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Mutations in the epidermal growth factor receptor (EGFR) gene are common driver oncogenes in non-small cell lung cancer (NSCLC). Studies have shown that afatinib is beneficial for NSCLC patients with rare EGFR mutations. However, the effectiveness of tyrosine kinase inhibitors (TKIs) against the G719X (G719A, G719C and G719S) mutation has not been fully established. Herein, using the CRISPR method, the EGFR G719X mutant cell lines were constructed to assess the sensitivity of the rare mutation G719X in NSCLC. WZ3146, a novel mutation-selective EGFR inhibitor, was conducted transcriptome sequencing and in vitro experiments. The results showed that WZ3146 induced cytotoxic effects, inhibited growth vitality and proliferation via ERK and AKT pathway in the EGFR G719X mutant cells. Our findings suggest that WZ3146 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation G719X.
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Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Receptores ErbB , Neoplasias Pulmonares , Mutação , Proteínas Proto-Oncogênicas c-akt , Humanos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Antineoplásicos/farmacologiaRESUMO
BACKGROUND: Currently, the conclusions of studies on subthalamic nucleus (STN) deep brain stimulation (DBS) for improving Parkinson's disease (PD) with depression are inconsistent, and the reasons for improvement or deterioration remain unclear. METHODS: The aim was to investigate the prognosis of PD with depression after bilateral STN-DBS and the factors related to the improvement in depression. The local and network effects of DBS on depression in PD (DPD) were further explored based on the volume of tissue activation (VTA). The study analyzed 80 primary PD patients who had undergone bilateral STN-DBS, comprising 47 patients with improved depression and 33 patients without improvement. Two groups of clinical profiles and stimulation parameters were compared, and the network models for improving depression were constructed. RESULTS: The improvement in depression was closely associated with improvement in anxiety (odd rate [OR] = 1.067, P = 0.006) and the standardized space left y-coordinate (OR = 0.253, P = 0.005). The VTA overlapping with the left motor STN subregion is most significantly associated with improvement in depression (RSpearman = 0.53, P < 0.001; RPearson = 0.43, P < 0.001). The y-coordinates in the improvement group were closer to the optimal stimulation site for improving motor symptoms. Finally, both the structural and functional network models indicate a positive correlation between depression improvement and the connectivity of the sensorimotor cortex. CONCLUSION: The amelioration of DPD is primarily attributed to the stimulation of bilateral motor STN, particularly on the left. However, this stimulatory effect manifests as an indirect influence.
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Storage is an important process involved in the postharvest treatment of grain-oilseed and is necessary for maintaining high quality and ensuring the long-term supply of these commodities in the food industry. Proper storage practices help prevent spoilage, maintain nutritional value, and preserve marketable quality. It is of great interest for storage to investigate flow, heat and mass transfer processes, and quality change for optimizing the operation parameters and ensuring the quality of grain-oilseed. This review discusses the mathematical models developed and applied to describe the physical field, biological field, and quality change during the storage of grain-oilseed. The advantages, drawbacks, and industrial relevance of the existing mathematical models were also critically evaluated, and an organic system was constructed by correlating them. Finally, the future research trends of the mathematical models toward the development of multifield coupling models based on biological fields to control quality were presented to provide a reference for further directions on the application of numerical simulations in this area. Meanwhile, artificial intelligence (AI) can greatly enhance our understanding of the coupling relationships within grain-oilseed storage. AI's strengths in both qualitative and quantitative analysis, as well as its effectiveness, make it an invaluable tool for this purpose.
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Grão Comestível , Armazenamento de Alimentos , Modelos Teóricos , Armazenamento de Alimentos/métodos , Grão Comestível/química , Sementes/química , Inteligência Artificial , Óleos de Plantas/químicaRESUMO
Two novel uranium(IV) orthophosphate framework compounds were obtained by the high-temperature flux method in CsCl-CsF eutectic salt. Cs2UIV(PO4)2 (1) and isostructural Cs2(UIV0.75CeIV0.25)(PO4)2 (2) are tetragonal structures bridged by (U/Ce)IV-O octacoordinated dodecahedra and PO4 tetrahedra, with Cs+ cations filling in the channels. The crystal structures exhibit good structural and thermal stability with a potential capacity to immobilize tetravalent radionuclides.
