RESUMO
Objective: Gastric intestinal metaplasia (IM) is a precancerous stage associated with gastric cancer. Despite the observed beneficial effects of metformin on IM, its molecular mechanism remains not fully elucidated. This study aims to reveal the effects and potential mechanisms of metformin in treating IM based on both bioinformatics and in vivo investigations. Methods: The seven public databases (GeneCards, DisGeNET, OMIM, SuperPred, Pharm Mapper, Swiss Target Prediction, TargetNet) were used in this work to identify targeted genes related to intestinal metaplasia (IM) and metformin. The shared targeted genes between metformin and IM were further analyzed by network pharmacology, while the interactions in-between were investigated by molecular docking. In parallel, the therapeutic effect of metformin was evaluated in IM mice model, while the core targets and pathways effected by metformin were verified in vivo. Results: We screened out 1,751 IM-related genes and 318 metformin-targeted genes, 99 common genes identified in between were visualized by constructing the protein-protein interaction (PPI) network. The top ten core targeted genes were EGFR, MMP9, HIF1A, HSP90AA1, SIRT1, IL2, MAPK8, STAT1, PIK3CA, and ICAM1. The functional enrichment analysis confirmed that carcinogenesis and HIF-1 signaling pathways were primarily involved in the metformin treatment of IM. Based on molecular docking and dynamics, we found metformin affected the function of its targets by inhibiting receptor binding. Furthermore, metformin administration reduced the progression of IM lesions in Atp4a-/- mice model significantly. Notably, metformin enhanced the expression level of MUC5AC, while inhibited the expression level of CDX2. Our results also showed that metformin modulated the expression of core targets in vivo by reducing the activity of NF-κB and the PI3K/AKT/mTOR/HIF-1α signaling pathway. Conclusion: This study confirms that metformin improves the efficacy of IM treatment by regulating a complex molecular network. Metformin plays a functional role in inhibiting inflammation/apoptosis-related pathways of further IM progression. Our work provides a molecular foundation for understanding metformin and other guanidine medicines in IM treatment.
RESUMO
BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal radiotherapy regimen, particularly in terms of total dose and planned range of irradiation field, remains unclear. This phase III clinical trial aimed to compare the survival benefits between different radiation doses and different target fields. METHODS: This trial compared two aspects of radiation treatment, total dose and field, using a two-by-two factorial design. The high-dose (HD) group received 59.4 Gy radiation, and the standard-dose (SD) group received 50.4 Gy. The involved field irradiation (IFI) group and elective nodal irradiation (ENI) group adopted different irradiation ranges. The participants were assigned to one of the four groups (HD+ENI, HD+IFI, SD+ENI and SD+IFI). The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS). The synergy indexwas used to measure the interaction effect between dose and field. RESULTS: The interaction analysis did not reveal significant synergistic effects between the dose and irradiation field. In comparison to the target field, patients in IFI or ENI showed similar OS (hazard ratio [HR] = 0.99, 95% CI: 0.80-1.23, p = 0.930) and PFS (HR = 1.02, 95% CI: 0.82-1.25). The HD treatment did not show significantly prolonged OS compared with SD (HR = 0.90, 95% CI: 0.72-1.11, p = 0.318), but it suggested improved PFS (25.2 months to 18.0 months). Among the four groups, the HD+IFI group presented the best survival, while the SD+IFI group had the worst prognosis. No significant difference in the occurrence of severe adverse events was found in dose or field comparisons. CONCLUSIONS: IFI demonstrated similar treatment efficacy to ENI in CCRT of ESCC. The HD demonstrated improved PFS, but did not significantly improve OS. The dose escalation based on IFI (HD+IFI) showed better therapeutic efficacy than the current recommendation (SD+ENI) and is worth further validation.
