BACKGROUND Three-dimensional organoid culture systems have been established as a robust tool for elucidating mechanisms and performing drug efficacy testing.The use of gastric organoid models holds significant promise...BACKGROUND Three-dimensional organoid culture systems have been established as a robust tool for elucidating mechanisms and performing drug efficacy testing.The use of gastric organoid models holds significant promise for advancing personalized medicine research.However,a comprehensive bibliometric review of this burgeoning field has not yet been published.AIM To analyze and understand the development,impact,and direction of gastric organoid research using bibliometric methods using data from the Web of Science Core Collection(WoSCC)database.METHODS This analysis encompassed literature pertaining to gastric organoids published between 2010 and 2023,as indexed in the WoSCC.CiteSpace and VOSviewer were used to depict network maps illustrating collaborations among authors,institutions and keywords related to gastric organoid.Citation,co-citation,and burst analysis methodologies were applied to assess the impact and progress of research.RESULTS A total of 656 relevant studies were evaluated.The majority of research was published in gastroenterology-focused journals.Globally,Yana Zavros,Hans Clevers,James M Wells,Sina Bartfeld,and Chen Zheng were the 5 most productive authors,while Hans Clevers,Huch Meritxell,Johan H van Es,Marc Van de Wetering,and Sato Toshiro were the foremost influential scientists in this area.Institutions from the University Medical Center Utrecht,Netherlands Institute for Developmental Biology(Utrecht),and University of Cincinnati(Cincinnati,OH,United States)made the most significant contributions.Currently,gastric organoids are used mainly in studies investigating gastric cancer(GC),Helicobacter pylori-infective gastritis,with a focus on the mechanisms of GC,and drug screening tests.CONCLUSION Key focus areas of research using gastric organoids include unraveling disease mechanisms and enhancing drug screening techniques.Major contributions from renowned academic institutions highlight this field’s dynamic growth.展开更多
Helium bubbles,which are typical radiation microstructures observed in metals or alloys,are usually investigated using transmission electron microscopy(TEM).However,the investigation requires human inputs to locate an...Helium bubbles,which are typical radiation microstructures observed in metals or alloys,are usually investigated using transmission electron microscopy(TEM).However,the investigation requires human inputs to locate and mark the bubbles in the acquired TEM images,rendering this task laborious and prone to error.In this paper,a machine learning method capable of automatically identifying and analyzing TEM images of helium bubbles is proposed,thereby improving the efficiency and reliability of the investigation.In the proposed technique,helium bubble clusters are first determined via the densitybased spatial clustering of applications with noise algorithm after removing the background and noise pixels.For each helium bubble cluster,the number of helium bubbles is determined based on the cluster size depending on the specific image resolution.Finally,the helium bubble clusters are analyzed using a Gaussian mixture model,yielding the location and size information on the helium bubbles.In contrast to other approaches that require training using numerous annotated images to establish an accurate classifier,the parameters used in the established model are determined using a small number of TEM images.The results of the model formulated according to the proposed approach achieved a higher F1 score validated through some helium bubble images manually marked.Furthermore,the established model can identify bubble-like objects that humans cannot facilely identify.This computationally efficient method achieves object recognition for material structure identification that may be advantageous to scientific work.展开更多
Solute carriers(SLCs) constitute the largest superfamily of membrane transporter proteins.These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of di...Solute carriers(SLCs) constitute the largest superfamily of membrane transporter proteins.These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions.They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake(e.g., SLC2A4/GLUT4), glucose reabsorption(e.g., SLC5A2/SGLT2), thermogenesis(e.g., SLC25A7/UCP-1), and ATP production(e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus(T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone(SLCO1B1/OATP1B1) and metformin(SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.展开更多
Serving as targeting ligands,aptamers have shown promise in precision medicine.However,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’clinical translation.To...Serving as targeting ligands,aptamers have shown promise in precision medicine.However,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’clinical translation.To bridge this gap,here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68(^(68)Ga)radiolabeled aptamers.The specificity and binding affinity of a radiolabeled aptamer,named ^(68)Ga[Ga]-NOTA-SGC8,were maintained as proven in vitro.Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity,potential mutation risks,or genotoxicity at high dosage(40 mg/kg).Based on this result,a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles,as well as biosafety,of the radiolabeled SGC8 aptamer in the human body.Taking advantage of the cutting-edge total-body PET,the aptamers’distribution pattern in the human body was acquired in a dynamic fashion.展开更多
