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Tubulointerstitial fibrosis is an inevitable consequence of all progressive chronic kidney disease (CKD) and contributes to a substantial health burden worldwide. Icariin, an active flavonoid glycoside obtained from Epimedium species, exerts potential antifibrotic effect. The study aimed to explore the protective effects of icariin against tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO)-induced CKD mice and TGF-ß1-treated HK-2 cells, and furthermore, to elucidate the underlying mechanisms. The results demonstrated that icariin significantly improved renal function, alleviated tubular injuries, and reduced fibrotic lesions in UUO mice. Furthermore, icariin suppressed renal inflammation, reduced oxidative stress as evidenced by elevated superoxide dismutase activity and decreased malondialdehyde level. Additionally, TOMM20 immunofluorescence staining and transmission electron microscope revealed that mitochondrial mass and morphology of tubular epithelial cells in UUO mice was restored by icariin. In HK-2 cells treated with TGF-ß1, icariin markedly decreased profibrotic proteins expression, inhibited inflammatory factors, and protected mitochondria along with preserving mitochondrial morphology, reducing reactive oxygen species (ROS) and mitochondrial ROS (mtROS) overproduction, and preserving membrane potential. Further investigations demonstrated that icariin could activate nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway both in vivo and in vitro, whereas inhibition of Nrf2 by ML385 counteracted the protective effects of icariin on TGF-ß1-induced HK-2 cells. In conclusion, icariin protects against renal inflammation and tubulointerstitial fibrosis at least partly through Nrf2-mediated attenuation of mitochondrial dysfunction, which suggests that icariin could be developed as a promising therapeutic candidate for the treatment of CKD.
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Insuficiencia Renal Crónica , Obstrucción Ureteral , Ratones , Animales , Riñón/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Flavonoides/farmacología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patología , Insuficiencia Renal Crónica/tratamiento farmacológico , Fibrosis , Inflamación/metabolismoRESUMEN
Objectives: Traditional Chinese medicine Cortex Eucommiae has been used to treat bone fracture for hundreds of years, which exerts a significant improvement in fracture healing. Aucubin, a derivative isolated from Cortex Eucommiae, has been demonstrated to possess anti-inflammatory, immunoregulatory, and antioxidative potential. In the present study, our aim was to explore its function in bone regeneration and elucidate the underlying mechanism. Materials and Methods: The effects of Aucubin on osteoblast and osteoclast were examined in mouse bone marrow-derived mesenchymal stem cells (BM-MSCs) and RAW 264.7 cells, respectively. Moreover, the lncRNA H19 and Wnt/ß-catenin signaling were detected by qPCR examination, western blotting, and luciferase activity assays. Using the femur fracture mice model, the in vivo effect of Aucubin on bone formation was monitored by X-ray, micro-CT, histomorphometry, and immunohistochemistry staining. Results: In the present study, Aucubin was found to significantly promote osteogenic differentiation in vitro and stimulated bone formation in vivo. Regarding to the underlying mechanism, H19 was found to be obviously upregulated by Aucubin in MSCs and thus induced the activation of Wnt/ß-catenin signaling. Moreover, H19 knockdown partially reversed the Aucubin-induced osteogenic differentiation and successfully suppressed the activation of Wnt/ß-catenin signaling. We therefore suggested that Aucubin induced the activation of Wnt/ß-catenin signaling through promoting H19 expression. Conclusion: Our results demonstrated that Aucubin promoted osteogenesis in vitro and facilitated fracture healing in vivo through the H19-Wnt/ß-catenin regulatory axis.
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BACKGROUND: Circß-catenin, our first reported circRNA, has been reported to mediate tumorigenesis in various cancers. However, its biological functions and underlying mechanisms in colorectal cancer (CRC) remain unknown. METHODS: The qRT-PCR examination was used to detect the expression of circß-catenin, miR-197-3p, and CTNND1 in cells and human tissues. Western blot was conducted to detect the protein expression levels. The biological function of circß-catenin was verified by MTT, colony formation, wound healing, and transwell assays. The in vivo effects of circß-catenin were verified by nude mice xenograft and metastasis models. The regulatory network of circß-catenin/miR-197-3p/CTNND1 was confirmed via dual-luciferase reporter and RIP assays. RESULTS: In the present study, circß-catenin was found to promote CRC cell proliferation and metastasis in vitro and in vivo. Mechanistically, circß-catenin served as miRNA decoy to directly bind to miR-197-3p, then antagonized the repression of the target gene CTNND1, and eventually promoted the malignant phenotype of CRC. More interestingly, the inverted repeated Alu pairs termed AluJb1/2 and AluY facilitated the biogenesis of circß-catenin, which could be partially reversed by EIF4A3 binding to Alu element AluJb2. CONCLUSIONS: Our findings illustrated a novel mechanism of circß-catenin in modulating CRC tumorigenesis and metastasis, which provides a potential therapeutic target for CRC patients.
