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In mammals, the transition from mitosis to meiosis facilitates the successful production of gametes. However, the regulatory mechanisms that control meiotic initiation remain unclear, particularly in the context of complex histone modifications. Herein, we show that KDM2A, acting as a lysine demethylase targeting H3K36me3 in male germ cells, plays an essential role in modulating meiotic entry and progression. Conditional deletion of Kdm2a in mouse pre-meiotic germ cells results in complete male sterility, with spermatogenesis ultimately arrested at the zygotene stage of meiosis. KDM2A deficiency disrupts H3K36me2/3 deposition in c-KIT+ germ cells, characterized by a reduction in H3K36me2 but a dramatic increase in H3K36me3. Furthermore, KDM2A recruits the transcription factor E2F1 and its co-factor HCFC1 to the promoters of key genes required for meiosis entry and progression, such as Stra8, Meiosin, Spo11, and Sycp1. Collectively, our study unveils an essential role for KDM2A in mediating H3K36me2/3 deposition and controlling the programmed gene expression necessary for the transition from mitosis to meiosis during spermatogenesis.
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Bone marrow-derived mesenchymal stem cells (BMSCs) have therapeutic potential for certain heart diseases. Previous studies have shown that stem cells inhibit cardiac hypertrophy; however, it is necessary to explore the mechanisms underlying this effect. This study aimed to investigate the possible mechanism underlying the inhibitory effect of BMSCs on cardiomyocyte hypertrophy. We induced cardiomyocyte hypertrophy in cultured rat cells through isoproterenol (ISO) treatment with or without BMSC coculture. A microarray was performed to analyze messenger RNA expression in response to ISO treatment and BMSC coculture. Pathway enrichment analysis showed that the expression of differential genes was closely related to the 5'-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and that the expression of forkhead box O 1 (FoxO1) was significantly increased in the presence of BMSCs. Furthermore, we determined the expression levels of p-AMPK/AMPK and p-FoxO1/FoxO1 by western blot analysis. The expression of p-AMPK/AMPK was upregulated, whereas that of p-FoxO1/FoxO1 was downregulated upon coculturing with BMSCs. The AMPK-specific antagonist Compound C inhibited the downregulation of p-FoxO1/FoxO1 induced by the BMSC coculture. Furthermore, treatment with the specific FoxO1 antagonist AS1842856 reduced the inhibitory effects of BMSCs on cardiomyocyte hypertrophy in vivo and in vitro. Our present study demonstrates the inhibition of cardiomyocyte hypertrophy by BMSCs, which occurs partly through the AMPK-FoxO1 signaling pathway.
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Cardiomegalia/genética , Células Madre Mesenquimatosas/metabolismo , Proteínas del Tejido Nervioso/genética , Transcripción Genética , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Cardiomegalia/patología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Perfilación de la Expresión Génica , Ontología de Genes , Isoproterenol/farmacología , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Transcripción Genética/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Chinese woodchucks (M. himalayana) were recently found to be susceptible to woodchuck hepatitis virus (WHV) infection. In this study, we aimed to determine the susceptibility to WHV infection of M. himalayana from different areas and their association with the animal genetic background exemplified by cytochrome B and MHC-DRB molecules. METHODS: Animals from four different areas in Qinghai province were inoculated with WHV59 strains. The virological markers including WHV surface antigen (WHsAg), WHV core antibody (WHcAb), and WHV DNA in serum were measured by ELISA and Real-time PCR, respectively. The sequences of cytochrome B gene and MHC-DRB molecules were obtained and sorted with Clustalx software. The nucleotide variation sites were identified using MEGA5 software. RESULTS: The animals from four different areas had different susceptibility to WHV infection. Animals from TR and TD areas had a high level of long-lasting viremia, while those from GD and WL areas had a low level of transient viremia after WHV inoculation. All of the animals belong to the same subspecies M. himalayana robusta identified by cytochrome B gene sequences. Based on their nucleotide variation pattern, 8 alleles of cytochrome B gene were identified, and 7 MHC-DRB alleles were identified. Allele A of cytochrome B and Allele Mamo-DRB1*02 of MHC-DRB was found to be frequent in animals from TR and TD areas, while Allele H of cytochrome B and Allele Mamo-DRB1*07 of MHC-DRB was predominant in animals from GD and WL areas. CONCLUSION: Chinese woodchucks from different areas differed in their susceptibility to WHV infection, though they belong to the same subspecies M. himalayana robusta. The genetic background exemplified by cytochrome B and MHC-DRB differed in Chinese woodchucks with different susceptibility to WHV infection.