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Candida albicans is a common opportunistic fungus in humans, whose morphological switch between yeast and hyphae forms represents a key virulence trait. Developing strategies to inhibit C. albicans hyphal growth may provide insights into designs of novel antivirulent therapeutics. Importantly, the gut commensal bacterium, Enterococcus faecalis, secretes a bacteriocin EntV which has potent antivirulent and antifungal effects against C. albicans in infection models; however, hampered by the challenges to access large quantities of bioactive EntV, the detailed understanding of its mechanisms on C. albicans has remained elusive. In this work, we biochemically reconstituted the proteolytic cleavage reaction to obtain recombinant EntV88-His6 on a large preparative scale, providing facile access to the C-terminal EntV construct. Under in vitro C. albicans hyphal assay with specific inducers, we demonstrated that EntV88-His6 exhibits potent bioactivity against GlcNAc-triggered hyphal growth. Moreover, with fluorescent FITC-EntV88-His6, we revealed that EntV88-His6 enters C. albicans via endocytosis and perturbs the proper localization of the polarisome scaffolding Spa2 protein. Our findings provide important clues on EntV's mechanism of action. Surprisingly, we showed that EntV88-His6 does not affect C. albicans yeast cell growth but potently exerts cytotoxicity against C. albicans under hyphal-inducing conditions in vitro. The combination of EntV88-His6 and GlcNAc displays rapid killing of C. albicans, rendering it a promising antivirulent and antifungal agent.
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Antifúngicos , Candida albicans , Enterococcus faecalis , Hifas , Candida albicans/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/química , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/genética , Bacteriocinas/farmacologia , Bacteriocinas/química , Testes de Sensibilidade Microbiana , Humanos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/química , Endocitose/efeitos dos fármacosRESUMO
BACKGROUND: Previous research on ABO blood types and stroke has been controversial, predominantly suggesting heightened risk of stroke in non-O blood types. Nonetheless, investigations into the correlation and underlying mechanisms between ABO blood groups and stroke subtypes, especially within Chinese cohorts, remain limited. METHODS: The ABO blood types of 9,542 ischaemic stroke (IS) patients were inferred using two ABO gene loci (c.261G > del; c.802G > A). The healthy population was derived from the 1000 Genomes Project. Patients were classified by the causative classification system (CCS). Volcano plot and gene ontology (GO) analysis were employed to explore protein differential expression among blood types. Additionally, HT29 and SW480 cell lines with downregulated ABO expression were generated to evaluate its impact on cholesterol uptake and efflux. RESULTS: A greater proportion of stroke patients had non-O blood types (70.46%) than did healthy individuals (61.54%). Notable differences in blood type distributions were observed among stroke subtypes, with non-O blood type patients mainly classified as having large artery atherosclerosis (LAA). Clinical baseline characteristics, such as the low-density lipoprotein cholesterol level, activated partial thromboplastin time and thrombin time, varied significantly among blood types. A volcano plot revealed 17 upregulated and 42 downregulated proteins in the O blood type. GO term analysis indicated that downregulated proteins were primarily associated with lipid metabolism pathways. In vitro experiments revealed that reducing ABO gene expression decreased cholesterol uptake and increased cholesterol efflux. CONCLUSIONS: This study revealed that the non-O blood type increased the risk of LAA stroke through cholesterol metabolism.
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Sistema ABO de Grupos Sanguíneos , Aterosclerose , Colesterol , Acidente Vascular Cerebral , Humanos , Sistema ABO de Grupos Sanguíneos/genética , Masculino , Colesterol/sangue , Feminino , Pessoa de Meia-Idade , Aterosclerose/sangue , Aterosclerose/genética , Idoso , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética , Fatores de Risco , LDL-Colesterol/sangue , Células HT29RESUMO
Soybean is a photoperiod-sensitive staple crop. Its photoperiodic flowering has major consequences for latitudinal adaptation and grain yield. Here, we identify and characterise a flowering locus named Time of flower 4b (Tof4b), which encodes E1-Like b (E1Lb), a homologue of the key soybean floral repressor E1. Tof4b protein physically associates with the promoters of two FLOWERING LOCUS T (FT) genes to repress their transcription and delay flowering to impart soybean adaptation to high latitudes. Three E1 homologues undergo subfunctionalisation and show differential subcellular localisation. Moreover, they all possess self-repression capability and each suppresses the two homologous counterparts. Subfunctionalisation and the transcriptional regulation of E1 genes collectively finetune flowering time and high-latitude adaptation in soybean. We propose a model for the functional fate of the three E1 genes after the soybean whole-genome duplication events, refine the molecular mechanisms underlying high-latitude adaption, and provide a potential molecular-breeding resource.
