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DPP-IV inhibitors, which are close to the natural hypoglycemic pathway of human physiology and have few side effects, have been extensively employed in the management of type 2 diabetes mellitus (T2DM). However, there are currently no specific blood indicators that can indicate or predict a patient's suitability for DPP-IV inhibitors. In this study, based on the self-developed high-specificity fluorescent substrate glycyl-prolyl-N-butyl-4-amino-1, 8-naphthimide (GP-BAN), a detection method of human serum DPP-IV activity was established and optimized. The method demonstrates a favorable lower limit of detection (LOD) at 0.32â¯ng/mL and a satisfactory lower limit of quantification (LOQ) of 1.12â¯ng/mL, and can be used for the detection of DPP-IV activity in trace serum (2⯵L). In addition, Vitalliptin and Sitagliptin showed similar IC50 values when human recombinant DPP-IV and human serum were used as enzyme sources, and the intra-day and inter-day precision obtained by the microplate analyzer were less than 15â¯%. These results indicate that the microplate reader based detection technique has good accuracy, repeatability and reproducibility. A total of 700 volunteers were recruited, and 646 serum samples were tested for DPP-IV activity. The results showed that serum DPP-IV activity was higher in patients with T2DM than in controls (P < 0.01). However, the statistical data of family history of diabetes, gender and age of diabetic patients showed no statistical significance, and there was no contrast difference. The DPP-IV activity of serum in T2DM patients ranged from 2.4 µmol/min/L to 78.6 µmol/min/L, with a huge difference of up to 32-fold. These results suggest that it is necessary to test DPP-IV activity in patients with T2DM when taking DPP-IV inhibitors to determine the applicability of DPP-IV inhibitors in T2DM patients. These results suggest that it is necessary to detect the activity of DPP-IV in blood before taking DPP-IV inhibitors in patients with T2DM to judge the applicability of DPP-IV inhibitors in patients with T2DM.
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Diabetes Mellitus Tipo 2 , Dipeptidil Peptidase 4 , Inibidores da Dipeptidil Peptidase IV , Limite de Detecção , Fosfato de Sitagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dipeptidil Peptidase 4/sangue , Reprodutibilidade dos Testes , Masculino , Pessoa de Meia-Idade , Feminino , Espectrometria de Fluorescência/métodos , Fluorescência , Idoso , Adulto , Hipoglicemiantes/sangue , Hipoglicemiantes/uso terapêuticoRESUMO
Nipah virus infection, one of the top priority diseases recognized by the World Health Organization, underscores the urgent need to develop effective countermeasures against potential epidemics and pandemics. Here, we identify a fully human single-domain antibody that targets a highly conserved cryptic epitope situated at the dimeric interface of the Nipah virus G protein (receptor binding protein, RBP), as elucidated through structures by high-resolution cryo-electron microscopy (cryo-EM). This unique binding mode disrupts the tetramerization of the G protein, consequently obstructing the activation of the F protein and inhibiting viral membrane fusion. Furthermore, our investigations reveal that this compact antibody displays enhanced permeability across the blood-brain barrier (BBB) and demonstrates superior efficacy in eliminating pseudovirus within the brain in a murine model of Nipah virus infection, particularly compared to the well-characterized antibody m102.4 in an IgG1 format. Consequently, this single-domain antibody holds promise as a therapeutic candidate to prevent Nipah virus infections and has potential implications for vaccine development.
