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Glomerulonephritis (GN) is the most common cause of end-stage renal failure worldwide; in most cases, it cannot be cured and can only delay the progression of the disease. At present, the main treatment methods include symptomatic therapy, immunosuppressive therapy, and renal replacement therapy. However, effective treatment of GN is hindered by issues such as steroid resistance, serious side effects, low bioavailability, and lack of precise targeting. With the widespread application of nanoparticles in medical treatment, novel methods have emerged for the treatment of kidney diseases. Targeted transportation of drugs, nucleic acids, and other substances to kidney tissues and even kidney cells through nanodrug delivery systems can reduce the systemic effects and adverse reactions of drugs and improve treatment effectiveness. The high specificity of nanoparticles enables them to bind to ion channels and block or enhance channel gating, thus improving inflammation. This review briefly introduces the characteristics of GN, describes the treatment status of GN, systematically summarizes the research achievements of nanoparticles in the treatment of primary GN, diabetic nephropathy and lupus nephritis, analyzes recent therapeutic developments, and outlines promising research directions, such as gas signaling molecule nanodrug delivery systems and ultrasmall nanoparticles. The current application of nanoparticles in GN is summarized to provide a reference for better treatment of GN in the future.
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Nefropatias Diabéticas , Glomerulonefrite , Nefrite Lúpica , Humanos , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/metabolismo , Rim/metabolismo , NanotecnologiaRESUMO
The role of m6A in ankylosing spondylitis (AS) remains largely obscure. In this study, we found that m6A modification was decreased in T cells of AS, and the abnormal m6A modification was attributed to the downregulation of methyltransferase-like 14 (METTL14). METTL14 exerted a critical role in regulating autophagy activity and inflammation via targeting Forkhead box O3a (FOXO3a). Mechanistically, the loss of METTL14 decreased the expression of FOXO3a, leading to the damage of autophagic flux and the aggravation of inflammation. Inversely, the forced expression of METTL14 upregulated the expression of FOXO3a, thereby activating autophagy and alleviating inflammation. Furthermore, our results revealed that METTL14 targeted FOXO3a mRNA and regulated its expression and stability in a m6A-dependent manner. These findings uncovered the functional importance of m6A methylation mechanisms in the regulation of autophagy and inflammation, which expanded our understanding of this interaction and was critical for the development of therapeutic strategies for AS.
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Adenina , Autofagia , Proteína Forkhead Box O3 , Inflamação , Metiltransferases , Espondilite Anquilosante , Humanos , Adenina/metabolismo , Autofagia/genética , Inflamação/genética , Metiltransferases/genética , Espondilite Anquilosante/genética , Espondilite Anquilosante/patologia , Proteína Forkhead Box O3/metabolismoRESUMO
Five new C21 -steroidal sapogenins (1-5) named cynotogenins J-N, were isolated from the acid hydrolysate of Cynanchum otophyllum roots. Their structures were established by extensive spectroscopic analysis (UV, IR, HR-ESI-MS, and NMR). Most notably, compounds 1-3 harboring a rare 5ß,6ß-epoxy group in the C21 -steroidal skeleton of Cynanchum plants. All compounds were evaluated for their cytotoxicities against multiple cancer cell lines, in which compounds 5 showed weak cytotoxicity against HepG2 cancer cells with IC50 values of 44.90â µM.
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Cynanchum , Sapogeninas , Cynanchum/química , Glicosídeos/química , Esteroides/química , Linhagem Celular Tumoral , Raízes de Plantas/química , Estrutura MolecularRESUMO
In order to study the structure-activity relationship (SAR) of C21-steroidal glycosides toward human cancer cell lines and explore more potential anticancer agents, a series of 3ß-O-neoglycosides of caudatin and its analogues were synthesized. The results revealed that most of peracetylated 3ß-O-monoglycosides demonstrated moderate to significant antiproliferative activities against four human cancer cell lines (MCF-7, HCT-116, HeLa, and HepG2). Among them, 3ß-O-(2,3,4-tri-O-acetyl-ß-L-glucopyranosyl)-caudatin (2k) exhibited the highest antiproliferative activity aganist HepG2 cells with an IC50 value of 3.11 µM. Mechanical studies showed that compound 2k induced both apoptosis and cell cycle arrest at S phase in a dose dependent manner. Overall, these present findings suggested that glycosylation is a promising scaffold to improve anticancer activity for naturally occurring C21-steroidal aglycones, and compound 2k represents a potential anticancer agent deserved further investigation.
