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2.
Front Pharmacol ; 15: 1397498, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38873411

RESUMO

Isorhynchophylline (IRN), a tetracyclic indole alkaloid, has anti-inflammatory and antioxidant activities against cardiovascular diseases and central nervous system disorders. Acute lung injury (ALI) is a manifestation of inflammation concentrated in the lungs and has a high incidence rate and mortality The purpose of this study is to explain the mechanism of IRN in the treatment of acute lung injury and to provide a new scheme for clinical treatment. The experimental mice were divided into three groups: CTRL, LPS, LPS+IRN. The mouse model of ALI was established by inhaling LPS solution through nose. After continuous administration of IRN solution for 7 days, the mice in LPS+IRN group were killed and the lung tissue was collected for detection. Proteomic (Data are available via ProteomeXchange with identifier PXD050432) results showed that 5727 proteins were detected in mouse lung tissues, and 16 proteins were screened out. IRN could reverse the trend of these differential proteins. In addition, IRN can act on integrin αM to reduce neutrophil recruitment and thereby produce anti-inflammatory effects and may suppress neutrophil migration through the leukocyte transendothelial migration pathway. TUNEL and RT-PCR experiments revealed that LPS-induced ALI in mice increases the apoptosis of lung tissues, damage to alveolar epithelial cells and levels of inflammatory factors. Treatment with IRN can repair tissues, improve lung tissue pathology and reduce lung inflammation.

3.
Nat Commun ; 15(1): 3689, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38693165

RESUMO

Human visual neurons rely on event-driven, energy-efficient spikes for communication, while silicon image sensors do not. The energy-budget mismatch between biological systems and machine vision technology has inspired the development of artificial visual neurons for use in spiking neural network (SNN). However, the lack of multiplexed data coding schemes reduces the ability of artificial visual neurons in SNN to emulate the visual perception ability of biological systems. Here, we present an artificial visual spiking neuron that enables rate and temporal fusion (RTF) coding of external visual information. The artificial neuron can code visual information at different spiking frequencies (rate coding) and enables precise and energy-efficient time-to-first-spike (TTFS) coding. This multiplexed sensory coding scheme could improve the computing capability and efficacy of artificial visual neurons. A hardware-based SNN with the RTF coding scheme exhibits good consistency with real-world ground truth data and achieves highly accurate steering and speed predictions for self-driving vehicles in complex conditions. The multiplexed RTF coding scheme demonstrates the feasibility of developing highly efficient spike-based neuromorphic hardware.


Assuntos
Potenciais de Ação , Redes Neurais de Computação , Neurônios , Percepção Visual , Humanos , Neurônios/fisiologia , Potenciais de Ação/fisiologia , Percepção Visual/fisiologia , Modelos Neurológicos
4.
Heliyon ; 10(9): e29899, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38699020

RESUMO

While the 5-year survival rate of patients with advanced non-small cell lung cancer (NSCLC) has seen some improvement, the majority of NSCLC patients fail to respond to immunotherapy with immune checkpoint inhibitors (ICIs). It is critical to identify effective biomarkers that can enhance the efficacy of immunotherapy. The clinical data in the current study were collected from NSCLC patients treated with ICIs, and two groups were classified according to treatment effect: good group with consistent efficacy, poor group with only progressiveness. Differences in intestinal microbiota between the two groups were analyzed using 16s rRNA sequencing. Beta diversity analysis indicated differences between the two groups that were available for differentiation. Comparison of the number of common or unique operational taxonomic units (OTUs) among different groups suggested that there were 53 unique OTUs in the good group and 51 unique OTUs in the poor group. At the phylum level, there was a difference between the two groups for several bacterial groups with the highest abundance values, among which Firmicutes, Actinobacteria and Fusobacteria were more abundant in the good group. Members of the genera Bifidobacterium and Lactobacillus were abundant in the good group, while the abundance of Bacteroides was low. Biomarkers in the poor group included Bacteroides, Bacteroidetes, Bacteroidia, Bacteroidales, Bacteroidaceae and Veillonellaceae. The intestinal microbiota composition affected the immunotherapy process for NSCLC, which might offer more rational instructions for the clinical application of ICIs in NSCLC patients.

