Brain-computer interfaces(BCIs)represent an emerging technology that facilitates direct communication between the brain and external devices.In recent years,numerous review articles have explored various aspects of BC...Brain-computer interfaces(BCIs)represent an emerging technology that facilitates direct communication between the brain and external devices.In recent years,numerous review articles have explored various aspects of BCIs,including their fundamental principles,technical advancements,and applications in specific domains.However,these reviews often focus on signal processing,hardware development,or limited applications such as motor rehabilitation or communication.This paper aims to offer a comprehensive review of recent electroencephalogram(EEG)-based BCI applications in the medical field across 8 critical areas,encompassing rehabilitation,daily communication,epilepsy,cerebral resuscitation,sleep,neurodegenerative diseases,anesthesiology,and emotion recognition.Moreover,the current challenges and future trends of BCIs were also discussed,including personal privacy and ethical concerns,network security vulnerabilities,safety issues,and biocompatibility.展开更多
Background:China accounts for one-quarter of the world’s diabetes population,with significant subnational disparities.However,none of the available data have provided comprehensive estimates and projections at both r...Background:China accounts for one-quarter of the world’s diabetes population,with significant subnational disparities.However,none of the available data have provided comprehensive estimates and projections at both regional and national levels in diabetes prevention and management.This study aimed to explore the temporal trends and geographical variations in the prevalence and non-fatal burden of diabetes by age and sex across China from 2005 to 2023,and to forecast diabetes prevalence through 2050.Methods:We conducted a population-based study based on the nationally representative surveys,and literature reviews.Using the DisMod-MR model and Chinese-specific disease disability weights,we estimated the non-fatal burdens of diabetes,including prevalence and years lived with disability(YLDs),across sexes,age groups,and locations.The temporal trend change was measured as the average annual percent change.The effect of the human development index on burdens was assessed by applying Spearman’s rank correlation analysis.We further projected diabetes prevalence to 2050 under 2 scenarios,the natural trend and the effective intervention on body mass index(BMI).Results:In 2023,an estimated 233 million individuals in China were living with diabetes.Compared to 2005,the agestandardized rate(ASR)of prevalence has increased by nearly 50%,from 7.53%(95%CI 7.00-8.10)to 13.7%(95%CI 12.6-14.8)in 2023.The ASR of YLDs was estimated at 19.1 per 1000 population(95%CI 18.6-19.5)in 2023,compared to 10.5 per 1000 population in 2005.The ASR of prevalence and YLDs was consistently higher in males than in females.The provinces with the highest diabetes prevalence and disease burden were Beijing,Tianjin,and Shanghai.Our forecast results suggest that if existing trends continue,the prevalence of obesity will reach 29.1%(95%CI 22.2-38.2)nationally by 2050,with some provinces in the northern region observing a prevalence of over 40%.Conversely,if effective obesity interventions were implemented,the growth in diabetes prevalence could potentially be suppressed by nearly 50%.Conclusions:The health burden and economic cost associated with diabetes are profound.There is an urgent need to scale up preventive efforts and improve population awareness to enhance disease management and achieve optimal treatment outcomes.展开更多
Drug delivery systems(DDS)have recently emerged as a promising approach for the unique advantages of drug protection and targeted delivery.However,the access of nanoparticles/drugs to the central nervous system(CNS)re...Drug delivery systems(DDS)have recently emerged as a promising approach for the unique advantages of drug protection and targeted delivery.However,the access of nanoparticles/drugs to the central nervous system(CNS)remains a challenge mainly due to the obstruction from brain barriers.Immune cells infiltrating the CNS in the pathological state have inspired the development of strategies for CNS foundation drug delivery.Herein,we outline the three major brain barriers in the CNS and the mechanisms by which immune cells migrate across the blood–brain barrier.We subsequently review biomimetic strategies utilizing immune cell-based nanoparticles for the delivery of nanoparticles/drugs to the CNS,as well as recent progress in rationally engineering immune cell-based DDS for CNS diseases.Finally,we discuss the challenges and opportunities of immune cell-based DDS in CNS diseases to promote their clinical development.展开更多
Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an imp...Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.展开更多
Antimicrobial resistance is a global public health threat,and the World Health Organization(WHO)has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed.The ...Antimicrobial resistance is a global public health threat,and the World Health Organization(WHO)has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed.The discovery and introduction of novel antibiotics are time-consuming and expensive.According to WHO’s report of antibacterial agents in clinical development,only 18 novel antibiotics have been approved since 2014.Therefore,novel antibiotics are critically needed.Artificial intelligence(AI)has been rapidly applied to drug development since its recent technical breakthrough and has dramatically improved the efficiency of the discovery of novel antibiotics.Here,we first summarized recently marketed novel antibiotics,and antibiotic candidates in clinical development.In addition,we systematically reviewed the involvement of AI in antibacterial drug development and utilization,including small molecules,antimicrobial peptides,phage therapy,essential oils,as well as resistance mechanism prediction,and antibiotic stewardship.展开更多
Bone tissue relies on the intricate interplay between blood vessels and nerve fibers,both are essential for many physiological and pathological processes of the skeletal system.Blood vessels provide the necessary oxyg...Bone tissue relies on the intricate interplay between blood vessels and nerve fibers,both are essential for many physiological and pathological processes of the skeletal system.Blood vessels provide the necessary oxygen and nutrients to nerve and bone tissues,and remove metabolic waste.Concomitantly,nerve fibers precede blood vessels during growth,promote vascularization,and influence bone cells by secreting neurotransmitters to stimulate osteogenesis.Despite the critical roles of both components,current biomaterials generally focus on enhancing intraosseous blood vessel repair,while often neglecting the contribution of nerves.Understanding the distribution and main functions of blood vessels and nerve fibers in bone is crucial for developing effective biomaterials for bone tissue engineering.This review first explores the anatomy of intraosseous blood vessels and nerve fibers,highlighting their vital roles in bone embryonic development,metabolism,and repair.It covers innovative bone regeneration strategies directed at accelerating the intrabony neurovascular system over the past 10 years.The issues covered included material properties(stiffness,surface topography,pore structures,conductivity,and piezoelectricity)and acellular biological factors[neurotrophins,peptides,ribonucleic acids(RNAs),inorganic ions,and exosomes].Major challenges encountered by neurovascularized materials during their clinical translation have also been highlighted.Furthermore,the review discusses future research directions and potential developments aimed at producing bone repair materials that more accurately mimic the natural healing processes of bone tissue.This review will serve as a valuable reference for researchers and clinicians in developing novel neurovascularized biomaterials and accelerating their translation into clinical practice.By bridging the gap between experimental research and practical application,these advancements have the potential to transform the treatment of bone defects and significantly improve the quality of life for patients with bone-related conditions.展开更多
