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1.
Nutrients ; 16(12)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38931268

RESUMO

Obesity is acknowledged as a significant risk factor for cardiovascular disease, often accompanied by increased inflammation and diabetes. Bioactive peptides derived from marine animal proteins show promise as safe and effective anti-obesity agents by regulating adipocyte differentiation through the AMPK signaling pathway. Therefore, this study aims to investigate the anti-obesity and anti-diabetic effects of bioactive compounds derived from a Meretrix lusoria Protamex enzymatic hydrolysate (MLP) fraction (≤1 kDa) through a 6-week treatment (150 mg/kg or 300 mg/kg, administered once daily) in leptin receptor-deficient db/db mice. The MLP treatment significantly decreased the body weight, serum total cholesterol, triglycerides, and LDL-cholesterol levels while also exhibiting a beneficial effect on hepatic and serum marker parameters in db/db mice. A histological analysis revealed a reduction in hepatic steatosis and epididymal fat following MLP treatment. Furthermore, poor glucose tolerance was improved, and hepatic antioxidant enzyme activities were elevated in MLP-treated mice compared to db/db control mice. Western blot analysis showed an increased expression of the AMPK protein after MLP treatment. In addition, the expression of lipogenic genes decreased in db/db mice. These findings indicate that bioactive peptides, which are known to regulate blood glucose levels, lipid metabolism, and adipogenesis, could be beneficial functional food additives and pharmaceuticals.


Assuntos
Fármacos Antiobesidade , Obesidade , Peptídeos , Animais , Obesidade/tratamento farmacológico , Camundongos , Masculino , Peptídeos/farmacologia , Fármacos Antiobesidade/farmacologia , Hidrolisados de Proteína/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Endogâmicos C57BL , Receptores para Leptina/metabolismo , Receptores para Leptina/genética , Adipogenia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos
2.
Arch Dermatol Res ; 316(6): 290, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38809465

RESUMO

Enz_MoriL is a naturally occurring substance extracted from the leaves of Morus alba L. through enzymatic conversion. Historically, M. alba L. has been recognized for its potential to promote hair regrowth. However, the precise mechanism by which Enz_MoriL affects human hair follicle dermal papilla cells (hDPCs) remains unclear. The aim of this study was to investigate the molecular basis of Enz_MoriL's effect on hair growth in hDPCs. Interferon-gamma (IFN-γ) was used to examine the effects of Enz_MoriL on hDPCs during the anagen and catagen phases, as well as under conditions mimicking alopecia areata (AA). Enz_MoriL demonstrated the ability to promote cell proliferation in both anagen and catagen stages. It increased the levels of active ß-catenin in the catagen stage induced by IFN-γ, leading to its nuclear translocation. This effect was achieved by increasing the phosphorylation of GSK3ß and decreasing the expression of DKK-1. This stimulation induced proliferation in hDPCs and upregulated the expression of the Wnt family members 3a, 5a, and 7a at the transcript level. Additionally, Enz_MoriL suppressed JAK1 and STAT3 phosphorylation, contrasting with IFN-γ, which induced them in the catagen stage. In conclusion, Enz_MoriL directly induced signals for anagen re-entry into hDPCs by affecting the Wnt/ß-catenin pathway and enhancing the production of growth factors. Furthermore, Enz_MoriL attenuated and reversed the interferon-induced AA-like environment by blocking the JAK-STAT pathway in hDPCs.