5.
J Cell Mol Med ; 28(9): e18319, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38742846

RESUMO

Knee osteoarthritis (KOA), a major health and economic problem facing older adults worldwide, is a degenerative joint disease. Glycyrrhiza uralensis Fisch. (GC) plays an integral role in many classic Chinese medicine prescriptions for treating knee osteoarthritis. Still, the role of GC in treating KOA is unclear. To explore the pharmacological mechanism of GC against KOA, UPLC-Q-TOF/MS was conducted to detect the main compounds in GC. The therapeutic effect of GC on DMM-induced osteoarthritic mice was assessed by histomorphology, µCT, behavioural tests, and immunohistochemical staining. Network pharmacology and molecular docking were used to predict the potential targets of GC against KOA. The predicted results were verified by immunohistochemical staining Animal experiments showed that GC had a protective effect on DMM-induced KOA, mainly in the improvement of movement disorders, subchondral bone sclerosis and cartilage damage. A variety of flavonoids and triterpenoids were detected in GC via UPLC-Q-TOF/MS, such as Naringenin. Seven core targets (JUN, MAPK3, MAPK1, AKT1, TP53, RELA and STAT3) and three main pathways (IL-17, NF-κB and TNF signalling pathways) were discovered through network pharmacology analysis that closely related to inflammatory response. Interestingly, molecular docking results showed that the active ingredient Naringenin had a good binding effect on anti-inflammatory-related proteins. In the verification experiment, after the intervention of GC, the expression levels of pp65 and F4/80 inflammatory indicators in the knee joint of KOA model mice were significantly downregulated. GC could improve the inflammatory environment in DMM-induced osteoarthritic mice thus alleviating the physiological structure and dysfunction of the knee joint. GC might play an important role in the treatment of knee osteoarthritis.


Assuntos
Glycyrrhiza uralensis , Simulação de Acoplamento Molecular , Farmacologia em Rede , Osteoartrite do Joelho , Animais , Glycyrrhiza uralensis/química , Camundongos , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Masculino , Modelos Animais de Doenças , Transdução de Sinais/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Camundongos Endogâmicos C57BL
6.
Artigo em Inglês | MEDLINE | ID: mdl-38804700

RESUMO

Summary: RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition. Learning points: Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib). LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation. Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation. We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.

7.
World J Psychiatry ; 14(5): 661-669, 2024 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-38808088

RESUMO

BACKGROUND: Although the specific pathogenesis of preterm birth (PTB) has not been thoroughly clarified, it is known to be related to various factors, such as pregnancy complications, maternal socioeconomic factors, lifestyle habits, reproductive history, environmental and psychological factors, prenatal care, and nutritional status. PTB has serious implications for newborns and families and is associated with high mortality and complications. Therefore, the prediction of PTB risk can facilitate early intervention and reduce its resultant adverse consequences. AIM: To analyze the risk factors for PTB to establish a PTB risk prediction model and to assess postpartum anxiety and depression in mothers. METHODS: A retrospective analysis of 648 consecutive parturients who delivered at Shenzhen Bao'an District Songgang People's Hospital between January 2019 and January 2022 was performed. According to the diagnostic criteria for premature infants, the parturients were divided into a PTB group (n = 60) and a full-term (FT) group (n = 588). Puerperae were assessed by the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS), based on which the mothers with anxiety and depression symptoms were screened for further analysis. The factors affecting PTB were analyzed by univariate analysis, and the related risk factors were identified by logistic regression. RESULTS: According to univariate analysis, the PTB group was older than the FT group, with a smaller weight change and greater proportions of women who underwent artificial insemination and had gestational diabetes mellitus (P < 0.05). In addition, greater proportions of women with reproductive tract infections and greater white blood cell (WBC) counts (P < 0.05), shorter cervical lengths in the second trimester and lower neutrophil percentages (P < 0.001) were detected in the PTB group than in the FT group. The PTB group exhibited higher postpartum SAS and SDS scores than did the FT group (P < 0.0001), with a higher number of mothers experiencing anxiety and depression (P < 0.001). Multivariate logistic regression analysis revealed that a greater maternal weight change, the presence of gestational diabetes mellitus, a shorter cervical length in the second trimester, a greater WBC count, and the presence of maternal anxiety and depression were risk factors for PTB (P < 0.01). Moreover, the risk score of the FT group was lower than that of the PTB group, and the area under the curve of the risk score for predicting PTB was greater than 0.9. CONCLUSION: This study highlights the complex interplay between postpartum anxiety and PTB, where maternal anxiety may be a potential risk factor for PTB, with PTB potentially increasing the incidence of postpartum anxiety in mothers. In addition, a greater maternal weight change, the presence of gestational diabetes mellitus, a shorter cervical length, a greater WBC count, and postpartum anxiety and depression were identified as risk factors for PTB.