The skeleton is innervated by different types of nerves and receives signaling from the nervous system to maintain homeostasis and facilitate regeneration or repair.Although the role of peripheral nerves and signals i...The skeleton is innervated by different types of nerves and receives signaling from the nervous system to maintain homeostasis and facilitate regeneration or repair.Although the role of peripheral nerves and signals in regulating bone homeostasis has been extensively investigated,the intimate relationship between the central nervous system and bone remains less understood,yet it has emerged as a hot topic in the bone field.In this review,we discussed clinical observations and animal studies that elucidate the connection between the nervous system and bone metabolism,either intact or after injury.First,we explored mechanistic studies linking specific brain nuclei with bone homeostasis,including the ventromedial hypothalamus,arcuate nucleus,paraventricular hypothalamic nucleus,amygdala,and locus coeruleus.We then focused on the characteristics of bone innervation and nerve subtypes,such as sensory,sympathetic,and parasympathetic nerves.Moreover,we summarized the molecular features and regulatory functions of these nerves.Finally,we included available translational approaches that utilize nerve function to improve bone homeostasis and promote bone regeneration.Therefore,considering the nervous system within the context of neuromusculoskeletal interactions can deepen our understanding of skeletal homeostasis and repair process,ultimately benefiting future clinical translation.展开更多
Background:Kinesin family member 13B(KIF13B),a crucial motor protein,exerts multiple cellular biological functions.However,the implication of KIF13B in metabolic dysfunction-associated fatty liver disease(MAFLD)has no...Background:Kinesin family member 13B(KIF13B),a crucial motor protein,exerts multiple cellular biological functions.However,the implication of KIF13B in metabolic dysfunction-associated fatty liver disease(MAFLD)has not been explored yet.This study aimed to investigate KIF13B’s role and underlying mechanism in MAFLD and proposes it as a potential pharmacological target.Methods:We assessed KIF13B expression in MAFLD patients and rodent models.The roles of Kif13b in lipid metabolism and MAFLD were investigated using whole-body Kif13b knockout mice,hepatocyte-specific Kif13b-deficient mice and hamsters exposed to different diets.The underlying mechanisms by which Kif13bgoverned hepatic lipid homeostasis and MAFLD progression were explored in vitro.Finally,the Kif13b’s impact on atherosclerotic development was studied in the context of MAFLD.Results:KIF13B expression was reduced in patients and murine models with MAFLD.Rodents with global or liver-specific knockout of the Kif13b gene exhibit spontaneous hepatic steatosis,which is further exacerbated by different overnutrition diets.Overexpression of human KIF13B by lentivirus effectively prevented metabolic dysfunction-associated steatohepatitis(MASH)in methionine-choline-deficient diet(MCD)-fed mice.Furthermore,Kif13b deficiency accelerates atherosclerosis in the context of MAFLD.Mechanistically,Kif13b depletion increases hepatic lipid synthesis and impairs mitochondrial oxidative phosphorylation.Further screening reveals that Kif13b interacts with AMP-activated catalytic subunit alpha 1(AMPKα1)to regulate the phosphorylation of AMPKα1,governing mitochondrial homeostasis and suppressing sterol regulatory element binding protein 1(Srebp1)-mediated denovo lipogenesis in the liver.Conclusion:This work establishes a causal relationship between KIF13B deficiency and MAFLD,emphasizing KIF13B as a potential therapeutic target for treating MAFLD.展开更多
In recent years,advancements in single-cell and spatial transcriptomics,which are highly regarded developments in the current era,particularly the emerging integration of single-cell and spatiotemporal transcriptomics...In recent years,advancements in single-cell and spatial transcriptomics,which are highly regarded developments in the current era,particularly the emerging integration of single-cell and spatiotemporal transcriptomics,have enabled a detailed molecular comprehension of the complex regulation of cell fate.The insights obtained from these methodologies are anticipated to significantly contribute to the development of personalized medicine.Currently,single-cell technology is less frequently utilized for prostate cancer compared with other types of tumors.Start-ing from the perspective of RNA sequencing technology,this review outlined the signifcance of single-cell RNA sequencing(scRNA-seq)in prostate cancer research,encompassing preclinical medicine and clinical applications.We summarize the differences between mouse and human prostate cancer as revealed by scRNA-seq studies,as well as a combination of multi-omics methods involving scRNA-seq to highlight the key molecular targets for the diagnosis,treatment,and drug resistance characteristics of prostate cancer.These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer.Furthermore,we explore the potential clinical applications stemming from other single-cell technologies in this review,paving the way for future research in precision medicine.展开更多
Scar formation resulting from burns or severe trauma can significantly compromise the structural integrity of skin and lead to permanent loss of skin appendages,ultimately impairing its normal physiological function.A...Scar formation resulting from burns or severe trauma can significantly compromise the structural integrity of skin and lead to permanent loss of skin appendages,ultimately impairing its normal physiological function.Accumulating evidence underscores the potential of targeted modulation of mechanical cues to enhance skin regeneration,promoting scarless repair by influencing the extracellular microenvironment and driving the phenotypic transitions.The field of skin repair and skin appendage regeneration has witnessed remarkable advancements in the utilization of biomaterials with distinct physical properties.However,a comprehensive understanding of the underlying mechanisms remains somewhat elusive,limiting the broader application of these innovations.In this review,we present two promising biomaterial-based mechanical approaches aimed at bolstering the regenerative capacity of compromised skin.The first approach involves leveraging biomaterials with specific biophysical properties to create an optimal scarless environment that supports cellular activities essential for regeneration.The second approach centers on harnessing mechanical forces exerted by biomaterials to enhance cellular plasticity,facilitating efficient cellular reprogramming and,consequently,promoting the regeneration of skin appendages.In summary,the manipulation of mechanical cues using biomaterial-based strategies holds significant promise as a supplementary approach for achieving scarless wound healing,coupled with the restoration of multiple skin appendage functions.展开更多
