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Nonimmune cells can have immunomodulatory roles that contribute to healthy development. However, the molecular and cellular mechanisms underlying the immunomodulatory functions of erythroid cells during human ontogenesis remain elusive. Here, integrated, single-cell transcriptomic studies of erythroid cells from the human yolk sac, fetal liver, preterm umbilical cord blood (UCB), term UCB and adult bone marrow (BM) identified classical and immune subsets of erythroid precursors with divergent differentiation trajectories. Immune-erythroid cells were present from the yolk sac to the adult BM throughout human ontogenesis but failed to be generated in vitro from human embryonic stem cells. Compared with classical-erythroid precursors, these immune-erythroid cells possessed dual erythroid and immune regulatory networks, showed immunomodulatory functions and interacted more frequently with various innate and adaptive immune cells. Our findings provide important insights into the nature of immune-erythroid cells and their roles during development and diseases.
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Células Precursoras Eritroides , Transcriptoma , Adulto , Diferenciación Celular/genética , Células Eritroides , Sangre Fetal , Humanos , Recién Nacido , Saco VitelinoRESUMEN
Hypoxia has become one of the most critical factors limiting the development of aquaculture. Crucian carp (Carassius auratus) is widely consumed fish in China, with excellent tolerance to hypoxic environment. However, the molecular mechanisms underlying hypoxia adaptation and tolerance in crucian carp remain unclear. Compared with the control, increased T-SOD, CAT, GSH-Px, T-AOC, ALT, and AST activities and MDA, TCHO, and TG contents, and decreased TP and ATP contents were observed after hypoxia stress. Based on RNA-seq, 2479 differentially expressed (DE) mRNAs and 60 DE miRNAs were identified, and numerous DE mRNAs involved in HIF signaling pathway (hif-1α, epo, vegfa, and ho), anaerobic metabolism (hk1/hk2, pfk, gapdh, pk, and ldh) and immune response (nlrp12, cxcr1, cxcr4, ccr9, and cxcl12) were significantly upregulated after hypoxia exposure. Integrated analysis found that ho, igfbp1, hsp70, and hk2 were predicted to be regulated by novel_867, dre-miR-125c-3p/novel_173, dre-miR-181b-5p, and dre-miR-338-5p/dre-miR-17a-3p, respectively, and targets of DE miRNAs were significantly enriched in MAPK signaling pathway, FoxO signaling pathway, and glycolysis/gluconeogenesis. Expression analysis showed that the mRNA levels of vegfa, epo, ho, hsp70, hsp90aa.1, igfbp1, ldh, hk1, pfk, pk, and gapdh exhibited a remarkable increase, whereas sdh and mdh were downregulated in the H3h, H12h, and H24h groups compared with the control. Furthermore, research found that hk2 is a target of dre-miR-17a-3p, overexpression of dre-miR-17a-3p significantly decreased the expression level of hk2, while the opposite results were obtained after dre-miR-17a-3p silencing. These results contribute to our understanding of the molecular mechanisms of hypoxia tolerance in crucian carp.
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MicroARNs , ARN Mensajero , Animales , MicroARNs/genética , MicroARNs/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Carpas/genética , Carpas/metabolismo , Hipoxia/metabolismo , Hipoxia/genética , Estrés Fisiológico , Transducción de Señal , Proteínas de Peces/genética , Proteínas de Peces/metabolismo , Carpa Dorada/genética , Carpa Dorada/metabolismoRESUMEN
Phospholipase A2 receptor 1 (PLA2R1) plays a crucial role in various diseases, including membranous nephropathy. However, the precise implications of PLA2R1 deficiency remain poorly understood. In this study, we created PLA2R1 knockout rats to explore potential consequences resulting from the loss of the PLA2R1 gene. Unexpectedly, our PLA2R1 knockout rats exhibited symptoms resembling those of chronic kidney disease after an 8-week observation period. Notably, several rats developed persistent proteinuria, a hallmark of renal dysfunction. Immunohistochemical and immunofluorescence analyses revealed insignificant glomerular fibrosis, reduced podocyte count, and augmented glomerular expression of complement C3 (C3) compared to immunoglobin A (IgA) and immunoglobin G(IgG) in the rat model. These findings suggest that the loss of PLA2R1 may contribute to the pathogenesis of membranous nephropathy and related conditions. Our knockout rat model provides a valuable tool for investigating the underlying pathology of PLA2R1-associated diseases, and may facilitate the development of targeted therapies for membranous nephropathy and other related disorders.
