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1.
Nat Prod Res ; : 1-18, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38586940

RESUMO

Herein, we isolated five natural alkaloids, iso-corydine (iso-CORY), corydine (CORY), sanguinarine (SAN), chelerythrine (CHE) and magnoflorine (MAG), from traditional medicinal herb Dicranostigma leptopodum (Maxim.) Fedde (whole herb) and elucidated their structures. Then we synthesised G5. NHAc-PBA as targeting dendrimer platform to encapsulate the alkaloids into G5. NHAc-PBA-alkaloid complexes, which demonstrated alkaloid-dependent positive zeta potential and hydrodynamic particle size. G5. NHAc-PBA-alkaloid complexes demonstrated obvious breast cancer MCF-7 cell targeting effect. Among the G5. NHAc-PBA-alkaloid complexes, G5.NHAc-PBA-CHE (IC50=13.66 µM) demonstrated the highest MCF-7 cell inhibition capability and G5.NHAc-PBA-MAG (IC50=24.63 µM) had equivalent inhibitory effects on cell proliferation that comparable to the level of free MAG (IC50=23.74 µM), which made them the potential breast cancer targeting formulation for chemotherapeutic application. This work successfully demonstrated a pharmaceutical research model of 'natural bioactive product isolation-drug formulation preparation-breast cancer cell targeting inhibition'.

2.
EBioMedicine ; 102: 105045, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38471394

RESUMO

BACKGROUND: Schizophrenia, a debilitating psychiatric disorder, displays considerable interindividual variation in clinical presentations. The ongoing debate revolves around whether this heterogeneity signifies a continuum of severity linked to a singular causative factor or a collection of distinct subtypes with unique origins. Within the realm of schizophrenia, the functional impairment of GluN2A, a subtype of the NMDA receptor, has been associated with an elevated risk. Despite GluN2A's expression across various neuronal types throughout the brain, its specific contributions to schizophrenia and its involvement in particular cell types or brain regions remain unexplored. METHODS: We generated age-specific, cell type-specific or brain region-specific conditional knockout mice targeting GluN2A and conducted a comprehensive analysis using tests measuring phenotypes relevant to schizophrenia. FINDINGS: Through the induction of germline ablation of GluN2A, we observed the emergence of numerous schizophrenia-associated abnormalities in adult mice. Intriguingly, GluN2A knockout performed at different ages, in specific cell types and within distinct brain regions, we observed overlapping yet distinct schizophrenia-related phenotypes in mice. INTERPRETATION: Our interpretation suggests that the dysfunction of GluN2A is sufficient to evoke heterogeneous manifestations associated with schizophrenia, indicating that GluN2A stands as a prominent risk factor and a potential therapeutic target for schizophrenia. FUNDING: This project received support from the Shanghai Municipal Science and Technology Major Project (Grant No. 2019SHZDZX02) awarded to Y.C. and the Natural Science Foundation of Shanghai (Grant No. 19ZR1468600 and 201409003800) awarded to G.Y.


Assuntos
Receptores de N-Metil-D-Aspartato , Esquizofrenia , Animais , Camundongos , Encéfalo/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo
3.
Stem Cell Res ; 76: 103326, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38324932