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Anticorpos Antivirais , Microscopia Crioeletrônica , Epitopos , Infecções por Henipavirus , Vírus Nipah , Anticorpos de Domínio Único , Vírus Nipah/imunologia , Humanos , Animais , Infecções por Henipavirus/imunologia , Infecções por Henipavirus/prevenção & controle , Infecções por Henipavirus/virologia , Epitopos/imunologia , Camundongos , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/química , Anticorpos Antivirais/imunologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/imunologia , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/química , Feminino , Células HEK293RESUMO
OBJECTIVE: Vascular invasion (VI) profoundly impacts the prognosis of hepatocellular carcinoma (HCC), yet the underlying biomarkers and mechanisms remain elusive. This study aimed to identify prognostic biomarkers for HCC patients with VI. METHODS: Transcriptome data from primary HCC tissues and HCC tissues with VI were obtained through the Genome Expression Omnibus database. Differentially expressed genes (DEGs) in the two types of tissues were analyzed using functional enrichment analysis to evaluate their biological functions. We examined the correlation between DEGs and prognosis by combining HCC transcriptome data and clinical information from The Cancer Genome Atlas database. Univariate and multivariate Cox regression analyses, along with the least absolute shrinkage and selection operator (LASSO) method were utilized to develop a prognostic model. The effectiveness of the model was assessed through time-dependent receiver operating characteristic (ROC) curve, calibration diagram, and decision curve analysis. RESULTS: In the GSE20017 and GSE5093 datasets, a total of 83 DEGs were identified. Gene Ontology analysis indicated that these DEGs were predominantly associated with xenobiotic stimulus, collagen-containing extracellular matrix, and oxygen binding. Additionally, Kyoto Encyclopedia of Genes and Genomes analysis revealed that the DEGs were primarily involved in immune defense and cellular signal transduction. Cox and LASSO regression further identified 7 genes (HSPA8, ABCF2, EAF1, MARCO, EPS8L3, PLA3G1B, C6), which were used to construct a predictive model in the training cohort. We used X-tile software to calculate the optimal cut-off value to stratify HCC patients into low-risk and high-risk groups. Notably, the high-risk group exhibited poorer prognosis than the low-risk group (P < 0.001). The model demonstrated area under the ROC curve (AUC) values of 0.815, 0.730, and 0.710 at 1-year, 3-year, and 5-year intervals in the training cohort, respectively. In the validation cohort, the corresponding AUC values were 0.701, 0.571, and 0.575, respectively. The C-index of the calibration curve for the training and validation cohorts were 0.716 and 0.665. Decision curve analysis revealed the model's efficacy in guiding clinical decision-making. CONCLUSIONS: The study indicates that 7 genes may be potential prognostic biomarkers and treatment targets for HCC patients with VI.
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QUESTION: Pseudomonas aeruginosa (Pa) is a common pathogen that contributes to progressive lung disease in Cystic Fibrosis (CF). Genetic factors other than CF-causing CFTR variations contribute approximately 85% of the variation in chronic Pa infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to Pa infection. MATERIALS AND METHODS: We conducted a genome-wide association study (GWAS) of chronic Pa infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic Pa infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bi-directional Mendelian Randomization analysis. RESULTS: Two novel genome-wide significant loci with lead SNPs rs62369766 (chr5p12; p-value= 1.98 ×10-8) and rs927553 (chr13q12.12; p-value= 1.91 × 10-8) were associated with chronic Pa infection age. The rs62369766 locus was validated using an independent French cohort (N=501). Furthermore, PRS constructed from CF lung function-associated SNPs was significantly associated with chronic Pa infection age (p-value=0.002). Finally, our analysis presented evidence for a causal effect of lung function on the chronic Pa infection age (Beta=0.782â years, p-value= 4.24 × 10-4). In the reverse direction, we observed a moderate effect (Beta=0.002, p-value=0.012). CONCLUSIONS: We identified two novel loci that are associated with chronic Pa infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between Pa infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections which accounts for significant remaining morbidity in CF.
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Recombinant human type 5 adenovirus (H101) is an oncolytic virus used to treat nasopharyngeal carcinoma. Owing to the deletion of the E1B-55kD and E3 regions, H101 is believed to selectively inhibit nasopharyngeal carcinoma. Whether H101 inhibits other type of tumors via different mechanisms remains unclear. In this study we investigated the effects of H101 on melanomas. We established B16F10 melanoma xenograft mouse model, and treated the mice with H101 (1 × 108 TCID50) via intratumoral injection for five consecutive days. We found that H101 treatment significantly inhibited B16F10 melanoma growth in the mice. H101 treatment significantly increased the infiltration of CD8+ T cells and reduced the proportion of M2-type macrophages. We demonstrated that H101 exhibited low cytotoxicity against B16F10 cells, but the endothelial cells were more sensitive to H101 treatment. H101 induced endothelial cell pyroptosis in a caspase-1/GSDMD-dependent manner. Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.