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Glomerulonefritis Membranosa , Receptores de Fosfolipasa A2 , Animales , Ratas , Autoanticuerpos , Glomerulonefritis Membranosa/genética , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/metabolismo , Receptores de Fosfolipasa A2/genética , Receptores de Fosfolipasa A2/metabolismoRESUMEN
The enhancement of sensitivity in biological analysis detection can reduce the probability of false positives of the biosensor. In this work, a novel self-on controlled-release electrochemiluminescence (CRE) biosensor was designed by multiple signal amplification and framework-enhanced stability strategies. As a result, the changes of the ECL signal were enhanced before and after the controlled-release process, achieving sensitive detection of prostate-specific antigen (PSA). Specifically, for one thing, Fe3O4@CeO2-NH2 with two paths for enhancing the generation of coreactant radicals was used as the coreaction accelerator to boost ECL performance. For another, due to the framework stability, zeolitic imidazolate framework-8-NH2 (ZIF-8-NH2) was combined with luminol to make the ECL signal more stable. Based on these strategies, the constructed CRE biosensor showed a strong self-on effect in the presence of PSA and high sensitivity in a series of tests. The detection range and limit of detection (LOD) were 5 fg/mL to 10 ng/mL and 2.8 fg/mL (S/N = 3), respectively, providing a feasible approach for clinical detection of PSA.
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Técnicas Biosensibles , Técnicas Electroquímicas , Mediciones Luminiscentes , Antígeno Prostático Específico , Antígeno Prostático Específico/análisis , Antígeno Prostático Específico/sangre , Técnicas Biosensibles/métodos , Técnicas Electroquímicas/métodos , Humanos , Límite de Detección , Masculino , Cerio/química , Luminol/químicaRESUMEN
Viral infections can result in metabolism rewiring of host cells, which in turn affects the viral lifecycle. Phosphoenolpyruvate (PEP), a metabolic intermediate in the glycolytic pathway, plays important roles in several biological processes including anti-tumor T cell immunity. However, whether PEP might participate in modulating viral infection remains largely unknown. Here, we demonstrate that PEP generally inhibits viral replication via upregulation of apoptosis-associated tyrosine kinase (AATK) expression. Targeted metabolomic analyses have shown that the intracellular level of PEP was increased upon viral infection. PEP treatment significantly restricted viral infection and hence declined subsequent inflammatory response both in vitro and in vivo. Besides, PEP took inhibitory effect on the stage of viral replication and also decreased the mortality of mice with viral infection. Mechanistically, PEP significantly promoted the expression of AATK. Knockdown of AATK led to enhanced viral replication and consequent increased levels of cytokines. Moreover, AATK deficiency disabled the antiviral effect of PEP. Together, our study reveals a previously unknown role of PEP in broadly inhibiting viral replication by promoting AATK expression, highlighting the potential application of activation or upregulation of the PEP-AATK axis in controlling viral infections.
