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1.
J Orthop Surg Res ; 19(1): 386, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951811

RESUMO

BACKGROUND: Bone defects, resulting from substantial bone loss that exceeds the natural self-healing capacity, pose significant challenges to current therapeutic approaches due to various limitations. In the quest for alternative therapeutic strategies, bone tissue engineering has emerged as a promising avenue. Notably, excretory proteins from Toxoplasma gondii (TgEP), recognized for their immunogenicity and broad spectrum of biological activities secreted or excreted during the parasite's lifecycle, have been identified as potential facilitators of osteogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs). Building on our previous findings that TgEP can enhance osteogenic differentiation, this study investigated the molecular mechanisms underlying this effect and assessed its therapeutic potential in vivo. METHODS: We determined the optimum concentration of TgEP through cell cytotoxicity and cell proliferation assays. Subsequently, hBMSCs were treated with the appropriate concentration of TgEP. We assessed osteogenic protein markers, including alkaline phosphatase (ALP), Runx2, and Osx, as well as components of the BMP/Smad signaling pathway using quantitative real-time PCR (qRT-PCR), siRNA interference of hBMSCs, Western blot analysis, and other methods. Furthermore, we created a bone defect model in Sprague-Dawley (SD) male rats and filled the defect areas with the GelMa hydrogel, with or without TgEP. Microcomputed tomography (micro-CT) was employed to analyze the bone parameters of defect sites. H&E, Masson and immunohistochemical staining were used to assess the repair conditions of the defect area. RESULTS: Our results indicate that TgEP promotes the expression of key osteogenic markers, including ALP, Runx2, and Osx, as well as the activation of Smad1, BMP2, and phosphorylated Smad1/5-crucial elements of the BMP/Smad signaling pathway. Furthermore, in vivo experiments using a bone defect model in rats demonstrated that TgEP markedly promoted bone defect repair. CONCLUSION: Our results provide compelling evidence that TgEP facilitates hBMSC osteogenic differentiation through the BMP/Smad signaling pathway, highlighting its potential as a therapeutic approach for bone tissue engineering for bone defect healing.


Assuntos
Diferenciação Celular , Células-Tronco Mesenquimais , Osteogênese , Ratos Sprague-Dawley , Transdução de Sinais , Toxoplasma , Células-Tronco Mesenquimais/metabolismo , Osteogênese/fisiologia , Humanos , Animais , Transdução de Sinais/fisiologia , Diferenciação Celular/fisiologia , Masculino , Toxoplasma/fisiologia , Ratos , Proteínas Smad/metabolismo , Proteínas de Protozoários/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Células Cultivadas
2.
Cancer Lett ; 596: 217018, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38844062

RESUMO

Relapse and treatment resistance pose significant challenges in the management of pediatric B cell acute lymphoblastic leukemia (B-ALL) and acute myeloid leukemia (AML). The efficacy of immunotherapy in leukemia remains limited due to factors such as the immunosuppressive tumor microenvironment (TME) and lack of suitable immunotherapeutic targets. Thus, an in-depth characterization of the TME in pediatric leukemia is warranted to improve the efficacy of immunotherapy. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the TME of pediatric B-ALL and AML, focusing specifically on bone-marrow-derived T cells. Moreover, we investigated the transcriptome changes during the initiation, remission, and relapse stages of pediatric AML. Our findings revealed that specific functional expression programs correlated with fluctuations in various T cell subsets, which may be associated with AML progression and relapse. Furthermore, our analysis of cellular communication networks led to the identification of VISTA, CD244, and TIM3 as potential immunotherapeutic targets in pediatric AML. Finally, we detected elevated proportions of γδ T cells and associated functional genes in samples from pediatric patients diagnosed with B-ALL and AML, which could inform the development of novel therapeutic approaches, potentially focusing on γδ T cells.


Assuntos
Leucemia Mieloide Aguda , Análise de Célula Única , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Análise de Célula Única/métodos , Criança , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Transcriptoma , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Perfilação da Expressão Gênica/métodos , Pré-Escolar , Masculino , Feminino , Antígenos B7/genética , Adolescente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Regulação Leucêmica da Expressão Gênica
5.
J Transl Med ; 22(1): 86, 2024 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-38246999

RESUMO

BACKGROUND: Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. METHOD: Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. RESULTS: The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation's Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. CONCLUSION: Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments.