Background:Acute liver injury(ALI)requires rapid hepatic regeneration to avert fatal liver failure.As key mechanisms,systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process.S...Background:Acute liver injury(ALI)requires rapid hepatic regeneration to avert fatal liver failure.As key mechanisms,systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process.Skeletal muscle,as a major metabolic organ system,undergoes significant remodeling during ALI.However,its specific regulatory contributions remain largely uncharacterized.Methods:Partial(2/3)hepatectomy and acetaminophen were used to induce ALI in male mice.RNA-sequencing(RNA-seq),assay for transposase-accessible chromatin by sequencing(ATAC-seq),chromatin immunoprecipitation,luciferase assay,Western blotting,TUNEL assay,immunohistochemistry,and phase separation assays were performed to reveal the transcriptional axis involved.Serum fibroblast growth factor binding protein 1(FGFBP1)protein levels in ALI patients were assessed via enzyme-linked immunosorbent assay.Results:Integrated analysis of RNA-seq and ATAC-seq following ALI identifies glucocorticoid(GC)signaling-mediated regulation of fibroblast growth factor 6(FGF6)in skeletal muscle metabolism.Muscle-specific knockdown of GC receptor(GR)exacerbates ALI and suppresses liver regeneration.Fgf6-knockout mice exhibited improved ALI and enhanced liver regeneration,with intramuscular injection of FGF6-neutralizing antibody rescuing the detrimental effects induced by GR knockdown.Further analysis of the FGF6 downstream target revealed that FGF6 regulates FGFBP1 expression through extracellular signal regulated kinase-activating transcription factor 3 signaling.Moreover,FGF6 regulates the heparin-dependent release kinetics of FGFBP1 by perturbing its liquid-liquid phase separation(LLPS)-driven condensate dynamics at the plasma membrane.Circulating FGFBP1 subsequently interacts with hepatic FGF5 through LLPS mechanisms to regulate liver regeneration.Conclusion:Our results demonstrate a molecular mechanism by which muscle-liver crosstalk can initiate and sustain liver regeneration via the FGF6-FGFBP1/FGF5 axis,providing a potential therapeutic target and treatment strategy for ALI.展开更多
Dear Editor,On March 8–15,2022,a board of international scientists assembled in Lyon to evaluate the carcinogenicity of cobalt metal,cobalt(Ⅱ)salts,antimony trioxide,and weaponsgrade tungsten alloy harboring nickel ...Dear Editor,On March 8–15,2022,a board of international scientists assembled in Lyon to evaluate the carcinogenicity of cobalt metal,cobalt(Ⅱ)salts,antimony trioxide,and weaponsgrade tungsten alloy harboring nickel and cobalt[1].The 131st International Agency for Research on Cancer(IARC)Monograph is the result of a 6–9-month work of perusing the literature,slide evaluation,data interpretation,and interim meetings.The assessment of cobalt,antimony,and nickelcontaining alloys will have tremendous consequences for the industry,health,and defense departments[1].展开更多
Dear Editor,Space flight(SF)is substantially increasing at present.The emergence of commercial suborbital SF,such as the Virgin Galactic with VSS Unity and VMS Eve spacecraft,is extending to civilians,being previously...Dear Editor,Space flight(SF)is substantially increasing at present.The emergence of commercial suborbital SF,such as the Virgin Galactic with VSS Unity and VMS Eve spacecraft,is extending to civilians,being previously confined to military and/or professional astronauts only.This new evidence offers additional opportunities for better characterizing the impact that the transition from Earth’s 1G to microgravity in space could have on the astronauts’health while comparing well-trained subjects such as the latt er to space newcomers[1].展开更多
Background:Chronic Gulf War Illness(GWI)is characterized by cognitive and mood impairments,as well as persistent neuroinflammation and oxidative stress.This study aimed to investigate the efficacy of Epidiolex®,a...Background:Chronic Gulf War Illness(GWI)is characterized by cognitive and mood impairments,as well as persistent neuroinflammation and oxidative stress.This study aimed to investigate the efficacy of Epidiolex®,a Food and Drug Administration(FDA)-approved cannabidiol(CBD),in improving brain function in a rat model of chronic GWI.Methods:Six months after exposure to low doses of GWI-related chemicals[pyridostigmine bromide,N,N-diethyl-meta-toluamide(DEET),and permethrin(PER)]along with moderate stress,rats with chronic GWI were administered either vehicle(VEH)or CBD(20 mg/kg,oral)for 16 weeks.Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory,object location memory,pattern separation,and sucrose preference.The effect of CBD on hyperalgesia was also examined.The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests.Results:GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia,whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia.Additionally,CBD treatment alleviated hyperalgesia in GWI rats.Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription(JAK/STAT)signaling.Furthermore,there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis.In contrast,the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling,normalized concentrations of proinflammatory cytokines and oxidative stress markers,and improved neurogenesis.Notably,CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus.Conclusions:The use of an FDA-approved CBD(Epidiolex®)has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI.Importantly,the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.展开更多
Dear Editor,The Hans Chinese(HC)ethnic group,comprising approximately 1.4 billion individuals,represents the largest workforce globally.Historically,HC has been predominantly isolated from other ethnic groups for over...Dear Editor,The Hans Chinese(HC)ethnic group,comprising approximately 1.4 billion individuals,represents the largest workforce globally.Historically,HC has been predominantly isolated from other ethnic groups for over 3 millennia,resulting in distinct genetic and physiological characteristics[1,2].Consequently,the energy required to maintain essential functions,represented by the basal metabolic rate(BMR),cannot be accurately assessed in HC with algorithms developed for European-American(EA)populations,even when controlling for diff erences in body size[3].Notably,the widely used Harris-Benedict equation tends to overestimate BMR,relative to measured BMR via indirect calorimetry,in more than 50%of HC individuals[3].Hence,HC generally expends less energy than EA under basal(resting)conditions.This raises an important question:does HC require lower energy expenditure than EA for equivalent external work?Th e present aimed to address this inquiry,while adjusting for key confounding factors such as age,sex,physical activity,aerobic capacity,BMR,and body composition.展开更多
Mitochondria,the most crucial energy-generating organelles in eukaryotic cells,play a pivotal role in regulating energy metabolism.However,their significance extends beyond this,as they are also indispensable in vital...Mitochondria,the most crucial energy-generating organelles in eukaryotic cells,play a pivotal role in regulating energy metabolism.However,their significance extends beyond this,as they are also indispensable in vital life processes such as cell proliferation,differentiation,immune responses,and redox balance.In response to various physiological signals or external stimuli,a sophisticated mitochondrial quality control(MQC)mechanism has evolved,encompassing key processes like mitochondrial biogenesis,mitochondrial dynamics,and mitophagy,which have garnered increasing attention from researchers to unveil their specific molecular mechanisms.In this review,we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC.Furthermore,the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail.We also discuss agonists or antagonists targeting MQC,aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.展开更多