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Glucólisis , Virosis , Ratones , Animales , Fosfoenolpiruvato/farmacologíaRESUMEN
Metallic 1T-MoS2 with high intrinsic electronic conductivity performs Pt-like catalytic activity for hydrogen evolution reaction (HER). However, obtaining pure 1T-MoS2 is challenging due to its high formation energy and metastable properties. Herein, an in situ SO4 2--anchoring strategy is reported to synthesize a thin layer of 1T-MoS2 loaded on commercial carbon. Single Pd atoms, constituting a substantial loading of 7.2 wt%, are then immobilized on the 1T-phase MoS2 via PdâS bonds to modulate the electronic structure and ensure a stable active phase. The resulting Pd1/1T-MoS2/C catalyst exhibits superior HER performance, featuring a low overpotential of 53 mV at the current density of 10 mA cm-2, a small Tafel slope of 37 mV dec-1, and minimal charge transfer resistance in alkaline electrolyte. Moreover, the catalyst also demonstrates efficacy in acid and neutral electrolytes. Atomic structural characterization and theoretical calculations reveal that the high activity of Pd1/1T-MoS2/C is attributed to the near-zero hydrogen adsorption energy of the activated sulfur sites on the two adjacent shells of atomic Pd.
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INTRODUCTION: Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by joint inflammation and bone damage, that not only restricts patient activity but also tends to be accompanied by a series of complications, seriously affecting patient prognosis. Peroxisome proliferator-activated receptor gamma (PPARG), a receptor that controls cellular metabolism, regulates the function of immune cells and stromal cells. Previous studies have shown that PPARG is closely related to the regulation of inflammation. However, the role of PPARG in regulating the pathological processes of RA is poorly understood. MATERIALS AND METHODS: PPARG expression was examined in the synovial tissues and peripheral blood mononuclear cells (PBMCs) from RA patients and the paw of collagen-induced arthritis (CIA) model rats. Molecular biology experiments were designed to examine the effect of PPARG and cannabidiol (CBD) on RAW264.7 cells and CIA rats. RESULTS: The results reveal that PPARG accelerates reactive oxygen species (ROS) clearance by promoting autophagy, thereby inhibiting ROS-mediated macrophage polarization and NLRP3 inflammasome activation. Notably, CBD may be a promising candidate for understanding the mechanism by which PPARG regulates autophagy-mediated inflammation. CONCLUSIONS: Taken together, these findings indicate that PPARG may have a role for distinguishing between RA patients and healthy control, and for distinguishing RA activity; moreover, PPARG could be a novel pharmacological target for alleviating RA through the mediation of autophagy. CBD can act as a PPARG agonist that alleviates the inflammatory progression of RA.
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Artritis Experimental , Artritis Reumatoide , Autofagia , Inflamación , PPAR gamma , Especies Reactivas de Oxígeno , Animales , Femenino , Humanos , Masculino , Ratones , Ratas , Artritis Experimental/inmunología , Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Artritis Reumatoide/inmunología , Autofagia/efectos de los fármacos , Cannabidiol/farmacología , Modelos Animales de Enfermedad , Inflamasomas/metabolismo , Inflamación/metabolismo , Inflamación/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , PPAR gamma/metabolismo , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismoRESUMEN
We observe significant orbital angular momentum (OAM)-helicity-dependent centroid shifts in the Fraunhofer patterns for the far-field diffraction of optical vortex beams passing through a thin single wire, thus suggesting the orbital Hall effect (OHE) of light in diffraction. Based on the OHE with a thin cross wire, we further experimentally develop a compact and robust alignment-free method to measure the OAM states of light. These findings indicate that not only does the OHE of light offer insights into vortex diffraction with broken rotational symmetry, it may also provide a reliable and efficient way to simplify the vortex measurement for waves of different natures.
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Extracellular traps (ETs) are a specialized form of innate immune defense in which leukocytes release ETs composed of chromatin and active proteins to eliminate pathogenic microorganisms. In addition to the anti-infection effect of ETs, researchers have also discovered their involvement in the pathogenesis of inflammatory disease, tumors, autoimmune disease, and allergic disease. Asthma is a chronic airway inflammatory disease involving multiple immune cells. The increased level of ETs in asthma patients suggests that ETs play an important role in the pathogenesis of asthma. Here we review the research work on the formation mechanism, roles, and therapeutic strategies of ETs released by neutrophils, eosinophils, and macrophages in asthma.