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Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of novel D-ring fused or substituted steroidal N-heterocycles were synthesized, and their chemical structures were characterized by spectroscopic analysis. The anticancer activity of these compounds against four human cancer cell lines (MCF-7, H1299, HeLa and HepG2) were evaluated and the structure-activity relationship (SAR) was also investigated. Compound 3c displayed significant inhibitory activity on the four cancer cells with IC50 values ranging from 3.88 to 10.05â µM. Overall, these studies indicated that construction of N-heterocyclic system with D-ring substituted containing a double bond at C-16 and C-17 or D-ring fused with [17,16-d]azolo[1,5-a]pyrimidine could be a promising strategy to improve antitumor activity for steroids deserved further investigation.
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Antineoplásicos , Humanos , Antineoplásicos/química , Pirimidinas/química , Esteroides/farmacologia , Esteroides/química , Relação Estrutura-Atividade , Células HeLa , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Proliferação de Células , Linhagem Celular TumoralRESUMO
The proton-coupled folate transporter (PCFT, SLC46A1) is required for folate intestinal absorption and transport across the choroid plexus. Recent work has identified a F392V mutation causing hereditary folate malabsorption. However, the residue properties responsible for this loss of function remains unknown. Using site-directed mutagenesis, we observed complete loss of function with charged (Lys, Asp, and Glu) and polar (Thr, Ser, and Gln) Phe-392 substitutions and minimal function with some neutral substitutions; however, F392M retained full function. Using the substituted-cysteine accessibility method (with N-biotinyl aminoethyl methanethiosulfonate labeling), Phe-392 mutations causing loss of function, although preserving membrane expression and trafficking, also resulted in loss of accessibility of the substituted cysteine in P314C-PCFT located within the aqueous translocation pathway. F392V function and accessibility of the P314C cysteine were restored by insertion of a G305L (suppressor) mutation. A S196L mutation localized in proximity to Gly-305 by homology modeling was inactive. However, when inserted into the inactive F392V scaffold, function was restored (mutually compensatory mutations), as was accessibility of the P314C cysteine residue. Reduced function, documented with F392H PCFT, was due to a 15-fold decrease in methotrexate influx Vmax, accompanied by a decreased influx Kt (4.5-fold) and Ki (3-fold). The data indicate that Phe-392 is required for rapid oscillation of the carrier among its conformational states and suggest that this is achieved by dampening affinity of the protein for its folate substrates. F392V and other inactivating Phe-392 PCFT mutations lock the protein in its inward-open conformation. Reach (length) and hydrophobicity of Phe-392 appear to be features required for full activity.
Assuntos
Transportador de Folato Acoplado a Próton/metabolismo , Sequência de Aminoácidos , Animais , Transporte Biológico , Cisteína/química , Cisteína/metabolismo , Deficiência de Ácido Fólico/patologia , Células HeLa , Humanos , Cinética , Síndromes de Malabsorção/patologia , Metotrexato/metabolismo , Mutagênese Sítio-Dirigida , Estrutura Terciária de Proteína , Transportador de Folato Acoplado a Próton/química , Transportador de Folato Acoplado a Próton/genéticaRESUMO
Depression is the most significant risk factor for suicide, yet the causes are complex and disease mechanism remains unclear. The incidence and disability rate of depression are very high and the efficacy of some traditional antidepressants is not completely satisfactory. Recently, some studies have found that benzofurans have anti-oxidation and anti-monoamine oxidase properties, which are related to depression. Euparin is a monomer compound of benzofuran, previous work by our team found that it improves the behavior of depressed mice. However, additional antidepressant effects and mechanisms of Euparin have not been reported. In this study, the Chronic Unpredictable Mild Stress (CUMS) model of mice was used to further investigate the effect and mechanism of Euparin on depression. Results showed that Euparin (8, 16 and 32 mg/kg) reduced depression-like behavior in mice compared with the model group. Meanwhile, all doses of Euparin were found to increase the contents of monoamine neurotransmitter and decrease monoamine oxidase and reactive oxygen species (ROS) levels in brain of depression mice. Additionally, Euparin restored CUMS-induced decrease of Spermidine/Spermine N1-Acetyltransferase 1 (SAT1), N-methyl-D-aspartate receptor subtype 2B (NMDAR2B) and brain derived neurotrophic factor (BDNF) expression. These findings demonstrate that Euparin has antidepressant properties, and its mechanism involves the SAT1/NMDAR2B/BDNF signaling pathway.