RESUMO

Hoxb5 exhibits preferential expression in hematopoietic stem cells (HSCs) and uniquely marks the long-term HSCs (LT-HSCs). Previous studies have demonstrated the remarkable capability of Hoxb5 to alter cell fates when enforced expression in blood progenitors, such as B cell progenitors and multipotent progenitors. Additionally, Hoxb5 deficiency does not hinder the generation of LT-HSCs. However, the specific impact of Hoxb5 deletion on LT-HSCs has remained unexplored. To address this, we developed a conditional Hoxb5 knockout-reporter mouse model, wherein Hoxb5 was knock out by the Vav-cre recombinase, and the endogenous Hoxb5 promoter drove the expression of the blue fluorescent protein (BFP). Our findings revealed that the primary recipients, who transplanted with HSCs indicating Hoxb5 deficiency by the presence of BFP (BFP-positive HSCs), exhibited comparable levels of donor chimerism and lineage chimerism to recipients transplanted with HSCs that spontaneously did not express Hoxb5 and thus lacked BFP expression (BFP-negative HSCs). However, during the secondary transplantation, recipients receiving total bone marrow (BM) from the primary recipients with BFP-positive HSCs showed significantly higher levels of donor chimerism and more robust multi-lineage chimerism compared to those receiving total BM from the primary recipients with BFP-negative HSCs. Our results indicate that deleting Hoxb5 in LT-HSCs transiently influences their lineage differentiation bias without compromising their long-term self-renewal capacity. These findings highlight the primary role of Hoxb5 in regulating lineage commitment decisions in LT-HSCs, while emphasizing that its presence is not indispensable for the maintenance of long-term self-renewal capacity.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Fatores de Transcrição , Animais , Camundongos , Medula Óssea , Diferenciação Celular/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos Knockout , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
Sci Total Environ ; 917: 170396, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38301783

RESUMO

Current techniques for microplastics (MPs) analysis are diverse. However, most techniques have individual limitations like the detection limit of spatial resolution, susceptibility, high cost, and time-consuming detection. In this study, we proposed a multi-spectroscopy method coupling µ-FTIR and µ-Raman analysis for one-stop MPs detection, in which barium fluoride was used as the substrate alternative to the filter membrane. Compared with commonly used filter membranes (alumina, silver, PTFE and nylon membranes), the barium fluoride substrate showed better spectroscopic detection performance on microscopic observation, broader transmittable wavenumber range for µ-FTIR (750-4000 cm-1) and µ-Raman (250-4000 cm-1) detection, thus suitable for the multi-spectroscopy analysis of spiked samples. Further, the real environmental and biological samples (indoor air, bottled water and human exhaled breath) were collected and detected to verify the applicability of the developed multi-spectroscopy method. The results indicated that the average content of detected MPs could be increased by 30.4 ± 29.9 % for indoor air, 17.1 ± 13.2 % for bottled water and 38.4 ± 16.0 % for human exhaled breath, respectively in comparison with widely used µ-Raman detection, which suggested that MPs exposure might be underestimated using single spectroscopy detection. Moreover, the majority of underestimated MPs were colored and smaller sized (<50 µm) MPs, which could pose higher risks to human body. In addition, the proposed method consumed lower sample pre-treatment costs and was environmental-friendly since the barium fluoride substrate could be used repeatedly after being cleaned by organic solvent with reliable results (n = 10, CV = 10 %, ICC = 0.961), which reduced the cost of MPs detection by at least 2.49 times compared with traditional methods using silver membrane.


Assuntos
Compostos de Bário , Água Potável , Fluoretos , Poluentes Químicos da Água , Humanos , Microplásticos , Plásticos/análise , Espectroscopia de Infravermelho com Transformada de Fourier , Água Potável/análise , Prata/análise , Monitoramento Ambiental , Poluentes Químicos da Água/análise
5.
J Neuroinflammation ; 21(1): 35, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38287411

