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Streptococcus anginosus (S. anginosus) was enriched in the gastric mucosa of patients with gastric cancer (GC). Here, we show that S. anginosus colonized the mouse stomach and induced acute gastritis. S. anginosus infection spontaneously induced progressive chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in conventional mice, and the findings were confirmed in germ-free mice. In addition, S. anginosus accelerated GC progression in carcinogen-induced gastric tumorigenesis and YTN16 GC cell allografts. Consistently, S. anginosus disrupted gastric barrier function, promoted cell proliferation, and inhibited apoptosis. Mechanistically, we identified an S. anginosus surface protein, TMPC, that interacts with Annexin A2 (ANXA2) receptor on gastric epithelial cells. Interaction of TMPC with ANXA2 mediated attachment and colonization of S. anginosus and induced mitogen-activated protein kinase (MAPK) activation. ANXA2 knockout abrogated the induction of MAPK by S. anginosus. Thus, this study reveals S. anginosus as a pathogen that promotes gastric tumorigenesis via direct interactions with gastric epithelial cells in the TMPC-ANXA2-MAPK axis.
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Gastritis , Neoplasias Gástricas , Infecciones Estreptocócicas , Streptococcus anginosus , Animales , Humanos , Ratones , Atrofia/patología , Carcinogénesis , Transformación Celular Neoplásica , Mucosa Gástrica , Gastritis/patología , Inflamación/patología , Proteínas Quinasas Activadas por Mitógenos , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Streptococcus anginosus/fisiología , Infecciones Estreptocócicas/patologíaRESUMEN
BACKGROUND & AIMS: Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of different fibers with colorectal tumorigenesis in mice. METHODS: Apcmin/+ mice and C57BL/6 mice with azoxymethane (AOM) injection were used as CRC mouse models. Mice were fed with mixed high-fiber diet (20% soluble fiber and 20% insoluble fiber), high-inulin diet, high-guar gum diet, high-cellulose diet, or diets with different inulin dose. Germ-free mice were used for validation. Fecal microbiota and metabolites were profiled by shotgun metagenomic sequencing and liquid chromatography-mass spectrometry, respectively. RESULTS: Mixed high-fiber diet promoted colorectal tumorigenesis with increased tumor number and tumor load in AOM-treated and Apcmin/+ mice. Antibiotics use abolished the pro-tumorigenic effect of mixed high-fiber diet, while transplanting stools from mice fed with mixed high-fiber diet accelerated tumor growth in AOM-treated germ-free mice. We therefore characterized the contribution of soluble and insoluble fiber in CRC separately. Our results revealed that soluble fiber inulin or guar gum, but not insoluble fiber cellulose, promoted colorectal tumorigenesis in AOM-treated and Apcmin/+ mice. Soluble fiber induced gut dysbiosis with Bacteroides uniformis enrichment and Bifidobacterium pseudolongum depletion, accompanied by increased fecal butyrate and serum bile acids and decreased inosine. We also identified a positive correlation between inulin dosage and colorectal tumorigenesis. Moreover, transplanting stools from mice fed with high-inulin diet increased colonic cell proliferation and oncogene expressions in germ-free mice. CONCLUSION: High-dose soluble but not insoluble fiber potentiates colorectal tumorigenesis in a dose-dependent manner by dysregulating gut microbiota and metabolites in mice.