Background:One-third of veterans returning from the 1990–1991 Gulf War reported a myriad of symptoms including cognitive dysfunction,skin rashes,musculoskeletal discomfort,and fatigue.This symptom cluster is now refe...Background:One-third of veterans returning from the 1990–1991 Gulf War reported a myriad of symptoms including cognitive dysfunction,skin rashes,musculoskeletal discomfort,and fatigue.This symptom cluster is now referred to as Gulf War Illness(GWI).As the underlying mechanisms of GWI have yet to be fully elucidated,diagnosis and treatment are based on symptomatic presentation.One confounding factor tied to the illness is the high presence of post-traumatic stress disorder(PTSD).Previous research efforts have demonstrated that both GWI and PTSD are associated with immunological dysfunction.As such,this research endeavor aimed to provide insight into the complex relationship between GWI symptoms,cytokine presence,and immune cell populations to pinpoint the impact of PTSD on these measures in GWI.Methods:Symptom measures were gathered through the Multidimensional fatigue inventory(MFI)and 36-item short form health survey(SF-36)scales and biological measures were obtained through cytokine&cytometry analysis.Subgrouping was conducted using Davidson Trauma Scale scores and the Structured Clinical Interview for Diagnostic and statistical manual of mental disorders(DSM)-5,into GWI with high probability of PTSD symptoms(GWIH)and GWI with low probability of PTSD symptoms(GWIL).Data was analyzed using analysis of variance(ANOVA)statistical analysis along with correlation graph analysis.We mapped correlations between immune cells and cytokine signaling measures,hormones and GWI symptom measures to identify patterns in regulation between the GWIH,GWIL,and healthy control groups.Results:GWI with comorbid PTSD symptoms resulted in poorer health outcomes compared with both healthy control(HC)and the GWIL subgroup.Significant differences were found in basophil levels of GWI compared with HC at peak exercise regardless of PTSD symptom comorbidity(ANOVA F=4.7,P=0.01)indicating its potential usage as a biomarker for general GWI from control.While the unique identification of GWI with PTSD symptoms was less clear,the GWIL subgroup was found to be delineated from both GWIH and HC on measures of IL-15 across an exercise challenge(ANOVA F>3.75,P<0.03).Additional differences in natural killer(NK)cell numbers and function highlight IL-15 as a potential biomarker of GWI in the absence of PTSD symptoms.Conclusions:We conclude that disentangling GWI and PTSD by defining trauma-based subgroups may aid in the identification of unique GWI biosignatures that can help to improve diagnosis and target treatment of GWI more effectively.展开更多
Background:Parkinson’s disease(PD)is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra(SN).Activation of the neuroinflammatory response has a pivotal role ...Background:Parkinson’s disease(PD)is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra(SN).Activation of the neuroinflammatory response has a pivotal role in PD.Mesenchymal stem cells(MSCs)have emerged as a promising therapeutic approach for various nerve injuries,but there are limited reports on their use in PD and the underlying mechanisms remain unclear.Methods:We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa(hOM)-MSCs on neural functional recovery in both PD models and patients,as well as the preventive effects on mouse models of PD.To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure,we employed single-cell RNA sequencing(scRNA-seq),assay for transposase accessible chromatin with high-throughput sequencing(ATAC-seq)combined with full-length transcriptome isoform-sequencing(ISO-seq),and functional assay.Furthermore,we present the findings from an initial cohort of patients enrolled in a phaseⅠfirstinhuman clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients.Results:A functional assay identified that transforming growth factor-β1(TGF-β1),secreted from hOM-MSCs,played a critical role in modulating mitochondrial function recovery in dopaminergic neurons.This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN,which are closely associated with neuroinflammatory responses.Mechanistically,exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-β1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B(ALK/PI3K/Akt)signaling pathway in microglia located in the SN of PD patients.Furthermore,intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD.Conclusions:These findings provide compelling evidence for the involvement of TGF-β1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD.Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD.Additionally,TGF-β1 may be used alone or combined with hOM-MSCs therapy for treating PD.展开更多
The lipid mediator platelet-activating factor(PAF)and its receptor(PAFR)signaling play critical roles in a wide range of physiological and pathophysiological conditions,including cancer growth and metastasis.The abili...The lipid mediator platelet-activating factor(PAF)and its receptor(PAFR)signaling play critical roles in a wide range of physiological and pathophysiological conditions,including cancer growth and metastasis.The ability of PAFR to interact with other oncogenic signaling cascades makes it a promising target for cancer treatment.Moreover,numerous natural and synthetic compounds,characterized by diverse pharmacological activities such as anti-inflammatory and anti-tumor effects,have been explored for their potential as PAF and PAFR antagonists.In this review,we provide comprehensive evidence regarding the PAF/PAFR signaling pathway,highlighting the effectiveness of various classes of PAF and PAFR inhibitors and antagonists across multiple cancer models.Notably,the synergistic effects of PAF and PAFR antagonists in enhancing the efficacy of chemotherapy and radiation therapy in several experimental cancer models are also discussed.Overall,the synthesis of literature review indicates that targeting the PAF/PAFR axis represents a promising approach for cancer treatment and also exerts synergy with chemotherapy and radiation therapy.展开更多
Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),h...Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),have demonstrated promise but encounter resistance challenges.Erlotinib(ER),a widely used EGFR TKI,often faces the emergence of resistance^([1]).Th erefore,understanding therapeutic targets for ER resistance is crucial.AKR1C3 plays a pivotal role as a key enzyme in the biosynthesis of androgens,serving as a regulator of hormone activity and prostaglandin F synthase.展开更多
基金supported by the National Key R&D Program of China(2021YFF1200602)the National Science Fund for Excellent Overseas Scholars(0401260011)+3 种基金the National Defense Science and Technology Innovation Fund of Chinese Academy of Sciences(c02022088)the Tianjin Science and Technology Program(20JCZDJC00810)the National Natural Science Foundation of China(82202798)the Shanghai Sailing Program(22YF1404200).
文摘Brain-computer interfaces(BCIs)represent an emerging technology that facilitates direct communication between the brain and external devices.In recent years,numerous review articles have explored various aspects of BCIs,including their fundamental principles,technical advancements,and applications in specific domains.However,these reviews often focus on signal processing,hardware development,or limited applications such as motor rehabilitation or communication.This paper aims to offer a comprehensive review of recent electroencephalogram(EEG)-based BCI applications in the medical field across 8 critical areas,encompassing rehabilitation,daily communication,epilepsy,cerebral resuscitation,sleep,neurodegenerative diseases,anesthesiology,and emotion recognition.Moreover,the current challenges and future trends of BCIs were also discussed,including personal privacy and ethical concerns,network security vulnerabilities,safety issues,and biocompatibility.
基金supported by the National Key Research and Development Program of China(2023YFC3605000).
