In this comprehensive evidence-based analysis of ulcerative colitis(UC),a causal role is identified for colonic epithelial hydrogen peroxide(H_(2)O_(2))in both the pathogenesis and relapse of this debilitating inflamm...In this comprehensive evidence-based analysis of ulcerative colitis(UC),a causal role is identified for colonic epithelial hydrogen peroxide(H_(2)O_(2))in both the pathogenesis and relapse of this debilitating inflammatory bowel disease.Studies have shown that H_(2)O_(2) production is significantly increased in the non-inflamed colonic epithelium of individuals with UC.H_(2)O_(2) is a powerful neutrophilic chemo-tactic agent that can diffuse through colonic epithelial cell membranes creating an interstitial chemotactic molecular“trail”that attracts adjacent intra-vascular neutrophils into the colonic epithelium leading to mucosal inflammation and UC.A novel therapy aimed at removing the inappropriate H_(2)O_(2) mediated chemotactic signal has been highly effective in achieving complete histologic resolution of colitis in patients experiencing refractory disease with at least one(biopsy-proven)histologic remission lasting 14 years to date.The evidence implies that therapeutic intervention to prevent the re-establishment of a pathologic H_(2)O_(2) mediated chemotactic signaling gradient will indefinitely preclude neutrophilic migration into the colonic epithelium constituting a functional cure for this disease.Cumulative data indicate that individuals with UC have normal immune systems and current treatment guidelines calling for the suppression of the immune response based on the belief that UC is caused by an underlying immune dysfunction are not supported by the evidence and may cause serious adverse effects.It is the aim of this paper to present experimental and clinical evidence that identifies H_(2)O_(2) produced by the colonic epithelium as the causal agent in the pathogenesis of UC.A detailed explanation of a novel therapeutic intervention to normalize colonic H_(2)O_(2),its rationale,components,and formulation is also provided.展开更多
Chronic hepatitis B (CHB) is a widespread infectious disease with unfavorable outcomes and life-threatening consequences for patients, in spite of modern vaccination and antiviral treatment modalities. Cutting-edge ex...Chronic hepatitis B (CHB) is a widespread infectious disease with unfavorable outcomes and life-threatening consequences for patients, in spite of modern vaccination and antiviral treatment modalities. Cutting-edge experimental approaches have demonstrated key pathways that involve cross-talk between viral particles and host immune cells. All events, including penetration of hepatitis B virus (HBV) particles into host cells, establishing persistence, and chronization of CHB infection, and possibility of complete elimination of HBV particles are controlled by the immune system. Researchers have paid special attention to the replication capacity of HBV in host cells, which is associated with cellular changes that reflect presentation of viral antigens and variability of HBV antigen features. In addition, specific HBV proteins have an immune-modulating ability to initiate molecular mechanisms that “avoid” control by the immune system. The relationship between immunological shifts and chronic infection stages has been intensively studied since it was recognized that the immune system is a direct participant in the recurrent (cyclic) nature of CHB. Understanding the wide diversity of molecular pathways and the crosstalk between innate and adaptive immune system components will provide fresh insight into CHB immune pathogenesis and the possibilities of developing new treatment strategies for this disease.展开更多
Over the last few years,neuro-cardiology has grown the awareness of the relationship between the brain and the heart,contributing to developing a modern interdisciplinary field of neuro-cardiology.To enhance the aware...Over the last few years,neuro-cardiology has grown the awareness of the relationship between the brain and the heart,contributing to developing a modern interdisciplinary field of neuro-cardiology.To enhance the awareness of the relationship between the brain and the heart,we concentrate on the brain function disability that results from cardiac dysfunction and the brain function impairment that results from cardiac dysfunction.It is usual for patients with cerebral ischemia to be preceded by cardiac impairment.The main triggers of cerebral ischemia involve arrhythmia,atrial fibrillation,etc.,reflecting a strong connection between the heart and the brain.Cerebral ischemia is linked to how the heart and brain communicate and affect each other at the pathophysiological stage.The formation of the heart-brain axis mechanism is important in its incidence and growth.The analysis explores the etiology and pathogenesis of cerebral ischemia centered on the heart-brain axis neuronal pathway and the mechanism of the relationship between the heart and brain,which offers important enrichment to the hypothesis of combined care of brain and heart and is extremely useful for gaining new knowledge for research and production of multi-target drugs for the prevention and treatment of cerebral ischemia.展开更多
Introduction Overweight and obesity are usually measured using body mass index(BMI),with overweight classifying as a BMI of 25-29.9 kg/m^(2),obesity as a BMI of≥30 kg/m^(2),and morbid obesity as a BMI of≥40 kg/m^(2)...Introduction Overweight and obesity are usually measured using body mass index(BMI),with overweight classifying as a BMI of 25-29.9 kg/m^(2),obesity as a BMI of≥30 kg/m^(2),and morbid obesity as a BMI of≥40 kg/m^(2).1 Overweight and obesity are major health crises,posing a threat to the current global health progress.2 In 2021,3.71 million deaths and 129 million disability-adjusted life-years(DALYs)were attributable to overweight and obesity.展开更多
Lysine-targeting reversible covalent inhibitors,particularly salicylaldehyde-based compounds such as the Food and Drug Administration(FDA)-approved drug Voxelotor,exhibit significant therapeutic potential but are limi...Lysine-targeting reversible covalent inhibitors,particularly salicylaldehyde-based compounds such as the Food and Drug Administration(FDA)-approved drug Voxelotor,exhibit significant therapeutic potential but are limited by challenges including instability and off-target effects.To overcome these limitations in kinase inhibitor A5,we devised a pH-responsive prodrug strategy by masking its reactive aldehyde group with an acid-labile hydrazone linkage and enhancing intracellular delivery through conjugation with FK506.The optimized prodrug demonstrated robust antitumor efficacy in K562 tumor-bearing mice.Furthermore,the incorporation of the photosensitizer chlorin e6(Ce6)led to the formation of self-assembled nanoparticles(AKNP),which not only improved physiological stability and prolonged tumor retention but also enabled light-triggered release of A5 in conjunction with photodynamic therapy(PDT).Our study thus presents a promising prodrug self-assembly strategy that combines the on-demand release of a novel lysine-targeting,reversible covalent kinase inhibitor with PDT in clinical cancer therapy.展开更多
Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord inj...Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord injury mainly relies on pharmacological and surgical interventions;however,significant challenges remain in the protection and repair of neural tissues.Autophagy,an intracellular process responsible for the degradation and recycling of macromolecular components,plays a vital role in spinal cord injury,alleviating the severity of injury by inhibiting cell apoptosis and inflammatory responses.In this review,we provide an overview of the physiological mechanisms underlying autophagy and spinal cord injury and detail the crosstalk between autophagy and other modes of cell death in spinal cord injury.In addition,we discuss the potential of targeting autophagy as a therapeutic strategy for spinal cord injury through approaches that focus on promoting or inhibiting this process,targeting specific autophagic substrates or pathways,and combining autophagy modulation with other neuroprotective or restorative interventions.In summary,this review proposes that strict regulation of autophagy may represent a viable strategy for the treatment of spinal cord injury.展开更多