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Citocromos b/genética , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Virus de la Hepatitis B de la Marmota/fisiología , Hepatitis B/genética , Marmota/genética , Animales , Anticuerpos Antivirales/sangre , Antígenos Virales/sangre , China , ADN Viral/sangre , Femenino , Estudios de Asociación Genética , Antecedentes Genéticos , Hepatitis B/virología , Masculino , Marmota/clasificación , Marmota/virología , Polimorfismo de Nucleótido SimpleRESUMEN
Lung cancer is the leading cause of cancer mortality worldwide and non-small-cell lung cancer (NSCLC) is the most common type. Marine plants provide rich resources for anticancer drug discovery. Fucoxanthin (FX), a Laminaria japonica extract, has attracted great research interest for its antitumor activities. Accumulating evidence suggests anti-proliferative effects of FX on many cancer cell lines including NSCLCs, but the detailed mechanisms remain unclear. In the present investigation, we confirmed molecular mechanisms and in vivo anti-lung cancer effect of FX at the first time. Flow cytometry, real-time PCR, western blotting and immunohistochemistry revealed that FX arrested cell cycle and induced apoptosis by modulating expression of p53, p21, Fas, PUMA, Bcl-2 and caspase-3/8. These results show that FX is a potent marine drug for human non-small-cell lung cancer treatment.
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Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Laminaria/química , Neoplasias Pulmonares/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Xantófilas/uso terapéutico , Células A549 , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Supresoras de Tumor/metabolismo , Xantófilas/aislamiento & purificación , Xantófilas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Nifedipine is a dihydropyridine calcium channel blocker used widely in the management of hypertension and other cardiovascular disorders. In this work, a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry method was developed and validated to determine nifedipine in dog plasma using nimodipine as the internal standard. Chromatographic separation was carried out on a C8 column. The mobile phase consisted of a mixture of acetonitrile, water and formic acid (60:40:0.2, v/v/v) at a flow rate of 0.5 mL/min. Detection was performed on a triple quadrupole tandem mass spectrometer in selected reaction monitoring mode via an atmospheric pressure chemical ionization source. The method has a lower limit of quantification of 0.20 ng/mL with consumption of plasma as low as 0.05 mL. The linear calibration curves were obtained in the concentration range of 0.20-50.0 ng/mL (r = 0.9948). The recoveries of the liquid extraction method were 74.5-84.1%. Intra-day and inter-day precisions were 4.1-8.8 and 6.7-7.4%, respectively. The quantification was not interfered with by other plasma components and the method was applied to determine nifedipine in plasma after a single oral administration of two controlled-release nifedipine tablets to beagle dogs.
