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Background: To estimate the global trends and disease burden of Clostridioides difficile infection (CDI) and its correlation with worldwide antibiotic consumption. Methods: Clostridioides difficile infection and antibiotic consumption data were retrieved from the Global Burden of Disease 2019, ResistanceMap-AntibiocUse, Food and Drug Administration (FDA) Adverse Event Reporting System, and Global Antimicrobial Resistance and Use Surveillance System. Jointpoint regression and age-period-cohort model were developed to show the global trends and burden of CDI. Correlation tests were calculated to explore the relationship between CDI and antibiotics. Results: Globally, CDI is the most significant one with a high-rocketing burden increase rate among 13 pathogens causing diarrheal deaths and disability-adjusted life years (DALYs). The age-standardised death rate (ASDR) increased from 0.19 in 1990 to 0.43 in 2019, in which the elderly and females are at higher risk. A rapid increase in ASDR in high to middle sociodemographic index (SDI) regions such as North America (average annual percentage change (AAPC) = 7.71%), Andean (AAPC = 7.82%), and Southern Latin America (AAPC = 11.08%) was identified. Antibiotic consumption has a significant positive correlation with CDI with different risk stratifications. Conclusions: The global burden of CDI has continuously increased for the past 30 years, especially in high to middle-SDI regions. World antibiotic consumption showed a strong positive correlation with CDI with different risk stratification. More effective prevention and control measures should be implemented in these critical regions, with a specific emphasis on vulnerable populations, to mitigate the spread of epidemics.
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Antibacterianos , Infecciones por Clostridium , Carga Global de Enfermedades , Salud Global , Humanos , Infecciones por Clostridium/epidemiología , Infecciones por Clostridium/mortalidad , Antibacterianos/uso terapéutico , Salud Global/estadística & datos numéricos , Persona de Mediana Edad , Femenino , Adulto , Anciano , Adolescente , Masculino , Lactante , Preescolar , Clostridioides difficile , Niño , Adulto Joven , Anciano de 80 o más AñosRESUMEN
Objective: Vitamin D/Vitamin D receptor (VD/VDR) signaling and the Notch pathway are involved in intestinal barrier restoration in colitis; however, their relationship and underlying mechanism are largely unknown. Therefore, this study aimed to investigate the role and mechanism of VD/VDR and the Notch pathways in intestinal barrier protection. Methods: Genetic Vdr knockout (VDR KO) and VD deficient (VDd) mice were established, and colitis was induced by feeding 2.5% dextran sodium sulfate (DSS) water. Mechanistic studies, including real-time PCR, immunofluorescence, Western blotting and dual-luciferase reporter assays, were performed on cultured Caco-2 cells and intestinal organoids. Results: VD deficiency and VDR genetical KO increased the severity of DSS-induced colitis in mice, which presented a higher disease activity index score, increased intestinal permeability, and more severe intestinal histological damage than controls, accompanied by decreased and disrupted claudin-1 and claudin-3. Moreover, inhibition of Notch pathway by LY411,575 aggravated the severity of DSS-induced colitis and intestinal injury. In Caco-2 cells and intestinal organoids, the expression of Notch-1, N1ICD and Hes1 decreased upon downregulation or KO of VDR but increased upon paricalcitol (PAR, a VDR agonist) treatment. Meanwhile, PAR rescued claudin-1 and claudin-3 impairments that resulted from TNF-α exposure but failed to restore claudin-3 upon Notch inhibition. The dual-luciferase reporter assay further suggested that VD/VDR positively regulated the Notch signaling pathway by modulating Notch-1 transcription. Conclusion: VD/VDR positively modulates Notch activation by promoting Notch-1 transcription to maintain intestinal tight junction integrity and barrier function. This highlights the VD/VDR-Notch pathway as a potential new therapeutic target for protecting the intestinal barrier against ulcerative colitis.