Demyelinating diseases of the central nervous system are common,yet few effective strategies for myelin repair and remyelination are available.An increasing number of studies highlight the role of microRNAs(miRNAs)as ...Demyelinating diseases of the central nervous system are common,yet few effective strategies for myelin repair and remyelination are available.An increasing number of studies highlight the role of microRNAs(miRNAs)as key regulators of demyelination.miRNA mimics and inhibitors,which are currently in preclinical development,have shown promise as novel therapeutic agents.However,the mechanisms by which they protect myelin are not fully understood.Using a mouse model of acute central nervous system demyelination induced by infection with Angiostrongylus cantonensis,we investigated alterations in miRNA expression in the mouse brain.Our findings revealed a significant early-stage increase in the levels of miR-200,particularly miR-200a and miR-200c.Subsequent analysis demonstrated that combined miR-200a and miR-200c overexpression improved neurobehavioral outcomes and attenuated demyelination in Angiostrongylus cantonensis-infected mice.Further lipid metabolomic profiling indicated that miR-200a and miR-200c synergistically inhibited the production of phosphatase and tensin homolog(PTEN)and activated the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway,as confirmed by double luciferase reporter assay and western blotting.Additionally,in vitro experiments showed that miR-200a and miR-200c protected oligodendrocyte precursor cells from lipopolysaccharide-induced damage and enhanced their survival.Our study indicates the critical role of miR-200a and miR-200c in protecting against central nervous system demyelination by targeting PTEN and modulating key survival pathways.Furthermore,our findings suggest that miR-200a and miR-200c are promising diagnostic biomarkers of and therapeutic targets for treating demyelination-related disorders.展开更多
Background and Aims:Multiple regulatory mechanisms play an important role in arsenic-induced liver injury.To investigate whether histone H3 lysine 4(H3K4)methyltransferase(SET7/9)and histone H3K4 demethyltransferase(L...Background and Aims:Multiple regulatory mechanisms play an important role in arsenic-induced liver injury.To investigate whether histone H3 lysine 4(H3K4)methyltransferase(SET7/9)and histone H3K4 demethyltransferase(LSD1/KDM1A)can regulate endoplasmic reticulum stress(ERS)-related apoptosis by modulating the changes of H3K4 methylations in liver cells treated with arsenic.Methods:Apoptosis,proliferation and cell cycles were quantified by flow cytometry and real-time cell analyzer.The expression of ERS-and epigenetic-related proteins was detected by Western blot analysis.The antisense SET7/9 expression vector and the overexpressed LSD1 plasmid were used for transient transfection of LO_(2) cells.The effects of NaAsO_(2) on the methylation of H3 in the promoter regions of 78 kDa glucose-regulated protein,activating transcription factor 4 and C/EBP-homologous protein were evaluated by chromatin immunoprecipitation assay.Results:The protein expression of LSD1(1.25±0.08 vs.1.77±0.08,p=0.02)was markedly decreased by treatment with 100μM NaAsO_(2),whereas the SET7/9(0.68±0.05 vs.1.10±0.13,p=0.002)expression level was notably increased,which resulted in increased H3K4me1/2(0.93±0.64,1.19±0.22 vs.0.71±0.13,0.84±0.13,p=0.03 and p=0.003).After silencing SET7/9 and overexpressing LSD1 by transfection,apoptosis rate(in percentage:3.26±0.34 vs.7.04±0.42,4.80±0.32 vs.7.52±0.38,p=0.004 and p=0.02)was significantly decreased and proliferation rate was notably increased,which is reversed after inhibiting LSD1(in percentage:9.31±0.40 vs.7.52±0.38,p=0.03).Furthermore,the methylation levels of H3 in the promoter regions of GRP78(20.80±2.40 vs.11.75±2.47,20.46±2.23 vs.14.37±0.91,p=0.03 and p=0.01)and CHOP(48.67±4.04 vs.16.67±7.02,59.33±4.51 vs.20.67±3.06,p=0.004 and p=0.001)were significantly increased in LO_(2) cells exposed to 100μM NaAsO_(2) for 24 h.Conclusions:Histone methyltransferase SET7/9 and histone demethyltransferase LSD1 jointly regulate the changes of H3K4me1/me2 levels in arsenic-induced apoptosis.NaAsO_(2) induces apoptosis in LO_(2) cells by activating the ERS-mediated apoptotic signaling pathway,at least partially by enhancing the methylation of H3 on the promoter regions of ERS-associated genes,including GRP78 and CHOP.展开更多
Ulcerative colitis has baffled researchers since the early 20th century.The pre-vailing explanation attributes the chronic recurring episodes of bloody diarrhea and abdominal pain to some form of immune abnormality,de...Ulcerative colitis has baffled researchers since the early 20th century.The pre-vailing explanation attributes the chronic recurring episodes of bloody diarrhea and abdominal pain to some form of immune abnormality,despite the lack of supporting evidence.This highlights the critical need for innovative research directions and methodologies to uncover the cause and develop a cure for this disease.By analyzing existing data from less than a dozen previously published studies,a novel,evidence-based pathogenesis was constructed,implicating colonic epithelial hydrogen peroxide as a causal factor in the development of this disease.This newly identified mechanism informed the creation of a ground-breaking class of therapeutics,known as reducing agents,which have demon-strated remarkable success in resolving colonic inflammation and restoring colonic health in patients with refractory ulcerative colitis.This paper outlines the timeline of these publications and reinterprets the findings within the context of contemporary biomedical science.展开更多
Objective Diabetic kidney disease is a serious complication of diabetes,which is the leading cause of end-stage renal disease worldwide.Approximately 40%of individuals with diabetes develop diabetic kidney disease.At ...Objective Diabetic kidney disease is a serious complication of diabetes,which is the leading cause of end-stage renal disease worldwide.Approximately 40%of individuals with diabetes develop diabetic kidney disease.At present,the most important drugs for diabetic kidney disease include renin-angiotensin-aldosterone system inhibitors,angiotensin receptor blockers,sodium-glucose cotransporter-2 inhibitors,and newly approved aldosterone receptor antagonists.However,to date,there are still no effective drugs to prevent diabetic kidney disease from progressing to end-stage renal disease.Network pharmacology combined with bioinformatics and pharmacology provides a powerful tool for studying the mechanism of drug action.Traditional Chinese medicine has accumulated rich experience in the treatment of diabetic kidney disease,and its multi-target,multi-component,and multi-pathway characteristics provide new ideas for modern medicine.This article reviews the research progress of network pharmacology and drug therapy in diabetic kidney disease.展开更多
Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease(PD),supporting the“body-first”hypothesis.However,there remains a notable absence of PD-specific...Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease(PD),supporting the“body-first”hypothesis.However,there remains a notable absence of PD-specific animal models induced by inflammatory cytokines.This study introduces a novel mouse model of PD driven by the proinflammatory cytokine CXCL1,identified in our previous research.The involvement of CXCL1 in PD pathogenesis was validated using subacute and chronic MPTP-induced mouse models.Based on these findings,2-month-old C57BL/6J mice were intravenously administered CXCL1(20 ng/kg/day)for 2 weeks(5 days per week),successfully replicating motor deficits and pathological alterations in the substantia nigra observed in the chronic MPTP model.These results demonstrate the potential of CXCL1-induced inflammation as a mechanism for PD modeling.The model revealed activation of the PPAR signaling pathway in CXCL1-mediated neuronal damage by CXCL1.Linoleic acid,a PPAR-γactivator,significantly mitigated MPTPand CXCL1-induced toxicity and reduced serum CXCL1levels.In addition,the CXCL1-injected mouse model shortened the timeline for developing chronic PD mouse model to 2 weeks,offering an efficient platform for studying inflammation-driven processes in PD.The findings provide critical insights into the inflammatory mechanisms underlying PD and identify promising therapeutic targets for intervention.展开更多