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Cromatografía Líquida de Alta Presión/métodos , Nifedipino/sangre , Espectrometría de Masas en Tándem/métodos , Animales , Perros , Modelos Lineales , Masculino , Nifedipino/química , Nifedipino/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The aim of this study was to investigate the effect of Bu-Shen-An-Tai recipe (BSATR) and its two components (Bushen recipe, and Huoxue recipe) on endometrial morphology during peri-implantation in superovulated mice. Mice were randomly divided into five groups, including the normal (N), model (M), Bushen (BS), Huoxue (HX) and Bu-Shen-An-Tai (BH) groups. The uteri were collected on day 4 of pregnancy, and the endometrium thickness, microvessel density (MVD) and number of pinopodes observed. Compared with the M group, the endometrial thickness in the BS, HX and BH groups was significantly increased and there was a significant difference in endometrial thickness between the BS and the BH groups. The mean MVD was significantly lower in the M group than in the N group, and there was a significant increase in MVD in the BS, HX and BH groups as compared with the M group. Compared with the M group, the pinopode scores in the endometrium were significantly increased in the HX and BH groups; and the BS group had significantly higher pinipode scores than the HX and BH groups. In conclusion, the results of the present study demonstrated that the recipes (Bushen, Huoxue and BSATR) could improve the endometrial environment by regulating the endometrial thickness, MVD and the number of pinopodes at the window of implantation. Moreover, the Huoxue recipe and the BSATR were more efficient than the Bushen recipe, with the BSATR tending to have the most beneficial effects.
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Medicamentos Herbarios Chinos/farmacología , Implantación del Embrión/fisiología , Endometrio/efectos de los fármacos , Ovulación/fisiología , Animales , Antígenos CD34/metabolismo , Medicamentos Herbarios Chinos/química , Endometrio/fisiología , Endometrio/ultraestructura , Femenino , Inmunohistoquímica , Ratones , Microscopía Electrónica de Rastreo , Microvasos/metabolismo , Microvasos/fisiología , Embarazo , Distribución Aleatoria , Factores de TiempoRESUMEN
OBJECTIVE: The contribution of hypoxia to the pathophysiology of vascular smooth muscle cells (VSMCs) has not yet been fully elucidated. This study evaluated the effect of hypoxia on the phenotype and function of SMCs derived from the human normal great saphenous veins (NGSVs). METHODS: Fifteen NGSV tissue samples were collected. SMCs were isolated and cultured. Proliferation, migration, adhesion, senescence, and the structure of cytoskeletal filaments in SMCs were observed. mRNA and protein expression of Bax, Bcl-2, caspase-3, matrix metalloproteinases (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 was detected by fluorescent quantitative polymerase chain reaction and immunoblotting in the cobalt chloride (CoCl2) and the control groups. RESULTS: A decrease in the number of cytoskeletal filaments was observed. mRNA and protein expression of Bas and caspase-3 was significantly decreased, while the quantity of proliferation, migration, adhesion, senescence, and mRNA and protein expression of Bcl-2, MMP-2, MMP-9, TIMP-1, and TIMP-2 in SMCs in the CoCl2 group were significantly increased compared with the control group. CONCLUSION: Under hypoxic conditions, the phenotype and function of SMCs derived from the human NGSVs were dysregulated, suggesting that VSMCs switch from the contractile phenotype to the secretory or synthetic phenotype, and more dedifferentiate, resulting in extracellular matrix deposition and apoptotic decrease through the intrinsic pathway.
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Cobalto , Metaloproteinasa 9 de la Matriz , Inhibidor Tisular de Metaloproteinasa-2 , Humanos , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Caspasa 3/metabolismo , Caspasa 3/farmacología , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Vena Safena/metabolismo , Músculo Liso Vascular/metabolismo , Fenotipo , Metaloproteinasa 2 de la Matriz/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/farmacología , ARN Mensajero/metabolismoRESUMEN
RATIONALE: Ileal perforation caused by the insertion of a drainage tube is a rare complication. Hence, the utilization of surgical drains in abdominal surgery remains controversial. At present, there is a trend to reduce the utilization of drains in abdominal surgery, although certain situations may necessitate their application. PATIENT CONCERNS: A 25-year-old Chinese woman presented with a history of right lower abdominal pain persisting for 10 days. Imaging examinations, including abdominal computed tomography and ultrasound, identified low-density lesions measuring 10 × 8 × 8cm3 in the right lower abdomen, which are consistent with perforated appendicitis complicated by a peri-appendiceal abscess. A laparoscopic appendectomy was carried out. On the 5th postoperative day, the drainage fluid changed to a grass-green color (80mL). Imaging with retrograde contrast through the drainage tube revealed that the 26 Fr silicon rubber drainage tube tip was positioned 50cm away from the ileocecal junction within the ileum. Both the ileal and ileocecal regions appeared well-developed. INTERVENTION AND OUTCOMES: Oral intake was suspended, and the patient received antacids, somatostatin, antibiotics, and total parenteral nutrition. On the 19th postoperative day, a follow-up imaging procedure using retrograde contrast through the drainage tube indicated that the tube tip was sealed. The treatment concluded on day 33 postoperatively, and the patient was discharged. DISCUSSION AND CONCLUSION: Ileal perforation due to an abdominal drainage tube following laparoscopic appendectomy constitutes a rare but serious complication. However, due to the adhesion and inflammatory changes around the abscess, laparoscopic dissection becomes a challenging and risky process, and the surgical skills and experiences are particularly important. Removing the abdominal drainage tube promptly based on the characteristics of the drainage fluid is recommended. The findings provide valuable insights for surgeons navigating similar challenges.
