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Transcatheter aortic valve implantation (TAVI) was originally devised as a treatment for patients with aortic stenosis (AS). It has since emerged as a beneficial alternative to surgical aortic valve replacement (SAVR), extending its reach to a broader array of patients. Our objective was to illustrate the developmental trends and focus areas in TAVI research. We sourced a total of 11,480 research papers on TAVI, published between 1994 and 2022, from the Web of Science Core Collection (WoSCC) database. We conducted a bibliometric analysis of these publications, generating cooperation maps, performing co-citation analysis of journals and references, and carrying out a cluster analysis of keywords. Our findings indicate that TAVI research grapples with numerous clinical challenges. We created knowledge maps that highlight contributing countries/institutions, authors, journals with high publication and citation rates, and notable references in this domain. North America and Europe have been at the forefront of research within the TAVI field. The institutions and authors from these regions exert significant influence in this area of study. Beginning in 2009, China has progressively expanded its research on TAVI over the past two decades. We anticipate that future research will increasingly focus on three key areas: implementation scope, lifelong management, outcomes and predicting the risk of TAVI. Research on TAVI is flourishing. Cooperation among different countries and institutions in this field must be strengthened in the future, especially for developing counties.
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The industrial separation of hydrocarbons relies on distillation. Organic solvent nanofiltration can provide an energy-efficient alternative. We prepared high performance organosiloxane membranes for fractionation of heavy aromatics. They achieved a high permeance up to 0.13 L m-2 h-1 bar-1, with a rejection rate of 88.7% for hydrocarbons with five aromatic rings.
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OBJECTIVE: The single-arm, phase II SORAYA trial (NCT04296890) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)-high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. METHODS: Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. RESULTS: At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. CONCLUSION: These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.
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Anticorpos Monoclonais Humanizados , Resistencia a Medicamentos Antineoplásicos , Receptor 1 de Folato , Imunoconjugados , Maitansina , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Receptor 1 de Folato/metabolismo , Pessoa de Meia-Idade , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Maitansina/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Adulto , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
Our center has observed a substantial increase in the detection rate of fetal left-right(LR) asymmetry disorders between March and May 2023. This finding has raised concerns because these pregnant women experienced the peak outbreak of SARS-CoV-2 in China during their first trimester. To explore the relationship between maternal SARS-CoV-2 infection and fetal LR asymmetry disorders. A retrospective collection of clinical and ultrasound data diagnosed as fetal LR asymmetry disorders was conducted from January 2018 to December 2023. The case-control study involved fetuses with LR asymmetry disorders and normal fetuses in a 1:1 ratio. We evaluated and compared the clinical and fetal ultrasound findings in pregnant women with SARS-CoV-2 infection and pregnant women without infection. The Student t-test was utilized to compare continuous variables, while the chi-squared test was employed for univariable analyses. The incidence rate of LR asymmetry disorders from 2018 to 2023 was as follows: 0.17, 0.63, 0.61, 0.57, 0.59, and 3.24, respectively. A total of 30 fetuses with LR asymmetry disorders and 30 normal fetuses were included. This case-control study found that SARS-CoV-2 infection (96.67% vs 3.33%, P = .026) and infection during the first trimester (96.55% vs 3.45%, P = .008) were identified as risk factors. The odds ratio values were 10.545 (95% CI 1.227, 90.662) and 13.067 (95% CI 1.467, 116.419) respectively. In cases of SARS-CoV-2 infection in the first trimester, the majority of infections (88.1%, 37/42) occurred between 5 and 6 weeks of gestation. We found that 43.7% (66/151) of fetuses with LR asymmetry disorder had associated malformations, 90.9% (60/66) exhibited cardiac malformations. SARS-CoV-2 infection during the first trimester significantly increases the risk of fetal LR asymmetry disorders, particularly when the infection occurs between 5 and 6 gestation weeks. The most common associated malformation is heart malformation.