Iron is the most abundant transition metal in the brain and is essential for brain development and neuronal function;however,its abnormal accumulation is also implicated in various neurological disorders.The olfactory...Iron is the most abundant transition metal in the brain and is essential for brain development and neuronal function;however,its abnormal accumulation is also implicated in various neurological disorders.The olfactory bulb(OB),an early target in neurodegenerative diseases,acts as a gateway for environmental toxins and contains diverse neuronal populations with distinct roles.This study explored the cell-specific vulnerability to iron in the OB using a mouse model of intranasal administration of ferric ammonium citrate(FAC).Olfactory function was assessed through olfactory discrimination tests,while iron levels in OB tissues,cerebrospinal fluid(CSF),and serum were quantified using inductively coupled plasma mass spectrometry(ICP-MS),immunohistochemical staining,and iron assays.Transcriptomic changes and immune responses were assessed using RNA sequencing and immune cell infiltration analysis.Results showed that intranasal FAC administration impaired olfactory function,accompanied by iron deposition in the olfactory mucosa and OB,as well as damage to olfactory sensory neurons.Notably,these effects occurred without elevations in CSF or serum iron levels.OB iron accumulation activated multiple immune cells,including microglia and astrocytes,but did not trigger ferroptosis.Spatial transcriptomic sequencing of healthy adult mouse OBs revealed significant cellular heterogeneity,with an abundance of neuroglia and neurons.Among neurons,GABAergic neurons were the most prevalent,followed by glutamatergic and dopaminergic neurons,while cholinergic and serotonergic neurons were sparsely distributed.Under iron-stressed conditions,oligodendrocytes,dopaminergic neurons,and glutamatergic neurons exhibited significant damage,while GABAergic neurons remained unaffected.These findings highlight the selective vulnerability of neuronal and glial populations to iron-induced stress,offering novel insights into the loss of specific cell types in the OB during iron dysregulation.展开更多
BACKGROUND Echinococcosis,caused by Echinococcus parasites,includes alveolar echinococcosis(AE),the most lethal form,primarily affecting the liver with a 90%mortality rate without prompt treatment.While radical surger...BACKGROUND Echinococcosis,caused by Echinococcus parasites,includes alveolar echinococcosis(AE),the most lethal form,primarily affecting the liver with a 90%mortality rate without prompt treatment.While radical surgery combined with antiparasitic therapy is ideal,many patients present late,missing hepatectomy opportunities.Ex vivo liver resection and autotransplantation(ELRA)offers hope for such patients.Traditional surgical decision-making,relying on clinical experience,is prone to bias.Machine learning can enhance decision-making by identifying key factors influencing surgical choices.This study innovatively employs multiple machine learning methods by integrating various feature selection techniques and SHapley Additive exPlanations(SHAP)interpretive analysis to deeply explore the key decision factors influencing surgical strategies.AIM To determine the key preoperative factors influencing surgical decision-making in hepatic AE(HAE)using machine learning.METHODS This was a retrospective cohort study at the First Affiliated Hospital of Xinjiang Medical University(July 2010 to August 2024).There were 710 HAE patients(545 hepatectomy and 165 ELRA)with complete clinical data.Data included demographics,laboratory indicators,imaging,and pathology.Feature selection was performed using recursive feature elimination,minimum redundancy maximum relevance,and least absolute shrinkage and selection operator regression,with the intersection of these methods yielding 10 critical features.Eleven machinelearning algorithms were compared,with eXtreme Gradient Boosting(XGBoost)optimized using Bayesian optimization.Model interpretability was assessed using SHAP analysis.RESULTS The XGBoost model achieved an area under the curve of 0.935 in the training set and 0.734 in the validation set.The optimal threshold(0.28)yielded sensitivity of 93.6%and specificity of 90.9%.SHAP analysis identified type of vascular invasion as the most important feature,followed by platelet count and prothrombin time.Lesions invading the hepatic vein,inferior vena cava,or multiple vessels significantly increased the likelihood of ELRA.Calibration curves showed good agreement between predicted and observed probabilities(0.2-0.7 range).The model demonstrated high net clinical benefit in Decision Curve Analysis,with accuracy of 0.837,recall of 0.745,and F1 score of 0.788.CONCLUSION Vascular invasion is the dominant factor influencing the choice of surgical approach in HAE.Machine-learning models,particularly XGBoost,can provide transparent and data-driven support for personalized decision-making.展开更多
Modern lifestyle and diet have increased the incidence rate of uric acid(UA)metabolism-related diseases like hyperuricemia(HUA)and gout,posing heavy economic burden to individual patients and their families and the so...Modern lifestyle and diet have increased the incidence rate of uric acid(UA)metabolism-related diseases like hyperuricemia(HUA)and gout,posing heavy economic burden to individual patients and their families and the society.UA metabolism is a complex physiological process involving the kidney,intestine,and other organs.A number of factors together regulate UA metabolism,including genetics,diet,hormones,and the gut microbiota.This review summaries the gut microbiota features in subjects with HUA and gout,and the therapeutic effects of implementing microecological therapies(probiotics,prebiotics,or fecal microbiota transplant)that target modulate the gut microbiota and its downstream metabolism on the disease.Current evidence shows that these strategies are safe and promising in alleviate inflammation,reduce UA,and restoring a healthy gut microbiota in subjects with UA metabolism-related diseases.However,most clinical data are generated by animal studies.Therefore,we propose that vigorous human intervention trials should be conducted in the future to evaluate the therapeutic effects of microecological therapies in managing HUA and gout.展开更多
Tianxiangdan(TXD),a traditional Chinese herbal remedy,demonstrates efficacy in mitigating myocardial ischemia-reperfusion(I/R)-induced damage.This study employed network pharmacology to evaluate the therapeutic target...Tianxiangdan(TXD),a traditional Chinese herbal remedy,demonstrates efficacy in mitigating myocardial ischemia-reperfusion(I/R)-induced damage.This study employed network pharmacology to evaluate the therapeutic targets and mechanisms of TXD in treating I/R.Highperformance liquid chromatography-mass spectrometry(HPLC-MS)identified 86 compounds in TXD.Network pharmacological analysis predicted potential target genes and their modes of action.Cardiac function,ischaemic ST changes,lactate dehydrogenase(LDH),malondialdehyde(MDA),superoxide dismutase(SOD)activity,myocardial fiber,and infarct size were assessed using in vivo and in vitro I/R injury models.Estrogen receptor alpha(ERα)protein expression and estradiol(E2)levels were measured to confirm TXD's impact on estrogen levels and ERαexpression.To examine if TXD reduces I/R injury through ERα,an AZD group(300 nmol·L^(-1)AZD9496 and 15%TXD serum)was compared to a TXD group(15%TXD serum).The study hypothesized that TXD upregulates the ERα-mediated iron metamorphosis pathway.I/R injury-induced ferroptosis was identified using a Fer-1 group(1.0μmol·L^(-1)Fer-1 and 15%TXD serum)to elucidate the potential association between ferroptosis and ERαproteins.A DCFH-DA probe detected reactive oxygen species(ROS)and Fe^(2+),while Western blotting assessed target protein expression.Both in vitro and in vivo experiments demonstrated that TXD attenuated I/R injury by reducing elevated ST-segment levels,improving cardiac injury biomarkers(LDH,MDA,and SOD),alleviating pathological features,and preventing I/R-induced loss of cell viability in vitro.The effects and mechanisms of TXD on I/R injury-associated ferroptosis were investigated using I/R-induced H9c2 cells.The TXD group showed significantly decreased ROS and Fe^(2+)levels,while the AZ group(treated with AZD9496)exhibited increased levels.The TXD group demonstrated enhanced expression of ERαand glutathione peroxidase 4(GPX4),with reduced levels of P53 protein and ferritinheavy polypeptide 1(FTH1).The AZ group exhibited contrasting effects on these expression levels.The literature indicated a novel connection between ERαand ferroptosis.TXD activates the ERαsignaling pathway,promoting protection against I/R-induced myocardial cell ferroptosis.This study provides evidence supporting TXD use for myocardial ischemia treatment,particularly in older female patients who may benefit from its therapeutic outcomes.展开更多
