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1.
Clin Exp Med ; 2023 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-36738306

RESUMO

Chronic lymphocytic leukemia (CLL) is a subtype of B-cell malignancy with high heterogeneity. XPO1 is highly expressed in many hematological malignancies, which predicts poor prognosis. In the study, we aimed to explore the prognostic role of XPO1 and the therapeutic effect of Selinexor, a selective inhibitor of nuclear export, which targets XPO1. We collected 200 CLL samples in our center to confirm XPO1 mRNA expression and analyzed the correlation between XPO1 expression and prognosis. Then, we decreased XPO1 expression with Selinexor to explore the effect of proliferation inhibition, cell cycle arrest, and apoptosis in CLL cell lines. RNA-Seq was performed to explore potential mechanisms. We analyzed XPO1 expression in a cohort of 150 treatment naive patients and another cohort of 50 relapsed and refractory (R/R) patients and found that XPO1 expression was upregulated in 76% of CLL patients compared with healthy donors. Survival analysis suggested that patients with increased XPO1 expression had inferior treatment-free survival (P = 0.022) and overall survival (P = 0.032). The inhibitor of XPO1, Selinexor, induced apoptosis in primary CLL cells. We showed the effects of Selinexor on proliferation inhibition, cell cycle arrest, and apoptosis in CLL cell lines with JVM3, MEC1, and ibrutinib-resistant (MR) cells via nuclear retention of cargo proteins of IκBα, p65, p50, and FOXO3a. Moreover, downregulation of the NF-κB and FOXO pathways was a common feature of the three CLL cell lines responding to Selinexor, indicating the potential application of XPO1 inhibitor even in the high-risk CLL cells. We identified XPO1 as an unfavorable prognostic factor for CLL patients and provided a rationale for further investigation of the clinically XPO1 targeted therapeutic strategy against CLL.

2.
Zhongguo Zhong Yao Za Zhi ; 48(2): 492-506, 2023 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-36725239

RESUMO

This study aimed to investigate the effective substances and mechanism of Yishen Guluo Mixture in the treatment of chronic glomerulonephritis(CGN) based on metabolomics and serum pharmacochemistry. The rat model of CGN was induced by cationic bovine serum albumin(C-BSA). After intragastric administration of Yishen Guluo Mixture, the biochemical indexes related to renal function(24-hour urinary protein, serum urea nitrogen, and creatinine) were determined, and the efficacy evaluations such as histopathological observation were carried out. The serum biomarkers of Yishen Guluo Mixture in the treatment of CGN were screened out by ultra-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry(UPLC-Q-TOF-MS) combined with multivariate statistical analysis, and the metabolic pathways were analyzed. According to the mass spectrum ion fragment information and metabolic pathway, the components absorbed into the blood(prototypes and metabolites) from Yishen Guluo Mixture were identified and analyzed by using PeakView 1.2 and MetabolitePilot 2.0.4. By integrating metabolomics and serum pharmacochemistry data, a mathematical model of correlation analysis between serum biomarkers and components absorbed into blood was constructed to screen out the potential effective substances of Yishen Guluo Mixture in the treatment of CGN. Yishen Guluo mixture significantly decreased the levels of 24-hour urinary protein, serum urea nitrogen, and creatinine in rats with CGN, and improved the pathological damage of the kidney tissue. Twenty serum biomarkers of Yishen Guluo Mixture in the treatment of CGN, such as arachidonic acid and lysophosphatidylcholine, were screened out, involving arachidonic acid metabolism, glycerol phosphatide metabolism, and other pathways. Based on the serum pharmacochemistry, 8 prototype components and 20 metabolites in the serum-containing Yishen Guluo Mixture were identified. According to the metabolomics and correlation analysis of serum pharmacochemistry, 12 compounds such as genistein absorbed into the blood from Yishen Guluo Mixture were selected as the potential effective substances for the treatment of CGN. Based on metabolomics and serum pharmacochemistry, the effective substances and mechanism of Yishen Guluo Mixture in the treatment of CGN are analyzed and explained in this study, which provides a new idea for the development of innovative traditional Chinese medicine for the treatment of CGN.