RESUMO
BACKGROUND: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that has been found to be associated with dysregulation of gastrointestinal functions and gut microbial homeostasis (the so-called "gut-brain axis"). ASD is often accompanied by poor performances in social interaction and repetitive behaviors. Studies on the gut-brain axis provide novel insights and candidate targets for ASD therapeutics and diagnosis. Based on the ASD mice model, this work aims to reveal the mechanisms behind the interaction of intestinal barrier function and probiotics in ASD mouse models. RESULTS: We found an altered intestinal barrier in both BTBR T+ Itpr3tf/J (BTBR) and valproic acid (VPA) mice, including increased intestinal permeability, decreased expression of intestinal tight junction proteins (claudin1, claudin3, and occludin), and increased levels of IL-6, TNF-α, and IFN-γ. Based on intestinal microbial alternation, C. butyricum can drive reduced expression of histone deacetylases 1 (HDAC1) and enhanced intestinal barrier function, significantly promoting behavioral abnormalities of ASD in BTBR mice. In parallel, we confirmed that C. butyricum was involved in the regulation of intestinal function by the Trek1 channel, indicating that it is a target of C. butyricum/butyric acid to improve intestinal barrier function in ASD mice. CONCLUSIONS: Our finding provides solid evidence for the gut microbiota involved in ASD through the brain-gut axis. In addition, the probiotics C. butyricum hold promise to improve gut health and ameliorate behavioral abnormalities associated with ASD.
RESUMO
Background: Gastrointestinal cancer poses a considerable global health risk, encompassing a heterogeneous spectrum of malignancies that afflict the gastrointestinal tract. It is significant to develop efficacious therapeutic agents, as they are indispensable for both the treatment and prevention of this formidable disease. Methods: In this study, we synthesized a novel thiophene derivative, designated as compound 1312. An assessment was performed to investigate its anti-proliferative activity in several cancer cell lines (GES-1, EC9706, SGC7901, and HT-29). Furthermore, we performed molecular biology techniques to investigate the inhibitory impact of compound 1312 on gastrointestinal cell lines SGC-7901 and HT-29. Results: Our findings reveal that compound 1312 exhibits significant efficacy in suppressing colony formation of cancer cells. Notably, it triggers cell cycle arrest at the G2/M phase in gastrointestinal cell lines SGC7901 and HT-29. Compound 1312 was confirmed to exert inhibitory effects on cell migration and invasion in SGC7901. Additionally, the compound elicits apoptotic cell death through the activation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) and the caspase signaling cascade. Furthermore, in vitro experiments revealed that compound 1312 effectively suppresses both the ß-tubulin cytoskeletal network and the Wnt/ß-catenin signaling pathway. These multifaceted anti-cancer activities highlight the potential of compound 1312 as a promising therapeutic agent for the treatment of gastrointestinal malignancies. Conclusion: This study indicates the promising potential of compound 1312 as a prospective candidate agent for gastrointestinal cancer treatment. Further comprehensive investigations are needed to explore its therapeutic efficacy in greater detail.
RESUMO
BACKGROUND: Human patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting that SE can trigger the development of epilepsy. Yet, the underlying mechanisms are not fully understood. The low-density lipoprotein receptor related protein (Lrp4), a receptor for proteoglycan-agrin, has been indicated to modulate seizure susceptibility. However, whether agrin-Lrp4 pathway also plays a role in the development of SE-induced TLE is not clear. METHODS: Lrp4f/f mice were crossed with hGFAP-Cre and Nex-Cre mice to generate brain conditional Lrp4 knockout mice (hGFAP-Lrp4-/-) and pyramidal neuron specific knockout mice (Nex-Lrp4-/-). Lrp4 was specifically knocked down in hippocampal astrocytes by injecting AAV virus carrying hGFAP-Cre into the hippocampus. The effects of agrin-Lrp4 pathway on the development of SE-induced TLE were evaluated on the chronic seizure model generated by injecting kainic acid (KA) into the amygdala. The spontaneous recurrent seizures (SRS) in mice were video monitored. RESULTS: We found that Lrp4 deletion from the brain but not from the pyramidal neurons elevated the seizure threshold and reduced SRS numbers, with no change in the stage or duration of SRS. More importantly, knockdown of Lrp4 in the hippocampal astrocytes after SE induction decreased SRS numbers. In accord, direct injection of agrin into the lateral ventricle of control mice but not mice with Lrp4 deletion in hippocampal astrocytes also increased the SRS numbers. These results indicate a promoting effect of agrin-Lrp4 signaling in hippocampal astrocytes on the development of SE-induced TLE. Last, we observed that knockdown of Lrp4 in hippocampal astrocytes increased the extracellular adenosine levels in the hippocampus 2 weeks after SE induction. Blockade of adenosine A1 receptor in the hippocampus by DPCPX after SE induction diminished the effects of Lrp4 on the development of SE-induced TLE. CONCLUSION: These results demonstrate a promoting role of agrin-Lrp4 signaling in hippocampal astrocytes in the development of SE-induced development of epilepsy through elevating adenosine levels. Targeting agrin-Lrp4 signaling may serve as a potential therapeutic intervention strategy to treat TLE.