RESUMO

BACKGROUND: Microglia is the major contributor of post-stroke neuroinflammation cascade and the crucial cellular target for the treatment of ischemic stroke. Currently, the endogenous mechanism underlying microglial activation following ischemic stroke remains elusive. Serglycin (SRGN) is a proteoglycan expressed in immune cells. Up to now, the role of SRGN on microglial activation and ischemic stroke is largely unexplored. METHODS: Srgn knockout (KO), Cd44-KO and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAO) to mimic ischemic stroke. Exogenous SRGN supplementation was achieved by stereotactic injection of recombinant mouse SRGN (rSRGN). Cerebral infarction was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Neurological functions were evaluated by the modified neurological severity score (mNSS) and grip strength. Microglial activation was detected by Iba1 immunostaining, morphological analysis and cytokines' production. Neuronal death was examined by MAP2 immunostaining and FJB staining. RESULTS: The expression of SRGN and its receptor CD44 was significantly elevated in the ischemic mouse brains, especially in microglia. In addition, lipopolysaccharide (LPS) induced SRGN upregulation in microglia in vitro. rSRGN worsened ischemic brain injury in mice and amplified post-stroke neuroinflammation, while gene knockout of Srgn exerted reverse impacts. rSRGN promoted microglial proinflammatory activation both in vivo and in vitro, whereas Srgn-deficiency alleviated microglia-mediated inflammatory response. Moreover, the genetic deletion of Cd44 partially rescued rSRGN-induced excessed neuroinflammation and ischemic brain injury in mice. Mechanistically, SRGN boosted the activation of NF-κB signal, and increased glycolysis in microglia. CONCLUSION: SRGN acts as a novel therapeutic target in microglia-boosted proinflammatory response following ischemic stroke.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Proteínas de Transporte Vesicular , Animais , Camundongos , Microglia/metabolismo , Isquemia Encefálica/metabolismo , Doenças Neuroinflamatórias , Acidente Vascular Cerebral/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/metabolismo , Proteoglicanas/metabolismo , AVC Isquêmico/metabolismo , Lesões Encefálicas/metabolismo
6.
Small ; 20(2): e2305670, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37658521

RESUMO

N-type Mg3 Sb2 -based thermoelectric materials show great promise in power generation due to their mechanical robustness, low cost of Mg, and high figure of merit (ZT) over a wide range of temperatures. However, their poor thermal stability hinders their practical applications. Here, MgB2 is introduced to improve the thermal stability of n-type Mg3 Sb2 . Enabled by MgB2 decomposition, extra Mg can be released into the matrix for Mg compensation thermodynamically, and secondary phases of Mg─B compounds can kinetically prevent Mg diffusion along grain boundaries. These synergetic effects inhibit the formation of Mg vacancies at elevated temperatures, thereby enhancing the thermal stability of n-type Mg3 Sb2 . Consequently, the Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 (MgB2 )0.03 sample exhibits negligible variation in thermoelectric performance during the 120-hour continuous measurement at 673 K. Moreover, the ZT of n-type Mg3 Sb2 can be maintained by adding MgB2 , reaching a high average ZT of ≈1.1 within 300-723 K. An eight-pair Mg3 Sb2 -GeTe-based thermoelectric device is also fabricated, achieving an energy conversion efficiency of ≈5.7% at a temperature difference of 438 K with good thermal stability. This work paves a new way to enhance the long-term thermal stability of n-type Mg3 Sb2 -based alloys and other thermoelectrics for practical applications.

8.
RSC Adv ; 13(44): 30771-30776, 2023 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-37869386

RESUMO

In this work, a 2-(2'-hydroxyphenyl)benzimidazole derived fluorescent probe, 2-(2'-hydroxy-4'-aminophenyl)benzimidazole (4-AHBI), was synthesized and its fluorescent behavior toward triphosgene were evaluated. The results showed that 4-AHBI exhibited high sensitivity (limit of detection, 0.08 nM) and excellent selectivity for triphosgene over other acyl chlorides including phosgene in CH2Cl2 solution. Moreover, 4-AHBI loaded test strips were prepared for the practical sensing of triphosgene.

9.
J Phys Chem Lett ; 14(41): 9150-9158, 2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37796231

RESUMO

Aqueous zinc-ion batteries are considered promising energy storage devices due to their superior electrochemical performance. Nevertheless, the uncontrolled dendrites and parasitic side reactions adversely affect the stability and durability of the Zn anode. To cope with these issues, inspired by the chelation behavior between metal ions and amino acids in the biological system, glutamic acid and aspartic acid are selected as electrolyte additives to stabilize the Zn anode. Experimental characterizations in conjunction with theoretical calculation results indicate that these additives can simultaneously modify the solvation structure of hydrated Zn2+ and preferentially adsorb onto the Zn anode, thereby restricting the occurrence of interfacial side reactions and enhancing the performance of the Zn anode. Benefiting from these synergistic effects, the as-assembled Zn-based batteries containing additive electrolytes achieved admirable electrochemical performance. From the viewpoint of electrolyte regulation, this work provides a bright direction toward the development of aqueous batteries.