Assuntos
Medicamentos de Ervas Chinesas , Glomerulonefrite , Ratos , Animais , Creatinina , Ácido Araquidônico , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/farmacologia , Glomerulonefrite/tratamento farmacológico , Metabolômica , Biomarcadores , Proteínas Sanguíneas , Ureia
3.
Front Pediatr ; 11: 1092388, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36726778

RESUMO

Introduction: Hyperkalemia is a rare but severe condition in young children and usually discovered as a result of hemolysis of the blood samples taken. However, patients with defects in either aldosterone biosynthesis or function can also present with hyperkalemia- as well hyponatremia-associated, and metabolic acidosis. It is a challenge to make an accurate diagnosis of these clinical conditions. We conducted this study to investigate the clinical and genetic features of aldosterone signaling defects associated hyperkalemia in young children. Method: A retrospective review was conducted at the pediatric department of the First Affiliated Hospital of Guangxi Medical University from 2012 to 2022. Results: 47 patients with hyperkalemia were enrolled, of which 80.9% (n = 38) were diagnosed with primary hypoaldosteronism, including congenital adrenal hyperplasia due to 21-hydroxylase deficiency (n = 32), isolated hypoaldosteronism (n = 1) due to CYP11B2 gene mutation and Xp21 contiguous gene deletion syndrome (n = 1). Additionally, 4 patients were clinically-diagnosed with primary adrenal insufficiency. Nine patients were confirmed with aldosterone resistance, of which one child was diagnosed with pseudohypoaldosteronism (PHA) type 1 with a mutation in the NR3C2 gene and 3 children were identified with PHA type 2 due to novel mutations in either the CUL3 or KLHL3 genes. Five patients had PHA type 3 because of pathologies of either the urinary or intestinal tracts. Conclusions: The etiologies of infants with hyperkalemia associated with aldosterone defects were mostly due to primary hypoaldosteronism. An elevated plasma aldosterone level may be a useful biomarker for the diagnosis an aldosterone functional defect in patients presented with hyperkalemia. However, a normal plasma aldosterone level does rule out an aldosterone defect in either its biosynthesis or function, especially in young infants. Molecular genetic analyses can greatly help to clarify the complexity of disorders and can be used to confirm the diagnosis.

4.
CNS Neurosci Ther ; 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36708130

RESUMO

AIMS: Amyloid beta (Aß) is an important pathological feature of Alzheimer's disease (AD). A disintegrin and metalloproteinase 10 (ADAM10) can reduce the production of toxic Aß by activating the nonamyloidogenic pathway of amyloid precursor protein (APP). We previously found that apicidin, which is a histone deacetylase (HDAC) inhibitor, can promote the expression of ADAM10 and reduce the production of Aß in vitro. This study was designed to determine the potential of apicidin treatment to reverse learning and memory impairments in an AD mouse model and the possible correlation of these effects with ADAM10. METHODS: Nine-month-old APP/PS1 mice and C57 mice received intraperitoneal injections of apicidin or vehicle for 2 months. At 11 months of age, we evaluated the memory performance of mice with Morris water maze (MWM) and context fear conditioning tests. The Aß levels were assessed in mouse brain using the immunohistochemical method and ELISA. The expression of corresponding protein involved in proteolytic processing of APP and the phosphorylation of tau were assessed by Western blotting. RESULTS: Apicidin reversed the deficits of spatial reference memory and contextual fear memory, attenuated the formation of Aß-enriched plaques, and decreased the levels of soluble and insoluble Aß40/42 in APP/PS1 mice. Moreover, apicidin significantly increased the expression of ADAM10, improved the level of sAPPα, and reduced the production of sAPPß, but did not affect the levels of phosphorylated tau in APP/PS1 mice. CONCLUSION: Apicidin significantly improves the AD symptoms of APP/PS1 mice by regulating the expression of ADAM10, which may contribute to decreasing the levels of Aß rather than decreasing the phosphorylation of tau.

5.
Med Phys ; 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36606328

RESUMO

BACKGROUND: Radiographic X-ray imaging is a common clinical examination. Current objective methods for quantifying image quality for radiographs struggle to capture the combined impact of factors throughout the imaging chain on the perceived image quality. Therefore, there is a need to further develop metrics that correlate with image quality as perceived by the observer. OBJECTIVES: We proposed the image feature index (IFI) to comprehensively quantify radiographic X-ray image quality. We also aimed to study the correlation between IFI and observer-perceived image quality for chest radiographs. MATERIALS AND METHODS: The IFI algorithm was developed, which measured the amount of information, textural features, and noise in the image. A total of 70 chest phantom radiographs were generated under 60-120 kV and 0.2-80 mAs. A vendor-proprietary exposure index (EI) and dose area product (DAP) were extracted from the DICOM header in addition to calculating IFI for each image to investigate the relationships between IFI, EI and DAP. The quality of the images was rated by three observers, and the correlation between IFI and subjective score of image quality was tested. Next, a retrospective study using a random sample of 50 clinical chest radiographs was performed, and the correlation between IFI and subjective score was tested. The correlation was determined by the Spearman test. RESULTS: The curves of IFI versus DAP and IFI versus EI both demonstrated a similar three-stage form where IFI is above zero: in the first stage, IFI increases rapidly with increased DAP or EI, whereas in the second stage, the slope of the curves decreased towards an asymptote, that is, minimal gain in IFI with increased DAP or EI-until they hit the inflection point and then descended sharply in the third stage. For both phantom and clinical chest images, IFI demonstrated good correlation with subjective score (r = 0.9084 for phantom images, r = 0.8153 for clinical images). CONCLUSIONS: IFI is a feasible and efficient descriptor for image quality for chest radiographs. Future studies with larger sample sizes and sample types are needed to confirm the feasibility of IFI for other exam types and anatomical views, thus fulfilling and extending the potential applications of IFI in quality control and radiation dose reduction.