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Apendicectomía , Apendicitis , Drenaje , Íleon , Laparoscopía , Humanos , Femenino , Adulto , Apendicectomía/métodos , Apendicectomía/efectos adversos , Drenaje/métodos , Laparoscopía/métodos , Laparoscopía/efectos adversos , Apendicitis/cirugía , Íleon/cirugía , Perforación Intestinal/etiología , Perforación Intestinal/cirugía , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugíaRESUMEN
Schwannomas localized in the sacrum are relatively infrequent, accounting for 1-5% of all spinal axis schwannomas; they present with vague symptoms or are symptomless, so often grow to a considerable size before detection. Sacral schwannomas occasionally present with enormous dimensions, and these tumors are termed giant sacral schwannomas. However, their surgical removal is challenging owing to an abundant vascularity. The present study retrospectively analyzed the clinical and follow-up data of a patient with a giant sacral schwannoma. The patient experienced numbness in the left buttock and lower extremity, with radiating pain in the sole of the foot that had persisted for 3 years. A presacral mass was found by computed tomography examination 6 months after the stool had become thin. A tumor resection was performed using the anterior abdominal approach. A schwannoma was diagnosed by postoperative pathology. The postoperative course was uneventful, with the complete resolution of symptoms during the 21-month clinical follow-up. Overall, the present study reports the case of a giant sacral schwannoma with pelvic pain that was resected without complications and also discusses its successful management. Additionally, the study presents a systematic review of the literature. We consider that the surgical treatment of giant sacral schwannomas with piecemeal subtotal excision can achieve good outcomes, avoiding unnecessary neurological deficits.
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Background: Aortic dissection (AD) poses a great threat to the life of patients; however, there is currently no documentation of a clear pathogenic mechanism of this disease. In recent years, ß-aminopropionitrile (BAPN)-induced AD in rodents has been widely used in basic research, which provides a good platform for exploring the pathogenesis of AD and drug modification. This study aimed to identify molecular markers and pathways for the diagnosis and treatment of AD by comparing a murine AD model and human AD transcriptome through a bioinformatics analysis. Methods: We constructed a BAPN-induced mice model and performed high-throughput sequencing analysis. The GSE147026 dataset of patients was obtained from the Gene Expression Omnibus database. We performed a subsequent bioinformatics analysis of human AD and the murine AD model using R software. The DESeq software package was used to analyze the differentially expressed genes (DEGs). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to analyze the enrichment pathways. Protein-protein interaction network construction and hub gene selection were based on STRING software analysis. Stepwise identification of potential drugs was performed online, while hub genes were validated immunohistochemically. Results: We compared the murine AD model and human AD transcriptome and found that both differentially expressed 463 genes. The cytokine-cytokine receptor interaction, tuberculosis, and phagosome pathways were significantly enriched. CDC20, CCNB2, and CCNB1 may be associated with AD development. Protein-drug interactions were also identified. Conclusions: This study is the first to reveal transcriptional changes in a murine BAPN-induced AD model versus human AD transcriptome. Furthermore, we identified the important hub genes, related pathways, and potential drugs by analyzing the overlapping DEGs between human AD and the murine AD model. Our results provide a basis for the further identification of potential molecular markers for diagnosing and treating AD.