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Proliferación Celular , Neoplasias Colorrectales , Progresión de la Enfermedad , Factor 4A Eucariótico de Iniciación , Ratones Desnudos , MicroARNs , ARN Circular , beta Catenina , MicroARNs/genética , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , ARN Circular/genética , Animales , Ratones , beta Catenina/metabolismo , beta Catenina/genética , Proliferación Celular/genética , Factor 4A Eucariótico de Iniciación/genética , Factor 4A Eucariótico de Iniciación/metabolismo , Catenina delta , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Masculino , Femenino , Movimiento Celular/genética , Ratones Endogámicos BALB CRESUMEN
Dysregulated lipolysis is a risk factor contributing to metabolic diseases and autophagy is known to be important in lipolysis. CTCF is involved in diverse cellular processes including adipogenesis, yet its role in lipolysis or autophagy remains unknown. We identified lipolytic genes were downregulated in CTCF knockdown adipocytes based on the RNA-seq data. Further validation showed that CTCF knockdown restrained adipocyte lipolysis while overexpression of CTCF had opposite effects. Similarly, overexpression and knockdown studies demonstrated that CTCF was a positive regulator of autophagy. Treatment with autophagy inducer relieved the suppression of lipolysis caused by CTCF knockdown, while autophagy inhibitor treatment alleviated lipolysis stimulated by CTCF overexpression, indicating that CTCF regulates adipocyte lipolysis through autophagy. Mechanistically, CTCF interacted with PPARγ to coordinately enhanced lipolytic capacity. Data of chip-seq, chip-qPCR and further experiments confirmed that CTCF and PPARγ separately stimulated transactivation of autophagy regulatory protein Beclin 1, while co-expression of the two displayed synergistic effects to regulate autophagy flux. Expectedly, overexpression of Beclin 1 abolished the blockage of lipolysis and autophagy caused by CTCF knockdown. Collectively, CTCF cooperates with PPARγ to regulate autophagy via directly modulating BECLIN 1 transcription, thereby leading to increased adipocyte lipolysis.
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Lipólisis , PPAR gamma , Ratones , Animales , PPAR gamma/metabolismo , Beclina-1/metabolismo , Adipocitos/metabolismo , Adipogénesis , Células 3T3-L1RESUMEN
Background: Transformation of endometriosis to malignancy is a rare occurrence. Clear cell ovarian cancer and endometrioid ovarian cancer are the two histotypes most consistently linked to endometriosis. The exact pathways leading to malignant transformation of endometriosis remain elusive. Case presentation: A 41-year-old woman presented to our hospital with a ten days history of abdominal pain which was not responsive to medication. Pathological examination revealed an unexpected finding of bilateral endometriosis associated with distinct malignancies: a clear cell carcinoma in the right ovary and a well-differentiated endometrioid carcinoma in the left ovary. Molecular analysis indicated a shared somatic driver mutation in ING1 in the eutopic endometrium and the bilateral ovaries while simultaneously exhibiting specific genetic alterations unique to each carcinoma. Notably, several common mutation sites were also identified, including previously reported common oncogenes (KRAS, PIK3CA, ARID1A). This finding prompts the hypothesis of a possible monoclonal origin of the two tumours. Conclusion: This case represents an exceedingly rare occurrence of two different histotypes of ovarian endometriosis-associated cancer manifesting simultaneously in bilateral ovaries. Based on genetic analysis, we hypothesize that these malignancies may have a monoclonal origin, providing insights into understanding the different biological mechanisms underlying carcinogenesis.