Assuntos
Alopecia em Áreas , Proliferação de Células , Folículo Piloso , Interferon gama , Via de Sinalização Wnt , beta Catenina , Humanos , Folículo Piloso/efeitos dos fármacos , Folículo Piloso/citologia , Folículo Piloso/metabolismo , Proliferação de Células/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Interferon gama/metabolismo , beta Catenina/metabolismo , Alopecia em Áreas/metabolismo , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/patologia , Células Cultivadas , Glicogênio Sintase Quinase 3 beta/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Janus Quinases/metabolismo , Derme/citologia , Derme/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Proteína Wnt-5a/metabolismo , Janus Quinase 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo
3.
Exp Mol Med ; 56(4): 788-798, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38658701

RESUMO

In recent years, Hi-C technology has revolutionized cancer research by elucidating the mystery of three-dimensional chromatin organization and its role in gene regulation. This paper explored the impact of Hi-C advancements on cancer research by delving into high-resolution techniques, such as chromatin loops, structural variants, haplotype phasing, and extrachromosomal DNA (ecDNA). Distant regulatory elements interact with their target genes through chromatin loops. Structural variants contribute to the development and progression of cancer. Haplotype phasing is crucial for understanding allele-specific genomic rearrangements and somatic clonal evolution in cancer. The role of ecDNA in driving oncogene amplification and drug resistance in cancer cells has also been revealed. These innovations offer a deeper understanding of cancer biology and the potential for personalized therapies. Despite these advancements, challenges, such as the accurate mapping of repetitive sequences and precise identification of structural variants, persist. Integrating Hi-C with multiomics data is key to overcoming these challenges and comprehensively understanding complex cancer genomes. Thus, Hi-C is a powerful tool for guiding precision medicine in cancer research and treatment.


Assuntos
Cromatina , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/patologia , Cromatina/genética , Cromatina/metabolismo , Genômica/métodos , Animais , Medicina de Precisão/métodos
4.
Exp Mol Med ; 56(3): 515-526, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38443594

RESUMO

Single-cell omics technologies have revolutionized molecular profiling by providing high-resolution insights into cellular heterogeneity and complexity. Traditional bulk omics approaches average signals from heterogeneous cell populations, thereby obscuring important cellular nuances. Single-cell omics studies enable the analysis of individual cells and reveal diverse cell types, dynamic cellular states, and rare cell populations. These techniques offer unprecedented resolution and sensitivity, enabling researchers to unravel the molecular landscape of individual cells. Furthermore, the integration of multimodal omics data within a single cell provides a comprehensive and holistic view of cellular processes. By combining multiple omics dimensions, multimodal omics approaches can facilitate the elucidation of complex cellular interactions, regulatory networks, and molecular mechanisms. This integrative approach enhances our understanding of cellular systems, from development to disease. This review provides an overview of the recent advances in single-cell and multimodal omics for high-resolution molecular profiling. We discuss the principles and methodologies for representatives of each omics method, highlighting the strengths and limitations of the different techniques. In addition, we present case studies demonstrating the applications of single-cell and multimodal omics in various fields, including developmental biology, neurobiology, cancer research, immunology, and precision medicine.


Assuntos
Multiômica , Medicina de Precisão , Medicina de Precisão/métodos
5.
Int J Mol Sci ; 25(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38542316

RESUMO

Nardostachys jatamansi is widely used as a traditional medicine in Asian countries. Numerous recent studies have reported the biological activities of its secondary metabolites and extracts. In this study, a total of 14 components were isolated, including cycloolivil and 2-(3'-hydroxy-5'-ethoxyphenyl)-3-hydroxylmethyl-7-methoxy-2,3-dihydrobenzofuran-5-carboxylic acid, which were first discovered in N. jatamansi. The isolated compounds were investigated for their anti-inflammatory effects on HaCaT keratinocytes and their potential to alleviate skin inflammation. The results of the screening revealed that cycloolivil and 4ß-hydroxy-8ß-methoxy-10-methylene-2,9-dioxatricyclo[4.3.1.03,7]decane reduced the production of inflammatory cytokines induced by TNF-α/IFN-γ, such as IL-6, IL-8, and RANTES, in keratinocytes. This study focused on exploring the biological effects of cycloolivil, and the results suggested that cycloolivil inhibits the expression of COX-2 proteins. Further mechanistic evaluations confirmed that the anti-inflammatory effects of cycloolivil were mediated by blockage of the NF-κB and JAK/STAT signaling pathways. These results suggest that cycloolivil isolated from N. jatamansi could be used to treat skin inflammatory diseases.