Sennoside A(SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in th...Sennoside A(SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, the impact of SA on insulin sensitivity was tested in high fat diet(HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR(homeostatic model assessment for insulin resistance) and glucose tolerance test(GTT). SA restored plasma level of glucagon-like peptide 1(GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids(SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota–GLP1 axis to improve glucose metabolism in the obese mice.展开更多
Dementia is characterized by synaptic and neuronal dysfunction in disease-specific brain regions.Repeated failure of dementia clinical trials with therapeutic drugs targeting abnormal protein aggregates has caused res...Dementia is characterized by synaptic and neuronal dysfunction in disease-specific brain regions.Repeated failure of dementia clinical trials with therapeutic drugs targeting abnormal protein aggregates has caused researchers to shift their focus to synaptic functions and increased the importance of clinically available imaging for synaptic density and the development of synapse-targeted intervention.Synaptic density imaging with positron emission tomography(PET)tracer enables non-invasive detection of synaptic loss and hence investigates the association with other neuropathological events exemplified by disease-specific abnormal protein accumulation.Many studies have reviewed the progress of synaptic density imaging;however,to our knowledge,there is no article yet that summarizes the research progress of multimodal imaging of synaptic density tracers combined with other dementia biomarkers.Moreover,synaptic function intervention for dementia therapy has not yet been summarized.In this review,first we detail the progress of synaptic density imaging including tracer development and preclinical/clinical application,followed by a discussion of multimodal imaging of synaptic density tracers combined with classic dementia biomarkers in the clinical research stage.Finally,we briefly summarize the synapse-targeted drugs for dementia therapy.展开更多
Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the ...Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.展开更多
CoproporphyrinⅢ(CPⅢ),a natural porphyrin derivative,has extensive applications in the biomedical and material industries.S.cerevisiae has previously been engineered to highly accumulate the CPⅢprecursor 5-aminolevu...CoproporphyrinⅢ(CPⅢ),a natural porphyrin derivative,has extensive applications in the biomedical and material industries.S.cerevisiae has previously been engineered to highly accumulate the CPⅢprecursor 5-aminolevulinic acid(ALA)through the C4 pathway.In this study,a combination of cytoplasmic metabolic engineering and mitochondrial compartmentalization was used to enhance CPⅢproduction in S.cerevisiae.By integrating pathway genes into the chromosome,the CPⅢtiter gradually increased to 32.5±0.5 mg/L in shake flask cultivation.Nevertheless,increasing the copy number of pathway genes did not consistently enhance CPⅢsynthesis.Hence,the partial synthesis pathway was compartmentalized in mitochondria to evaluate its effectiveness in increasing CPⅢproduction.Subsequently,by superimposing the mitochondrial compartmentalization strategy on cytoplasmic metabolic engineered strains,the CPⅢtiter was increased to 64.3±1.9 mg/L.Furthermore,augmenting antioxidant pathway genes to reduce reactive oxygen species(ROS)levels effectively improved the growth of engineered strains,resulting in a further increase in the CPⅢtiter to 82.9±1.4 mg/L.Fed-batch fermentations in a 5 L bioreactor achieved a titer of 402.8±9.3 mg/L for CPⅢ.This study provides a new perspective on engineered yeast for the microbial production of porphyrins.展开更多
Farnesoid X receptor(FXR)is a ligand-activated nuclear receptor and plays important roles in the regulation of metabolism and homeostasis of several important physiological substances,such as bile acids,glucose,and li...Farnesoid X receptor(FXR)is a ligand-activated nuclear receptor and plays important roles in the regulation of metabolism and homeostasis of several important physiological substances,such as bile acids,glucose,and lipids.As such,FXR has become a promising therapeutic target for the treatment of several metabolic diseases and liver disorders.Recently,fargesone A(FA),a natural product from Magnolia fargesii was identified to be a novel,potent FXR agonist that demonstrated good in vitro and in vivo activities.However,the detailed interaction mechanism of FA with FXR remains unclear.In this study,we employed multiple computational approaches including molecular docking,molecular dynamics simulation,and binding free energy calculation to address the issue.By comparisons of the structural dynamics and binding free energies,an optimal binding mode was identified,in which FA interacts with FXR via a direct hydrogen bond with His447 and hydrophobic interactions with multiple residues,such as Leu287,Met290,Met328,Ile352,and Trp454.Two mutants,namely,H447F and L287N,were further constructed to validate the importance of the identified residues.We anticipate that these findings could be helpful for future rational design of new FA analogues targeting FXR.展开更多
