2.33 months. All patients showed radiographic union. At the final follow-up, all patients had full ROM and a negative posterior drawer test. The mean Lysholm score significantly improved from 45.28 ± 8.92 preoperatively to 91.83 ± 4.18 at the final follow-up (P < 0.001), and the mean IKDC score improved from 41.98 ± 6.06 preoperatively to 90.89 ± 5.32 at the final follow-up (P < 0.001). CONCLUSION: The modified arthroscopic M-shaped suture fixation technique is a reliable and effective treatment for tibia avulsion fractures of the PCL, with excellent fracture healing and functional recovery.

HTR1B regulates mitochondrial homeostasis and mitophagy by activating the ERK/ MAPK signalling pathway during human embryonic arrest.

Background: Previous studies have shown that serotonin and its receptors are widely distributed in mammalian reproductive tisssues and play an important role in embryonic development. However, the specific effects of the serotonergic system on embryonic arrest (EA) and the underlying mechanism require further investigation. Methods: Chorionic villi were collected from patients with EA and healthy pregnant women. Western blotting (WB) and immunohistochemistry (IHC) were used to detect serotonin receptor 1B (HTR1B) levels and evaluate mitochondrial function. Additionally, HTR-8/SVneo cells were transfected with an HTR1B overexpression plasmid. Quantitative real-time polymerase chain reaction(qRT-PCR), Cell Counting Kit-8 (CCK-8), and wound healing assays were utilized to evaluate mitophagy level, cell proliferation and cell migration, respectively. Results: We discovered elevated HTR1B levels in the chorionic villi of the patients with EA compared to controls. Concurrently, we observed enhanced levels of nucleus-encoded proteins including mitofilin, succinate dehydrogenase complex subunit A (SDHA), and cytochrome c oxidase subunit 4 (COXIV), along with the mitochondrial fusion protein optic atrophy 1(OPA1), fission proteins mitochondrial fission protein 1(FIS1) and mitochondrial fission factor (MFF) in the EA group. Additionally, there was an excessive mitophagy levels in EA group. Furthermore, a notable activation of mitogen-activated protein kinase (MAPK) signaling pathway proteins including extracellular regulating kinase (ERK), c-Jun N-terminal kinase (JNK), and P38 was observed in the EA group. By overexpressing HTR1B in HTR-8/SVneo cells, we observed a significant reduction in cell proliferation and migration. HTR1B overexpression also caused an increase in levels of SDHA and FIS1, as well as an upregulation of mitophagy. Notably, the ERK inhibitor U0126 effectively mitigated these effects. Conclusion: These findings show that HTR1B influences mitochondrial homeostasis, promoting excessive mitophagy and impairing cell proliferation and migration by activating the MAPK signalling pathway during post-implantation EA. Therefore, HTR1B may serve as a potential therapeutic target for patients with EA.

Transcriptome sequencing of garlic reveals key genes related to the heat stress response.

With global warming, heat stress has become an important factor that seriously affects crop yield and quality. Therefore, understanding plant responses to heat stress is important for agricultural practice, but the molecular mechanism of high-temperature tolerance in garlic remains unclear. In this study, 'Xusuan No. 6' was used as the experimental material. After heat stress for 0 (CK), 2 and 24 h, transcriptome sequencing was used to screen metabolic pathways and differentially expressed genes (DEGs) closely related to heat stress and was further verified by quantitative real-time polymerase chain reaction (qRT-PCR). A total of 86,110 unigenes obtained from the raw transcriptome sequencing data were spliced. After 2 h of heat treatment, the expression levels of 8898 genes increased, and 3829 genes were decreased in leaves. After 24 h, the expression levels of 7167 genes were upregulated, and 3176 genes were downregulated. Gene Ontology enrichment analysis showed that DEGs were mainly enriched in seven categories: cellular processes, metabolic processes, binging, catalytic activity, cellular anatomical entity and protein-containing complex response to stimulus. Kyoto Encyclopedia of Genes and Genomes pathway enrichment showed that DEGs are involved in protein processing in the endoplasmic reticulum, plant hormone signal transduction, phenylpropanoid biosynthesis, and photosynthetic antenna proteins. Six genes were selected and further verified by qRT-PCR. In this study, the full-length transcriptome of garlic was constructed, and the regulatory genes related to the heat resistance of garlic were studied. Taken together, these findings can provide a theoretical basis for the cloning of heat resistance genes in garlic and for the analysis of heat resistance mechanisms.

Disease burden, management strategies, and unmet needs in α-thalassemia due to hemoglobin H disease.

Alpha-thalassemia is an inherited blood disorder caused by impaired α-globin chain production, leading to anemia and other complications. Hemoglobin H (HbH) disease is caused by a combination of mutations generally affecting the expression of three of four α-globin alleles; disease severity is highly heterogeneous, largely driven by genotype. Notably, non-deletional mutations cause a greater degree of ineffective erythropoiesis and hemolysis, higher transfusion burden, and increased complication risks versus deletional mutations. There are limited treatment options for HbH disease, and effective therapies are needed. This review discusses the pathophysiology of HbH disease, current management strategies, unmet needs, and emerging treatment options.