8.
Dose Response ; 22(2): 15593258241251594, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725454

RESUMO

Background: Acute lung injury (ALI) is a serious illness that has few treatment options available. Tribuloside, a natural flavonoid extracted from the Tribulus Terrestris plant in China, is potent in addressing many health issues such as headaches, dizziness, itching, and vitiligo. Objective: This study intends to explore the mechanisms of action of Tribuloside in treating ALI through a combination of network pharmacology and experimental validation. Methods: We obtained the 2D structure and SMILES number of Tribuloside from the PubChem database. We used the SwissTargetPrediction database to identify pharmacological targets. We found 1215 targets linked to ALI by examining the GeneCards database. We used the String database and Cytoscape software to create the "drug or disease-target" network as well as the protein-protein interactions (PPI). Key targets were identified by evaluating associated biological processes and pathway enrichment. A Venny Diagram showed 49 intersection points between Tribuloside and ALI. Molecular docking with AutoDockTools found that Tribuloside had a high affinity for IL6, BCL2, TNF, STAT3, IL1B, and MAPK3, the top 6 targets in the PPI network by Degree values. To test Tribuloside's therapeutic efficacy in ALI, an acute lung damage model in mice was constructed using lipopolysaccharide. Tribuloside treatment reduced inflammatory cell infiltration, decreased fibrotic area, repaired damaged alveoli, and suppressed inflammatory factors IL-6, TNF-α, and IL-1ß in the lungs through many pathways and targets. Conclusion: This study reveals that Tribuloside has the potential to treat ALI by targeting various pathways and targets, according to network pharmacology predictions and experimental confirmation.

9.
Int J Biol Macromol ; 271(Pt 2): 132708, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38815948

RESUMO

κ-Carrageenan (κ-Car) is an important material for preparing food gels and hydrogels. However, κ-Car gel has issues with high hardness and low water-holding capacity. Modification strategy of micronization is proposed for the first time to explore its influence on texture properties and gelling process of κ-Car gel, and to investigate the feasibility of κ-Car as a food matrix with low strength. κ-Car undergoing 60 min of micronization, the d(0.9) decreased by 79.33 %, SBET and Vtotal increased by 89.23 % and 95.27 %. The swelling rate and degree of gelling process increased significantly, and the microstructure changed from loose large pores to dense small pores resembling a "honeycomb". Importantly, the hardness of gel-60, Milk-60 and PNS-60 decreased by 72.52 %, 49.25 % and 81.37 %. In addition, WHC of gel-60, Milk-60 and PNS-60 was improved. IDDSI tests showed that κ-Car gels, milk gels and PNS gels can be categorized as level 6 (soft and bite-sized), except for PNS-60, which belongs to level 5 (crumbly and moist). Furthermore, the texture and bitter masking effect of milk gels and PNS gels were improved. In conclusion, this study demonstrated that micronization can be a novel approach to improve the gel properties of κ-Car, laying the groundwork for developing dysphagia foods.