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COVID-19 , Complicações Infecciosas na Gravidez , Primeiro Trimestre da Gravidez , SARS-CoV-2 , Humanos , Feminino , Gravidez , COVID-19/epidemiologia , COVID-19/complicações , Complicações Infecciosas na Gravidez/epidemiologia , Adulto , Estudos Retrospectivos , Estudos de Casos e Controles , China/epidemiologia , Ultrassonografia Pré-Natal , Fatores de Risco , Feto/virologia , Doenças Fetais/epidemiologia , Doenças Fetais/virologiaRESUMO
AIMS: This study aimed to investigate the relationship between ulcerative colitis (UC) and anxiety and explore its central mechanisms using colitis mice. METHODS: Anxiety-like behavior was assessed in mice induced by 3% dextran sodium sulfate (DSS) using the elevated plus maze and open-field test. The spatial transcriptome of the hippocampus was analyzed to assess the distribution of excitatory and inhibitory synapses, and Toll-like receptor 4 (TLR4) inhibitor TAK-242 (10 mg/kg) and AAV virus interference were used to examine the role of peripheral inflammation and central molecules such as Glutamate Receptor Metabotropic 1 (GRM1) in mediating anxiety behavior in colitis mice. RESULTS: DSS-induced colitis increased anxiety-like behaviors, which was reduced by TAK-242. Spatial transcriptome analysis of the hippocampus showed an excitatory-inhibitory imbalance mediated by glutamatergic synapses, and GRM1 in hippocampus was identified as a critical mediator of anxiety behavior in colitis mice via differential gene screening and AAV virus interference. CONCLUSION: Our work suggests that the hippocampus plays an important role in brain anxiety caused by peripheral inflammation, and over-excitation of hippocampal glutamate synapses by GRM1 activation induces anxiety-like behavior in colitis mice. These findings provide new insights into the central mechanisms underlying anxiety in UC and may contribute to the development of novel therapeutic strategies for UC-associated anxiety.
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Ansiedade , Hipocampo , Inflamação , Receptores de Glutamato Metabotrópico , Animais , Masculino , Camundongos , Ansiedade/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Sulfato de Dextrana , Hipocampo/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/genéticaRESUMO
OBJECTIVE: Evaluate the antitumor activity and safety profile of the triplet combination of mirvetuximab soravtansine (MIRV), carboplatin, and bevacizumab in recurrent, platinum-sensitive ovarian cancer. METHODS: Participants with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer (1-2 prior lines of therapy) received MIRV (6 mg/kg adjusted ideal body weight), carboplatin (AUC5), and bevacizumab (15 mg/kg) once every 3 weeks. Carboplatin could be discontinued after 6 cycles per investigator discretion; continuation of MIRV+bevacizumab as maintenance therapy was permitted. Eligibility included folate receptor alpha (FRα) expression by immunohistochemistry (≥50% of cells with ≥2+ intensity; PS2+ scoring); prior bevacizumab was allowed. Tumor response, duration of response (DOR), progression-free survival (PFS), and adverse events (AEs) were assessed. RESULTS: Forty-one participants received triplet therapy, with a median of 6, 12, and 13 cycles of carboplatin, MIRV, and bevacizumab, respectively. The confirmed objective response rate was 83% (9 complete and 25 partial responses). The median DOR was 10.9 months; median PFS was 13.5 months. AEs (any grade) occurred as expected, based on each agent's safety profile; most common were diarrhea (83%), nausea (76%), fatigue (73%), thrombocytopenia (71%), and blurred vision (68%). Most cases were mild to moderate (grade ≤2), except for thrombocytopenia, for which most drug-related discontinuations occurred, and neutropenia. CONCLUSIONS: This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Carboplatina , Carcinoma Epitelial do Ovário , Receptor 1 de Folato , Imunoconjugados , Maitansina , Neoplasias Ovarianas , Humanos , Feminino , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Idoso , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Adulto , Maitansina/análogos & derivados , Maitansina/efeitos adversos , Maitansina/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Intervalo Livre de Progressão , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias das Tubas Uterinas/tratamento farmacológico , Idoso de 80 Anos ou mais , Neoplasias Peritoneais/tratamento farmacológico , Trombocitopenia/induzido quimicamenteRESUMO
Nanocatalytic tumor therapy based on Fenton nanocatalysts has attracted considerable attention because of its therapeutic specificity, enhanced outcomes, and high biocompatibility. Nevertheless, the rate-determining step in Fenton chemistry, which involves the transition of a high-valence metallic center (FeIII ) to a Fenton-active low-valence metallic center (FeII ), has hindered advances in nanocatalyst-based therapeutics. In this study, we constructed mesoporous single iron atomic nanocatalysts (mSAFe NCs) by employing catechols from dopamine to coordinate and isolate single iron atoms. The catechols also serve as reductive ligands, generating a field-effect-based cocatalytic system that instantly reduces FeIII species to FeII species within the mSAFe NCs. This self-motivated cocatalytic strategy enabled by mSAFe NCs accelerates the kinetics of the Fenton catalytic reaction, resulting in remarkable performance for nanocatalytic tumor therapy both in vitro and in vivo.