6.
J Natl Compr Canc Netw ; 21(1): 60-66.e5, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36630898

RESUMO

BACKGROUND: Our study aimed to evaluate the efficacy and feasibility of neoadjuvant anti-PD-1 treatment for localized mismatch repair-deficient (dMMR) colorectal cancer (CRC). PATIENTS AND METHODS: The study cohort included patients with localized dMMR CRC who received PD-1 inhibitors as neoadjuvant therapy from 3 medical centers in Southern China. Main eligibility criteria included age between 18 and 75 years, ECOG performance status of 0 or 1, and receipt of ≥2 doses of PD-1 inhibitors. RESULTS: A total of 73 patients were included. Most of the tumors were locally advanced, including 19 (26.0%) T4a and 29 (39.7%) T4b. Most patients (79.5%) received PD-1 inhibitor monotherapy. Objective response per radiologic assessment was achieved in 62 (84.9%) patients, including 17 (23.3%) with complete response (CR) and 45 (61.6%) with partial response, with a median time to response of 9.6 weeks. Patients with T4a/4b disease had a similar response rate as those with T2-3 disease (84.0% vs 85.4%; P=.999). As of writing, a total of 50 patients have undergone surgery. Pathologic CR was achieved in most (57.1%) patients and remained high (59.5%) even among the 38 patients with T4a/4b disease. The 17 patients with CR did not undergo surgery and adopted a watch-and-wait strategy. After a median follow-up of 17.2 months (range, 3.4-45.1 months), the overall median recurrence-free and overall survivals were not reached. Among patients undergoing surgery or achieving CR, the 2-year tumor-specific disease-free and overall survival rates were both 100%. During neoadjuvant treatment, grade 3-4 adverse events occurred in 8 patients; 4 required acute intervention. Severe postoperative complications were recorded in 4 patients, 3 of whom required a second surgery. CONCLUSIONS: Neoadjuvant therapy with PD-1 blockade is highly effective for localized dMMR CRC, with an acceptable safety profile and low recurrence rate. This treatment holds promise for becoming the new standard of care for localized dMMR CRCs.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Terapia Neoadjuvante , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Reparo de Erro de Pareamento de DNA , Neoplasias do Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Imunoterapia , Instabilidade de Microssatélites
7.
Anim Nutr ; 12: 215-226, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36712406

RESUMO

This study was to determine the effects of riboflavin deficiency (RD) on intestinal development, jejunum mucosa proteome, cecal short-chain fatty acids (SCFA) profiling, and cecal microbial diversity and community of starter Pekin ducks. Male white Pekin ducks (1 d old, n = 240) were allocated into 2 groups, with 12 replicates and 10 birds per replicate in each group. For 21 d, all ducks had ad libitum access to either an RD or a riboflavin adequate (control, CON) diet, formulated by supplementing a basal diet with 0 or 10 mg riboflavin per kg of diet, respectively. Compared to the CON group, growth retardation, high mortality, and poor riboflavin status were observed in the RD group. Furthermore, RD reduced the villus height and the ratio of villus height to crypt depth of jejunum and ileum (P < 0.05), indicating morphological alterations of the small intestine. In addition, dietary RD enhanced relative cecum weight and decreased cecal SCFA concentrations (P < 0.05), including propionate, isobutyrate, butyrate, and isovalerate. The jejunum mucosa proteomics showed that 208 proteins were upregulated and 229 proteins were downregulated in the RD group compared to those in the CON group. Among these, RD mainly suppressed intestinal absorption and energy generation processes such as glycolysis and gluconeogenesis, fatty acid beta oxidation, tricarboxylic acid cycle, and oxidative phosphorylation, leading to impaired ATP generation. In addition, RD decreased the community richness and diversity of the bacterial community in the cecum of ducks. Specifically, RD reduced the abundance of butyrate-producing bacteria in the cecum (P < 0.05), such as Eubacterium coprostanoligenes, Prevotella and Faecalibacterium. Dietary RD resulted in growth depression and intestinal hypofunction of Pekin ducks, which could be associated with impaired intestinal absorption and energy generation processes in intestinal mucosa, as well as gut microbiota dysbiosis. These findings contribute to our understanding of the mechanisms of intestinal hypofunction due to RD.

