RESUMEN
OBJECTIVE: To analyze the relationship between serum cystatin C (CysC), ß2-microglobulin (ß2-MG) and the efficacy of demethylation therapy in patients with acute myeloid leukemia (AML). METHODS: A prospective cohort study was conducted on 98 AML patients admitted to the Affiliated Hospital of Inner Mongolia Medical University from February 2019 to January 2022. All patients were treated with decitabine (DAC) + HAG regimen, 28 days as a course and treated for 3-4 courses. At the end of each course of treatment, the treatment effect of the patients was evaluated, and the patients who achieved complete remission (CR) transferred to consolidation therapy, while the patients who did not reach CR at the end of the course of treatment were considered as treatment failure. The examination items before treatment include routine blood parameters, serum CysC, and ß2-MG, and general clinical data of the patients were collected. According to the statistical results, logistic regression model was used to analyze the relationship between serum CysC, ß2-MG and the efficacy of demethylation therapy in AML patients. The ROC curves were drawn, and the predictive efficacy of serum CysC, ß2-MG on demethylation therapy in AML patients was evaluated by the area under the curve (AUC). RESULTS: Of the 98 AML patients enrolled in the study, 5 cases were excluded during the treatment period, and 93 cases finally completed the chemotherapy courses. Among them, 23 patients achieved CR after the initial induction chemotherapy (course 1-2), and 11 patients achieved CR after the re-induction chemotherapy (course 3-4). The success rate of demethylation therapy was 36.56 % (34/93). Compared with the patients in treatment success group, patients in treatment failure group had a higher proportion of intermediate- and adverse-risk, lower levels of platelet (PLT) and hemoglobin (Hb), and higher expression levels of serum CysC and ß2-MG, all of which were statistically significant (P < 0.05). Logistic regression analysis showed that high expression of serum CysC, ß2-MG and adverse-risk were independent risk factors for failure of demethylation treatment in AML patients (OR >1, P < 0.05). The ROC curves showed that the AUC values of serum CysC, ß2-MG alone and combined in predicting the efficacy of demethylation therapy in AML patients were 0.788, 0.785 and 0.834, respectively. CONCLUSION: The failure of demethylation therapy in AML patients is related to the high expression of serum CysC and ß2-MG, and detection of serum CysC and ß2-MG before treatment can predict the risk of demethylation therapy failure in AML patients.
Asunto(s)
Cistatina C , Leucemia Mieloide Aguda , Microglobulina beta-2 , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/sangre , Estudios Prospectivos , Microglobulina beta-2/sangre , Cistatina C/sangre , Desmetilación , Inducción de Remisión , Decitabina , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana EdadRESUMEN
Background: Recently, male fertility preservation before cancer treatment has become more prevalent. The research in this field has progressed over time, with some studies having a major impact and providing guidance for further research. However, the trends and hotspots of research on fertility preservation in male cancer patients may have changed; exploring them is essential for relevant research progress. Design: We extracted relevant studies from the Web of Science Core Collection database, capturing information on the countries of study, affiliations, authors, keywords, as well as co-citations of references and journals. To identify publication trends, research strengths, key subjects, prominent topics, and emerging areas, we conducted a bibliometric analysis using CiteSpace. Results: We included 3201 articles on fertility preservation in male cancer patients published over January 1999 to December 2023 were included. Although the relevant research growth rate was slow initially, the number of publications increased annually. Of all study countries, the United States, Germany, and Japan reported the earliest studies; the United States published the highest number of relevant studies. The US institutions remained at the forefront for all 25 years, and the US researcher Ashok Agarwal published the most articles. Literature co-citation analyses indicated a transformation in the study participants; they comprised a younger demographic (i.e., a large number of adolescent male patients underwent fertility preservation); moreover, fertility preservation techniques evolved from sperm cryopreservation to testicular tissue cryopreservation. Research on reproductive outcomes of sperm cryopreservation was the recent hotspot in male fertility preservation research, and the impact of immunotherapy and checkpoint inhibitors on male fertility requires further research. Conclusions: Male fertility preservation will be a major future research focus, with closer connections and collaborations between countries and organizations. Our results present the historical data on the development of research on male fertility preservation in cancer patients, providing relevant insights for future research and development in this study area.