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OBJECTIVE: The limited understanding of the molecular mechanism for oral submucosal fibrosis (OSF) poses challenges to the development of effective prevention and treatment strategies. The lack of suitable animal models is a major hindrance. Therefore, this study aimed to address this issue by comparing commonly used arecoline-induced water drinking and injection mouse models. MATERIALS AND METHODS: The mice were subjected to two protocols: receiving 2 mg/mL arecoline in drinking water and 4 mg/mL arecoline saline solution injections every other day. Tissues were collected at regular 4-week intervals, with a final time point of 20 weeks. Stereo microscopy and histomorphological analysis were performed on live and harvested tissues, respectively. RESULTS: During arecoline treatment, collagen deposition and myofibroblast proliferation progressively increased in both models. Changes in the collagen I/III ratio indicated that both models exhibited characteristics of the early and intermediate stages of OSF after 20 weeks of arecoline induction. The water-drinking model also demonstrated multi-organ fibrosis involving the tongue, lungs, and small intestine. CONCLUSION: Both the water drinking and injection mouse models effectively induced OSF, but the water-drinking model better mirrored the observed pathogenesis in patients with OSF. These models provide valuable tools for investigating the mechanisms underlying OSF.
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Porcine Epidemic Diarrhea Virus (PEDV) is a highly contagious and pathogenic virus that causes symptoms such as diarrhea, vomiting, weight loss, and even death in piglets. Due to its high transmission rate, PEDV has resulted in significant global losses. Although some vaccines have been developed and utilized to prevent PEDV, their effectiveness is limited due to the virus's mutations. Therefore, it is imperative to investigate new strategies to combat PEDV. Remdesivir, a classic antiviral drug for coronaviruses, has been proven in our experiment to effectively suppress PEDV replication in Vero and LLC-PK1 cells. Additionally, the cell experiment demonstrated its direct inhibition of PEDV RNA-dependent RNA polymerase (RdRp) enzyme activity. Molecular docking simulations were employed to predict the binding site of remdesivir and PEDV RdRp. Moreover, we observed that remdesivir does not impact the production of inflammatory factors and exhibits antagonistic effects with exogenous nucleosides. Furthermore, we conducted RNA-Seq analysis to investigate the global changes in transcriptome of infected cells treated with remdesivir. Overall, our findings indicate that remdesivir holds promise as a potential candidate for the treatment of PEDV infection.
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The increasing ground-level ozone (O3) pollution resulting from rapid global urbanization and industrialization has negative effects on many plants. Nonetheless, many gaps remain in our knowledge of how ornamental plants respond to O3. Rose (Rosa hybrida L.) is a commercially important ornamental plant worldwide. In this study, we exposed four rose cultivars ("Schloss Mannheim," "Iceberg," "Lüye," and "Spectra") to either unfiltered ambient air (NF), unfiltered ambient air plus 40 ppb O3 (NF40), or unfiltered ambient air plus 80 ppb O3 (NF80). Only the cultivar "Schloss Mannheim" showed significant O3-related effects, including foliar injury, reduced chlorophyll content, reduced net photosynthetic rate, reduced stomatal conductance, and reduced stomatal apertures. In "Schloss Mannheim," several transcription factor genes-HSF, WRKY, and MYB genes-were upregulated by O3 exposure, and their expression was correlated with that of NCED1, PP2Cs, PYR/PYL, and UGTs, which are related to ABA biosynthesis and signaling. These results suggest that HSF, WRKY, and MYB transcription factors and ABA are important components of the plant response to O3 stress, suggesting a possible strategy for cultivating O3-tolerant rose varieties.
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This review presents a systematic analysis of the studies on volatiles in Dendrobium. Among the various components, aromatic terpenes are a crucial component in the development of the aromatic characteristics of Dendrobium and other plants. Recent advancements in detection and sequencing technology have resulted in a considerable rise in research on the biosynthetic processes of aromatic terpenes in Dendrobium and other flowering plants. Nevertheless, the inquiry into the precise means by which plants regulate the proportion of diverse aromatic terpenes in their floral scent, thereby preserving their olfactory traits, requires further investigation. A conjecture on the botanical perfumer mechanism, which condensed the findings of earlier studies, was put forward to address this area of interest. Specific transcription factors likely govern the coordinated expression of multiple key terpene synthase (TPS) genes during the flowering stage of plants, thereby regulating the proportional biosynthesis of diverse aromatic terpenes and sustaining the distinctive aromatic properties of individual plants. This review serves as a significant theoretical reference for further investigations into aromatic volatile compounds in Dendrobium.