RESUMO
BACKGROUND: Gastric intestinal metaplasia (GIM) is an essential precancerous lesion. Although the reversal of GIM is challenging, it potentially brings a state-to-art strategy for gastric cancer therapeutics (GC). The lack of the appropriate in vitro model limits studies of GIM pathogenesis, which is the issue this work aims to address for further studies. METHOD: The air-liquid interface (ALI) model was adopted for the long-term culture of GIM cells in the present work. This study conducted Immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR), transcriptomic sequencing, and mucoproteomic sequencing (MS) techniques to identify the pathways for differential expressed genes (DEGs) enrichment among different groups, furthermore, to verify novel biomarkers of GIM cells. RESULT: Our study suggests that GIM-ALI model is analog to the innate GIM cells, which thus can be used for mucus collection and drug screening. We found genes MUC17, CDA, TRIM15, TBX3, FLVCR2, ONECUT2, ACY3, NMUR2, and MAL2 were highly expressed in GIM cells, while GLDN, SLC5A5, MAL, and MALAT1 showed down-regulated, which can be used as potential biomarkers for GIM cells. In parallel, these genes that highly expressed in GIM samples were mainly involved in cancer-related pathways, such as the MAPK signal pathway and oxidative phosphorylation signal pathway. CONCLUSION: The ALI model is validated for the first time for the in vitro study of GIM. GIM-ALI model is a novel in vitro model that can mimic the tissue micro-environment in GIM patients and further provide an avenue for studying the characteristics of GIM mucus. Our study identified new markers of GIM as well as pathways associated with GIM, which provides outstanding insight for exploring GIM pathogenesis and potentially other related conditions.
Assuntos
Metaplasia , Humanos , Ar , Modelos Biológicos , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Estômago/patologia , Organoides/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Regulação Neoplásica da Expressão Gênica , Transcriptoma/genética , Intestinos/patologiaRESUMO
Background: Many studies demonstrated the safety and efficacy of SBRT in the treatment of elderly patients with early-stage non-small cell lung cancer (NSCLC). However, those studies focused on patients with peripheral lung cancer. This study aimed to evaluate the clinical efficacy and toxicity of SBRT in elderly patients with stage I-II central NSCLC in single institution. Methods: From April 2009 to January 2020, a retrospective study was conducted on patients ≥ 65 years old with stage I-II NSCLC that was centrally localized and treated with SBRT at a single institution. Absolute C-reactive protein (CRP)/albumin ratio (CAR) and body mass index (BMI) recorded at pretreatment were analyzed. Endpoints included overall survival (OS), progression-free survival (PFS), cancer-specific death, noncancer-specific death, local progression (LP) and distant progression (DP). Results: Stereotactic body radiation treatment (SBRT) was administered to a total of 44 patients. The most common dose fractionation schedule was 60 Gy given in 5 fractions. The median PFS of the cohort was 31 months (95% CI, 19.47-42.53 months). The median OS of all patients was 69 months (95% CI, 33.8-104.2 months). The median time to noncancer-specific death was 54.5 months. The median time to cancer-specific death was 36 months. The cumulative incidences of cancer-specific death at 1 year, 5 years, and 10 years were 11.63% (95%CI, 4.2-23.23%), 42.99% (95%CI, 27.56-57.53%), and 65.94% (95%CI, 45.76-80.1%), respectively. pre-SBRT BMI of ≤ 22.77 (HR 4.60, 95% CI 1.84-11.51, P=0.001) and pre-SBRT CAR of ≤0.91 (HR 5.19, 95% CI 2.15-12.52, P<0.000) were significant predictors of higher OS on multivariable analysis. The median times to LP and DP were 10 months and 11 months, respectively. In terms of acute toxicity, grade 1 including cough (38.64%), radiation pneumonitis (29.55%), anemia (25%), and fatigue (20.45%) was often observed. There was no evidence of grade 4 or 5 acute toxicity. In terms of late toxicity, 2 patients developed grade 1 pulmonary fibrosis during follow-up. Conclusion: This study showed that SBRT can effectively control local tumor progression, and have acceptable toxicity for elderly patients with centrally located stage I-II NSCLC. Lower pre-SBRT BMI and lower pre-SBRT CAR were associated with a decreased risk of cancer-specific death.