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Benzofuranos/farmacologia , Depressão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/complicações , Acetiltransferases/metabolismo , Animais , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Benzofuranos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/diagnóstico , Depressão/patologia , Depressão/psicologia , Modelos Animais de Doenças , Dopamina , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serotonina/metabolismo , Organismos Livres de Patógenos Específicos , Estresse Psicológico/psicologiaRESUMO
Fanconi anemia (FA) is a rare recessive disorder associated with chromosomal fragility. FA patients are at very high risk of cancers, especially head and neck squamous cell carcinomas and squamous cell carcinomas caused by infection of human papillomaviruses (HPVs). By integrating into the host genome, HPV oncogenes E6 and E7 drive the genomic instability to promote DNA damage and gene mutations necessary for carcinogenesis in FA patients. Furthermore, E6 and E7 oncoproteins not only inhibit p53 and retinoblastoma but also impair the FANC/BRCA signaling pathway to prevent DNA damage repair and alter multiple signals including cell-cycle checkpoints, telomere function, cell proliferation, and interference of the host immune system leading to cancer development in FA patients. In this review, we summarize recent advances in unraveling the molecular mechanisms of FA susceptibility to HPV-induced cancers, which facilitate rational preventive and therapeutic strategies.
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Carcinoma de Células Escamosas/epidemiologia , Anemia de Fanconi/complicações , Neoplasias de Cabeça e Pescoço/epidemiologia , Infecções por Papillomavirus/complicações , Carcinogênese , Carcinoma de Células Escamosas/etiologia , Neoplasias de Cabeça e Pescoço/etiologia , Interações Hospedeiro-Patógeno , Humanos , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/fisiologiaRESUMO
In the pavement industry, there is a pressing need for the reuse of recycled asphalt pavement (RAP) materials. However, the rutting deformation in existing pavement structures is often overlooked in the design of recycled asphalt pavement, which hinders long-term performance prediction and durability assessment. This study examined the viscoelastic properties and fatigue performance of recycled asphalt mixtures. Different combinations of surface layers with varying RAP contents and binder layers with different rutting damage levels were designed. A 3D-Move Analysis model was used to analyze the dynamic mechanical response of these structures under moving loads. Results showed that the stiffness of recycled asphalt mixture increased with the RAP content, but the fatigue performance decreased by 39.4% when the RAP content reached 50%. Incorporating 50% RAP in the surface layer can reduce the compressive stress caused by vehicle loading, thus reducing the vertical compression strain and permanent deformation of the asphalt layers and the subgrade. However, the surface layer with higher RAP content is exposed to intense alternating tensile and compressive strains, leading to poor fatigue durability. The dynamic mechanical behavior of recycled asphalt pavement structures was found to be significantly impacted by the characteristics of the binder layer. The lower dynamic modulus of the binder layer (e.g., 18 mm rutting depth) can lead to more deformation and an increased risk of fatigue cracking. Moreover, the dynamic performance of mixtures with 0% and 50% RAP in the surface layer is even more affected by changes in the binder layer properties. It is recommended to consider the design of dynamic modulus combinations of existing binder layer materials and surface materials with higher RAP, in order to increase the utilization of RAP for high-grade highways and improve the stress distribution to enhance their durability.