10.
Int J Mol Sci ; 25(10)2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38791374

RESUMO

Cryptococcus neoformans (C. neoformans) is a pathogenic fungus that can cause life-threatening meningitis, particularly in individuals with compromised immune systems. The current standard treatment involves the combination of amphotericin B and azole drugs, but this regimen often leads to inevitable toxicity in patients. Therefore, there is an urgent need to develop new antifungal drugs with improved safety profiles. We screened antimicrobial peptides from the hemolymph transcriptome of Blaps rhynchopetera (B. rhynchopetera), a folk Chinese medicine. We found an antimicrobial peptide named blap-6 that exhibited potent activity against bacteria and fungi. Blap-6 is composed of 17 amino acids (KRCRFRIYRWGFPRRRF), and it has excellent antifungal activity against C. neoformans, with a minimum inhibitory concentration (MIC) of 0.81 µM. Blap-6 exhibits strong antifungal kinetic characteristics. Mechanistic studies revealed that blap-6 exerts its antifungal activity by penetrating and disrupting the integrity of the fungal cell membrane. In addition to its direct antifungal effect, blap-6 showed strong biofilm inhibition and scavenging activity. Notably, the peptide exhibited low hemolytic and cytotoxicity to human cells and may be a potential candidate antimicrobial drug for fungal infection caused by C. neoformans.


Assuntos
Antifúngicos , Peptídeos Antimicrobianos , Besouros , Cryptococcus neoformans , Testes de Sensibilidade Microbiana , Cryptococcus neoformans/efeitos dos fármacos , Animais , Antifúngicos/farmacologia , Antifúngicos/química , Besouros/microbiologia , Besouros/efeitos dos fármacos , Peptídeos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos/química , Humanos , Biofilmes/efeitos dos fármacos , Sequência de Aminoácidos
11.
World J Urol ; 42(1): 364, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38819448

RESUMO

OBJECTIVES: Renal cell carcinoma (RCC) is infrequent among young adults. Few studies reported the outcome of RCC in young adults by pathological subtypes. The purpose of this study was to explore the clinicopathological features, survival outcomes and prognostic factors of young adult patients with clear cell (CCRCC) and non-clear cell renal cell carcinoma (NCCRCC). METHODS: This study included young adult patients aged 18-40 years who were diagnosed as renal cell carcinoma (RCC) between 2012 and 2022 at Peking University Third Hospital. All patients underwent either partial nephrectomy or radical nephrectomy, and some received adjuvant therapy. A comparative analysis was performed to investigate the differences in clinicopathological characteristics between the cohort of CCRCC and NCCRCC. Kaplan-Meier survival analysis was utilized to plot survival curves for young adults with RCC. The univariate and multifactorial prognostic analyses were conducted using the log-rank test and COX proportional hazards model. RESULTS: A total of 300 RCC patients aged 18-40 years were performed, of which 201 were diagnosed with CCRCC (67%) and 99 were diagnosed with NCCRCC(33%). The NCCRCC included 29 cases (9.7%) of chromophobe RCC, 28 cases (9.3%) of MiT family translocation RCC, 22 cases (7.3%) of papillary RCC, 11 cases (3.7%) of low malignant potential multifocal cystic RCC, and 6 cases of unclassified RCC (2.0%), 2 cases of mucinous tubule and spindle cell carcinoma (0.7%), and 1 case of FH-deficient RCC (0.3%).The mean age was 33.4 ± 6.1 years old. The overall and progression free 5-year survival rate was 99.1 and 95.3%, respectively. The NCCRCC cohort demonstrated a statistically significant decrease in progression-free survival (PFS) rate when compared to the CCRCC cohort (p < 0.001). There was no statistically significant difference observed in overall survival (OS) (p = 0.069). Pathological stage was a significant independent predictor for OS (p = 0.045). Pathological stage and nuclear grade were both independent predictors for PFS (p = 0.020; p = 0.005). CONCLUSIONS: The clinical and pathological features of young adults diagnosed with CCRCC exhibit notable distinctions from those of NCCRCC patients. The survival outcome was significantly influenced by the pathological stage, while both the nuclear grade and pathological stage had a significant impact on tumor progression. This study offered significant contributions to the understanding of the clinicopathological characteristics and prognostic determinants of renal cell carcinoma (RCC) in young adults.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/terapia , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Adulto , Masculino , Adulto Jovem , Feminino , Prognóstico , Adolescente , Taxa de Sobrevida , Estudos Retrospectivos , Nefrectomia
12.
J Affect Disord ; 356: 88-96, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38588729

