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1.
Br J Haematol ; 2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38613241

RESUMO

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

2.
Nat Aging ; 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491289

RESUMO

Hearing loss is associated with an increased risk of Alzheimer disease (AD). However, the mechanisms of hearing loss promoting the onset of AD are poorly understood. Here we show that hearing loss aggravates cognitive impairment in both wild-type mice and mouse models of AD. Embryonic growth/differentiation factor 1 (GDF1) is downregulated in the hippocampus of deaf mice. Knockdown of GDF1 mimics the detrimental effect of hearing loss on cognition, while overexpression of GDF1 in the hippocampus attenuates the cognitive impairment induced by deafness. Strikingly, overexpression of GDF1 also attenuates cognitive impairment in APP/PS1 transgenic mice. GDF1 activates Akt, which phosphorylates asparagine endopeptidase and inhibits asparagine endopeptidase-induced synaptic degeneration and amyloid-ß production. The expression of GDF1 is downregulated by the transcription factor CCAAT-enhancer binding protein-ß. These findings indicate that hearing loss could promote AD pathological changes by inhibiting the GDF1 signaling pathway; thus, GDF1 may represent a therapeutic target for AD.

3.
Plant Direct ; 8(2): e564, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38312996

RESUMO

Barley is one of the world's earliest domesticated crops, which is widely used for beer production, animal feeding, and health care. Barley seed germination, particularly in increasingly saline soils, is key to ensure the safety of crop production. However, the mechanism of salt-affected seed germination in barley remains elusive. Here, two different colored barley varieties were used to independently study the regulation mechanism of salt tolerance during barley seed germination. High salinity delays barley seed germination by slowing down starch mobilization efficiency in seeds. The starch plate test revealed that salinity had a significant inhibitory effect on α-amylase activity in barley seeds. Further, NaCl treatment down-regulated the expression of Amy1, Amy2 and Amy3 genes in germinated seeds, thereby inhibiting α-amylase activity. In addition, the result of embryogenic culture system in vitro showed that the shoot elongation of barley was significantly inhibited by salt stress. These findings indicate that it is a feasible idea to study the regulation mechanism of salinity on barley seed germination and embryo growth from the aspect of starch-related source-sink communication.

4.
BMC Urol ; 24(1): 38, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347470

RESUMO

BACKGROUND: Prostatic fibrosis, characterized by the accumulation of myofibroblasts and collagen deposition, is closely associated with LUTS and may lead to mechanical obstruction of the urethra. Additionally, Metabolic Syndrome (MetS), characterized by central obesity, high blood sugar, lipid metabolism disorders, and hypertension, is increasingly recognized as a proinflammatory condition linked to prostate inflammation. METHODS: Clinical data from 108 subjects who underwent transurethral resection of the prostate or bipolar plasmakinetic enucleation of the prostate were prospectively collected between June 2021 and August 2022. Patients were divided in two groups according to whether or not they had a diagnosis of MetS. Specimens were stained with Masson trichrome and the periurethral prostatic fibrosis extent was evaluated using quantitative morphometry. RESULTS: Forty-three patients (39.8%) were diagnosed with MetS. Patients with MetS showed a significantly greater extent of prostatic fibrosis than the others (68.1 ± 17.1% vs. 42.5 ± 18.2%, P < 0.001), and there was a positive correlation between the number of positive MetS parameters and the extent of prostatic fibrosis (R2 = 0.4436, P < 0.001). Multivariate regression analysis revealed that central obesity (B = 2.941, 95% confidence interval, 1.700-3.283), elevated fasting glucose (B = 1.036, 95% confidence interval, 0.293-1.780), reduced HDL cholesterol (B = 0.910, 95% confidence interval, 0.183-1.636) and elevated triglycerides (B = 1.666, 95% confidence interval, 0.824-2.508) were positively correlated to prostatic fibrosis. Elevated blood pressure, however, was unrelated to prostatic fibrosis (B = 0.009, 95% confidence interval, -0.664-0.683). CONCLUSIONS: The present findings suggest that prostatic fibrosis is positively correlated with MetS and its components including central obesity, elevated fasting glucose, reduced high density lipoprotein cholesterol and elevated triglycerides.