8.
Analyst ; 148(3): 628-635, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36602005

RESUMO

Biofilms are known to be a great challenge for their anti-bacterial activity as they obstruct drug action for deeper and more thorough bacteria-killing effects. Therefore, developing highly effective antibacterial agents to destroy biofilms and eradicate bacteria is of great significance. Herein, a new type of nanocomposites (denoted as poly(4-cyanostyrene)@silver@polylysine) is proposed, in which polylysine (PLL) could rapidly capture the biofilms and exhibit excellent antibacterial efficacy together with decorated silver (Ag) nanoparticles (NPs) through the charge effect and Ag+ release. Notably, nearly 100% antibacterial rates against Gram-positive bacterium (Staphylococcus aureus, S. aureus) and Gram-negative bacterium (Escherichia coli, E. coli) were achieved. More importantly, poly(4-cyanostyrene) with biological silent Raman imaging capacity is able to illustrate the relationship between antibacterial efficiency and biofilm breakage. In short, such novel nanocomposites can improve the bioavailability of each component and display tremendous potential in antibacterial applications.


Assuntos
Nanopartículas Metálicas , Nanocompostos , Escherichia coli , Prata/farmacologia , Polilisina/farmacologia , Staphylococcus aureus , Antibacterianos/farmacologia , Biofilmes
9.
BMC Geriatr ; 23(1): 44, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36694126

RESUMO

BACKGROUND: Research on potentially inappropriate medications (PIM) and medication-related problems (MRP) among the Chinese population with chronic diseases and polypharmacy is insufficient. OBJECTIVES: This study aimed to investigate the prevalence of PIM and MRP among older Chinese hospitalized patients with chronic diseases and polypharmacy and analyze the associated factors. METHODS: A retrospective cross-sectional study was conducted in five tertiary hospitals in Beijing. Patients aged ≥ 65 years with at least one chronic disease and taking at least five or more medications were included. Data were extracted from the hospitals' electronic medical record systems. PIM was evaluated according to the 2015 Beers criteria and the 2014 Screening Tool of Older Persons' Prescriptions (STOPP) criteria. MRPs were assessed and classified according to the Helper-Strand classification system. The prevalence of PIM and MRP and related factors were analyzed. RESULTS: A total of 852 cases were included. The prevalence of PIM was 85.3% and 59.7% based on the Beers criteria and the STOPP criteria. A total of 456 MRPs occurred in 247 patients. The most prevalent MRP categories were dosages that were too low and unnecessary medication therapies. Hyperpolypharmacy (taking ≥ 10 drugs) (odds ratio OR 3.736, 95% confidence interval CI 1.541-9.058, P = 0.004) and suffering from coronary heart disease (OR 2.620, 95%CI 1.090-6.297, P = 0.031) were the influencing factors of inappropriate prescribing (the presence of either PIM or MRP in a patient). CONCLUSION: PIM and MRP were prevalent in older patients with chronic disease and polypharmacy in Chinese hospitals. More interventions are urgently needed to reduce PIM use and improve the quality of drug therapies.


Assuntos
Polimedicação , Lista de Medicamentos Potencialmente Inapropriados , Humanos , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Estudos Retrospectivos , Prescrição Inadequada/efeitos adversos , Prescrições , Doença Crônica , Centros de Atenção Terciária
10.
J Immunother Cancer ; 11(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36596591

RESUMO

BACKGROUND: Loss of major histocompatibility complex class I (MHC-I) in tumor cells limits the use of immune checkpoint blockade (ICB) in colorectal cancer. Nevertheless, the regulatory mechanism of MHC-I downregulation in tumor cells has not been fully elucidated. Overexpression of CEMIP in tumor tissues is associated with a poor prognosis in colorectal cancer. Here, in this research, we aim to address the role of CEMIP in mediating MHC-I expression in tumor cells and investigate the underlying regulatory mechanisms. METHOD: Protein levels were analyzed by western blotting. Flow cytometry analysis was used to examine immune cells. Protein-protein interactions were investigated by co-immunoprecipitation and proximity ligation assays. The intracellular trafficking of MHC-I was revealed by an immunofluorescent technique. In addition, the effect of CEMIP on tumor growth and the antitumor efficacy of targeting CEMIP in combination with ICB therapy were evaluated in murine models of colorectal cancer. RESULTS: We reported that CEMIP specifically downregulated the expression of MHC-I on the surface of murine and human colon cancer cells, hindering the cytotoxicity of CD8+ T cells. We also demonstrated that CEMIP restricted CD8+ T-cell antitumor activities both in vitro and in vivo due to impaired MHC-I-mediated antigen presentation. Correspondingly, the combination of CEMIP inhibition and ICB impeded tumor growth and enhanced therapeutic efficacy. Mechanistically, CEMIP acted as an adaptor for the interaction betweenMHC-I and clathrin, which drove MHC-I internalization via clathrin-dependent endocytosis. Furthermore, CEMIP anchored internalized MHC-I to lysosomes for degradation, disrupting the recycling of MHC-I to the cell surface. CONCLUSION: Overall, our study unveils a novel regulatory mechanism of MHC-I on tumor cell surfaces by CEMIP-mediated internalization and degradation. Furthermore, targeting CEMIP provides an effective strategy for colorectal cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias Colorretais , Humanos , Animais , Camundongos , Evasão da Resposta Imune , Antígenos de Histocompatibilidade Classe I , Clatrina/metabolismo
11.
Biomed Pharmacother ; 158: 114137, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36525817