Assuntos
Doenças Cardiovasculares , Ácido Oleanólico , Animais , Simulação de Acoplamento Molecular , Farmacologia em Rede , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , PPAR gama
6.
Food Chem Toxicol ; 183: 114307, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38052408

RESUMO

Uric acid (UA) is the final metabolite of purines in the liver that can cause hyperuricemia at high levels. The kidneys are the main excretory organs for UA. The excessive accumulation of UA in the kidneys causes the development of hyperuricemia that often leads to renal injury. Eupatilin (Eup) is a flavonoid natural product that possesses various pharmacological properties such as antioxidant, anti-cancer, and anti-inflammatory. We were interested in exploring the potential role of Eup in lowering UA and nephroprotective. We initially investigated the effects of Eup on xanthin oxidase (XOD) activity in vitro, followed by investigating its ability to lower UA levels, anti-inflammatory effects, nephroprotective effects, and the underlying mechanisms using hyperuricemia rats sustained at high UA level. The results showed that Eup had an inhibitory effect on XOD activity in vitro and significantly reduced serum UA, creatinine, BUN, IL-1ß and IL-6 levels in hyperuricemic rats, ameliorating inflammation, renal oxidative stress and pathological injury. Furthermore, Eup inhibited ADA and XOD enzyme activities in the liver and serum and modulated GLUT9, URAT1 and ABCG2 protein expression in the kidneys and ileum. Our findings provide a scientific basis for suggesting Eup as an option for a potential treatment for hyperuricemia.


Assuntos
Hiperuricemia , Ratos , Animais , Hiperuricemia/tratamento farmacológico , Hiperuricemia/metabolismo , Xantina Oxidase , Rim , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Ácido Úrico/metabolismo , Anti-Inflamatórios/farmacologia
7.
Int J Mol Med ; 52(4)2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37594122

RESUMO

Toxoplasma gondii excretory/secretory proteins (TgESPs) are a group of proteins secreted by the parasite and have an important role in the interaction between the host and Toxoplasma gondii (T. gondii). They can participate in various biological processes in different cells and regulate cellular energy metabolism. However, the effect of TgESPs on energy metabolism and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) has remained elusive. In the present study, TgESPs were extracted from the T. gondii RH strain and used to treat BMSCs to observe the effect of TgESPs on energy metabolism and osteogenic differentiation of BMSCs and to explore the molecular mechanisms involved. The osteogenic differentiation and energy metabolism of BMSCs were evaluated using Alizarin Red S staining, qRT-PCR, western blot, immunofluorescence and Seahorse extracellular flux assays. The results indicated that TgESPs activated the Wnt/ß­catenin signaling pathway to enhance glycolysis and lactate production in BMSCs, and promoted cell mineralization and expression of osteogenic markers. In conclusion, the present study uncovered the potential mechanism by which TgESPs regulate BMSCs, which will provide a theoretical reference for the study of the function of TgESPs in the future.


Assuntos
Células-Tronco Mesenquimais , Toxoplasma , Via de Sinalização Wnt , Osteogênese/genética , Diferenciação Celular , Glicólise
8.
J Obstet Gynaecol Res ; 49(10): 2436-2445, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37462066

RESUMO

AIM: The genetic basis of empty follicle syndrome (EFS) is largely unknown, and the aim of this study was to investigate the genetic causes of EFS in primary infertile women. METHODS: Four affected women diagnosed with anovulation were recruited, and whole exome sequencing (WES) was requested for the genetic diagnosis of the cases. One hundred healthy controls were verified by Sanger sequencing. RESULTS: A novel homozygous variant of the LHCGR gene (NM_000233:c.1847C>A) was revealed in one affected individual by WES. Trios analysis of the mutation revealed an autosomal recessive pattern. This LHCGR variant was absent in 100 healthy controls and predicted to be highly damaging to the function of LHCGR. CONCLUSIONS: The novel variant extends the mutational spectrum of the LHCGR gene associated with female sterility, which promotes the prognostic value of testing for LHCGR mutations in infertile women with EFS.