Assuntos
Síndrome Metabólica , Hiperplasia Prostática , Ressecção Transuretral da Próstata , Masculino , Humanos , Próstata/patologia , Síndrome Metabólica/complicações , Estudos Prospectivos , Hiperplasia Prostática/cirurgia , Obesidade Abdominal/complicações , Obesidade Abdominal/patologia , Obesidade Abdominal/cirurgia , Fibrose , Triglicerídeos , Glucose
5.
Cancer Med ; 13(2): e6955, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38379328

RESUMO

BACKGROUND: Gene mutations play a crucial role in the occurrence and development of tumors, particularly in breast cancer (BC). Neoadjuvant therapy (NAT) has shown greater clinical benefit in HER2-positive breast cancer. However, further clinical investigation is needed to fully understand the correlation between genetic mutations and NAT efficacy and the long-term prognosis in HER2-positive BC. METHODS: This was a retrospective cohort study of 222 patients receiving NAT between 2017 and 2021 in the Department of Breast Surgery of Fudan University Shanghai Cancer Center. Tumor samples from these patients were subjected to Next Generation Sequencing (NGS) to analyze mutations in 513 cancer-related genes. This study aimed to investigate the association between these genetic mutations and postoperative pathological complete response (pCR), as well as their impact on disease-free survival (DFS). RESULTS: In total, 48.65% patients reached pCR, ER-negative status (p < 0.001), PR-negative status (p < 0.001), Ki67 ≥ 20 (p = 0.011), and dual-targeted therapy (p < 0.001) were all associated with enhanced pCR rates. The frequency of somatic alterations in TP53 (60%), PIK3CA (15%), and ERBB2 (11%) was highest. In the HER2+/HR- cohort, patients who achieved pCR had a significant benefit in prognosis (HR = 3.049, p = 0.0498). KMT2C (p = 0.036) and TP53 (p = 0.037) mutations were significantly increased in patients with DFS events. Moreover, TP53 mutations had prognostic significance in HER2-positive BC patients with HR-negative (HR = 3.712, p = 0.027) and pCR (HR = 6.253, p = 0.027) status and who received herceptin-only targeted therapy (HR = 4.145, p = 0.011). CONCLUSIONS: The genetic mutation profiles of Chinese HER2+ patients who received NAT were discrepant with respect to HR status or DFS events. TP53 mutations have significant prognostic value in patients with NAT for HER2-positive BC and patients benefit differently depending on HR status, the neoadjuvant regimen and response, which highlights the significance of genetic factors in treatment customization based on individual genetic and clinical characteristics.


Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Humanos , Feminino , Estudos Retrospectivos , China , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Prognóstico , Mutação , Proteína Supressora de Tumor p53/genética
6.
Aging Cell ; : e14124, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38380563

RESUMO

DJ-1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ-1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ-1 on the lysine 182 (K182) residue in an age-dependent manner. The N-homocysteinylation (N-hcy) of DJ-1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N-hcy of DJ-1 restores its protective effect. These results indicate that the N-hcy of DJ-1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N-hcy of DJ-1 may exert neuroprotective effect against PD.

7.
Cell Commun Signal ; 22(1): 156, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38424607

RESUMO

Exosomes are nanoscale extracellular vesicles present in bodily fluids that mediate intercellular communication by transferring bioactive molecules, thereby regulating a range of physiological and pathological processes. Exosomes can be secreted from nearly all cell types, and the biological function of exosomes is heterogeneous and depends on the donor cell type and state. Recent research has revealed that the levels of exosomes released from the endosomal system increase in cells undergoing programmed cell death. These exosomes play crucial roles in diseases, such as inflammation, tumors, and autoimmune diseases. However, there is currently a lack of systematic research on the differences in the biogenesis, secretion mechanisms, and composition of exosomes under different programmed cell death modalities. This review underscores the potential of exosomes as vital mediators of programmed cell death processes, highlighting the interconnection between exosome biosynthesis and the regulatory mechanisms governing cell death processes. Furthermore, we accentuate the prospect of leveraging exosomes for the development of innovative biomarkers and therapeutic strategies across various diseases.