10.
Nat Neurosci ; 26(10): 1751-1761, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37709995

RESUMO

Ketamine was thought to induce rapid antidepressant responses by inhibiting GluN2B-containing N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), which presents a promising opportunity to develop better antidepressants. However, adverse side effects limit the broader application of ketamine and GluN2B inhibitors are yet to be approved for clinical use. It is unclear whether ketamine acts solely through GluN2B-dependent mechanisms. The present study reports that the loss of another major NMDAR subunit, GluN2A, in adult mouse brains elicits robust antidepressant-like responses with limited impact on the behaviors that mimic the psychomimetic effects of ketamine. The antidepressant-like behavioral effects of broad NMDAR channel blockers, such as ketamine and MK-801 (dizocilpine), were mediated by the suppression of GluN2A, but not by the inhibition of GluN2B. Moreover, treatment with ketamine or MK-801 rapidly increased the intrinsic excitability of hippocampal principal neurons through GluN2A, but not GluN2B. Together, these findings indicate that GluN2A mediates ketamine-triggered rapid antidepressant-like responses.


Assuntos
Antidepressivos , Ketamina , Receptores de N-Metil-D-Aspartato , Animais , Camundongos , Antidepressivos/farmacologia , Maleato de Dizocilpina/farmacologia , Hipocampo/metabolismo , Ketamina/farmacologia , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
11.
Plast Reconstr Surg ; 2023 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-37561989

RESUMO

BACKGROUND: Adolescents with temporomandibular joint (TMJ) anterior disc displacement (ADD) frequently develop dentofacial deformities. It is unknown if adjunctive arthroscopic discopexy compared to orthodontic treatment alone increases condylar growth and then improves dentofacial deformity. This study aimed to determine whether arthroscopic discopexy before functional appliance (joint-occlusal treatment) or single functional appliance (occlusal treatment) increases condylar growth and improves dentofacial deformity among adolescents with TMJ ADD. METHODS: A multicenter, randomized, parallel controlled trial was conducted in three centers in China. Adolescents diagnosed with TMJ ADD and dentofacial deformity were enrolled. Eligible participants were randomly assigned to a joint-occlusal group or occlusal group at a ratio of 2:1. MRI, cephalometric radiographs were evaluated at baseline, 8 months and 14 months. The primary outcome was changes in condylar height from 14 months to baseline. Secondary outcomes were changes in skeletal position. RESULTS: A total of 240 patients (14.65±1.88 years of age) were randomized (joint-occlusal group: 160; occlusal group: 80). The overall difference in condylar height between groups was 3.65 mm (95% CI, 3.10 to 4.19; p < 0.001). The between-group differences in condylar height on the left and right sides were 3.60 mm (95% CI, 2.92 to 4.28; p < 0.001) and 3.69 mm (95% CI, 3.06 to 4.32; p < 0.001), respectively. Significant between-group differences were noted in skeletal position (all p < 0.001). CONCLUSIONS: Joint-occlusal treatment can promote condylar growth and improve dentofacial deformity in adolescents after 14 months when compared with single occlusal treatment.

12.
STAR Protoc ; 4(3): 102494, 2023 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-37543942

RESUMO

The nocturnal and cryptic nature of bats makes it difficult to determine their foraging behavior and predatory sensory cues. Here, we present a protocol for determining the behavioral strategies and sensory cues of bat predation on airborne prey. We describe steps for indoor foraging behavior simulation, dual-choice acoustic playback, and visual presentation experiments. This protocol was used to study the avivorous bat, Ia io, but it can be adapted for studying other aerial-hawking bats and even other taxa. For complete details on the use and execution of this protocol, please refer to Gong et al. (2022).1.