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Neoplasias Colorrectales , Microbioma Gastrointestinal , Ratones , Animales , Inulina/farmacología , Ratones Endogámicos C57BL , Carcinogénesis , Fibras de la Dieta/metabolismo , Celulosa/farmacología , Azoximetano , Neoplasias Colorrectales/patologíaRESUMEN
OBJECTIVE: Squalene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour immune microenvironment in MASH-HCC remains unclear. DESIGN: We established hepatocyte-specific Sqle transgenic (tg) and knockout mice, which were subjected to a choline-deficient high-fat diet plus diethylnitrosamine to induce MASH-HCC. SQLE function was also determined in orthotopic and humanised mice. Immune landscape alterations of MASH-HCC mediated by SQLE were profiled by single-cell RNA sequencing and flow cytometry. RESULTS: Hepatocyte-specific Sqle tg mice exhibited a marked increase in MASH-HCC burden compared with wild-type littermates, together with decreased tumour-infiltrating functional IFN-γ+ and Granzyme B+ CD8+ T cells while enriching Arg-1+ myeloid-derived suppressor cells (MDSCs). Conversely, hepatocyte-specific Sqle knockout suppressed tumour growth with increased cytotoxic CD8+ T cells and reduced Arg-1+ MDSCs, inferring that SQLE promotes immunosuppression in MASH-HCC. Mechanistically, SQLE-driven cholesterol accumulation in tumour microenvironment underlies its effect on CD8+ T cells and MDSCs. SQLE and its metabolite, cholesterol, impaired CD8+ T cell activity by inducing mitochondrial dysfunction. Cholesterol depletion in vitro abolished the effect of SQLE-overexpressing MASH-HCC cell supernatant on CD8+ T cell suppression and MDSC activation, whereas cholesterol supplementation had contrasting functions on CD8+ T cells and MDSCs treated with SQLE-knockout supernatant. Targeting SQLE with genetic ablation or pharmacological inhibitor, terbinafine, rescued the efficacy of anti-PD-1 treatment in MASH-HCC models. CONCLUSION: SQLE induces an impaired antitumour response in MASH-HCC via attenuating CD8+ T cell function and augmenting immunosuppressive MDSCs. SQLE is a promising target in boosting anti-PD-1 immunotherapy for MASH-HCC.
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The use of different template surfaces in crystallization experiments can directly influence the nucleation kinetics, crystal growth, and morphology of active pharmaceutical ingredients (APIs). Consequently, templated nucleation is an attractive approach to enhance crystal nucleation kinetics and preferentially nucleate desired crystal polymorphs for solid-form drug molecules, particularly large and flexible molecules that are difficult to crystallize. Herein, we investigate the effect of polymer templates on the crystal nucleation of clotrimazole and ketoprofen with both experiments and computational methods. Crystallization was carried out in toluene solvent for both APIs with a template library consisting of 12 different polymers. In complement to the experimental studies, we developed a computational workflow based on molecular dynamics (MD) and derived descriptors from the simulations to score and rank API-polymer interactions. The descriptors were used to measure the energy of interaction (EOI), hydrogen bonding, and rugosity (surface roughness) similarity between the APIs and polymer templates. We used a variety of machine learning models (14 in total) along with these descriptors to predict the crystallization outcome of the polymer templates. We found that simply rank-ordering the polymers by their API-polymer interaction energy descriptors yielded 92% accuracy in predicting the experimental outcome for clotrimazole and ketoprofen. The most accurate machine learning model for both APIs was found to be a random forest model. Using these models, we were able to predict the crystallization outcomes for all polymers. Additionally, we have performed a feature importance analysis using the trained models and found that the most predictive features are the energy descriptors. These results demonstrate that API-polymer interaction energies are correlated with heterogeneous crystallization outcomes.
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BACKGROUND & AIMS: Recent studies have highlighted the role of the gut microbiota and their metabolites in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). We aimed to identify specific beneficial bacterial species that could be used prophylactically to prevent NAFLD-HCC. METHODS: The role of Bifidobacterium pseudolongum was assessed in two mouse models of NAFLD-HCC: diethylnitrosamine + a high-fat/high-cholesterol diet or + a choline-deficient/high-fat diet. Germ-free mice were used for the metabolic study of B. pseudolongum. Stool, portal vein and liver tissues were collected from mice for non-targeted and targeted metabolomic profiles. Two human NAFLD-HCC cell lines (HKCI2 and HKCI10) were co-cultured with B. pseudolongum-conditioned media (B.p CM) or candidate metabolites. RESULTS: B. pseudolongum was the top depleted bacterium in mice with NAFLD-HCC. Oral gavage of B. pseudolongum significantly suppressed NAFLD-HCC formation in two mouse models (p < 0.01). Incubation