Despite the diverse etiologies of drug-induced liver injury(DILI),innate immunity activation is a common feature involved in DILI progression.However,the involvement of innate immunity regulation in inflammation resol...Despite the diverse etiologies of drug-induced liver injury(DILI),innate immunity activation is a common feature involved in DILI progression.However,the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure.Herein,we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI.First,we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury(AILI)mouse model.Interestingly,both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury.Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration,which are associated with an increased number of hepatic M2 macrophages.Mechanistically,CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1-and CCR5-mediated activation of the MAPK and NF-κB pathways.We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model.Our data demonstrate CCL5 induction during DILI,identify CCL5 as a novel innate immunity regulator in macrophage polarization,and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.展开更多
Multimodal combinatorial therapy merges different modes of therapies in one platform,which can overcome several clinical challenges such as premature drug loss during blood circulation and significantly improve treatm...Multimodal combinatorial therapy merges different modes of therapies in one platform,which can overcome several clinical challenges such as premature drug loss during blood circulation and significantly improve treatment efficiency.Here we report a combinatorial therapy nanoplatform that enables dual photothermal therapy and pH-stimulus-responsive chemotherapy.By super-assembly of mesoporous silica nanoparticles(MSN)with metal-phenolic networks(MPN),anti-cancer drugs can be loaded in the MSN matrix,while the outer MPN coating allows dual photothermal and pH-responsive properties.Upon near-infrared light irradiation,the MSN@MPN nanoplatform exhibits excellent photothermal effect,and demonstrates outstanding pH-triggered drug release property.In vitro cell experiments suggest the MSN@MPN system exhibits superior biocompatibility and can effectively kill tumor cells after loading anti-cancer drugs.Consequently,the MSN@MPN system shows promising prospects in clinical application for tumor therapy.展开更多
Carbon dots(CDs)are metal-free fluorescent materials that can be used in optical and electronic devices,but few studies have focused on one-step synthesis routes for CDs with tunable color and high photoluminescence q...Carbon dots(CDs)are metal-free fluorescent materials that can be used in optical and electronic devices,but few studies have focused on one-step synthesis routes for CDs with tunable color and high photoluminescence quantum yield(PLQY).Herein,CDs with tunable light emission were synthesized using a novel amide-assisted solvothermal approach.The as-prepared CDs were well dispersed and homogeneous,with average diameters of approximately 2.0–4.0 nm,depending on the dopants.Owing to the surface states with different ratios of nitrogen-and oxygen-related species,different CDs can exhibit blue,green,red,or white emission with relatively high PLQYs of 61.6%,41.3%,29.1%and 19.7%,respectively.XPS measurements,in conjunction with DFT calculations,indicate that nitrogen substitution(pyridinic/pyrrolic nitrogen)dominates the blue emission,while introducing oxygen functional groups lowered the LUMO energy level,which resulted in redder emission.In addition,the CDs are demonstrated as a bioimaging probe in both in vitro and in vivo assays,and the white light CDs have been demonstrated to be potential fluorescent materials for white-light-emitting diode(WLED).展开更多
Radiopharmaceuticals have become indispensable tools in precision medicine,revolutionizing diagnostic imaging and targeted therapeutic strategies.This manuscript provides an overview of advancements globally and in Ch...Radiopharmaceuticals have become indispensable tools in precision medicine,revolutionizing diagnostic imaging and targeted therapeutic strategies.This manuscript provides an overview of advancements globally and in China,focusing on the classification and clinical applications of radiopharmaceuticals,particularly in oncology and neurology.Recent progress includes PET/SPECT diagnostic agents and therapeutic radionuclides that provide precise treatment while limiting damage to healthy tissues.Emerging technologies,such as artificial intelligence,novel ligands,advanced radionuclides,and combination therapies,present promising avenues to further enhance the efficacy and accessibility of the field.Despite these achievements,challenges remain in production,regulatory,and costs,underscoring the need for ongoing innovation and international collaboration to fully realize the potential of radiopharmaceuticals in personalized healthcare and optimize patient outcomes.展开更多
基金the National Natural Science Foundation of China,No.82174309National Natural Science Foundation of China,No.81973774+1 种基金National Administration of Traditional Chinese Medicine:2019 Project of Building Evidence-Based Practice Capacity for TCM,No.ZZ13-042-2 and No.2019XZZX-XH013Shuguang Hospital Siming Foundation Research Special Project,No.SGKJ-202304.