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Asma , Eosinófilos , Trampas Extracelulares , Macrófagos , Neutrófilos , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunología , Humanos , Asma/inmunología , Asma/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , AnimalesRESUMEN
Because of its high specific capacity and superior rate performance, porous carbon is regarded as a potential anode material for lithium-ion batteries (LIBs). However, porous carbon materials with wide pore diameter distributions suffer from low structural stability and low electrical conductivity during the application process. During this study, the calcium carbonate nanoparticle template method is used to prepare coal tar pitch-derived porous carbon (CTP-X). The coal tar pitch-derived porous carbon has a well-developed macroporous-mesoporous-microporous hierarchical porous network structure, which provides abundant active sites for Li+ storage, significantly reduces polarization and charge transfer resistance, shortens the diffusion path and promotes the rapid transport of Li+. More specifically, the CTP-2 anode shows high charge capacity (496.9â mAh g-1 at 50â mA g-1), excellent rate performance (413.6â mAh g-1 even at 500â mA g-1), and high cycling stability (capacity retention rate of about 100 % after 1,000 cycles at 2â A g-1). The clean and eco-friendly large-scale utilization of coal tar pitch will facilitate the development of high-performance anodes in the field of LIBs.
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OBJECTIVE: The aim of this study was to investigate the relationship between thyroid autoantibodies (TGAb and TPOAb) and X chromosome monosomy in the chorionic tissue of patients with missed early miscarriage. METHODS: The baseline data, thyroid function, thyroid antibody and the chromosomes from the chorionic tissue of 228 patients with missed early miscarriage were examined. RESULTS: (1) Among the 228 patients, 121 had a normal chromosome number, and 107 had an abnormal chromosome number. The majority of them were autosomal trisomy, of which trisomy 16 (40.19%) was predominant. Sex chromosome monosomy (28.04%) was secondary. (2) Among the 228 patients, 208 patients in this study had normal thyroid function (including 134 cases of negative thyroid antibodies and 74 cases of positive thyroid antibodies alone); 6 patients had abnormal thyroid function (including 2 cases of clinical hyperthyroidism, 3 cases of subclinical hypothyroidism, 1 case of hypothyroxinemia); and 14 patients had normal TSH and elevated T4 alone.(3) After exclusion of patients with thyroid function abnormalities, there were no significant differences in baseline data between the normal chromosome group and the abnormal chromosome group (P > 0.05). However, there was a significant difference in TGAb and TPOAb between the normal chromosome and abnormal chromosome group with 45, X karyotype, with a higher proportion of TGAb and/or TPOAb positivity in the 45, X karyotype group (P < 0.05). Additionally, compared to TGAb and/or TPOAb-positive patients, the risk of X chromosome monosomy was significantly reduced in TGAb and TPOAb-negative patients (P < 0.05). Moreover, both TGAb and TPOAb titer values in the X chromosome monosomy group were higher than those in the chromosomally normal group (P < 0.05). CONCLUSION: There is a correlation between TGAb, TPOAb and X chromosome monosomy in the chorionic tissue of patients with missed early miscarriage, although the mechanism remains to be further investigated.
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Autoanticuerpos , Cromosomas Humanos X , Monosomía , Humanos , Femenino , Adulto , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Cromosomas Humanos X/genética , Embarazo , Monosomía/genética , Aborto Retenido/genética , Aborto Retenido/sangre , Corion , Glándula Tiroides/inmunología , Adulto JovenRESUMEN
Methyltransferase like 3 (METTL3), a primary N6-methyladenosine (m6A) methyltransferase, has been implicated in various biological and pathological processes including immune responses. However, the functions and mechanisms of METTL3 in pathogenic T helper (Th)17 cells are poorly understood. Here we found significantly decreased METTL3 expression along with reduced m6A levels in eyeballs and T cells of experimental autoimmune uveitis (EAU). Overexpression of METTL3 ameliorated the development of EAU and suppressed pathogenic Th17 cell responses in vivo and in vitro. Mechanistically, METTL3 promoted the expression of absent, small, or homeotic-like 1 (ASH1L) via enhancing its stability in a YT521-B homology domain containing 2 (YTHDC2)-dependent manner, which further decreased the expression of IL-17 and IL-23 receptor (IL-23R), resulting in reduced pathogenic Th17 responses. Together, our data reveal a pivotal role of METTL3 in regulating pathogenic Th17 responses, which may contribute to human uveitis therapy.