of NAFLD-HCC cells with B.p CM significantly suppressed cell proliferation, inhibited the G1/S phase transition and induced apoptosis. Acetate was identified as the critical metabolite generated from B. pseudolongum in B.p CM, an observation that was confirmed in germ-free mice. Acetate inhibited cell proliferation and induced cell apoptosis in NAFLD-HCC cell lines and suppressed NAFLD-HCC tumor formation in vivo. B. pseudolongum restored heathy gut microbiome composition and improved gut barrier function. Mechanistically, B. pseudolongum-generated acetate reached the liver via the portal vein and bound to GPR43 (G coupled-protein receptor 43) on hepatocytes. GPR43 activation suppressed the IL-6/JAK1/STAT3 signaling pathway, thereby preventing NAFLD-HCC progression. CONCLUSIONS: B. pseudolongum protected against NAFLD-HCC by secreting the anti-tumor metabolite acetate, which reached the liver via the portal vein. B. pseudolongum holds potential as a probiotic for the prevention of NAFLD-HCC. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) is an increasing healthcare burden worldwide. There is an urgent need to develop effective agents to prevent NAFLD-HCC progression. Herein, we show that the probiotic Bifidobacterium pseudolongum significantly suppressed NAFLD-HCC progression by secreting acetate, which bound to hepatic GPR43 (G coupled-protein receptor 43) via the gut-liver axis and suppressed the oncogenic IL-6/JAK1/STAT3 signaling pathway. Bifidobacterium pseudolongum holds potential as a novel probiotic for NAFLD-HCC prevention.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Interleucina-6/metabolismo , Hígado/patología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Acetatos , MicrobiotaRESUMEN
BACKGROUND AND AIMS: Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites. METHODS: HFD or control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apcmin/+ model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography-mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy. RESULTS: HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apcmin/+ mice compared with control diet-fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipessp.Marseille-P5997 and Alistipessp.5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression. CONCLUSIONS: HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.
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Bacterias/metabolismo , Colon/microbiología , Neoplasias Colorrectales/microbiología , Dieta Alta en Grasa , Microbioma Gastrointestinal , Animales , Antibacterianos/farmacología , Azoximetano , Bacterias/efectos de los fármacos , Traslocación Bacteriana , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/ultraestructura , Colon/metabolismo , Colon/ultraestructura , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/ultraestructura , Modelos Animales de Enfermedad , Disbiosis , Trasplante de Microbiota Fecal , Heces/microbiología , Genes APC , Vida Libre de Gérmenes , Humanos , Lisofosfolípidos/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Permeabilidad , Células Tumorales CultivadasRESUMEN
BACKGROUND & AIMS: N6-Methyladenosine (m6A) is the most prevalent RNA modification and recognized as an important epitranscriptomic mechanism in colorectal cancer (CRC). We aimed to exploit whether and how tumor-intrinsic m6A modification driven by methyltransferase like 3 (METTL3) can dictate the immune landscape of CRC. METHODS: Mettl3 knockout mice, CD34+ humanized mice, and different syngeneic mice models were used. Immune cell composition and cytokine level were analyzed by flow cytometry and Cytokine 23-Plex immunoassay, respectively. M6A sequencing and RNA sequencing were performed to identify downstream targets and pathways of METTL3. Human CRC specimens (n = 176) were used to evaluate correlation between METTL3 expression and myeloid-derived suppressor cell (MDSC) infiltration. RESULTS: We demonstrated that silencing of METTL3 in CRC cells reduced MDSC accumulation to sustain activation and proliferation of CD4+ and CD8+ T cells, and eventually suppressed CRC in ApcMin/+Mettl3+/- mice, CD34+ humanized mice, and syngeneic mice models. Mechanistically, METTL3 activated the m6A-BHLHE41-CXCL1 axis by analysis of m6A sequencing, RNA sequencing, and cytokine arrays. METTL3 promoted BHLHE41 expression in an m6A-dependent manner, which subsequently induced CXCL1 transcription to enhance MDSC migration in vitro. However, the effect was negligible on BHLHE41 depletion, CXCL1 protein or CXCR2 inhibitor SB265610 administration, inferring that METTL3 promotes MDSC migration via BHLHE41-CXCL1/CXCR2. Consistently, depletion of MDSCs by anti-Gr1 antibody or SB265610 blocked the tumor-promoting effect of METTL3 in vivo. Importantly, targeting METTL3 by METTL3-single guide RNA or specific inhibitor potentiated the effect of anti-programmed cell death protein 1 (anti-PD1) treatment. CONCLUSIONS: Our study identifies METTL3 as a potential therapeutic target for CRC immunotherapy whose inhibition reverses immune suppression through the m6A-BHLHE41-CXCL1 axis. METTL3 inhibition plus anti-PD1 treatment shows promising antitumor efficacy against CRC.