Assuntos
Infertilidade Feminina , Doenças Ovarianas , Humanos , Feminino , Infertilidade Feminina/genética , Mutação de Sentido Incorreto , Sequenciamento do Exoma , Mutação
9.
Clin Lymphoma Myeloma Leuk ; 23(9): 660-666, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37301632

RESUMO

Treatment outcomes for children with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) remained poor despite the use of intensive chemotherapy, imatinib or dasatinib, and consolidative allogeneic hematopoietic cell transplantation. Oleverembatinib, a third-generation ABL inhibitor, was found to be highly effective and safe in adults with chronic myeloid leukemia and in some adults with relapsed or refractory Ph+ ALL. We reviewed the efficacy and safety profile of olverembatinib treatment in 6 children with relapsed Ph+ ALL and 1 with T-ALL and ABL class fusion, all of whom had previously received dasatinib or intolerance to dasatinib. The median duration of olverembatinib treatment was 70 days (range: 4-340) and the median cumulative dose was 600 mg (range: 80-3810). Complete remission with negative minimal residual level (<0.01%) was achieved in 4 of the 5 evaluable patients, 2 of whom were treated with olvermbatinib as a single agent. Safety profile in 6 evaluable patients was excellent with grade 2 extremity pain occurred in 2 patients and grade 2 myopathy of lower extremity and grade 3 fever in 1 patient each. Olverembatinib appeared to be safe and effective in children with relapsed Ph+ ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Inibidores de Proteínas Quinases , Adulto , Humanos , Criança , Dasatinibe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas de Fusão bcr-abl/genética
10.
J Hypertens ; 41(8): 1323-1332, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37260264

RESUMO

BACKGROUND: Dysfunctional neurons and microglia in the rostral ventrolateral medulla (RVLM) have been implicated in the pathogenesis of stress-induced hypertension (SIH). Functional perturbation of microglial synaptic engulfment can induce aberrant brain circuit activity. IFN-γ is a pleiotropic cytokine that plays a role in regulating neuronal activity. However, existing research on the exploration of the effects of microglia on synapses in the RVLM is lacking, particularly on the function of IFN-γ in microglial synaptic engulfment involved in SIH. METHODS: A SIH rat model was established by electric foot shocks combined with noise stimulation. The underlying mechanism of IFN-γ on synaptic density and microglial synaptic engulfment was investigated through in-vivo and in-vitro experiments involving gain of function, immunofluorescence, quantitative real-time PCR, western blot, and morphometric analysis. Furthermore, the function of IFN-γ in neuronal activity, renal sympathetic nerve activity (RSNA), and blood pressure (BP) regulation was determined through in-vivo and in-vitro experiments involving Ca 2+ imaging, immunofluorescence, platinum-iridium electrode recording, ELISA, the femoral artery cannulation test, and the tail-cuff method. RESULTS: The BP, heart rate, RSNA, plasma norepinephrine, and the number of c-Fos-positive neurons in SIH rats increased compared with those in control rats. Pre and postsynaptic densities in the RVLM also increased in SIH rats. IFN-γ and CCL2 expression levels were significantly reduced in the RVLM of the SIH group, whose microglia also exhibited an impaired capacity for synapse engulfment. IFN-γ elevation increased CCL2 expression and microglial synaptic engulfment and decreased synaptic density in vivo and in vitro . However, CCL2 inhibition reversed these effects. Moreover, the reduction of neuronal excitability, RSNA, plasma norepinephrine, and BP by IFN-γ was abrogated through CCL2 expression. CONCLUSION: IFN-γ deficiency in the RVLM impaired the microglial engulfment of synapses by inhibiting CCL2 expression and increasing synaptic density and neuronal excitability, thereby contributing to SIH progression. Targeting IFN-γ may be considered a potential strategy to combat SIH.


Assuntos
Hipertensão , Microglia , Animais , Ratos , Pressão Sanguínea , Rim/inervação , Bulbo , Microglia/metabolismo , Microglia/patologia , Sistema Nervoso Simpático , Interferon gama/metabolismo
11.
J Neuroinflammation ; 20(1): 137, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37264405