RESUMEN
Tyrosine phosphorylation, a common post-translational modification process for proteins, is involved in a variety of biological processes. However, the abundance of tyrosine-phosphorylated proteins is very low, making their identification by mass spectrometry (MS) is difficult; thus, milligrams of the starting material are often required for their enrichment. For example, tyrosine phosphorylation plays an important role in T cell signal transduction. However, the number of primary T cells derived from biological tissue samples is very small, and these cells are difficult to culture and expand; thus, the study of T cell signal transduction is usually carried out on immortalized cell lines, which can be greatly expanded. However, the data from immortalized cell lines cannot fully mimic the signal transduction processes observed in the real physiological state, and they usually lead to conclusions that are quite different from those of primary T cells. Therefore, a highly sensitive proteomic method was developed for studying tyrosine phosphorylation modification signals in primary T cells. To address the issue of the limited T cells numbers, a comprehensive protocol was first optimized for the isolation, activation, and expansion of primary T cells from mouse spleen. CD3+ primary T cells were successfully sorted; more than 91% of the T cells collected were well activated on day 2, and the number of T cells expanded to over 7-fold on day 4. Next, to address the low abundance of tyrosine-phosphorylated proteins, we used SH2-superbinder affinity enrichment and immobilized Ti4+affinity chromatography (Ti4+-IMAC) to enrich the tyrosine-phosphorylated polypeptides of primary T cells that were co-stimulated with anti-CD3 and anti-CD28. These polypeptides were resolved using nanoscale liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS). Finally, 282 tyrosine phosphorylation sites were successfully identified in 1 mg of protein, including many tyrosine phosphorylation sites on the immunoreceptor tyrosine-based activation motif (ITAM) in the intracellular region of the T cell receptor membrane protein CD3, as well as the phosphotyrosine sites of ZAP70, LAT, VAV1, and other proteins related to signal transduction under costimulatory conditions. In summary, to solve the technical problems of the limited number of primary cells, low abundance of tyrosine-phosphorylated proteins, and difficulty of detection by MS, we developed a comprehensive proteomic method for the in-depth analysis of tyrosine phosphorylation modification signals in primary T cells. This protocol may be applied to map signal transduction networks that are closely related to physiological states.
Asunto(s)
Fosfoproteínas , Proteoma , Linfocitos T , Tirosina , Animales , Ratones , Fosforilación , Fosfoproteínas/análisis , Proteoma/análisis , Proteómica/métodos , Transducción de SeñalRESUMEN
Three-amino-loop-extension (TALE) family belongs to the homeobox gene superfamily and occurs widely in plants, playing a crucial role in regulating their growth and development. Currently, genome-wide analysis of the TALE family has been completed in many plants. However, the systematic identification and hormone response analysis of the TALE gene family in barley are still lacking. In this study, 21 TALE candidate genes were identified in barley, which can be divided into KNOX and BELL subfamilies. Barley TALE members in the same subfamily of the phylogenetic tree have analogically conserved motifs and gene structures, and segmental duplications are largely responsible for the expansion of the HvTALE family. Analysis of TALE orthologous and homologous gene pairs indicated that the HvTALE family has mainly undergone purifying selective pressure. Through spatial structure simulation, HvKNOX5-HvKNOX6 and HvKNOX5-HvBELL11 complexes are all formed through hydrogen bonding sites on both the KNOX2 and homeodomain (HD) domains of HvKNOX5, which may be essential for protein interactions among the HvTALE family members. Expression pattern analyses reveal the potential involvement of most HvTALE genes in responses to exogenous hormones. These results will lay the foundation for regulation and function analyses of the barley TALE gene family in plant growth and development by hormone regulation.