文摘Background:China accounts for one-quarter of the world’s diabetes population,with significant subnational disparities.However,none of the available data have provided comprehensive estimates and projections at both regional and national levels in diabetes prevention and management.This study aimed to explore the temporal trends and geographical variations in the prevalence and non-fatal burden of diabetes by age and sex across China from 2005 to 2023,and to forecast diabetes prevalence through 2050.Methods:We conducted a population-based study based on the nationally representative surveys,and literature reviews.Using the DisMod-MR model and Chinese-specific disease disability weights,we estimated the non-fatal burdens of diabetes,including prevalence and years lived with disability(YLDs),across sexes,age groups,and locations.The temporal trend change was measured as the average annual percent change.The effect of the human development index on burdens was assessed by applying Spearman’s rank correlation analysis.We further projected diabetes prevalence to 2050 under 2 scenarios,the natural trend and the effective intervention on body mass index(BMI).Results:In 2023,an estimated 233 million individuals in China were living with diabetes.Compared to 2005,the agestandardized rate(ASR)of prevalence has increased by nearly 50%,from 7.53%(95%CI 7.00-8.10)to 13.7%(95%CI 12.6-14.8)in 2023.The ASR of YLDs was estimated at 19.1 per 1000 population(95%CI 18.6-19.5)in 2023,compared to 10.5 per 1000 population in 2005.The ASR of prevalence and YLDs was consistently higher in males than in females.The provinces with the highest diabetes prevalence and disease burden were Beijing,Tianjin,and Shanghai.Our forecast results suggest that if existing trends continue,the prevalence of obesity will reach 29.1%(95%CI 22.2-38.2)nationally by 2050,with some provinces in the northern region observing a prevalence of over 40%.Conversely,if effective obesity interventions were implemented,the growth in diabetes prevalence could potentially be suppressed by nearly 50%.Conclusions:The health burden and economic cost associated with diabetes are profound.There is an urgent need to scale up preventive efforts and improve population awareness to enhance disease management and achieve optimal treatment outcomes.
基金supported by the National Natural Science Foundation of China(82204634,82174047,81622051)the Zhejiang Provincial Natural Science Foundation of China(LQ22H280010)the Foundation of Zhejiang Chinese Medical University(2021ZR03).
文摘Drug delivery systems(DDS)have recently emerged as a promising approach for the unique advantages of drug protection and targeted delivery.However,the access of nanoparticles/drugs to the central nervous system(CNS)remains a challenge mainly due to the obstruction from brain barriers.Immune cells infiltrating the CNS in the pathological state have inspired the development of strategies for CNS foundation drug delivery.Herein,we outline the three major brain barriers in the CNS and the mechanisms by which immune cells migrate across the blood–brain barrier.We subsequently review biomimetic strategies utilizing immune cell-based nanoparticles for the delivery of nanoparticles/drugs to the CNS,as well as recent progress in rationally engineering immune cell-based DDS for CNS diseases.Finally,we discuss the challenges and opportunities of immune cell-based DDS in CNS diseases to promote their clinical development.
基金supported by the National Natural Science Foundation of China(82270386,82070252,and 8207025)the Zhejiang Provincial Medical and Health Science and Technology Plan(2023RC020)the Zhejiang Provincial Natural Science Foundation(LR21H020001).
文摘Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.
基金supported by the National Natural Science Foundation of China(32300157)the Shanghai Municipal Science and Technology Commission(19411964900)+1 种基金the Major Research and Development Project of Innovative Drugs,Ministry of Science and Technology of China(2017ZX09304005)the Wellcome Trust.
文摘Antimicrobial resistance is a global public health threat,and the World Health Organization(WHO)has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed.The discovery and introduction of novel antibiotics are time-consuming and expensive.According to WHO’s report of antibacterial agents in clinical development,only 18 novel antibiotics have been approved since 2014.Therefore,novel antibiotics are critically needed.Artificial intelligence(AI)has been rapidly applied to drug development since its recent technical breakthrough and has dramatically improved the efficiency of the discovery of novel antibiotics.Here,we first summarized recently marketed novel antibiotics,and antibiotic candidates in clinical development.In addition,we systematically reviewed the involvement of AI in antibacterial drug development and utilization,including small molecules,antimicrobial peptides,phage therapy,essential oils,as well as resistance mechanism prediction,and antibiotic stewardship.
基金supported by the Foundation of National Clinical Research Center for Oral Diseases(LCA202204)the Key Research and Development Program of Shaanxi(2024GH-YBXM-19)+7 种基金the Clinical New Technology Program of Air Force Medical University(LX2023-306)the China Postdoctoral Science Foundation(2019M653969)the Thousand Talents Plan of Shaanxi Province(to Jing Wang)the National Natural Science Foundation of China(82101069,22205257)the Logistics Independent Research Project of PLA(to Yang Jiao)the Beijing Natural Science Foundation(7242279),the Beijing Nova Program(20230484283)the Beijing Municipal Science&Technology Commission(Z221100007422130)the Open Project of State Key Laboratory of Trauma and Chemical poisoning(SKLO202401).
文摘Bone tissue relies on the intricate interplay between blood vessels and nerve fibers,both are essential for many physiological and pathological processes of the skeletal system.Blood vessels provide the necessary oxygen and nutrients to nerve and bone tissues,and remove metabolic waste.Concomitantly,nerve fibers precede blood vessels during growth,promote vascularization,and influence bone cells by secreting neurotransmitters to stimulate osteogenesis.Despite the critical roles of both components,current biomaterials generally focus on enhancing intraosseous blood vessel repair,while often neglecting the contribution of nerves.Understanding the distribution and main functions of blood vessels and nerve fibers in bone is crucial for developing effective biomaterials for bone tissue engineering.This review first explores the anatomy of intraosseous blood vessels and nerve fibers,highlighting their vital roles in bone embryonic development,metabolism,and repair.It covers innovative bone regeneration strategies directed at accelerating the intrabony neurovascular system over the past 10 years.The issues covered included material properties(stiffness,surface topography,pore structures,conductivity,and piezoelectricity)and acellular biological factors[neurotrophins,peptides,ribonucleic acids(RNAs),inorganic ions,and exosomes].Major challenges encountered by neurovascularized materials during their clinical translation have also been highlighted.Furthermore,the review discusses future research directions and potential developments aimed at producing bone repair materials that more accurately mimic the natural healing processes of bone tissue.This review will serve as a valuable reference for researchers and clinicians in developing novel neurovascularized biomaterials and accelerating their translation into clinical practice.By bridging the gap between experimental research and practical application,these advancements have the potential to transform the treatment of bone defects and significantly improve the quality of life for patients with bone-related conditions.
基金supported by the Health&Medical Research Fund(18190481)the General Research Fund(14120520).