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(1) Background: Arteriovenous fistulas (AVFs) are the preferred site for hemodialysis. Unfortunately, approximately 60% of patients suffer from AVF failure within one year. Oxidative stress plays an important role in the occurrence and development of AVF. However, the underlying mechanisms remain unclear. Therefore, specific oxidative stress-related biomarkers are urgently needed for the diagnosis and treatment of AVF failure. (2) Methods: Bioinformatics analysis was carried out on dataset GSE119296 to screen for PTGS2 as a candidate gene related to oxidative stress and to verify the expression level and diagnostic efficacy of PTGS2 in clinical patients. The effects of NS398, a PTGS2 inhibitor, on hemodynamics, smooth muscle cell proliferation, migration, and oxidative stress were evaluated in a mouse AVF model. (3) Results: Based on 83 oxidative stress-related differentially expressed genes, we identified the important pathways related to oxidative stress. PTGS2 may have diagnostic and therapeutic efficacy for AVF failure. We further confirmed this finding using clinical specimens and validation datasets. The animal experiments illustrated that NS398 administration could reduce neointimal area (average decrease: 49%) and improve peak velocity (average increase: 53%). (4) Conclusions: Our study identified PTGS2 as an important oxidative stress-related biomarker for AVF failure. Targeting PTGS2 reduced oxidative stress and improved hemodynamics in an AVF mouse model.
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For more than half a century, arteriovenous fistula (AVFs) has been recognized as a lifeline for patients requiring hemodialysis (HD). With its higher long-term patency rate and lower probability of complications, AVF is strongly recommended by guidelines in different areas as the first choice for vascular access for HD patients, and its proportion of application is gradually increasing. Despite technological improvements and advances in the standards of postoperative care, many deficiencies are still encountered in the use of AVF related to its high incidence of failure due to unsuccessful maturation to adequately support HD and the development of neointimal hyperplasia (NIH), which narrows the AVF lumen. AVF failure is linked to the activation and migration of vascular cells and the remodeling of the extracellular matrix, where complex interactions between cytokines, adhesion molecules, and inflammatory mediators lead to poor adaptive remodeling. Oxidative stress also plays a vital role in AVF failure, and a growing amount of data suggest a link between AVF failure and oxidative stress. In this review, we summarize the present understanding of the pathophysiology of AVF failure. Furthermore, we focus on the relation between oxidative stress and AVF dysfunction. Finally, we discuss potential therapies for addressing AVF failure based on targeting oxidative stress.
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The hepatocytes, as the main cells in the liver, exert liver functions by expressing innate immune receptors. The innate immune receptors include Toll-like receptors (TLRs), RIG-like receptors (retinoic acid inducible gene I-like receptors, RLRs) and NOD-like receptors (nucleotide binding oligomerization domain-like receptors, NLRs). The hepatocytes, recognize extracellular pathogen-associated molecular patterns (PAMPs) and intracellular damage-associated molecular patterns (DAMPs) through the above receptors. After the activation of the innate immune receptors, the hepatocytes produce cytokines, such as interferon (IFN), to protect the liver, through a series of signaling cascades.