RESUMEN
Homogeneous gold catalysis has attracted much recent attention due to diverse activation modes of gold(i) towards unsaturated organic groups. Because of attractive aurophilic interaction, structural transformations of metalated species into high nuclear clusters are often proposed in gold catalysis, while to date little is known about their assembly behaviors and catalytic activity. In this work, based on stoichiometric Au(i)-mediated enyne cyclization reactions, we achieve a discrete vicinal dicarbanion-centered Au4 intermediate and three assembled Au11, Au28, and Au14 clusters held together by several aryl dicarbanions. Spectral monitoring, kinetic and theoretical investigations confirm that these discrete and assembled intermediates display four different pathways upon catalyzing the cyclization reaction of the same 1,5-enyne substrate. The discrete Au4 cluster undergoes a full protodeauration process to generate active [Au(PPh3)]+ species for catalytic use. In contrast, the net-like Au11 cluster experiences a substrate-induced dissociation to generate a semi-stable Au10 unit and an active [alkyne-Au(PPh3)]+ fragment for further transformation. The dumbbell-like Au28 cluster is prone to cleavage of the central Au-Au linkage and each Au14 moiety exposes a coordination unsaturated site to activate a substrate molecule. However, the synthetic closed-Au14 cluster with full ligand protection is no longer catalytically active.
RESUMEN
BACKGROUND: COVID-19 had a tremendous impact on surgical residency education and training. With little experience or training in using online learning in pedagogically informed ways, some surgical educators and learners experienced the disadvantages of online learning which may have contributed to a greater sense of burnout in the pandemic. The purpose of this study is to survey the level of burnout in surgical educators and assess educators' perspectives on factors that increased or decreased burnout in synchronous online teaching during the pandemic. METHODS: A cross-sectional study consisting of 4 sections was sent to surgical educators at the University of Toronto. Demographic data, validated surveys on burnout and videoconferencing fatigue (the Maslach Burnout Inventory-Educators Survey (MBI-ES) and the Zoom Exhaustion and Fatigue (ZEF) scale respectively), and quantitative questions about teaching factors in synchronous online environments were collected and analyzed. RESULTS: The MBI-ES demonstrated a high degree of emotional exhaustion, and depersonalization and a moderate degree of personal accomplishment in surgeon educators. The ZEF scale noted moderate fatigue across all domains. Although educators noted online learning to be a moderate factor contributing to burnout during the pandemic, there was no correlation between the number of hours or percentage of time teaching online to burnout or zoom fatigue scores. The largest reported contributing factor to online learning leading to burnout was lack of connection to learners, whereas the largest mitigating factor was decreased travel time. INTERPRETATIONS: The study found a moderate degree of exhaustion and burnout among surgical educators in Canada during COVID-19 and examined how aspects of online synchronous learning may have contributed to or helped mitigate these experiences. Based on this, we present approaches and educational theories to improve the online learning experience for surgical educators going forward.
Asunto(s)
Agotamiento Profesional , COVID-19 , Educación a Distancia , Humanos , Agotamiento Profesional/epidemiología , Estudios Transversales , COVID-19/epidemiología , Masculino , Femenino , Adulto , Pandemias , Docentes Médicos/psicología , Cirugía General/educación , SARS-CoV-2 , Encuestas y Cuestionarios , Internado y Residencia , Persona de Mediana Edad , Especialidades Quirúrgicas/educación , OntarioRESUMEN
We present the results for the complete next-to-leading order electroweak corrections to ppâHH at the Large Hadron Collider, focusing on the dominant gluon-gluon fusion process. While the corrections at the total cross-section level are approximately -4%, those near the energy of HH production threshold exceed +15%, and corrections at the high-energy region are around -10%, leading to a shape distortion for the differential distributions. Our findings substantially diminish the theoretical uncertainties associated with this pivotal process, providing valuable input for understanding the shape of the Higgs boson potential upon comparison with experimental measurements.