Background:The Vietnamese swine represents a promising animal model due to its anatomical,physiological,and pathophysiological similarities to humans.Notably,the arrangement of lobes and ducts in the mammary glands is...Background:The Vietnamese swine represents a promising animal model due to its anatomical,physiological,and pathophysiological similarities to humans.Notably,the arrangement of lobes and ducts in the mammary glands is highly comparable to that of humans and is histologically indistinguishable.Leveraging these advantages through the chemical induction of carcinogenesis in this model offers a robust approach to mimic human exposure to carcinogenic compounds.Methods:This study elaborates on a protocol for developing a representative model of MNU-induced invasive breast carcinoma in three Vietnamese swine,validated histologically and immunologically.It evaluates not only the tissue similarity with humans,but also the development of chemically induced mammary tumors in an immunologically competent animal.Moreover,this study addresses the existing gap in histological knowledge regarding mammary tissue in the porcine model.Results:Our findings suggest that this model encompasses the full spectrum of cancer.It incorporates the key elements of a tumor microenvironment that enable tumor growth and propagation,such as immune cells,blood vessels,fibroblasts,extracellular matrix,fatty acids,and signaling molecules.Conclusions:This model offers significant potential to advance the understanding of cancer pathogenesis and facilitate the development of innovative therapeutic strategies by closely replicating human tumor biology.展开更多
Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an i...Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.展开更多
Background:Ethylhexyl triazone(EHT)and diethylhexyl butamido triazone(HEB)both belong to the recently developed class of triazine ultraviolet filters.However,their toxicity profiles remain unclear.Objective:To assess ...Background:Ethylhexyl triazone(EHT)and diethylhexyl butamido triazone(HEB)both belong to the recently developed class of triazine ultraviolet filters.However,their toxicity profiles remain unclear.Objective:To assess the genotoxic and phototoxic effects of EHT and HEB.Methods:The genotoxicity of EHT and HEB was assessed using in vitro bacterial reverse mutation assays,chromosomal aberration assays,and micronucleus assays.Meanwhile,their phototoxicity was evaluated using in vitro 3T3 neutral red uptake(NRU)phototoxicity assays and in vivo skin phototoxicity tests.Results:In the bacterial reverse mutation assay,the number of bacterial colonies was not significantly higher in the EHT and HEB groups than in the solvent control group.Similarly,the chromosomal aberration assay revealed no increase in aberration rates after either EHT or HEB treatment.In the micronucleus assay,the frequency of micronuclei was comparable between the treatment and control groups.Finally,based on the 3T3 NRU phototoxicity assay,both EHT and HEB(photo-irritation factor<2 and mean photo effect value<0.1)were classified as non-phototoxic.The skin phototoxicity test in vivo showed the same results as in vitro.Conclusion:Results from a series of genotoxicity and phototoxicity assays indicate that EHT and HEB possess neither genotoxic nor phototoxic potential.These findings provide experimental evidence supporting the safety of EHT and HEB for topical applications.展开更多
Upconversion luminescent(UCL)materials have broad application prospects in the field of temperature sensing;thus,improving the luminescence performance and temperature measurement sensitivity of upconversion phosphors...Upconversion luminescent(UCL)materials have broad application prospects in the field of temperature sensing;thus,improving the luminescence performance and temperature measurement sensitivity of upconversion phosphors is highly important.In this study,SrAl_(2)Si_(2)O_(8)with good thermal stability was doped with Ho^(3+)and Yb^(3+),and the optimal concentration was determined to be S rAl_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)(in mole fraction).A series of(Sr_(0.87-x)Ba_(x))Al_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)phosphor samples was prepared by using a cationic substitution strategy and further doping Ba^(2+)to replace the Sr^(2+)lattice in the matrix.The re sults show that the introduction of Ba^(2+)effectively replaces Sr^(2+)and significantly increases the upconversion fluorescence emission intensity of SrAl_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)by approximately 2.9times.The temperature sensing properties of SrAl_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)and Sr_(0.3)7Ba_(0.5)0Al_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)were investigated.The Ho^(3+)-based5F5and5S2/5F4nonthermal coupled energy level fluorescence intensity ratio(FIR)techniques in the Ba_(0.3)7S r_(0.50)Al_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)phosphors show a maximum temperature measurement absolute sensitivity of 4.32%/K at 573 K and a maximum relative sensitivity of 1.08%/K at 373 K;these values are 5.8 and 3.2 times greater,respectively,than that of the non-Ba^(2+)-doped SrAl_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)phosphor.These results not only confirm the effectiveness of the cation substitution strategy in enhancing the upconversion luminescence performance and temperature sensing characteristics but also provide a scientific basis for the design of high-performance optical temperature sensors.展开更多
Triple-negative breast cancer (TNBC) is an aggressive and often fatal disease, especially since the brain metastasis of TNBC has been a particularly severe manifestation. However, brain metastasis in TNBC at early sta...Triple-negative breast cancer (TNBC) is an aggressive and often fatal disease, especially since the brain metastasis of TNBC has been a particularly severe manifestation. However, brain metastasis in TNBC at early stages often lacks noticeable symptoms, making it challenging to detect. Near-infrared II (NIR-II) fluorescence microscopic imaging obtains long wavelength, which enables reduced scattering, high spatial resolution and minimal autofluorescence, it is also a favorable imaging method for tumor diagnosis. PbS@CdS quantum dots (QDs) are one of the popular NIR-II fluorescence nanoprobes for well brightness. In this study, NIR-II emissive PbS@CdS QDs were utilized and further encapsulated with thiol-terminated poly(ethylene oxide) (SH-PEG, MW = 5000) to form PbS@CdS@PEG QDs nanoparticles (NPs). The obtained PbS@CdS@PEG QDs NPs were then characterized and further studied in detail. The PbS@CdS@PEG QDs NPs had large absorption spectra, exhibited strong NIR-II fluorescence emission at approximately 1300nm, and possessed good NIR-II fluorescence properties. Then, the mice model of early-stage brain metastases of TNBC was established, and the PbS@CdS@PEG QDs NPs were injected into the tumor-bearing mice for NIR-II fluorescence microscopic bioimaging. The brain vessels and tumors of the living mice were detected with high spatial resolution under the NIR-II fluorescence microscopic imaging system with irradiation of 808nm laser. The tumor tissues were further restricted and prepared as thin slices. The NIR-II fluorescence signals were collected from the tumor slices with high spatial resolution and signal-to-background ratio (SBR). Thus, the PbS@CdS@PEG QDs NPs-assisted NIR-II fluorescence microscopic system can effectively achieve targeting brain metastases of TNBC imaging, offering a novel and promising approach for TNBC-specific diagnosis.展开更多
文摘In this comprehensive evidence-based analysis of ulcerative colitis(UC),a causal role is identified for colonic epithelial hydrogen peroxide(H_(2)O_(2))in both the pathogenesis and relapse of this debilitating inflammatory bowel disease.Studies have shown that H_(2)O_(2) production is significantly increased in the non-inflamed colonic epithelium of individuals with UC.H_(2)O_(2) is a powerful neutrophilic chemo-tactic agent that can diffuse through colonic epithelial cell membranes creating an interstitial chemotactic molecular“trail”that attracts adjacent intra-vascular neutrophils into the colonic epithelium leading to mucosal inflammation and UC.A novel therapy aimed at removing the inappropriate H_(2)O_(2) mediated chemotactic signal has been highly effective in achieving complete histologic resolution of colitis in patients experiencing refractory disease with at least one(biopsy-proven)histologic remission lasting 14 years to date.The evidence implies that therapeutic intervention to prevent the re-establishment of a pathologic H_(2)O_(2) mediated chemotactic signaling gradient will indefinitely preclude neutrophilic migration into the colonic epithelium constituting a functional cure for this disease.Cumulative data indicate that individuals with UC have normal immune systems and current treatment guidelines calling for the suppression of the immune response based on the belief that UC is caused by an underlying immune dysfunction are not supported by the evidence and may cause serious adverse effects.It is the aim of this paper to present experimental and clinical evidence that identifies H_(2)O_(2) produced by the colonic epithelium as the causal agent in the pathogenesis of UC.A detailed explanation of a novel therapeutic intervention to normalize colonic H_(2)O_(2),its rationale,components,and formulation is also provided.