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Linfocitos T CD8-positivos , Neoplasias Colorrectales , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Quimiocina CXCL1 , Neoplasias Colorrectales/patología , Citocinas/metabolismo , Humanos , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , Ratones Noqueados , Compuestos de Fenilurea , ARN Guía de Kinetoplastida , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , TriazolesRESUMEN
Emerging photoelectrocatalytic (PEC) systems integrate the advantages of photocatalysis and electrocatalysis and are considered as a promising technology for solving the global organic pollution problem in water environments. Among the photoelectrocatalytic materials applied for organic pollutant degradation, graphitic carbon nitride (CN) has the combined advantages of environmental compatibility, stability, low cost, and visible light response. However, pristine CN has disadvantages such as low specific surface area, low electrical conductivity, and high charge complexation rate, and how to improve the degradation efficiency of PEC reaction and the mineralization rate of organic matter is the main problem faced in this field. Therefore, this paper reviews the progress of various functionalized CN used for PEC reaction in recent years, and the degradation efficiency of these CN-based materials is critically evaluated. First, the basic principles of PEC degradation of organic pollutants are outlined. Then, engineering strategies to enhance the PEC activity of CN (including morphology control, elemental doping, and heterojunction construction) are focused on, and the structure-activity relationships between these engineering strategies and PEC activity are discussed. In addition, the important role of influencing factors on the PEC system is summarized in terms of mechanism, to provide guidance for the subsequent research. Finally, suggestions and perspectives are provided for the preparation of efficient and stable CN-based photoelectrocatalysts for practical wastewater treatment applications.
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Contaminantes Ambientales , AguaRESUMEN
OBJECTIVE: Cigarette smoking is a major risk factor for colorectal cancer (CRC). We aimed to investigate whether cigarette smoke promotes CRC by altering the gut microbiota and related metabolites. DESIGN: Azoxymethane-treated C57BL/6 mice were exposed to cigarette smoke or clean air 2 hours per day for 28 weeks. Shotgun metagenomic sequencing and liquid chromatography mass spectrometry were parallelly performed on mice stools to investigate alterations in microbiota and metabolites. Germ-free mice were transplanted with stools from smoke-exposed and smoke-free control mice. RESULTS: Mice exposed to cigarette smoke had significantly increased tumour incidence and cellular proliferation compared with smoke-free control mice. Gut microbial dysbiosis was observed in smoke-exposed mice with significant differential abundance of bacterial species including the enrichment of Eggerthella lenta and depletion of Parabacteroides distasonis and Lactobacillus spp. Metabolomic analysis showed increased bile acid metabolites, especially taurodeoxycholic acid (TDCA) in the colon of smoke-exposed mice. We found that E. lenta had the most positive correlation with TDCA in smoke-exposed mice. Moreover, smoke-exposed mice manifested enhanced oncogenic MAPK/ERK (mitogen-activated protein kinase/extracellular signalregulated protein kinase 1/2) signalling (a downstream target of TDCA) and impaired gut barrier function. Furthermore, germ-free mice transplanted with stools from smoke-exposed mice (GF-AOMS) had increased colonocyte proliferation. Similarly, GF-AOMS showed increased abundances of gut E. lenta and TDCA, activated MAPK/ERK pathway and impaired gut barrier in colonic epithelium. CONCLUSION: The gut microbiota dysbiosis induced by cigarette smoke plays a protumourigenic role in CRC. The smoke-induced gut microbiota dysbiosis altered gut metabolites and impaired gut barrier function, which could activate oncogenic MAPK/ERK signalling in colonic epithelium.