RESUMEN
Objective: it aimed to explore the value of multislice helical computed tomography (MSCT) in the diagnosis and surgical treatment of primary tracheal tumors. Methods: 64 patients with the primary tracheal tumor who were diagnosed in Wuxi Second People's Hospital from March 2020 to March 2021 were selected as the research objects. MSCT imaging was performed on all patients, and suitable surgical methods. The pathological results were compared with original CT, CT virtual endoscopy (CTVE), and Comparisons were made using CT three-dimensional reconstruction images to evaluate the accuracy of MSCT diagnosis. Parameters such as postoperative complications and survival rates were observed to assess surgical effectiveness and safety. Results: Compared with original CT images (70%, 72%, 70%), the diagnostic accuracy of VR images (80%, 80%, 80%), MPVR images (85%, 90%, 92%), and CTVE images (100%, 100%, 100%) was remarkably improved (P<0.05). The three-year survival rate of patients with smooth muscle tumors, malignant tumors, salivary gland adenoma, papillary tumors, and inflammatory polyp was markedly lower than that of the one-year survival rate, with a significant difference (P<0.05). The incidence of postoperative complications was 14.1%, with three cases resulting in complication-related deaths. Conclusion: the diagnostic accuracy of MSCT imaging of primary tracheal tumor was high. The diagnostic accuracy of CTVE was higher than that of VR and MPVR. Besides, surgical treatment of primary tracheal tumor had a substantial effect, with no serious postoperative complications.
RESUMEN
Inner Mongolia cashmere goat is an excellent livestock breed formed through long-term natural selection and artificial breeding, and is currently a world-class dual-purpose breed producing cashmere and meat. Multi trait animal model is considered to significantly improve the accuracy of genetic evaluation in livestock and poultry, enabling indirect selection between traits. In this study, the pedigree, genotype, environment, and phenotypic records of early growth traits of Inner Mongolia cashmere goats were used to build multi trait animal model., Then three methods including ABLUP, GBLUP, and ssGBLUP wereused to estimate the genetic parameters and genomic breeding values of early growth traits (birth weight, weaning weight, average daily weight gain before weaning, and yearling weight). The accuracy and reliability of genomic estimated breeding value are further evaluated using the five fold cross validation method. The results showed that the heritability of birth weight estimated by three methods was 0.13-0.15, the heritability of weaning weight was 0.13-0.20, heritability of daily weight gain before weaning was 0.11-0.14, and the heritability of yearling weight was 0.09-0.14, all of which belonged to moderate to low heritability. There is a strong positive genetic correlation between weaning weight and daily weight gain before weaning, daily weight gain before weaning and yearling weight, with correlation coefficients of 0.77-0.79 and 0.56-0.67, respectively. The same pattern was found in phenotype correlation among traits. The accuracy of the estimated breeding values by ABLUP, GBLUP, and ssGBLUP methods for birth weight is 0.5047, 0.6694, and 0.7156, respectively; the weaning weight is 0.6207, 0.6456, and 0.7254, respectively; the daily weight gain before weaning was 0.6110, 0.6855, and 0.7357 respectively; and the yearling weight was 0.6209, 0.7155, and 0.7756, respectively. In summary, the early growth traits of Inner Mongolia cashmere goats belong to moderate to low heritability, and the speed of genetic improvement is relatively slow. The genetic improvement of other growth traits can be achieved through the selection of weaning weight. The ssGBLUP method has the highest accuracy and reliability in estimating genomic breeding value of early growth traits in Inner Mongolia cashmere goats, and is significantly higher than that from ABLUP method, indicating that it is the best method for genomic breeding of early growth weight in Inner Mongolia cashmere goats.
