N-doping has significant influence in manipulating the properties of TiO_(2),and this has stimulated the development of N-donor-functionalized titanium-oxo clusters(TOCs)as molecular models to study the structure-prop...N-doping has significant influence in manipulating the properties of TiO_(2),and this has stimulated the development of N-donor-functionalized titanium-oxo clusters(TOCs)as molecular models to study the structure-property relationship.However,the structural type and photoresponsive application are still limited for such TOCs,especially regarding the high-nuclearity TOCs that contain structure unit of TiO_(2)for photocatalysis.Herein,we showed the synthesis of a series of high-nuclearity TOCs 1-3 compounds usingπ-conjugated 1,10-phenanthroline(phen)as chromophore and N-donor functional ligand.Compound 1 features cocrystal structure composed of one[Ti_(26)]~(2+)and half[Ti_(22)]~(2+),which renders it as the first cocrystallized TOC containing two positively charged species and phen-functionalized TOC showing the highest nuclearity up to 37 Ti centers.By adjusting the synthetic conditions,the individual{Ti_(22)}and{Ti_(26)}clusters can also be isolated as Compounds 2 and 3,respectively.The core structure of{Ti_(22)}is mainly constructed from four lacunary{Ti_(4)}derived from pentagonal{Ti(Ti)_5}unit,while{Ti_(26)}is built from four complete{Ti(Ti)_5}unit.Notably,a{Ti_8O_(14)}structure unit of anatase TiO_(2)can be identified in{Ti_(26)}.Based on the unique structural features and proper photophysical and photochemical properties of Compounds 1-3,they are applied for photocatalytic sulfoxidation.Owing to the presence of anatase structure unit in{Ti_(26)}and the synergistic effect from{Ti_(22)}and{Ti_(26)},the catalytic performance presents in the order of Compound 1>Compound 3>Compound 2.This work provides excellent models to understand the structureproperty relationship from the perspective of cocrystallization and Ti-O binding model and will further promote the application of TOCs as functional catalysts for organic transformation.展开更多
The redox properties of ceria make it suitable as a catalyst or support in oxidation reactions.Ceria-supported transition metal nanoparticles or isolated single atoms provide a metal-support interface that reduces the...The redox properties of ceria make it suitable as a catalyst or support in oxidation reactions.Ceria-supported transition metal nanoparticles or isolated single atoms provide a metal-support interface that reduces the energy cost to remove interfacial oxygen atoms,providing active oxygen species that can participate in Mars van Krevelen oxidation processes.CO oxidation is a key probe reaction to test the reducibility of ceria-supported catalysts and is also practically important in the elimination of CO at relatively low temperatures in various applications.Preferential oxidation of CO(PROX)in excess H2 controls the CO concentration to ultra-low levels to prevent poisoning of hydrogen oxidation electrocatalysts.The reactivity of catalysts in CO oxidation and selectivity towards CO over H2 in PROX is dependent on the type and dispersion of metal species,the structural and chemical properties of Ce O2,and the synthetic preparation methods of the catalysts.In this review,we summarize recently published works on catalytic CO oxidation and PROX reactions on ceria-supported metal nanoparticles and single atoms.We summarize the reactivity on different supported metals,and on different Ce O2 surfaces with the same metal.We summarize the most likely reaction mechanisms as suggested by density functional theory calculations.The factors contributing to selectivity towards CO oxidation in PROX reactions on various supported metals are also discussed.展开更多
In this paper,we investigate local properties in the system of completely integral mapping spaces.We introduce notions of injectivity,local reflexivity,exactness,nuclearity,finite-represent ability and WEP in the syst...In this paper,we investigate local properties in the system of completely integral mapping spaces.We introduce notions of injectivity,local reflexivity,exactness,nuclearity,finite-represent ability and WEP in the system of completely integral mapping spaces.First we obtain that any finite-dimensional operator space is injective in the system of completely integral mapping spaces.Furthermore we prove that C is the unique nuclear operator space and the unique exact operator space in this system.We also show that C is the unique operator space which is finitely representable in{T_(n)}n∈Nin this system.As corollaries,Kirchberg’s conjecture and QWEP conjecture in the system of completely integral mapping spaces are false.展开更多
Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is cha...Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.展开更多
We read with great interest the study by Zhang et al on Yiyi Fuzi Baijiang powder(YFB),which exemplifies the power of modern methods to validate traditional Chinese medicine(TCM).The key insight is that YFB doesn’t m...We read with great interest the study by Zhang et al on Yiyi Fuzi Baijiang powder(YFB),which exemplifies the power of modern methods to validate traditional Chinese medicine(TCM).The key insight is that YFB doesn’t merely alter“good”or“bad”bacteria but restores the gut microbiota’s holistic equilibrium.This is powerfully shown by its paradoxical reduction of anaerobic probiotics like Bifidobacterium,rectifying the diseased,hypoxic environment,causing their aberrant overgrowth.This challenges the conventional probiotic paradigm and underscores a core TCM principle:Herbal formulas treat disease by restoring the body’s overall functional balance.Future research should focus on the interplay between herbal components,intestinal oxygen,and microbial metabolites to further unravel this sophisticated dialogue.展开更多