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Moléculas de Patrón Molecular Asociado a Patógenos , Receptores de Reconocimiento de Patrones , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/metabolismo , Inmunidad Innata , Receptores Toll-Like/metabolismo , Proteínas NLR/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas Portadoras , Hepatocitos/metabolismo , Interferones/metabolismo , Citocinas/metabolismo , Tretinoina/metabolismo , Nucleótidos/metabolismoRESUMEN
Fibrosis is the final common pathway of inflammatory diseases in various organs. The inflammasomes play an important role in the progression of fibrosis as innate immune receptors. There are four main members of the inflammasomes, such as NOD-like receptor protein 1 (NLRP1), NOD-like receptor protein 3 (NLRP3), NOD-like receptor C4 (NLRC4), and absent in melanoma 2 (AIM2), among which NLRP3 inflammasome is the most studied. NLRP3 inflammasome is typically composed of NLRP3, ASC and pro-caspase-1. The activation of inflammasome involves both "classical" and "non-classical" pathways and the former pathway is better understood. The "classical" activation pathway of inflammasome is that the backbone protein is activated by endogenous/exogenous stimulation, leading to inflammasome assembly. After the formation of "classic" inflammasome, pro-caspase-1 could self-activate. Caspase-1 cleaves cytokine precursors into mature cytokines, which are secreted extracellularly. At present, the "non-classical" activation pathway of inflammasome has not formed a unified model for activation process. This article reviews the role of NLRP1, NLRP3, NLRC4, AIM2 inflammasome, Caspase-1, IL-1ß, IL-18 and IL-33 in the fibrogenesis.
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Fibrosis/etiología , Inflamasomas/fisiología , Animales , Proteínas Adaptadoras de Señalización CARD/fisiología , Proteínas de Unión al Calcio/fisiología , Caspasa 1/fisiología , Humanos , Inflamasomas/clasificación , Interleucina-1beta/fisiología , Interleucina-33/fisiología , Riñón/patología , Cirrosis Hepática/etiología , Miocardio/patología , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Proteínas NLR/fisiología , Fibrosis Pulmonar/etiologíaRESUMEN
Autophagy plays a dual role in the responses to the gut microflora. The present study aimed to examine the effects of Lactobacillus rhamnosus (L. rhamnosus) on Fusobacterium nucleatum (F. nucleatum)induced intestinal dysfunction and to elucidate the underlying mechanisms, with particular focus on autophagy. Inflammatory models were established by treatment with L. rhamnosus following F. nucleatum intervention using cells or a mouse model of dextran sulfate sodium (DSS)induced acute colitis. Autophagosomes were visualized by confocal microscopy following transfection with a tandem GFPmCherryLC3 construct and also by transmission electron microscopy. Autophagyassociated protein levels were examined by western blot analysis and immunohistochemistry. It was observed that F. nucleatum induced the production of proinflammatory cytokines in Caco2 cells and aggravated DSSinduced acute colitis. The autophagic flux was impaired following infection with F. nucleatum. L. rhamnosus treatment attenuated the inflammation induced by F. nucleatum infection and effectively recovered the impaired autophagic flux. In addition, the production of proinflammatory cytokines induced by F. nucleatum was enhanced with autophagy inhibitors or the RNA interference of autophagyrelated gene 16 like 1 (Atg16L1) in Caco2 cells. Notably, this inhibition of autophagy weakened the effects of L. rhamnosus. Finally, the PI3K/AKT/mTOR pathway was found to be involved in this process. On the whole, the present study demonstrates that the mediation of autophagy by L. rhamnosus may be involved in the protective effects against F. nucleatumrelated intestinal inflammation. Thus, L. rhamnosus treatment may prove to be a novel therapeutic strategy for F. nucleatumrealated gut disorders.