Asunto(s)
Cruzamiento , Cabras , Animales , Cabras/genética , Cabras/crecimiento & desarrollo , Fenotipo , Genómica/métodos , Femenino , Masculino , Peso al Nacer/genética , Modelos GenéticosRESUMEN
This study aims to investigate the impact of Kuntai Capsules(KTC) on polycystic ovarian syndrome(PCOS) rat models and explore the underlying mechanism. Fifty female SD rats were randomly divided into five groups(10 rats in each group), including control group, model group, low-, medium-, and high-dose KTC group. Except for the control group, the other groups were injected with dehydroepiandrosterone(DHEA) combined with a high-fat diet(HFD) to induce the PCOS rat model for 28 days. 0.315, 0.63, and 1.26 g·kg~(-1)·d~(-1) KTC was dissolved in the same amount of normal saline and given to low-, medium-, and high-dose KTC groups by gavage. Both control group and model group were given the same amount of normal saline for 15 days. After administration, fasting blood glucose(FBG) was measured by a glucose meter. Fasting insulin(FINS), luteinizing hormone(LH), testosterone(T), and follicle-stimulating hormone(FSH) were detected by enzyme-linked immunosorbent assay(ELISA), and LH/FSH ratio and insulin resistance index(HOMA-IR) were calculated. The pathological morphology of ovarian tissue was observed by hematoxylin-eosin(HE) staining. The expression levels of collagen α type â ¢ 1 chain(COL3A1), apoptotic factors Bax, and Bcl-2 were detected using Western blot and immunofluorescence. The mRNA expressions of COL3A1, Bax, and Bcl-2 in ovarian tissue were performed by real-time PCR(RT-PCR). The results show that compared with the control group, the body weight, serum levels of FBG, FINS, LH, T, LH/FSH, and HOMA-IR are higher in model group(P<0.05 or P<0.01), and the level of FSH is lower(P<0.05). In model group, a large number of white blood cells are found in the vaginal exfoliated cells, mainly in the interictal phase. There are more cystic prominences on the surface of the ovary. The thickness of the granular cell layer is reduced, and oocytes are absent. COL3A1 and Bax protein expression levels are increased(P<0.01), while Bcl-2 protein expression levels are decreased(P<0.05) in the ovarian tissue COL3A1 and Bax mRNA expression levels are increased in ovarian tissue(P<0.05). Compared with the model group, the body weight, FBG, FINS, LH, T, LH/FSH, and HOMA-IR in low-, medium-, and high-dose KTC groups are decreased(P<0.05 or P<0.01), while the levels of FSH in medium-, and high-dose KTC groups are increased(P<0.05 or P<0.01). Low-, medium-, and high-dose KTC groups gradually show a stable interictal phase. The surface of the ovary is smooth. Oocytes and mature follicles can be seen in ovarian tissue, and the thickness of the granular cell layer is increased. The expression level of COL3A1 protein decreases in low-and medium-dose KTC groups(P<0.05 or P<0.01), and that of Bax protein decreases in low-dose KTC group(P<0.05 or P<0.01), and the expression level of Bcl-2 protein increases in low-dose KTC group(P<0.01). The expression levels of COL3A1 and Bax mRNA decreased in the low-dose KTC group(P<0.05), while the expression levels of Bcl-2 mRNA increased(P<0.05). In summary, KTC can inhibit ovarian granulosa cell apoptosis and reduce follicular atresia by regulating the AGE-RAGE signaling pathway. It can promote insulin secretion, reduce blood sugar and body weight, restore serum hormone levels, improve symptoms of PCOS, alleviate morphological damage of the ovary, and restore ovarian function, which is of great value in the treatment of PCOS.
Asunto(s)
Síndrome del Ovario Poliquístico , Humanos , Ratas , Femenino , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/genética , Proteína X Asociada a bcl-2 , Solución Salina , Ratas Sprague-Dawley , Atresia Folicular , Transducción de Señal , Peso Corporal , Hormona Folículo Estimulante , ARN MensajeroRESUMEN
We report on the observation of photoassociation resonances in ultracold collisions between ^{23}Na^{40}K molecules and ^{40}K atoms. We perform photoassociation in a long-wavelength optical dipole trap to form deeply bound triatomic molecules in electronically excited states. The atom-molecule Feshbach resonance is used to enhance the free-bound Franck-Condon overlap. The photoassociation into well-defined quantum states of excited triatomic molecules is identified by observing resonantly enhanced loss features. These loss features depend on the polarization of the photoassociation lasers, allowing us to assign rotational quantum numbers. The observation of ultracold atom-molecule photoassociation resonances paves the way toward preparing ground-state triatomic molecules, provides a new high-resolution spectroscopy technique for polyatomic molecules, and is also important to atom-molecule Feshbach resonances.