The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response...The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response fails to restore endoplasmic reticulum homeostasis,it can trigger proinflammatory and pro-death signals,which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases.This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases.The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise.Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies,including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid,which enhance protein folding and reduce endoplasmic reticulum stress.Small molecule modulators that influence endoplasmic reticulum stress sensors,including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1,are also potential therapeutic agents.Additionally,inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1,a key endoplasmic reticulum stress sensor,represent another class of drugs that could prevent the formation of toxic aggregates.The activation of nuclear receptors,such as PPAR and FXR,may also help mitigate ER stress.Furthermore,enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins.Combination treatments that involve endoplasmicreticulum-stress-targeting drugs and gene therapies are also being explored.Despite these potential therapeutic strategies,significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration,and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective,well-tolerated drugs.The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects,which have hindered their clinical translation.Moreover,signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance.Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies.In conclusion,while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases,additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.展开更多
Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal ce...Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.展开更多
The authors define the equi-nuclearity of uniform Roe algebras of a family of metric spaces. For a discrete metric space X with bounded geometry which is covered by a family of subspaces {Xi}i=1^∞, if {C^＊（Xi）}i=1...The authors define the equi-nuclearity of uniform Roe algebras of a family of metric spaces. For a discrete metric space X with bounded geometry which is covered by a family of subspaces {Xi}i=1^∞, if {C^＊（Xi）}i=1^∞ are equi-nuclear and under some proper gluing conditions, it is proved that C＊（X） is nuclear. Furthermore, it is claimed that in general, the coarse Roe algebra C^＊ （X） is not nuclear.展开更多
The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular an...The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.展开更多
Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has...Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3(NLRP3). However, whether sirtuin 2-mediated pathways induce a pro-or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.展开更多
Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0...Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.展开更多
The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia ...The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.展开更多
A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to ...A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity.After 4 weeks of tail suspension,there were no notable alterations in retinal function and morphology,while after 8 weeks of tail suspension,significant reductions in retinal function were observed,and the outer nuclear layer was thinner,with abundant apoptotic cells.To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina,proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension.The results showed that the expression levels of fibroblast growth factor 2(also known as basic fibroblast growth factor)and glial fibrillary acidic protein,which are closely related to Müller cell activation,were significantly upregulated.In addition,Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks,respectively,of simulated weightlessness.These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness.展开更多
Objective Safranal is a natural product from saffron(Crocus sativus L.)with anti-inflammatory and nephroprotective potential.This study aimed to explore the role of safranal in a cationic bovine serum albumin(C-BSA)-i...Objective Safranal is a natural product from saffron(Crocus sativus L.)with anti-inflammatory and nephroprotective potential.This study aimed to explore the role of safranal in a cationic bovine serum albumin(C-BSA)-induced rat model of membranous glomerulonephritis(MGN).Methods After model establishment,Sprague–Dawley rats were administered 100 or 200 mg/kg safranal by gavage.A biochemical analyser was used to measure the urine protein levels and serum levels of renal function parameters.Hematoxylin–eosin and immunofluorescence staining of kidney tissues were performed to examine histopathological changes and assess the expression of IgG,C3,and Sirt1.Western blotting was performed to measure the protein levels of podocin,nephrin,Sirt1,and factors involved in the NF-κB/p65 pathway.Inflammatory