文摘BACKGROUND Three-dimensional organoid culture systems have been established as a robust tool for elucidating mechanisms and performing drug efficacy testing.The use of gastric organoid models holds significant promise for advancing personalized medicine research.However,a comprehensive bibliometric review of this burgeoning field has not yet been published.AIM To analyze and understand the development,impact,and direction of gastric organoid research using bibliometric methods using data from the Web of Science Core Collection(WoSCC)database.METHODS This analysis encompassed literature pertaining to gastric organoids published between 2010 and 2023,as indexed in the WoSCC.CiteSpace and VOSviewer were used to depict network maps illustrating collaborations among authors,institutions and keywords related to gastric organoid.Citation,co-citation,and burst analysis methodologies were applied to assess the impact and progress of research.RESULTS A total of 656 relevant studies were evaluated.The majority of research was published in gastroenterology-focused journals.Globally,Yana Zavros,Hans Clevers,James M Wells,Sina Bartfeld,and Chen Zheng were the 5 most productive authors,while Hans Clevers,Huch Meritxell,Johan H van Es,Marc Van de Wetering,and Sato Toshiro were the foremost influential scientists in this area.Institutions from the University Medical Center Utrecht,Netherlands Institute for Developmental Biology(Utrecht),and University of Cincinnati(Cincinnati,OH,United States)made the most significant contributions.Currently,gastric organoids are used mainly in studies investigating gastric cancer(GC),Helicobacter pylori-infective gastritis,with a focus on the mechanisms of GC,and drug screening tests.CONCLUSION Key focus areas of research using gastric organoids include unraveling disease mechanisms and enhancing drug screening techniques.Major contributions from renowned academic institutions highlight this field’s dynamic growth.
基金supported by the National Natural Science Foundation of China(Nos.12005128,81830052)Construction Project of Shanghai Key Laboratory of Molecular Imaging(No.18DZ2260400)and Shanghai Municipal Education Commission(Class II Plateau Disciplinary Construction Program of Medical Technology of SUMHS,2018–2020).
文摘Helium bubbles,which are typical radiation microstructures observed in metals or alloys,are usually investigated using transmission electron microscopy(TEM).However,the investigation requires human inputs to locate and mark the bubbles in the acquired TEM images,rendering this task laborious and prone to error.In this paper,a machine learning method capable of automatically identifying and analyzing TEM images of helium bubbles is proposed,thereby improving the efficiency and reliability of the investigation.In the proposed technique,helium bubble clusters are first determined via the densitybased spatial clustering of applications with noise algorithm after removing the background and noise pixels.For each helium bubble cluster,the number of helium bubbles is determined based on the cluster size depending on the specific image resolution.Finally,the helium bubble clusters are analyzed using a Gaussian mixture model,yielding the location and size information on the helium bubbles.In contrast to other approaches that require training using numerous annotated images to establish an accurate classifier,the parameters used in the established model are determined using a small number of TEM images.The results of the model formulated according to the proposed approach achieved a higher F1 score validated through some helium bubble images manually marked.Furthermore,the established model can identify bubble-like objects that humans cannot facilely identify.This computationally efficient method achieves object recognition for material structure identification that may be advantageous to scientific work.
基金supported by grants from National Natural Science Foundation of China(81903961 to Jiamei Le,32271220 to Jianping Ye)National Key Research and Development Program of China(2020YFA0909000)+2 种基金National Natural Science Foundation of China(82127807)Shanghai Key Laboratory of Molecular Imaging(18DZ2260400,China)the Climbing Program of Shanghai University of Medicine and Health Sciences(A1-2601-23-311007,China).