文摘Chronic hepatitis B (CHB) is a widespread infectious disease with unfavorable outcomes and life-threatening consequences for patients, in spite of modern vaccination and antiviral treatment modalities. Cutting-edge experimental approaches have demonstrated key pathways that involve cross-talk between viral particles and host immune cells. All events, including penetration of hepatitis B virus (HBV) particles into host cells, establishing persistence, and chronization of CHB infection, and possibility of complete elimination of HBV particles are controlled by the immune system. Researchers have paid special attention to the replication capacity of HBV in host cells, which is associated with cellular changes that reflect presentation of viral antigens and variability of HBV antigen features. In addition, specific HBV proteins have an immune-modulating ability to initiate molecular mechanisms that “avoid” control by the immune system. The relationship between immunological shifts and chronic infection stages has been intensively studied since it was recognized that the immune system is a direct participant in the recurrent (cyclic) nature of CHB. Understanding the wide diversity of molecular pathways and the crosstalk between innate and adaptive immune system components will provide fresh insight into CHB immune pathogenesis and the possibilities of developing new treatment strategies for this disease.
基金supported by NSFC Projects of International Cooperation and Exchanges(NO.81720108004)National Natural Science Foundation of China(NO.81974019)+5 种基金The Research Team Project of Natural Science Foundation of Guangdong Province of China(NO.2017A030312007)Science and Technology Planning Project of Guangdong Province(NO.2022B1212010010)The key program of guangzhou science research plan(NO.201904020047)The Special Project of Dengfeng Program of Guangdong Provincial People’s Hospital(NO.DFJH201812NO.KJ012019119NO.KJ012019423.)
文摘Over the last few years,neuro-cardiology has grown the awareness of the relationship between the brain and the heart,contributing to developing a modern interdisciplinary field of neuro-cardiology.To enhance the awareness of the relationship between the brain and the heart,we concentrate on the brain function disability that results from cardiac dysfunction and the brain function impairment that results from cardiac dysfunction.It is usual for patients with cerebral ischemia to be preceded by cardiac impairment.The main triggers of cerebral ischemia involve arrhythmia,atrial fibrillation,etc.,reflecting a strong connection between the heart and the brain.Cerebral ischemia is linked to how the heart and brain communicate and affect each other at the pathophysiological stage.The formation of the heart-brain axis mechanism is important in its incidence and growth.The analysis explores the etiology and pathogenesis of cerebral ischemia centered on the heart-brain axis neuronal pathway and the mechanism of the relationship between the heart and brain,which offers important enrichment to the hypothesis of combined care of brain and heart and is extremely useful for gaining new knowledge for research and production of multi-target drugs for the prevention and treatment of cerebral ischemia.
文摘Introduction Overweight and obesity are usually measured using body mass index(BMI),with overweight classifying as a BMI of 25-29.9 kg/m^(2),obesity as a BMI of≥30 kg/m^(2),and morbid obesity as a BMI of≥40 kg/m^(2).1 Overweight and obesity are major health crises,posing a threat to the current global health progress.2 In 2021,3.71 million deaths and 129 million disability-adjusted life-years(DALYs)were attributable to overweight and obesity.
基金supported by the grants from National Key R&D Program of China(No.2022YFA1104800)Shenzhen Science and Technology Program(No.JCYJ20210324124214038)+4 种基金National Natural Science Foundation of China(Nos.52072418,82300016)Natural Science Foundation of Guangdong Province(No.2023A1515140072)Shenzhen Key Laboratory of Neural Cell Reprogramming and Drug Research,Social Development Science and Technology Key Project of Dongguan(No.20231800940512)the National Medical Research Council(NMRC,No.23-0740-A0001)the Ministry of Education(MOE,No.T2EP10222-0002)of Singapore.
文摘Lysine-targeting reversible covalent inhibitors,particularly salicylaldehyde-based compounds such as the Food and Drug Administration(FDA)-approved drug Voxelotor,exhibit significant therapeutic potential but are limited by challenges including instability and off-target effects.To overcome these limitations in kinase inhibitor A5,we devised a pH-responsive prodrug strategy by masking its reactive aldehyde group with an acid-labile hydrazone linkage and enhancing intracellular delivery through conjugation with FK506.The optimized prodrug demonstrated robust antitumor efficacy in K562 tumor-bearing mice.Furthermore,the incorporation of the photosensitizer chlorin e6(Ce6)led to the formation of self-assembled nanoparticles(AKNP),which not only improved physiological stability and prolonged tumor retention but also enabled light-triggered release of A5 in conjunction with photodynamic therapy(PDT).Our study thus presents a promising prodrug self-assembly strategy that combines the on-demand release of a novel lysine-targeting,reversible covalent kinase inhibitor with PDT in clinical cancer therapy.
基金funded by the National Natural Science Foundation of China,No.82271395(to GL),the Guangdong Basic and Applied Basic Research Foundation,No.2023A1515030073(to GL)the grants from University of Macao Research Committee,China,No.MYRG2022-00074-ICMS(to CTV)Guangzhou Science and Technology Program Project,No.2025A04J4740(to GL).
文摘Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord injury mainly relies on pharmacological and surgical interventions;however,significant challenges remain in the protection and repair of neural tissues.Autophagy,an intracellular process responsible for the degradation and recycling of macromolecular components,plays a vital role in spinal cord injury,alleviating the severity of injury by inhibiting cell apoptosis and inflammatory responses.In this review,we provide an overview of the physiological mechanisms underlying autophagy and spinal cord injury and detail the crosstalk between autophagy and other modes of cell death in spinal cord injury.In addition,we discuss the potential of targeting autophagy as a therapeutic strategy for spinal cord injury through approaches that focus on promoting or inhibiting this process,targeting specific autophagic substrates or pathways,and combining autophagy modulation with other neuroprotective or restorative interventions.In summary,this review proposes that strict regulation of autophagy may represent a viable strategy for the treatment of spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.82372277(to ZW),82272361(to XS),82271395(to GL)Guangdong Province Basic and Applied Basic Research Fund Project,No.2024A1515010615(to XS)+1 种基金Guangdong Province Natural Youth Promotion Project,No.2314070000241(to GL)Guangzhou Science and Technology Project,No.2025A04J4740(to GL).