13.
Environ Toxicol ; 38(10): 2462-2475, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37449723

RESUMO

Circ_LRP6 is participated in the occurrence and development of numerous tumors. Nevertheless, its roles and mechanism in osteosarcoma (OS) is unknown. This study aims to illustrate this point. With the use of qRT-PCR, the level of circ_LRP6, miR-122-5p, miR-204-5p and HMGB1 was identified. To observe cell proliferation, migration and invasion, we adopted CCK-8 and Transwell assays in the present study. Besides, to prove the existing interaction, bioinformatics analysis and dual luciferase reporting assays were employed. The influence of circ_LRP6 on osteosarcoma in vivo was evaluated by subcutaneous tumor formation model in nude mice. In osteosarcoma tissues, circ_LRP6 and HMGB1 are strongly denoted, whereas miR-122-5p and miR-204-5p are under-expressed. Circ_LRP6 knockdown could significantly hinder the proliferation, migration and invasion of osteosarcoma cells. Circ_LRP6 hindered the proliferation of osteosarcoma in vivo. Bioinformatics predicted that miR-122-5p and miR-204-5p functioned as direct targets of circ_LRP6, and HMGB1 were possible target genes of miR-122-5p and miR-204-5p. The findings indicated that the low level of miR-122-5p and miR-204-5p and the overexpression of HMGB1 could partially restore and reduce the inhibitory impact of circ_LRP6 on the proliferation, migration and invasion of osteosarcoma cells. Circ_LRP6 affects osteosarcoma progression via the miR-122-5p/miR-204-5p/HMGB1 axis, and is shown to be a molecular biomarker.


Assuntos
Neoplasias Ósseas , Proteína HMGB1 , MicroRNAs , Osteossarcoma , Animais , Camundongos , Proteína HMGB1/genética , Camundongos Nus , Osteossarcoma/genética , Proliferação de Células/genética , Neoplasias Ósseas/genética , MicroRNAs/genética , Linhagem Celular Tumoral
14.
Mov Ecol ; 11(1): 32, 2023 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-37287053

RESUMO

BACKGROUND: The niche breadth of an animal population comprises both within-individual and between-individual variation (individual specialization). Both components can be used to explain changes in population niche breadth, and this has been extensively investigated in dietary niche dimension studies. However, little is known about how changes in food resources or environmental factors across seasons affect changes in individual and population space use within the same population. METHODS: In this study, we used micro-GPS loggers to capture the space use of individuals and of a population of the great evening bat (Ia io) in summer and autumn. We used I. io as a model to investigate how individual spatial niche breadth and spatial individual specialization affect changes in population niche breadth (home range and core area sizes) across seasons. Additionally, we explored the drivers of individual spatial specialization. RESULTS: We found that the population home range and the core area of I. io did not increase in autumn when insect resources were reduced. Moreover, I. io showed different specialization strategies in the two seasons: higher spatial individual specialization in summer and lower individual specialization but broader individual niche breadth in autumn. This trade-off may maintain the dynamic stability of the population spatial niche breadth across seasons and facilitate the population response to changes in food resources and environmental factors. CONCLUSIONS: Like diet, spatial niche breadth of a population also may be determined by a combination of individual niche breadth and individual specialization. Our work provides new insights into the evolution of niche breadth from the spatial dimension.