RESUMO
Motivation-driven mating is a basic affair for the maintenance of species. However, the underlying molecular mechanisms that control mating motivation are not fully understood. Here, we report that NRG1-ErbB4 signaling in the medial amygdala (MeA) is pivotal in regulating mating motivation. NRG1 expression in the MeA negatively correlates with the mating motivation levels in adult male mice. Local injection and knockdown of MeA NRG1 reduce and promote mating motivation, respectively. Consistently, knockdown of MeA ErbB4, a major receptor for NRG1, and genetic inactivation of its kinase both promote mating motivation. ErbB4 deletion decreases neuronal excitability, whereas chemogenetic manipulations of ErbB4-positive neuronal activities bidirectionally modulate mating motivation. We also identify that the effects of NRG1-ErbB4 signaling on neuronal excitability and mating motivation rely on hyperpolarization-activated cyclic nucleotide-gated channel 3. This study reveals a critical molecular mechanism for regulating mating motivation in adult male mice.
Assuntos
Motivação , Transdução de Sinais , Camundongos , Masculino , Animais , Neurônios/metabolismo , Receptor ErbB-4/metabolismo , Tonsila do Cerebelo/metabolismo , Neuregulina-1/metabolismoRESUMO
Glioma is still an incurable disease with high invasiveness. Heat shock 70 kDa protein 4 (HSPA4) is a member of the HSP110 family, and is associated with the development and progression of various cancers. In the current study, we assessed the expression of HSPA4 in clinical samples, and found that HSPA4 was up-regulated in glioma tissues and correlated with tumor recurrence and grade. Survival analyses demonstrated that glioma patients with high HSPA4 expression had lower overall survival and disease-free survival times. In vitro knockdown of HSPA4 inhibited glioma cell proliferation, mediated cell cycle arrest at G2 phase and apoptosis, and reduced the migration ability. In vivo, the growth of HSPA4-knockdown xenografts was markedly suppressed compared to the tumors formed by HSPA4-positive control cells. Additionally, Gene set enrichment analyses disclosed that HSPA4 was associated with the PI3K/Akt signaling pathway. The regulatory effect of the AKT activator SC79 on cell proliferation and apoptosis was suppressed by HSPA4 knockdown, indicating that HSPA4 is capable of promoting glioma development. In summary, these data showed that HSPA4 is likely to play a pivotal role in the progression of glioma, and consequently may be a promising therapeutic target for glioma therapy.