文摘Solute carriers(SLCs) constitute the largest superfamily of membrane transporter proteins.These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions.They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake(e.g., SLC2A4/GLUT4), glucose reabsorption(e.g., SLC5A2/SGLT2), thermogenesis(e.g., SLC25A7/UCP-1), and ATP production(e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus(T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone(SLCO1B1/OATP1B1) and metformin(SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.
基金the National Key Research and Development Program of China(No.2020YFA0909000 and 2020YFA0210800)the National Science Foundation of China(No.22204102,52161160307,91953000,and 2182781)+2 种基金Shanghai Sailing Program,Shanghai Committee of Science and Technology,China(No.21YF1425700)Excellent Academic Leader Programme of Shanghai Health Commission(2022XD033)Core Facility of Basic Medical Sciences in Shanghai Jiao Tong University School of Medicine,and the Innovative Research Team of High-Level Local Universities in Shanghai,China.
文摘Serving as targeting ligands,aptamers have shown promise in precision medicine.However,the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers’clinical translation.To bridge this gap,here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68(^(68)Ga)radiolabeled aptamers.The specificity and binding affinity of a radiolabeled aptamer,named ^(68)Ga[Ga]-NOTA-SGC8,were maintained as proven in vitro.Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity,potential mutation risks,or genotoxicity at high dosage(40 mg/kg).Based on this result,a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles,as well as biosafety,of the radiolabeled SGC8 aptamer in the human body.Taking advantage of the cutting-edge total-body PET,the aptamers’distribution pattern in the human body was acquired in a dynamic fashion.
基金supported by the National Natural Science Foundation of China(81874377)to Yongning Sunthe National Natural Science Foundation of China(81220108006)to Weiping Jia and Jianping Yesupported by the internal fund of the Shanghai Jiaotong University Affiliated Sixth People’s Hospital East(Shanghai,China)to Jianping Ye and Yongning Sun
文摘Sennoside A(SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative, which is often used in the treatment of constipation and obesity. However, its activity remains unknown in the regulation of insulin sensitivity. In this study, the impact of SA on insulin sensitivity was tested in high fat diet(HFD)-induced obese mice through dietary supplementation. At a dosage of 30 mg/kg/day, SA improved insulin sensitivity in the mice after 8-week treatment as indicated by HOMA-IR(homeostatic model assessment for insulin resistance) and glucose tolerance test(GTT). SA restored plasma level of glucagon-like peptide 1(GLP1) by 90% and mRNA expression of Glp1 by 80% in the large intestine of HFD mice. In the mechanism, SA restored the gut microbiota profile, short chain fatty acids(SCFAs), and mucosal structure in the colon. A mitochondrial stress was observed in the enterocytes of HFD mice with ATP elevation, structural damage, and complex dysfunction. The mitochondrial response was induced in enterocytes by the dietary fat as the same responses were induced by palmitic acid in the cell culture. The mitochondrial response was inhibited in HFD mice by SA treatment. These data suggest that SA may restore the function of microbiota–GLP1 axis to improve glucose metabolism in the obese mice.
基金funding support from the National Natural Science Foundation of China(81971016)Shanghai Science and Technology program(21010502300)Construction project of Shanghai Key Laboratory of Molecular Imaging(18DZ2260400).
文摘Dementia is characterized by synaptic and neuronal dysfunction in disease-specific brain regions.Repeated failure of dementia clinical trials with therapeutic drugs targeting abnormal protein aggregates has caused researchers to shift their focus to synaptic functions and increased the importance of clinically available imaging for synaptic density and the development of synapse-targeted intervention.Synaptic density imaging with positron emission tomography(PET)tracer enables non-invasive detection of synaptic loss and hence investigates the association with other neuropathological events exemplified by disease-specific abnormal protein accumulation.Many studies have reviewed the progress of synaptic density imaging;however,to our knowledge,there is no article yet that summarizes the research progress of multimodal imaging of synaptic density tracers combined with other dementia biomarkers.Moreover,synaptic function intervention for dementia therapy has not yet been summarized.In this review,first we detail the progress of synaptic density imaging including tracer development and preclinical/clinical application,followed by a discussion of multimodal imaging of synaptic density tracers combined with classic dementia biomarkers in the clinical research stage.Finally,we briefly summarize the synapse-targeted drugs for dementia therapy.