RESUMO

BACKGROUND: Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been associated with the pathogenesis of stress-induced hypertension (SIH). Neuronal mitochondrial dysfunction is involved in many pathological and physiological processes. However, the impact of neuroinflammation on neuronal mitochondrial homeostasis and the involved signaling pathway in the RVLM during SIH are largely unknown. METHODS: The morphology and phenotype of microglia and the neuronal mitochondrial injury in vivo were analyzed by immunofluorescence, Western blot, RT-qPCR, transmission electron microscopy, and kit detection. The underlying mechanisms of microglia-derived tumor necrosis factor-α (TNF-α) on neuronal mitochondrial function were investigated through in vitro and in vivo experiments such as immunofluorescence and Western blot. The effect of TNF-α on blood pressure (BP) regulation was determined in vivo via intra-RVLM microinjection of TNF-α receptor antagonist R7050. RESULTS: The results demonstrated that BP, heart rate (HR), renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE), and electroencephalogram (EEG) power increased in SIH rats. Furthermore, the branching complexity of microglia in the RVLM of SIH rats decreased and polarized into M1 phenotype, accompanied by upregulation of TNF-α. Increased neuronal mitochondria injury was observed in the RVLM of SIH rats. Mechanistically, Sirtuin 3 (Sirt3) and p-AMPK expression were markedly downregulated in both SIH rats and TNF-α-treated N2a cells. AMPK activator A769662 upregulated AMPK-Sirt3 signaling pathway and consequently reversed TNF-α-induced mitochondrial dysfunction. Microinjection of TNF-α receptor antagonist R7050 into the RVLM of SIH rats significantly inhibited the biological activities of TNF-α, increased p-AMPK and Sirt3 levels, and alleviated neuronal mitochondrial injury, thereby reducing c-FOS expression, RSNA, plasma NE, and BP. CONCLUSIONS: This study revealed that microglia-derived TNF-α in the RVLM impairs neuronal mitochondrial function in SIH possibly through inhibiting the AMPK-Sirt3 pathway. Therefore, microglia-derived TNF-α in the RVLM may be a possible therapeutic target for the intervention of SIH.


Assuntos
Hipertensão , Sirtuína 3 , Ratos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Doenças Neuroinflamatórias , Microglia/metabolismo , Hipertensão/metabolismo , Pressão Sanguínea , Mitocôndrias/patologia , Bulbo/metabolismo
12.
Materials (Basel) ; 16(10)2023 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-37241284

RESUMO

The infinite effective thermal conductivity (IETC) can be considered to be an equivalence of the effective zero index in photonics. A recent highly rotating metadevice has been discovered to approach near IETC, subsequently demonstrating a cloaking effect. However, this near IETC, related to a rotating radius, is quite inhomogeneous, and the high-speed rotating motor also needs a high energy input, limiting its further applications. Herein, we propose and realize an evolution of this homogeneous zero-index thermal metadevice for robust camouflaging and super-expanding through out-of-plane modulations rather than high-speed rotation. Both the theoretical simulations and experiments verify a homogeneous IETC and the corresponding thermal functionalities beyond cloaking. The recipe for our homogeneous zero-index thermal metadevice involves an external thermostat, which can be easily adjusted for various thermal applications. Our study may provide meaningful insights into the design of powerful thermal metadevices with IETCs in a more flexible way.

13.
Neurobiol Dis ; 183: 106173, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37247681

RESUMO

Neuronal hyperexcitation in the rostral ventrolateral medulla (RVLM) drives heightened sympathetic nerve activity and contributes to the etiology of stress-induced hypertension (SIH). Maintenance of mitochondrial functions is central to neuronal homeostasis. PDZD8, an endoplasmic reticulum (ER) transmembrane protein, tethers ER to mitochondria. However, the mechanisms of PDZD8-mediated ER-mitochondria associations regulating neuronal mitochondrial functions and thereby mediating blood pressure (BP) in the RVLM of SIH were largely unknown. SIH rats were subjected to intermittent electric foot shocks plus noise for 2 h twice daily for 15 consecutive days. The underlying mechanisms of PDZD8 were investigated through in vitro experiments by using small interfering RNA and through in vivo experiments, such as intra-RVLM microinjection and Western blot analysis. The function of PDZD8 on BP regulation in the RVLM was determined in vivo via the intra-RVLM microinjection of adeno-associated virus (AAV)2-r-Pdzd8. We found that the c-Fos-positive RVLM tyrosine hydroxylase (TH) neurons, renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE) level, BP, and heart rate (HR) were elevated in SIH rats. ER-mitochondria associations in RVLM neurons were significantly reduced in SIH rats. PDZD8 was mainly expressed in RVLM neurons, and mRNA and protein levels were markedly decreased in SIH rats. In N2a cells, PDZD8 knockdown disrupted ER-mitochondria associations and mitochondrial structure, decreased mitochondrial membrane potential (MMP) and respiratory metabolism, enhanced ROS levels, and reduced catalase (CAT) activity. These effects suggested that PDZD8 dysregulation induced mitochondrial malfunction. By contrast, PDZD8 upregulation in the RVLM of SIH rats could rescue neuronal mitochondrial function, thereby suppressing c-Fos expression in TH neurons and decreasing RSNA, plasma NE, BP, and HR. Our results indicated that the dysregulation of PDZD8-mediated ER-mitochondria associations led to the loss of the activity homeostasis of RVLM neurons by disrupting mitochondrial functions, thereby participating in the regulation of SIH pathology.