Assuntos
NF-kappa B , Nardostachys , Fenóis , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Nardostachys/metabolismo , Interferon gama/metabolismo , Queratinócitos/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo
6.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473792

RESUMO

Lindera erythrocarpa, a flowering plant native to eastern Asia, has been reported to have neuroprotective activity. However, reports on the specific bioactive compounds in L. erythrocarpa are finite. The aim of this study was to investigate the anti-neuroinflammatory and neuroprotective effects of the compounds isolated from L. erythrocarpa. Dihydropashanone, a compound isolated from L. erythrocarpa extract, was found to have protected mouse hippocampus HT22 cells from glutamate-induced cell death. The antioxidant and anti-inflammatory properties of dihydropashanone in mouse microglial BV2 and HT22 cells were explored in this study. The results reveal that dihydropashanone inhibits lipopolysaccharide-induced inflammatory response and suppresses the activation of nuclear factor (NF)-κB in BV2 cells. In addition, dihydropashanone reduced the buildup of reactive oxygen species in HT22 cells and induced activation of the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 signaling pathway in BV2 and HT22 cells. Our results suggest that dihydropashanone reduces neuroinflammation by decreasing NF-κB activation in microglia cells and protects neurons from oxidative stress via the activation of the Nrf2/HO-1 pathway. Thus, our data suggest that dihydropashanone offers a broad range of applications in the treatment of neurodegenerative illnesses.


Assuntos
Lindera , Doenças Neurodegenerativas , Camundongos , Animais , Lindera/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Anti-Inflamatórios/farmacologia , NF-kappa B/metabolismo
7.
J Ethnopharmacol ; 324: 117813, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38281691

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fatsia japonica is a traditional medicine used to treat various diseases, including inflammation-related disorders. However, its antineuroinflammatory and neuroprotective effects remain unclear. AIM OF THE STUDY: We aimed to evaluate the anti-neuroinflammatory and neuroprotective effects of F. japonica extract to identify the underlying mechanisms. MATERIALS AND METHODS: The components of F. japonica extract were profiled using ultra-high-performance liquid chromatography-mass spectrometry. The effects of F. japonica extract were investigated in BV2 microglia and HT22 hippocampal cells. Furthermore, in vivo effects of F. japonica extract were assessed using zebrafish models treated with H2O2 and LPS to evaluate the effects of in vivo. RESULTS: We identified 27 compounds in the F. japonica extract. F. japonica extract demonstrated anti-inflammatory properties by suppressing LPS-induced inflammatory responses in both BV2 cells and zebrafish, along with inhibiting the activation of the nuclear factor (NF)-κB (p65) pathway. The protective effects of this extract were also observed on glutamate-treated HT22 cells and in H2O2-induced zebrafish. Furthermore, F. japonica extract upregulated nuclear factor E2-related (Nrf) 2/heme oxygenase (HO)-1 expression in BV2 and HT22 cells. CONCLUSIONS: F. japonica extract exerted anti-neuroinflammatory and neuroprotective effects through Nrf2/HO-1 and the NF-κB pathway.


Assuntos
Fármacos Neuroprotetores , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/metabolismo , Peixe-Zebra , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Lipopolissacarídeos/farmacologia , Peróxido de Hidrogênio/metabolismo , Linhagem Celular , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Microglia , Heme Oxigenase-1/metabolismo
8.
Molecules ; 28(21)2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37959718

RESUMO

Neuroinflammation activated by microglia affects inflammatory pain development. This study aimed to explore the anti-inflammatory properties and mechanisms of 1,6,7-trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxyxanthone (THMX) from Cudrania tricuspidata in microglia activation-mediated inflammatory pain. In RAW 264.7 and BV2 cells, THMX has been shown to reduce lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory mediators and cytokines, including nitric oxide (NO), prostaglandin (PG) E2, interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α). THMX also decreased LPS-induced phosphorylation of mitogen-activated protein kinase (MAPK) and the activation of p65 nuclear factor kappa B (NF-κB). Interestingly, THMX also activated heme oxygenase (HO)-1 expression. These findings suggest that THMX is a promising biologically active compound against inflammation through preventing MAPKs and NF-ĸB and activating HO-1 signaling pathways.