RESUMO

OBJECTIVE: Subthreshold depression is an essential precursor and risk factor for major depressive disorder, and its accurate identification and timely intervention are important for reducing the prevalence of major depressive disorder. Therefore, we used functional near-infrared spectroscopic imaging (fNIRS) to explore the characteristics of the brain neural activity of college students with subthreshold depression in the verbal fluency task. METHODS: A total of 72 subthreshold depressed college students (SDs) and 67 healthy college students (HCs) were recruited, and all subjects were subjected to a verbal fluency task (VFT) while a 53-channel fNIRS device was used to collect the subjects' cerebral blood oxygenation signals. RESULTS: The results of the independent samples t-test showed that the mean oxyhemoglobin in the right dorsolateral prefrontal (ch34, ch42, ch45) and Broca's area (ch51, ch53) of SDs was lower than that of HCs. The peak oxygenated hemoglobin of SDs was lower in the right dorsolateral prefrontal (ch34) and Broca's area (ch51, ch53).The brain functional connectivity strength was lower than that of HCs. Correlation analysis showed that the left DLPFC and Broca's area were significantly negatively correlated with the depression level. CONCLUSION: SDs showed abnormally low, inadequate levels of brain activation and weak frontotemporal brain functional connectivity. The right DLPFC has a higher sensitivity for the differentiation of depressive symptoms and is suitable as a biomarker for the presence of depressive symptoms. Dysfunction in Broca's area can be used both as a marker of depressive symptoms and as a biomarker, indicating the severity of depressive symptoms.


Assuntos
Depressão , Oxiemoglobinas , Espectroscopia de Luz Próxima ao Infravermelho , Humanos , Oxiemoglobinas/metabolismo , Masculino , Feminino , Adulto Jovem , Adulto , Depressão/fisiopatologia , Depressão/metabolismo , Área de Broca/fisiopatologia , Córtex Pré-Frontal Dorsolateral/fisiopatologia , Córtex Pré-Frontal Dorsolateral/metabolismo , Córtex Pré-Frontal/fisiopatologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/diagnóstico por imagem
13.
Front Immunol ; 15: 1381340, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38633246

RESUMO

Background: In addition to abnormal liver inflammation, the main symptoms of non-alcoholic steatohepatitis (NASH) are often accompanied by gastrointestinal digestive dysfunction, consistent with the concept of spleen deficiency (SD) in traditional Chinese medicine. As an important metabolic sensor, whether peroxisome proliferator-activated receptor alpha (PPARα) participates in regulating the occurrence and development of NASH with SD (NASH-SD) remains to be explored. Methods: Clinical liver samples were collected for RNA-seq analysis. C57BL/6J mice induced by folium sennae (SE) were used as an SD model. qPCR analysis was conducted to evaluate the inflammation and metabolic levels of mice. PPARα knockout mice (PPARαko) were subjected to SE and methionine-choline-deficient (MCD) diet to establish the NASH-SD model. The phenotype of NASH and the inflammatory indicators were measured using histopathologic analysis and qPCR as well. Results: The abnormal expression of PPARα signaling, coupled with metabolism and inflammation, was found in the results of RNA-seq analysis from clinical samples. SD mice showed a more severe inflammatory response in the liver evidenced by the increases in macrophage biomarkers, inflammatory factors, and fibrotic indicators in the liver. qPCR results also showed differences in PPARα between SD mice and control mice. In PPARαko mice, further evidence was found that the lack of PPARα exacerbated the inflammatory response phenotype as well as the lipid metabolism disorder in NASH-SD mice. Conclusion: The abnormal NR signaling accelerated the vicious cycle between lipotoxicity and inflammatory response in NAFLD with SD. Our results provide new evidence for nuclear receptors as potential therapeutic targets for NAFLD with spleen deficiency.


