RESUMO
Quantum correlation, as an intrinsic property of quantum mechanics, has been widely employed to test the fundamental physical principles and explore the quantum-enhanced technologies. However, such correlation would be drowned and even destroyed in the conditions of high levels of loss and noise, which drops into the classical realm and renders quantum advantage ineffective. Especially in low light conditions, conventional linear classifiers are unable to extract and distinguish quantum and classical correlations with high accuracy. Here we experimentally demonstrate the classification of quantum correlation using deep learning to meet the challenge in the quantum imaging scheme. We design the convolutional neural network to learn and classify the correlated photons efficiently with only 0.1 signal photons per pixel. We show that decreasing signal intensity further weakens the correlation and makes an accurate linear classification impossible, while the deep learning method has a strong robustness of such task with the accuracy of 99.99%. These results open up a new perspective to optimize the quantum correlation in low light conditions, representing a step towards diverse applications in quantum-enhanced measurement scenarios, such as super-resolution microscope, quantum illumination, etc.
RESUMO
BACKGROUND AND AIMS: Antibiotics (ATBx) and acetaminophen (APAP) are widely used worldwide. APAP is the most common cause of acute liver injury (ALI) and might be used in combination with ATBx in clinics. However, the impact of ATBx on APAP-induced ALI has rarely been studied. METHODS: First, we compared the effects of seven ATBx on APAP-induced ALI. Then, we analysed faecal, serum and liver samples to investigate the impact of the gut microbiota on this process. Finally, we assessed the role of short-chain fatty acids in this process. RESULTS: In this work, we found that the ALI was significantly aggravated in the mice treated with ampicillin (Amp) instead of other ATBx. Amp exposure reduced the diversity and altered the composition of gut microbiota. The altered gut microbiota aggravated APAP-induced ALF, which was proven by faecal microbiota transplantation from ATBx-treated mice. Metagenomic analysis showed a significantly decreased Lactobacillus abundance in Amp-treated mice. Gavage with Lactobacillus, especially Lactobacillus rhamnosus, significantly reversed the severer ALF induced by APAP and Amp. Moreover, Lactobacillus supplementation increased butyrate-producing clostridia and lowered butyrate levels in Amp-treated mice. In accordance, butyrate supplementation could also alleviate Amp-aggravated ALI. In addition, inhibition of nuclear factor erythroid 2-related factor 2 counteracted the protective effect of butyrate on aggravated ALI induced by Amp and APAP. CONCLUSION: Together, this study revealed a potential health impact of Amp that may exacerbate liver damage when co-exposed to excess APAP.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Microbioma Gastrointestinal , Animais , Camundongos , Acetaminofen/toxicidade , Butiratos/farmacologia , Fígado , Ampicilina/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Camundongos Endogâmicos C57BLRESUMO
Nonalcoholic steatohepatitis (NASH) is the major cause of liver dysfunction. Animal and population studies have shown that mitochondrial aldehyde dehydrogenase (ALDH2) is implicated in fatty liver disease. However, the role of ALDH2 in NASH and the underlying mechanisms remains unclear. To address this issue, ALDH2 knockout (ALDH2-/-) mice and wild-type littermate mice were fed a methionine-and choline-deficient (MCD) diet to induce a NASH model. Fecal, serum, and liver samples were collected and analyzed to investigate the impact of the gut microbiota and bile acids on this process. We found that MCD-fed ALDH2-/- mice exhibited increased serum pro-inflammation cytokines, hepatic inflammation and fat accumulation than their wild-type littermates. MCD-fed ALDH2-/- mice exhibited worsened MCD-induced intestinal inflammation and barrier damage, and gut microbiota disorder. Furthermore, mice receiving microbiota from MCD-fed ALDH2-/- mice had increased severity of NASH compared to those receiving microbiota from MCD-fed wild-type mice. Notably, the intestinal Lactobacillus was significantly reduced in MCD-fed ALDH2-/- mice, and gavage with Lactobacillus cocktail significantly improved MCD-induced NASH. Finally, we found that ALDH2-/- mice had reduced levels of bile salt hydrolase and specific bile acids, especially lithocholic acid (LCA), accompanied by downregulated expression of the intestinal FXR-FGF15 pathway. Supplementation of LCA in ALDH2-/- mice upregulated intestinal FXR-FGF15 pathway and alleviated NASH. In summary, ALDH2 plays a critical role in the development of NASH through modulation of gut microbiota and bile acid. The findings suggest that supplementing with Lactobacillus or LCA could be a promising therapeutic approach for treating NASH exacerbated by ALDH2 deficiency.