Assuntos
Moraceae , NF-kappa B , NF-kappa B/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Transdução de Sinais , Microglia/metabolismo , Interleucina-6/metabolismo , Dor/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ciclo-Oxigenase 2/metabolismo
9.
Nat Commun ; 14(1): 6943, 2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37932264

RESUMO

Chromatin conformation reorganization is emerging as an important layer of regulation for gene expression and lineage specification. Yet, how lineage-specific transcription factors contribute to the establishment of cell type-specific 3D chromatin architecture in the immune cells remains unclear, especially for the late stages of T cell subset differentiation and maturation. Regulatory T cells (Treg) are mainly generated in the thymus as a subpopulation of T cells specializing in suppressing excessive immune responses. Here, by comprehensively mapping 3D chromatin organization during Treg cell differentiation, we show that Treg-specific chromatin structures were progressively established during its lineage specification, and highly associated with Treg signature gene expression. Additionally, the binding sites of Foxp3, a Treg lineage specifying transcription factor, were highly enriched at Treg-specific chromatin loop anchors. Further comparison of the chromatin interactions between wide-type Tregs versus Treg cells from Foxp3 knock-in/knockout or newly-generated Foxp3 domain-swap mutant mouse revealed that Foxp3 was essential for the establishment of Treg-specific 3D chromatin architecture, although it was not dependent on the formation of the Foxp3 domain-swapped dimer. These results highlighted an underappreciated role of Foxp3 in modulating Treg-specific 3D chromatin structure formation.


Assuntos
Cromatina , Linfócitos T Reguladores , Camundongos , Animais , Cromatina/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Diferenciação Celular/genética
10.
Nat Prod Res ; : 1-8, 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37820035

RESUMO

Chemical investigation of corn silk resulted in the isolation of nine secondary metabolites, including a new ent-kaurane diterpenoid, zeamaysditerpene A (1) and eight known compounds, stigmaydene A (2), stigmaydene J (3), stigmaydene L (4), stigmane D (5), demethyltorosaflavone D (6), chrysoeriol 6-C-ß-boivinopyranosyl-7-O-ß-D-glucopyranoside (7), deoxypodophyllotoxin (8), and α-peltatin glucoside (9). Their structures were elucidated using a combination of spectroscopic methods, including 1D and 2D NMR and HRESIQTOF mass spectra. The absolute configuration of 1 was deduced by applying electronic circular dichroism (ECD) calculation method. Among the isolates, only 6 displayed significant inhibition against PTP1B activity in a dose-dependent manner, with an IC50 value of 10.7 ± 0.1 µM. Furthermore, molecular docking simulation was carried out to explore the action perspective of 6 inside the enzyme PTP1B. This finding suggests that 6 might be a potential lead for the development of a new anti-diabetic agent.