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BACKGROUND: HCC is a leading cause of cancer-related death. The role of reactive oxygen species (ROS) in HCC remains elusive. Since a primary ROS source is the mitochondrial electron transport chain complex Ι and the NADH:ubiquinone Oxidoreductase Subunit B3 (NDUFB3), a complex I subunit, is critical for complex I assembly and regulates the associated ROS production, we hypothesize that some HCCs progress by hijacking NDUFB3 to maintain ROS homeostasis. METHODS: NDUFB3 in human HCC lines was either knocked down or overexpressed. The cells were then analyzed in vitro for proliferation, migration, invasiveness, colony formation, complex I activity, ROS production, oxygen consumption, apoptosis, and cell cycle. In addition, the in vivo growth of the cells was evaluated in nude mice. Moreover, the role of ROS in the NDUFB3-mediated changes in the HCC lines was determined using cellular and mitochondrion-targeted ROS scavengers. RESULTS: HCC tissues showed reduced NDUFB3 protein expression compared to adjacent healthy tissues. In addition, NDUFB3 knockdown promoted, while its overexpression suppressed, HCC cells' growth, migration, and invasiveness. Moreover, NDUFB3 knockdown significantly decreased, whereas its overexpression increased complex I activity. Further studies revealed that NDUFB3 overexpression elevated mitochondrial ROS production, causing cell apoptosis, as manifested by the enhanced expressions of proapoptotic molecules and the suppressed expression of the antiapoptotic molecule B cell lymphoma 2. Finally, our data demonstrated that the apoptosis was due to the activation of the c-Jun N-terminal kinase (JNK) signaling pathway and cell cycle arrest at G0/G1 phase. CONCLUSIONS: Because ROS plays essential roles in many biological processes, such as aging and cancers, our findings suggest that NDFUB3 can be targeted for treating HCC and other human diseases.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Ratones Desnudos , NAD , Especies Reactivas de Oxígeno , Ubiquinona , Homeostasis , OxidorreductasasRESUMEN
BACKGROUND: Diversion colitis (DC) is a prevalent complication of colostomy characterized by intestinal inflammation. This study aimed to investigate the therapeutic potential of somatostatin (SST) in managing DC. METHODS: After establishing a rat DC model, SST was administered via Mini Osmotic Pumps 2001W at a pumping rate of 1.0 µL/h. Various techniques, including hematoxylin and eosin staining, periodic acid-Schiff staining, immunofluorescence staining, and electron microscopy were employed to assess the effects of SST. Intestinal barrier functions were evaluated using Evans blue, enzyme-linked immunosorbent assay, and MacConkey agar. RESULTS: After SST treatment, the significant weight loss and associated high mortality in the DC group were successfully mitigated. Upregulation of claudin-3 and claudin-4 restored mechanical barriers in colon epithelial tissue, whereas protection of goblet cells and stimulation of mucus secretion enhanced mucus barriers. SST effectively reduced leaky gut and alleviated systemic inflammation. CONCLUSION: This study provides initial evidence supporting the efficacy of SST in the treatment of DC. It offers insights into the role of SST in DC by elucidating its ability to restore damaged intestinal barriers.
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Colitis , Colostomía , Animales , Ratas , Colostomía/efectos adversos , Ríos , Colitis/tratamiento farmacológico , Colitis/cirugía , Somatostatina/uso terapéutico , InflamaciónRESUMEN
Glutamate dehydrogenase 1 (GLUD1) is an important enzyme in glutamine metabolism. Previously, we found GLUD1 was down-regulated in tumor tissues of hepatocellular carcinoma (HCC) patients by proteomics study. To explore its role in the progression of HCC, the expressional level of GLUD1 was firstly examined and presented as that both the protein and mRNA levels were down-regulated in tumor tissues compared to the normal liver tissues. GLUD1 overexpression significantly inhibited HCC cells proliferation, migration, invasion and tumor growth both in vitro and in vivo, while GLUD1 knocking-down promoted HCC progression. Metabolomics study of GLUD1 overexpressing and control HCC cells showed that 129 differentially expressed metabolites were identified, which mainly included amino acids, bases, and phospholipids. Moreover, metabolites in mitochondrial oxidative phosphorylation system (OXPHOS) were differentially expressed in GLUD1 overexpressing cells. Mechanistic studies showed that GLUD1 overexpression enhanced mitochondrial respiration activity and reactive oxygen species (ROS) production. Excessive ROS lead to mitochondrial apoptosis that was characterized by increased expression levels of p53, Cytochrome C, Bax, Caspase 3 and decreased expression level of Bcl-2. Furthermore, we found that the p38/JNK MAPK pathway was activated in GLUD1 overexpressing cells. N-acetylcysteine (NAC) treatment eliminated cellular ROS and blocked p38/JNK MAPK pathway activation, as well as cell apoptosis induced by GLUD1 overexpression. Taken together, our findings suggest that GLUD1 inhibits HCC progression through regulating cellular metabolism and oxidative stress state, and provide that ROS generation and p38/JNK MAPK pathway activation as promising methods for HCC treatment.