Assuntos
Hepatopatia Gordurosa não Alcoólica , PPAR alfa , Animais , Camundongos , Inflamação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR alfa/metabolismo , Baço/metabolismo , Baço/patologia
14.
Nano Lett ; 24(18): 5610-5617, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38669343

RESUMO

Halide perovskites (HPs) metasurfaces have recently attracted significant interest due to their potential to not only further enhance device performance but also reveal the unprecedented functionalities and novel photophysical properties of HPs. However, nanopatterning on HPs is critically challenging as they are readily destructed by the organic solvents in the standard lithographic processes. Here, we present a novel, subtle, and fully nondestructive HPs metasurface fabrication strategy based on cryogenic electron-beam writing. This technique allows for high-precision patterning and in situ imaging of HPs with excellent compatibility. As a proof-of-concept, broadband absorption enhanced metasurfaces were realized by patterning nanopillar arrays on CH3NH3PbI3 film, which results in photodetectors with approximately 14-times improvement on responsivity and excellent stability. Our findings highlight the great feasibility of cryogenic electron-beam writing for producing perovskite metasurface and unlocking the unprecedented photoelectronic properties of HPs.

15.
Mol Plant Pathol ; 25(3): e13425, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38462784

RESUMO

Phosphatases are important regulators of protein phosphorylation and various cellular processes, and they serve as counterparts to kinases. In this study, our comprehensive analysis of oomycete complete proteomes unveiled the presence of approximately 3833 phosphatases, with most species estimated to have between 100 and 300 putative phosphatases. Further investigation of these phosphatases revealed a significant increase in protein serine/threonine phosphatases (PSP) within oomycetes. In particular, we extensively studied the metallo-dependent protein phosphatase (PPM) within the PSP family in the model oomycete Phytophthora sojae. Our results showed notable differences in the expression patterns of PPMs throughout 10 life stages of P. sojae, indicating their vital roles in various stages of oomycete pathogens. Moreover, we identified 29 PPMs in P. sojae, and eight of them possessed accessory domains in addition to phosphate domains. We investigated the biological function of one PPM protein with an extra PH domain (PPM1); this protein exhibited high expression levels in both asexual developmental and infectious stages. Our analysis confirmed that PPM1 is indeed an active protein phosphatase, and its accessory domain does not affect its phosphatase activity. To delve further into its function, we generated knockout mutants of PPM1 and validated its essential roles in mycelial growth, sporangia and oospore production, as well as infectious stages. To the best of our knowledge, this study provides the first comprehensive inventory of phosphatases in oomycetes and identifies an important phosphatase within the expanded serine/threonine phosphatase group in oomycetes.


Assuntos
Oomicetos , Phytophthora , Proteoma/metabolismo , Phytophthora/metabolismo , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Serina/metabolismo
16.
Psychophysiology ; 61(7): e14564, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38487932