11.
Chem Biol Interact ; 385: 110718, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37777167

RESUMO

Strategies for reducing inflammation in neurodegenerative diseases have attracted increasing attention. Herein, we discovered and evaluated the neuroprotective potential of fungal metabolites isolated from the Antarctic fungus Pseudogymnoascus sp. (strain SF-7351). The chemical investigation of the EtOAc extract of the fungal strain isolate revealed a novel naturally occurring epi-macrosphelide J (1), a novel secondary metabolite macrosphelide N (2), and three known compounds, namely macrosphelide A (3), macrosphelide B (4), and macrosphelide J (5). Their structures were established unambiguously using spectroscopic methods, such as one-dimensional and two-dimensional nuclear magnetic resonance (1D and 2D-NMR) spectroscopy, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), and gauge-including atomic orbital (GIAO) NMR chemical shift calculations, with the support of the advanced statistical method DP4+. Among the isolated metabolites, the absolute configuration of epi-macrosphelide J (1) was further confirmed using single-crystal X-ray diffraction analysis. The neuroprotective effects of the isolated metabolites were evaluated in lipopolysaccharide (LPS)-induced BV2 and glutamate-stimulated HT22 cells. Only macrosphelide B (4) displayed substantial protective effects in both BV2 and HT22 cells. Molecular mechanisms underlying this activity were investigated using western blotting and molecular docking studies. Macrosphelide B (4) inhibited the inflammatory response by reducing the nuclear translocation of NF-κB (p65) in LPS-induced BV2 cells and induced the Nrf2/HO-1 signaling pathway in both BV2 and HT22 cells. The neuroprotective effect of macrosphelide B (4) is related to the interaction between Keap1 and p65. These results suggest that macrosphelide B (4), present in the fungus Pseudogymnoascus sp. (strain SF-7351), may serve as a candidate for the treatment of neurodegenerative diseases.

12.
Clin Cosmet Investig Dermatol ; 16: 2561-2572, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37750085

RESUMO

Purpose: This study is to report a case of chronic atopic dermatitis (AD) with eosinophilia, which did not respond to conventional therapy and was improved by Daesiho-tang (DSHT). Patients and Methods: The patient visited our clinic with symptoms of atopic dermatitis including skin lesions and pruritus. Based on her symptoms, DSHT was prescribed. At each visit, the Scoring Atopic Dermatitis (SCORAD), Dermatology Life Quality Index (DLQI), and accompanying systemic symptoms (ASS) were measured. Multiple Allergen Simultaneous Test (MAST) was initially performed for 108 allergens and analyzed by Western blotting using an Alternate Scoring Method (ASM) according to the specific IgE concentration. Also, peripheral blood laboratory (Lab) tests were performed three times during the patient's visit. Results: After taking DSHT, the total SCORAD score improved from 62.9 to 23.5, while the patient's ASS also improved. The DLQI score improved from 19 to 5. The total number of eosinophils in the peripheral blood, which showed a mild increase, recovered from 17.2% (0.98 x103/µL) to 4.5% (0.24 x103/µL). The total IgE slightly decreased, while AST and ALT were also restored to normal ranges. Conclusion: Based on this case, DSHT is considered a potential alternative treatment for AD.

13.
Int J Stem Cells ; 16(4): 363-375, 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-37643761

RESUMO

Stem cells are the foundational cells for every organ and tissue in our body. Cell-based therapeutics using stem cells in regenerative medicine have received attracting attention as a possible treatment for various diseases caused by congenital defects. Stem cells such as induced pluripotent stem cells (iPSCs) as well as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), and neuroprogenitors stem cells (NSCs) have recently been studied in various ways as a cell-based therapeutic agent. When various stem cells are transplanted into a living body, they can differentiate and perform complex functions. For stem cell transplantation, it is essential to determine the suitability of the stem cell-based treatment by evaluating the origin of stem, the route of administration, in vivo bio-distribution, transplanted cell survival, function, and mobility. Currently, these various stem cells are being imaged in vivo through various molecular imaging methods. Various imaging modalities such as optical imaging, magnetic resonance imaging (MRI), ultrasound (US), positron emission tomography (PET), and single-photon emission computed tomography (SPECT) have been introduced for the application of various stem cell imaging. In this review, we discuss the principles and recent advances of in vivo molecular imaging for application of stem cell research.