Assuntos
Glioma , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Glioma/genética , Glioma/patologia , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Linhagem Celular Tumoral , Apoptose , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP110/genética , Proteínas de Choque Térmico HSP110/metabolismoRESUMO
Avian influenza scare is a human psychological factor that asserts both positive and negative effects on the transmission of zoonotic avian influenza. In order to study the dichotomous effect of avian influenza scare on disease transmission, taking H7N9 avian influenza as a typical case, a two-patch epidemic model is proposed. The global dynamics and the threshold criteria are established by LaSalle invariant principle and the theory of asymptotic autonomous system. To mitigate the negative effects and curb illegal poultry trade, a game-theoretic model is adopted to explore the optimal policy of culling subsidies to reasonably compensate stakeholders for their economic losses resulting from the scare. The optimal policy of culling subsidy is found to heavily depend on the penalty of illegal poultry trade, the stakeholders' income, the intensity of control measures, and the prevalence level of the disease. The negative effect of avian influenza scare on disease transmission is considerably more significant than the positive effect. In order to avoid a widespread outbreak of zoonotic avian influenza across the region, a comprehensive national global control strategy is essential and effective, even in the presence of the negative effect of the avian influenza scare.
Assuntos
Subtipo H7N9 do Vírus da Influenza A , Influenza Aviária , Influenza Humana , Animais , Humanos , Influenza Humana/epidemiologia , Surtos de Doenças/prevenção & controle , Aves Domésticas , China/epidemiologiaRESUMO
Aim: Pancreatic cancer (PC) is a devastating malignancy characterized by its aggressive nature and poor prognosis. However, the relationship of PC with peripheral metabolites remains not fully investigated. The study aimed to explore the causal linkage between PC and peripheral metabolite profiles. Methods: Employing publicly accessible genome-wide association studies (GWAS) data, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. The primary analysis employed the inverse-variance weighted (IVW) method. To address potential concerns about horizontal pleiotropy, we also employed supplementary methods such as maximum likelihood, weighted median, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). Results: We ascertained 20 genetically determined peripheral metabolites with causal linkages to PC while high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) particles accounted for the vast majority. Specifically, HDL particles exhibited an elevated PC risk while VLDL particles displayed an opposing pattern. The converse MR analysis underscored a notable alteration in 17 peripheral metabolites due to PC, including branch chain amino acids and derivatives of glycerophospholipid. Cross-referencing the bidirectional MR results revealed a reciprocal causation of PC and X-02269 which might form a self-perpetuating loop in PC development. Additionally, 1-arachidonoylglycerophosphocholine indicated a reduced PC risk and an increase under PC influence, possibly serving as a negative feedback regulator. Conclusion: Our findings suggest a complex interplay between pancreatic cancer and peripheral metabolites, with potential implications for understanding the etiology of pancreatic cancer and identifying novel early diagnosis and therapeutic targets. Moreover, X-02269 may hold a pivotal role in PC onset and progression.
RESUMO
Conserved long non-coding RNAs (lncRNAs) have not thoroughly been studied in many cancers, including gastric cancer (GC). We have identified a novel lncRNA PTCHD4-AS which was highly conserved between humans and mice and naturally downregulated in GC cell lines and tissues. Notably, PTCHD4-AS was found to be transcriptionally induced by DNA damage agents and its upregulation led to cell cycle arrest at the G2/M phase, in parallel, it facilitated the cell apoptosis induced by cisplatin (CDDP) in GC. Mechanistically, PTCHD4-AS directly bound to the DNA mismatch repair protein MSH2-MSH6 dimer, and facilitated the binding of dimer to ATM, thereby promoting the expression of phosphorylated ATM, p53 and p21. Here we conclude that the upregulation of PTCHD4-AS inhibits proliferation and increases CDDP sensitivity of GC cells via binding with MSH2-MSH6 dimer, activating the ATM-p53-p21 pathway.