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Flores , Regulação da Expressão Gênica de Plantas , Glycine max , Fotoperíodo , Proteínas de Plantas , Glycine max/genética , Glycine max/metabolismo , Flores/genética , Flores/crescimento & desenvolvimento , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Adaptação Fisiológica/genética , Regiões Promotoras Genéticas/genética , Duplicação Gênica , Plantas Geneticamente Modificadas , Filogenia , Genes de PlantasRESUMO
Parkinson's disease (PD) is a common age-related neurodegenerative disorder, which may be largely due to the mitochondrial dysfunction and impaired mitophagy. Thus, it is of great importance to seek novel therapeutic strategies for PD targeting mitochondrial function and mitophagy. Cytarabine is a marine-derived antimetabolite used in the treatment of acute leukemia, which is also used in the study of the nervous system. In this study, we found that cytarabine pretreatment significantly inhibited the apoptosis and necrosis in the ROT-induced SH-SY5Y cell PD model and reduced the oxidative stress, as evidenced by the reduced MDA levels and the increased levels of SOD, GSH, and total antioxidant capacity. Cytarabine can also enhance mitochondrial vitality, improve mitochondrial respiratory function, and preserve mitochondrial morphology. Cytarabine also enhanced the expression of the mitophagy-related proteins PINK1, Parkin, VDAC1, and DJ-1, and its actions can be reversed by treatment with AMPK inhibitor - Compound C (CC), suggesting that AMPK activation may be involved in cytarabine-enhanced mitophagy. Furthermore, cytarabine can also ameliorate the motor symptoms in the MPTP-induced PD-like mice model, and attenuate the neuropathy in the substantia nigra (SN) of PD mice, while Compound C antagonized cytarabine's beneficial effects. In summary, marine-derived compound cytarabine could resist neurological damage both in vitro and in vivo by activating AMPK to increase PINK1/Parkin-induced mitophagy, serving as a promising disease modulator for treating neurodegenerative disease.
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Proteínas Quinases Ativadas por AMP , Citarabina , Modelos Animais de Doenças , Mitofagia , Proteínas Quinases , Ubiquitina-Proteína Ligases , Animais , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Humanos , Camundongos , Linhagem Celular Tumoral , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , Citarabina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Apoptose/efeitos dos fármacosRESUMO
The length of hypocotyl affects the height of soybean and lodging resistance, thus determining the final grain yield. However, research on soybean hypocotyl length is scarce, and the regulatory mechanisms are not fully understood. Here, we identified a module controlling the transport of sucrose, where sucrose acts as a messenger moved from cotyledon to hypocotyl, regulating hypocotyl elongation. This module comprises four key genes, namely MYB33, SWEET11, SWEET21 and GA2ox8c in soybean. In cotyledon, MYB33 is responsive to sucrose and promotes the expression of SWEET11 and SWEET21, thereby facilitating sucrose transport from the cotyledon to the hypocotyl. Subsequently, sucrose transported from the cotyledon up-regulates the expression of GA2ox8c in the hypocotyl, which ultimately affects the length of the hypocotyl. During the domestication and improvement of soybean, an allele of MYB33 with enhanced abilities to promote SWEET11 and SWEET21 has gradually become enriched in landraces and cultivated varieties, SWEET11 and SWEET21 exhibit high conservation and have undergone a strong purified selection and GA2ox8c is under a strong artificial selection. Our findings identify a new molecular pathway in controlling soybean hypocotyl elongation and provide new insights into the molecular mechanism of sugar transport in soybean.