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Porcine epidemic diarrhea virus (PEDV) is a swine coronavirus that is highly infectious and prone to variation. Vaccines derived from traditional PEDV strains provide less protection against PEDV-variant strains. Furthermore; there is a complex diversity of sequences among various PEDV-variant strains. Therefore; there is an urgent need to develop alternative antiviral strategies to defend against PEDV. Molnupiravir is a nucleotide analogue that could replace natural nucleosides to restrain viral RNA replication. Our study provided evidence for the dose-dependent inhibition of PEDV replication by molnupiravir in Vero cells. Molnupiravir also exhibited a strong inhibitory effect on viral RNA and protein production. Our results demonstrated that molnupiravir inhibits PEDV RNA-dependent RNA polymerase (RdRp) activity and induces a high frequency of mutations in the PEDV genome. Further studies revealed that molnupiravir can reverse changes in the transcriptome caused by viral infection. In conclusion, our results indicated that molnupiravir has the potential to be an effective treatment for PEDV infection.
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Infecciones por Coronavirus , Coronavirus , Virus de la Diarrea Epidémica Porcina , Enfermedades de los Porcinos , Chlorocebus aethiops , Animales , Porcinos , Células Vero , Virus de la Diarrea Epidémica Porcina/genética , Hidroxilaminas/farmacología , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/veterinaria , Enfermedades de los Porcinos/prevención & controlRESUMEN
miR-144/451 and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulate two antioxidative systems that have been identified to maintain redox homeostasis in erythroid cells by removing excess reactive oxygen species (ROS). Whether these two genes coordinate to affect ROS scavenging and the anemic phenotype, or which gene is more important for recovery from acute anemia, has not been explored. To address these questions, we crossed miR-144/451 knockout (KO) and Nrf2 KO mice and examined the phenotype change in the animals as well as the ROS levels in erythroid cells either at baseline or under stress condition. Several discoveries were made in this study. First, Nrf2/miR-144/451 double-KO mice unexpectedly exhibit similar anemic phenotypes as miR-144/451 single-KO mice during stable erythropoiesis, although compound mutations of miR-144/451 and Nrf2 lead to higher ROS levels in erythrocytes than single gene mutations. Second, Nrf2/miR-144/451 double-mutant mice exhibit more dramatic reticulocytosis than miR-144/451 or Nrf2 single-KO mice during days 3 to 7 after inducing acute hemolytic anemia using phenylhydrazine (PHZ), indicating a synergistic effect of miR-144/451 and Nrf2 on PHZ-induced stress erythropoiesis. However, the coordination does not persist during the whole recovery stage of PHZ-induced anemia; instead, Nrf2/miR-144/451 double-KO mice follow a recovery pattern similar to miR-144/451 single-KO mice during the remaining period of erythropoiesis. Third, the complete recovery from PHZ-induced acute anemia in miR-144/451 KO mice takes longer than in Nrf2 KO mice. Our findings demonstrate that complicated crosstalk between miR-144/451 and Nrf2 does exist and the crosstalk of these two antioxidant systems is development-stage-dependent. Our findings also demonstrate that miRNA deficiency could result in a more profound defect of erythropoiesis than dysfunctional transcription factors.
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Anemia Hemolítica , MicroARNs , Factor 2 Relacionado con NF-E2 , Animales , Ratones , Anemia Hemolítica/genética , Anemia Hemolítica/inducido químicamente , Antioxidantes/farmacología , Eritrocitos , Hemólisis , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genética , Especies Reactivas de Oxígeno , MicroARNs/genéticaRESUMEN
BACKGROUND: Osteosarcomas (OS) is a kind of malignant bone tumor which occurs primarily in children and adolescents, and the clinical therapeutics remain disappointing. As a new programmed cell death, ferroptosis is characterized by iron dependent and intracellular oxidative accumulation, which provides a potential alternative intervene for the OS treatment. Baicalin, a major bioactive flavone derived from traditional Chinese medicine Scutellaria baicalensis, has been proved to have anti-tumor properties in OS. Whether ferroptosis participated in the baicalin mediated anti-OS activity is an interesting project. PURPOSE: To explore the pro-ferroptosis effect and mechanisms of baicalin in OS. METHODS/STUDY DESIGN: Pro-ferroptosis effect of baicalin on cell death, cell proliferation, iron accumulation, lipid peroxidation production was determined in MG63 and 143B cells. The levels of glutathione (GSH), oxidized (GSSG) glutathione and malondialdehyde (MDA) were determined by enzyme linked immunosorbent assay (ELISA). The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Glutathione peroxidase 4 (GPX4) and xCT were detected by western blot in baicalin-mediated ferroptosis regulation. In vivo, a xenograft mice model was adopted to explore the anticancer effect of baicalin. RESULTS: In the present study, it was found that baicalin significantly suppress tumor cell growth in vitro and in vivo. By promoting the Fe accumulation, ROS formation, MDA production and suppressing the ratio of GSH/GSSG, baicalin was found to trigger ferroptosis in OS and ferroptosis inhibitor ferrostatin-1 (Fer-1) successfully reversed these suppressive effects, indicating that ferroptosis participated in the baicalin mediated anti-OS activity. Mechanistically, baicalin physically interacted with Nrf2, a critical regulator of ferroptosis, and influenced its stability via inducing ubiquitin degradation, which suppressed the Nrf2 downstream targets GPX4 and xCT expression, and led to stimulating ferroptosis. CONCLUSIONS: Our findings for the first time indicated that baicalin exerted anti-OS activity through a novel Nrf2/xCT/GPX4-dependent ferroptosis regulatory axis, which hopefully provides a promising candidate for OS treatment.