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Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.
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Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Oxaliplatino/farmacología , Terapia Neoadyuvante/métodos , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/genética , Quimioradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromatina , Resultado del Tratamiento , Factores de Transcripción de Dominio TEA , Ubiquitina-Proteína Ligasas , Proteínas de Unión a RetinoblastomaRESUMEN
Objectives: Vitamin D (VitD) and Vitamin D receptor (VDR) are suggested to play protective roles in the intestinal barrier in ulcerative colitis (UC). However, the underlying mechanisms remain elusive. Evidence demonstrates that Na+/H+ exchanger isoform 8 (NHE8, SLC9A8) is essential in maintaining intestinal homeostasis, regarded as a promising target for UC therapy. Thus, this study aims to investigate the effects of VitD/VDR on NHE8 in intestinal protection. Methods: VitD-deficient mice, VDR-/- mice and NHE8-/- mice were employed in this study. Colitis mice were established by supplementing DSS-containing water. Caco-2 cells and 3D-enteroids were used for in vitro studies. VDR siRNA (siVDR), VDR over-expression plasmid (pVDR), TNF-α and NF-κb p65 inhibitor QNZ were used for mechanical studies. The expression of interested proteins was detected by multiple techniques. Results: In colitis mice, paricalcitol upregulated NHE8 expression was accompanied by restoring colonic mucosal injury. In VitD-deficient and VDR-/- colitis mice, NHE8 expression was compromised with more serious mucosal damage. Noteworthily, paricalcitol could not prevent intestinal barrier dysfunction and histological destruction in NHE8-/- mice. In Caco-2 cells and enteroids, siVDR downregulated NHE8 expression, further promoted TNF-α-induced NHE8 downregulation and stimulated TNF-α-induced NF-κb p65 phosphorylation. Conversely, QNZ blocked TNF-α-induced NHE8 downregulation in the absence or presence of siVDR. Conclusions: Our study indicates depressed NHE8 expression is responsible for VitD-deficient-induced colitis aggravation. These findings provide novel insights into the molecular mechanisms of VitD/VDR in intestine protection in UC.