cytokine levels in renal homogenates were determined by ELISA.Results Safranal at 100 or 200 mg/kg reduced kidney weight(2.07±0.15 g and 2.05±0.15 g)and the kidney somatic index(0.83±0.08%and 0.81±0.08%)in MGN rats compared with those in the model group without drug administration(2.62±0.17 g and 1.05±0.1%).C-BSA increased the urine protein level to 117.68±10.52 mg/day(compared with the sham group,5.03±0.45 mg/day),caused dysregulation of renal function indicators,and induced glomerular expansion and inflammatory cell infiltration in the rat kidney samples.All the biochemical and histological changes were improved by safranal administration.Safranal at two doses also increased the fluorescence intensities of IgG(0.1±0.009 and 0.088±0.008)and C3(0.065±0.006 and 0.048±0.004)compared with those in the MGN group(0.15±0.013 and 0.086±0.008).Additionally,safranal reversed the downregulation of podocin,nephrin,and Wilms tumor protein-1(WT1)levels and reversed the high inflammatory cytokine levels in MGN rats.Mechanistically,safranal activated Sirt1 signalling to interfere with NF-κB signalling in the kidney tissues of MGN rats.Conclusions Safranal ameliorates renal damage,inflammation,and podocyte injury in MGN by upregulating SIRT1 and inhibiting NF-κB signalling.展开更多
The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,...The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.展开更多
The Monte Carlo(MC)method offers significant advantages in handling complex geometries and physical processes in particle transport problems and has become a widely used approach in reactor physics analysis,radiation ...The Monte Carlo(MC)method offers significant advantages in handling complex geometries and physical processes in particle transport problems and has become a widely used approach in reactor physics analysis,radiation shielding design,and medical physics.However,with the rapid advancement of new nuclear energy systems,the Monte Carlo method faces challenges in efficiency,accuracy,and adaptability,limiting its effectiveness in meeting modern design requirements.Overcoming technical obstacles related to high-fidelity coupling,high-resolution computation,and intelligent design is essential for using the Monte Carlo method as a reliable tool in numerical analysis for these new nuclear energy systems.To address these challenges,the Nuclear Energy and Application Laboratory(NEAL)team at the University of South China developed a multifunctional and generalized intelligent code platform called MagicMC,based on the Monte Carlo particle transport method.MagicMC is a developing tool dedicated to nuclear applications,incorporating intelligent methodologies.It consists of two primary components:a basic unit and a functional unit.The basic unit,which functions similarly to a standard Monte Carlo particle transport code,includes seven modules:geometry,source,transport,database,tally,output,and auxiliary.The functional unit builds on the basic unit by adding functional modules to address complex and diverse applications in nuclear analysis.MagicMC introduces a dynamic Monte Carlo particle transport algorithm to address time-space particle transport problems within emerging nuclear energy systems and incorporates a CPU-GPU heterogeneous parallel framework to enable high-efficiency,high-resolution simulations for large-scale computational problems.Anticipating future trends in intelligent design,MagicMC integrates several advanced features,including CAD-based geometry modeling,global variance reduction methods,multi-objective shielding optimization,high-resolution activation analysis,multi-physics coupling,and radiation therapy.In this paper,various numerical benchmarks-spanning reactor transient simulations,material activation analysis,radiation shielding optimization,and medical dosimetry analysis-are presented to validate MagicMC.The numerical results demonstrate MagicMC's efficiency,accuracy,and reliability in these preliminary applications,underscoring its potential to support technological advancements in developing high-fidelity,high-resolution,and high-intelligence MC-based tools for advanced nuclear applications.展开更多
Background:Nuclear receptor-binding SET domain 2(NSD2)is a histone methyltrans-ferase,that catalyzes dimethylation of lysine 36 of histone 3(H3K36me2)and is asso-ciated with active transcription of a series of genes.N...Background:Nuclear receptor-binding SET domain 2(NSD2)is a histone methyltrans-ferase,that catalyzes dimethylation of lysine 36 of histone 3(H3K36me2)and is asso-ciated with active transcription of a series of genes.NSD2 is overexpressed in multiple types of solid human tumors and has been proven to be related to unfavorable prog-nosis in several types of tumors.Methods:We established a mouse model in which the NSD2 gene was conditionally knocked out in intestinal epithelial cells.We used azoxymethane and dextran sodium sulfate to chemically induce murine colorectal cancer.The development of colorectal tumors were investigated using post-necropsy quantification,immunohistochemistry,and enzyme-linked immunosorbent assay(ELISA).Results:Compared with wild-type(WT)control mice,NSD2^(fl/fl)-Vil1-Cre mice exhib-ited significantly decreased tumor numbers,histopathological changes,and cytokine expression in colorectal tumors.Conclusions:Conditional knockout of NSD2 in intestinal epithelial cells significantly inhibits colorectal cancer progression.展开更多
BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear f...BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.展开更多
Excessive osteoclastogenesis-mediated osteoporosis has been recognized as a global health concern.Candidate compounds derived from medicinal plants or functional foods are promising to treat osteoporosis due to their ...Excessive osteoclastogenesis-mediated osteoporosis has been recognized as a global health concern.Candidate compounds derived from medicinal plants or functional foods are promising to treat osteoporosis due to their high safety and efficiency.(−)-Epigallocatechin-3-gallate(EGCG)is the most abundant and biologically active polyphenol in green tea.It can inhibit osteoclastogenesis in vitro by blocking receptor activator of nuclear factor(NF)-κB(RANK)signaling pathways.This study used the ovariectomized(OVX)mouse model to estimate the therapeutic effect of EGCG on osteoporosis and verified the molecular mechanism in vivo.The results revealed that EGCG significantly inhibited the OVX-induced body weight gain.Moreover,no adverse effects were observed on blood glucose,histomorphological features,weights,as well as indices of liver and kidney in OVX mice.EGCG could significantly ameliorate bone loss in OVX mice by inhibiting osteoclastogenesis.This effect was evidenced by the reduced number of osteoclasts and the increased trabecular bone area in the femurs.Moreover,EGCG inhibited the activities of c-telopeptide of type I collagen(CTX-I)and tartrate-resistant acid phosphatase 5b(TRACP-5b)and strengthened bone gla protein(BGP)and procollagen I N-terminal peptide(PINP)activities in OVX mice.Mechanistically,EGCG significantly downregulated the expression of osteoclastogenesis-related marker genes and proteins,including nuclear factor of activated T cells,cytoplasmic 1(NFATc1),c-Fos,tartrate-resistant acid phosphatase(TRAP),c-Src,and cathepsin K.In addition,the phosphorylation levels of p65,c-Jun N-terminal kinase(JNK),extracellular signal-regulated kinase 1/2(ERK1/2),p38,and protein kinase B(AKT)were significantly suppressed in OVX mice.It was found that EGCG could alleviate OVX-induced bone loss in mice by suppressing osteoclastogenesis by blocking the NF-κB,mitogen-activated protein kinase(MAPK),and AKT signaling pathways.EGCG has the potential to prevent and treat osteoclast-related diseases such as osteoporosis.展开更多
BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed th...BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed that nuclear receptor subfamily 4 group A member 1(NR4A1)may serve as a novel pathogenic element in DKD;however,the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.AIM To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.METHODS Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD.Typically,45 mmol/L glucose[high glucose(HG)]was used to activate HK-2 cells to mimic the DKD model in vitro.HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.RESULTS NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells.Concurrently,NOD-like receptor protein 3(NLRP3)and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathways were triggered,and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro.These alterations were significantly reversed via NR4A1 silencing.CONCLUSION Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.展开更多
基金financially supported by the National Natural Science Foundation of China(Nos.21901037,21901038 and 92161111)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning+1 种基金the Fundamental Research Funds for the Central Universities(No.2232019G-07)the International Cooperation Fund of Science and Technology Commission of Shanghai Municipality(No.21130750100)。
文摘N-doping has significant influence in manipulating the properties of TiO_(2),and this has stimulated the development of N-donor-functionalized titanium-oxo clusters(TOCs)as molecular models to study the structure-property relationship.However,the structural type and photoresponsive application are still limited for such TOCs,especially regarding the high-nuclearity TOCs that contain structure unit of TiO_(2)for photocatalysis.Herein,we showed the synthesis of a series of high-nuclearity TOCs 1-3 compounds usingπ-conjugated 1,10-phenanthroline(phen)as chromophore and N-donor functional ligand.Compound 1 features cocrystal structure composed of one[Ti_(26)]~(2+)and half[Ti_(22)]~(2+),which renders it as the first cocrystallized TOC containing two positively charged species and phen-functionalized TOC showing the highest nuclearity up to 37 Ti centers.By adjusting the synthetic conditions,the individual{Ti_(22)}and{Ti_(26)}clusters can also be isolated as Compounds 2 and 3,respectively.The core structure of{Ti_(22)}is mainly constructed from four lacunary{Ti_(4)}derived from pentagonal{Ti(Ti)_5}unit,while{Ti_(26)}is built from four complete{Ti(Ti)_5}unit.Notably,a{Ti_8O_(14)}structure unit of anatase TiO_(2)can be identified in{Ti_(26)}.Based on the unique structural features and proper photophysical and photochemical properties of Compounds 1-3,they are applied for photocatalytic sulfoxidation.Owing to the presence of anatase structure unit in{Ti_(26)}and the synergistic effect from{Ti_(22)}and{Ti_(26)},the catalytic performance presents in the order of Compound 1>Compound 3>Compound 2.This work provides excellent models to understand the structureproperty relationship from the perspective of cocrystallization and Ti-O binding model and will further promote the application of TOCs as functional catalysts for organic transformation.