Assuntos
Neoplasias Gástricas , Proteína Supressora de Tumor p53 , Camundongos , Humanos , Animais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Dimerização , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Cisplatino/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
BACKGROUND: Early diagnosis and treatment effectiveness of early-onset coronary artery disease (EOCAD) are crucial, and non-invasive predictive biomarkers are needed for young adults. We aimed to evaluate the usefulness of the triglyceride-glucose (TyG) index, a novel marker of insulin resistance, in identifying young CAD patients and predicting their risk of developing target lesion failure (TLF). METHODS: We recruited EOCAD patients (luminal narrowing ≥ 70%) and controls free from CAD (luminal narrowing < 30%), both aged 45 years or younger, from 38 hospitals in China between 2017 and 2020. EOCAD patients who underwent successful percutaneous coronary intervention were followed for incident TLF. TyG index was defined as Ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. We used logistic regression and Cox proportional hazards modeling to evaluate the association of TyG index with prevalent EOCAD and incident TLF, respectively. The discriminatory ability of TyG index was assessed by the area under the receiver-operating characteristic curve (AUC). RESULTS: Among the included 1513 EOCAD patients (39.6 ± 4.4 years, 95.4% male) and 1513 age-matched controls (39.0 ± 4.4 years, 46.4% male), TyG index was positively associated with the prevalence of EOCAD (adjusted odds ratio: 1.40, 95% confidence interval [CI] 1.23-1.60, per standard deviation [SD] increase in TyG index). The addition of TyG index to an empirical risk model provided an improvement in diagnostic ability for EOCAD, with a net reclassification improvement of 0.10 (95% CI 0.03-0.17, p = 0.005). During a medium of 33 month (IQR: 31-34 months) follow-up, 43 (3.3%) patients experienced TLF. Multivariate Cox regression model revealed that TyG index was an independent risk factor for TLF (adjusted hazard ratio [HR]: 2.410, 95% CI 1.07-5.42 comparing the top to bottom TyG index tertile groups; HR: 1.30, 95% CI 1.01-1.73, per SD increase in TyG index). Compared with a model of conventional risk factors alone, the addition of the TyG index modestly improved the AUC (0.722-0.734, p = 0.04) to predict TLF. CONCLUSIONS: TyG index is positively associated with prevalent EOCAD and incident TLF. TyG index appeared to be a valuable component of future efforts to improve CAD risk stratification and TLF outcome prediction among young adults.
Assuntos
Aterosclerose , Doença da Artéria Coronariana , Humanos , Masculino , Adulto Jovem , Feminino , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/terapia , Glucose , Glicemia , Triglicerídeos , Fatores de Risco , Biomarcadores , Medição de RiscoRESUMO
Scientists have made great efforts to understand the evolution of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) to provide crucial information to public health experts on strategies to control this viral pathogen. The pandemic of the coronavirus disease that began in 2019, COVID-19, lasted nearly three years, and nearly all countries have set different epidemic prevention policies for this virus. The continuous evolution of SARS-CoV-2 alters its pathogenicity and infectivity in human hosts, thus the policy and treatments have been continually adjusted. Based on our previous study on the dynamics of binding ability prediction between the COVID-19 spike protein and human ACE2, the present study mined over 10 million sequences and epidemiological data of SARS-CoV-2 during 2020-2022 to understand the evolutionary path of SARS-CoV-2. We analyzed and predicted the mutation rates of the whole genome and main proteins of SARS-CoV-2 from different populations to understand the adaptive relationship between humans and COVID-19. Our study identified a correlation of the mutation rates from each protein of SARS-CoV-2 and various human populations. Overall, this analysis provides a scientific basis for developing data-driven strategies to confront human pathogens.