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Neoplasias Óseas , Ferroptosis , Osteosarcoma , Humanos , Animales , Ratones , Factor 2 Relacionado con NF-E2 , Disulfuro de Glutatión , Osteosarcoma/tratamiento farmacológico , Modelos Animales de Enfermedad , Neoplasias Óseas/tratamiento farmacológicoRESUMEN
The immune checkpoint inhibitor (ICI), anti-programmed cell death receptor-1 (PD-1) antibody, has gained widespread approval for treating various malignancies. Among the immune-related adverse reactions (irAEs) during ICI treatment, the lichenoid reaction is noteworthy. Sintilimab, a new PD-1 inhibitor, has secured approval in China for treating refractory non-Hodgkin's lymphoma, and phase I/II clinical trials for other solid tumors are ongoing both domestically and abroad. This paper presents a case of a mucocutaneous lichenoid reaction associated with sintilimab therapy, its diagnosis, and management. Our study, using multiplex immunofluorescence staining, reveals localized infiltration of CD4+ and CD8+ T lymphocytes in the subepithelial lamina propria region with upregulated PD-1 expression, implying an association between PD-1 expression upregulation and lichenoid reactions provoked by PD-1 monoclonal antibody. We provide a summary of clinical characteristics and treatment guidelines for lichenoid reactions induced by ICIs from previous reports, highlighting the success of a combined therapeutic regimen of oral antihistamines and topical corticosteroids in controlling symptoms without interrupting ICI treatment.
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OBJECTIVE: To investigate the expression of miR-451 during erythroid differentiation and its correlation with hematological diseases. METHODS: The expression of miR-451 in erythroid differentiation of mouse hematopoietic stem cells (derived from fetal liver) was analyzed by cell culture, flow cytometry, magnetic bead sorting and qRT-PCR. The expression of miR-451 during erythroid differentiation of mouse erythroid leukemia cells (MEL) was analyzed by cell culture and qRT-PCR. The expression of miR-451 in peripheral blood of mice was detected by qRT-PCR, and the expression of miR-451 in fetal liver (14.5 days) was analyzed by microarray. The nucleated erythroid cells from bone marrow of wild type (WT) mice and ß-thalassemia (ß-thal) mice were sorted by flow cytometry, and the levels of miR-451 and erythroid genes were detected by qRT-PCR. The expression of miR-451 in peripheral blood of patients with clinical hematological diseases was detected by qRT-PCR. RESULTS: During the differentiation of mouse hematopoietic stem cells (derived from fetal liver) and MEL cells, the expression levels of miR-451 increased gradually. Compared with WT mice, the expression levels of miR-451 in peripheral blood, 14.5-day fetal liver cells and nucleated erythroid cells (sorted from bone marrow) of ß-thal mice were significantly increased(P<0.05). Many erythroid differentiation genes in nucleated erythroid cells (sorted from bone marrow) of ß-thal mice decreased. Compared with healthy controls, the expression levels of miR-451 was increased in peripheral blood of patients with ß-thalassemia and iron deficiency anemia, while the expression levels of miR-451 was decreased in patients with aplastic anemia and myelodysplastic syndrome. CONCLUSION: During erythroid differentiation, the expression levels of miR-451 increases gradually. In hematological diseases, the expression levels of miR-451 is different from that of normal controls, which is expected to become an auxiliary diagnostic index for clinical hematological diseases.