Assuntos
Hipertensão , Ratos , Animais , Pressão Sanguínea , Hipertensão/etiologia , Hipertensão/metabolismo , Mitocôndrias/metabolismo , Antioxidantes/farmacologia , Neurônios/metabolismo , Homeostase , Retículo Endoplasmático/metabolismo , Bulbo/metabolismo
14.
Front Surg ; 10: 1172971, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37251579

RESUMO

Introduction: A case of subtrochanteric Seinsheimer II B fracture was retrospectively analyzed to determine the causes of failure and the possible problems with femoral reconstruction intramedullary nailing. Methods: This study focused on a case of an elderly patient with Seinsheimer type IIB fracture treated with minimally invasive femoral reconstruction intramedullary nailing. By retrospectively analyzing the intraoperative and postoperative course, we can identify the reasons that may lead to the surgical failure in order to avoid similar problems in the future. Result: It was observed that the nail was dislodged after surgery, and the broken end was displaced again. Through our analysis and research, we believe that non-anatomical reduction, deviation of needle insertion point, improper selection of surgical methods, mechanical and biomechanical effects, doctor-patient communication and non-die-cutting cooperation, and non-compliance with doctor's orders may be related to the success of surgery. Conclusion: Femoral reconstruction intramedullary nailing is used for the treatment of subtrochanteric Seinsheimer II B fractures; however, non-anatomical reduction, choice of needle insertion point, inappropriate choice of surgical method, mechanical and biomechanical effects, doctor-patient communication and cooperation without die-cutting, and non-compliance with doctor's advice may result in surgical failure. According to the analysis of individuals, under the premise of an accurate needle entry point, minimally invasive closed reduction PFNA or open reduction of broken ends and intramedullary nail ligation for femoral reconstruction can be used in Seinsheimer type IIB fractures. It can effectively avoid the instability of reduction and the insufficiency of the biomechanics caused by osteoporosis.

15.
Angew Chem Int Ed Engl ; 62(26): e202303539, 2023 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-37083315

RESUMO

Hypertension, as a leading risk factor for cardiovascular diseases, is associated with oxidative stress and impairment of endogenous antioxidant mechanisms, but there is still a tremendous knowledge gap between hypertension treatment and nanomedicines. Herein, we report a specific nanozyme based on ultrathin two-dimensional (2D) niobium carbide (Nb2 C) MXene, termed Nb2 C MXenzyme, to fight against hypertension by achieving highly efficient reactive oxygen species elimination and inflammatory factors inhibition. The biocompatible Nb2 C MXenzyme displays multiple enzyme-mimicking activities, involving superoxide dismutase, catalase, glutathione peroxidase, and peroxidase, inducing cytoprotective effects by resisting oxidative stress, thereby alleviating inflammatory response and reducing blood pressure, which is systematically demonstrated in a stress-induced hypertension rat model. This strategy not only opens new opportunities for nanozymes to treat hypertension but also expands the potential biomedical applications of 2D MXene nanosystems.


Assuntos
Antioxidantes , Hipertensão , Ratos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Catalase/metabolismo , Superóxido Dismutase/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio , Hipertensão/tratamento farmacológico
16.
J Autoimmun ; 136: 103026, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37001436

