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关键词： Pluripotent stem cells   Liver   Organoids   Disease models   Drug discovery   AcLDL   acetylated low-density lipoprotein   ACTA2   actin alpha 2   AFP   alpha fetoprotein   ALB   Albumin   ALCAM   activated leukocyte cell adhesion molecule   AHR   Aryl hydrocarbon receptor   aHSCs   activated HSCs   ALGS   Alagille syndrome   ASBT   Apical sodium-dependent bile acid transporter   αSMA   α-smooth muscle actin   BMP   bone morphogenetic protein   CFTR   Cystic fibrosis transmembrane conductance regulator   COL1A1   type I collagen alpha 1 chain   CCl   4   carbon tetrachloride   CBP   CREB binding protein   CPM   Carboxypeptidase M   CPs   cholangiocyte progenitors   cAMP   cyclic AMP   CYGB   Cytoglobin   CYPs   cytochrome P450s   CYP1A1   cytochrome P450 1A1   DE   definitive endoderm   DKK1   Dickkopf homology 1   EB   embryoid body   ECM   extracellular matrix   F8   factor 8   FVIII   factor VIII   Fah   Fumarylacetoacetate hydrolase   FCGR2B   Fc gamma receptor IIb   FCN   Ficolin   FGF   fibroblast growth factor   FLK1   fetal liver kinase 1   FLT4   fms related receptor tyrosine kinase 4   FOXA3   Forkhead Box A3   GFAP   glial fibrillary acidic protein   GGT   gamma-glutamyl transferase   HBOs   hepatobiliary organoids   HBV   Hepatitis B Virus   HDAC   Histone Deacetylase   HGF   hepatocyte growth factor   HLCs   hepatocyte-like cells   HNF4α   hepatocyte nuclear factor 4 alpha   HOs   hepatic organoids   HSCs   hepatic stellate cells   hPSCs   human pluripotent stem cells   Il   Interleukin   Il2rg   Interleukin 2 Receptor Subunit Gamma   KDR   Kinase insert domain receptor   Klf4   Kruppel-like factor 4   KRT19   keratin 19   LC-MS/MS   Liquid chromatography/Mass spectrometry   LRAT   lecithin retinol acyltransferase   LOX   lysyl oxidase   LSECs   liver sinusoidal endothelial cells   LPCs   liver progenitor cells   LYVE1   lymphatic vessel endothelial hyaluronan receptor 1   MASH   metabolic dysfunction-associated steatohepatitis   MDK   midkine   NASH   non-alcoholic steatohepatitis   NCAM   neural cell adhesion molecule   NES   nestin   NGFR   nerve growth factor receptor   OSM   Oncostatin M   PDGF   Platelet-derived growth factor   PDMS   dimethylpolysiloxane   PDX1   Pancreatic and duodenal homeobox 1   PHHs   primary human hepatocytes   PSCs   pluripotent stem cells   qHSCs  

摘要： The liver comprises hepatic parenchymal cells, primarily hepatocytes, and non-parenchymal cells such as liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and cholangiocytes. These cell types interact with each other to maintain homeostasis through metabolism, detoxification, and protein synthesis. Such cellular interactions also play crucial roles in regulating the onset and progression of liver diseases. Consequently, the development of in vitro multicellular liver models is vital for elucidating the mechanisms underlying liver diseases and for evaluating the efficacy and toxicity of novel therapeutic drugs. Given their ability to proliferate and differentiate into diverse cell types in vitro , human pluripotent stem cells (hPSCs), including embryonic stem cells and induced PSCs, offer valuable potential for generating various liver cell types and constructing liver disease models for drug discovery research. Furthermore, patient-derived or gene-edited iPSCs can be employed to model genetic liver disorders. This review summarizes the development of differentiation protocols for hPSC-derived hepatocytes, LSECs, HSCs, and cholangiocytes, as well as their applications in drug discovery research.