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MicroARNs , Talasemia beta , Ratones , Animales , Talasemia beta/genética , Diferenciación Celular , MicroARNs/genéticaRESUMEN
INTRODUCTION: Disseminated intravascular coagulation (DIC) is a syndrome characterized by coagulopathy, microthrombus, and multiple organ failure. The complement system in DIC is overactivated, and the functions of complement and coagulation pathways are closely related. Our previous screening revealed that salvianolic acid A (SAA) has anti-complement activity. The hyper-activated complement system was involved in the lipopolysaccharide (LPS) induced DIC in rats. The effects of SAA anti-complement action on LPS-induced DIC in rats were investigated. METHODS: The complement activity of the classical pathway and alternative pathway was detected through an in vitro hemolysis assay. The binding sites of SAA and complement C3b were predicted by molecular docking. LPS-induced disseminated coagulation experiments were performed on male Wistar rats to assess coagulation function, complement activity, inflammation, biochemistry, blood routine, fibrinolysis, and survival. RESULTS: SAA had an anti-complement activity in vivo and in vitro and inhibited the complement activation in the classical and alternative pathway of complement. The infusion of LPS into the rats impaired the coagulation function, increased the plasma inflammatory cytokine level, complemented activation, reduced the clotting factor levels, fibrinogen, and platelets, damaged renal, liver, and lung functions, and led to a high mortality rate (85%). SAA treatment of rats inhibited complement activation and attenuated the significant increase in D-dimer, interleukin-6, alanine aminotransferase, and creatinine. It ameliorated the decrease in plasma levels of fibrinogen and platelets and reversed the decline in activity of protein C and antithrombin III. The treatment reduced kidney, liver, and lung damage, and significantly improved the survival rate of rats (46.2 and 78.6% for the low- and high-dose groups, respectively). CONCLUSION: SAA reduced LPS-induced DIC by inhibiting complement activation. It has considerable potential in DIC treatment.
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Ácidos Cafeicos , Activación de Complemento , Coagulación Intravascular Diseminada , Lactatos , Alanina Transaminasa , Animales , Antitrombina III/metabolismo , Factores de Coagulación Sanguínea/metabolismo , Ácidos Cafeicos/farmacología , Complemento C3b , Creatinina , Coagulación Intravascular Diseminada/inducido químicamente , Coagulación Intravascular Diseminada/tratamiento farmacológico , Fibrinógeno/metabolismo , Interleucina-6 , Lactatos/farmacología , Lipopolisacáridos , Masculino , Simulación del Acoplamiento Molecular , Proteína C/metabolismo , Ratas , Ratas WistarRESUMEN
Background: Sepsis is associated with a high mortality rate. A major cause of death in sepsis patients is respiratory failure, which is characterized by oxidative injury, epithelial apoptosis, and increased lung permeability. MicroRNAs (miRs) are important regulators of sepsis progression. Methods: This study aimed to explore the role of miR-144/451 in sepsis in mice. Experimental sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Results: CLP significantly induced systemic inflammation, lung permeability, and lung epithelial apoptosis with downregulated messenger RNA (mRNA) levels of antioxidant enzymes. The miR-144/451 knockout mice had a lower 48-hour survival rate, higher plasma tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels, and greater pulmonary permeability compared with wild-type mice after CLP. CLP also markedly increased interstitial hemorrhage, collapsed more alveolar sacs, and increased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive and Bcl-2-associated X (Bax)-positive cells in miR-144/451 knockout lung tissues, with elevated mRNA levels of Bax and reduced activities of catalase (Cat), glutathione peroxidase 1(Gpx1). MiR-451 negatively regulated 14-3-3ζ expression evidenced in miR-144/451 knockout lungs and the A549 cell line. In lipopolysaccharide (LPS)-induced A549 cells, miR-451 overexpression remarkably suppressed the production of reactive oxygen species, inhibited cell apoptosis, and enhanced levels of FoxO3 protein and related enzymes. Conclusions: Deletion of the miR-144/451 cluster aggravated sepsis-induced oxidative injury of lung epithelial cells.