14.
Nutrients ; 15(9)2023 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-37432237

RESUMO

Atopic dermatitis is a chronic skin disease that affects millions of people all over the world. The objective of this study was to evaluate the inhibitory effects of the roots of Glycyrrhiza uralensis (GU) and Donkey Hide Gelatin (DHG) water extracts on DNCB-induced NC/Nga mice and TNF-α/IFN-γ treated keratinocytes or LPS-stimulated macrophages. The combined treatment using the water extracts of GU and DHG improved the skin symptom evaluation score and skin histology, with increased expression of the skin barrier proteins Claudin 1 and Sirt 1 in lesion areas. The IFN-γ activity was promoted in PBMCs, ALN, and dorsal skin tissue, while the absolute cell number was reduced for T cells so that the production and expression of serum IgE and cytokines were suppressed. In TNF-α/IFN-γ induced HaCaT cells, IL-6, IL-8, MDC, and RANTES were all inhibited by GU and DHG water extracts, while ICAM-1 and COX-2 levels were similarly downregulated. In addition, GU and DHG water extracts decreased LPS-mediated nitric oxide, IL-6, TNF-α, and PGE2 in RAW 264.7 cells, and the expression of iNOS and COX-2 also decreased. Notably, the DHG:GU ratio of 4:1 was shown to have the best effects of all ratios. In conclusion, GU and DHG have anti-skin inflammatory potentials that can be used as alternative ingredients in the formula of functional foods for people with atopic dermatitis.


Assuntos
Dermatite Atópica , Glycyrrhiza uralensis , Animais , Camundongos , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Dinitroclorobenzeno , Gelatina , Ciclo-Oxigenase 2 , Interleucina-6 , Lipopolissacarídeos , Fator de Necrose Tumoral alfa , Alimento Funcional
15.
Nano Lett ; 23(16): 7341-7349, 2023 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-37506062

RESUMO

Effective tumor regression has been observed with chimeric antigen receptor (CAR) T cells; however, the development of an affordable, safe, and effective CAR-T cell treatment remains a challenge. One of the major obstacles is that the suboptimal genetic modification of T cells reduces their yield and antitumor activity, necessitating the development of a next-generation T cell engineering approach. In this study, we developed a nonviral T cell nanoengineering system that allows highly efficient delivery of diverse functional nanomaterials into primary human T cells in a genetically stable and scalable manner. Our platform leverages the unique cell deformation and restoration process induced by the intrinsic inertial flow in a microchannel to create nanopores in the cellular membrane for macromolecule internalization, leading to effective transfection with high scalability and viability. The proposed approach demonstrates considerable potential as a practical alternative technique for improving the current CAR-T cell manufacturing process.


Assuntos
Imunoterapia Adotiva , Linfócitos T , Humanos , Imunoterapia Adotiva/métodos , Transfecção , Receptores de Antígenos de Linfócitos T/genética
16.
Nature ; 617(7961): 540-547, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37165195

RESUMO

Throughout an individual's lifetime, genomic alterations accumulate in somatic cells1-11. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome12-14, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.


Assuntos
Colo , Elementos de DNA Transponíveis , Mucosa Intestinal , Retroelementos , Humanos , Carcinogênese/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Elementos de DNA Transponíveis/genética , Genômica , Elementos Nucleotídeos Longos e Dispersos/genética , Retroelementos/genética , Envelhecimento/genética , Frequência do Gene , Mosaicismo , Epigenômica , Genoma Humano/genética , Colo/metabolismo , Mucosa Intestinal/metabolismo , Desenvolvimento Embrionário/genética
17.
Int J Mol Sci ; 24(8)2023 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-37108534

RESUMO

Skin is the first line of defense in the body against external stimulation and injury. Inflammation and oxidative stress in skin cells are the initiators and promoters of several skin diseases. Latifolin is a natural flavonoid isolated from Dalbergia odorifera T. Chen. This study aimed to evaluate the anti-inflammatory and antioxidant properties of latifolin. The anti-inflammatory effects were evaluated using tumor necrosis factor-α/interferon-γ (TNF-α/IFN-γ)-treated HaCaT cells, revealing that latifolin inhibited the secretion of Interleukin 6 (IL-6); Interleukin 8 (IL-8); Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES); and Macrophage-derived chemokine (MDC) while decreasing the expression of Intercellular Adhesion Molecule 1 (ICAM-1). The results of western blots and immunofluorescence demonstrated that the activation of Janus kinase 2 (JAK2), Signal transducer and activator of transcription 1 (STAT1), Signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) cells signaling pathways were significantly inhibited by latifolin. The antioxidant properties were evaluated using t-BHP-induced BJ-5ta cells. Latifolin increased the viability of t-BHP-induced BJ-5ta cells. Additionally, fluorescent staining of reactive oxygen species (ROS) showed that the production of ROS was inhibited by latifolin. Additionally, latifolin reduced the phosphorylation of p38 and JNK. The results indicate that latifolin has potential anti-inflammatory and antioxidant properties, and may be a candidate natural compound for the treatment of skin diseases.