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Background: Lung cancer is the most common primary malignant tumor of the lung, and as one of the malignant tumors that pose the greatest threat to the health of the population, the incidence rate has remained high in recent years. Previous studies have shown that KLRB1 is transcriptionally repressed in lung adenocarcinoma and correlates with lung adenocarcinoma prognosis. The objective of this study is to investigate the intrinsic mechanisms by which KLRB1 affects the malignant phenotypes of lung adenocarcinoma such as immune infiltration, proliferation, growth and metastasis. Methods: We assessed the expression levels of KLRB1 in publicly available databases and investigated its associations with clinical and pathological variables. Enrichment analysis was subsequently conducted to investigate possible signaling pathways and their associated biological functions. Statistical analysis, including Spearman correlation and the application of multigene prediction models, was utilized to assess the relationship between the expression of KLRB1 and the infiltration of immune cells. The diagnostic and prognostic value of KLRB1 was evaluated using Kaplan-Meier survival curves, diagnostic receptor operating characteristic (ROC) curves, histogram models, and Cox regression analysis. Specimens from lung adenocarcinoma (LUAD) patients were collected, the expression level of KLRB1 was detected by protein blotting analysis, and the expression level of KLRB1 was detected at the mRNA level by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Small interfering RNA (siRNA) was used to silence gene expression, and Transwell, Cell Counting Kit-8 (CCK-8) and colony formation assays were subsequently performed to analyze the effects of KLRB1 on LUAD cell migration, invasion and proliferation. Results: KLRB1 expression was lower in lung cancer tissue than in surrounding healthy tissue. Genes differentially expressed in the low and high KLRB1 expression groups were found to be significantly enriched in pathways related to immunity. KLRB1 exerted an impact on the MAPK/ERK signaling pathway, thereby modulating the growth and proliferation of LUAD cells. KLRB1 expression is linked to prognosis, immune infiltration, and cell migration and proliferation in LUAD. Conclusions: The evidence revealed a correlation between KLRB1 and both prognosis and immune infiltration in LUAD patients.
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DNA methylation is one of the earliest and most significant epigenetic mechanisms discovered. DNA methylation refers, in general, to the addition of a methyl group to a specific base in the DNA sequence under the catalysis of DNA methyltransferase, with Sadenosine methionine as the methyl donor, via covalent bonding and chemical modifications. DNA methylation is an important factor in inducing cancer. There are different types of DNA methylation, and methylation at different sites plays different roles. It is well known that the progression of colorectal cancer (CRC) is affected by the methylation of key genes. The present review did not only discuss the potential relationship between DNA methylation and CRC but also discussed how DNA methylation affects the development of CRC by affecting key genes. Furthermore, the clinical significance of DNA methylation in CRC was highlighted, including that of the therapeutic targets and biomarkers of methylation; and the importance of DNA methylation inhibitors was discussed as a novel strategy for treatment of CRC. The present review did not only focus upon the latest research findings, but earlier reviews were also cited as references to older literature.
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Neoplasias Colorretais , Metilação de DNA , Epigênese Genética , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , AnimaisRESUMO
Spinal cord injury (SCI) represents a catastrophic neurological condition resulting in long-term loss of motor, autonomic, and sensory functions. Recently, ferroptosis, an iron-regulated form of cell death distinct from apoptosis, has emerged as a potential therapeutic target for SCI. In this study, we developed an injectable hydrogel composed of carboxymethyl cellulose (CMC), and quaternized chitosan (QCS), loaded with modified polydopamine nanoparticles (PDA NPs), referred to as CQP hydrogel. This hydrogel effectively scavenged reactive oxygen species (ROS), prevented the accumulation of Fe2+ and lipid peroxidation associated with ferroptosis, and restored mitochondrial functions in primary neuronal cells. When administered to animal models (rats) with SCI, the CQP hydrogels improved motor function by regulating iron homeostasis, inhibiting ferroptosis, and mitigating oxidative stress injury. Both in vitro and in vivo studies corroborated the capacity of CQP hydrogels to promote the shift from M1 to M2 polarization of microglia/macrophages. These findings suggest that CQP hydrogels, functioning as a localized iron-chelating system, have potential as biomaterials to enhance recovery from SCI by targeting ferroptosis and modulating anti-inflammatory macrophages activity.
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Carboximetilcelulose Sódica , Quitosana , Ferroptose , Hidrogéis , Indóis , Nanopartículas , Polímeros , Traumatismos da Medula Espinal , Carboximetilcelulose Sódica/química , Carboximetilcelulose Sódica/farmacologia , Quitosana/química , Quitosana/farmacologia , Animais , Polímeros/química , Hidrogéis/química , Hidrogéis/farmacologia , Nanopartículas/química , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Indóis/química , Indóis/farmacologia , Ratos , Ferroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Ratos Sprague-Dawley , Modelos Animais de Doenças , Ferro/químicaRESUMO
OBJECTIVE: Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). METHODS: Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. RESULTS: We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. CONCLUSIONS: Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.