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Fear overgeneralization is widely accepted as a pathogenic marker of post-traumatic stress disorder (PTSD). Recently, GABAergic interneurons have been regarded as key players in the regulation of fear memory. The role of hippocampal GABAergic interneurons in contextual fear generalization of PTSD remains incompletely understood. In the present study, we established a rat model of PTSD with inescapable foot shocks (IFS) and observed the loss of GABAergic interneuron phenotype in the hippocampal cornu ammonis-1 (CA1) subfield. To determine whether the loss of GABAergic interneuron phenotype was associated with fear generalization in PTSD rats, we used adeno-associated virus (AAV) to reduce the expression of GAD67 in CA1 and observed its effect on fear generalization. The results showed that the reduction of GAD67 in CA1 enhanced contextual fear generalization in rats. We investigated whether the PERK pathway was involved in the GABAergic interneuron injury. Increased expression of p-PERK, CHOP, and Caspase12 in GABAergic interneurons of PTSD rats was observed. Then, we used salubrinal, an endoplasmic reticulum stress inhibitor, to modulate the PERK pathway. The salubrinal treatment significantly protected the GABAergic interneurons and relieved fear generalization in PTSD rats. In addition, the results showed that salubrinal down-regulated the expression of CHOP and Caspase12 in GABAergic interneurons of PTSD rats. In conclusion, this study provided evidence that the loss of GABAergic interneuron phenotype in CA1 may contribute to contextual fear generalization in PTSD. The PERK pathway is involved in the GABAergic interneuron injury of PTSD rats and modulating it can protect GABAergic interneurons and constrain contextual fear generalization.
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Região CA1 Hipocampal , Medo , Neurônios GABAérgicos , Interneurônios , Ratos Sprague-Dawley , Transtornos de Estresse Pós-Traumáticos , Animais , Ratos , Interneurônios/metabolismo , Medo/fisiologia , Medo/psicologia , Masculino , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/psicologia , Região CA1 Hipocampal/metabolismo , Neurônios GABAérgicos/metabolismo , Generalização Psicológica/fisiologia , Glutamato Descarboxilase/metabolismoRESUMO
In this study, Pediococcus pentosaceus C-2-1 and C23221 contained genes encoding penocin and pediocin PA-1, mined by antiSMASH. The penocin structural gene pedA from Pediococcus pentosaceus C-2-1 was successfully expressed in Escherichia coli BL21. The presence of a 6.5 kDa recombinant penocin was confirmed by Tricine-SDS-PAGE, and the specific activity increased by 1.54-fold. The bacteriocins produced by Pediococcus pentosaceus C23221 were purified using acetic ether extraction, Sepharose Fast Flow, Sephadex G-25 gel chromatography, and reversed-phase high-performance liquid chromatography (RP-HPLC); the amino acid sequence of this bacteriocin was identical to pediocin PA-1 by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), which confirmed the expression of pediocin PA-1 gene; and the specific activity increased by 24.39-fold. The heterologous expression and purification of bacteriocins have proved the expression of pediocin-like produced by Pediococcus pentosaceus. This provides a theoretical basis for the subsequent development and application of pediocin-like.
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The tertiary mutation C797S in the structural domain of the EGFR kinase is a common cause of resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs). In this study, we used a potent, selective and irreversible inhibitor, BDTX-189, to target EGFR C797S triple mutant cells for cell activity. The study constructed the H1975-C797S (EGFR L858R/T790 M/C797S) cell line using the CRISPR/Cas9 method and investigated its potential as a fourth-generation tyrosine kinase inhibitor via chemosensitivity approach. The results demonstrated its ability to induce cytotoxic effects, and inhibit EGFR L858R/T790 M/C797S cell growth and proliferation in a dose-dependent manner. Meanwhile, BDTX-189 reduces the protein phosphorylation levels of EGFR, ERK, and AKT, promoting apoptosis. Furthermore, BDTX-189 not only inhibits common EGFR triple mutations but also effectively inhibits EGFR L858R mutation and EGFR L858R/T790 M mutation. These findings support the cytotoxic effect of BDTX-189 and its inhibitory effect on cell division and proliferation with the EGFR C797S triple mutation.