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Compostos Férricos , Neoplasias , Humanos , Ferro , Neoplasias/tratamento farmacológico , Compostos Ferrosos , Catecóis , Peróxido de Hidrogênio , CatáliseRESUMO
The clinical utilization of doxorubicin (Dox) in various malignancies is restrained by its major adverse effect: irreversible cardiomyopathy. Extensive studies have been done to explore the prevention of Dox cardiomyopathy. Currently, ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy. Sorting Nexin 3 (SNX3), the retromer-associated cargo binding protein with important physiological functions, was identified as a potent therapeutic target for cardiac hypertrophy in our previous study. However, few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy. In this study, a decreased level of SNX3 in Dox-induced cardiomyopathy was observed. Cardiac-specific Snx3 knockout (Snx3-cKO) significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly. SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro, and cardiac-specific Snx3 transgenic (Snx3-cTg) mice were more susceptible to Dox-induced ferroptosis and cardiomyopathy. Mechanistically, SNX3 facilitated the recycling of transferrin 1 receptor (TFRC) via direct interaction, disrupting iron homeostasis, increasing the accumulation of iron, triggering ferroptosis, and eventually exacerbating Dox-induced cardiomyopathy. Overall, these findings established a direct SNX3-TFRC-ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRC-dependent ferroptosis.
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BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).
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Carcinoma Epitelial do Ovário , Maitansina , Neoplasias Ovarianas , Feminino , Humanos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/uso terapêutico , Maitansina/administração & dosagem , Maitansina/efeitos adversos , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Receptor 1 de Folato/antagonistas & inibidores , Receptor 1 de Folato/genética , Resistencia a Medicamentos Antineoplásicos/genética , Compostos de Platina/farmacologiaRESUMO
Objectives: This study aimed to evaluate the feasibility of direct visualization of a normal fetal palate and detect cleft palate in the first trimester with a novel three-dimensional ultrasound (3D US) technique, Crystal and Realistic Vue (CRV) rendering technology. Methods: Two-dimensional (2D) images and 3D volumes of healthy and cleft palate fetuses at 11-13+6 weeks were obtained prospectively. 2D ultrasound views included the coronal view of the retronasal triangle and the midsagittal view of the face. 3D-CRV views were analyzed by multiplanar mode display. The pregnancy outcomes of all fetuses were determined during the follow-up period. Results: In our study, 124 fetuses were recruited, including 100 healthy fetuses and 24 cleft palate fetuses. The cleft palate with lip was observed in 23 fetuses (bilateral in 15, unilateral in 6, median in 2), and one cleft palate was only found in the abnormal group. The bilateral (n = 12) and median (n = 2) cleft palates with lips and the cleft palate alone (n = 1) were associated with other anatomical or chromosomal abnormalities, and one unilateral cleft palate with cleft lip had concomitant NT thickening. In the cleft palate fetus group, 16 fetuses suffered intrauterine death, which was associated with other structural or chromosomal abnormalities in 14 fetuses, seven cases were terminated after consultation, and one was delivered at term. The coronal view of the retronasal triangle and the midsagittal view was easily obtained in all fetuses. 3D-CRV images of palatal parts were clearly obtained in all cases. Unilateral, bilateral, and median cleft palates with cleft lips were visually demonstrated and classified by the 3D-CRV technique. Conclusion: It is feasible to identify the palate by 3D-CRV in the first trimester in both healthy and cleft palate fetuses. Together with 2D ultrasonography as a complementary diagnostic tool, 3D-CRV is helpful in classifying the cleft palate with a reasonable degree of certainty.