文摘Demyelinating diseases of the central nervous system are common,yet few effective strategies for myelin repair and remyelination are available.An increasing number of studies highlight the role of microRNAs(miRNAs)as key regulators of demyelination.miRNA mimics and inhibitors,which are currently in preclinical development,have shown promise as novel therapeutic agents.However,the mechanisms by which they protect myelin are not fully understood.Using a mouse model of acute central nervous system demyelination induced by infection with Angiostrongylus cantonensis,we investigated alterations in miRNA expression in the mouse brain.Our findings revealed a significant early-stage increase in the levels of miR-200,particularly miR-200a and miR-200c.Subsequent analysis demonstrated that combined miR-200a and miR-200c overexpression improved neurobehavioral outcomes and attenuated demyelination in Angiostrongylus cantonensis-infected mice.Further lipid metabolomic profiling indicated that miR-200a and miR-200c synergistically inhibited the production of phosphatase and tensin homolog(PTEN)and activated the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway,as confirmed by double luciferase reporter assay and western blotting.Additionally,in vitro experiments showed that miR-200a and miR-200c protected oligodendrocyte precursor cells from lipopolysaccharide-induced damage and enhanced their survival.Our study indicates the critical role of miR-200a and miR-200c in protecting against central nervous system demyelination by targeting PTEN and modulating key survival pathways.Furthermore,our findings suggest that miR-200a and miR-200c are promising diagnostic biomarkers of and therapeutic targets for treating demyelination-related disorders.
基金The present study was supported by the National Natural Science Foundation of China(Grant No.81100284)Guizhou Science and Technology Cooperation Platform Personnel[2018](Grant No.5779-10,5779-19)Science and Technology Foundation of Guizhou Province(Grant No.ZK[2021]-364)。
文摘Background and Aims:Multiple regulatory mechanisms play an important role in arsenic-induced liver injury.To investigate whether histone H3 lysine 4(H3K4)methyltransferase(SET7/9)and histone H3K4 demethyltransferase(LSD1/KDM1A)can regulate endoplasmic reticulum stress(ERS)-related apoptosis by modulating the changes of H3K4 methylations in liver cells treated with arsenic.Methods:Apoptosis,proliferation and cell cycles were quantified by flow cytometry and real-time cell analyzer.The expression of ERS-and epigenetic-related proteins was detected by Western blot analysis.The antisense SET7/9 expression vector and the overexpressed LSD1 plasmid were used for transient transfection of LO_(2) cells.The effects of NaAsO_(2) on the methylation of H3 in the promoter regions of 78 kDa glucose-regulated protein,activating transcription factor 4 and C/EBP-homologous protein were evaluated by chromatin immunoprecipitation assay.Results:The protein expression of LSD1(1.25±0.08 vs.1.77±0.08,p=0.02)was markedly decreased by treatment with 100μM NaAsO_(2),whereas the SET7/9(0.68±0.05 vs.1.10±0.13,p=0.002)expression level was notably increased,which resulted in increased H3K4me1/2(0.93±0.64,1.19±0.22 vs.0.71±0.13,0.84±0.13,p=0.03 and p=0.003).After silencing SET7/9 and overexpressing LSD1 by transfection,apoptosis rate(in percentage:3.26±0.34 vs.7.04±0.42,4.80±0.32 vs.7.52±0.38,p=0.004 and p=0.02)was significantly decreased and proliferation rate was notably increased,which is reversed after inhibiting LSD1(in percentage:9.31±0.40 vs.7.52±0.38,p=0.03).Furthermore,the methylation levels of H3 in the promoter regions of GRP78(20.80±2.40 vs.11.75±2.47,20.46±2.23 vs.14.37±0.91,p=0.03 and p=0.01)and CHOP(48.67±4.04 vs.16.67±7.02,59.33±4.51 vs.20.67±3.06,p=0.004 and p=0.001)were significantly increased in LO_(2) cells exposed to 100μM NaAsO_(2) for 24 h.Conclusions:Histone methyltransferase SET7/9 and histone demethyltransferase LSD1 jointly regulate the changes of H3K4me1/me2 levels in arsenic-induced apoptosis.NaAsO_(2) induces apoptosis in LO_(2) cells by activating the ERS-mediated apoptotic signaling pathway,at least partially by enhancing the methylation of H3 on the promoter regions of ERS-associated genes,including GRP78 and CHOP.
文摘Ulcerative colitis has baffled researchers since the early 20th century.The pre-vailing explanation attributes the chronic recurring episodes of bloody diarrhea and abdominal pain to some form of immune abnormality,despite the lack of supporting evidence.This highlights the critical need for innovative research directions and methodologies to uncover the cause and develop a cure for this disease.By analyzing existing data from less than a dozen previously published studies,a novel,evidence-based pathogenesis was constructed,implicating colonic epithelial hydrogen peroxide as a causal factor in the development of this disease.This newly identified mechanism informed the creation of a ground-breaking class of therapeutics,known as reducing agents,which have demon-strated remarkable success in resolving colonic inflammation and restoring colonic health in patients with refractory ulcerative colitis.This paper outlines the timeline of these publications and reinterprets the findings within the context of contemporary biomedical science.
文摘Objective Diabetic kidney disease is a serious complication of diabetes,which is the leading cause of end-stage renal disease worldwide.Approximately 40%of individuals with diabetes develop diabetic kidney disease.At present,the most important drugs for diabetic kidney disease include renin-angiotensin-aldosterone system inhibitors,angiotensin receptor blockers,sodium-glucose cotransporter-2 inhibitors,and newly approved aldosterone receptor antagonists.However,to date,there are still no effective drugs to prevent diabetic kidney disease from progressing to end-stage renal disease.Network pharmacology combined with bioinformatics and pharmacology provides a powerful tool for studying the mechanism of drug action.Traditional Chinese medicine has accumulated rich experience in the treatment of diabetic kidney disease,and its multi-target,multi-component,and multi-pathway characteristics provide new ideas for modern medicine.This article reviews the research progress of network pharmacology and drug therapy in diabetic kidney disease.
基金supported by the National Natural Science Foundation of China (32471049,32170984,32471188,32200802)Natural Science Foundation of Shandong Province (ZR2023QH110)。
文摘Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease(PD),supporting the“body-first”hypothesis.However,there remains a notable absence of PD-specific animal models induced by inflammatory cytokines.This study introduces a novel mouse model of PD driven by the proinflammatory cytokine CXCL1,identified in our previous research.The involvement of CXCL1 in PD pathogenesis was validated using subacute and chronic MPTP-induced mouse models.Based on these findings,2-month-old C57BL/6J mice were intravenously administered CXCL1(20 ng/kg/day)for 2 weeks(5 days per week),successfully replicating motor deficits and pathological alterations in the substantia nigra observed in the chronic MPTP model.These results demonstrate the potential of CXCL1-induced inflammation as a mechanism for PD modeling.The model revealed activation of the PPAR signaling pathway in CXCL1-mediated neuronal damage by CXCL1.Linoleic acid,a PPAR-γactivator,significantly mitigated MPTPand CXCL1-induced toxicity and reduced serum CXCL1levels.In addition,the CXCL1-injected mouse model shortened the timeline for developing chronic PD mouse model to 2 weeks,offering an efficient platform for studying inflammation-driven processes in PD.The findings provide critical insights into the inflammatory mechanisms underlying PD and identify promising therapeutic targets for intervention.