基金funding of this work by the National Science Foundation,Division of Chemical,Bioengineering,Environmental and Transport Systems(CBET)through Award#1800507 and 1510435。
文摘The redox properties of ceria make it suitable as a catalyst or support in oxidation reactions.Ceria-supported transition metal nanoparticles or isolated single atoms provide a metal-support interface that reduces the energy cost to remove interfacial oxygen atoms,providing active oxygen species that can participate in Mars van Krevelen oxidation processes.CO oxidation is a key probe reaction to test the reducibility of ceria-supported catalysts and is also practically important in the elimination of CO at relatively low temperatures in various applications.Preferential oxidation of CO(PROX)in excess H2 controls the CO concentration to ultra-low levels to prevent poisoning of hydrogen oxidation electrocatalysts.The reactivity of catalysts in CO oxidation and selectivity towards CO over H2 in PROX is dependent on the type and dispersion of metal species,the structural and chemical properties of Ce O2,and the synthetic preparation methods of the catalysts.In this review,we summarize recently published works on catalytic CO oxidation and PROX reactions on ceria-supported metal nanoparticles and single atoms.We summarize the reactivity on different supported metals,and on different Ce O2 surfaces with the same metal.We summarize the most likely reaction mechanisms as suggested by density functional theory calculations.The factors contributing to selectivity towards CO oxidation in PROX reactions on various supported metals are also discussed.
基金Supported by the National Natural Science Foundation of China(Grant No.11871423)Zhejiang Provincial Natural Science Foundation of China(Grant No.LQ21A010015)。
文摘In this paper,we investigate local properties in the system of completely integral mapping spaces.We introduce notions of injectivity,local reflexivity,exactness,nuclearity,finite-represent ability and WEP in the system of completely integral mapping spaces.First we obtain that any finite-dimensional operator space is injective in the system of completely integral mapping spaces.Furthermore we prove that C is the unique nuclear operator space and the unique exact operator space in this system.We also show that C is the unique operator space which is finitely representable in{T_(n)}n∈Nin this system.As corollaries,Kirchberg’s conjecture and QWEP conjecture in the system of completely integral mapping spaces are false.
基金supported by grants from the Zhejiang Provincial TCM Science and Technology Plan Project,No.2023ZL156(to YH)Ningbo Top Medical and Health Research Program,No.2022020304(to XG)+1 种基金the Natural Science Foundation of Ningbo,No.2023J019(to YH)Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province,No.2022E10026(to YH)。
文摘Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.
文摘We read with great interest the study by Zhang et al on Yiyi Fuzi Baijiang powder(YFB),which exemplifies the power of modern methods to validate traditional Chinese medicine(TCM).The key insight is that YFB doesn’t merely alter“good”or“bad”bacteria but restores the gut microbiota’s holistic equilibrium.This is powerfully shown by its paradoxical reduction of anaerobic probiotics like Bifidobacterium,rectifying the diseased,hypoxic environment,causing their aberrant overgrowth.This challenges the conventional probiotic paradigm and underscores a core TCM principle:Herbal formulas treat disease by restoring the body’s overall functional balance.Future research should focus on the interplay between herbal components,intestinal oxygen,and microbial metabolites to further unravel this sophisticated dialogue.
基金supported by the Natural Science Foundation of Shaanxi Province(Key Program),No.2021JZ-60(to HZ)。
文摘The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response fails to restore endoplasmic reticulum homeostasis,it can trigger proinflammatory and pro-death signals,which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases.This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases.The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise.Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies,including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid,which enhance protein folding and reduce endoplasmic reticulum stress.Small molecule modulators that influence endoplasmic reticulum stress sensors,including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1,are also potential therapeutic agents.Additionally,inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1,a key endoplasmic reticulum stress sensor,represent another class of drugs that could prevent the formation of toxic aggregates.The activation of nuclear receptors,such as PPAR and FXR,may also help mitigate ER stress.Furthermore,enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins.Combination treatments that involve endoplasmicreticulum-stress-targeting drugs and gene therapies are also being explored.Despite these potential therapeutic strategies,significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration,and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective,well-tolerated drugs.The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects,which have hindered their clinical translation.Moreover,signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance.Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies.In conclusion,while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases,additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.
基金the Scientific and Technological Research Council of Türkiye(TÜBİTAK)Under the International Postdoctoral Research Fellowship Program(2219),No.1059B192400980the National Postdoctoral Research Fellowship Program(2218),No.122C158.
文摘Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.
基金supported by the National Natural Science Foundation of China(Nos.10731020,10971023)the Shu Guang Project of Shanghai Municipal Education Commission and Shanghai Education DepartmentFoundation(No.07SG38)the Foundation of the Ministry of Education of China
文摘The authors define the equi-nuclearity of uniform Roe algebras of a family of metric spaces. For a discrete metric space X with bounded geometry which is covered by a family of subspaces {Xi}i=1^∞, if {C^＊（Xi）}i=1^∞ are equi-nuclear and under some proper gluing conditions, it is proved that C＊（X） is nuclear. Furthermore, it is claimed that in general, the coarse Roe algebra C^＊ （X） is not nuclear.