RESUMO
BACKGROUND: The importance of the composition of an energy-restricted diet in the treatment of metabolic syndrome (MetS) is unknown. OBJECTIVES: In this study we aimed to investigate the benefits of a novel dietary treatment (50% calorie restriction diet composed of yogurt, fruit, and vegetables [CR-YD]) in mice with MetS. METHODS: Forty 7-wk-old male C57BL/6 J mice were randomly assigned to 4 groups (n = 10/group) that were fed for 14 wk ad libitum with a normal diet (ND; 10%:70%:20% energy from fat: carbohydrate: protein) or for 12 wk with a high-fat diet (HFD; 60:20:20) or the HFD followed by 2 wk of feeding with a 50% calorie-restricted HFD (CR-HFD) or YD (CR-YD, 21.2%:65.4%:13.4% energy). Body weight, fat deposition, hepatic steatosis, serum concentrations of inflammatory biomarkers, and glucose homeostasis were assessed. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in MetS. RESULTS: The HFD group had 50% greater body weight and 475% greater fat deposition than the ND group (P < 0.05). Compared with the HFD group, the CR-HFD and CR-YD groups had 22% and 31% lower body weight and 49% and 75% less fat deposition, respectively (P < 0.05). Compared with the CR-HFD group, the CR-YD group had 11% lower body weight, 96% less fat deposition, 500% less hepatic steatosis, 75% lower glucose, and 450% more hepatic Akkermansia bacteria (P < 0.05). The CR-YD group also had 50% lower histopathology scores and 1.35-fold higher levels of Claudin4 than the CR-HFD group (P < 0.05). The HFD + CR-YD fecal group had 10.6% lower body weight, 119% lower steatosis, and 17.9% lower glucose (P < 0.05) than the HFD + CR-HFD fecal group. CONCLUSIONS: Compared with CR alone, the CR-YD diet has a better therapeutic effect in mice with HFD-induced MetS.
Assuntos
Fígado Gorduroso , Microbioma Gastrointestinal , Síndrome Metabólica , Masculino , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Verduras , Síndrome Metabólica/terapia , Obesidade/metabolismo , Frutas , Iogurte , Camundongos Endogâmicos C57BL , Peso Corporal , Glucose/farmacologiaRESUMO
Optical underwater target imaging and detection have been a tough but significant challenge in deep-sea exploration. Distant reflected signals drown in various underwater noises due to strong absorption and scattering, resulting in degraded image contrast and reduced detection range. Single-photon feature operating at the fundamental limit of the classical electromagnetic waves can broaden the realm of quantum technologies. Here we experimentally demonstrate a thresholded single-photon imaging and detection scheme to extract photon signals from the noisy underwater environment. We reconstruct the images obtained in a high-loss underwater environment by using photon-limited computational algorithms. Furthermore, we achieve a capability of underwater detection down to 0.8 photons per pulse at Jerlov type III water up to 50 meters, which is equivalent to more than 9 attenuation lengths. The results break the limits of classical underwater imaging and detection and may lead to many quantum-enhanced applications, like air-to-sea target tracking and deep-sea optical exploration.