基金supported by the National Key Research and Development Program of China,No. 2023YFF0714200 (to CW)the National Natural Science Foundation of China,Nos. 82472038 and 82202224 (both to CW)+3 种基金the Shanghai Rising-Star Program,No. 23QA1407700 (to CW)the Construction Project of Shanghai Key Laboratory of Molecular Imaging,No. 18DZ2260400 (to CW)the National Science Foundation for Distinguished Young Scholars,No. 82025019 (to CL)the Greater Bay Area Institute of Precision Medicine (Guangzhou)(to CW)。
文摘Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.
基金supported by the grant from the National Key Research and Development Program of China(2021YFC2100300)2023 Double World-class Project Key Program“Intelligent Biomanufacturing”.
文摘CoproporphyrinⅢ(CPⅢ),a natural porphyrin derivative,has extensive applications in the biomedical and material industries.S.cerevisiae has previously been engineered to highly accumulate the CPⅢprecursor 5-aminolevulinic acid(ALA)through the C4 pathway.In this study,a combination of cytoplasmic metabolic engineering and mitochondrial compartmentalization was used to enhance CPⅢproduction in S.cerevisiae.By integrating pathway genes into the chromosome,the CPⅢtiter gradually increased to 32.5±0.5 mg/L in shake flask cultivation.Nevertheless,increasing the copy number of pathway genes did not consistently enhance CPⅢsynthesis.Hence,the partial synthesis pathway was compartmentalized in mitochondria to evaluate its effectiveness in increasing CPⅢproduction.Subsequently,by superimposing the mitochondrial compartmentalization strategy on cytoplasmic metabolic engineered strains,the CPⅢtiter was increased to 64.3±1.9 mg/L.Furthermore,augmenting antioxidant pathway genes to reduce reactive oxygen species(ROS)levels effectively improved the growth of engineered strains,resulting in a further increase in the CPⅢtiter to 82.9±1.4 mg/L.Fed-batch fermentations in a 5 L bioreactor achieved a titer of 402.8±9.3 mg/L for CPⅢ.This study provides a new perspective on engineered yeast for the microbial production of porphyrins.
基金supported by the Construction Project of Shanghai Key Laboratory of Molecular Imaging,China(No.18DZ2260400).
文摘Farnesoid X receptor(FXR)is a ligand-activated nuclear receptor and plays important roles in the regulation of metabolism and homeostasis of several important physiological substances,such as bile acids,glucose,and lipids.As such,FXR has become a promising therapeutic target for the treatment of several metabolic diseases and liver disorders.Recently,fargesone A(FA),a natural product from Magnolia fargesii was identified to be a novel,potent FXR agonist that demonstrated good in vitro and in vivo activities.However,the detailed interaction mechanism of FA with FXR remains unclear.In this study,we employed multiple computational approaches including molecular docking,molecular dynamics simulation,and binding free energy calculation to address the issue.By comparisons of the structural dynamics and binding free energies,an optimal binding mode was identified,in which FA interacts with FXR via a direct hydrogen bond with His447 and hydrophobic interactions with multiple residues,such as Leu287,Met290,Met328,Ile352,and Trp454.Two mutants,namely,H447F and L287N,were further constructed to validate the importance of the identified residues.We anticipate that these findings could be helpful for future rational design of new FA analogues targeting FXR.
基金This work was supported by the National Key Research and Development Program of China(2017YFC0908100 to Q.X.)the National Key Sci-Tech Special Project of China(2018ZX10723204-006-004 to X.K.)+1 种基金the National Natural Science Foundation of China(81873582 and 81670562 to X.K.,81670598 to Q.X.,31870905 and 31671453 to H.W.)the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support(20171911 to X.K.).
文摘Despite the diverse etiologies of drug-induced liver injury(DILI),innate immunity activation is a common feature involved in DILI progression.However,the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure.Herein,we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI.First,we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury(AILI)mouse model.Interestingly,both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury.Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration,which are associated with an increased number of hepatic M2 macrophages.Mechanistically,CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1-and CCR5-mediated activation of the MAPK and NF-κB pathways.We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model.Our data demonstrate CCL5 induction during DILI,identify CCL5 as a novel innate immunity regulator in macrophage polarization,and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.