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Poluição Ambiental , Gastrópodes , Animais , Fadiga , HidrocarbonetosRESUMO
Objective: This study aims to investigate the clinical application value of high-frequency ultrasound technology in diagnosing subcutaneous lipohypertrophy at insulin injection sites in diabetes patients. Methods: All diabetes patients treated in our hospital from January 2022 to January 2023 were selected as the study subjects. The incidence of subcutaneous lipohypertrophy was calculated at the end of the study period. All patients were screened, and those meeting the inclusion criteria were registered, and basic data were collected. Patients were screened for subcutaneous lipohypertrophy using conventional clinical examination (control group) and high-frequency ultrasound technology (study group). Results: The study found that the incidence of subcutaneous lipohypertrophy in diabetes patients receiving insulin injections in our hospital from January 2022 to January 2023 was 80.99%. The average longitudinal diameter of subcutaneous lipohypertrophy in these patients was 11.66 (7.56, 21.44) mm, the transverse diameter was 12.04 (8.96, 18.29) mm, depth was (5.62±2.17) mm, and the area was 188.79 (76.85, 331.78) mm². The clinical detection rate in the study group was higher than that in the control group (P<0.05). The quantity of detected sites was greater in the study group compared to the control group (P<0.05). Conclusion: The incidence of subcutaneous lipohypertrophy in diabetes patients receiving insulin injections is relatively high clinically, and high-frequency ultrasound technology demonstrates significant potential in diagnosis. By providing high-resolution imaging and quantitative data, it effectively improves the clinical detection rate and clarifies symptoms. This technology is likely to become an important auxiliary tool in future diabetes treatment, providing more precise treatment plans for patients.
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Liver disease is a severe public health concern worldwide. There is a close relationship between the liver and cytokines, and liver inflammation from a variety of causes leads to the release and activation of cytokines. The functions of cytokines are complex and variable, and are closely related to their cellular origin, target molecules and mode of action. Interleukin (IL)-20 has been studied as a pro-inflammatory cytokine that is expressed and regulated in some diseases. Furthermore, accumulating evidences has shown that IL-20 is highly expressed in clinical samples from patients with liver disease, promoting the production of pro-inflammatory molecules involved in liver disease progression, and antagonists of IL-20 can effectively inhibit liver injury and produce protective effects. This review highlights the potential of targeting IL-20 in liver diseases, elucidates the potential mechanisms of IL-20 inducing liver injury, and suggests multiple viable strategies to mitigate the pro-inflammatory response to IL-20. Genomic CRISPR/Cas9-based screens may be a feasible way to further explore the signaling pathways and regulation of IL-20 in liver diseases. Nanovector systems targeting IL-20 offer new possibilities for the treatment and prevention of liver diseases.
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Papillary renal cell carcinoma (PRCC) is a highly heterogeneous cancer, and PRCC patients with advanced/metastatic subgroup showed obviously shorter survival compared to other kinds of renal cell carcinomas. However, the molecular mechanism and prognostic predictors of PRCC remain unclear and are worth deep studying. The aim of this study is to identify novel molecular classification and construct a reliable prognostic model for PRCC. The expression data were retrieved from TCGA, GEO, GTEx and TARGET databases. CRISPR data was obtained from Depmap database. The key genes were selected by the intersection of CRISPR-Cas9 screening genes, differentially expressed genes, and genes with prognostic capacity in PRCC. The molecular classification was identified based on the key genes. Drug sensitivity, tumor microenvironment, somatic mutation, and survival were compared among the novel classification. A prognostic model utilizing multiple machine learning algorithms based on the key genes was developed and tested by independent external validation set. Our study identified three clusters (C1, C2 and C3) in PRCC based on 41 key genes. C2 had obviously higher expression of the key genes and lower survival than C1 and C3. Significant differences in drug sensitivity, tumor microenvironment, and mutation landscape have been observed among the three clusters. By utilizing 21 combinations of 9 machine learning algorithms, 9 out of 41 genes were chosen to construct a robust prognostic signature, which exhibited good prognostic ability. SERPINH1 was identified as a critical gene for its strong prognostic ability in PRCC by univariate and multiple Cox regression analyses. Quantitative real-time PCR and Western blot demonstrated that SERPINH1 mRNA and protein were highly expressed in PRCC cells compared with normal human renal cells. This study exhibited a new molecular classification and prognostic signature for PRCC, which may provide a potential biomarker and therapy target for PRCC patients.