RESUMO
Calorie restriction can modulate the gut microbiota and protect against many diseases including ischemic stroke. However, the role of calorie-restriction-induced microbiota alteration remained unknown in ischemic stroke rehabilitation. Here we conducted 30% reduction of caloric intake on mice for four weeks, to evaluate its role on ischemic stroke rehabilitation. Significantly, this calorie restriction led to better long-term rehabilitation in comparison of normal control. Notably, the transplantation of gut microbiome from calorie-restriction-treated mice to post-stroke mice was eligible to obtain better long-term rehabilitation of stroke mice. Bifidobacterium identified by 16â¯S ribosomal RNA sequencing were enriched in those of calorie-restriction mice. Then we administrated Bifidobacterium to stroke mice and found Bifidobacterium treatment could successfully improve the long-term rehabilitation of cerebral ischemia mice. Furthermore, the metabolomics analysis revealed a panel of upshifting metabolites, suggesting that calorie restriction greatly altered the gut microbiota composition and its metabolism. Hence, we discovered the novel effect of CR on long-term rehabilitation of ischemic stroke and the underlying role of gut microbiota, which might provide novel thoughts for the clinical post-stroke rehabilitation.
Assuntos
Bactérias/crescimento & desenvolvimento , Eixo Encéfalo-Intestino , Encéfalo/fisiopatologia , Restrição Calórica , Microbioma Gastrointestinal , AVC Isquêmico/reabilitação , Reabilitação do Acidente Vascular Cerebral , Animais , Bactérias/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Disbiose , AVC Isquêmico/metabolismo , AVC Isquêmico/microbiologia , AVC Isquêmico/fisiopatologia , Camundongos , Recuperação de Função Fisiológica , Fatores de TempoRESUMO
Topology manifesting in many branches of physics deepens our understanding on state of matters. Topological photonics has recently become a rapidly growing field since artificial photonic structures can be well designed and constructed to support topological states, especially a promising large-scale implementation of these states using photonic chips. Meanwhile, due to the inapplicability of Hall conductance to photons, it is still an elusive problem to directly measure the integer topological invariants and topological phase transitions in photonic system. Here, we present a direct observation of topological winding numbers by using bulk-state photon dynamics on a chip. Furthermore, we for the first time experimentally observe the topological phase transition points via single-photon dynamics. The integrated topological structures, direct measurement in the single-photon regime and strong robustness against disorder add the key elements into the toolbox of "quantum topological photonics" and may enable topologically protected quantum information processing in large scale.
RESUMO
Aim: To evaluate the impact of socioeconomic factors (SEFs) on survival of renal cell carcinoma (RCC) patients. Materials & methods: RCC patients diagnosed between 2007 and 2015 were collected from the SEER database. The crude and multivariate Cox regression analysis was used to identify the independent prognostic factors and quantity the mortality risks for overall survival (OS). Results: Three SEFs including marital status, insurance status and median household income were identified as prognostic factors for OS. SEF-stage was built based on the three SEFs. Moreover, the SEF-stage 1 had superior OS than SEF-stage 2 within the respective American Joint Committee on Cancer stages. Conclusion: The SEF-stage was an independently prognostic factor for OS in RCC. Incorporation of SEF-stage into the American Joint Committee on Cancer staging system might be beneficial for better survival prediction and clinical management. However, further studies were needed to validate these findings in other populations.