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Autofagia , Colitis/metabolismo , Infecciones por Fusobacterium/metabolismo , Fusobacterium nucleatum/metabolismo , Lacticaseibacillus rhamnosus/metabolismo , Células CACO-2 , Colitis/inducido químicamente , Colitis/patología , Sulfato de Dextran/toxicidad , Infecciones por Fusobacterium/inducido químicamente , Infecciones por Fusobacterium/patología , HumanosRESUMEN
By establishing the Fusobacterium nucleatum (F. nucleatum) infected-bone mesenchymal stem cells (BMSCs) transplantation model in APCMin/+ mice, we investigated the role of BMSCs in the development of intestinal tumors induced by F. nucleatum. ApcMin/++F. nucleatum + BMSCs mice showed increased susceptibility to intestinal tumors and accelerated tumor growth. BMSCs could also enhance tumor-initiating capability, invasive traits after F. nucleatum infection in vitro, and tumorigenicity in a nude murine model. Mechanistically, BMSCs were recruited to the submucosa, migrated to the mucosal layer, and might activate the canonical Wnt/ß-catenin/TGIF axis signaling. Further mechanistic results illustrated increased production of the Wnt3a protein was found in ApcMin/++F. nucleatum + BMSCs mice, and BMSCs were likely the major source of Wnt3a. Intriguingly, a deletion of Wnt3a via BMSC interference or antagonist analogs led to a significantly attenuated capacity of ApcMin/++F. nucleatum mice to generate intestinal tumors. The findings suggest that BMSCs have the potential to migrate and accelerate F. nucleatum-induced colorectal tumorigenesis by modulating Wnt3a secretion; knockdown of BMSC-derived Wnt3a or antagonist analogs could attenuate carcinogenesis. Thus, Wnt3a might be a potential pharmaceutical target for the prevention and treatment of F. nucleatum-related colorectal cancer.
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Neoplasias Colorrectales/terapia , Infecciones por Fusobacterium/complicaciones , Fusobacterium nucleatum/patogenicidad , Células Madre Mesenquimatosas/citología , Proteína Wnt3A/genética , Animales , Células CACO-2 , Línea Celular Tumoral , Neoplasias Colorrectales/microbiología , Femenino , Infecciones por Fusobacterium/genética , Infecciones por Fusobacterium/terapia , Técnicas de Silenciamiento del Gen , Células HT29 , Humanos , Masculino , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Ratones , Vía de Señalización Wnt , Proteína Wnt3A/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Experimental research has successfully established an adult offspring animal model of nonalcoholic fatty liver disease (NAFLD), but the female offspring model of NAFLD in young age has not been well characterized yet. The aim of this study was to present a direct comparison of the maternal versus postweaning female juvenile NAFLD and nonalcoholic steatohepatitis (NASH) animal models. Four different female mouse models were established and compared using different high-fat diet feeding (HF) strategies in maternal mice and their offspring. The models were non-HF maternal mice and HF offspring with high-high fat (C/HHF), non-HF maternal mice and HF offspring with low-high fat (C/LHF), HF maternal mice and offspring both with high-high fat (HHF/HHF), and HF maternal mice and offspring both with low-high fat (LHF/LHF). A female control group (C/C) was also established. The offspring mice were raised to the age of 8 weeks and then euthanized. Blood glucose levels, lipid profiles, liver function, and triglycerides/total cholesterol contents were examined. Hepatic morphology and superoxide anion levels were evaluated. The nicotinamide-adenine dinucleotide phosphate activity and related regulatory subunits protein expression in the liver tissue were also determined. Our data demonstrated that offspring fat intake contributed to the successful establishment of NAFLD and maternal-offspring fat intake contributed to the successful establishment of NASH in juvenile female mice. Offspring high-fat exposure might be associated with the development of NAFLD and maternal high-fat exposure might be associated with the development of NASH in juvenile female offspring. Higher calories from a fat diet program (both in maternal and offspring) are more prone to inducing liver injury in offspring. In addition, the combination of the aforementioned two factors could aggravate this process. Moreover, oxidative stress was prominent in the juvenile female mouse model of NAFLD/NASH, and the mechanism might be related to the activation of liver NADPH oxidase.