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Proteínas de Unión al ADN , N-Metiltransferasa de Histona-Lisina , Metiltransferasas , Células Th17 , Uveítis , Proteínas de Unión al ADN/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , ARN Mensajero/genética , Uveítis/genética , Uveítis/metabolismo , Animales , Enfermedades Autoinmunes , Modelos Animales de EnfermedadRESUMEN
Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer's disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry-the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer's disease, and microproteins.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/metabolismo , ADN Mitocondrial/genética , Biomarcadores/líquido cefalorraquídeo , MicropéptidosRESUMEN
BACKGROUND: Extracellular ATP-AMP-adenosine metabolism plays a pivotal role in modulating tumor immune responses. Previous studies have shown that the conversion of ATP to AMP is primarily catalysed by Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39), a widely studied ATPase, which is expressed in tumor-associated immune cells. However, the function of ATPases derived from tumor cells themselves remains poorly understood. The purpose of this study was to investigate the role of colon cancer cell-derived ATPases in the development and progression of colon cancer. METHODS: Bioinformatic and tissue microarray analyses were performed to investigate the expression of ATPase family members in colon cancer. An ATP hydrolysis assay, high-performance liquid chromatography (HPLC), and CCK8 and colony formation assays were used to determine the effects of ENTPD2 on the biological functions of colon cancer cells. Flow cytometric and RNA-seq analyses were used to explore the function of CD8+ T cells. Immunoelectron microscopy and western blotting were used to evaluate the expression of ENTPD2 in exosomes. Double-labelling immunofluorescence and western blotting were used to examine the expression of ENTPD2 in serum exosomes and colon cancer tissues. RESULTS: We found that ENTPD2, rather than the well-known ATPase CD39, is highly expressed in cancer cells and is significantly positively associated with poor patient prognosis in patients with colon cancer. The overexpression of ENTPD2 in cancer cells augmented tumor progression in immunocompetent mice by inhibiting the function of CD8+ T cells. Moreover, ENTPD2 is localized primarily within exosomes. On the one hand, exosomal ENTPD2 reduces extracellular ATP levels, thereby inhibiting P2X7R-mediated NFATc1 nuclear transcription; on the other hand, it facilitates the increased conversion of ATP to adenosine, hence promoting adenosine-A2AR pathway activity. In patients with colon cancer, the serum level of exosomal ENTPD2 is positively associated with advanced TNM stage and high tumor invasion depth. Moreover, the level of ENTPD2 in the serum exosomes of colon cancer patients is positively correlated with the ENTPD2 expression level in paired colon cancer tissues, and the ENTPD2 level in both serum exosomes and tissues is significantly negatively correlated with the ENTPD2 expression level in tumor-infiltrating CD8+ T cells. CONCLUSION: Our study suggests that exosomal ENTPD2, originated from colon cancer cells, contributes to the immunosuppressive microenvironment by promoting ATP-adenosine metabolism. These findings highlight the importance of exosome-derived hydrolytic enzymes as independent entities in shaping the tumor immune microenvironment.