Assuntos
Carcinoma de Células Renais/mortalidade , Neoplasias Renais/mortalidade , Adolescente , Adulto , Carcinoma de Células Renais/diagnóstico , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/diagnóstico , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Vigilância em Saúde Pública , Programa de SEER , Fatores Socioeconômicos , Carga Tumoral , Adulto JovemRESUMO
Annonaceous acetogenins are a well-established family of natural products with significant bioactivities, especially high cytotoxic and antitumor activities. AA005 is an annonaceous acetogenin mimic that has shown significant cytotoxicity against a variety of cancer cell lines, but its in vivo antitumor effects have not been demonstrated so far, and its anticancer mechanisms remain ambiguous. In this study, we investigated the effects of AA005 on human colon cancer cell lines in vivo. Human colon carcinoma cell line SW620 xenograft nude mice were treated with AA005 (5 mg/kg/day, i.p.) for 21 days. AA005 administration markedly inhibited the tumor growth via promoting nuclear translocation of apoptosis-inducing factor (AIF) and inducing AIF-dependent cell death. Subsequent studies in human colon carcinoma cell lines SW620 and RKO in vitro revealed that after the colon cancer cells exposed to AA005, downregulation of a B-cell lymphoma 2 family protein, myeloid cell leukemia-1 (Mcl-1), was an early event due to the inhibition of Mcl-1 mRNA level and protein synthesis in a time-dependent manner. Intriguingly, knockdown of Mcl-1 using small interfering RNA markedly accelerated the nuclear translocation of AIF and upregulation of receptor interacting protein-1, and enhanced AA005-mediated lethality, whereas ectopic expression of Mcl-1 substantially attenuated AA005-mediated lethality in the colon cancer cells. Finally, silencing Mcl-1 expression markedly enhanced AA005-induced lethality in SW620 xenograft nude mice, demonstrating a pivotal role of Mcl-1 downregulation in mediating the in vivo antitumor effects of AA005. Taken together, this study demonstrates for the first time the anticancer effects of AA005 against human colon cancer cell lines in vivo, which is mediated through the downregulation of Mcl-1.
Assuntos
Acetogeninas/química , Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Álcoois Graxos/uso terapêutico , Lactonas/uso terapêutico , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Animais , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo , Álcoois Graxos/química , Humanos , Lactonas/química , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND AND AIMS: Hepatitis virus and alcohol are the main factors leading to liver damage. Synergy between hepatitis B virus (HBV) and alcohol in promoting liver cell damage and disease progression has been reported. However, the interaction of HBV and ethanol in hepatic steatosis development has not been fully elucidated. METHODS: Eight-week-old male C57BL/6 mice were treated with or without HBV, ethanol, or the combination of HBV and ethanol (HBV+EtOH), followed by a three-week high-fat diet (HFD) regimen. Liver histology, serum biomarkers, and liver triglyceride levels were analysed. Furthermore, a meta-analysis of the effects of alcohol and HBV on hepatic steatosis in populations was performed. RESULTS: Hepatic steatosis was significantly more severe in the HBV+EtOH group than in the other groups. The serum alanine aminotransferase, aspartate aminotransferase and liver triglyceride levels in the HBV+EtOH group were also significantly higher than those in the other groups. The HBeAg and HBsAg levels in the HBV+EtOH group were significantly higher than those in the pair-fed HBV-infected mice. In addition, the meta-analysis showed that alcohol consumption increased the risk of hepatic steatosis by 43% in HBV-infected patients (pooled risk ratio (RR)=1.43, P<0.01). CONCLUSIONS: Alcohol and HBV synergistically promote high-fat diet-induced hepatic steatosis in mice. In addition, alcohol consumption increases the risk of hepatic steatosis in HBV-infected patients.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Dieta Hiperlipídica , Etanol/farmacologia , Fígado Gorduroso/patologia , Hepatite B Crônica/patologia , Fígado/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/epidemiologia , Animais , Modelos Animais de Doenças , Fígado Gorduroso/epidemiologia , Fígado Gorduroso/virologia , Hepatite B Crônica/epidemiologia , Humanos , Fígado/patologia , Fígado/virologia , CamundongosRESUMO
Essential hypertension is a leading global public health issue, billions of people suffered from it every year. Recently, multiple evidence suggests that DNA methylation play an important role in regulating blood pressure. Here, we tested the risk for essential hypertension conferred by single nucleotide polymorphisms (SNPs) within DNA methyltransferase 1 (DNMT1). Three loci (rs2228611, rs2228612, and rs16999593) were selected to be analyzed in 3410 cases and 1307 normal controls in southern Chinese aged 60 or above. No significant association with essential hypertension was observed for rs2228612 and rs16999593. A higher risk of essential hypertension was found in the minor A allele of rs2228611 in the codominant and recessive model (P < 0.05). After stratified by sex, this association was found in male but not female. Furthermore, this difference was abolished after BMI adjustment in the whole population and reduced in male. In addition, the mutation rate of rs2228611 was higher in the obesity group compared with the normal weight group of male. Intriguingly, rs2228611 was also a risk factor of essential hypertension in normal weight male. These findings indicated that rs2228611 might contribute to male hypertension via BMI-dependent mechanisms in obesity male and BMI-independent mechanisms in normal weight male.
Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , Hipertensão Essencial/genética , Predisposição Genética para Doença/genética , Idoso , Alelos , Povo Asiático/genética , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores SexuaisRESUMO
Essential hypertension (EH) is a worldwide problem. Acetaldehyde dehydrogenase 2 (ALDH2) gene has been suggested to be correlated with EH. However, the results are inconsistent. This study aimed to investigate the associations of ALDH2 rs671 polymorphism with EH in a Chinese Han population in Shanghai. Genotype of ALDH2 rs671 was analyzed in 1923 EH patients and 1115 control subjects. We found no association between ALDH2 rs671 and EH risk or EH-related quantitative blood chemistry values. Furthermore, a meta-analysis was performed and the summary results from 11220 patients and 8339 control subjects were consistent with our findings. These results indicated that rs671 of ALDH2 may not associate with the risk of EH.
Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Hipertensão Essencial/genética , Predisposição Genética para Doença , Idoso , Povo Asiático/genética , China , Hipertensão Essencial/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Introduction: Lactation mastitis seriously severely affects the health of lactating females and their infants, yet the underlying causes of clinical lactation mastitis remain unclear. Methods: In this study, we used microbiota-humanized mice as a model to investigate the role of gut microbiota in lactation mastitis. We compared the fecal microbiota of lactation mastitis patients and healthy individuals and conducted fecal microbiota transplantation (FMT) experiments in an antibiotic-pretreated mouse model to test whether gut microbes contribute to human lactation mastitis. Results: Our results showed that gut microbiota diversity was reduced and dysbiosis was present in lactating mastitis patients. FMT from lactation mastitis patients (M-FMT), but not from healthy individuals (H-FMT), to antibiotic-treated mice resulted in lactation mastitis. The inflammation in mice caused by gut microbiota from lactating mastitis patients appears to be pervasive, as hepatocytes from mice that received feces from lactating mastitis patients showed marked swelling. In addition, serum pro-inflammatory factors, including IL-4, IL-17, MPO, IL-6, IL-1ß, and TNF-α, were significantly increased in the M-FMT group. The Firmicutes/Bacteroidetes ratio (F/B), a biomarker of gut dysbiosis, was significantly increased in the M-FMT group. At the phylum level, Actinobacteria were significantly increased, and Verrucomicrobia were significantly decreased in the M-FMT group. At the genus level, Ruminococcus and Faecalibacterium were significantly reduced, while Parabacteroides were significantly increased in the feces of both patients with lactation mastitis and M-FMT mice. Moreover, our study revealed an "amplification effect" on microbiota differences and mastitis disease following human-to-mouse FMT. Conclusion: Collectively, our findings demonstrate that the gut microbiota in lactating mastitis patients is dysbiotic and contributes to the pathogenesis of mastitis.
RESUMO
Calorie restriction (CR) and intermittent fasting (IF) without malnutrition reduce the risk of cancer development. Separately, CR and IF can also lead to gut microbiota remodelling. However, whether the gut microbiota has a role in the antitumour effect related to CR or IF is still unknown. Here we show that CR, but not IF, protects against subcutaneous MC38 tumour formation through a mechanism that is dependent on the gut microbiota in female mice. After CR, we identify enrichment of Bifidobacterium through 16S rRNA sequencing of the gut microbiome. Moreover, Bifidobacterium bifidum administration is sufficient to rescue the antitumour effect of CR in microbiota-depleted mice. Mechanistically, B. bifidum mediates the CR-induced antitumour effect through acetate production and this effect is also dependent on the accumulation of interferon-γ+CD8+ T cells in the tumour microenvironment. Our results demonstrate that CR can modulate the gut taxonomic composition, which should be of oncological significance in tumour growth kinetics and cancer immunosurveillance.