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Jejum , Lisossomos , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Humanos , Lisossomos/metabolismo , Jejum/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Camundongos Endogâmicos C57BL , Proteínas Ribossômicas/metabolismo , Proteínas Ribossômicas/genética , Masculino , Hepatócitos/metabolismo , Biossíntese de Proteínas , Autofagia , Fígado/metabolismo , Camundongos KnockoutRESUMO
Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer associated fibroblasts (CAFs). The mechanisms underlying this conversion, including regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to target CAFs therapeutically have so far failed. Here, we show that signals from epithelial cells expressing oncogenic KRAS -a hallmark pancreatic cancer mutation- activate fibroblast autocrine signaling, which drives expression of the cytokine interleukin-33 (IL-33). Stromal IL-33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces IL-33 secretion. Using compartment-specific IL-33 knockout mice, we observed that lack of stromal IL-33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells and lymphocytes. Notably, loss of stromal IL-33 leads to an increase in CD8+ T cell infiltration and activation, and, ultimately, reduced tumor growth.
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Chronic pain has emerged as a significant public health issue, seriously affecting patients' quality of life and psychological well-being, with a lack of effective pharmacological treatments. Numerous studies have indicated that macrophages play a crucial role in inflammatory pain, and targeting neuro-immune interactions for drug development may represent a promising direction for pain management. Chilobrachys jingzhao (C. jingzhao) is used as a folk medicine of the Li nationality with the efficacy of eliminating swelling, detoxicating, and relieving pain, and the related products are widely used in the market. However, the chemical constituents of C. jingzhao have not been reported, and the pharmacodynamic substance and the precise functional mechanism are unrevealed. Here we isolated a cyclic dipeptide, cyclo(L-Pro-L-Trp) (CPT) from C. jingzhao for the first time. CPT remarkably alleviated formalin-induced inflammatory pain and significantly inhibited inflammatory responses. In vivo, CPT attenuated neutrophil infiltration and plantar tissue edema and suppressed the mRNA expression of pro-inflammatory molecules. In vitro, CPT suppressed inflammation triggered by lipopolysaccharide (LPS) in both RAW 264.7 and iBMDM cells, reducing expressions of inducible nitric oxide synthase (iNOS), superoxide, and pro-inflammatory molecules. A mechanistic study revealed that CPT exerted an anti-inflammatory activity by blocking the mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, as well as alleviating the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). Our results elucidated the pharmacodynamic material basis of C. jingzhao, and CPT can be a promising lead for alleviating inflammation and inflammatory pain.
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Anti-Inflamatórios , Formaldeído , Inflamação , NF-kappa B , Transdução de Sinais , Fator 6 Associado a Receptor de TNF , Animais , NF-kappa B/metabolismo , Camundongos , Fator 6 Associado a Receptor de TNF/metabolismo , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Masculino , Transdução de Sinais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Células RAW 264.7 , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Dor/tratamento farmacológico , Dor/induzido quimicamente , Analgésicos/uso terapêutico , Analgésicos/farmacologia , Humanos , Edema/tratamento farmacológico , Edema/induzido quimicamente , Edema/imunologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologiaRESUMO
Oral microorganisms are closely related to oral health, the occurrence of some oral diseases is associated with changes in the oral microbiota, and many studies have demonstrated that traditional smoking can affect the oral microbial community. However, due to the short time since the emergence of e-cigarettes, fewer studies are comparing oral microorganisms for users of e-cigarettes versus cigarettes. We collected saliva from 40 non-smokers (NS), 46 traditional cigarette smokers (TS), and 27 e-cigarette consumers (EC), aged between 18 and 35 years. We performed 16S rRNA gene sequencing on the saliva samples collected to study the effects of e-cigarettes versus traditional cigarettes on the oral microbiome. The results showed that compared with the NS group, the alpha diversity of oral flora in saliva was altered in the TS group, with no significant change in the e-cigarette group. Compared with the NS and EC groups, the relative abundance of Actinomyces and Prevotella was increased in the TS group. However, compared with the NS and TS groups, the relative abundance of Veillonella was increased, and the relative abundance of Porphyromonas and Peptostreptococcus was decreased in the EC group. These results showed that both e-cigarettes and traditional cigarettes could alter the structure and composition of oral microbiota. The use of traditional cigarettes promotes the growth of some anaerobic bacteria, which may contribute to dental decay and bad breath over time. E-cigarettes have a different effect on the structure and composition of the oral microbial community compared to conventional cigarettes. In order to better understand the effects of e-cigarettes and traditional cigarettes on users' mouths, future studies will investigate the relationship between diseases such as dental caries and periodontitis and changes in oral microbial species levels.