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Colitis Ulcerosa , Colitis , Deficiencia de Vitamina D , Humanos , Animales , Ratones , Células CACO-2 , Factor de Necrosis Tumoral alfa/metabolismo , FN-kappa B/metabolismo , Colitis/metabolismo , Mucosa Intestinal/metabolismo , Vitamina D/metabolismo , Deficiencia de Vitamina D/metabolismo , Ratones Endogámicos C57BL , Sulfato de Dextran/efectos adversos , Colitis Ulcerosa/metabolismoRESUMEN
As ecosystems subject to periodic tides, estuarine wetlands have a significant capacity to sequester carbon over time. Understanding the distribution patterns of soil carbon components and identifying the key factors influencing these patterns are key to gaining insight into the function of "blue carbon" in coastal wetlands. To clarify the response of soil carbon components to wetland types and hydrological effects in estuarine wetlands, the typical estuarine wetlands in Jiaozhou Bay, China were selected as the study area, and the soil organic carbon (SOC), dissolved organic carbon (DOC), microbial biomass carbon (MBC), soil inorganic carbon (SIC) and dissolved inorganic carbon (DIC) under different wetland types and hydrological effects were investigated. The results showed that the SOC, SIC, and MBC contents were significantly influenced by the wetland types. The SOC and MBC contents were as follows: mudflat (GT) > Phragmites australis wetland (PA) > Suaeda salsa wetland (SS). The overall content of SIC was highest in PA, followed by GT and SS. Hydrological effects had significant influence on the soil MBC, DOC and DIC contents. With the increase hydrological effects, the soil MBC content decreased by 38.89%-72.22%, while the DOC and DIC contents increased by 15.13%-19.89% and 13.41%-86.70%, respectively. The results of the correlation analysis and structural equation model indicated that wetland types and hydrological effects directly or indirectly (through changes in soil pH, bulk density, water content, and salinity) drove the changes in soil carbon contents in estuarine wetlands. Altogether, our findings implied that the alterations of wetland types and hydrological effects will affect the blue carbon function of estuarine wetlands. In the future, for accurate assessment of a blue carbon budget for estuarine wetlands, the differences in wetland types and hydrological effects of different areas should be considered.
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Ecosistema , Humedales , Suelo/química , Carbono/análisis , Bahías , Poaceae , China , Materia Orgánica DisueltaRESUMEN
Background: Cholestasis is a common pathological process in a variety of liver diseases that may lead to liver fibrosis, cirrhosis, and even liver failure. Cholestasis relief has been regarded as a principal target in the management of multiple chronic cholestasis liver diseases like primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) at present. However, complicated pathogenesis and limited acknowledgments fettered therapeutic development. Therefore, this study aimed to systematically analyze miRNA-mRNA regulatory networks in cholestatic liver injury in order to provide new treatment strategies. Methods: Gene Expression Omnibus (GEO) database (GSE159676) was used to screen differentially expressed hepatic miRNAs and mRNAs in the PSC vs. control comparison and the PBC vs. control comparison, respectively. MiRWalk 2.0 tool was used to predict miRNA-mRNA pairs. Subsequently, functional analysis and immune cell infiltration analysis were performed to explore the pivotal functions of the target genes. RT-PCR was used to verify the result. Results: In total, a miRNA-mRNA network including 6 miRNAs (miR-122, miR-30e, let-7c, miR-107, miR-503, and miR-192) and 8 hub genes (PTPRC, TYROBP, LCP2, RAC2, SYK, TLR2, CD53, and LAPTM5) was constructed in cholestasis. Functional analysis revealed that these genes were mainly involved in the regulation of the immune system. Further analysis revealed that resting memory CD4 T cells and monocytes could potentially participate in cholestatic liver injury. The expressions of DEMis and eight hub genes were verified in ANIT-induced and BDL-induced cholestatic mouse models. Furthermore, SYK was found to have an impact on the response to UDCA, and its mechanism was possibly associated with complement activation and monocyte reduction. Conclusion: In the present study, a miRNA-mRNA regulatory network was constructed in cholestatic liver injury, which mostly mediated immune-related pathways. Moreover, the targeted gene SYK and monocytes were found to be related to UDCA response in PBC.