Assuntos
Restrição Calórica , Microbioma Gastrointestinal , Feminino , Animais , Camundongos , Linfócitos T CD8-Positivos , RNA Ribossômico 16S/genéticaRESUMO
The gut microbiota was emerging as critical regulatory elements in shaping the outcome of cancer immunotherapy. However, the underlying mechanisms by which the gut commensal species enhance antitumor immunity remain largely unexplored. Here, we show that the gut microbiota from healthy individuals conferred considerable sensitivity to anti-PD-1 in the colorectal cancer (CRC) tumor-bearing mice, whereas gut microbiota from CRC patients failed to do so. By 16S rRNA gene sequencing, we identified Lactobacillus that was significantly increased in the mice with good response to anti-PD-1, and significantly correlated with anti-tumor immunity. After a series of screening, we isolated a novel Lacticaseibacillus strain, named L. paracasei sh2020. L. paracasei sh2020 showed the most notable anti-tumor immunity in the mice with gut dysbiosis. Mechanistically, the antitumor immune response elicited by L. paracasei sh2020 was dependent on CD8+ T cell. In vitro and in vivo studies revealed that L. paracasei sh2020 stimulation triggered the upregulated expression of CXCL10 in the tumors and subsequently enhanced CD8+ T cell recruitment. Meanwhile, the modulation of gut microbiota caused by L. paracasei sh2020 enhanced its antitumor effect and gut barrier function. Overall, our study offered novel insights into the mechanism by which gut microbiota shaped the outcome of cancer immunotherapy and, more importantly, the novel strain L. paracasei sh2020 might serve as an easy and effective way to promote anti-PD-1 effect in clinical practice.
Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Lacticaseibacillus paracasei , Probióticos , Animais , Neoplasias Colorretais/tratamento farmacológico , Humanos , Lacticaseibacillus paracasei/genética , Camundongos , Probióticos/farmacologia , Probióticos/uso terapêutico , RNA Ribossômico 16S/genética , Carga TumoralRESUMO
Dietary intake of probiotic yogurt, which has beneficial effects on intestinal microecology, is associated with a lower incidence of hypertension. Recent studies have shown that the gut microbiota plays a vital role in the development of hypertension. However, the impact of the gut microbiota in the antihypertensive effect of probiotic yogurt remains unclear. Here, we evaluated the impact of the gut microbiota in the antihypertensive effect of probiotic yogurt in spontaneously hypertensive rats (SHR). SHR were treated with probiotic yogurt (0.2 mL per 100 g body weight) (SHR-Y group) for seven weeks and compared with whole milk-treated (0.2 mL per 100 g body weight) SHR (SHR group) and with normotensive Wistar-Kyoto rats (WKY group). The blood pressure and heart function of the rats in the WKY, SHR, and SHR-Y groups were measured. Fecal microbiota was assessed by 16S ribosomal RNA (16S rRNA) gene sequencing. To investigate whether probiotic yogurt prevents hypertension in spontaneously hypertensive rats through the gut microbiota, we co-housed SHR rats (SHRCOH) with SHR-Y rats (SHRCOH-Y), thus allowing the transfer of microbiota via coprophagy. Compared with whole milk, supplementation of probiotic yogurt significantly reduced the blood pressure, heart rate (HR), and cardiac function. We found that the probiotic yogurt modified the gut microbiota populations and increased the alpha diversity. Gut microbiota remodeling by co-housing partly rescued the increase of blood pressure and impaired the cardiac function of SHR rats. Moreover, probiotic yogurt modulated the gut microbiota in mice by increasing the abundance of short-chain fatty acid (SCFA)-producing bacteria and SCFA levels (acetic acid, propionic acid, butyric acid, and valeic acid) in the feces. Together, the presented data revealed that probiotic yogurt exhibited antihypertensive effects in SHR rats via remodeling of the gut microbiota.