Assuntos
Exossomos , Vesículas Extracelulares , Exossomos/metabolismo , Vesículas Extracelulares/metabolismo , Comunicação Celular , Biomarcadores/metabolismo , Apoptose
8.
Mol Hum Reprod ; 30(3)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38310328

RESUMO

Preterm birth (PTB) is a major problem affecting perinatal health, directly increasing the mortality risk of mother and infant that often results from the breakdown of the maternal-fetal immune balance. Increasing evidence shows the essential role of mucosal-associated invariant T (MAIT) cells to balance antibacterial function and immune tolerance function during pregnancy. However, the phenotype and function of placental MAIT cells and their specific mechanisms in PTB remain unclear. Here, we report that MAIT cells in placentas from PTBs show increased activation levels and decreased IFN-γ secretion capacity compared with those from normal pregnancies. Moreover, our data indicate gravidity is a factor affecting placental MAIT cells during pregnancies. Multi-omics analysis indicated aberrant immune activation and abnormal increase of lipids and lipid-like metabolites in the PTB placental microenvironment. Moreover, the proportion and activation of MAIT cells were positively correlated with the abnormal increase of lipids and lipid-like metabolites. Together, our work revealed that abnormal activation and impaired function of MAIT cells may be related to abnormal elevation of lipids and lipid-like metabolites in PTB.


Assuntos
Células T Invariantes Associadas à Mucosa , Nascimento Prematuro , Recém-Nascido , Gravidez , Lactente , Humanos , Feminino , Placenta , Feto , Lipídeos
9.
PLoS Biol ; 22(1): e3002470, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38206965

RESUMO

The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1-277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1-277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1-277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD.


Assuntos
Doença de Alzheimer , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Clatrina/metabolismo , Endocitose , Camundongos Transgênicos , Proteínas tau/genética , Proteínas tau/metabolismo
10.
Recent Pat Anticancer Drug Discov ; 19(3): 383-395, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38214322

RESUMO

BACKGROUND: Glioma is characterized by a high recurrence rate, while the results of the traditional imaging methods (including magnetic resonance imaging, MRI) to distinguish recurrence from treatment-related changes (TRCs) are poor. Prostate-specific membrane antigen (PSMA) (US10815200B2, Deutsches Krebsforschungszentrum, German Cancer Research Center) is a type II transmembrane glycoprotein overexpressed in glioma vascular endothelium, and it is a promising target for imaging and therapy. OBJECTIVE: The study aimed to assess the performance of PSMA positron emission tomography/ magnetic resonance (PET/MR) for diagnosing recurrence and predicting prognosis in glioma patients. MATERIALS AND METHODS: Patients suspected of glioma recurrence who underwent 18F-PSMA-1007 PET/MR were prospectively enrolled. Eight metabolic parameters and fifteen texture features of the lesion were extracted from PSMA PET/MR. The ability of PSMA PET/MR to diagnose glioma recurrence was investigated and compared with conventional MRI. The diagnostic agreement was assessed using Cohen κ scores and the predictive parameters of PSMA PET/MR were obtained. Kaplan-Meier method and Cox proportional hazard model were used to analyze recurrence- free survival (RFS) and overall survival (OS). Finally, the expression of PSMA was analyzed by immunohistochemistry (IHC). RESULTS: Nineteen patients with a mean age of 48.11±15.72 were assessed. The maximum tumorto- parotid ratio (TPRmax) and texture features extracted from PET and T1-weighted contrast enhancement (T1-CE) MR showed differences between recurrence and TRCs (all p <0.05). PSMA PET/MR and conventional MRI exhibited comparable power in diagnosing recurrence with specificity and PPV of 100%. The interobserver concordance was fair between the two modalities (κ = 0.542, p = 0.072). The optimal cutoffs of metabolic parameters, including standardized uptake value (SUV, SUVmax, SUVmean, and SUVpeak) and TPRmax for predicting recurrence were 3.35, 1.73, 1.99, and 0.17 respectively, with the area under the curve (AUC) ranging from 0.767 to 0.817 (all p <0.05). In grade 4 glioblastoma (GBM) patients, SUVmax, SUVmean, SUVpeak, TBRmax, TBRmean, and TPRmax showed improved performance of AUC (0.833-0.867, p <0.05). Patients with SUVmax, SUVmean, or SUVpeak more than the cutoff value had significantly shorter RFS (all p <0.05). In addition, patients with SUVmean, SUVpeak, or TPRmax more than the cutoff value had significantly shorter OS (all p <0.05). PSMA expression of glioma vascular endothelium was observed in ten (10/11, 90.9%) patients with moderate-to-high levels in all GBM cases (n = 6/6, 100%). CONCLUSION: This primitive study shows multiparameter PSMA PET/MR to be useful in identifying glioma (especially GBM) recurrence by providing excellent tumor background comparison, tumor heterogeneity, recurrence prediction and prognosis information, although it did not improve the diagnostic performance compared to conventional MRI. Further and larger studies are required to define its potential clinical application in this setting.