基金supported by the National Natural Science Foundation of China,Nos.82271327 (to ZW),82072535 (to ZW),81873768 (to ZW),and 82001253 (to TL)。
文摘The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.
基金funded by FEDER/Ministerio de Ciencia,Innovación y Universidades Agencia Estatal de Investigación/Project(PID2020-119729GB-100,REF/AEI/10.13039/501100011033)(to EP)a predoctoral fellowship from the Spanish Ministry of Universities(FPU)and Amigos de la Universidad de Navarra(to NSS)“Programa MRR Investigo 2023”(to MGB and MMD)。
文摘Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide(NAD~+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3(NLRP3). However, whether sirtuin 2-mediated pathways induce a pro-or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.
基金supported by the National Natural Science Foundation of China,Nos.82204360(to HM)and 82270411(to GW)National Science and Technology Innovation 2030 Major Program,No.2021ZD0200900(to YL)。
文摘Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.
基金supported by the National Natural Science Foundation of China,Nos.82071387(to HT),81971172(to YW)the Natural Science Foundation of Zhejiang Province,China,No.LY22H090012(to HT)the Basic Research Project of Wenzhou City,China,No.Y20220923(to MZ)。
文摘The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.
基金supported by the Army Laboratory Animal Foundation of China,No.SYDW[2020]22(to TC)the Shaanxi Provincial Key R&D Plan General Project of China,No.2022SF-236(to YM)the National Natural Science Foundation of China,No.82202070(to TC)。
文摘A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity.After 4 weeks of tail suspension,there were no notable alterations in retinal function and morphology,while after 8 weeks of tail suspension,significant reductions in retinal function were observed,and the outer nuclear layer was thinner,with abundant apoptotic cells.To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina,proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension.The results showed that the expression levels of fibroblast growth factor 2(also known as basic fibroblast growth factor)and glial fibrillary acidic protein,which are closely related to Müller cell activation,were significantly upregulated.In addition,Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks,respectively,of simulated weightlessness.These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness.
基金supported by the National Natural Science Foundation of China(Nos.82474412 and 82074364)the Innovation Program of Wuhan-Basic Research in 2022(No.2022020801020506)the Natural Science Foundation of Hubei Province(No.2022CFC024).
文摘Objective Safranal is a natural product from saffron(Crocus sativus L.)with anti-inflammatory and nephroprotective potential.This study aimed to explore the role of safranal in a cationic bovine serum albumin(C-BSA)-induced rat model of membranous glomerulonephritis(MGN).Methods After model establishment,Sprague–Dawley rats were administered 100 or 200 mg/kg safranal by gavage.A biochemical analyser was used to measure the urine protein levels and serum levels of renal function parameters.Hematoxylin–eosin and immunofluorescence staining of kidney tissues were performed to examine histopathological changes and assess the expression of IgG,C3,and Sirt1.Western blotting was performed to measure the protein levels of podocin,nephrin,Sirt1,and factors involved in the NF-κB/p65 pathway.Inflammatory cytokine levels in renal homogenates were determined by ELISA.Results Safranal at 100 or 200 mg/kg reduced kidney weight(2.07±0.15 g and 2.05±0.15 g)and the kidney somatic index(0.83±0.08%and 0.81±0.08%)in MGN rats compared with those in the model group without drug administration(2.62±0.17 g and 1.05±0.1%).C-BSA increased the urine protein level to 117.68±10.52 mg/day(compared with the sham group,5.03±0.45 mg/day),caused dysregulation of renal function indicators,and induced glomerular expansion and inflammatory cell infiltration in the rat kidney samples.All the biochemical and histological changes were improved by safranal administration.Safranal at two doses also increased the fluorescence intensities of IgG(0.1±0.009 and 0.088±0.008)and C3(0.065±0.006 and 0.048±0.004)compared with those in the MGN group(0.15±0.013 and 0.086±0.008).Additionally,safranal reversed the downregulation of podocin,nephrin,and Wilms tumor protein-1(WT1)levels and reversed the high inflammatory cytokine levels in MGN rats.Mechanistically,safranal activated Sirt1 signalling to interfere with NF-κB signalling in the kidney tissues of MGN rats.Conclusions Safranal ameliorates renal damage,inflammation,and podocyte injury in MGN by upregulating SIRT1 and inhibiting NF-κB signalling.