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This study aimed to investigate the effects of electroacupuncture (EA) treatment on Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration was used establish PD mice model. The number of neurons is determined by TH staining. mRNA expression is detected by RT-qPCR. Protein expression was detected by Western blot. Gene expression is determined by immunofluorescence and immunohistochemistry. The functions of neurons are determined by TUNEL and flow cytometry assay. The binding sites of nuclear factor kappa B (NF-κB) RELA on the promoter of NLRP3 are predicted by JASPAR and verified by luciferase and ChIP assays. The results showed that EA treatment improves motor dysfunction in patients with PD. In vivo assays show that MPTP administration induces the loss of neurons in mice, which is restored by EA treatment. Moreover, EA treatment alleviates motor deficits in MPTP-induced PD mice. EA treatment also inhibits the enrichment of pro-inflammatory cytokines and lactodehydrogenase and suppresses neuronal pyroptosis. EA treatment increases the expression of METTL9. However, METTL9 deficiency dampens the effects of EA treatment and induces neuronal pyroptosis. Additionally, METTL9 promotes histidine methylation of NF-κB RELA, resulting the inhibition of epigenetic transcription of NLRP3. EA treatment restores neuronal function and improves motor dysfunction via promoting METTL9 histidine methylation of NF-κB/ NLRP3 signaling.
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Eletroacupuntura , Metiltransferases , Doença de Parkinson , Animais , Eletroacupuntura/métodos , Camundongos , Doença de Parkinson/terapia , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Humanos , Metiltransferases/metabolismo , Metiltransferases/genética , Histidina/metabolismo , NF-kappa B/metabolismo , Modelos Animais de Doenças , Metilação , Masculino , Fator de Transcrição RelA/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Camundongos Endogâmicos C57BL , 1-Metil-4-Fenil-1,2,3,6-Tetra-HidropiridinaRESUMO
Pleurotus tuoliensis is a unique species discovered in Xinjiang, China, which is recognized for its significant edible, medicinal, and economic value. It has been successfully incorporated into industrial production. Controversy has emerged concerning the evolution and environmental adaptability of this species due to inadequate interspecific ecology and molecular data. This study examines the germplasm resources of P. tuoliensis in the Xinjiang region. A total of 225 wild and cultivated strains of P. tuoliensis were gathered from seven representative regions. Phylogenetic analysis revealed that seven populations were notably segregated into three distinct groups, primarily attributed to environmental factors as the underlying cause for this differentiation. Population historical size data indicate that P. tuoliensis underwent two expansion events, one between 2 and 0.9 Mya (Miocene) and the other between 15 and 4 Mya (Early Pleistocene). The ancient climate fluctuations in the Xinjiang region might have contributed to the comparatively modest population size during the Pliocene epoch. Moreover, through the integration of biogeography and ancestral state reconstruction, it was determined that group C of P. tuoliensis emerged initially and subsequently dispersed to groups D and B, in that order. Subsequently, group D underwent independent evolution, whereas group B continued to diversify into groups A and EFG. The primary factor influencing this mode of transmission route is related to the geographical conditions and prevailing wind direction of each group. Subsequent research endeavors focused on assessing the domestication adaptability of P. tuoliensis to different substrates. It was found that the metabolic processes adapted during the domestication process were mainly related to energy metabolism, DNA repair, and environmental adaptability. Processes adapted to the host adaptability include responses to the host (meiosis, cell cycle, etc.) and stress in the growth environment (cysteine and methionine metabolism, sulfur metabolism, etc.). This study analyzed the systematic evolution and genetic differentiation of P. tuoliensis in Xinjiang. The identified loci and genes provide a theoretical basis for the subsequent improvement of germplasm resources and conducting molecular breeding.