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The problem-based learning (PBL) is increasingly used in undergraduate education. However, the application of integrated PBL to medical undergraduate education has not been well assessed. An observational study was designed to compare integrated PBL combined with lecture-based classroom (LBC) with traditional LBC teaching in 2 semesters of a Medical School in China. This study was conducted from March 2021 to July 2022. A total of 118 undergraduates majoring in clinical medicine were randomly allocated in 2 groups, 1 group receiving the integrated PBL + LBC teaching (experimental group, n = 60) and another group receiving LBC teaching (control group, n = 58). The experimental group attended the integrated PBL courses for the basic and clinical medicine conducted in the 6th and 8th semesters, respectively, as well as taking the LBC courses. The experimental group was required to preview the course materials before class, make presentations in class and take online feedback questionnaires after class, while the control group was required to preview the textbooks and listen to the traditional LBC courses. The students' scores of these 2 groups were compared, and feedback questionnaires were performed to evaluate the effectiveness of the experimental group over the control group. Results showed that the experimental group scored significantly higher than the control group in Clinical Skills (95% confidence interval [CI] 4.19-5.89), Internal Medicine I (95% CI: 1.85-9.93), Internal Medicine II (95% CI: 8.07-15.90), Introduction to Surgery (95% CI: 5.08-10.25), Surgery (General Surgery) (95% CI: 7.82-12.72), Surgery (Specialty) (95% CI: 6.47-9.97), and Clinical Medical Level Test (95% CI: 1.60-5.15) (all P < .01). In the feedback questionnaires of integrated PBL, up to 80% and 90% of students were satisfied with the teaching methods and lecturers, respectively. More than 80% of students agreed that the integrated PBL improved their abilities to learn independently, understand knowledge, and to raise, analyze and solve problems. In terms of stress in and out of class, a small number of students, <36.7%, felt stressed. The integrated PBL combined with LBC is an effective teaching approach, which may provide new ideas for teaching research and reform on undergraduate medical education in clinical medicine specialty and other medical majors.
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Educação de Graduação em Medicina , Aprendizagem Baseada em Problemas , Humanos , Faculdades de Medicina , China , Medicina InternaRESUMO
Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze, Transcranial Doppler TCD, hematoxylin-eosin (HE) staining, Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR pathway.
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Demência Vascular , Selênio , Ratos , Animais , Demência Vascular/tratamento farmacológico , Demência Vascular/metabolismo , Selênio/farmacologia , Selênio/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Cálcio/metabolismo , Estresse Oxidativo , Hipocampo , Neurônios/metabolismo , Aprendizagem em LabirintoRESUMO
Diabetic cardiomyopathy (DCM) is a kind of idiopathic heart disease, which is one of the main complications of diabetes and seriously threatens the life of diabetic patients. Rubiadin, an anthraquinone compound extracted from the stems and roots of rubiaceae, has been widely discussed for its anti-diabetes, anti-oxidation and other pharmacological effects. However, Rubiadin can cause drug-induced liver injury. Therefore, A-cycloglycosylated derivative of Rubiadin (ACDR) was obtained by modifying its structure. The purpose of this study was to investigate the effect of ACDR on DCM cardiac injury and its mechanism. The DCM animal model was established by streptozotocin, and the success of DCM was verified by blood glucose level, echocardiographic evidence of impaired myocardial functions along with enhanced myocardial fibrosis. We performed liver function tests, morphological staining of the heart and tests for oxidative stress to evaluate cardiac functional and structural changes. Finally, the expression of Na+/H+ exchanger (NHE1) protein was analyzed by immunohistochemistry and western bolt, and the expression of hairy/enhancer-of-split related with YRPW motif 1 (Hey1) and P-p38 protein was detected by immunofluorescence chemistry and western blotting. The results showed that ACDR can improve cardiac dysfunction, reduce myocardial injury, reduce oxidative stress, and protect the liver in DCM rats. Interestingly, all variations were countered by LiCl. Our study suggests that, along with controlling hyperglycemia, ACDR may improve DCM by reducing NHE1 expression, further inhibiting P-p38 activity and increasing Hey1 expression to reduce oxidative stress.