基金supported by National Natural Science Foundation of China(grant numbers 82072523 to Zhiyong Hou)Postdoctoral program of Clinical medicine of Hebei Medical University(grant numbers PD2023012 to Sujuan Xu)+2 种基金Excellent postdoctoral research funding project of Hebei Province(grant numbers B2023005011 to Sujuan Xu)The 16th special grant of China Postdoctoral Science Foundation(grant numbers 2023T160182 to Sujuan Xu)Natural Science Foundation of Hebei Province,China(grant numbers H2023206230 to Yingchao Yin,H2024206186 to Sujuan Xu).
文摘The delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts maintains bone homeostasis.Nuclear receptors(NRs)are now understood to be crucial in bone physiology and pathology.However,the function of the Farnesoid X receptor(FXR),a member of the NR family,in regulating bone homeostasis remains incompletely understood.In this study,in vitro and in vivo models revealed delayed bone development and an osteoporosis phenotype in mice lacking FXR in bone marrow mesenchymal stem cells(BMSCs)and osteoblasts due to impaired osteoblast differentiation.Mechanistically,FXR could stabilize RUNX2 by inhibiting Thoc6-mediated ubiquitination,thereby promoting osteogenic activity in BMSCs.Moreover,activated FXR could directly bind to the Thoc6 promoter,suppressing its expression.The interaction between RUNX2 and Thoc6 was mediated by the Runt domain of RUNX2 and the WD repeat of Thoc6.Additionally,Obeticholic acid(OCA),an orally available FXR agonist,could ameliorate bone loss in an ovariectomy(OVX)-induced osteoporotic mouse model.Taken together,our findings suggest that FXR plays pivotal roles in osteoblast differentiation by regulating RUNX2 stability and that targeting FXR may be a promising therapeutic approach for osteoporosis.
基金supported by the National Natural Science Foundation of China(Nos.12475174 and U2267207)YueLuShan Center Industrial Innovation(No.2024YCII0108)+2 种基金Natural Science Foundation of Hunan Province(No.2022JJ40345)Science and Technology Innovation Project of Hengyang(No.202250045336)the Project of State Key Laboratory of Radiation Medicine and Protection,Soochow University(No.GZK12023031)。
文摘The Monte Carlo(MC)method offers significant advantages in handling complex geometries and physical processes in particle transport problems and has become a widely used approach in reactor physics analysis,radiation shielding design,and medical physics.However,with the rapid advancement of new nuclear energy systems,the Monte Carlo method faces challenges in efficiency,accuracy,and adaptability,limiting its effectiveness in meeting modern design requirements.Overcoming technical obstacles related to high-fidelity coupling,high-resolution computation,and intelligent design is essential for using the Monte Carlo method as a reliable tool in numerical analysis for these new nuclear energy systems.To address these challenges,the Nuclear Energy and Application Laboratory(NEAL)team at the University of South China developed a multifunctional and generalized intelligent code platform called MagicMC,based on the Monte Carlo particle transport method.MagicMC is a developing tool dedicated to nuclear applications,incorporating intelligent methodologies.It consists of two primary components:a basic unit and a functional unit.The basic unit,which functions similarly to a standard Monte Carlo particle transport code,includes seven modules:geometry,source,transport,database,tally,output,and auxiliary.The functional unit builds on the basic unit by adding functional modules to address complex and diverse applications in nuclear analysis.MagicMC introduces a dynamic Monte Carlo particle transport algorithm to address time-space particle transport problems within emerging nuclear energy systems and incorporates a CPU-GPU heterogeneous parallel framework to enable high-efficiency,high-resolution simulations for large-scale computational problems.Anticipating future trends in intelligent design,MagicMC integrates several advanced features,including CAD-based geometry modeling,global variance reduction methods,multi-objective shielding optimization,high-resolution activation analysis,multi-physics coupling,and radiation therapy.In this paper,various numerical benchmarks-spanning reactor transient simulations,material activation analysis,radiation shielding optimization,and medical dosimetry analysis-are presented to validate MagicMC.The numerical results demonstrate MagicMC's efficiency,accuracy,and reliability in these preliminary applications,underscoring its potential to support technological advancements in developing high-fidelity,high-resolution,and high-intelligence MC-based tools for advanced nuclear applications.