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Actinas , Neoplasias da Mama , Calgranulina A , Calgranulina B , Movimento Celular , Transição Epitelial-Mesenquimal , Humanos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Feminino , Actinas/metabolismo , Calgranulina B/metabolismo , Calgranulina B/genética , Calgranulina A/metabolismo , Calgranulina A/genética , Linhagem Celular Tumoral , Invasividade Neoplásica , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Receptor para Produtos Finais de Glicação Avançada/genética , PolimerizaçãoRESUMO
BACKGROUND: Mucinous breast carcinoma (MBC) is often misdiagnosed as fibroadenoma (FA),which can lead to inappropriate or delayed treatments. This study aimed to establish an efficient ultrasound (US)-based diagnostic model to distinguish MBC subtypes from FAs. METHODS: Between January 2017 and February 2024, 240 lesions were enrolled, comprising 65 cases of pure mucinous breast carcinoma (PMBC), 47 cases of mixed mucinous breast carcinoma (MMBC), and 128 cases of FAs. Ten US feature variables underwent principal component analysis (PCA). Models were constructed based on components explaining over 75% of the total variation, with varimax rotation applied for interpretability. Comprehensive models were developed to distinguish PMBCs and MMBCs from FAs. RESULTS: Six principal components were selected, achieving a cumulative contribution rate of 77.46% for PMBCs vs. FAs and 78.62% for MMBCs vs. FAs. The principal component of cystic-solid composition and posterior acoustic enhancement demonstrated the highest diagnostic value for distinguishing PMBCs from FAs (AUC: 0.86, ACC: 80.31%). Features including vascularization, irregular shape, ill-defined border, and larger size exhibited the highest diagnostic value for distinguishing MMBCs from FAs (AUC: 0.90, ACC: 87.43%). The comprehensive models showed excellent clinical value in distinguishing PMBCs (AUC = 0.86, SEN = 86.15%, SPE = 73.44%, ACC = 77.72%) and MMBCs (AUC = 0.92, SEN = 80.85%, SPE = 95.31%, ACC = 91.43%) from FAs. CONCLUSION: This diagnostic model holds promise for effectively distinguishing PMBCs and MMBCs from FAs, assisting radiologists in mitigating diagnostic biases and enhancing diagnostic efficiency.
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In contemporary times, tumors have emerged as the primary cause of mortality in the global population. Ongoing research has shed light on the significance of neurotransmitters in the regulation of tumors. It has been established that neurotransmitters play a pivotal role in tumor cell angiogenesis by triggering the transformation of stromal cells into tumor cells, modulating receptors on tumor stem cells, and even inducing immunosuppression. These actions ultimately foster the proliferation and metastasis of tumor cells. Several major neurotransmitters have been found to exert modulatory effects on tumor cells, including the ability to restrict emergency hematopoiesis and bind to receptors on the postsynaptic membrane, thereby inhibiting malignant progression. The abnormal secretion of neurotransmitters is closely associated with tumor progression, suggesting that focusing on neurotransmitters may yield unexpected breakthroughs in tumor therapy. This article presents an analysis and outlook on the potential of targeting neurotransmitters in tumor therapy.
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Progressão da Doença , Neoplasias , Neurotransmissores , Humanos , Neurotransmissores/metabolismo , Neoplasias/patologia , Neoplasias/metabolismo , Animais , Neovascularização Patológica/patologia , Neovascularização Patológica/metabolismoRESUMO
We aimed to analyze the feasibility of endovascular treatment for brucellosis-related aorta-iliac artery pseudoaneurysm. We did a statistical analysis that among the 11 cases, the thoracic aorta was involved in 3 cases, the abdominal aorta was involved in 6 cases, and the iliac artery was involved in 2 cases. Five patients had a history of contact with cattle and sheep, 3 had a history of drinking raw milk, 10 patients had a fever before the operation, and 11 patients had positive serum agglutination test. Blood culture was positive in 2 patients. All patients were given anti-brucellosis treatment immediately after diagnosis. One died of aortic rupture 5 days after emergency endovascular gastrointestinal bleeding. Endovascular-covered stent implantation and active anti-brucellosis therapy were used to treat 10 patients. The follow-up period was 8 years without aortic complications or death for all patients. We think early diagnosis and a combination of anti-brucellosis drugs and endovascular therapy may be the first choice for treating the pseudoaneurysm caused by Brucella.