RESUMO

Homocysteine (Hcy) is one of the independent risk factors of cardiovascular disease. Sodium tanshinone IIA sulfonate (STS) is a hydrophilic derivate of tanshinone IIA which is the main active constitute of Chinese Materia Medica Salviae Miltiorrhizae Radix et Rhizoma, and exhibits multiple pharmacological activities. However, whether STS could prevent from Hcy-induced endothelial cell injury is unknown. We found that STS dramatically reversed Hcy-induced cell death concentration dependently in human umbilical vascular endothelial cells (HUVECs). STS ameliorated the endothelial cell cycle progression, proliferation and cell migratory function impaired by Hcy, which might be co-related to the inhibition of intracellular oxidative stress and mitochondrial dysfunction. STS also elevated the phosphorylation of AKT and MAPKs and protein expression of sirtuin1 (SIRT1), NRF2 and HO-1 which were suppressed by Hcy. The protective effect of STS against Hcy-induced endothelial cell toxicity was partially attenuated by PI3K, AKT, MEK, ERK, SIRT1, NRF2 and HO-1 inhibitors. Besides, knockdown of SIRT1 by its siRNA dramatically decreased the endothelial protective effect of STS accompanied with suppression of SIRT1, NRF2, HO-1 and phosphorylated AKT. The activation of AKT or NRF2 partially reversed SIRT1-knockdown impaired cyto-protective effect of STS against Hcy-induced cell injury. Furthermore, STS prevented from Hcy-induced intracellular nicotinamide N-methyltransferase (NNMT) reduction along with elevation of intracellular methylnicotinamide (MNA), and MNA enhanced STS protecting against Hcy induced endothelial death. Knockdown of NNMT reduced the protective effect of STS against Hcy induced endothelial cell injury. Collectively, STS presented potent endothelial protective effect against Hcy and the underlying molecular mechanisms were involved in the suppression of intracellular oxidative stress and mitochondria dysfunction by activation of AKT/MAPKs, SIRT1/NRF2/HO-1 and NNMT/MNA signaling pathways.


Assuntos
Fator 2 Relacionado a NF-E2 , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Sirtuína 1/metabolismo , Estresse Oxidativo , Células Endoteliais da Veia Umbilical Humana , Nicotinamida N-Metiltransferase/metabolismo
12.
J Food Sci ; 88(1): 328-340, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36510379

RESUMO

This study synthesized titanium dioxide (TiO2 ) nanoparticles (NPs) from mango leaf extract and investigated the features and antibacterial capabilities of three different. The microscopic morphological observation, scanning electron microscopy, and transmission electron microscopy results showed that all three NPs showed agglomeration phenomenon, and the TN-1 sample existed as large agglomerates, whereas the agglomeration phenomenon of TN-3 sample was improved by the modified, without large agglomerates. The biosynthetic TN-2 and TN-3 NPs were spherical and uniform in size, whereas those of the TN-3 sample was the smallest, ranging from 10 to 30 nm. X-ray diffraction and Raman spectroscopy results exhibited that these were highly pure anatase NPs. The result of ultraviolet (UV)-visible-near-infrared spectral analysis showed that the TN-2 and TN-3 samples displayed higher UV absorption properties than the TN-1 samples and were highest in the modified NPs, which was more suitable for preparing chitosan-based nanocomposite material in future experiments and studies. The colony diameters of the TN-1, TN-2, and TN-3 treatment groups were 7.99, 7.80, and 6.86 mm, respectively, after 120 min of UV light induction at a wavelength of 365 nm. Significant differences were evident between the TN-3 and the other two groups (p < 0.05), indicating that the TN-3 sample more effectively inhibited Penicillium steckii than the other TiO2 NPs. PRACTICAL APPLICATION: Nanomaterials coated film preservation is widely used in fruit and vegetable preservation. In this paper, TiO2 nanomaterials will be green synthesized using mango leaf and structurally characterized, whereas antibacterial tests will be conducted against the mango fruit-specific bacterium Penicillium steckii, which will provide a theoretical basis for the storage and preservation of mango.