基金supported by the National Key Research and Development Program of China (2022YFF0710705)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-0 13)+2 种基金funding support from the Special Research Fund for Central UniversitiesPeking Union Medical College (3332022182)the 111 Project (B20095)
文摘Background:Nuclear receptor-binding SET domain 2(NSD2)is a histone methyltrans-ferase,that catalyzes dimethylation of lysine 36 of histone 3(H3K36me2)and is asso-ciated with active transcription of a series of genes.NSD2 is overexpressed in multiple types of solid human tumors and has been proven to be related to unfavorable prog-nosis in several types of tumors.Methods:We established a mouse model in which the NSD2 gene was conditionally knocked out in intestinal epithelial cells.We used azoxymethane and dextran sodium sulfate to chemically induce murine colorectal cancer.The development of colorectal tumors were investigated using post-necropsy quantification,immunohistochemistry,and enzyme-linked immunosorbent assay(ELISA).Results:Compared with wild-type(WT)control mice,NSD2^(fl/fl)-Vil1-Cre mice exhib-ited significantly decreased tumor numbers,histopathological changes,and cytokine expression in colorectal tumors.Conclusions:Conditional knockout of NSD2 in intestinal epithelial cells significantly inhibits colorectal cancer progression.
基金Supported by Xi’an Science and Technology Plan Project,No.23YXYJ0162Shaanxi Province Traditional Chinese Medicine Research and Innovation Talent Plan Project,No.TZKN-CXRC-16+2 种基金Project of Shaanxi Administration of Traditional Chinese Medicine,No.SZYKJCYC-2025-JC-010Shaanxi Province Key Research and Development Plan Project-Social Development Field,No.S2025-YF-YBSF-0391the Science and Technology Innovation Cultivation Program of Longhua Hospital affiliated to Shanghai University of Chinese Medicine,No.YD202220。
文摘BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.
基金supported by grants from the National Natural Science Foundation of China(82404638)the Xingdian Talent Plan of Yunnan Province(XDYC-QNRC-2023-0427,XDYC-YLXZ 2022-0025)the Natural Science Foundation of Yunnan Province(202101BD070001-034,202101BD070001-049,202201AT070267,202201AU070183).
文摘Excessive osteoclastogenesis-mediated osteoporosis has been recognized as a global health concern.Candidate compounds derived from medicinal plants or functional foods are promising to treat osteoporosis due to their high safety and efficiency.(−)-Epigallocatechin-3-gallate(EGCG)is the most abundant and biologically active polyphenol in green tea.It can inhibit osteoclastogenesis in vitro by blocking receptor activator of nuclear factor(NF)-κB(RANK)signaling pathways.This study used the ovariectomized(OVX)mouse model to estimate the therapeutic effect of EGCG on osteoporosis and verified the molecular mechanism in vivo.The results revealed that EGCG significantly inhibited the OVX-induced body weight gain.Moreover,no adverse effects were observed on blood glucose,histomorphological features,weights,as well as indices of liver and kidney in OVX mice.EGCG could significantly ameliorate bone loss in OVX mice by inhibiting osteoclastogenesis.This effect was evidenced by the reduced number of osteoclasts and the increased trabecular bone area in the femurs.Moreover,EGCG inhibited the activities of c-telopeptide of type I collagen(CTX-I)and tartrate-resistant acid phosphatase 5b(TRACP-5b)and strengthened bone gla protein(BGP)and procollagen I N-terminal peptide(PINP)activities in OVX mice.Mechanistically,EGCG significantly downregulated the expression of osteoclastogenesis-related marker genes and proteins,including nuclear factor of activated T cells,cytoplasmic 1(NFATc1),c-Fos,tartrate-resistant acid phosphatase(TRAP),c-Src,and cathepsin K.In addition,the phosphorylation levels of p65,c-Jun N-terminal kinase(JNK),extracellular signal-regulated kinase 1/2(ERK1/2),p38,and protein kinase B(AKT)were significantly suppressed in OVX mice.It was found that EGCG could alleviate OVX-induced bone loss in mice by suppressing osteoclastogenesis by blocking the NF-κB,mitogen-activated protein kinase(MAPK),and AKT signaling pathways.EGCG has the potential to prevent and treat osteoclast-related diseases such as osteoporosis.
基金Supported by Research Fund for Academician Lin He New Medicine,No.JYHL2022FMS02.
文摘BACKGROUND The pathophysiology of diabetic kidney disease(DKD)is complex.Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression.Previous studies have revealed that nuclear receptor subfamily 4 group A member 1(NR4A1)may serve as a novel pathogenic element in DKD;however,the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.AIM To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.METHODS Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD.Typically,45 mmol/L glucose[high glucose(HG)]was used to activate HK-2 cells to mimic the DKD model in vitro.HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.RESULTS NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells.Concurrently,NOD-like receptor protein 3(NLRP3)and phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathways were triggered,and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro.These alterations were significantly reversed via NR4A1 silencing.CONCLUSION Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.