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Apoptose , Proliferação de Células , Receptores ErbB , Mutação , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/químicaRESUMO
Early life stress (ELS) can cause long-term changes by epigenetic factors, especially histone acetylation modification, playing a crucial role, affect normal cognition, mood, and behavior, and increase susceptibility to post-traumatic stress disorder (PTSD) in adulthood. It has been found that paeoniflorin (PF) can cross the blood-brain barrier to exert anti-PTSD effects on adult PTSD rats. However, whether PF can alleviate the harmful effects caused by ELS in adulthood has not yet been reported. Therefore, to explore the relationship between ELS and PTSD susceptibility in adulthood and its mechanism, in this study, SPS was used as a stressor of ELS, and the mathematical tool Z-normalization was employed as an evaluation criterion of behavioral resilience susceptibility. To investigate the regulatory mechanism of PF on histone acetylation in the hippocampus and amygdala of ELS rats in adulthood, using changes in HATs/HDACs as the entry point, meanwhile, the epigenetic marks (H3K9 and H4K12) in the key brain regions of ELS (hippocampus and amygdala) were evaluated, and the effects of PF on behavioral representation and PTSD susceptibility were observed. This study found that ELS lead to a series of PTSD-like behaviors in adulthood and caused imbalance of HATs/HDACs ratio in the hippocampus and amygdala, which confirms that ELS is an important risk factor for the development of PTSD in adulthood. In addition, paeoniflorin may improve ELS-induced PTSD-like behaviors and reduce the susceptibility of ELS rats to develop PTSD in adulthood by modulating the HATs/HDACs ratio in the hippocampus and amygdala.
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Tonsila do Cerebelo , Glucosídeos , Hipocampo , Histonas , Monoterpenos , Transtornos de Estresse Pós-Traumáticos , Estresse Psicológico , Animais , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Monoterpenos/farmacologia , Monoterpenos/uso terapêutico , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Histonas/metabolismo , Ratos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/metabolismo , Masculino , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Ratos Sprague-Dawley , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismoRESUMO
Currently, evidence from observational studies suggests dietary fiber intake may be associated with decreased risk of food allergy. As a type of dietary fiber, resistant starch was also widely reported to possess anti-allergic properties. However, there is a relative paucity of studies assessing the influence of resistant starch types on their anti-allergic activity and its possible underlying mechanisms. In the current study, the anti-allergic effects of RS3-type (retrograded starch), RS4-type (chemically modified starch, cross-bonded), and RS5-type (starch-palmitic acid complex) of lotus seed resistant starch were evaluated in the OVA (100 mg/kg)-induced food allergic mice model. The results showed that oral administration of RS3 or RS4 lotus seed resistant starch (0.3 g/100 g b.w.) for 25 days significantly improved adverse symptoms of food allergy such as weight loss, increases in allergy symptom score and diarrhea rate; with significant reduction of serum specific antibody IgE, TNF-α, IL-4 levels and improved Th1/Th2 balance being observed. The mechanism may involve the regulation of lotus seed resistant starch on intestinal flora and the metabolites short-chain fatty acids and bile acids. Taken together, the findings may enhance understanding towards ameliorative effects of resistant starch on food allergy, and offer valuable insights for the exploration of novel anti-allergic bioactive compounds.