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Adenosina Trifosfatasas , Linfocitos T CD8-positivos , Neoplasias del Colon , Exosomas , Animales , Femenino , Humanos , Masculino , Ratones , Adenosina Trifosfato/metabolismo , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , Exosomas/metabolismo , Reprogramación Metabólica , Receptor de Adenosina A2A , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismoRESUMEN
The poor delivery efficiency of nanotherapeutic drugs and their potential off-target toxicity significantly limit their effectiveness and extensive application. An active targeting system with high efficiency and few side effects is a promising strategy for tumor therapy. Herein, a multifunctional nanomedicine Nb2C-PAA-DOX@Apt-M (NDA-M) was constructed for targeted photothermal/chemotherapy (PTT/CHT) combined tumor therapy. The specific targeting ability of aptamer could effectively enhance the absorption of nanomedicine by the MCF-7 cell. By employing Apt-M, the NDA-M nanosheets demonstrated targeted delivery to MCF-7 cells, resulting in enhanced intracellular drug concentration. Under 1060 nm laser irradiation, a rapid temperature increase of the NDA-M was observed within the tumor region to achieve PTT. Meanwhile, CHT was triggered when DOX release was induced by photothermal/acid stimulation. The experimental results demonstrated that aptamer-mediated targeting achieved enhanced PTT/CHT efficacy both in vitro and in vivo. Notably, NDA-M induced complete ablation of solid tumors without any adverse side effects in mice. This study demonstrated new and promising tactics for the development of nanomaterials for targeted tumor therapy.
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Aptámeros de Nucleótidos , Doxorrubicina , Nanomedicina , Terapia Fototérmica , Humanos , Animales , Ratones , Aptámeros de Nucleótidos/química , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/farmacología , Células MCF-7 , Femenino , Nanomedicina/métodos , Terapia Fototérmica/métodos , Ratones Endogámicos BALB C , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Terapia Combinada/métodosRESUMEN
Radiotherapy is essential to cancer treatment, while it inevitably injures surrounding normal tissues, and bone tissue is one of the most common sites prone to irradiation. Bone marrow mesenchymal stem cells (BMMSCs) are sensitive to irradiation and the irradiated dysfunction of BMMSCs may be closely related to irradiation-induced bone damage. Macropahges play important role in regulating stem cell function, bone metabolic balance and irradiation response, but the effects of macrophages on irradiated BMMSCs are still unclear. This study aimed to investigate the role of macrophages and macrophage-derived exosomes in restoring irradiated BMMSCs function. The effects of macrophage conditioned medium (CM) and macrophage-derived exosomes on osteogenic and fibrogenic differentiation capacities of irradiated BMMSCs were detected. The key microribonucleic acids (miRNAs) and targeted proteins in exosomes were also determined. The results showed that irradiation significantly inhibited the proliferation of BMMSCs, and caused differentiation imbalance of BMMSCs, with decreased osteogenic differentiation and increased fibrogenic differentiation. M2 macrophage-derived exosomes (M2D-exos) inhibited the fibrogenic differentiation and promoted the osteogenic differentiation of irradiated BMMSCs. We identified that miR-142-3p was significantly overexpressed in M2D-exos and irradiated BMMSCs treated with M2D-exos. After inhibition of miR-142-3p in M2 macrophage, the effects of M2D-exos on irradiated BMMSCs differentiation were eliminated. Furthermore, transforming growth factor beta 1 (TGF-ß1), as a direct target of miR-142-3p, was significantly decreased in irradiated BMMSCs treated with M2D-exos. This study indicated that M2D-exos could carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-ß1. These findings pave a new way for promising and cell-free method to treat irradiation-induced bone damage.