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Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Ratos , Animais , Cardiomiopatias Diabéticas/etiologia , Diabetes Mellitus Experimental/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Antraquinonas/farmacologiaRESUMO
In type 2 diabetes mellitus (T2DM), oxidative stress induces endothelial dysfunction (ED), which is closely related to the formation of atherosclerosis. However, there are few effective drugs to prevent and cure it. Citronellal (CT) is an aromatic active substance extracted from citronella plants. Recently, CT has been shown to prevent ED, but the underlying mechanism remains unclear. The purpose of this study was to investigate whether CT ameliorated T2DM-induced ED by inhibiting the TRPM2/NHE1 signal pathway. Transient receptor potential channel M2 (TRPM2) is a Ca2+-permeable cation channel activated by oxidative stress, which damages endothelial cell barrier function and further leads to ED or atherosclerosis in T2DM. The Na+/H+ exchanger 1 (NHE1), a transmembrane protein, also plays an important role in ED. Whether TRPM2 and NHE1 are involved in the mechanism of CT improving ED in T2DM still needs further study. Through the evaluations of ophthalmoscope, HE and Oil red staining, vascular function, oxidative stress level, and mitochondrial membrane potential evaluation, we observed that CT not only reduced the formation of lipid deposition but also inhibited ED and suppressed oxidative stress-induced mitochondrial damage in vasculature of T2DM rats. The expressions of NHE1 and TRPM2 was up-regulated in the carotid vessels of T2DM rats; NHE1 expression was also upregulated in endothelial cells with overexpression of TRPM2, but CT reversed the up-regulation of NHE1 in vivo and in vitro. In contrast, CT had no inhibitory effect on the expression of NHE1 in TRPM2 knockout mice. Our study show that CT suppressed the expression of NHE1 and TPRM2, alleviated oxidative stress-induced mitochondrial damage, and imposed a protective effect on ED in T2DM rats.
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This study is to investigate the effect of the major chemical composition in rhizome of Pterocypsela elata, lactuside B, on expression of bcl-2, bax mRNA and their protein in rats' cerebral cortex after cerebral ischemia-reperfusion injury. First, middle cerebral artery ischemia-reperfusion injury model was established, and each group was treated with the corresponding medicines. Animals were separately sacrificed at 24 h and 72 h. The brain infarct volumes were detected by TTC dye, bcl-2 and bax mRNA expression was checked by RT-PCR, and the proteins of bcl-2 and bax were explored by two-step immunohistochemistry in cerebral cortex of rats. Lactuside B can reduce brain infarct volume of cerebral cortex of rats, increase the expression of bcl-2 mRNA and decrease that of bax mRNA. Moreover, the ratio of bcl-2 to bax mRNA is higher in 12.5 and 25 mg kg(-1) dose group, respectively, which is significantly different from that of model group (P < 0.05 or P < 0.01). Generally, either 12.5 or 25 mg kg(-1) dose group is better than positive control medicine nimodipine (P < 0.05 or P < 0.01). In addition, the expression of bcl-2 and bax protein is consistent with their gene expression. Infarct volume and the ratio of bcl-2 to bax mRNA expression are significantly different (P < 0.05 or P < 0.01) between 72 h and 24 h group. The results demonstrated that lactuside B could play a good role in resisting cerebral ischemia by upregulating the expression of bcl-2 mRNA and protein and downregulating that of bax mRNA and protein.
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Isquemia Encefálica/metabolismo , Glucosídeos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Traumatismo por Reperfusão/metabolismo , Proteína X Associada a bcl-2/metabolismo , Animais , Apoptose/efeitos dos fármacos , Asteraceae/química , Isquemia Encefálica/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Relação Dose-Resposta a Droga , Glucosídeos/administração & dosagem , Glucosídeos/isolamento & purificação , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Plantas Medicinais/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Rizoma/química , Vasodilatadores/administração & dosagem , Vasodilatadores/isolamento & purificação , Vasodilatadores/farmacologia , Proteína X Associada a bcl-2/genéticaRESUMO
OBJECTIVE: To observe the clinicopathologic and genetic features of follicular variant of peripheral T-cell lymphoma (FV-PTCL), with particular attention to the relationship of this type of lymphoma with angioimmunoblastic T-cell lymphoma (AITL). METHODS: The clinical data, hematoxylin and eosin-stained sections of lymph node biopsies from 2 FV-PTCL cases were reviewed. Immunohistochemical phenotyping and detection of EBV-encoded RNAs (EBER) through in situ hybridization (ISH) were performed. The EnVision two-step method was used for all antibodies except CXCL13 (by using three-step streptavidin immunoperoxidase method). Analysis of clonality and ITK/SYK gene rearrangement was conducted using PCR and RT-PCR assays, respectively. RESULTS: Clinically, the two patients presented with superficial lymphadenopathy similarly. Histologically, case 1 showed a follicular/nodular lymphoid proliferation without marked germinal centers. The neoplastic cells comprised mainly medium sized cells with abundant, sometimes clear cytoplasms. Similar histologic findings were seen in case 2 in addition to a concurrent component mimicking typical AITL noticed. Of both cases, the neoplastic cells showed positive reactivity to CD3, CD4, CD10, PD1, and CXCL13. Positive hybridization signals for EBER were only seen in case 2, and double stains demonstrated that those EBV-positive cells were mostly the reactive transformed B-cells. Monoclonal T-cell proliferation was proved by the rearranged TCR gene detection in both cases. Neither of the current cases expressed ITK/SYK fusion transcripts. CONCLUSION: FV-PTCL shows the similar or overlapped morphological and immunophenotypic features to those of AITL, possibly suggesting the presence of a potential relationship between these two types of lymphomas.