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Antialérgicos , Modelos Animais de Doenças , Lotus , Ovalbumina , Sementes , Animais , Lotus/química , Camundongos , Sementes/química , Antialérgicos/farmacologia , Amido Resistente/farmacologia , Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/tratamento farmacológico , Imunoglobulina E/sangue , Amido/química , Amido/farmacologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacosRESUMO
Purpose: To explore the clinical characteristics, treatment, and long-term prognosis of mycoplasma pneumoniae pneumonia (MPP) combined with pulmonary embolism (PE) in children. Patients and Methods: The medical records of 16 children who were diagnosed with MPP associated with PE between January 2016 and January 2023 at Children's Hospital, Zhejiang University School of Medicine were retrospectively reviewed. Results: The average age patients were 8.24 ± 1.99 years. All cases were diagnosed with refractory mycoplasma pneumoniae pneumonia (RMPP) and presented complications in the form of necrotizing pneumonia (NP). The main symptoms observed were cough and fever (n = 16, 100%), chest pain (n = 8, 50%), dyspnea (n = 8, 50%), and hemoptysis (n = 4, 25%). In these cases, 12 patients had involvement of the pulmonary artery, 3 patients experienced issues with the pulmonary vein, and 1 patient had simultaneous involvement of both the pulmonary artery and pulmonary vein. Among the 12 pulmonary artery embolism cases, 6 involved the right pulmonary artery, 4 involved the left pulmonary artery, and 2 involved both the right and left pulmonary arteries. The mean D-dimer level was 8.50 ± 4.76 mg/L. All patients received anticoagulant therapy, and after treatment, there was a significant improvement in their symptoms and lung lesions. Conclusion: Children with RMPP, chest pain, hemoptysis, and elevated D-dimer levels should be closely monitored for the potential development of PE. The co-occurrence of MPP and PE often involves the presence of NP. In cases of confirmed PE, anticoagulation therapy may be a suitable consideration. PE and NP resulting from MPP generally had a favorable overall prognosis.
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PURPOSE: EGFR classical mutations respond well to EGFR tyrosine kinase inhibitors. However, it is uncertain whether currently available EGFR-TKIs are effective against rare EGFR mutations and compound mutations. Herein, the effectiveness of almonertinib and alflutinib, the third-generation tyrosine kinase inhibitors developed in China, on rare EGFR S768I mutations and compound mutations is identified. METHODS: In this study, using CRISPR method, four EGFR S768I mutation cell lines were constructed, and the sensitivity of EGFR to almonertinib and alflutinib was tested, with positive controls being the 1st (gefitinib), 2nd (afatinib), and 3rd (osimertinib) generation drugs. RESULTS: The present results indicate that almonertinib and alflutinib can effectively inhibit cell viability and proliferation in rare EGFR S768I mutations through the ERK or AKT pathways in a time-dependent manner, by blocking the cell cycle and inhibiting apoptosis. CONCLUSIONS: These findings suggest that almonertinib and alflutinib may be potential therapeutic options for non-small cell lung cancer patients with the EGFR S768I mutation.
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Liposomes were modified with different proportions of ß-conglycinin (7S) and glycinin (11S) to form Lip-7S and Lip-11S. The morphology, interaction and in vitro simulated digestion of liposomes were studied. The particle size of Lip-7S was smaller than that of Lip-11S. When the values of Lip-7S and Lip-11S were 1:1 and 1:0.75, respectively, the ζ-potential had the maximum absolute value and the dispersion of the system was good. The results of multispectral analysis showed that hydrogen-bond and hydrophobic interaction dominated protein-modified liposomes, the protein structure adsorbed on the surface of liposomes changed, the content of α-helix decreased, and the structure of protein-modified liposomes became denser. The surface hydrophobicity and micropolarity of liposomes decreased with the increase of protein ratio, and tended to be stable after Lip-7S (1:1) and Lip-11S (1:0.75). Differential scanning calorimetry showed that Lip-7S had higher phase transition temperature (≥170.5 °C) and better rigid structure. During simulated digestion, Lip-7S (22.5 %) released less Morin than Lip (40.6 %) and Lip-11S (26.2 %), and effectively delayed the release of FFAs. The environmental stability of liposomes was effectively improved by protein modification, and 7S had better modification effect than 11S. This provides a theoretical basis for 7S and 11S modified liposomes, and also provides a data reference for searching for new materials for stabilization of liposomes.