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Exosomas , Células Madre Mesenquimatosas , MicroARNs , MicroARNs/genética , MicroARNs/metabolismo , Osteogénesis , Factor de Crecimiento Transformador beta1/metabolismo , Exosomas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Macrófagos/metabolismoRESUMEN
BACKGROUND: Ku70 participates in several pathological processes through mediating repair of DNA double-strand breaks. Our previous study has identified a highly conserved long noncoding RNA cardiac ischemia reperfusion associated Ku70 interacting lncRNA (CIRKIL) that was upregulated in myocardial infarction. The study aims to investigate whether CIRKIL regulates myocardial ischemia/reperfusion (I/R) through binding to Ku70. METHODS: CIRKIL transgenic and knockout mice were subjected to 45-minute ischemia and 24-hour reperfusion to establish myocardial I/R model. RNA pull-down and RNA immunoprecipitation assay were used to detect the interaction between CIRKIL and Ku70. RESULTS: The expression of CIRKIL was increased in I/R myocardium and H2O2-treated cardiomyocytes. Overexpression of CIRKIL increased the expression of γH2A.X, a specific marker of DNA double-strand breaks and aggravated cardiomyocyte apoptosis, whereas knockdown of CIRKIL produced the opposite changes. Transgenic overexpression of CIRKIL aggravated cardiac dysfunction, enlarged infarct area, and worsened cardiomyocyte damage in I/R mice. Knockout of CIRKIL alleviated myocardial I/R injury. Mechanistically, CIRKIL directly bound to Ku70 to subsequently decrease nuclear translocation of Ku70 and impair DNA double-strand breaks repair. Concurrent overexpression of Ku70 mitigated CIRKIL overexpression-induced myocardial I/R injury. Furthermore, knockdown of human CIRKIL significantly suppressed cell damage induced by H2O2 in adult human ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: CIRKIL is a detrimental factor in I/R injury acting via regulating nuclear translocation of Ku70 and DNA double-strand breaks repair. Thus, CIRKIL might be considered as a novel molecular target for the treatment of cardiac conditions associated with I/R injury.
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Enfermedad de la Arteria Coronaria , Células Madre Pluripotentes Inducidas , Infarto del Miocardio , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , ARN Largo no Codificante , Animales , Apoptosis , Enfermedad de la Arteria Coronaria/metabolismo , ADN/metabolismo , Humanos , Peróxido de Hidrógeno/toxicidad , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Ratones Noqueados , Infarto del Miocardio/metabolismo , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ReperfusiónRESUMEN
A type of fermented bile acids (FBAs) has been produced through a biological method, and its effects on growth performance, metabolism, and intestinal microbiota in largemouth bass were investigated. The results demonstrated that incorporating 0.03 %-0.05 % FBAs diet could improve the final weight, weight gain and specific growth rate, and decrease the feed conversion ratio. Dietary FBAs did not significantly affect the levels of high-density lipoprotein, low-density lipoprotein, and triglycerides, but decreased the activities of α-amylase in most groups. Adding FBAs to the diet significantly increased the integrity of the microscopic structure of the intestine, thickened the muscular layer of the intestine, and notably enhanced its intestinal barrier function. The addition of FBAs to the diet increased the diversity of the gut microbiota in largemouth bass. At the phylum level, there was an increase in the abundance of Proteobacteria, Firmicutes, Tenericutes and Cyanobacteria and a significant decrease in Actinobacteria and Bacteroidetes. At the genus level, the relative abundance of beneficial bacteria Mycoplasma in the GN6 group and Coprococcus in the GN4 group significantly increased, while the pathogenic Enhydrobacter was inhibited. Meanwhile, the highest levels of AKP and ACP were observed in the groups treated with 0.03 % FBAs, while the highest levels of TNF-α and IL-10 were detected in the group treated with 0.04 % FBAs. Additionally, the highest levels of IL-1ß, IL-8T, GF-ß, IGF-1, and IFN-γ were noted in the group treated with 0.06 % FBAs. These results suggested that dietary FBAs improved growth performance and intestinal wall health by altering lipid metabolic profiles and intestinal microbiota in largemouth bass.