RESUMEN
Objective: Therapeutic regimens are relatively scarce among patients with treatment-refractory metastatic colorectal cancer (CRC). This study aimed to determine the feasibility and tolerability of anlotinib plus PD-1 blockades in patients with treatment-refractory metastatic CRC retrospectively. Methods: A total of 68 patients with previously treated metastatic CRC who received anlotinib plus PD-1 blockades in clinical practice were included in this study retrospectively. Demographic and clinical characteristics of the patients, therapeutic outcomes and safety profile during administration were collected and briefly analyzed. All subjects were followed up regularly. Therapeutic outcomes, including drug response and prognosis, were presented, and a safety profile was depicted to illustrate the adverse reactions. Results: A total of 68 patients with treatment-refractory metastatic CRC who received anlotinib plus PD-1 blockades in clinical practice were included in the final analysis. Best therapeutic response during treatment indicated that partial response was observed in 11 patients, stable disease was noted in 41 patients, and progressive disease was found in 16 patients, producing an objective response rate of 16.2% (95% CI: 8.4%-27.1%) and a disease control rate of 76.5% (95% CI: 64.6%-85.9%). Prognostic analysis suggested that the median progression-free survival (PFS) of the 68 patients was 5.3 months (95% CI: 3.01-7.59), and the median overall survival (OS) was 12.5 months (95% CI: 9.40-15.60). Of the 11 patients who responded, the median duration of response was 6.7 months (95% CI: 2.89-10.53). Safety profile during treatment showed that patients experienced adverse reactions regardless of grade, and grade ≥3 adverse reactions were found in 61 patients (89.7%) and 41 patients (60.3%), respectively. Common adverse reactions were hypertension, myelosuppression (including leukopenia, neutropenia, thrombocytopenia, and anemia), fatigue, and hand-foot syndrome. Conclusion: Anlotinib plus PD-1 blockades demonstrated encouraging efficacy and acceptable safety profile in patients with treatment-refractory metastatic CRC preliminarily in clinical practice. This conclusion should be confirmed in prospective clinical trials.
RESUMEN
Arthritis is the most prevalent joint disease and is characterized by articular cartilage degradation, synovial inflammation, and changes in periarticular and subchondral bone. Recent studies have reported that Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) have significant effects on the proliferation, migration, and survival of chondrocytes and fibroblast-like synovial cells (FLSs). YAP/TAZ signaling pathway, as well as the related Hippo-YAP signaling pathway, are responsible for the condition of cells and articular cartilage in joints. They are tightly regulated to maintain metabolism in chondrocytes and FLSs because abnormal expression may result in cartilage damage. However, the roles and mechanisms of the Hippo-YAP pathway in arthritis remain largely unknown. This review summarizes the roles and key functions of YAP/TAZ and the Hippo-YAP signaling pathway in FLSs and chondrocytes for the induction of proliferation, migration, survival, and differentiation in rheumatoid arthritis (RA) and osteoarthritis (OA) research. We also discuss the therapeutic strategies involving YAP/TAZ and the related Hippo-YAP signaling pathway involved in OA.
RESUMEN
Pericentric inversion of chromosome 9 (inv[9]) is a common chromosomal structural variant, but its impact on clinical outcomes remains debated. The screening criteria of sperm banks are rarely mentioned to individuals with inv(9). In this study, we evaluated the fertility of sperm donors with inv(9) who met eligibility criteria for sperm banks (inv[9]-eligible donors). From March 2004 to May 2022, chromosomal analysis of 16 124 sperm donors at CITIC-Xiangya Human Sperm Bank in Hunan Province (Changsha, China) found that 251 (1.6%) had chromosome variations, with inv(9) being the most prevalent at 1.1%. All 169 inv(9)-eligible donors were contacted to collect fertility outcome data, along with 206 eligible donors without inv(9) as controls. In addition, semen samples from inv(9)-eligible donors and eligible donors underwent assessments of sperm fluorescence in situ hybridization (FISH), mitochondrial membrane potential, DNA fragmentation index, acrosome integrity, reactive oxygen species (ROS), and sperm morphology. Results showed that inv(9) did not significantly increase reproductive risks overall. Despite detecting ROS level differences, the clinical impact may be insignificant. This study provides new data on the inv(9) population that can serve as a valuable reference for decision-making by sperm banks as well as for genetic counseling and clinical guidance for individuals carrying inv(9) variant.
Asunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 9 , Espermatozoides , Donantes de Tejidos , Humanos , Masculino , Adulto , Espermatozoides/metabolismo , Cromosomas Humanos Par 9/genética , Fertilidad/genética , China , Bancos de Esperma , Hibridación Fluorescente in Situ , Fragmentación del ADNRESUMEN
Objective: Schisandrin B (Sch B) is a bioactive dibenzocyclooctadiene derizative that is prevalent in the fruit of Schisandra chinensis. Numerous studies have demonstrated that Sch B has a neuroprotective action by reducing oxidative stress and effectively preventing inflammation. It follows that Sch B is a potential treatment for Alzheimer's disease (AD). However, the drug's solubility, bioavailability, and lower permeability of the blood-brain barrier (BBB) can all reduce its efficacy during the therapy process. Therefore, this study constructed borneol-modified schisandrin B micelles (Bor-Sch B-Ms), which increase brain targeting by accurately delivering medications to the brain, effectively improving bioavailability. High therapeutic efficacy has been achieved at the pathological site. Methods: Bor-Sch B-Ms were prepared using the thin film dispersion approach in this article. On the one hand, to observe the targeting effect of borneol, we constructed a blood-brain barrier (BBB) model in vitro and studied the ability of micelles to cross the BBB. On the other hand, the distribution of micelle drugs and their related pharmacological effects on neuroinflammation, oxidative stress, and neuronal damage were studied through in vivo administration in mice. Results: In vitro studies have demonstrated that the drug uptake of bEnd.3 cells was increased by the borneol alteration on the surface of the nano micelles, implying that Bor-Sch B-Ms can promote the therapeutic effect of N2a cells. This could result in more medicines entering the BBB. In addition, in vivo studies revealed that the distribution and circulation time of medications in the brain tissue were significantly higher than those in other groups, making it more suitable for the treatment of central nervous system diseases. Conclusion: As a novel nanodrug delivery system, borneol modified schisandrin B micelles have promising research prospects in the treatment of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Barrera Hematoencefálica , Canfanos , Lignanos , Compuestos Policíclicos , Ratones , Animales , Micelas , Enfermedad de Alzheimer/tratamiento farmacológico , Células Endoteliales , CiclooctanosRESUMEN
The global practice of cryopreservation of human semen is commonplace in Assisted Reproductive Technology (ART) labs and sperm banks. However, information on the effects of long-term cryopreservation on semen is limited to clinical data summaries and descriptions. For this study, we prepared 4 semen specimens of fresh semen, 4 specimens cryostored for at least 1 year, 3 specimens cryostored for at least 5 years, 4 specimens cryostored for at least 10 years, and 3 specimens cryostored for at least 15 years. Total RNA was extracted from each sample, amplified, labeled, and mapped to the known primary microRNA (miRNA) in the miRBase database, enabling the prediction of novel miRNAs. We found that cryopreservation can lead to changes in miRNA expression, and with the increase in storage time, these changes became more pronounced. Meanwhile, the expression of let-7d-3p, let-7c-5p and let-7i-3p miRNAs changed dynamically over cryostorage time in frozen-thawed human sperm. Furthermore, we analyzed the time-dependent dynamics of cryostorage-expressed miRNAs and their target mRNAs and found that half of the target genes were expressed in oocytes. These intersection genes were mainly enriched in cancer and cytoskeletal signaling pathways. Our findings showed that the miRNA expression profile of cryopreserved human semen is modified by long-term storage. Furthermore, as the storage time increases, the impact on human sperm becomes more pronounced in terms of miRNAs, which may have an effect on subsequent fertilization and embryonic development.
Asunto(s)
MicroARNs , Semen , Embarazo , Femenino , Humanos , Masculino , Espermatozoides , Criopreservación , Bancos de Esperma , MicroARNs/genéticaRESUMEN
Two new rare trachylobane euphoratones A-B (1-2), together with five known diterpenoids (compounds 3-7), were isolated from the aerial parts of Euphorbia atoto. Their structures were unambiguously elucidated through HRESIMS, 1D and 2D NMR spectral analysis. Compounds 1, 3, 4 and 7 showed weak anti-inflammatory activities (IC50 77.49 ± 6.34, 41.61 ± 14.49, 16.00 ± 1.71 and 33.41 ± 4.52 µM, respectively), compared to the positive control quercetin (IC50 15.23 ± 0.65 µM).