Assuntos
Nanopartículas Metálicas , Nanopartículas , Antifúngicos/farmacologia , Nanopartículas/química , Titânio/farmacologia , Titânio/química , Antibacterianos/farmacologia , Antibacterianos/química , Difração de Raios X , Nanopartículas Metálicas/química
13.
Chem Biol Interact ; 369: 110304, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36509116

RESUMO

Inorganic arsenic is highly toxic, widely distributed in the human environment and may result in multisystem diseases and several types of cancers. The BCL-2-interacting mediator of cell death protein (BIM) is a key modulator of the intrinsic apoptosis pathway. Interestingly, in the present study, we found that arsenic trioxide (As2O3) decreased BIMEL levels in human bronchial epithelial cell line BEAS-2B and increased BIMEL levels in human lung carcinoma cell line A549 and mouse Sertoli cell line TM4. Mechanismly, the 26S proteasome inhibitors MG132 and bortezomib could effectively inhibit BIMEL degradation induced by As2O3 in BEAS-2B cells. As2O3 activated extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways, but only the ERK1/2 MAPK inhibitor PD98059 blocked BIMEL degradation induced by As2O3. Furthermore, As2O3 induced-phosphorylation of BIMEL at multiple sites was inhibited by ERK1/2 MAPK inhibitor PD98059. Inhibition of As2O3-induced ERK1/2 MAPK phosphorylation increased the levels of BIMEL and cleaved-caspase-3 proteins and decreased BEAS-2B cell viability. As2O3 also markedly mitigated tunicamycin-induced apoptosis of BEAS-2B cells by increasing ERK1/2 phosphorylation and BIMEL degradation. Our results suggest that As2O3-induced activation of the ERK1/2 MAPK pathway increases phosphorylation of BIMEL and promotes BIMEL degradation, thereby alleviating the role of apoptosis in As2O3-induced cell death. This study provides new insights into how to maintain the survival of BEAS-2B cells before malignant transformation induced by high doses of As2O3.


Assuntos
Apoptose , Sistema de Sinalização das MAP Quinases , Camundongos , Animais , Humanos , Trióxido de Arsênio/farmacologia , Fosforilação , Proteínas Quinases Ativadas por Mitógeno/metabolismo
14.
Expert Syst Appl ; 213: 118885, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36188673

RESUMO

With the amount of medical waste rapidly increasing since the corona virus disease 2019 (COVID-19) pandemic, medical waste treatment risk evaluation has become an important task. The transportation of medical waste is an essential process of medical waste treatment. This paper aims to develop an integrated model to evaluate COVID-19 medical waste transportation risk by integrating an extended type-2 fuzzy total interpretive structural model (TISM) with a Bayesian network (BN). First, an interval type-2 fuzzy based transportation risk rating scale is introduced to help experts express uncertain evaluation information, in which a new double alpha-cut method is developed for the defuzzification of the interval type-2 fuzzy numbers (IT2FNs). Second, TISM is combined with IT2FNs to construct a hierarchical structural model of COVID-19 medical waste transportation risk factors under a high uncertain environment; a new bidirectional extraction method is proposed to describe the hierarchy of risk factors more reasonably and accurately. Third, the BN is integrated with IT2FNs to make a comprehensive medical waste transportation risk evaluation, including identifying the sensitive factors and diagnosing the event's causation. Then, a case study of COVID-19 medical waste transportation is displayed to demonstrate the effectiveness of the proposed model. Further, a comparison of the proposed model with the traditional TISM and BN model is conducted to stress the advantages of the proposed model.

15.
Eur J Pharmacol ; 940: 175471, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36549502

RESUMO

OBJECTIVE: To identify small molecules blocking La-RNA interactions by using structural dynamics, molecular biology, and in vivo efficacy experiments. METHODS: A docking virtual assay on the Chemdiv database was used to screen La binders, and their affinity were measured by surface plasmon resonance (SPR). A novel fluorescence polarization (FP) assay referring to the binding of La protein and 3'UUUOH was established to identify the inhibitors. Their activity on ovarian cancer cell proliferation, apoptosis and cell cycle were evaluated using Cell Counting Kit 8 (CCK8) and flow cytometry assay, respectively. Their in vivo efficacy against ovarian cancer growth were evaluated in a cell line-derived xenograft (CDX) model of A2780 cells. RESULTS: From a total of 20 compounds with high potential binding activity with La protein, two small molecule compounds 4424-1120 and 8017-5932 with relatively stronger inhibition ability on La-RNA interactions were identified. These two compounds shared the same active centers with hydroxyimidazole and hydroxybenzene to interact with La protein through residues ARG57, GLN20 and GLN136. The in vitro assays showed that 4424-1120 and 8017-5932 effectively cause G0/G1 cell cycle arrest, inhibit cell proliferation, reduce cell invasion and promote apoptosis in ovarian cancer cells. In a CDX model on BALB/C Nude mice, we found that the growth rate of the tumor was inhibited by 4424-1120. CONCLUSION: Our results demonstrated compound 4424-1120 shows good antitumor activity and safety in vitro and in vivo, and it provides a new idea for the discovery of antitumor lead compounds from small drug-like molecules.