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Fumar Cigarrillos , Neoplasias Colorrectales , Microbioma Gastrointestinal , Animales , Ratones , Microbioma Gastrointestinal/fisiología , Disbiosis/microbiología , Fumar Cigarrillos/efectos adversos , Ratones Endogámicos C57BL , Carcinogénesis , Neoplasias Colorrectales/microbiologíaRESUMEN
OBJECTIVE: Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis. DESIGN: Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses. RESULTS: SQLE messenger RNA and protein expression was upregulated in CRC (p<0.01) and predict poor survival of patients with CRC. SQLE promoted CRC cell proliferation by inducing cell cycle progression and suppressing apoptosis. In azoxymethane-induced CRC model, Sqle tg mice showed increased tumourigenesis compared with wild-type mice (p<0.01). Integrative metagenomic and metabolomic analyses unveiled gut dysbiosis in Sqle tg mice with enriched pathogenic bacteria, which was correlated to increased secondary bile acids. Consistent with detrimental effect of secondary bile acids, gut barrier function was impaired in Sqle tg mice, with reduced tight junction proteins Jam-c and occludin. Transplantation of Sqle tg mice stool to germ-free mice impaired gut barrier function and stimulated cell proliferation compared with control mice stool. Finally, we demonstrated that terbinafine, a SQLE inhibitor, could be repurposed for CRC by synergising with oxaliplatin and 5-fluorouracil to inhibit CRC growth. CONCLUSION: This study demonstrates that SQLE mediates oncogenesis via cell intrinsic effects and modulation of gut microbiota-metabolite axis. SQLE represents a therapeutic target and prognostic marker in CRC.
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Neoplasias Colorrectales , Escualeno-Monooxigenasa , Animales , Azoximetano , Ácidos y Sales Biliares , Carcinogénesis/genética , Proliferación Celular/genética , Colesterol , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/microbiología , Disbiosis , Fluorouracilo , Ratones , Ocludina , Oxaliplatino , ARN Mensajero , Escualeno-Monooxigenasa/genética , Escualeno-Monooxigenasa/metabolismo , TerbinafinaRESUMEN
BACKGROUNDS & AIMS: Squalene epoxidase (SQLE) is the rate-limiting enzyme for cholesterol biosynthesis. We elucidated the functional significance, molecular mechanisms, and clinical impact of SQLE in nonalcoholic steatohepatitis (NASH). METHODS: We performed studies with hepatocyte-specific Sqle overexpression transgenic (Sqle tg) mice and mice given high-fat high-cholesterol (HFHC) or methionine- and choline-deficient (MCD) diet to induce NASH. SQLE downstream target carbonic anhydrase III (CA3) was identified using co-immunoprecipitation and Western Blot. Some mice were given SQLE inhibitor (terbinafine) and CA3 inhibitor (acetazolamide) to study the therapeutic effects in NASH. Human samples (N = 217) including 65 steatoses, 80 NASH, and 72 healthy controls were analyzed for SQLE levels in liver tissue and in serum. RESULTS: SQLE is highly up-regulated in human NASH and mouse models of NASH. Sqle tg mice triggered spontaneous insulin resistance, hepatic steatosis, liver injury, and accelerated HFHC or MCD diet-induced NASH development. Mechanistically, SQLE tg mice caused hepatic cholesterol accumulation, thereby triggering proinflammatory nuclear factor-κB signaling and steatohepatitis. SQLE directly bound to CA3, which induced sterol regulatory element-binding protein 1C activation, acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase1 expression and de novo hepatic lipogenesis. Combined targeting SQLE (terbinafine) and CA3 (acetazolamide) synergistically ameliorated NASH in mice with superior efficacy to either drug alone. Serum SQLE with CA3 could distinguish patients with NASH from steatosis and healthy controls (area under the receiver operating characteristic curve, 0.815; 95% confidence interval, 0.758-0.871). CONCLUSIONS: SQLE drives the initiation and progression of NASH through inducing cholesterol biosynthesis, and SQLE/CA3 axis-mediated lipogenesis. Combined targeting of SQLE and CA3 confers therapeutic benefit in NASH. Serum SQLE and CA3 are novel biomarkers for the noninvasive diagnosis of patients with NASH.