关键词： 正畸   釉质脱矿   口腔菌群   分泌型免疫球蛋白A  

摘要： 目的 解析正畸患者发生釉质脱矿的关键因素,确定与釉质脱矿发生相关的生物标志物,并探讨青少年正畸患者釉质脱矿与口腔菌群的相关性。方法 选取2组患者,每组各22人,S组佩戴自锁托槽,M组佩戴传统金属托槽。在正畸基线期及3个月后收集龈上菌斑进行菌群分析,同时收集患者唾液并测定分泌型免疫球蛋白A(sIgA)的含量。每月复诊时,对釉质脱矿(EDI)、菌斑指数(PLI)、牙龈指数(GI)、牙周指数(PI)等临床指标进行统计和分析。结果 正畸3个月后,所有患者釉质脱矿发生率显著升高,平均脱矿率较治疗前增加20%以上,其中S组Fusobacterium、Campylobacter、Neisseria和Prevotella菌属的丰度显著增加(P<0.05),而M组Rothia菌属丰度显著上升(P<0.05);Arthrobacter、Bacillus、Acinetobacter、Prevotella、Campylobacter菌属丰度与釉质脱矿评分及菌斑指数评分呈正相关;唾液中sIgA的含量与釉质脱矿的发生呈负相关,S组正畸后唾液sIgA含量显著下降(P<0.01)。结论 佩戴自锁托槽的正畸患者更易发生釉质脱矿,Campylobacter和Prevotella菌属可能是加剧青少年正畸患者釉质脱矿的关键微生物。唾液中sIgA含量的下降可能预示着正畸患者釉质脱矿的风险增加。

关键词： Abacavir   Antiretroviral therapy   Clinical guideline   HIV   HLA-B*57:01 screening   Hypersensitivity reaction  

摘要： Objective Approximately 5–8 % of the population carries the HLA-B*57:01 allele, which increases the risk of severe hypersensitivity reactions to abacavir. Current guidelines and an FDA black box warning recommend HLA-B*57:01 screening for all patients before starting abacavir. We assessed the proportion of patients who undergo screening before initiating abacavir to evaluate adherence to guidelines. Design A retrospective cohort study using national IQVIA® PharMetrics Plus reimbursement data. Methods Data from the 2014-2022 IQVIA® PharMetrics Plus March 2023 dataset were analyzed. We identified patients aged ≥ 18 years who were newly prescribed abacavir, with ≥ 12 months of continuous enrollment before their first abacavir prescription. We examined the proportion of individuals who received HLA-B*57:01 screening any time before their initial abacavir prescription and conducted a multivariable logistic regression analysis on the receipt of HLA-B*57:01 screening adjusting for sex, age, year, and region. Results We identified 7,391 patients newly prescribed abacavir between 2014 and 2022. Approximately 46 % received an HLA-B*57:01 screen before initiation of abacavir. Annual screening rates ranged from 44 % to 50 % between 2015 and 2018 and dropped to 17 % by 2022. Screening was less likely to occur after 2018, compared to earlier in the study period, and more likely for younger as well as male patients. Conclusions These findings highlight broader challenges in HIV guideline adherence, emphasizing the need for ongoing evaluation and systematic interventions to improve implementation and patient safety.

关键词： Aging   Sepsis   NLRP3   IL-1 beta   IL-18   CLP model  

摘要： Aims: To investigate the impact of age on sepsis outcomes and explore potential therapeutic targets using the mouse model. Materials and methods: Sepsis was induced via cecal ligation and puncture (CLP) in naturally aged mice (18 months) and young mice (3 months). Sepsis severity, mortality rates, bacterial loads, and cytokine levels (IL-18 and IL-1(3) were compared between the two groups. NLRP3 expression was analyzed in various organs. Additionally, NLRP3 inhibitor MCC950 and specific antibodies against IL-18 and IL-1(3 were administered to assess their therapeutic effects. Note: This study was partially based on human samples. Key findings: Aged mice demonstrated more severe sepsis symptoms and increased mortality compared to young mice. Elevated levels of IL-18 and IL-1(3 were observed in aged septic mice, indicative of augmented NLRP3 inflammasome activation. Human data corroborated these findings, showing higher serum levels of IL-18 and IL1(3 in older sepsis patients. Treatment with NLRP3 inhibition (MCC950) and antibodies against IL-18 and IL-1(3 alleviated sepsis symptoms in aged mice, suggesting these pathways as potential therapeutic targets. Significance: The study highlights the critical role of the NLRP3-IL-18/IL-1(3 axis in age-related disparities in sepsis outcomes and suggests potential therapeutic targets for improving outcomes in aged sepsis patients.