Assuntos
Neoplasias Ovarianas , Animais , Camundongos , Humanos , Feminino , Neoplasias Ovarianas/metabolismo , RNA , Linhagem Celular Tumoral , Camundongos Nus , Camundongos Endogâmicos BALB C , Proliferação de Células , Apoptose , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Ophthalmol ; 2022: 9724160, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36457950

RESUMO

Background: The aim of this study was to apply bioinformatic analysis to develop a robust miRNA signature and construct a nomogram model in uveal melanoma (UM) to improve prognosis prediction. Methods: miRNA and mRNA sequencing data for 80 UM patients were obtained from The Cancer Genome Atlas (TCGA) database. The patients were further randomly assigned to a training set (n = 40, used to identify key miRNAs) and a testing set (n = 40, used to internally verify the signature). Then, miRNAs data of GSE84976 and GSE68828 were downloaded from Gene Expression Omnibus (GEO) database for outside verification. Combining univariate analysis and LASSO methods for identifying a robust miRNA biomarker in training set and the signature was validated in testing set and outside dataset. A prognostic nomogram was constructed and combined with decision curve as well as reduction curve analyses to assess the application of clinical usefulness. Finally, we constructed a miRNA-mRNA regulator network in UM and conducted pathway enrichment analysis according to the mRNAs in the network. Results: In total, a 3-miRNA was identified and validated that can robustly predict UM patients' survival. According to univariate and multivariate cox analyses, age at diagnosis, tumor node metastasis (TNM) classification, stage, and the 3-miRNA signature significantly correlated with the survival outcomes. These characteristics were used to establish nomogram. The nomogram worked well for predicting 1 and 3 years of overall survival time. The decision curve of nomogram revealed a good clinical usefulness of our nomogram. What's more, a miRNA-mRNA network was constructed. Pathway enrichment showed that this network was largely involved in mRNA processing, the mRNA surveillance pathway, the spliceosome, and so on. Conclusions: We developed a 3-miRNA biomarker and constructed a prognostic nomogram, which may afford a quantitative tool for predicting the survival of UM. Our finding also provided some new potential targets for the treatment of UM.

17.
Glob Chang Biol ; 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36459482

RESUMO

Over the past decades, global warming has led to a lengthening of the time window during which temperatures remain favorable for carbon assimilation and tree growth, resulting in a lengthening of the green season. The extent to which forest green seasons have tracked the lengthening of this favorable period under climate warming, however, has not been quantified to date. Here, we used remote sensing data and long-term ground observations of leaf-out and coloration for six dominant species of European trees at 1773 sites, for a total of 6060 species-site combinations, during 1980-2016 and found that actual green season extensions (GS: 3.1 ± 0.1 d decade-1 ) lag four times behind extensions of the potential thermal season (TS: 12.6 ± 0.1 d decade-1 ). Similar but less pronounced differences were obtained using satellite-derived vegetation phenology observations, i.e., a lengthening of 4.4 ± 0.13 d decade-1 and 7.5 ± 0.13 d decade-1 for GS and TS, respectively. This difference was mainly driven by the larger advance in the onset of the thermal season compared to the actual advance of leaf-out dates (spring mismatch: 7.2 ± 0.1 d decade-1 ), but to a less extents caused by a phenological mismatch between GS and TS in autumn (2.4 ± 0.1 d decade-1 ). Our results showed that forest trees do not linearly track the new thermal window extension, indicating more complex interactions between winter and spring temperatures and photoperiod and a justification of demonstrating that using more sophisticated models that include the influence of chilling and photoperiod are needed to accurately predict spring phenological changes under warmer climate. They urge caution if such mechanisms are omitted to predict, for example, how vegetative health and growth, species distribution, and crop yields will change in the future.

18.
Front Oncol ; 12: 1059978, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465357

RESUMO

Background: RNA-binding protein (RBP) regulates acute myeloid leukemia (AML) by participating in mRNA editing and modification. Pyroptosis also plays an immunomodulatory function in AML. Therefore, this study aimed to identify pyroptosis-related RBP genes that could predict the prognosis of AML patients. Methods: AML related expression data were downloaded from the UCSC website and Gene Expression Omnibus (GEO) database. Pyroptosis-RPB-related differentially expressed genes (PRBP-DEGs) were conducted with a protein-protein interactions (PPI) network to screen out the key PRBP-DEGs, based on which a risk model was constructed by Cox analysis, and evaluated by plotting Receiver operating characteristic (ROC) curves and survival curves. Independent prognostic analysis was performed and a nomogram was constructed. Finally, enrichment analysis was performed for high and low risk groups. Reuslts: A total of 71 PRBP-DEGs were obtained and a pyroptosis-RPB-related risk model was constructed based on IFIT5, MRPL14, MRPL21, MRPL39, MVP, and PUSL1 acquired from Cox analysis. RiskScore, age, and cytogenetics risk category were identified as independent prognostic factors, and the nomogram based on these independent prognostic factors could accurately predict 1-, 3- and 5-year survival of AML patients. Gene set enrichment analysis (GSEA) showed that the high-risk and low-risk groups were mainly enriched in metabolic- and immune-related processes and pathways. Conclusion: In this study, a risk score model correlated with metabolism based on RNA-binding proteins associated with cell pyroptosis in acute myeloid leukemia was established, which provided a theoretical basis and reference value for therapeutic studies and prognosis of AML.