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Anhidrasa Carbónica III/metabolismo , Colesterol/biosíntesis , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Escualeno-Monooxigenasa/metabolismo , Animales , Biomarcadores/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Hepatocitos/metabolismo , Humanos , Resistencia a la Insulina , Lipogénesis , Hígado/metabolismo , Ratones , Ratones Transgénicos , Enfermedad del Hígado Graso no Alcohólico/etiología , Regulación hacia ArribaRESUMEN
To evaluate the operating range and morphology of the surgical safe zone for oblique lumbar interbody fusion (OLIF). Twenty embalmed full-torso cadaveric specimens were dissected. The oblique corridor and the distance between adjacent lumbar arteries were measured in a static state and with psoas major retraction. The morphology and size of the safe zone for OLIF and the location of the lumbar sympathetic trunk were also recorded. The oblique corridor of the L1-L5 segments was significantly greater in the retracted state than in the static state (p < 0.05). With psoas major retraction, the distances between adjacent lumbar arteries at L1-4 were significantly greater (p < 0.05) than those in the static state. The lumbar sympathetic trunk is just located in the safe zone and travels downward adjacent to the psoas major. The shape of the safe zone for OLIF was approximately an oblique upward parallelogram at L1/2 and L2/3, an isosceles trapezoid at L3/4, and an irregular quadrangle or triangle at L4/5. The safe zone for OLIF at L1/2, L2/3, and L3/4 was significantly larger during retraction than in the static state (p < 0.05). On the lateral side of the lumbar spine there is a natural surgical safe zone for OLIF, which can provide a sufficient operating space. The safe zone has a certain morphological pattern in L1-5 segments and psoas major retraction can significantly enlarge it.
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Fusión Vertebral , Cadáver , Humanos , Vértebras Lumbares/cirugía , Región Lumbosacra , Músculos PsoasRESUMEN
BACKGROUND & AIMS: Alterations in the intestinal microbiota affect development of colorectal cancer and drug metabolism. We studied whether the intestinal microbiota affect the ability of aspirin to reduce colon tumor development in mice. METHODS: We performed studies with APCmin/+ mice and mice given azoxymethane and dextran sulfate sodium to induce colorectal carcinogenesis. Some mice were given antibiotics to deplete intestinal microbes, with or without aspirin, throughout the entire experiment. Germ-free mice were studied in validation experiments. Colon tissues were collected and analyzed by histopathology, quantitative reverse-transcription polymerase chain reaction, and immunoblots. Blood samples and gut luminal contents were analyzed by liquid chromatography/mass spectrometry and an arylesterase activity assay. Fecal samples were analyzed by 16S ribosomal RNA gene and shotgun metagenome sequencing. RESULTS: Administration of aspirin to mice reduced colorectal tumor number and load in APCmin/+ mice and mice given azoxymethane and dextran sulfate sodium that had been given antibiotics (depleted gut microbiota), but not in mice with intact microbiota. Germ-free mice given aspirin developed fewer colorectal tumors than conventionalized germ-free mice given aspirin. Plasma levels of aspirin were higher in mice given antibiotics than in mice with intact gut microbiota. Analyses of luminal contents revealed that aerobic gut microbes, including Lysinibacillus sphaericus, degrade aspirin. Germ-free mice fed L sphaericus had lower plasma levels of aspirin than germ-free mice that were not fed this bacterium. There was an inverse correlation between aspirin dose and colorectal tumor development in conventional mice, but this correlation was lost with increased abundance of L sphaericus. Fecal samples from mice fed aspirin were enriched in Bifidobacterium and Lactobacillus genera, which are considered beneficial, and had reductions in Alistipes finegoldii and Bacteroides fragili, which are considered pathogenic. CONCLUSIONS: Aspirin reduces development of colorectal tumors in APCmin/+ mice and mice given azoxymethane and dextran sulfate sodium, depending on the presence of intestinal microbes. L sphaericus in the gut degrades aspirin and reduced its chemopreventive effects in mice. Fecal samples from mice fed aspirin were enriched in beneficial bacteria, with reductions in pathogenic bacteria.