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BACKGROUND: Vitamin D receptor (VDR) and SLC26A3 (DRA) have been identified as pivotal protective factors in maintaining gut homeostasis in IBD patients. However, the specific mechanism underlying the increased intestinal susceptibility to inflammation induced by the loss of VDR and whether DRA participates in the role of VDR regulating intestinal epithelial barrier function are undefined. AIM: The current study is undertaken to elucidate the regulatory effects of VDR on DRA and VDR prevents intestinal epithelial barrier dysfunction via up-regulating the expression of DRA. METHODS: WT and VDR-/- mice are used as models for intestinal epithelial response. Paracellular permeability is measured by TEER and FD-4 assays. Immunohistochemistry, immunofluorescence, qPCR and immunoblotting are performed to determine the effects of VDR and DRA on gut epithelial barrier function. RESULTS: VDR-/- mice exhibits significant hyperpermeability of intestine with greatly decreased levels of ZO-1 and Claudin1 proteins. DRA is located on the intestinal epithelial apical membrane and is tightly modulated by VDR in vivo and in vitro via activating ERK1/2 MAPK signaling pathway. Notably, the current study for the first time demonstrates that VDR maintains intestinal epithelial barrier integrity via up-regulating DRA expression and the lack of DRA induced by VDR knockdown leads to a more susceptive condition for intestine to DSS-induced colitis. CONCLUSION: Our study provides evidence and deep comprehension regarding the role of VDR in modulating DRA expression in gut homeostasis and makes novel contributions to better generally understanding the links between VDR, DRA and intestinal epithelial barrier function.
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Antiportadores , Colitis , Receptores de Calcitriol , Transportadores de Sulfato , Animales , Humanos , Ratones , Antiportadores/efectos adversos , Antiportadores/metabolismo , Células CACO-2 , Antiportadores de Cloruro-Bicarbonato/metabolismo , Antiportadores de Cloruro-Bicarbonato/farmacología , Células Epiteliales/metabolismo , Mucosa Intestinal/metabolismo , Ratones Endogámicos C57BL , Receptores de Calcitriol/metabolismo , Transportadores de Sulfato/genética , Transportadores de Sulfato/metabolismoRESUMEN
The intestinal barrier is a dynamic entity that is organized as a multilayer system and includes various intracellular and extracellular elements. The gut barrier functions in a coordinated manner to impede the passage of antigens, toxins, and microbiome components and simultaneously preserves the balanced development of the epithelial barrier and the immune system and the acquisition of tolerance to dietary antigens and intestinal pathogens.Numerous scientific studies have shown a significant association between gut barrier damage and gastrointestinal and extraintestinal diseases such as inflammatory bowel disease, celiac disease and hepatic fibrosis. Various internal and external factors regulate the intestinal barrier. Gastrointestinal peptides originate from enteroendocrine cells in the luminal digestive tract and are critical gut barrier regulators. Recent studies have demonstrated that gastrointestinal peptides have a therapeutic effect on digestive tract diseases, enhancing epithelial barrier activity and restoring the gut barrier. This review demonstrates the roles and mechanisms of gastrointestinal polypeptides, especially somatostatin (SST) and vasoactive intestinal peptide (VIP), in intestinal barrier regulation.
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Enfermedades Gastrointestinales , Enfermedades Inflamatorias del Intestino , Células Enteroendocrinas , Humanos , Mucosa Intestinal , Péptido Intestinal VasoactivoRESUMEN
Somatostatin receptor 5 (SSTR5) is involved in intestinal barrier protection during colitis through modulating tight junction (TJ) proteins, but the mechanisms of SSTR5 in TJ regulation are largely unknown. Therefore, the present study was designed to illuminate how SSTR5 modulated intestinal barrier function and TJ proteins. In this study, activation of SSTR5 by its special agonist L817,818 effectively ameliorated impaired intestinal barrier function in TNF-α-pretreated cells and mice with colitis. Restoration of intestinal barrier function was dependent on upregulation of claudin-4 and ZO-1. Suppression of SSTR5 signaling through specific siRNA or the antagonist BIM23056 markedly exacerbated TNF-α-induced claudin-4 and ZO-1 damage. L817,818 treatment markedly suppressed TNF-α-induced NF-κB p65 phosphorylation, myosin light chain kinase (MLCK) upregulation and myosin light chain (MLC) phosphorylation. Exposure to a NF-κB inhibitor (QNZ) or MLCK inhibitor (ML-7) effectively inhibited compromised claudin-4 and ZO-1 induced by BIM23056/TNF-α. These observations indicate that activation of SSTR5 protects intestinal barrier function by upregulating claudin-4 and ZO-1 expression, which is mediated by NF-κB-MLCK-MLC signaling. Taken together, our findings suggest that SSTR5 might represent a promising target for colitis therapy.