关键词： Isoquercitrin   Intestinal ischemia-reperfusion   Intestinal flora   Nrf2/HO-1   Inflammatory cytokines   AMI   acute mesenteric ischemia   bZIP   subfamily of basic-leucine-zipper   ASC   apoptosis-associated speck-like protein containing a CARD   CCK-8   cell counting kit-8   CNC   cap'n'collar   HE   hematoxylin and eosin   HO-1   heme oxgenase-1   I/R   ischemia-reperfusion   II/R   intestinal ischemia-reperfusion   IEC-6   intestinal crypt epithelial cell line 6   IL   interleukin   KC   keratinocyte-derived cytokine   Keap1   Kelch-like ECH-associated protein 1   MDA   malondialdehyde   NLRP3   nucleotide-binding domain leucine-rich–containing family pyrin domain–containing-3   Nrf2   nuclear factor erythroid 2-related factor 2   OGD/R   oxygen-glucose deprivation/reoxygenation   SEM   standard error of the mean   SMA   superior mesenteric artery   ZO-1   zonula occludens-1  

摘要： Intestinal ischemia-reperfusion (II/R) injury, frequently observed in clinical emergencies such as trauma, infection, and transplantation, leads to severe epithelial necrosis, loss of villi, and alarmingly high mortality rates (50 %–90 %), yet current pharmaceutical treatments largely prove ineffective. This study employs network pharmacology alongside in vivo and in vitro experiments to explore the potential of isoquercitrin, a flavonoid abundant in various dietary sources and known for its anti-inflammatory and antioxidant properties, in mitigating intestinal II/R injury. We found that isoquercitrin significantly reinforced the integrity of the intestinal barrier and markedly alleviated damage associated with II/R injury. Additionally, it enhanced the intestinal microbiota structure by promoting microbial diversity and supporting beneficial bacterial populations. According to network pharmacology analyses, isoquercitrin may prevent II/R injury by modulating redox-related pathways and regulating inflammatory responses mediated by the NLRP3 inflammasome. This protective effect is evidenced by reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as an increased GSH/GSSG ratio and enhanced superoxide dismutase (SOD) activity. Isoquercitrin also inhibited NLRP3 inflammasome activation and decreased the expression of downstream factors, including Caspase-1, IL-1β, IL-6, and keratinocyte-derived cytokine (KC). The observed effects correlate with enhancement of nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased expression of heme oxygenase-1 (HO-1) in a dose-dependent manner, and these beneficial effects were abolished by both ML385 (an Nrf2 inhibitor) and siNrf2. Thus, activating the Nrf2/HO-1 signaling pathway is crucial to isoquercitrin's protective role in intestinal II/R injury. The present findings underscore the therapeutic potential of isoquercitrin in managing intestinal II/R injury.

关键词： Local sleep   Sleep regulation   Sleep organization   Sleep evolution   Microbes   Peptidoglycan   Holobiont   Interleukin 1   AcPb   brain specific interleukin 1 receptor accessory protein   AI   activity integrator   ATP   adenosine triphosphate   EEG   electroencephalogram   EI   environmental integrator   ERP   evoked response potential   GHRH   growth hormone releasing hormone   IL1   interleukin 1 beta   IR   immunoreactive   MP   muramyl peptide   NF-ĸB   nuclear factor kappa B   NGF   nerve growth factor   NO   nitric oxide   NREM   non-rapid eye movement   PG   peptidoglycan   Pglyrp1 and -2   peptidoglycan recognition proteins 1 and 2   SCN   suprachiasmatic nucleus   SRN   sleep regulatory network   SRS   sleep regulatory substance   TNF   tumor necrosis factor alpha  