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Anticarcinógenos/farmacocinética , Aspirina/farmacocinética , Neoplasias Colorrectales/prevención & control , Microbioma Gastrointestinal/fisiología , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Antibacterianos/efectos adversos , Anticarcinógenos/administración & dosificación , Aspirina/administración & dosificación , Azoximetano/toxicidad , Bacillaceae/genética , Bacillaceae/aislamiento & purificación , Bacillaceae/metabolismo , Bacteroides fragilis/genética , Bacteroides fragilis/aislamiento & purificación , Bacteroides fragilis/metabolismo , Bacteroidetes/genética , Bacteroidetes/aislamiento & purificación , Bacteroidetes/metabolismo , Disponibilidad Biológica , Carcinogénesis/inducido químicamente , Carcinogénesis/efectos de los fármacos , Colitis/inducido químicamente , Colitis/genética , Colon/efectos de los fármacos , Colon/metabolismo , Colon/microbiología , Colon/patología , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/patología , ADN Bacteriano/aislamiento & purificación , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Heces/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Vida Libre de Gérmenes , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Transgénicos , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: Cervical cancer is the 4th highest cause of female reproductive tract malignancies. Multiple loci have been identified as important determinant factors for tumor susceptibility. In this report, we aimed to explore the roles of gene polymorphisms affecting x-ray repair cross complementing 1 (XRCC1), the tumor protein p53 (TP53), and fibroblast growth factor receptor 3 (FGFR3) in the context of susceptibility to cervical cancer. Additionally, we assessed the impact of single nucleotide polymorphism-single nucleotide polymorphism (SNP-SNP) interaction of these three genes in the context of cervical cancer risk in Chinese women. METHODS: A case-control study consisted of 340 women located in Chongqing. Of these women, 121 were diagnosed with cervical cancer, 118 served as healthy controls, and 101 were specifically recruited elderly patients above the age of 80 who showed no history of cervical cancer. Three SNPs (XRCC1 rs25487, TP53 rs1042522, and FGFR3 rs121913483) were examined using mutation analysis of mismatch amplification PCR (MAMA-PCR) on samples obtained from peripheral blood. RESULTS: Our results indicated that females from southwestern China all exhibited a wild-type phenotype at FGFR3 rs121913483. We also observed that the rs25487 mutation was significantly increased within the cervical cancer population. A 2-locus SNP-SNP interaction pattern (rs25487 and rs1042522) was significantly associated with cervical cancer risk (cases vs. negative controls: OR = 4.63, 95% CI = 1.83-11.75; cases vs. elderly group: OR = 17.61, 95% CI = 4.34-71.50). CONCLUSIONS: This is the first study to identify a novel interaction between the XRCC1 and TP53 genes that is highly associated with susceptibility to cervical cancer risk in a female population in southwestern China.
Asunto(s)
Proteína p53 Supresora de Tumor/genética , Neoplasias del Cuello Uterino/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , China , Femenino , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteína p53 Supresora de Tumor/sangre , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/epidemiología , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/sangreRESUMEN
DCZ3301, a novel aryl-guanidino compound, was previously found to have potent anti-tumor activity in myeloma and B-cell lymphoma. In the present study, we investigated the effects of DCZ3301 on T-cell leukemia/lymphoma cells both in vitro and in vivo via cell proliferation, cell cycle analysis, apoptosis assay, mitochondrial membrane potential (MMP) assay, western blot analysis and tumor xenograft models. We found that DCZ3301 inhibited the viability of T-cell leukemia/lymphoma cells in a dose- and time-dependent manner. DCZ3301-induced G2/M cell cycle arrest, associated with downregulation of CDK1, cyclin B1, and cdc25C. DCZ3301 also induced cell apoptosis by decreasing MMP in T-cell leukemia/lymphoma cells, but had no significant pro-apoptotic effect on normal peripheral blood mononuclear cells (PBMCs). In addition, DCZ3301-induced apoptosis may be mediated by the caspase-dependent pathway and suppressing the phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we showed that DCZ3301 treatment effectively inhibited tumor growth, with no significant side effects, in xenograft mouse models. In conclusion, these results suggest that DCZ3301 may be regarded as a new therapeutic strategy for T-cell leukemia/lymphoma patients.