Geniposide alleviates heart failure with preserved ejection fraction in mice by regulating cardiac oxidative stress via MMP2/SIRT1/GSK3ß pathway.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L-NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3ß, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 µM) significantly alleviated H2O2-induced oxidative stress through the MMP2/SIRT1/GSK3ß pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3ß pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF. GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3ß, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3ß signaling pathway.

Establishment of a transgene-free iPS cell line (SDCHi007-A) from a young patient bearing a ATP1A2 mutation and suffering from Epilepsy.

Epilepsy is a chronic neurological disease. Here we describe the generation of induced pluripotent stem cells (iPSCs) from a patient diagnosed as epilepsy caused by ATP1A2 gene mutation. Induced pluripotent stem cells (iPSCs) were developed using non-integrating episomal vectors containing OCT4, SOX2, KLF4, BCL-XL and C-MYC. The established iPSC line (SDCHi007-A) displayed pluripotent cell morphology, high expression levels of pluripotency markers, differentiation potential in vitro, normal karyotype, and remaining the original ATP1A2 gene mutation.

Ruxolitinib in treatment-naive or corticosteroid-refractory paediatric patients with chronic graft-versus-host disease (REACH5): interim analysis of a single-arm, multicentre, phase 2 study.

BACKGROUND: Chronic graft-versus-host disease (GVHD) is a debilitating, and sometimes life threatening, complication of allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the activity, pharmacokinetics, and safety of ruxolitinib added to corticosteroids in paediatric patients (ie, <18 years) with moderate-to-severe chronic GVHD. METHODS: In this single-arm, phase 2 study, patients were recruited at 21 hospitals or clinics across 14 countries in Asia, Europe, and Canada. Eligible patients were aged 28 days to younger than 18 years, had undergone allogenic HSCT, and had been diagnosed with treatment-naive or corticosteroid-refractory moderate-to-severe chronic GVHD, per 2014 National Institutes of Health consensus criteria. Patients received oral ruxolitinib dosing on the basis of their age at the start of treatment: those aged 12 years to younger than 18 years received 10 mg twice daily (age ≥12 to <18 years group), those aged 6 years to younger than 12 years (age ≥6 to <12 years group) received 5 mg twice daily, and those aged 2 years to younger than 6 years received 4 mg/m2 twice daily (age ≥2 to <6 years group). Treatment was to be administered in 28-day cycles for approximately 36 months, alongside supportive treatment per institutional guidelines. The primary activity endpoint was overall response rate at cycle 7 day 1. Activity and safety analyses are reported in the full analysis set, which included all patients who received at least one dose of ruxolitinib. Here we report the prespecified interim analysis, scheduled to occur after all patients had completed 1 year of treatment or discontinued treatment, and the results for the primary endpoint evaluation reported here is to be considered final. This study is registered with ClinicalTrials.gov, NCT03774082, enrolment is complete, and the study is ongoing. FINDINGS: Between May 20, 2020, and Sept 17, 2021, 48 patients were screened, of whom 45 were enrolled and received at least one dose of study drug (median age was 11·0 years [IQR 7·2-14·3], 16 [36%] were female, 29 [64%] were male, 21 [47%] were White, one [2%] was Black or African American, 23 [51%] were Asian, 17 [38%] were treatment-naive, 28 [62%] were corticosteroid-refractory). As of data cutoff (Oct 19, 2022), after a median ruxolitinib exposure of 55·1 weeks (IQR 13·1-75·3), the overall response rate at cycle 7 day 1 was 40·0% (18 of 45; 90% CI 27·7-53·3), with responses seen in seven (41%) of 17 treatment-naive patients and 11 (39%) of 28 corticosteroid-refractory patients. The most common treatment-related adverse events of grade 3 or worse were neutropenia (eight [18%] of 45) and thrombocytopenia (six [13%]). Seven (16%) patients had grade 3 or worse serious treatment-related adverse events; the most common was hyponatraemia (two [4%] of 45). Three (7%) patients died while on-treatment (within 30 days of treatment discontinuation), one due to Aspergillus infection, one due to septic shock, and one due to acute respiratory distress syndrome; none were considered to be related to study drug. INTERPRETATION: Pending final analysis, this study suggests that ruxolitinib is active and well tolerated in both treatment-naive and corticosteroid-refractory patients aged 2 years to younger than 18 years with chronic GVHD, thereby supporting its use in this patient population. The safety profile of ruxolitinib in this patient population is consistent with that of adults. Final analysis of this study will provide further information on the long-term benefits of ruxolitinib in children with chronic GVHD. FUNDING: Novartis.