Assuntos
Falso Aneurisma , Brucelose , Procedimentos Endovasculares , Humanos , Falso Aneurisma/terapia , Falso Aneurisma/microbiologia , Falso Aneurisma/etiologia , Falso Aneurisma/diagnóstico , Brucelose/complicações , Brucelose/diagnóstico , Masculino , Procedimentos Endovasculares/métodos , Feminino , Pessoa de Meia-Idade , Adulto , Stents , Idoso , Aneurisma Infectado/microbiologia , Aneurisma Infectado/diagnóstico , Aneurisma Infectado/terapia , Artéria Ilíaca/cirurgia , Aneurisma Ilíaco/microbiologia , Aneurisma Ilíaco/cirurgia , Aneurisma Ilíaco/terapia , Aneurisma Ilíaco/diagnóstico por imagem , Antibacterianos/uso terapêutico , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Although the negative association of tobacco smoking with osteoporosis is well-documented, little is known regarding the shared genetic basis underlying these conditions. In this study, we aim to investigate a shared genetic architecture between smoking and heel estimated bone mineral density (eBMD), a reliable proxy for osteoporosis. We conducted a comprehensive genome-wide cross-trait analysis to identify genetic correlation, pleiotropic loci and causal relationship of smoking with eBMD, leveraging summary statistics of the hitherto largest genome-wide association studies conducted in European ancestry for smoking initiation (Nsmoker = 1 175 108, Nnonsmoker = 1 493 921), heaviness (cigarettes per day, N = 618 489), cessation (Ncurrent smoker = 304 244, Nformer smoker = 843 028), and eBMD (N = 426 824). A significant negative global genetic correlation was found for smoking cessation and eBMD (${r}_g$ = -0.051, P = 0.01), while we failed to identify a significant global genetic correlation of smoking initiation or heaviness with eBMD. Partitioning the whole genome into independent blocks, we observed 6 significant shared local signals for smoking and eBMD, with 22q13.1 showing the strongest regional genetic correlation. Such a genetic overlap was further supported by 71 pleiotropic loci identified in the cross-trait meta-analysis. Mendelian randomization identified no causal effect of smoking initiation (beta = -0.003 g/cm2, 95% CI = -0.033 to 0.027) or heaviness (beta = -0.017 g/cm2, 95% CI = -0.072 to 0.038) on eBMD, but a putative causal effect of genetic predisposition to being a current smoker was associated with a lower eBMD compared to former smokers (beta = -0.100 g/cm2, 95% CI = -0.181 to -0.018). Our study demonstrates a pronounced biological pleiotropy as well as a putative causal link between current smoking status and eBMD, providing novel insights into the primary prevention and modifiable intervention of osteoporosis by advocating individuals to avoid, reduce or quit smoking as early as possible.
We conducted a comprehensive genome-wide cross-trait analysis to investigate the shared genetic basis and causal relationship underlying smoking and osteoporosis. Our findings revealed that smoking and eBMD are inherently linked through biological pleiotropy. Importantly, our study discovered that quitting smoking significantly reduced the risk of lower eBMD. We recommend individuals to avoid, reduce, or quit smoking as early as possible to protect bone health.
Assuntos
Densidade Óssea , Estudo de Associação Genômica Ampla , Fumar , Humanos , Densidade Óssea/genética , Fumar/genética , Fumar/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Osteoporose/genética , Abandono do Hábito de Fumar , Polimorfismo de Nucleotídeo Único , Osso e Ossos/metabolismoRESUMO
The need for tumor postoperative treatments aimed at recurrence prevention and tissue regeneration have raised wide considerations in the context of the design and functionalization of implants. Herein, an injectable hydrogel system encapsulated with anti-tumor, anti-oxidant dual functional nanoparticles has been developed in order to prevent tumor relapse after surgery and promote wound repair. The utilization of biocompatible gelatin methacryloyl (GelMA) was geared towards localized therapeutic intervention. Zeolitic imidazolate framework-8@ceric oxide (ZIF-8@CeO2, ZC) nanoparticles (NPs) were purposefully devised for their proficiency as reactive oxygen species (ROS) scavengers. Furthermore, injectable GelMA hydrogels loaded with ZC NPs carrying doxorubicin (ZC-DOX@GEL) were tailored as multifunctional postoperative implants, ensuring the efficacious eradication of residual tumor cells and alleviation of oxidative stress. In vitro and in vivo experiments were conducted to substantiate the efficacy in cancer cell elimination and the prevention of tumor recurrence through the synergistic chemotherapy approach employed with ZC-DOX@GEL. The acceleration of tissue regeneration and in vitro ROS scavenging attributes of ZC@GEL were corroborated using rat models of wound healing. The results underscore the potential of the multifaceted hydrogels presented herein for their promising application in tumor postoperative treatments.