Assuntos
COVID-19 , Médicos , Humanos , SARS-CoV-2/genética , COVID-19/epidemiologia , Pandemias , Taxa de MutaçãoRESUMO
Background/aims: Some studies showed that probiotics could improve the composition and structure of gut microbiota. Changes in the gut microbiota may alter bile acid (BAs) composition and kinetics, improving non-alcoholic fatty liver disease (NAFLD). However, it still needs to be clarified how probiotics improve both the metabolism of BAs and NAFLD. This study aimed to reveal the regulatory mechanisms of cholesterol-lowering (CL) probiotics on NAFLD from aspects involved in BA metabolism in FXR gene knockout (FXR-/-) mice. Methods: FXR-/- male mice were randomly divided into three groups based on different interventions for 16 weeks, including normal diet (ND), high-fat diet (HFD), and probiotic intervention in the HFD (HFD+P) group. 16s rDNA sequencing and ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were utilized to analyze the changes in gut microbiota and fecal bile acids in mice. Results: We found that the intervention of the CL probiotics improved liver lipid deposition and function in HFD-induced NAFLD mice by decreasing the levels of total cholesterol (TC; p = 0.002) and triglyceride (TG; p = 0.001) in serum, as well as suppressing liver inflammation, such as interleukin-1 beta (IL-1ß; p = 0.002) and tumor necrosis factor-alpha (TNF-α; p < 0.0001). 16S rDNA sequencing and metabolomic analyses showed that probiotics effectively reduced the abundance of harmful gut microbiota, such as Firmicutes (p = 0.005), while concomitantly increasing the abundance of beneficial gut microbiota in NAFLD mice, such as Actinobacteriota (p = 0.378), to improve NAFLD. Compared with the ND group, consuming an HFD elevated the levels of total BAs (p = 0.0002), primary BAs (p = 0.017), and secondary BAs (p = 0.0001) in mice feces, while the intervention with probiotics significantly reduced the increase in the levels of fecal total bile acids (p = 0.013) and secondary bile acids (p = 0.017) induced by HFD. Conclusion: The CL probiotics were found to improve liver function, restore microbiota balance, correct an abnormal change in the composition and content of fecal bile acids, and repair the damaged intestinal mucosal barrier in mice with NAFLD, ultimately ameliorating the condition. These results suggested that CL probiotics may be a promising and health-friendly treatment option for NAFLD.
RESUMO
Rabies is an acute zoonotic infectious disease caused by rabies virus. In 2015, the World Health Organization proposed the goal of eliminating dog-induced human rabies by 2030. In response to this goal positively, China has been dedicated to the control and elimination of rabies mainly caused by dogs, for nearly 10 years. By applying infectious disease dynamics, in this paper, we establish a dog-human rabies transmission model to forecast future epidemic trends of rabies, assess whether the goal of eliminating dog-induced human rabies cases in China can be achieved in 2030, and further evaluate and suggest the follow-up sustained preventive measures after the elimination of human rabies. By analyzing and simulating above dynamic model, it is concluded that rabies has been well controlled in China in recent years, but dog-induced human rabies cannot be eliminated by 2030 according to current situation. In addition, we propose to improve rabies control efforts by increasing the immunization coverage rate of rural domestic dogs, controlling the number of stray dogs and preventing the import of rabies virus in wild animals. Immunization coverage rate of rural domestic dogs which is currently less than 10% is far from requirement, and it needs to reach 50%-60% to meet the goal of 2030. Since it is difficult to immunize stray dogs, we suggest to control the number of stray dogs below 15.27 million to achieve the goal. If the goal of eliminating human rabies is reached in 2030, the essential immunization coverage needs to be maintained for 18 years to reduce the number of canine rabies cases to zero. Lastly, to prevent transmission of rabies virus from wild animals to dogs, the thresholds of the number of dogs and the immunization coverage rate of dogs after eliminating canine rabies cases are also discussed.
RESUMO
Black-bone fowl are different from ordinary broilers in appearance and are considered to have rich nutritional properties. However, the metabolism of therapeutic drugs in black-bone fowl remains unclear. This study aimed to determine the tissue residue depletion kinetics of trimethoprim and sulfachloropyridazine in Yugan black-bone fowl, after daily oral administrations for 5 days at 4 mg/kg bw/day trimethoprim and 20 mg/kg bw/day sulfachloropyridazine, and to calculate the withdrawal times. After consecutive oral administrations, the tissues (liver, kidney, muscle and skin/fat) were collected at each of the following time points (0.16, 1, 3, 5, 7, 9, 20, 30 and 40 days). A newly-devised LC-MS/MS method was used to analyse the concentrations of trimethoprim and sulfachlorpyridazine in target tissues. The results showed that sulfachloropyridazine was rapidly metabolised in broilers, and there was no residue in all tissues 3 days post-administration. The concentration of trimethoprim in black-bone fowl skin/fat is the highest, and its metabolism rate is low. After 40 days, the concentration of trimethoprim in skin/fat is still as high as 140.1 ± 58.0 µg/kg, exceeding the maximum residue limit. In order to protect consumers' health, it is suggested that the withdrawal time of TMP in Yugan black-bone fowl is 69 days.