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Antígenos de Plantas , Globulinas , Lipossomos , Proteínas de Armazenamento de Sementes , Proteínas de Soja , Globulinas/química , Proteínas de Armazenamento de Sementes/química , Proteínas de Soja/química , Lipossomos/química , Antígenos de Plantas/química , Interações Hidrofóbicas e Hidrofílicas , Digestão , Tamanho da Partícula , Ligação de HidrogênioRESUMO
Taurocholic acid (TCA) is abundant in the rat intestine and has multiple health benefits. In the gut, intestinal microbiota can transform TCA into different bile acid (BA) derivatives, with the composition of microbiota playing a crucial role in the transformation process. This study aims to investigate how lotus seed resistant starch (LRS) can regulate microbiota to influence BA transformation. A fecal fermentation study was conducted in vitro, using either LRS, high-amylose maize starch (HAMS), or glucose (GLU) to analyze microbiota composition, BA content, and metabolic enzyme activities over different fermentation times. Bioinformatics analysis found that LRS increased the relative abundance of Enterococcus, Bacillus, and Lactobacillus, and decreased Escherichia-Shigella, compared with HAMS and GLU. LRS also reduced total BA content and accelerated the conversion of TCA to cholic acid, deoxycholic acid, and other derivatives. These results reveal that LRS and GLU tend to mediate the dehydroxy pathway, whereas HAMS tends to secrete metabolic enzymes in the epimerization pathway. Therefore, the evidence that LRS may regulate TCA bioconversion may benefit human colon health research and provide an important theoretical basis, as well as offer new concepts for the development of functional foods.
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Fermentação , Microbioma Gastrointestinal , Lotus , Sementes , Ácido Taurocólico , Lotus/metabolismo , Sementes/metabolismo , Sementes/química , Animais , Ácido Taurocólico/metabolismo , Ratos , Amido Resistente/metabolismo , Ácidos e Sais Biliares/metabolismo , Fezes/microbiologia , Masculino , Amido/metabolismoRESUMO
Transparent immunodeficient animal models not only enhance in vivo imaging investigations of visceral organ development but also facilitate in vivo tracking of transplanted tumor cells. However, at present, transparent and immunodeficient animal models are confined to zebrafish, presenting substantial challenges for real-time, in vivo imaging studies addressing specific biological inquiries. Here, we employed a mitf-/-/prkdc-/-/il2rg-/- triple-knockout strategy to establish a colorless and immunodeficient amphibian model of Xenopus tropicalis. By disrupting the mitf gene, we observed the loss of melanophores, xanthophores, and granular glands in Xenopus tropicalis. Through the endogenous mitf promoter to drive BRAFV600E expression, we confirmed mitf expression in melanophores, xanthophores and granular glands. Moreover, the reconstruction of the disrupted site effectively reinstated melanophores, xanthophores, and granular glands, further highlighting the crucial role of mitf as a regulator in their development. By crossing mitf-/- frogs with prkdc-/-/il2rg-/- frogs, we generated a mitf-/-/prkdc-/-/il2rg-/- Xenopus tropicalis line, providing a colorless and immunodeficient amphibian model. Utilizing this model, we successfully observed intravital metastases of allotransplanted xanthophoromas and migrations of allotransplanted melanomas. Overall, colorless and immunodeficient Xenopus tropicalis holds great promise as a valuable platform for tumorous and developmental biology research.
Assuntos
Anuros , Peixe-Zebra , Animais , Citoplasma , Xenopus/genética , Peixe-Zebra/genética , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismoRESUMO
The bacteriocin-producing Lactiplantibacillus plantarum SL47 was isolated from conventional fermented sausages, and the bacteriocin SL47 was purified using ethyl acetate, Sephadex G-25 gel chromatography, and reversed-phase high-performance liquid chromatography (RP-HPLC). Bacteriocin SL47 was identified by HPLC-MS/MS combined with whole-genome sequencing, and the results showed it consisted of plantaricin A, J, K, and N. Further characterization analysis showed that the bacteriocin SL47 was highly thermostable (30 min, 121 °C), pH stable (2-10), sensitive to protease and exhibited broad-spectrum antibacterial ability against Gram-positive and Gram-negative bacteria. The mechanism of action showed that the bacteriocin SL47 increased cell membrane permeability, and 2 × minimum inhibitory concentration (MIC) treatment for 40 min caused apoptosis of Staphylococcus aureus F2. The count of S. aureus in the sausage that was inoculated with L. plantarum SL47 and bacteriocin SL47 decreased by about 64% and 53% of that in the initial stage, respectively. These results indicated the potential of L. plantarum SL47 and bacteriocin SL47 as a bio-preservative in meat products.