19.
Front Pharmacol ; 13: 1021150, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36467066

RESUMO

Background: Pharmacotherapy is one of the primary treatments for patients with Assisted reproductive technology (ART). Despite the publication of various research on ART treatment, there is no clear conclusion regarding the choice of drug treatment in China. Our research intends to examine the trend of widely prescribed medications for ART patients in China. For instance, the study examines the logic of drug indications, usage, and dose in patient prescriptions. Methods: We did a cross-sectional study of the data from the hospital prescription analysis cooperation project supervised by the China Medical Association. The information is extracted from the prescriptions of reproductive assistance outpatients from January 2016 to December 2020. We used the U.S. Food and Drug Administration (FDA) classification to quantify the frequency of drug use and the categories of drugs. We manually extract the information of patients who require ART treatment, divide the patients into various age groups and geographies, followed by study the indications, utilization, and rationale of the most important therapeutic medications. Results: Among the 225225 patients included in this study, Guangzhou (47.83%), Shanghai (19.84%), and Zhengzhou (9.36%) were the top three cities. In the past 5 years, the average age was 32.99, and 60.38% of women were between the age of 25 and 34. The main therapeutic medicines taken by each patient, primarily hormone therapies, were tallied. Eleven types of primary therapeutic medicines were employed. Different progesterone preparations (47472, 21.08%), chorionic gonadotrophin gondotrophin for injection (38932, 17.29%), dydrogesterone tables (33591, 14.91%), and triptorelin for injection (26959, 11.97%) rounded out the top five. According to the data on outpatient medications in major cities in China, the variety and proportion of injections are the highest, including the most frequent types of ovulation induction and urotropia, as well as triptorelin and progesterone. Even though the total dosage of urotropin was the highest in 5 years, it showed a declining trend. The dosages of progesterone and didroxyprogesterone increased, with progesterone showing the most rapid increase. The top five most expensive prescription medications are triptorelin, urotropin, progesterone, didroxyprogesterone, and leuprorelin, in that order. Goserelin, leuprorelin, triptorelin, growth hormone, and didroxyprogesterone are among the top five most expensive medications per capita. Conclusion: The average age of patients has not increased considerably over the past 5 years. However, the opportunity cost of childbirth for women has increased, which has significantly enhanced their willingness for childbearing intentions. The medication selection is reasonable overall. In this study, the recommended dosages of first-line medicines (urotropin and chorionic gonadotropin) are likewise high. In contrast, the dosage of oral first-line treatment for ovarian stimulation in unexplained infertility is modest, and the dosage of progesterone is steadily increasing. In addition, the price of certain medicines is high, which will increase the patients' financial burden. Future research will focus on enhancing the degree of rational drug use among outpatients and realizing the economical, safe, and effective use of pharmaceuticals to lessen the economic burden of patients.

20.
Curr Microbiol ; 80(1): 32, 2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36480068

RESUMO

A new aerobic bacterial strain, designated strain YIM B02290T, was isolated from the soil of Machangqing, Dali city, Yunnan Province, China. Cells were Gram-stain-positive, sporogenous, rod-shaped, and motile with peritrichous flagella. Strain YIM B02290T showed the highest 16S rRNA gene sequence similarity with Brevibacillus laterosporus (97.6%) and Brevibacillus halotolerans (97.6%). The ANI and dDDH values between strain YIM B02290T and the two reference strains Brevibacillus laterosporus LAM00312T and Brevibacillus halotolerans DSM 25T are 72.6% and 72.2%, 20.2% and 19.5% based on the draft genome sequence, respectively. The major cellular fatty acids contain anteiso-C15: 0 and iso-C15: 0. The diagnostic diamino acid of the cell-wall peptidoglycan was meso-diaminopimelic acid. The predominant menaquinone was identified as menaquinone-7. The main polar lipids of strain YIM B02290T were diphosphatidylglycerol, phosphatidylglycerol, phospholipid, phosphatidyl monomethylethanolamine. The genomic DNA G + C content was 40.6 mol%. All results showed that strain YIM B02290T represents a novel species of the genus Brevibacillus, for which the name Brevibacillus daliensis sp. nov. is proposed. The type strain is YIM B02290T (= CCTCC AB 2021094T = CGMCC 1.18802T = KCTC 43376T).


Assuntos
Solo , RNA Ribossômico 16S/genética , China
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