RESUMO

Acquired aplastic anemia (AA) is recognized as an immune-mediated disorder resulting from active destruction of hematopoietic cells in bone marrow (BM) by effector T lymphocytes. Bulk genomic landscape analysis and transcriptomic profiling have contributed to a better understanding of the recurrent cytogenetic abnormalities and immunologic cues associated with the onset of hematopoietic destruction. However, the functional mechanistic determinants underlying the complexity of heterogeneous T lymphocyte populations as well as their correlation with clinical outcomes remain to be elucidated. To uncover dysfunctional mechanisms acting within the heterogeneous marrow-infiltrating immune environment and examine their pathogenic interplay with the hematopoietic stem/progenitor pool, we exploited single-cell mass cytometry for BM mononuclear cells of severe AA (SAA) patients pre- and post-immunosuppressive therapy, in contrast to those of healthy donors. Alignment of BM cellular composition with hematopoietic developmental trajectories revealed potential functional roles for non-canonically activated CD4+ naïve T cells in newly-diagnosed pediatric cases of SAA. Furthermore, single-cell transcriptomic profiling highlighted a population of Th17-polarized CD4+CAMK4+ naïve T cells showing activation of the IL-6/JAK3/STAT3 pathway, while gene signature dissection indicated a predisposition to proinflammatory pathogenesis. Retrospective validation from our SAA cohort of 231 patients revealed high plasma levels of IL-6 as an independent risk factor of delayed hematopoietic response to antithymocyte globulin-based immunosuppressive therapy. Thus, IL-6 warrants further investigation as a putative therapeutic target in SAA.


Assuntos
Anemia Aplástica , Humanos , Criança , Anemia Aplástica/genética , Anemia Aplástica/patologia , Interleucina-6/genética , Estudos Retrospectivos , Células Th17 , Análise de Célula Única , Janus Quinase 3 , Fator de Transcrição STAT3/genética
17.
CNS Neurosci Ther ; 29(7): 1830-1847, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36852438

RESUMO

AIMS: The rostral ventrolateral medulla (RVLM) is an essential vasomotor center responsible for regulating the development of stress-induced hypertension (SIH). Long non-coding RNAs (lncRNAs) play critical roles in various physiopathology processes, but existing research on the functions of RVLM lncRNAs on SIH has been lacking. In this study, we investigated the roles of RVLM lncRNAs in SIH. METHODS: Genome-wide lncRNA profiles in RVLM were determined by RNA sequencing in a SIH rat model established using electric foot shocks plus noises. The hypotensive effect of lncRNA INPP5F and the underlying mechanisms of lncRNA INPP5F on SIH were explored through in vivo and in vitro experiments, such as intra-RVLM microinjection and immunofluorescence. RESULTS: We discovered 10,179 lncRNA transcripts, among which the lncRNA INPP5F expression level was significantly decreased in SIH rats. Overexpression of lncRNA INPP5F in RVLM dramatically reduced the blood pressure, sympathetic nerve activity, and neuronal excitability of SIH rats. LncRNA INPP5F overexpression markedly increased Cttn expression and reduced neural apoptosis by activating the PI3K-AKT pathway, and its inhibition had opposite effects. Mechanistically, lncRNA INPP5F acted as a sponge of miR-335, which further regulated the Cttn expression. CONCLUSION: LncRNA INPP5F was a key factor that inhibited SIH progression, and the identified lncRNA INPP5F/miR-335/Cttn/PI3K-AKT/apoptosis axis represented one of the possible mechanisms. LncRNA INPP5F could serve as a therapeutic target for SIH.


Assuntos
Hipertensão , MicroRNAs , RNA Longo não Codificante , Ratos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Hipertensão/genética , Hipertensão/metabolismo , Bulbo/metabolismo , Pressão Sanguínea , MicroRNAs/genética , MicroRNAs/metabolismo , Sistema Nervoso Simpático/metabolismo , Cortactina/metabolismo , Cortactina/farmacologia
18.
Front Med ; 17(3): 518-526, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36807106

RESUMO

Venous thromboembolism (VTE) is a complication in children with acute lymphoblastic leukemia (ALL). The Chinese Children's Cancer Group-ALL-2015 protocol was carried out in China, and epidemiology, clinical characteristics, and risk factors associated with VTE were analyzed. We collected data on VTE in a multi-institutional clinical study of 7640 patients with ALL diagnosed in 20 hospitals from January 2015 to December 2019. First, VTE occurred in 159 (2.08%) patients, including 90 (56.6%) during induction therapy and 108 (67.92%) in the upper extremities. T-ALL had a 1.74-fold increased risk of VTE (95% CI 1.08-2.8, P = 0.022). Septicemia, as an adverse event of ALL treatment, can significantly promote the occurrence of VTE (P < 0.001). Catheter-related thrombosis (CRT) accounted for 75.47% (n = 120); and, symptomatic VTE, 58.49% (n = 93), which was more common in patients aged 12-18 years (P = 0.023), non-CRT patients (P < 0.001), or patients with cerebral thrombosis (P < 0.001). Of the patients with VTE treated with anticoagulation therapy (n = 147), 4.08% (n = 6) had bleeding. The VTE recurrence rate was 5.03% (n = 8). Patients with VTE treated by non-ultrasound-guided venous cannulation (P = 0.02), with residual thrombus (P = 0.006), or with short anticoagulation period (P = 0.026) had high recurrence rates. Thus, preventing repeated venous puncture and appropriately prolonged anticoagulation time can reduce the risk of VTE recurrence.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Trombose , Tromboembolia Venosa , Humanos , Criança , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , População do Leste Asiático , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Fatores de Risco , Trombose/induzido quimicamente , China/epidemiologia , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Recidiva
19.
Int J Med Sci ; 19(13): 1879-1887, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36438924