文摘The skeleton is innervated by different types of nerves and receives signaling from the nervous system to maintain homeostasis and facilitate regeneration or repair.Although the role of peripheral nerves and signals in regulating bone homeostasis has been extensively investigated,the intimate relationship between the central nervous system and bone remains less understood,yet it has emerged as a hot topic in the bone field.In this review,we discussed clinical observations and animal studies that elucidate the connection between the nervous system and bone metabolism,either intact or after injury.First,we explored mechanistic studies linking specific brain nuclei with bone homeostasis,including the ventromedial hypothalamus,arcuate nucleus,paraventricular hypothalamic nucleus,amygdala,and locus coeruleus.We then focused on the characteristics of bone innervation and nerve subtypes,such as sensory,sympathetic,and parasympathetic nerves.Moreover,we summarized the molecular features and regulatory functions of these nerves.Finally,we included available translational approaches that utilize nerve function to improve bone homeostasis and promote bone regeneration.Therefore,considering the nervous system within the context of neuromusculoskeletal interactions can deepen our understanding of skeletal homeostasis and repair process,ultimately benefiting future clinical translation.
基金supported by the National Natural Science Foundation of China(82270479,82070460)the Beijing Natural Science Foundation(7242084 to Xun-De Xian)the National Key Research and Development Program of China from the Ministry of Science and Technology(2021YFF0702802 to Yu-Hui Wang).
文摘Background:Kinesin family member 13B(KIF13B),a crucial motor protein,exerts multiple cellular biological functions.However,the implication of KIF13B in metabolic dysfunction-associated fatty liver disease(MAFLD)has not been explored yet.This study aimed to investigate KIF13B’s role and underlying mechanism in MAFLD and proposes it as a potential pharmacological target.Methods:We assessed KIF13B expression in MAFLD patients and rodent models.The roles of Kif13b in lipid metabolism and MAFLD were investigated using whole-body Kif13b knockout mice,hepatocyte-specific Kif13b-deficient mice and hamsters exposed to different diets.The underlying mechanisms by which Kif13bgoverned hepatic lipid homeostasis and MAFLD progression were explored in vitro.Finally,the Kif13b’s impact on atherosclerotic development was studied in the context of MAFLD.Results:KIF13B expression was reduced in patients and murine models with MAFLD.Rodents with global or liver-specific knockout of the Kif13b gene exhibit spontaneous hepatic steatosis,which is further exacerbated by different overnutrition diets.Overexpression of human KIF13B by lentivirus effectively prevented metabolic dysfunction-associated steatohepatitis(MASH)in methionine-choline-deficient diet(MCD)-fed mice.Furthermore,Kif13b deficiency accelerates atherosclerosis in the context of MAFLD.Mechanistically,Kif13b depletion increases hepatic lipid synthesis and impairs mitochondrial oxidative phosphorylation.Further screening reveals that Kif13b interacts with AMP-activated catalytic subunit alpha 1(AMPKα1)to regulate the phosphorylation of AMPKα1,governing mitochondrial homeostasis and suppressing sterol regulatory element binding protein 1(Srebp1)-mediated denovo lipogenesis in the liver.Conclusion:This work establishes a causal relationship between KIF13B deficiency and MAFLD,emphasizing KIF13B as a potential therapeutic target for treating MAFLD.
基金Chinese Scholarship Council(202206240086)National Natural Science Foundation of China(81974099,82170785,81974098,82170784)+4 种基金National Key Research and Development Program of China(2021YFC2009303)programs from Science and Technology Department of Sichuan Province(2021YFH0172)Young Investigator Award of Sichuan University 2017(2017SCU04A17)Technology Innovation Research and Development Project of Chengdu Science and Technology Bureau(2019-YF05-00296-SN)Sichuan University-Panzhihua science and technology cooperation special fund(2020CDPZH-4).
文摘In recent years,advancements in single-cell and spatial transcriptomics,which are highly regarded developments in the current era,particularly the emerging integration of single-cell and spatiotemporal transcriptomics,have enabled a detailed molecular comprehension of the complex regulation of cell fate.The insights obtained from these methodologies are anticipated to significantly contribute to the development of personalized medicine.Currently,single-cell technology is less frequently utilized for prostate cancer compared with other types of tumors.Start-ing from the perspective of RNA sequencing technology,this review outlined the signifcance of single-cell RNA sequencing(scRNA-seq)in prostate cancer research,encompassing preclinical medicine and clinical applications.We summarize the differences between mouse and human prostate cancer as revealed by scRNA-seq studies,as well as a combination of multi-omics methods involving scRNA-seq to highlight the key molecular targets for the diagnosis,treatment,and drug resistance characteristics of prostate cancer.These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer.Furthermore,we explore the potential clinical applications stemming from other single-cell technologies in this review,paving the way for future research in precision medicine.
基金supported in part by the National Nature Science Foundation of China(92268206,81830064)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-059)+4 种基金the Military Medical Research Projects(145AKJ260015000X,2022-JCJQ-ZB-09600)the Military Key Basic Research of Foundational Strengthening Program(2020-JCJQ-ZD-256-021)the Science Foundation of National Defense Science and Technology for Excellent Young(2022-JCJQ-ZQ-017)the Military Medical Research and Development Projects(AWS17J005,2019-126)the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province(YSPTZX202317).
文摘Scar formation resulting from burns or severe trauma can significantly compromise the structural integrity of skin and lead to permanent loss of skin appendages,ultimately impairing its normal physiological function.Accumulating evidence underscores the potential of targeted modulation of mechanical cues to enhance skin regeneration,promoting scarless repair by influencing the extracellular microenvironment and driving the phenotypic transitions.The field of skin repair and skin appendage regeneration has witnessed remarkable advancements in the utilization of biomaterials with distinct physical properties.However,a comprehensive understanding of the underlying mechanisms remains somewhat elusive,limiting the broader application of these innovations.In this review,we present two promising biomaterial-based mechanical approaches aimed at bolstering the regenerative capacity of compromised skin.The first approach involves leveraging biomaterials with specific biophysical properties to create an optimal scarless environment that supports cellular activities essential for regeneration.The second approach centers on harnessing mechanical forces exerted by biomaterials to enhance cellular plasticity,facilitating efficient cellular reprogramming and,consequently,promoting the regeneration of skin appendages.In summary,the manipulation of mechanical cues using biomaterial-based strategies holds significant promise as a supplementary approach for achieving scarless wound healing,coupled with the restoration of multiple skin appendage functions.
基金supported by the NSFC Distinguished Young Scholars Fund(82325010)the National Natural Science Foundation of China(82370874)+4 种基金the Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20212700)the Major Natural Science Project of the Scientific Research and Innovation Plan of Shanghai Municipal Commission of Education(2023ZKZD17)the Shanghai Research Center for Endocrine and Metabolic Diseases(2022ZZ01002)the Shanghai Key Discipline of Public Health Grants Award(GWVI-11.1-20)the Basic Scientific Research Project(General Cultivation Program)of Shanghai Sixth People’s Hospital(ynms202203).