RESUMO

Anxiety is a common psychological disorder associated with other mental disorders, with depression being the most common comorbidity. Few studies have examined the neural mechanisms underlying anxiety after controlling for depression. This study aimed to explore whether there are differences in cortical activation in anxiety patients with different severities whose depression are normal. In the current study, depression levels were normal for 366 subjects-139 healthy subjects, 117 with mild anxiety, and 110 with major anxiety. Using the Hospital Anxiety and Depression Scale (HADS) and a verbal fluency task (VFT) to test subjects' anxiety and depression and cognitive function, respectively. A 53-channel guided near-infrared spectroscopic imaging technology (fNIRS) detected the concentration of oxyhemoglobin (oxy-Hb). Correlation analysis between anxiety severity and oxy-Hb concentration in the brain cortex was performed, as well as ANOVA analysis of oxy-Hb concentration among the three anxiety severity groups. The results showed that anxiety severity was significantly and negatively correlated with oxy-Hb concentrations in the left frontal eye field (lFEF) and in the right dorsolateral prefrontal area (rDLPFC). The oxy-Hb concentration in the lFEF and the rDLPFC were significantly lower in the major anxiety disorder group than that in the control group. This suggests that decreased cortical activity of the lFEF and rDLPFC may be neural markers of anxiety symptoms after controlling for depression. Anxiety symptoms without depression may be result from the dysfunction of the cognitive control network (CCN) which includes the lFEF and rDLPFC.


Assuntos
Espectroscopia de Luz Próxima ao Infravermelho , Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Ansiedade/fisiopatologia , Oxiemoglobinas/metabolismo , Depressão/fisiopatologia , Pessoa de Meia-Idade , Função Executiva/fisiologia , Transtornos de Ansiedade/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia
17.
Sci Total Environ ; 919: 170905, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38350568

RESUMO

Prenatal exposure to perfluorooctane sulfonate (PFOS) is associated with adverse health effects, including congenital heart disease, yet the underlying mechanisms remain elusive. Herein, we aimed to evaluate the embryotoxicity of PFOS using C57BL/6 J mice to characterize fetal heart defects after PFOS exposure, with the induction of human embryonic stem cells (hESC) into cardiomyocytes (CMs) as a model of early-stage heart development. We also performed DNA methylation analysis to clarify potential underlying mechanisms and identify targets of PFOS. Our results revealed that PFOS caused septal defects and excessive ventricular trabeculation cardiomyopathy at 5 mg/kg/day in embryonic mice and inhibited the proliferation and pluripotency of ESCs at concentrations >20 µM. Moreover, it decreased the beating rate and the population of CMs during cardiac differentiation. Decreases were observed in the abundances of NPPA+ trabecular and HEY2+ compact CMs. Additionally, DNA methyl transferases and ten-eleven translocation (TET) dioxygenases were regulated dynamically by PFOS, with TETs inhibitor treatment inducing significant decreases similar as PFOS. 850 K DNA methylation analysis combined with expression analysis revealed several potential targets of PFOS, including SORBS2, FHOD1, SLIT2, SLIT3, ADCY9, and HDAC9. In conclusion, PFOS may reprogram DNA methylation, especially demethylation, to induce cardiac toxicity, causing ventricular defects in vivo and abnormal cardiac differentiation in vitro.


Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Gravidez , Feminino , Humanos , Camundongos , Animais , Metilação de DNA , Camundongos Endogâmicos C57BL , Diferenciação Celular , Miócitos Cardíacos , Fluorocarbonos/toxicidade , Ácidos Alcanossulfônicos/toxicidade
18.
Life Sci ; 343: 122536, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38423170

RESUMO

AIMS: The main pathological features of osteoarthritis (OA) include the degeneration of articular cartilage and a decrease in matrix synthesis. Chondrocytes, which contribute to matrix synthesis, play a crucial role in the development of OA. Liquiritin, an effective ingredient extracted from Glycyrrhiza uralensis Fisch., has been used for over 1000 years to treat OA. This study aims to investigate the impact of liquiritin on OA and its underlying mechanism. MATERIALS AND METHODS: Gait and hot plate tests assessed mouse behavior, while Micro-CT and ABH/OG staining observed joint morphological changes. The TUNEL kit detected chondrocyte apoptosis. Western blot and immunofluorescence techniques determined the expression levels of cartilage metabolism markers COL2 and MMP13, as well as apoptosis markers caspase3, bcl2, P53, and PUMA. KEGG analysis and molecular docking technology were used to verify the relationship between liquiritin and P53. KEY FINDINGS: Liquiritin alleviated pain sensitivity and improved gait impairment in OA mice. Additionally, we found that liquiritin could increase COL2 levels and decrease MMP13 levels both in vivo and in vitro. Importantly, liquiritin reduced chondrocyte apoptosis induced by OA, through decreased expression of caspase3 expression and increased expression of bcl2 expression. Molecular docking revealed a strong binding affinity between liquiritin and P53. Both in vivo and in vitro studies demonstrated that liquiritin suppressed the expression of P53 and PUMA in cartilage. SIGNIFICANCE: This indicated that liquiritin may alleviate OA progression by inhibiting the P53/PUMA signaling pathway, suggesting that liquiritin is a potential strategy for the treatment of OA.