15.
Small ; 19(44): e2303840, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37381087

RESUMO

N-type Mg3 (Bi, Sb)2 -based thermoelectric (TE) alloys show great promise for solid-state power generation and refrigeration, owing to their excellent figure-of-merit (ZT) and using cheap Mg. However, their rigorous preparation conditions and poor thermal stability limit their large-scale applications. Here, this work develops an Mg compensating strategy to realize n-type Mg3 (Bi, Sb)2 by a facile melting-sintering approach. "2D roadmaps" of TE parameters versus sintering temperature and time are plotted to understand the Mg-vacancy-formation and Mg-diffusion mechanisms. Under this guidance, high weight mobility of 347 cm2  V-1  s-1 and power factor of 34 µW cm-1  K-2 can be obtained for Mg3.05 Bi1.99 Te0.01 , and a peak ZT≈1.55 at 723 K and average ZT≈1.25 within 323-723 K can be obtained for Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 . Moreover, this Mg compensating strategy can also improve the interfacial connecting and thermal stability of corresponding Mg3 (Bi, Sb)2 /Fe TE legs. As a consequence, this work fabricates an 8-pair Mg3 Sb2 -GeTe-based power-generation device reaching an energy conversion efficiency of ≈5.0% at a temperature difference of 439 K, and a one-pair Mg3 Sb2 -Bi2 Te3 -based cooling device reaching -10.7 °C at the cold side. This work paves a facile way to obtain Mg3 Sb2 -based TE devices at low cost and also provides a guide to optimize the off-stoichiometric defects in other TE materials.

16.
Cell Mol Biol (Noisy-le-grand) ; 69(4): 133-140, 2023 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-37329534

RESUMO

The progression of several cancers, including lung cancer, has been linked to long non-coding RNAs (lncRNAs) (LC). The current research concentrated on elucidating the effects of MALAT1 on the course of LC and investigating potential pathways. The qPCR and in situ hybridization (ISH) assays were used to measure MALAT1 expression in LC tissues. Additionally, the overall survival (OS), a percentage of LC patients with various MALAT1 levels was examined. Additionally, it was determined whether MALAT1 was expressed in LC cells through qPCR analysis. LC cells' proliferation, apoptosis, and metastasis were all examined concerning MALAT1 utilizing the following techniques: EdU, CCK-8, western blot and flow cytometry. This study predicted and verified the correlation between MALAT1, microRNA (miR)-338-3p as well as pyrroline-5-carboxylate reductase 2 using bioinformatics and dual-luciferase reporters (PYCR2). On the activity and function of MALAT1/miR-338-3p/PYCR2 in LC cell activities, more study was conducted. The amount of MALAT1 was raised in LC tissues and cells. Low OS was seen in patients with elevated MALAT1 expression. By inhibiting MALAT1, LC cells saw decreased migration, invasion, and proliferation as well as an increase in apoptosis. Additionally, PYCR2 appeared as an objective of miR-338-3p, while MALAT1 was a target of miR-338-3p. Additionally, the over-expression of miR-338-3p had effects that were comparable to those of MALAT1 down-regulation. The function of miR-338-3p inhibitor on the functional activities of LC cells co-transfected with sh-MALAT1 was partially recovered by PYCR2 inhibition. MALAT1/miR-338-3p/PYCR2 maybe the novel target for LC therapy.


Assuntos
Carcinoma , Neoplasias Pulmonares , MicroRNAs , Pirrolina Carboxilato Redutases , RNA Longo não Codificante , Humanos , Carcinoma/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Pirrolina Carboxilato Redutases/genética , RNA Longo não Codificante/genética , Neoplasias Pulmonares/genética
17.
Neuron ; 111(12): 1898-1913.e5, 2023 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-37040764

RESUMO

Aberrant low γ-secretase activity is associated with most of the presenilin mutations that underlie familial Alzheimer's disease (fAD). However, the role of γ-secretase in the more prevalent sporadic AD (sAD) remains unaddressed. Here, we report that human apolipoprotein E (ApoE), the most important genetic risk factor of sAD, interacts with γ-secretase and inhibits it with substrate specificity in cell-autonomous manners through its conserved C-terminal region (CT). This ApoE CT-mediated inhibitory activity is differentially compromised in different ApoE isoforms, resulting in an ApoE2 > ApoE3 > ApoE4 potency rank order inversely correlating to their associated AD risk. Interestingly, in an AD mouse model, neuronal ApoE CT migrates to amyloid plaques in the subiculum from other regions and alleviates the plaque burden. Together, our data reveal a hidden role of ApoE as a γ-secretase inhibitor with substrate specificity and suggest that this precision γ-inhibition by ApoE may protect against the risk of sAD.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Camundongos , Animais , Humanos , Apolipoproteína E2/genética , Apolipoproteína E4/genética , Apolipoproteína E3/genética , Secretases da Proteína Precursora do Amiloide , Apolipoproteínas E/genética , Doença de Alzheimer/genética , Peptídeos beta-Amiloides
18.
Stem Cell Reports ; 18(3): 720-735, 2023 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-36801005