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Amidas/farmacología , Colitis/metabolismo , Naftalenos/farmacología , Oligopéptidos/farmacología , Receptores de Somatostatina/metabolismo , Factor de Necrosis Tumoral alfa/efectos adversos , Animales , Células CACO-2 , Claudina-4/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Ratones , Transducción de Señal/efectos de los fármacos , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
BACKGROUND: Perianal/perineal rhabdomyosarcomas (PRMS) are easily misdiagnosed soft tissue tumours with a poor prognosis. This study was designed to analyze the clinical, diagnostic, pathological and prognostic features of PRMS, and to explore currently available therapeutic modalities. METHODS: Clinical data of PRMS patients admitted to the Sixth Affiliated Hospital and the Cancer Center of Sun Yat-sen University and from related Chinese literature published from 1987 to 2018 were collected and analyzed. The Chi-square test was used to evaluate the differences between each group. The Kaplan-Meier methods were applied to estimate and compare survival rates. RESULTS: A total of 35 patients were included in this study; 20 identified within related Chinese literatures and 15 from our center admitted during the period of 1997-2019. Out of these cases, 34 presented with perianal masses and the remaining one manifested as an inguinal mass. Moreover, 20 patients complained of pain and 16 of them were misdiagnosed as perianal abscesses, in which the presence of pain contributed to the misdiagnosis (p < 0.05). The average time interval between symptom onset and pathological diagnosis was 3.1 months. Next, 13 cases were classified into IRS group III/IV and 20 cases into stages 3/4. Additionally, 14 and 9 cases received the pathological diagnoses of embryonal rhabdomyosarcoma and alveolar rhabdomyosarcoma, respectively. Regarding the patients' survival rates, five patients survived for more than 2 years, and three of them survived for more than 5 years. The overall 2 years and 5 years survival rates were 32% and 24%, respectively. The symptom of pain and misdiagnosis both contributed to the poor prognosis in these patients (p < 0.05). MRI showed that the PRMS were closely related to external anal sphincter in 10 cases. CONCLUSION: PRMS are easily misdiagnosed lesions, which often leads to an unfavourable outcome in affected patients. Patients with painful perianal masses should be evaluated to exclude PRMS. MRI revealed that PRMS are closely related to the external anal sphincter. Multidisciplinary management is recommended in the treatment of PRMS.
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Neoplasias del Ano/patología , Rabdomiosarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Adolescente , Adulto , Canal Anal/diagnóstico por imagen , Neoplasias del Ano/mortalidad , Neoplasias del Ano/cirugía , Niño , Preescolar , Diagnóstico Diferencial , Errores Diagnósticos , Humanos , Biopsia Guiada por Imagen , Lactante , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Persona de Mediana Edad , Perineo/diagnóstico por imagen , Pronóstico , Recto/diagnóstico por imagen , Rabdomiosarcoma/mortalidad , Rabdomiosarcoma/cirugía , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/cirugía , Tasa de Supervivencia , Resultado del Tratamiento , Ultrasonografía , Adulto JovenRESUMEN
Invasion and metastasis are the major causes leading to the high mortality of colon cancer. Ginsenoside Rg3 (Rg3), as a bioactive ginseng compound, is suggested to possess antimetastasis effects in colon cancer. However, the underlying molecular mechanisms remain unclear. In this study, we reported that Rg3 could effectively inhibit colon cancer cell invasion and metastasis through in vivo and in vitro studies. In addition, Rg3 suppressed the epithelial-mesenchymal transition (EMT) of HCT15 cells and SW48 cells evidenced by detecting EMT related markers E-cadherin, vimentin, and snail expression. Furthermore, inhibition of Notch signaling by LY411,575 or specific Hes1 siRNA obviously repressed colon cancer cell migration and metastasis, and induced increase in E-cadherin and decrease in vimentin and snail. Meanwhile, the expression of NICD and Hes1 was obviously decreased in the presence of Rg3. However, Rg3 failed to suppress EMT in Hes1 overexpressed colon cancer cells. In particular, Rg3 significantly reversed IL-6-induced EMT promotion and blocked IL-6- induced NICD and Hes1 upregulations. Overall, these findings suggested that Rg3 could inhibit colon cancer migration and metastasis via suppressing Notch-Hes1-EMT signaling.