基金supported by the National Natural Science Foundation of China (32471188,32170984,82301787)。
文摘Iron is the most abundant transition metal in the brain and is essential for brain development and neuronal function;however,its abnormal accumulation is also implicated in various neurological disorders.The olfactory bulb(OB),an early target in neurodegenerative diseases,acts as a gateway for environmental toxins and contains diverse neuronal populations with distinct roles.This study explored the cell-specific vulnerability to iron in the OB using a mouse model of intranasal administration of ferric ammonium citrate(FAC).Olfactory function was assessed through olfactory discrimination tests,while iron levels in OB tissues,cerebrospinal fluid(CSF),and serum were quantified using inductively coupled plasma mass spectrometry(ICP-MS),immunohistochemical staining,and iron assays.Transcriptomic changes and immune responses were assessed using RNA sequencing and immune cell infiltration analysis.Results showed that intranasal FAC administration impaired olfactory function,accompanied by iron deposition in the olfactory mucosa and OB,as well as damage to olfactory sensory neurons.Notably,these effects occurred without elevations in CSF or serum iron levels.OB iron accumulation activated multiple immune cells,including microglia and astrocytes,but did not trigger ferroptosis.Spatial transcriptomic sequencing of healthy adult mouse OBs revealed significant cellular heterogeneity,with an abundance of neuroglia and neurons.Among neurons,GABAergic neurons were the most prevalent,followed by glutamatergic and dopaminergic neurons,while cholinergic and serotonergic neurons were sparsely distributed.Under iron-stressed conditions,oligodendrocytes,dopaminergic neurons,and glutamatergic neurons exhibited significant damage,while GABAergic neurons remained unaffected.These findings highlight the selective vulnerability of neuronal and glial populations to iron-induced stress,offering novel insights into the loss of specific cell types in the OB during iron dysregulation.
基金Supported by Natural Science Foundation of Xinjiang Uygur Autonomous Region,No.2022D01D17State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia,No.SKL-HIDCA-2024-2.
文摘BACKGROUND Echinococcosis,caused by Echinococcus parasites,includes alveolar echinococcosis(AE),the most lethal form,primarily affecting the liver with a 90%mortality rate without prompt treatment.While radical surgery combined with antiparasitic therapy is ideal,many patients present late,missing hepatectomy opportunities.Ex vivo liver resection and autotransplantation(ELRA)offers hope for such patients.Traditional surgical decision-making,relying on clinical experience,is prone to bias.Machine learning can enhance decision-making by identifying key factors influencing surgical choices.This study innovatively employs multiple machine learning methods by integrating various feature selection techniques and SHapley Additive exPlanations(SHAP)interpretive analysis to deeply explore the key decision factors influencing surgical strategies.AIM To determine the key preoperative factors influencing surgical decision-making in hepatic AE(HAE)using machine learning.METHODS This was a retrospective cohort study at the First Affiliated Hospital of Xinjiang Medical University(July 2010 to August 2024).There were 710 HAE patients(545 hepatectomy and 165 ELRA)with complete clinical data.Data included demographics,laboratory indicators,imaging,and pathology.Feature selection was performed using recursive feature elimination,minimum redundancy maximum relevance,and least absolute shrinkage and selection operator regression,with the intersection of these methods yielding 10 critical features.Eleven machinelearning algorithms were compared,with eXtreme Gradient Boosting(XGBoost)optimized using Bayesian optimization.Model interpretability was assessed using SHAP analysis.RESULTS The XGBoost model achieved an area under the curve of 0.935 in the training set and 0.734 in the validation set.The optimal threshold(0.28)yielded sensitivity of 93.6%and specificity of 90.9%.SHAP analysis identified type of vascular invasion as the most important feature,followed by platelet count and prothrombin time.Lesions invading the hepatic vein,inferior vena cava,or multiple vessels significantly increased the likelihood of ELRA.Calibration curves showed good agreement between predicted and observed probabilities(0.2-0.7 range).The model demonstrated high net clinical benefit in Decision Curve Analysis,with accuracy of 0.837,recall of 0.745,and F1 score of 0.788.CONCLUSION Vascular invasion is the dominant factor influencing the choice of surgical approach in HAE.Machine-learning models,particularly XGBoost,can provide transparent and data-driven support for personalized decision-making.
基金the National Natural Science Foundation of China(32325040)the Research Fund for the National Key R&D Program of China(2022YFD2100700).
文摘Modern lifestyle and diet have increased the incidence rate of uric acid(UA)metabolism-related diseases like hyperuricemia(HUA)and gout,posing heavy economic burden to individual patients and their families and the society.UA metabolism is a complex physiological process involving the kidney,intestine,and other organs.A number of factors together regulate UA metabolism,including genetics,diet,hormones,and the gut microbiota.This review summaries the gut microbiota features in subjects with HUA and gout,and the therapeutic effects of implementing microecological therapies(probiotics,prebiotics,or fecal microbiota transplant)that target modulate the gut microbiota and its downstream metabolism on the disease.Current evidence shows that these strategies are safe and promising in alleviate inflammation,reduce UA,and restoring a healthy gut microbiota in subjects with UA metabolism-related diseases.However,most clinical data are generated by animal studies.Therefore,we propose that vigorous human intervention trials should be conducted in the future to evaluate the therapeutic effects of microecological therapies in managing HUA and gout.
基金supported by the National Natural Science Foundation of China (No. 8196140154)the Natural Science Foundation of Xinjiang Uygur Autonomous Region (Nos.2023D01C139 and 2023D01C63)the State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund (No. SKL-HIDCA-2020-8)。
文摘Tianxiangdan(TXD),a traditional Chinese herbal remedy,demonstrates efficacy in mitigating myocardial ischemia-reperfusion(I/R)-induced damage.This study employed network pharmacology to evaluate the therapeutic targets and mechanisms of TXD in treating I/R.Highperformance liquid chromatography-mass spectrometry(HPLC-MS)identified 86 compounds in TXD.Network pharmacological analysis predicted potential target genes and their modes of action.Cardiac function,ischaemic ST changes,lactate dehydrogenase(LDH),malondialdehyde(MDA),superoxide dismutase(SOD)activity,myocardial fiber,and infarct size were assessed using in vivo and in vitro I/R injury models.Estrogen receptor alpha(ERα)protein expression and estradiol(E2)levels were measured to confirm TXD's impact on estrogen levels and ERαexpression.To examine if TXD reduces I/R injury through ERα,an AZD group(300 nmol·L^(-1)AZD9496 and 15%TXD serum)was compared to a TXD group(15%TXD serum).The study hypothesized that TXD upregulates the ERα-mediated iron metamorphosis pathway.I/R injury-induced ferroptosis was identified using a Fer-1 group(1.0μmol·L^(-1)Fer-1 and 15%TXD serum)to elucidate the potential association between ferroptosis and ERαproteins.A DCFH-DA probe detected reactive oxygen species(ROS)and Fe^(2+),while Western blotting assessed target protein expression.Both in vitro and in vivo experiments demonstrated that TXD attenuated I/R injury by reducing elevated ST-segment levels,improving cardiac injury biomarkers(LDH,MDA,and SOD),alleviating pathological features,and preventing I/R-induced loss of cell viability in vitro.The effects and mechanisms of TXD on I/R injury-associated ferroptosis were investigated using I/R-induced H9c2 cells.The TXD group showed significantly decreased ROS and Fe^(2+)levels,while the AZ group(treated with AZD9496)exhibited increased levels.The TXD group demonstrated enhanced expression of ERαand glutathione peroxidase 4(GPX4),with reduced levels of P53 protein and ferritinheavy polypeptide 1(FTH1).The AZ group exhibited contrasting effects on these expression levels.The literature indicated a novel connection between ERαand ferroptosis.TXD activates the ERαsignaling pathway,promoting protection against I/R-induced myocardial cell ferroptosis.This study provides evidence supporting TXD use for myocardial ischemia treatment,particularly in older female patients who may benefit from its therapeutic outcomes.