Asunto(s)
Amidas/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Leucemia de Células T/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piridinas/farmacología , Amidas/química , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Células Jurkat , Leucemia de Células T/metabolismo , Leucemia de Células T/patología , Linfoma de Células T/metabolismo , Linfoma de Células T/patología , Estructura Molecular , Piridinas/química , Transducción de Señal/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In dual-wavelength interferometry (DWI), by combing the advantage of the shorter synthetic-wavelength and the immune algorithm of phase ambiguity, we propose an improved phase retrieval method with both high accuracy and large measurement range, which is a pair of contradiction in the reported DWI method. First, we calculate the height of measured object at longer synthetic-wavelength through using the wrapped phases of two single-wavelengths. Second, by combining the immune algorithm of phase ambiguity and the height of measured object at longer synthetic-wavelength, we can perform the phase unwrapping of the larger one of the two single-wavelengths, then achieve accurate height at single-wavelength named as the transition height. Finally, we perform phase unwrapping of shorter synthetic-wavelength through using the immune algorithm of phase ambiguity and the transition height, and then the height at shorter synthetic-wavelength can be achieved. Compared with the reported method, in addition to maintaining the advantage of high accuracy, the proposed method does not need the additional wavelength, so the corresponding measurement procedures is greatly simplified. Simulation and experimental results demonstrate the performance of proposed method.
RESUMEN
A general spatial phase-shifting (GSPS) interferometry method is proposed to achieve phase retrieval from one-frame spatial carrier frequency interferogram. By optimizing the internal signal retrieving function of the spatial phase-shifting (SPS) method, the accuracy, anti-noise ability and speed of phase retrieval can be significantly improved, meanwhile the corresponding local calculation property is reserved. Especially, in the case that the ratio of the spatial carrier to the phase variation rate are small, the proposed method reveals obvious advantage in the accuracy improvement relative to the conventional SPS methods, so the more details of measured sample can be effectively reserved through introducing smaller spatial carrier frequency, and this will facilitate its application in interference microscopy. The principle analysis, numerical simulation and experimental result are employed to verify the performance of the proposed GSPS method.
RESUMEN
Computational studies were carried out to explore the mechanisms of Rh2(OAc)4-catalyzed transannulation of pyridotriazole with phenylacetylene and benzonitrile, respectively. For the Rh2(OAc)4-catalyzed divergent cyclization with phenylacetylene, the major product (cyclopropene derivative) might be formed via [2 + 2] cycloaddition to yield a metallacyclobutene intermediate followed by a reductive elimination pathway, where carboxylate ligand lability is considered to release a vacant equatorial site for the formation of Rh-carbenoid. The cyclopropenation of phenylacetylene via a commonly proposed [2 + 1] cycloaddition pathway, where the tetrabridged framework of Rh2(OAc)4 is preserved, however, might not play a dominant role. This is because the competing formal [2 + 3] pathway leading to the indolizine as a minor product is more likely to occur. The main factors responsible for the chemoselectivity in cyclization with phenylacetylene are discussed. For the Rh2(OAc)4-catalyzed transannulation of pyridotriazole with benzonitrile, a stepwise formal [2 + 3] pathway via a ylide intermediate is proposed regardless of whether the tetrabridged framework of Rh2(OAc)4 is preserved or not.
RESUMEN
NICS(1) calculations have been performed on the 8π and 10π singlet states and the 9π triplet state of (CO)4, (CS)4, and (CSe)4. The results show that transfer of electrons from the b2g σ MO into the a2u π MO decreases the NICS(1) value, indicating an increase in the diamagnetic ring current. The decreases in the calculated NICS(1) values are substantially larger in (CO)4 than in (CS)4 or (CSe)4. This finding is rationalized by the larger coefficients on the carbons in the a2u MO of (CO)4 than in the a2u MOs of (CS)4 and (CSe)4.
RESUMEN
In simultaneous phase-shifting dual-wavelength interferometry, by matching both the phase-shifting period number and the fringe number in interferogram of two wavelengths to the integers, the phase with high accuracy can be retrieved through combining the principle component analysis (PCA) and least-squares iterative algorithm (LSIA). First, by using the approximate ratio of two wavelengths, we can match both the temporal phase-shifting period number and the spatial fringe number in interferogram of two wavelengths to the integers. Second, using above temporal and spatial hybrid matching condition, we can achieve accurate phase shifts of single-wavelength of phase-shifting interferograms through using PCA algorithm. Third, using above phase shifts to perform the iterative calculation with the LSIA method, the wrapped phases of single-wavelength can be determined. Both simulation calculation and experimental research demonstrate that by using the temporal and spatial hybrid matching condition, the PCA + LSIA based phase retrieval method possesses significant advantages in accuracy, stability and processing time.