Assuntos
Cartilagem Articular , Flavanonas , Glucosídeos , Osteoartrite , Animais , Camundongos , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Cartilagem Articular/patologia , Condrócitos/metabolismo , Flavanonas/farmacologia , Glucosídeos/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , Simulação de Acoplamento Molecular , Osteoartrite/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
19.
Theranostics ; 14(3): 1126-1146, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38250036

RESUMO

Background: Neurons in the ventral tegmental area (VTA) are sensitive to stress and their maladaptation have been implicated in the psychiatric disorders such as anxiety and addiction, etc. The cellular properties of the VTA neurons in response to different stressors related to different emotional processing remain to be investigated. Methods: By combining immediate early gene (IEG)-dependent labeling, rabies virus tracing, ensemble-specific transcriptomic analysis and fiber photometry recording in the VTA of male mice, the spatial distribution, brain-wide connectivity and cellular signaling pathways in the VTA neuronal ensembles in response to morphine (Mor-Ens) or foot shock (Shock-Ens) stimuli were investigated. Results: Optogenetic activation of the Mor-Ens drove approach behavior, whereas chemogenetic activation of the Shock-Ens increased the anxiety level in mice. Mor-Ens were clustered and enriched in the ventral VTA, contained a higher proportion of dopaminergic neurons, received more inputs from the dorsal medial striatum and the medial hypothalamic zone, and exhibited greater axonal arborization in the zona incerta and ventral pallidum. Whereas Shock-Ens were more dispersed, contained a higher proportion of GABAergic neurons, and received more inputs from the ventral pallidum and the lateral hypothalamic area. The downstream targets of the G protein and ß-arrestin pathways, PLCß3 and phosphorylated AKT1Thr308, were relatively enriched in the Mor-Ens and Shock-Ens, respectively. Cariprazine, the G-protein-biased agonist for the dopamine D2 receptor, increased the response of Mor-Ens to sucrose water and decreased the anxiety-like behavior during morphine withdrawal, whereas the ß-arrestin-biased agonist UNC9994 decreased the response of Shock-Ens to tail suspension. Conclusions: Taken together, these findings reveal the heterogeneous connectivity and signaling pathways of the VTA neurons in response to morphine and foot shock, providing new insights for development of specific interventions for psychiatric disorders caused by various stressors associated with different VTA neuronal functions.


Assuntos
Neurônios Dopaminérgicos , Área Tegmentar Ventral , Humanos , Masculino , Animais , Camundongos , Transdução de Sinais , beta-Arrestinas , Derivados da Morfina
20.
Acta Pharmacol Sin ; 45(4): 714-727, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38191912

RESUMO

The O-linked-ß-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced apoptosis remain to be elucidated. Here, we show that treatment with H2O2 inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved caspase 3 and accelerated apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H2O2-induced apoptosis, respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished OSMI-1-induced apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H2O2-treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H2O2-induced apoptosis of N2a cells.


Assuntos
Apoptose , Proteína Forkhead Box O1 , Peróxido de Hidrogênio , Fator de Transcrição STAT3 , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/metabolismo , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Glicosilação , Acilação , Fator de Transcrição STAT3/metabolismo , Proteína Forkhead Box O1/metabolismo , Animais , Camundongos , Linhagem Celular Tumoral
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