基金C.E.Vera-Tizatl(CVU:708156)thank the National Council for Science and Technology(CONACYT,Mexico)for the scholarship granted。
文摘Background:The Vietnamese swine represents a promising animal model due to its anatomical,physiological,and pathophysiological similarities to humans.Notably,the arrangement of lobes and ducts in the mammary glands is highly comparable to that of humans and is histologically indistinguishable.Leveraging these advantages through the chemical induction of carcinogenesis in this model offers a robust approach to mimic human exposure to carcinogenic compounds.Methods:This study elaborates on a protocol for developing a representative model of MNU-induced invasive breast carcinoma in three Vietnamese swine,validated histologically and immunologically.It evaluates not only the tissue similarity with humans,but also the development of chemically induced mammary tumors in an immunologically competent animal.Moreover,this study addresses the existing gap in histological knowledge regarding mammary tissue in the porcine model.Results:Our findings suggest that this model encompasses the full spectrum of cancer.It incorporates the key elements of a tumor microenvironment that enable tumor growth and propagation,such as immune cells,blood vessels,fibroblasts,extracellular matrix,fatty acids,and signaling molecules.Conclusions:This model offers significant potential to advance the understanding of cancer pathogenesis and facilitate the development of innovative therapeutic strategies by closely replicating human tumor biology.
基金supported by the National Natural Science Foundation of China(32171131,32371013,82071429,82471274,and 32371181)Shandong Province Natural Science Foundation(2021ZDSYS11,ZR2019ZD31,and ZR2022MC098)the Taishan Scholars Construction Project.
文摘Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
基金supported by the National Natural Science Foundation of China(No.81600459)National Natural Science Foundation of Hubei Province(No.2016CFB312)+3 种基金Talent Introduction Project of Hubei Polytechnic University(No.15xjz03R)Industry-University Collaboration(No.KY2023-269)Hubei Key Laboratory of Kidney Disease Pathogenesis and Intervention Foundation(No.SB202103)Provincial College Student Innovation and Entrepreneurship Training Program(No.S202210920011).
文摘Background:Ethylhexyl triazone(EHT)and diethylhexyl butamido triazone(HEB)both belong to the recently developed class of triazine ultraviolet filters.However,their toxicity profiles remain unclear.Objective:To assess the genotoxic and phototoxic effects of EHT and HEB.Methods:The genotoxicity of EHT and HEB was assessed using in vitro bacterial reverse mutation assays,chromosomal aberration assays,and micronucleus assays.Meanwhile,their phototoxicity was evaluated using in vitro 3T3 neutral red uptake(NRU)phototoxicity assays and in vivo skin phototoxicity tests.Results:In the bacterial reverse mutation assay,the number of bacterial colonies was not significantly higher in the EHT and HEB groups than in the solvent control group.Similarly,the chromosomal aberration assay revealed no increase in aberration rates after either EHT or HEB treatment.In the micronucleus assay,the frequency of micronuclei was comparable between the treatment and control groups.Finally,based on the 3T3 NRU phototoxicity assay,both EHT and HEB(photo-irritation factor<2 and mean photo effect value<0.1)were classified as non-phototoxic.The skin phototoxicity test in vivo showed the same results as in vitro.Conclusion:Results from a series of genotoxicity and phototoxicity assays indicate that EHT and HEB possess neither genotoxic nor phototoxic potential.These findings provide experimental evidence supporting the safety of EHT and HEB for topical applications.
基金Project supported by the National Natural Science Foundation of China(12264050)Natural Science Foundation of Xinjiang Uygur Autonomous Region(2022D01C727)Talent Project of Tianchi Doctoral Program in Xinjiang Uygur Autonomous Region(0301050903)。
文摘Upconversion luminescent(UCL)materials have broad application prospects in the field of temperature sensing;thus,improving the luminescence performance and temperature measurement sensitivity of upconversion phosphors is highly important.In this study,SrAl_(2)Si_(2)O_(8)with good thermal stability was doped with Ho^(3+)and Yb^(3+),and the optimal concentration was determined to be S rAl_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)(in mole fraction).A series of(Sr_(0.87-x)Ba_(x))Al_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)phosphor samples was prepared by using a cationic substitution strategy and further doping Ba^(2+)to replace the Sr^(2+)lattice in the matrix.The re sults show that the introduction of Ba^(2+)effectively replaces Sr^(2+)and significantly increases the upconversion fluorescence emission intensity of SrAl_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)by approximately 2.9times.The temperature sensing properties of SrAl_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)and Sr_(0.3)7Ba_(0.5)0Al_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)were investigated.The Ho^(3+)-based5F5and5S2/5F4nonthermal coupled energy level fluorescence intensity ratio(FIR)techniques in the Ba_(0.3)7S r_(0.50)Al_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)phosphors show a maximum temperature measurement absolute sensitivity of 4.32%/K at 573 K and a maximum relative sensitivity of 1.08%/K at 373 K;these values are 5.8 and 3.2 times greater,respectively,than that of the non-Ba^(2+)-doped SrAl_(2)Si_(2)O_(8):1%Ho^(3+),12%Yb^(3+)phosphor.These results not only confirm the effectiveness of the cation substitution strategy in enhancing the upconversion luminescence performance and temperature sensing characteristics but also provide a scientific basis for the design of high-performance optical temperature sensors.
基金supported by the National Natural Science Foundation of China(NSFC)under Grant Nos.62035011,82202220 and 82060326State Key Laboratory of Pathogenesis,Prevention and treat ment of High Incident Diseases in central Asia(Nos.SKL-HIDCA-2022-3 and SKL-HIDCA-2022-GJ1)+3 种基金the Xinjiang Uygur Autonomous Region Regional Collaborative Innovation Special Science and Technology Assistance Program(No.2022E02130)Xinjiang Uygur Autonomous Region Natural Sci ence Foundation Key Project(No.2022D01D40)Outstanding Youth Project(2023D01E06)Y.Gao and C.Zhang authors contributed equally to this work.
文摘Triple-negative breast cancer (TNBC) is an aggressive and often fatal disease, especially since the brain metastasis of TNBC has been a particularly severe manifestation. However, brain metastasis in TNBC at early stages often lacks noticeable symptoms, making it challenging to detect. Near-infrared II (NIR-II) fluorescence microscopic imaging obtains long wavelength, which enables reduced scattering, high spatial resolution and minimal autofluorescence, it is also a favorable imaging method for tumor diagnosis. PbS@CdS quantum dots (QDs) are one of the popular NIR-II fluorescence nanoprobes for well brightness. In this study, NIR-II emissive PbS@CdS QDs were utilized and further encapsulated with thiol-terminated poly(ethylene oxide) (SH-PEG, MW = 5000) to form PbS@CdS@PEG QDs nanoparticles (NPs). The obtained PbS@CdS@PEG QDs NPs were then characterized and further studied in detail. The PbS@CdS@PEG QDs NPs had large absorption spectra, exhibited strong NIR-II fluorescence emission at approximately 1300nm, and possessed good NIR-II fluorescence properties. Then, the mice model of early-stage brain metastases of TNBC was established, and the PbS@CdS@PEG QDs NPs were injected into the tumor-bearing mice for NIR-II fluorescence microscopic bioimaging. The brain vessels and tumors of the living mice were detected with high spatial resolution under the NIR-II fluorescence microscopic imaging system with irradiation of 808nm laser. The tumor tissues were further restricted and prepared as thin slices. The NIR-II fluorescence signals were collected from the tumor slices with high spatial resolution and signal-to-background ratio (SBR). Thus, the PbS@CdS@PEG QDs NPs-assisted NIR-II fluorescence microscopic system can effectively achieve targeting brain metastases of TNBC imaging, offering a novel and promising approach for TNBC-specific diagnosis.