Assuntos
Glioblastoma , Glioma , Adulto , Humanos , Pessoa de Meia-Idade , Glioma/diagnóstico por imagem , Glioma/patologia , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Tomografia por Emissão de Pósitrons , Prognóstico , Compostos Radiofarmacêuticos
11.
J Nanobiotechnology ; 22(1): 18, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38172932

RESUMO

Exosomes are nanoscale extracellular vesicles secreted by cells and enclosed by a lipid bilayer membrane containing various biologically active cargoes such as proteins, lipids, and nucleic acids. Engineered exosomes generated through genetic modification of parent cells show promise as drug delivery vehicles, and they have been demonstrated to have great therapeutic potential for treating cancer, cardiovascular, neurological, and immune diseases, but systematic knowledge is lacking regarding optimization of drug loading and assessment of delivery efficacy. This review summarizes current approaches for engineering exosomes and evaluating their drug delivery effects, and current techniques for assessing exosome drug loading and release kinetics, cell targeting, biodistribution, pharmacokinetics, and therapeutic outcomes are critically examined. Additionally, this review synthesizes the latest applications of exosome engineering and drug delivery in clinical translation. The knowledge compiled in this review provides a framework for the rational design and rigorous assessment of exosomes as therapeutics. Continued advancement of robust characterization methods and reporting standards will accelerate the development of exosome engineering technologies and pave the way for clinical studies.


Assuntos
Exossomos , Vesículas Extracelulares , Neoplasias , Humanos , Exossomos/metabolismo , Distribuição Tecidual , Sistemas de Liberação de Medicamentos/métodos , Vesículas Extracelulares/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Preparações Farmacêuticas/metabolismo
13.
Stem Cell Res ; 74: 103286, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38141357

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Affected patients experience gradual loss of their spinal cord and cortical motor neurons with consequent muscle weakness and emaciation, and eventual respiratory failure. The pathogenesis of ALS remains largely unknown although the FUS (sarcoma fusion gene) gene is known to be one of the major pathogenic genes. We have generated an induced pluripotent stem cell line SMUSHi002-A from an ALS patient who carries a heterozygous mutation c.1562G > A in FUS. This cell line will serve as a useful model to investigate disease pathogenesis and develop potential therapeutic approaches for ALS.