Assuntos
Anti-Hipertensivos/farmacologia , Alimento Funcional , Probióticos/farmacologia , Iogurte , Animais , Pressão Sanguínea/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Clear cell renal cell carcinoma (ccRCC) is resistant to conventional therapy due to the deletion of the von Hippel-Lindau (VHL) gene, and novel treatment options are urgently needed. Here, using tissue microarray analysis of 445 cancer tissues and 326 adjacent normal renal tissues obtained from patients with ccRCC, we present the early growth response-1 (EGR1) protein levels are significantly decreased in ccRCC cancer tissues. Consistently, the EGR1 mRNA expression also decreased in cancer tissues based on the transcriptomic data for 599 tumor and normal samples from The Cancer Genome Atlas. Moreover, Patients with ccRCC presenting low EGR1 expression are more prone to exhibit metastasis and a poor prognosis than those with high EGR1 expression. By multivariate Cox regression analysis, EGR1 is determined to serve as an independent prognostic factor for patients with ccRCC. Further cellular biochemical function analyses show that EGR1 may inhibit proliferation, invasion and metastasis of ccRCC. These findings will deepen our understanding of EGR1 function and shed light on precise treatment for ccRCC patients.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Neoplasias Renais/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/metabolismo , Feminino , Humanos , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
Background: Anti-PD-1-based immunotherapy has emerged as a promising therapy for several cancers. However, it only benefits a small subset of colorectal cancer (CRC) patients. Mounting data supports the pivotal role of gut microbiota in shaping immune system. Pectin, a widely consumed soluble fiber, has been reported to ameliorate the imbalance of gut microbiota. Therefore, we aimed to explore the effect and the underlying mechanisms of pectin in improving anti-PD-1 mAb efficacy. Methods: The C57BL/6 mice were treated with a broad-spectrum antibiotic (ATB) cocktail to depleted endogenous gut microbiota and subsequently humanized with feces from healthy controls or newly diagnosed CRC patients. The antitumor efficacies of anti-PD-1 mAb combined with or without pectin were assessed using these mice. Flow cytometry and immunohistochemistry (IHC) were conducted to investigate the tumor immune microenvironment after treatment. The gut microbiota profiles and short-chain fatty acids (SCFAs) levels were determined by 16S ribosomal RNA (16S rRNA) gene sequencing and gas chromatography-mass spectrometry (GC-MS), respectively. The effect of gut microbiota on anti-PD-1 mAb efficacy after pectin supplement was further tested by fecal microbiota transplantation (FMT). Results: The anti-PD-1 mAb efficacy was largely impaired in the mice humanized with feces from newly diagnosed CRC patients compared to those from healthy controls. However, pectin significantly enhanced the anti-PD-1 mAb efficacy in the tumor-bearing mice humanized with CRC patient gut microbiota. Flow cytometry and IHC analysis revealed increased T cell infiltration and activation in the tumor microenvironment of mice treated with anti-PD-1 mAb plus pectin. In vivo depletion of CD8+ T cells diminished the anti-tumor effect of anti-PD-1 mAb combined with pectin. 16S rRNA gene sequencing showed that pectin significantly increased gut microbial diversity and beneficially regulated microbial composition. In addition, we identified unique bacterial modules that were significantly enriched in the anti-PD-1 mAb + pectin group, which composed of butyrate-producing bacteria indicative of good response to immunotherapy. Meanwhile, GC-MS showed that pectin altered the level of SCFA butyrate. Furthermore, butyrate, a main product of dietary fiber in gut microbial fermentation, was found to be sufficient to promote T cells infiltration and thus enhance the efficacy of anti-PD-1 mAb. In addition, FMT demonstrated the effects of pectin were dependent on gut microbiota. Importantly, the beneficial effects of pectin were confirmed in the mice humanized with gut microbiota from patient with resistance to anti-PD-1 mAb. Conclusion: Pectin facilitated the anti-PD-1 mAb efficacy in CRC via regulating the T cell infiltration in the tumor microenvironment, which was potentially mediated by the metabolite butyrate.