摘要： We posit that organism sleep is regulated from the interactions between two semi-autonomous regulatory systems, the classic sleep/wake regulatory circuits and a local cell activity-driven system. Sleep regulatory circuits mold local sleep into a species’ niche but are not required for sleep. In contrast, local sleep mechanisms initiate sleep-like states in small networks and are responsive to microbial pattern recognition receptors. Local sleep-like phenomena manifest in brain in vivo and in vitro . Sleep regulatory substances e.g., cytokines and adenosine, are released by cell activity and as such provide an index of neural network activity. They are evolutionary ancient molecules existing prior to the evolution of complex vertebrate sleep. Further, bacterial cell wall components can initiate sleep in insomniac mammals lacking key hypothalamic regulatory circuits, suggesting our ancient holobiont condition underlies sleep regulation. We review how interleukin-1 promotes sleep/sleep-like states at various tissue organization levels. We provide a basis for understanding sleep as an emergent property of cellular networks and a process beginning at the cellular level and progressing as modified by multiple physiological regulatory circuits to whole animal sleep. We conclude; sleep mechanisms are shared across various levels of tissue organization and are part of interspecies regulatory networks.

关键词： Alphaherpesvirus   Herpes simplex encephalitis   Pseudorabies virus   Neurotropism   Mouse model   Nectin-1   12N   hypoglossal nucleus   AI   agranular insular cortex   AO   anterior olfactory nucleus   BSA   bovine serum albumin   CeM   central amygdaloid nucleus   Cer   cerebellum   Cg   cingulate gyrus   CNS   central nervous system   CPu   caudate putamen   Cu   cuneate nucleus   d p. i   days post infection   DEn   dorsal endopiriform nucleus   DG   dentate gyrus   DpMe   deep mesencephalic nucleus   Ect   ecotorhinal cortex   FCS   fetal calf serum   FR   reticular formation   gfp   green fluorescent protein   HCMV   human cytomegalievirus   Hpc   hippocampus   HSE   Herpes Simplex Encephalitis   HSV-1   Herpes Simplex Virus 1   IFN   interferon   IL   infralimbic cortex   IO   inferior olive   LEnt   lateral entorhinal cortex   LH   lateral hypothalamic area   LS   lateral septal nucleus   M1   primary motor cortex   MEM   minimum essential medium   MO   medial orbital cortex   MOI   multiplicity of infection   MTL   mesiotemporal lobe   PBS   phosphate buffered saline   PFA   paraformaldehyde   PFU   plaque forming units   Pir   piriform cortex   Pn   pontine nucleus   PRh   perirhinal cortex   PrL   prelimbic cortex   PrV   Pseudorabies virus   PrV-Ka   PrV-Kaplan   PVA   paraventricular thalamic nucleus   Py   pyramidal cell layer of the hippocampus   Re   reuniens thalamic nucleus   RK13   rabbit kidney cells   ROI   region of interest   RT   room temperature   S1   primary somatosensory cortex   Sol   nucleus of the solitary tract   Sp5   spinal trigeminal nucleus   SpVe   spinal vestibular nucleus   SuM   supramammilary nucleus   TG   trigeminal ganglion   V1   primary visual cortex   V2   secondary visual cortex   VPL   ventral posteriolateral thalamic nucleus   VPM   ventral posteriomedial thalamic nucleus  

摘要： Alphaherpesviruses, such as Herpes Simplex Virus 1 (HSV-1) and Pseudorabies Virus (PrV), exhibit pronounced neurotropism. HSV-1 can cause Herpes simplex encephalitis (HSE), primarily affecting the mesiotemporal lobe. CD1 mice inoculated with a PrV mutant (PrV-ΔUL21/US3Δkin) showed striking analogies to HSE, including comparable virus distribution and inflammatory patterns, providing a suitable model to analyze the specificity of the invasion route of alphaherpesviruses. Here, we investigated the strong preference for the mesiotemporal lobe by artificial targeted stereotactic inoculation of PrV-ΔUL21/US3Δkin and wildtype PrV-Kaplan into the temporal lobe or cerebellum in a kinetic approach. In the most severely affected brain areas viral antigen was quantified and correlated with the expression of the alphaherpesvirus entry receptor nectin-1. Temporal lobe inoculated mice showed viral antigen starting at 2dpi in this location. In contrast, only a low amount of viral antigen was found in the cerebellum after cerebellar inoculation but massive staining was observed in the mesiotemporal lobe at 7dpi. Correspondingly, cultured cerebral cortical neurons exhibited higher viral titers than cerebellar neurons, reflecting alphaherpesviral tropism for cerebral regions. Mice inoculated in the temporal lobe developed symptoms earlier than those inoculated into the cerebellum. PrV-Kaplan resulted in rapid lethality within 2 days, with antigen distribution mirroring that of PrV-ΔUL21/US3Δkin. High nectin-1 expression correlated strongly with viral antigen presence in the mesiotemporal lobe, piriform and prefrontal cortices. In summary, our studies demonstrate the high susceptibility of the mesiotemporal, piriform and prefrontal cortices upon artificial PrV inoculation, and highlight the suitability of this model for future investigations on HSE.