Assuntos
Esclerose Amiotrófica Lateral , Células-Tronco Pluripotentes Induzidas , Doenças Neurodegenerativas , Humanos , Esclerose Amiotrófica Lateral/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios Motores/metabolismo , Mutação/genética , Proteína FUS de Ligação a RNA/genética
14.
Int J Nanomedicine ; 18: 7923-7940, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38152837

RESUMO

Exosomes are nano-sized membrane vesicles that transfer bioactive molecules between cells and modulate various biological processes under physiological and pathological conditions. By applying bioengineering technologies, exosomes can be modified to express specific markers or carry therapeutic cargo and emerge as novel platforms for the treatment of cancer, neurological, cardiovascular, immune, and infectious diseases. However, there are many challenges and uncertainties in the clinical translation of exosomes. This review aims to provide an overview of the recent advances and challenges in the translation of engineered exosomes, with a special focus on the methods and strategies for loading drugs into exosomes, the pros and cons of different loading methods, and the optimization of exosome production based on the drugs to be encapsulated. Moreover, we also summarize the current clinical applications and prospects of engineered exosomes, as well as the potential risks and limitations that need to be addressed in exosome engineering, including the standardization of exosome preparation and engineering protocols, the quality and quantity of exosomes, the control of drug release, and the immunogenicity and cytotoxicity of exosomes. Overall, engineered exosomes represent an exciting frontier in nanomedicine, but they still face challenges in large-scale production, the maintenance of storage stability, and clinical translation. With continuous advances in this field, exosome-based drug formulation could offer great promise for the targeted treatment of human diseases.


Assuntos
Exossomos , Neoplasias , Humanos , Exossomos/patologia , Sistemas de Liberação de Medicamentos/métodos , Nanomedicina/métodos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Bioengenharia
15.
Sci Adv ; 9(44): eadj1092, 2023 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-37910610

RESUMO

Parkinson's disease (PD) is characterized by the pathologic aggregation and prion-like propagation of α-synuclein (α-syn). Emerging evidence shows that fungal infections increase the incidence of PD. However, the molecular mechanisms by which fungi promote the onset of PD are poorly understood. Here, we show that nasal infection with Saccharomyces cerevisiae (S. cerevisiae) in α-syn A53T transgenic mice accelerates the aggregation of α-syn. Furthermore, we found that Sup35, a prion protein from S. cerevisiae, is the key factor initiating α-syn pathology induced by S. cerevisiae. Sup35 interacts with α-syn and accelerates its aggregation in vitro. Notably, injection of Sup35 fibrils into the striatum of wild-type mice led to α-syn pathology and PD-like motor impairment. The Sup35-seeded α-syn fibrils showed enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Together, these observations indicate that the yeast prion protein Sup35 initiates α-syn pathology in PD.


Assuntos
Doença de Parkinson , Saccharomyces cerevisiae , alfa-Sinucleína , Animais , Camundongos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Camundongos Transgênicos , Doença de Parkinson/metabolismo , Proteínas Priônicas/metabolismo , Príons/metabolismo , Saccharomyces cerevisiae/metabolismo
16.
Front Mol Neurosci ; 16: 1209703, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37781096

RESUMO

Neurodegenerative diseases (NDDs) pose an increasingly prevalent threat to the well-being and survival of elderly individuals worldwide. NDDs include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and so on. They are characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system and share several cellular and molecular mechanisms, including protein aggregation, mitochondrial dysfunction, gene mutations, and chronic neuroinflammation. Glycogen synthase kinase-3 beta (GSK-3ß) is a serine/threonine kinase that is believed to play a pivotal role in the pathogenesis of NDDs. Here we summarize the structure and physiological functions of GSK3ß and explore its involvement in NDDs. We also discussed its potential as a therapeutic target.

17.
Nat Commun ; 14(1): 6670, 2023 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-37865646

RESUMO

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identified transgelin-2 (TG2) expressed on neurons as the receptor for sTREM2. The microglia-derived sTREM2 binds to TG2, induces RhoA phosphorylation at S188, and deactivates the RhoA-ROCK-GSK3ß pathway, ameliorating tau phosphorylation. The sTREM2 (77-89) fragment, which is the minimal active sequence of sTREM2 to activate TG2, mimics the inhibitory effect of sTREM2 on tau phosphorylation. Overexpression of sTREM2 or administration of the active peptide rescues tau pathology and behavioral defects in the tau P301S transgenic mice. Together, these findings demonstrate that the sTREM2-TG2 interaction mediates the cross-talk between microglia and neurons. sTREM2 and its active peptide may be a potential therapeutic intervention for tauopathies including AD.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Humanos , Doença de Alzheimer/metabolismo , Fosforilação , Camundongos Transgênicos , Peptídeos/metabolismo , Cognição , Proteínas tau/metabolismo , Biomarcadores/metabolismo , Peptídeos beta-Amiloides/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
18.
Food Chem X ; 19: 100827, 2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37780339