Assuntos
Sulfacloropiridazina , Trimetoprima , Animais , Sulfacloropiridazina/metabolismo , Galinhas , Cromatografia Líquida , Espectrometria de Massas em TandemRESUMO
Streptococcus suis (S. suis) is one of the most important pathogens affecting pig production worldwide. It can be also transmitted to human through the behaviors of eating undercooked pork or slaughtering sick pigs. A meta-analysis was conducted to estimate the prevalence across different geographical areas in China. Forty-three articles were included and distributed in 22 provinces of China. The prevalence of S. suis infection in pigs varied from 4.2% to 93.7%, with a summary estimate of 40.8% (95%CI, 32.9-48.6%). Six provinces, classified as frequent outbreaks in human cases, had a higher prevalence (52.7%, 95%CI: 43.7-61.6%) than other provinces (36.0%, 95%CI: 27.0-44.9%). Jiangsu province had the highest prevalence with 73.1% (95%CI: 70.42-75.68%), followed by Hunan (59.64%, 95%CI: 55.83-63.37%), Shanxi (55.56%, 95%CI: 47.05-63.83%), and Guangxi (50.55%, 95%CI: 49.45-51.64%). The prevalence has been decreasing gradually, from 47.6% (95%CI: 38.1-57.1%) before 2010, then dropped to 39.1% (95%CI: 25.5-52.8%) during 2011-2015, and reached the lowest in recent five years (2016-2020), with 34.3% (95%CI: 23.1-45.4%). The study findings showed that S. suis was presented in pig populations of most provinces of China, which indicated that effective control measures in pigs should be implemented. Our results also provided solid evidence for the early warning and prevention of human S. suis infection in China, which would mitigate the risk to humans.
RESUMO
Malignant glioma is characterized by rapid tumor cell proliferation and high recurrence risk. In terms of its treatment, the therapeutic effects of maximum resection and postoperative radiotherapy with adjuvant chemotherapy as well as many other new therapeutic techniques such as antiangiogenic therapy and immunotherapy remain poor. Glioma recurrence, especially local recurrence, is an important reason of glioma treatment failure. Intraoperative radiotherapy (IORT) enables exclusion of radiation-sensitive normal tissue from the radiation field in operation and then the application of a single high-dose precision irradiation to the residual tumor or tumor bed. IORT has great application potential in the control of local recurrence of malignant tumors. This paper thus aims to review the current status and prospects of IORT's application in malignant glioma treatment.
RESUMO
Objectives: We investigated the behavioral associated factors and prevalence of common anorectal disease (hemorrhoids, perianal pruritus, anal fistula, and others) among Uyghur male adults in southern Xinjiang. Methods: We conducted a cross-sectional study with a random sampling method from December 2020 to March 2021. Uyghur males aged 18 years and older were selected from Kashgar Prefecture in Xinjiang. The prevalence was evaluated by a bilingual questionnaire (including socio- demographic information, dietary habit, lifestyle, and behavioral habits) and anorectal examinations. The chi-square test was used for categorical variables. Logistic regression analysis was used to identify potential associated factors.Results: A total of 402 Uygur males aged ≥ 18 years were included in the final analysis. Of those, 192 (47.8%) participants were identified with common anorectal disease (CAD). Older age, lower education attainment, being a farmer, having lower personal annual income, having a high level of alcohol consumption, performing less anus-rinsing after defecation, and having less pubic hair removal were significantly associated with CAD. Conclusions: Common anorectal disease is a significant public health concern for the Uygur male population. Anus-rinsing after defecation and pubic hair removal are ethnic-specific behaviors among Uygur and could be preventive strategies for CAD.