Asunto(s)
Diterpenos , Euphorbia , Estructura Molecular , Euphorbia/química , Espectroscopía de Resonancia Magnética , Diterpenos/farmacología , Diterpenos/química , Antiinflamatorios/farmacología , Antiinflamatorios/químicaRESUMEN
The aggregation of α-Syn is a pivotal mechanism in Parkinson's disease (PD). Effectively maintaining α-Syn proteostasis involves both inhibiting its aggregation and promoting disaggregation. In this study, we developed a series of aromatic amide derivatives based on Rhein. Two of these compounds, 4,5-dihydroxy-N-(3-hydroxyphenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a5) and 4,5-dihydroxy-N-(2-hydroxy-4-chlorophenyl)-9,10-dioxo-9,10-dihydroanthracene-2-carboxamide (a8), exhibited good binding affinities to α-Syn residues, demonstrating promising inhibitory activity against α-Syn aggregation in vitro, with low IC50 values (1.35 and 1.08 µM, respectivly). These inhibitors acted throughout the entire aggregation process by stabilizing α-Syn's conformation and preventing the formation of ß-sheet aggregates. They also effectively disassembled preformed α-Syn oligomers and fibrils. Preliminary mechanistic insights indicated that they bound to the specific domain within fibrils, inducing fibril instability, collapse, and the formation of smaller aggregates and monomeric α-Syn units. This research underscores the therapeutic potential of Rhein's aromatic amides in targeting α-Syn aggregation for PD treatment and suggests broader applications in managing and preventing neurodegenerative diseases.
Asunto(s)
Antracenos , Enfermedad de Parkinson , Humanos , alfa-Sinucleína , Antraquinonas/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/prevención & control , Enfermedad de Parkinson/metabolismo , Antracenos/química , Antracenos/farmacologíaRESUMEN
Endoplasmic reticulum membrane protein complex subunit 6 (EMC6) plays an important function in both physiological and pathological states of cells. Nevertheless, there are few studies focused on the role of EMC6 in tumors. At first, we performed a series of bioinformatics analyses on 33 kinds of cancers, including differential expression analysis, tumor mutational burden analysis, prognostic analysis, and clinicopathological staging analysis. Then, we corroborated the important role of EMC6 in lung cancer by cytological and in vivo experiments. We found that the reduction of EMC6 expression did effectively inhibit the proliferation, invasion, and metastasis of A549. Finally, EMC6 is indeed involved in the regulation of ferroptosis, cuproptosis, and immune response in LUAD. In a word, our study not only comprehensively analyzed the functional mechanisms of EMC6 in all cancers but also validated the regulatory role of EMC6 in lung cancer for the first time.
RESUMEN
The prognosis of pancreatic adenocarcinoma (PDAC) remains poor, with a 5-year survival rate of 12%. Although radiotherapy is effective for the locoregional control of PDAC, it does not have survival benefits compared with systemic chemotherapy. Most patients with localized PDAC develop distant metastasis shortly after diagnosis. Upfront chemotherapy has been suggested so that patients with localized PDAC with early distant metastasis do not have to undergo radical local therapy. Several potential tissue markers have been identified for selecting patients who may benefit from local radiotherapy, thereby prolonging their survival. This review summarizes these biomarkers including SMAD4, which is significantly associated with PDAC failure patterns and survival. In particular, Krüppel-like factor 10 (KLF10) is an early response transcription factor of transforming growth factor (TGF)-ß. Unlike TGF-ß in advanced cancers, KLF10 loss in two-thirds of patients with PDAC was associated with rapid distant metastasis and radioresistance; thus, KLF10 can serve as a predictive and therapeutic marker for PDAC. For patients with resectable PDAC, a combination of KLF10 and SMAD4 expression in tumor tissues may help select those who may benefit the most from additional radiotherapy. Future trials should consider upfront systemic therapy or include molecular biomarker-enriched patients without early distant metastasis.