RESUMO

Regenerating prolonged multi-lineage hematopoiesis from pluripotent stem cells (PSCs), an unlimited cell source, is a crucial aim of regenerative hematology. In this study, we used a gene-edited PSC line and revealed that simultaneous expression of three transcription factors, Runx1, Hoxa9, and Hoxa10, drove the robust emergence of induced hematopoietic progenitor cells (iHPCs). The iHPCs engrafted successfully in wild-type animals and repopulated abundant and complete myeloid-, B-, and T-lineage mature cells. The generative multi-lineage hematopoiesis distributed normally in multiple organs, persisted over 6 months, and eventually declined over time with no leukemogenesis. Transcriptome characterization of generative myeloid, B, and T cells at the single-cell resolution further projected their identities to natural cell counterparts. Thus, we provide evidence that co-expression of exogenous Runx1, Hoxa9, and Hoxa10 simultaneously leads to long-term reconstitution of myeloid, B, and T lineages using PSC-derived iHPCs as the cell source.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core , Células-Tronco Pluripotentes , Animais , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Diferenciação Celular/genética , Animais Selvagens , Hematopoese , Células Sanguíneas , Linhagem da Célula/genética
20.
BMC Genomics ; 24(1): 23, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647013

RESUMO

BACKGROUND: It is inevitable to change the function or expression of genes during the environmental adaption of species. Both the giant panda (Ailuropoda melanoleuca) and red panda (Ailurus fulgens) belong to Carnivora and have developed similar adaptations to the same dietary switch to bamboos at the morphological and genomic levels. However, the genetic adaptation at the gene expression level is unclear. Therefore, we aimed to examine the gene expression patterns of giant and red panda convergent specialized bamboo-diets. We examined differences in liver and pancreas transcriptomes between the two panda species and other non-herbivorous species. RESULTS: The clustering and PCA plots suggested that the specialized bamboo diet may drive similar expression shifts in these two species of pandas. Therefore, we focused on shared liver and pancreas DEGs (differentially expressed genes) in the giant and red panda relative to other non-herbivorous species. Genetic convergence occurred at multiple levels spanning carbohydrate metabolism, lipid metabolism, and lysine degradation. The shared adaptive convergence DEGs in both organs probably be an evolutionary response to the high carbohydrate, low lipid and lysine bamboo diet. Convergent expression of those nutrient metabolism-related genes in both pandas was an intricate process and subjected to multi-level regulation, including DNA methylation and transcription factor. A large number of lysine degradation and lipid metabolism related genes were hypermethylated in promoter regions in the red panda. Most genes related to carbohydrate metabolism had reduced DNA methylation with increased mRNA expression in giant pandas. Unlike the red panda, the core gene of the lysine degradation pathway (AASS) doesn't exhibit hypermethylation modification in the giant panda, and dual-luciferase reporter assay showed that transcription factor, NR3C1, functions as a transcriptional activator in AASS transcription through the binding to AASS promoter region. CONCLUSIONS: Our results revealed the adaptive expressions and regulations of the metabolism-related genes responding to the unique nutrients in bamboo food and provided data accumulation and research hints for the future revelation of complex mechanism of two pandas underlying convergent adaptation to a specialized bamboo diet.


Assuntos
Ailuridae , Dieta , Ursidae , Animais , Dieta/veterinária , Expressão Gênica , Lisina/metabolismo , Ursidae/genética , Ursidae/metabolismo , Ailuridae/genética , Ailuridae/metabolismo
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