Assuntos
Dalbergia , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Linhagem Celular , Queratinócitos/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Int J Mol Sci ; 24(8)2023 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-37108568

RESUMO

Compounds derived from Curcuma longa L. (C. longa) have been extensively studied and reported to be effective and safe for the prevention and treatment of various diseases, but most research has been focused on curcuminoids derived from C. longa. As neurodegenerative diseases are associated with oxidation and inflammation, the present study aimed to isolate and identify active compounds other than curcuminoids from C. longa to develop substances to treat these diseases. Seventeen known compounds, including curcuminoids, were chromatographically isolated from the methanol extracts of C. longa, and their chemical structures were identified using 1D and 2D NMR spectroscopy. Among the isolated compounds, intermedin B exhibited the best antioxidant effect in the hippocampus and anti-inflammatory effect in microglia. Furthermore, intermedin B was confirmed to inhibit the nuclear translocation of NF-κB p-65 and IκBα, exerting anti-inflammatory effects and inhibiting the generation of reactive oxygen species, exerting neuroprotective effects. These results highlight the research value of active components other than curcuminoids in C. longa-derived compounds and suggest that intermedin B may be a promising candidate for the prevention of neurodegenerative diseases.


Assuntos
NF-kappa B , Fármacos Neuroprotetores , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Microglia/metabolismo , Curcuma/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Hipocampo/metabolismo , Diarileptanoides/farmacologia , Lipopolissacarídeos/farmacologia
19.
Int J Mol Sci ; 24(8)2023 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-37108731

RESUMO

Linderone is a major compound in Lindera erythrocarpa and exhibits anti-inflammatory effects in BV2 cells. This study investigated the neuroprotective effects and mechanisms of linderone action in BV2 and HT22 cells. Linderone suppressed lipopolysaccharide (LPS)-induced inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokines (e.g., tumor necrosis factor alpha, interleukin-6, and prostaglandin E-2) in BV2 cells. Linderone treatment also inhibited the LPS-induced activation of p65 nuclear factor-kappa B, protecting against oxidative stress in glutamate-stimulated HT22 cells. Furthermore, linderone activated the translocation of nuclear factor E2-related factor 2 and induces the expression of heme oxygenase-1. These findings provided a mechanistic explanation of the antioxidant and anti-neuroinflammatory effects of linderone. In conclusion, our study demonstrated the therapeutic potential of linderone in neuronal diseases.


Assuntos
Lindera , NF-kappa B , NF-kappa B/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Lindera/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Linhagem Celular , Microglia/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
20.
Mol Cells ; 46(2): 86-98, 2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36859473

RESUMO

The genome is almost identical in all the cells of the body. However, the functions and morphologies of each cell are different, and the factors that determine them are the genes and proteins expressed in the cells. Over the past decades, studies on epigenetic information, such as DNA methylation, histone modifications, chromatin accessibility, and chromatin conformation have shown that these properties play a fundamental role in gene regulation. Furthermore, various diseases such as cancer have been found to be associated with epigenetic mechanisms. In this study, we summarized the biological properties of epigenetics and single-cell epigenomic profiling techniques, and discussed future challenges in the field of epigenetics.


Assuntos
Cromatina , Epigênese Genética , Animais , Metilação de DNA , Epigenômica , Processamento de Proteína Pós-Traducional , Mamíferos
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