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Alimentación Animal , Lubina , Ácidos y Sales Biliares , Dieta , Microbioma Gastrointestinal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ácidos y Sales Biliares/metabolismo , Alimentación Animal/análisis , Lubina/crecimiento & desarrollo , Lubina/inmunología , Dieta/veterinaria , Intestinos/microbiología , Fermentación , Metaboloma , Suplementos Dietéticos/análisis , Distribución AleatoriaRESUMEN
INTRODUCTION: Steroid-refractory cGVHD (SR-cGVHD) presents new great challenges for treatment. We have reported imatinib monotherapy was effective to SR-cGVHD, but the CR rate was not satisfactory and the benefit was not showed specific to some target organs, previously. Imatinib and statin drugs have been recognized to regulate T-cell function, statins also have been demonstrated endothelia protection, but whether this combination therapy was able to improve the efficacy remains unknown. Therefore, we designed this prospective, single-arm, open-label trial to investigate the efficacy of imatinib-based combination therapy in the treatment of SR-cGVHD for the first time. METHODS: 60 SR-cGVHD patients were entered into this trial to investigated the combination of imatinib mesylate and atorvastatin calcium for the treatment of SR-cGVHD. The primary endpoint included the overall response rate (ORR) after 6 months of combined treatment. The secondary endpoints included an evaluation of survival, changes in T-cell subsets and adverse events. RESULTS: At baseline, 45% (27/60) of patients had moderate cGVHD, and 55.0% (33/60) of patients had severe cGVHD. At the 6-month follow-up, a clinical response was achieved in 70.0% of patients, and a complete response (CR) was achieved in 26.7%. A total of 11.7% (7/60) of patients stopped immunosuppressive therapy at this point. After 6 months of treatment, the ORR rates of the liver, skin, eyes and oral cavity were 80.6%, 78.1%, 61.5%, and 60.9%, respectively, with the liver also having the highest CR of 58.1%. The patients with moderate cGVHD had a better CR rate than those with severe cGVHD (55.6% vs. 3.0%, P<0.0001). The overall survival in patients who with ORR was improved (P = 0.0106). Lung involvement is an independent risk factor to affected ORR achievement (P = 0.021, HR = 0.335, 95%CI 0.133-0.847), and the dosage of steroids was reduced in ORR patients. In clinical response patients, the ratio of CD8+ T cells (P = 0.0117) and Th17 cells (P = 0.0171) decreased, while the number of Treg cells (P = 0.0147) increased after 3 months. The most common adverse events were edema, nausea, and neutropenia which were 13.3%, 11.7%, and 11.7%, respectively. CONCLUSION: Combination treatment with imatinib mesylate and atorvastatin calcium was effective in treating SR-cGVHD and significantly decreased target organ injury, especially liver damage, indicating that T-cell regulatory function may play an important role in this process.
RESUMEN
BACKGROUND: Peptide transporter 1 (PepT1) transports bacterial oligopeptide products and induces inflammation of the bowel. Nutritional peptides compete for the binding of intestinal bacterial products to PepT1. We investigated the mechanism of short-peptide-based enteral nutrition (SPEN) on the damage to the gut caused by the bacterial oligopeptide product muramyl dipeptide (MDP), which is transported by PepT1. The gut-lung axis is a shared mucosal immune system, and immune responses and disorders can affect the gut-respiratory relationship. METHODS AND RESULTS: Sprague-Dawley rats were gavaged with solutions containing MDP, MDP + SPEN, MDP + intact-protein-based enteral nutrition (IPEN), glucose as a control, or glucose with GSK669 (a NOD2 antagonist). Inflammation, mitochondrial damage, autophagy, and apoptosis were explored to determine the role of the PepT1-nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-beclin-1 signaling pathway in the small intestinal mucosa. MDP and proinflammatory factors of lung tissue were explored to determine that MDP can migrate to lung tissue and cause inflammation. Induction of proinflammatory cell accumulation and intestinal damage in MDP gavage rats was associated with increased NOD2 and Beclin-1 mRNA expression. IL-6 and TNF-α expression and apoptosis were increased, and mitochondrial damage was severe, as indicated by increased mtDNA in the MDP group compared with controls. MDP levels and expression of proinflammatory factors in lung tissue increased in the MDP group compared with the control group. SPEN, but not IPEN, eliminated these impacts. CONCLUSIONS: Gavage of MDP to rats resulted in damage to the gut-lung axis. SPEN reverses the adverse effects of MDP. The PepT1-NOD2-beclin-1 pathway plays a role in small intestinal inflammation, mitochondrial damage, autophagy, and apoptosis.