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Antineoplásicos , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Ginsenósidos/farmacología , Metástasis de la Neoplasia/genética , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factor de Transcripción HES-1/metabolismo , Animales , Humanos , Interleucina-6/antagonistas & inhibidores , Masculino , Ratones Endogámicos BALB C , Células Tumorales CultivadasRESUMEN
Gravity is one of the important environmental factors that influence the physiologies and behaviors of animals and humans, and changes in gravity elicit a variety of physiological and behavioral alterations that include impaired movement coordination, vertigo, spatial disorientation, and perceptual illusions. To elucidate the effects of gravity on human physiology and behavior, we examined changes in wrist and trunk activities and heart rate during parabolic flight and the activity of wrist and trunk in water immersion experiments. Data from 195 person-time parabolas performed by eight subjects revealed that the trunk motion counts decreased by approximately half during ascending legs (hypergravity), relative to the data acquired before the parabolic flights. In contrast, the wrist activity remained unchanged. The results from the water immersion experiments demonstrated that in the underwater condition, both the wrist and trunk activities were significantly decreased but the latter decreased to a much lower level. Together, these data suggest that gravitational alterations can result in differential influences on the motions of the wrist and the trunk. These findings might be important for understanding the degeneration of skeleton and muscular system and performance of astronauts in microgravity.
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Gravedad Alterada , Movimiento (Física) , Actividad Motora , Adulto , Frecuencia Cardíaca , Humanos , Masculino , Muñeca , Adulto JovenRESUMEN
OBJECTIVE: To study the difference between the dynamic responses of human body and human surrogate under 30 degrees supine position, and to discuss impact probability of substituting human body with human surrogate in impact tests. METHOD: Five volunteers experienced half-sine impact pulses, averaged 4.76, 8.96, 11.33 G, lasting for 40-60 ms on an impact tower. The human surrogate was exposed to half-sine impact pulses, averaged 6.77, 10.39, 16.93, 21.11, 24.98, 31.11 G, lasting for 40-60 ms, two times for each G level. ECG changes of the volunteers were continuously monitored before, during and after each impact. RESULT: Output responses at forehead and chest of human body and human surrogate increased with input increments. But there was obvious difference of the dynamic responses between human body and the surrogate to impact of low G levels. Heart rate of each volunteer had temporary increase during the process of impact, and returned to normal level soon after the impact. CONCLUSION: There is difference in a certain extend between the dynamic responses of human body and human surrogate. The ECG changes are induced mainly by mental stress during process of impact.
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Aceleración , Frecuencia Cardíaca/fisiología , Hipergravedad , Maniquíes , Posición Supina/fisiología , Adulto , Fenómenos Biomecánicos , Electrocardiografía , Estudios de Evaluación como Asunto , HumanosRESUMEN
The present study was to determine the effects of simulated microgravity (SM) on the pulmonary artery (PA) and aorta(TA), and to disclose the changes in pathophysiology of cardiovascular deconditioning(CVD) induced by SM and to explore the effects of NOS inhibitor (N-nitro-L-arginine methylester, L-NAME) on CVD. The high hemodynamics in pulmonary and systemic circulation of human bodies appeared during the initial period and super-regulatory phenomena under 6°head-down tilt bed.
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Landing impact is the dynamic factor that manned spaceship will inevitably meet after the mission has been completed, and impact force may cause damages to human tissues [correction of tissuses] and organs, even death. This paper described the characteristics of pathological and dynamic response of human body to landing impact, and discussed various related factors such as impact angle, fetters, design of cushion, harness and terrain condition. Medical evaluation of +Gx, +Gz, +/- Gy impacts were summarized.