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Currently, various porcine reproductive and respiratory syndrome virus (PRRSV) variants emerged worldwide with different genetic characteristics and pathogenicity, increasing the difficulty of PRRS control. In this study, a PRRSV strain named HBap4-2018 was isolated from swine herds suffering severe respiratory disease with high morbidity in Hebei Province of China in 2018. The genome of HBap4-2018 is 15,003 nucleotides in length, and compared with NADC30-like PRRSV, nsp2 of HBap4-2018 has an additional continuous deletion of five amino acids. Phylogenetic analysis based on complete genome and ORF5 showed that HBap4-2018 belonged to lineage 8 of PRRSV-2, which was characterized by highly variable genome. However, HBap4-2018 was classified into lineage 1 based on phylogenetic analysis of nsp2, sharing higher amino acid homology (85.3%-85.5%) with NADC30-like PRRSV. Further analysis suggested that HBap4-2018 was a novel natural recombinant PRRSV with three recombinant fragments in the genome, of which highly pathogenic PRRSV (HP-PRRSV) served as the major parental strains, while NADC30-like PRRSV served as the minor parental strains. Five recombination break points were identified in nsp2, nsp3, nsp5, nsp9 and ORF6, respectively, presenting a novel recombinant pattern in the genome. Piglets inoculated with HBap4-2018 presented typical clinical signs with a mortality rate of 60%. High levels of viremia and obvious macroscopic and histopathological lesions in the lungs were observed, revealing the high pathogenicity of HBap4-2018 in piglets.
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Síndrome Respiratorio y de la Reproducción Porcina , Virus del Síndrome Respiratorio y Reproductivo Porcino , Secuencia de Aminoácidos , Animales , China , Variación Genética , Genoma Viral , Filogenia , Virus del Síndrome Respiratorio y Reproductivo Porcino/genética , PorcinosRESUMEN
The agricultural insurance subsidy policy (AISP) encourages farmers to expand production scale by mitigating production risks. Under the high-input production patterns of traditional agriculture, the implementation of AISP is conducive to increase farmers' income, but it also leads to the destruction of the agricultural environment. Achieving agricultural green development (AGD) has been hindered in China. In this context, this paper attempts to analyze the impact of AISP on farmers' income and the agricultural environment. Based on the panel data of 316 prefecture-level cities from 2003 to 2012 in China, this paper empirically tests the effects of AISP by employing methods such as time-varying difference-in-difference (DID). The results show that AISP has significantly promoted the growth of farmers' incomes but has negatively impacted the agricultural environment. Furthermore, the mechanism analysis shows that the policy effects are realized by affecting the quantity of main productive fixed assets (Mpfa) and grain sown area per capita (Gsa). In addition, the policy effect is heterogeneous in different regions. Therefore, the government should appropriately raise the subsidy standard for farmers who adopt environmental-friendly production patterns. At the same time, the government should give more subsidies to the large grain-producing areas.
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Política Fiscal , Seguro , Agricultura , China , Agricultores , HumanosRESUMEN
BACKGROUND: Immune checkpoint blockade (ICB) therapy has yielded successful clinical responses in treatment of a minority of patients in certain cancer types. Substantial efforts were made to establish biomarkers for predicting responsiveness to ICB. However, the systematic assessment of these ICB response biomarkers remains insufficient. METHODS: We collected 22 transcriptome-based biomarkers for ICB response and constructed multiple benchmark datasets to evaluate the associations with clinical response, predictive performance, and clinical efficacy of them in pre-treatment patients with distinct ICB agents in diverse cancers. RESULTS: Overall, "Immune-checkpoint molecule" biomarkers PD-L1, PD-L2, CTLA-4 and IMPRES and the "Effector molecule" biomarker CYT showed significant associations with ICB response and clinical outcomes. These immune-checkpoint biomarkers and another immune effector IFN-gamma presented predictive ability in melanoma, urothelial cancer (UC) and clear cell renal-cell cancer (ccRCC). In non-small cell lung cancer (NSCLC), only PD-L2 and CTLA-4 showed preferable correlation with clinical response. Under different ICB therapies, the top-performing biomarkers were usually mutually exclusive in patients with anti-PD-1 and anti-CTLA-4 therapy, and most of biomarkers presented outstanding predictive power in patients with combined anti-PD-1 and anti-CTLA-4 therapy. CONCLUSIONS: Our results show these biomarkers had different performance in predicting ICB response across distinct ICB agents in diverse cancers.