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Microbioma Gastrointestinal/fisiologia , Pectinas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Animais , Bactérias , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/metabolismo , Microambiente Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Psoriasis is a chronic autoinflammatory skin disease, and its aetiology remains incompletely understood. Recently, gut microbial dysbiosis is found to be tightly associated with psoriasis. OBJECTIVE: We sought to reveal the causal role of gut microbiota dysbiosis in psoriasis pathogenesis and investigate the protective effect of healthy commensal bacteria against imiquimod -induced psoriasis-like skin response. METHODS: By using fecal microbial transplantation (FMT), 16S rRNA gene-based taxonomic profiling and Lactobacillus supplement, we have assessed the effect of FMT from healthy individuals on psoriasis-like skin inflammation and associated immune disorders in imiquimod-induced psoriasis mice. RESULTS: Here, by using psoriasis mice humanized with the stools from healthy donors and psoriasis patients, the imiquimod-induced psoriasis in mice with psoriasis patient stool was found to be significantly aggravated as compared to the mice with healthy donor stools. Further analysis showed fecal microbiota of healthy individuals protected against Treg/Th17 imbalance in psoriasis. Moreover, we found the gut and skin microbiome in mice receipted with gut microbiota of healthy individuals (HD) differed from those of mice receipted with gut microbiota of psoriasis patients (PSD). 16S rRNA sequencing revealed that Lactobacillus reuteri was greatly enriched in fecal and cutaneous microbiome of HD mice as compared to PSD mice. Intriguingly, supplement with Lactobacillus reuteri was sufficient to increase the expression of anti-inflammatory gene IL-10, reduce Th17 cells counts and confer resistance to imiquimod-induced inflammation on the mice with gut microbiota dysbiosis. CONCLUSION: Our results suggested that the gut microbiota dysbiosis is the potential causal factor for psoriasis and the gut microbiota may serve as promising therapy target for psoriasis patients.
RESUMO
OBJECTIVES: Tumour cell proliferation requires high metabolism to meet the bioenergetics and biosynthetic needs. Dauer in Caenorhabditis elegans is characterized by lower metabolism, and we established an approach with C elegans to find potential tumour therapy targets. MATERIALS AND METHODS: RNAi screening was used to find dauer-related genes, and these genes were further analysed in glp-1(-) mutants for tumour-suppressing testing. The identified tumour-related genes were verified in clinical tumour tissues. RESULTS: The lifespan of glp-1(-) mutants was found to be extended by classical dauer formation signalling. Then, 61 of 287 kinase-coding genes in Caenorhabditis elegans were identified as dauer-related genes, of which 27 were found to be homologous to human oncogenes. Furthermore, 12 dauer-related genes were randomly selected for tumour-suppressing test, and six genes significantly extended the lifespan of glp-1(-) mutants. Of these six genes, F47D12.9, W02B12.12 and gcy-21 were newly linked to dauer formation. These three new dauer-related genes significantly suppressed tumour cell proliferation and thus extended the lifespan of glp-1(-) mutants in a longevity- or dauer-independent manner. The mRNA expression profiles indicated that these dauer-related genes trigged similar low metabolism pattern in glp-1(-) mutants. Notably, the expression of homolog gene DCAF4L2/F47D12.9, TSSK6/W02B12.12 and NPR1/gcy-21 was found to be higher in glioma compared with adjacent normal tissue. In addition, the high expression of TSSK6/W02B12.12 and NPR1/gcy-21 correlated with a worse survival in glioma patients. CONCLUSIONS: Dauer gene screening in combination with tumour-suppressing test in glp-1(-) mutants provided a useful approach to find potential targets for tumour therapy via suppressing tumour cell proliferation and rewiring tumour cell metabolism.