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To observe the pharmacokinetic and tissue-distribution characters of 5-flourouracil magnetic albumin deuto-microsphere (5-Fu-MAD) in normal and tumor-bearing mice, HPLC method for the determination of 5-Fu in plasma and tissues was established and applied to determine 5-Fu in mouse plasma and tissue samples. A Flame atomic absorption spectrometer was used to detect the iron concentration in mouse tissue. Plasma concentration-time curves of free 5-Fu, 5-Fu-MAD and 5-Fu-MAD plus the magnetic frame (MF) conformed to two compartment model of first order absorption and they had C(max) of 34.9, 7.95 and 5.97 mg x L(-1); T1/2 (Ke) of 22.26, 76.0 and 124.6 min, V(d) of 3.28, 30.7 and 66.1 L x kg; AUC(0-t), of 233.9, 78.3 and 50.2 mg x min x L(-1); AUC(0-infinity) of 237.2, 89.3 and 68.1 mg x min x L(-1), respectively. The distribution of 5-Fu and iron was the highest in the plenty blood perfusion organs like the liver, tumor, spleen and lung, while lower in the kidney and heart and lowest in brain and muscle. The tissue distribution of muscle and tumor increased significantly when a magnetic frame was inserted there. The pharmacokinetics and tissue distribution of 5-Fu-MAD exhibited sustained-release and target characteristics.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Fluorouracilo/farmacocinética , Neoplasias Hepáticas Experimentales/prevención & control , Microesferas , Albúminas/química , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Área Bajo la Curva , Línea Celular Tumoral , Preparaciones de Acción Retardada , Femenino , Fluorouracilo/administración & dosificación , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Magnetismo , Masculino , Ratones , Distribución Aleatoria , Distribución TisularRESUMEN
Psoralea corylifolia L. (PC) is a traditional Chinese herb used to treat yang deficiency of the spleen and kidney in pediatric disease. Recent studies have shown its liver protection and anti-oxidative effects. The aim of this study was to explore the effect and mechanism of PC on nonalcoholic steatohepatitis in juvenile mice. The juvenile mouse model of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) was established by being fed a high-fat diet in maternal-offspring manner. PC granules were prepared and the quality was assessed. The main components were identified by high performance liquid chromatography. Then, different dosages of PC were administered for 6 weeks. Homeostatic model assessment of insulin resistance, plasma liver enzymes, hepatic morphology, hepatic superoxide anion, and triglyceride/total cholesterol levels were examined. The changes of nuclear factor-κB (NF-κB) activity phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) and protein kinase C-α (PKC-α)/nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase signaling pathways in hepatic tissues were also determined. Our data demonstrated that PC significantly improved liver dysfunction, liver triglyceride/total cholesterol accumulation and insulin resistance in juvenile NAFLD/NASH mice. PC also alleviated hepatic steatosis, inflammatory cell infiltration, and fibroplasia in the portal area. Additionally, PC inhibited the activation of NF-κB and the mRNA expression of inflammatory factors while enhancing PI3K/Akt signaling in hepatic tissues. PC could also reduce hepatic superoxide anion levels, and NADPH oxidase activity as well as p47phox protein expression and PKCα activation in hepatic tissues. The results suggest that PC is effective in the treatment of NASH in juvenile mice. The mechanism may be related to the attenuation of hepatic oxidative stress through the PKC-α/NADPH oxidase signaling pathway.
RESUMEN
AIM: To observe the effect of phenolic alkaloids of Menispermum dauricum (PAMD) on the hemodynamics, coronary circulation and oxygen metabolism of the myocardium in anesthetized dogs. METHODS: In this study, the changes of LVSP, LVEDP and +/- dp/dtmax, the flow of coronary artery and myocardial energy metabolism were measured in anesthetized dog with PAMD or NS. RESULTS: In the anesthetized dogs, compared with pre-treatment status, PAMD at 3.5 and 7.0 mg.kg-1 caused decreases in the left ventricular systolic pressure(LVSP), +/- dp/dtmax, heart rate, the rate of oxygen utilization, the coronary and general peripheral resistance. It was found to increase myocardial oxygen and coronary flow. There were no significant change in the left ventricular end diastolic pressure (LVEDP). CONCLUSION: PAMD can ameliorate hemodynamics, coronary circulation and myocardial metabolism.