Assuntos
Rearranjo Gênico do Linfócito T , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patologia , Idoso , Antígenos CD/metabolismo , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Reguladoras de Apoptose/metabolismo , Quimiocina CXCL13/metabolismo , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Endostatinas/uso terapêutico , Feminino , Humanos , Linfadenopatia Imunoblástica/genética , Linfadenopatia Imunoblástica/metabolismo , Linfadenopatia Imunoblástica/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Queratinas/metabolismo , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/metabolismo , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Prednisona/uso terapêutico , Receptor de Morte Celular Programada 1 , Proteínas Tirosina Quinases/genética , Proteínas Recombinantes , Indução de Remissão , Quinase Syk , Vincristina/uso terapêuticoRESUMO
t(6;11) translocation renal cell carcinoma (RCC) is classified as a subset of the MiT family translocation RCCs and characterized by harboring the Alpha-TFEB fusion gene. However, the development mechanism of this tumor and its effective treatment have not been fully identified yet. The purpose of this study was to explore the relationship between TFEB and BCL-2 in Alpha-TFEB stably transfected cell lines and in t(6;11) RCC tumor tissue. An Alpha-TFEB eukaryotic expression vector was constructed and stably transfected into CaKi-2 and HK-2 cells. RT-PCR and real-time RT-PCR were used to measure the mRNA expressions of TFEB and BCL-2, and immunohistochemistry, Western blot and dual immunofluorescence assays were used to evaluate the TFEB and BCL-2 protein expressions. MTT proliferation assays and flow cytometry were also performed. Furthermore, luciferase reporter assays were used to evaluate the BCL-2 promoter activity. An Alpha-TFEB eukaryotic expression vector was successfully constructed and stably transfected into CaKi-2 and HK-2 cells (named CaKi-2-TFEB and HK-2-TFEB cells). Compared with the CaKi-2 and HK-2 groups, the TFEB and BCL-2 mRNA expression levels were significantly upregulated in the CaKi-2-TFEB and HK-2-TFEB groups respectively. The TFEB and BCL-2 protein expressions showed a similar result. The overexpression of TFEB and BCL-2 promoted cell proliferation and inhibited cell apoptosis. Moreover, the overexpression of TFEB upregulated the promoter activity of BCL-2. Our data suggest that the overexpression of TFEB promotes BCL-2 expression by upregulating its promoter activity and ultimately results in the development of t(6;11) translocation RCC. BCL-2 inhibitors may serve as potential therapeutic targets for t(6;11) translocation RCC.
RESUMO
We explored the effects of disturbance densities on the spatial pattern and the association of tree species in the coniferous broadleaved mixed forest in Pangquangou Nature Reserve of Guandi Mountain. Using three factors including canopy density, stand density and number of stumps, we classified the disturbance intensities of different forest stands into three levels, non-disturbance, moderate disturbance, and severe disturbance. The spatial distribution pattern and the association of different tree species were analyzed by spatial point pattern K2 function. The results showed that the diameter distribution of trees in undisturbed plots was inverted 'J' type, while that of moderate disturbance and serious disturbance plots was under bimodal curve distribution. The stand distribution pattern showed a small-scale aggregated distribution under undisturbed and moderately distur-bance, and a random distribution under heavy disturbance. At the small scale, the coniferous and broadleaved species showed no correlation in undisturbed stands, were positively correlated in moderately disturbed stands, and negatively correlated in seriously disturbed stands. At large scale, they were no correlated in both moderately and seriously disturbed stands. The results suggested that abundance of trees with small diameter in the forests was negatively with disturbance intensity, which led to the lower degree of intraspecific aggregation at small scale. Meanwhile, appropriate levels of disturbance would benefit the collaborative use of environmental resources for trees. Our results revealed the impacts of disturbance density on forest community structure and could provide theoretical basis for forest management.