RESUMO

In this research, the different methods (acid extraction, alkaline extraction and enzymatic extraction) were used to extract soluble dietary fiber (SDF) from pomegranate peel and compared with water extraction. Results revealed that all three extraction methods influenced the structure, physicochemical and functional properties of SDF. Especially, SDF extracted by enzymes (E-SDF) and SDF extracted by alkali (A-SDF) had higher yield (27.30% and 27.17%), molecular weight and thermal stability than SDF extracted by water (W-SDF). Higher oil holding capacity (OHC) was found in SDF extracted by acid (C-SDF) (3.18 g/g), A-SDF (3.18 g/g) and E-SDF (5.36 g/g) compared with W-SDF. In addition, A-SDF showed the smallest particle size, lowest ζ-potential and highest viscosity among the tested samples. E-SDF presented a more porous structure, better glucose adsorption capacity (GAC) and antioxidant activity than C-SDF and A-SDF. To sum up, A-SDF and E-SDF may have great potential to be functional food ingredients in the food industry.

19.
J Med Virol ; 95(9): e29076, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37671751

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause the ongoing pandemic of coronavirus disease 2019 (COVID19). One key feature associated with COVID-19 is excessive pro-inflammatory cytokine production that leads to severe acute respiratory distress syndrome. Although the cytokine storm induces inflammatory cell death in the host, which type of programmed cell death mechanism that occurs in various organs and cells remains elusive. Using an in vitro culture model of polarized human airway epithelium (HAE), we observed that necroptosis, but not apoptosis or pyroptosis, plays an essential role in the damage of the epithelial barrier of polarized HAE infected with SARS-CoV-2. Pharmacological inhibitors of necroptosis, necrostatin-2 and necrosulfonamide, efficiently prevented cell death and epithelial barrier dysfunction caused by SARS-CoV-2 infection. Moreover, the silencing of genes that are involved in necroptosis, RIPK1, RIPK3, and MLKL, ameliorated airway epithelial damage of the polarized HAE infected with SARS-CoV-2. This study, for the first time, confirms that SARS-CoV-2 infection triggers necroptosis that disrupts the barrier function of human airway epithelia in vitro.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Necroptose , Apoptose , Epitélio
20.
Front Aging Neurosci ; 15: 1241750, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37771520

RESUMO

Background: Tau phosphorylation is a pathological hallmark of Alzheimer's disease (AD). Previously, we reported that the γ-adducin 1-357 fragment is present in the brains of AD patients. However, it remains unknown how γ-adducin regulates tau phosphorylation. Objective: The aim of this project is to investigate the effects of the γ-adducin 1-357 fragment on tau phosphorylation and the kinases involved in this process. Methods: Full-length γ-adducin or the γ-adducin 1-357 fragment was expressed in HEK293 cells, SH-SY5Y cells, and primary neurons. The phosphorylation of tau Ser396 was determined using Western blot and immunofluorescence. Tau P301S transgenic mice were injected with adeno-associated virus encoding full-length γ-adducin or γ-adducin 1-357 fragment to determine the phosphorylation of tau. Results: The γ-adducin 1-357 fragment enhances tau phosphorylation at Ser396. Additionally, the expression of the γ-adducin 1-357 fragment leads to the activation of glycogen synthase kinase-3ß (GSK-3ß). This effect was mitigated by the GSK-3ß inhibitor 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). Conclusion: The γ-adducin 1-357 fragment enhances tau phosphorylation by activating GSK3ß. These results support that the fragmentation of γ-adducin may play a pivotal role in tau pathology.

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