文摘Background:Acute liver injury(ALI)requires rapid hepatic regeneration to avert fatal liver failure.As key mechanisms,systemic metabolic remodeling and inter-organ crosstalk are critical for this regenerative process.Skeletal muscle,as a major metabolic organ system,undergoes significant remodeling during ALI.However,its specific regulatory contributions remain largely uncharacterized.Methods:Partial(2/3)hepatectomy and acetaminophen were used to induce ALI in male mice.RNA-sequencing(RNA-seq),assay for transposase-accessible chromatin by sequencing(ATAC-seq),chromatin immunoprecipitation,luciferase assay,Western blotting,TUNEL assay,immunohistochemistry,and phase separation assays were performed to reveal the transcriptional axis involved.Serum fibroblast growth factor binding protein 1(FGFBP1)protein levels in ALI patients were assessed via enzyme-linked immunosorbent assay.Results:Integrated analysis of RNA-seq and ATAC-seq following ALI identifies glucocorticoid(GC)signaling-mediated regulation of fibroblast growth factor 6(FGF6)in skeletal muscle metabolism.Muscle-specific knockdown of GC receptor(GR)exacerbates ALI and suppresses liver regeneration.Fgf6-knockout mice exhibited improved ALI and enhanced liver regeneration,with intramuscular injection of FGF6-neutralizing antibody rescuing the detrimental effects induced by GR knockdown.Further analysis of the FGF6 downstream target revealed that FGF6 regulates FGFBP1 expression through extracellular signal regulated kinase-activating transcription factor 3 signaling.Moreover,FGF6 regulates the heparin-dependent release kinetics of FGFBP1 by perturbing its liquid-liquid phase separation(LLPS)-driven condensate dynamics at the plasma membrane.Circulating FGFBP1 subsequently interacts with hepatic FGF5 through LLPS mechanisms to regulate liver regeneration.Conclusion:Our results demonstrate a molecular mechanism by which muscle-liver crosstalk can initiate and sustain liver regeneration via the FGF6-FGFBP1/FGF5 axis,providing a potential therapeutic target and treatment strategy for ALI.
文摘Dear Editor,On March 8–15,2022,a board of international scientists assembled in Lyon to evaluate the carcinogenicity of cobalt metal,cobalt(Ⅱ)salts,antimony trioxide,and weaponsgrade tungsten alloy harboring nickel and cobalt[1].The 131st International Agency for Research on Cancer(IARC)Monograph is the result of a 6–9-month work of perusing the literature,slide evaluation,data interpretation,and interim meetings.The assessment of cobalt,antimony,and nickelcontaining alloys will have tremendous consequences for the industry,health,and defense departments[1].
基金supported by the Hyperbaric Med School of the Department of Biomedical Sciences at the University of Padova,the Italian Air Force,and the Institute of Clinical Physiology(Milan)-National Research Council(IFC-CNR).
文摘Dear Editor,Space flight(SF)is substantially increasing at present.The emergence of commercial suborbital SF,such as the Virgin Galactic with VSS Unity and VMS Eve spacecraft,is extending to civilians,being previously confined to military and/or professional astronauts only.This new evidence offers additional opportunities for better characterizing the impact that the transition from Earth’s 1G to microgravity in space could have on the astronauts’health while comparing well-trained subjects such as the latt er to space newcomers[1].
基金supported by grants from Jazz Pharmaceuticals Inc.the Texas A&M University of School of Medicine to AKS
文摘Background:Chronic Gulf War Illness(GWI)is characterized by cognitive and mood impairments,as well as persistent neuroinflammation and oxidative stress.This study aimed to investigate the efficacy of Epidiolex®,a Food and Drug Administration(FDA)-approved cannabidiol(CBD),in improving brain function in a rat model of chronic GWI.Methods:Six months after exposure to low doses of GWI-related chemicals[pyridostigmine bromide,N,N-diethyl-meta-toluamide(DEET),and permethrin(PER)]along with moderate stress,rats with chronic GWI were administered either vehicle(VEH)or CBD(20 mg/kg,oral)for 16 weeks.Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory,object location memory,pattern separation,and sucrose preference.The effect of CBD on hyperalgesia was also examined.The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests.Results:GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia,whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia.Additionally,CBD treatment alleviated hyperalgesia in GWI rats.Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription(JAK/STAT)signaling.Furthermore,there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis.In contrast,the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling,normalized concentrations of proinflammatory cytokines and oxidative stress markers,and improved neurogenesis.Notably,CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus.Conclusions:The use of an FDA-approved CBD(Epidiolex®)has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI.Importantly,the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.
基金supported by the Research Grant Council of Hong Kong-Early Career Scheme(106210224)and the Seed Fund(104006024).
文摘Dear Editor,The Hans Chinese(HC)ethnic group,comprising approximately 1.4 billion individuals,represents the largest workforce globally.Historically,HC has been predominantly isolated from other ethnic groups for over 3 millennia,resulting in distinct genetic and physiological characteristics[1,2].Consequently,the energy required to maintain essential functions,represented by the basal metabolic rate(BMR),cannot be accurately assessed in HC with algorithms developed for European-American(EA)populations,even when controlling for diff erences in body size[3].Notably,the widely used Harris-Benedict equation tends to overestimate BMR,relative to measured BMR via indirect calorimetry,in more than 50%of HC individuals[3].Hence,HC generally expends less energy than EA under basal(resting)conditions.This raises an important question:does HC require lower energy expenditure than EA for equivalent external work?Th e present aimed to address this inquiry,while adjusting for key confounding factors such as age,sex,physical activity,aerobic capacity,BMR,and body composition.
基金supported by the National Natural Science Foundation of China(8210082163,81800343)the Fundamental Research Fund for the Central Universities(2042021kf0081)+1 种基金the Science Fund for Creative Research Groups of the Natural Science Foundation of Hubei Province(2020CFA027)the Doctor of Excellence Program of the First Hospital of Jilin University(JDYY-DEP-2023043).
文摘Mitochondria,the most crucial energy-generating organelles in eukaryotic cells,play a pivotal role in regulating energy metabolism.However,their significance extends beyond this,as they are also indispensable in vital life processes such as cell proliferation,differentiation,immune responses,and redox balance.In response to various physiological signals or external stimuli,a sophisticated mitochondrial quality control(MQC)mechanism has evolved,encompassing key processes like mitochondrial biogenesis,mitochondrial dynamics,and mitophagy,which have garnered increasing attention from researchers to unveil their specific molecular mechanisms.In this review,we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC.Furthermore,the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail.We also discuss agonists or antagonists targeting MQC,aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.