基金This work was supported by the National Key Research and Development Program of China(Nos.2019YFC1604600,2017YFA0206901,2017YFA0206900)the National Natural Science Foundation of China(Nos.21705027,21974029,81830052),the Construction project of Shanghai Key Laboratory of Molecular Imaging(No.18DZ2260400)+3 种基金the Shanghai Municipal Education Commission(Class II Plateau Disciplinary C onstruction Program of Medical Technology of SUMHS,2018-2020)the Australia National Health and Medical Research Council(NHMRC)(No.APP1163786)the Scientia Fellowship program at UNSW,the MCTL Visiting Fellowship Program,Shanghai Key Laboratory of Molecular Imaging(No.18DZ2260400)the Natural Science Foundation of Shanghai,and the Recruitm ent Program of Global Experts of China and Shanghai.
文摘Multimodal combinatorial therapy merges different modes of therapies in one platform,which can overcome several clinical challenges such as premature drug loss during blood circulation and significantly improve treatment efficiency.Here we report a combinatorial therapy nanoplatform that enables dual photothermal therapy and pH-stimulus-responsive chemotherapy.By super-assembly of mesoporous silica nanoparticles(MSN)with metal-phenolic networks(MPN),anti-cancer drugs can be loaded in the MSN matrix,while the outer MPN coating allows dual photothermal and pH-responsive properties.Upon near-infrared light irradiation,the MSN@MPN nanoplatform exhibits excellent photothermal effect,and demonstrates outstanding pH-triggered drug release property.In vitro cell experiments suggest the MSN@MPN system exhibits superior biocompatibility and can effectively kill tumor cells after loading anti-cancer drugs.Consequently,the MSN@MPN system shows promising prospects in clinical application for tumor therapy.
基金the financial support from the Chenguang Scholar Project of Shanghai Education Commission(Nos.19CG52,19CG53)National Natural Science Foundation of China(No.62071300)+3 种基金Science and Technology Commission of Shanghai Municipality(Nos.19ZR1435200,20490761100)Program of Shanghai Academic/Technology Research Leader(No.19XD1422900)Cross-program of Medical&Engineering(University of Shanghai for Science and Technology)Foundation of State Key Laboratory of High-efficiency Utilization of Coal and Green Chemical Engineering(No.2021-K33)。
文摘Carbon dots(CDs)are metal-free fluorescent materials that can be used in optical and electronic devices,but few studies have focused on one-step synthesis routes for CDs with tunable color and high photoluminescence quantum yield(PLQY).Herein,CDs with tunable light emission were synthesized using a novel amide-assisted solvothermal approach.The as-prepared CDs were well dispersed and homogeneous,with average diameters of approximately 2.0–4.0 nm,depending on the dopants.Owing to the surface states with different ratios of nitrogen-and oxygen-related species,different CDs can exhibit blue,green,red,or white emission with relatively high PLQYs of 61.6%,41.3%,29.1%and 19.7%,respectively.XPS measurements,in conjunction with DFT calculations,indicate that nitrogen substitution(pyridinic/pyrrolic nitrogen)dominates the blue emission,while introducing oxygen functional groups lowered the LUMO energy level,which resulted in redder emission.In addition,the CDs are demonstrated as a bioimaging probe in both in vitro and in vivo assays,and the white light CDs have been demonstrated to be potential fluorescent materials for white-light-emitting diode(WLED).
基金supported by the construction project of Shanghai Key Laboratory of Molecular Imaging of China(No.18DZ2260400)the research grants from the National Natural Science Foundation of China(No.82127807)the National Key Research and Development Program of China(No.2020YFA0909000).
文摘Radiopharmaceuticals have become indispensable tools in precision medicine,revolutionizing diagnostic imaging and targeted therapeutic strategies.This manuscript provides an overview of advancements globally and in China,focusing on the classification and clinical applications of radiopharmaceuticals,particularly in oncology and neurology.Recent progress includes PET/SPECT diagnostic agents and therapeutic radionuclides that provide precise treatment while limiting damage to healthy tissues.Emerging technologies,such as artificial intelligence,novel ligands,advanced radionuclides,and combination therapies,present promising avenues to further enhance the efficacy and accessibility of the field.Despite these achievements,challenges remain in production,regulatory,and costs,underscoring the need for ongoing innovation and international collaboration to fully realize the potential of radiopharmaceuticals in personalized healthcare and optimize patient outcomes.