关键词： Cytokines   Interleukin   Petri nets   Signaling   IL-6   IL-22   Knockout analysis  

摘要： The cytokines interleukin 6 (IL-6) and interleukin 22 (IL-22) are involved in multiple signaling pathways in a variety of cells, e.g. the activation of the acute-phase response, cell homeostasis and tissue repair. However, high concentrations of IL-6 and IL-22 are associated with worse outcomes for patients with liver pathologies such as cirrhosis and chronic liver failure. Consequently, these pathways are tightly controlled by regulatory proteins. Despite their importance to liver function, the signaling pathways activated by IL-6 and IL-22 have still not been fully understood. We have built a Petri net model of the IL-6 and IL-22 pathways to improve our understanding of cytokine regulation. The model includes cytokines binding to their respective receptors. Following receptor binding, the JAK/STAT pathways can be activated, leading to RNA transcription. This process is regulated by various inhibitors. We analyzed the model for invariants to control for correctness and completeness of the model. We applied in silico knockout experiments to explore how critical different proteins appear for the functioning of the pathways and compared them to previous in vivo experiments from the scientific literature. We used our model to perform asynchronous simulations, which led us to the hypothesis that the higher levels of IL-6 in comparison to IL-22 in some pathologies may compensate for the slower assembly of the IL-6 receptor complex due to its higher structural complexity. We performed stochastic simulations of partial cytokine agonists confirming prior experimental results showing biased phosphorylation of STAT1/3 for lower cytokine receptor-binding dwell times.

关键词： 天然产物   细胞焦亡   炎性小体   炎症   脊髓损伤   继发性损伤   神经功能   经典途径  

摘要： 背景:神经炎症是脊髓损伤后病情加重的主要原因。近年来,细胞焦亡因显著的促炎特征而受到广泛关注。部分天然产物通过调控脊髓损伤后的细胞焦亡水平,能显著抑制炎症反应,改善受损的神经功能,为脊髓损伤提供了新的治疗思路。目的:总结天然产物调控细胞焦亡治疗脊髓损伤的作用机制,以期为今后脊髓损伤的治疗研究提供借鉴和参考。方法:以“spinal cord injury,pyroptosis,inflammasome,natural products,natural compounds,Traditional Chinese Medicine”“脊髓损伤,细胞焦亡,炎性小体,天然产物,天然化合物,中药”为检索词,在PubMed、Web of Science、万方、中国知网检索自建库以来至2024年9月的有关文献,按照纳入和排除标准,最终得到75篇相关文献。结果与结论:①细胞焦亡是脊髓损伤的重要促炎途径,控制细胞焦亡是改善受损神经功能的有效方式;②部分天然产物可以通过NLRP3/Caspase-1经典焦亡途径、核因子κB相关通路、Nrf2/HO-1等其他上游通路和自噬来调控细胞焦亡,从而影响脊髓损伤后的组织炎症水平,加快神经功能恢复;③这些天然产物的抗细胞焦亡作用多依赖于NLRP3经典焦亡途径,尚缺少关于其他焦亡途径的研究;④该领域仍存在很多问题,如这些天然产物目前没有相应的临床研究证据支持;⑤天然产物在调控细胞焦亡中具有巨大的潜能,有望成为治疗脊髓损伤的有力武器。