基金suppor ted by the US Depar tment of Defense Congressionally Directed Medical Research Program (CDMRP)awards (http://cdmrp.army.mil/) W81XWH-16-1-0632 (Craddock PI),W81XWH-16-1-0552 (Craddock PI),W81XWH-18-1-0549 (Sullivan PI),W81XWH-13-2-0072 (Sullivan PI),and W81XWH-09-2-0071 (Klimas PI)a Veterans Affairs Merit Award (4987.69) to Dr.Nancy Klimas。
文摘Background:One-third of veterans returning from the 1990–1991 Gulf War reported a myriad of symptoms including cognitive dysfunction,skin rashes,musculoskeletal discomfort,and fatigue.This symptom cluster is now referred to as Gulf War Illness(GWI).As the underlying mechanisms of GWI have yet to be fully elucidated,diagnosis and treatment are based on symptomatic presentation.One confounding factor tied to the illness is the high presence of post-traumatic stress disorder(PTSD).Previous research efforts have demonstrated that both GWI and PTSD are associated with immunological dysfunction.As such,this research endeavor aimed to provide insight into the complex relationship between GWI symptoms,cytokine presence,and immune cell populations to pinpoint the impact of PTSD on these measures in GWI.Methods:Symptom measures were gathered through the Multidimensional fatigue inventory(MFI)and 36-item short form health survey(SF-36)scales and biological measures were obtained through cytokine&cytometry analysis.Subgrouping was conducted using Davidson Trauma Scale scores and the Structured Clinical Interview for Diagnostic and statistical manual of mental disorders(DSM)-5,into GWI with high probability of PTSD symptoms(GWIH)and GWI with low probability of PTSD symptoms(GWIL).Data was analyzed using analysis of variance(ANOVA)statistical analysis along with correlation graph analysis.We mapped correlations between immune cells and cytokine signaling measures,hormones and GWI symptom measures to identify patterns in regulation between the GWIH,GWIL,and healthy control groups.Results:GWI with comorbid PTSD symptoms resulted in poorer health outcomes compared with both healthy control(HC)and the GWIL subgroup.Significant differences were found in basophil levels of GWI compared with HC at peak exercise regardless of PTSD symptom comorbidity(ANOVA F=4.7,P=0.01)indicating its potential usage as a biomarker for general GWI from control.While the unique identification of GWI with PTSD symptoms was less clear,the GWIL subgroup was found to be delineated from both GWIH and HC on measures of IL-15 across an exercise challenge(ANOVA F>3.75,P<0.03).Additional differences in natural killer(NK)cell numbers and function highlight IL-15 as a potential biomarker of GWI in the absence of PTSD symptoms.Conclusions:We conclude that disentangling GWI and PTSD by defining trauma-based subgroups may aid in the identification of unique GWI biosignatures that can help to improve diagnosis and target treatment of GWI more effectively.
基金supported by the Key Research and Development Program of Hunan Province of China(2020SK2102)the Hunan Provincial Natural Science Foundation of China(2023JJ40420)+5 种基金the Changsha Municipal Natural Science Foundation(kq2208154)the Scientific Research Project of Hunan Provincial Health Commission(B202304088074)the Scientific Research Project of Hunan Provincial Health Commission(202203105045)the National Natural Science Foundation of China(82301435,82201484)the Hunan Provincial Natural Science Foundation of China(2024JJ4083)the Graduate Research and Innovation Project of Hunan Education Department(CX20220528).
文摘Background:Parkinson’s disease(PD)is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra(SN).Activation of the neuroinflammatory response has a pivotal role in PD.Mesenchymal stem cells(MSCs)have emerged as a promising therapeutic approach for various nerve injuries,but there are limited reports on their use in PD and the underlying mechanisms remain unclear.Methods:We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa(hOM)-MSCs on neural functional recovery in both PD models and patients,as well as the preventive effects on mouse models of PD.To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure,we employed single-cell RNA sequencing(scRNA-seq),assay for transposase accessible chromatin with high-throughput sequencing(ATAC-seq)combined with full-length transcriptome isoform-sequencing(ISO-seq),and functional assay.Furthermore,we present the findings from an initial cohort of patients enrolled in a phaseⅠfirstinhuman clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients.Results:A functional assay identified that transforming growth factor-β1(TGF-β1),secreted from hOM-MSCs,played a critical role in modulating mitochondrial function recovery in dopaminergic neurons.This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN,which are closely associated with neuroinflammatory responses.Mechanistically,exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-β1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B(ALK/PI3K/Akt)signaling pathway in microglia located in the SN of PD patients.Furthermore,intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD.Conclusions:These findings provide compelling evidence for the involvement of TGF-β1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD.Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD.Additionally,TGF-β1 may be used alone or combined with hOM-MSCs therapy for treating PD.
基金support from the National Institutes of Health grants R21 ES033806(RPS)is greatly acknowledged.
文摘The lipid mediator platelet-activating factor(PAF)and its receptor(PAFR)signaling play critical roles in a wide range of physiological and pathophysiological conditions,including cancer growth and metastasis.The ability of PAFR to interact with other oncogenic signaling cascades makes it a promising target for cancer treatment.Moreover,numerous natural and synthetic compounds,characterized by diverse pharmacological activities such as anti-inflammatory and anti-tumor effects,have been explored for their potential as PAF and PAFR antagonists.In this review,we provide comprehensive evidence regarding the PAF/PAFR signaling pathway,highlighting the effectiveness of various classes of PAF and PAFR inhibitors and antagonists across multiple cancer models.Notably,the synergistic effects of PAF and PAFR antagonists in enhancing the efficacy of chemotherapy and radiation therapy in several experimental cancer models are also discussed.Overall,the synthesis of literature review indicates that targeting the PAF/PAFR axis represents a promising approach for cancer treatment and also exerts synergy with chemotherapy and radiation therapy.
基金supported by the Health and Medical Research Fund,Food and Health Bureau,Hong Kong SAR Government(HMRF 07180186).
文摘Dear Editor,Lung adenocarcinoma(LUAD)is a major subtype of non-small cell lung cancer with global health implications.Targeted therapies,such as epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),have demonstrated promise but encounter resistance challenges.Erlotinib(ER),a widely used EGFR TKI,often faces the emergence of resistance^([1]).Th erefore,understanding therapeutic targets for ER resistance is crucial.AKR1C3 plays a pivotal role as a key enzyme in the biosynthesis of androgens,serving as a regulator of hormone activity and prostaglandin F synthase.