RESUMO

Docosahexaenoic acid (DHA) has been reported potentiate osteogenic differentiation, while Docosapentaenoic acid (DPA), another Omega-3 fatty acid, its contribution to the osteogenic differentiation of human bone-marrow-derived mesenchymal stromal cells (hBMSCs) is not entirely elucidated. The Alizarin Red S (ARS) staining and the expression of osteogenesis­associated genes were analyzed during osteogenic induction by DPA. Then, bioinformatics analysis and dual luciferase reporter assays were investigated to confirm the interactions between miR-9-5p and alkaline phosphatase (ALP). miR-9-5p mimics / inhibitor were transfected to human hBMSCs and the osteogenic assay above was also performed. Furthermore, DPA significantly promoted the phosphorylation of ERK via miR-9-5p. PD98059, a highly specific and potent ERK1/2 inhibitor, inhibited the activation of ALP and partially reversed the role of DPA during osteogenic differentiation. These data indicated that DPA promoted osteogenic differentiation of hBMSCs potentially through miR-9-5p/ERK/ALP signaling pathway, providing a potentially useful therapeutic strategy for patients to improve bone loss.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Humanos , Osteogênese/genética , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Células Cultivadas , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais/genética
20.
Histol Histopathol ; 37(8): 769-777, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35229281

RESUMO

Asiatic acid can attenuate osteoporosis through suppressing adipogenic differentiation and osteoclastic differentiation. Oxidative stress enhances osteoclastic differentiation but represses osteogenic differentiation to promote osteoporosis. However, the role and mechanism of asiatic acid in osteoporosis have not been reported. Firstly, mice were fed with high-fat-diet (HFD) with or without asiatic acid for 16 weeks. Data from an automatic biochemical analyzer showed that HFD induced down-regulation of high-density lipoprotein (HDL) and an increase of serum levels of triglyceride (TG), total cholesterol (TC) and low-density lipoprotein (LDL). However, asiatic acid administration attenuated the decrease of HDL and increase of serum TG, TC and LDL in osteoporotic mice. Secondly, HFD induced high levels of malondialdehyde (MDA) and reactive oxygen species (ROS), low levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in osteoporotic mice. However, the levels of MDA, ROS, SOD and GSH-Px in osteoporotic mice were reversed by asiatic acid administration. (this section is unclear and requires revision) Asiatic acid administration reduced expression of c-telopeptide of type 1 collagen (CTX-1), enhanced alkaline phosphatase (ALP) and procollagen type 1 N-terminal propeptide (P1NP) in HFD-induced osteoporotic mice. (this section is unclear and requires revision) Thirdly, asiatic acid promoted calcium deposition in bone marrow cells and osteogenic differentiation in osteoporotic mice, but decreased ALP in bone marrow cells. Lastly, asiatic acid enhanced SIRT1 and nuclear FOXO1 (Nu-FOXO1) expression, while it reduced Acetyl FOXO1 (Ac-FOXO1) in osteoporotic mice. In conclusion, asiatic acid might inhibit oxidative stress and promote osteogenic differentiation through activating SIRT1/FOXO1 to attenuate HFD-induced osteoporosis in mice.


Assuntos
Osteoporose , Sirtuína 1 , Fosfatase Alcalina/metabolismo , Animais , Cálcio/metabolismo , Colesterol , Colágeno Tipo I/metabolismo , Dieta Hiperlipídica/efeitos adversos , Proteína Forkhead Box O1 , Glutationa Peroxidase/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Malondialdeído , Camundongos , Osteogênese , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osteoporose/prevenção & controle , Estresse Oxidativo , Triterpenos Pentacíclicos , Pró-Colágeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Superóxido Dismutase/metabolismo , Triglicerídeos
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