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Endometrial cancer (EC) is a prevalent epithelial malignancy in the uterine corpus's endometrium and myometrium. Regulating apoptosis of endometrial cancer cells has been a promising approach for treating EC. Recent in-vitro and in-vivo studies show that numerous extracts and monomers from natural products have pro-apoptotic properties in EC. Therefore, we have reviewed the current studies regarding natural products in modulating the apoptosis of EC cells and summarized their potential mechanisms. The potential signaling pathways include the mitochondria-dependent apoptotic pathway, endoplasmic reticulum stress (ERS) mediated apoptotic pathway, the mitogen-activated protein kinase (MAPK) mediated apoptotic pathway, NF-κB-mediated apoptotic pathway, PI3K/AKT/mTOR mediated apoptotic pathway, the p21-mediated apoptotic pathway, and other reported pathways. This review focuses on the importance of natural products in treating EC and provides a foundation for developing natural products-based anti-EC agents.
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Irritable bowel syndrome (IBS) and ulcerative colitis (UC) are two intestinal diseases with different pathological changes. Electroacupuncture (EA) at Zusanli (ST36) on both IBS and UC is widely used in clinic practice. But it is unclear whether acupuncture at one acupoint can treat two different intestinal diseases at different layers of intestinal barrier. To address this question, we explored three intestinal barrier lesions in IBS and UC mice with the aid of transcriptome data analysis and studied the efficacy of EA at ST36 on them. The transcriptome data analysis showed that both UC and IBS had disrupted intestinal barrier in various layers. And both UC and IBS had epithelial barrier lesions with reduction of ZO-1, Occludin and Claudin-1, while UC rather than IBS had the destruction of the mucus barrier with less MUC2 expression. As to the vascular barrier, UC showed a higher CD31 level and mesenteric blood flow reduction, while IBS showed a lower PV-1 level. EA at ST36 can significantly improve the above lesions of intestinal barrier of IBS and UC. Our results gave more details about the comprehensive protective effect of EA for UC and IBS. We guess the effect of acupuncture may be a kind of homeostasis regulation.
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Colite Ulcerativa , Eletroacupuntura , Síndrome do Intestino Irritável , Camundongos , Animais , Síndrome do Intestino Irritável/terapia , Síndrome do Intestino Irritável/patologia , Colite Ulcerativa/terapia , Colite Ulcerativa/patologia , Eletroacupuntura/métodos , Intestinos/patologia , Pontos de AcupunturaRESUMO
Introduction: Chromoblastomycosis (CBM) is a form of chronic mycosis that affects the skin and mucous membranes and is caused by species of dematiaceous fungi including Exophiala spp., Phialophora spp., and Fonsecaea spp. The persistence of this disease and limitations associated with single-drug treatment have complicated efforts to adequately manage this condition. Methods: In this study, a microdilution assay was used to explore the synergistic antifungal activity of everolimus (EVL) in combination with itraconazole (ITC), voriconazole (VRC), posaconazole (POS), and amphotericin B (AMB) against a range of clinical dematiaceous fungal isolates. Results: These analyses revealed that the EVL+POS and EVL+ITC exhibited superior in vitro synergistic efficacy, respectively inhibiting the growth of 64% (14/22) and 59% (13/22) of tested strains. In contrast, the growth of just 9% (2/22) of tested strains was inhibited by a combination of EVL+AMB, and no synergistic efficacy was observed for the combination of EVL+VRC. Discussion: Overall, these findings indicate that EVL holds promise as a novel drug that can be synergistically combined with extant antifungal drugs to improve their efficacy, thereby aiding in the treatment of CBM.
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Antifúngicos , Micoses , Humanos , Antifúngicos/farmacologia , Everolimo/uso terapêutico , Anfotericina B/farmacologia , Micoses/tratamento farmacológico , Voriconazol , Testes de Sensibilidade Microbiana , FungosRESUMO
This review outlined evidence that purinergic signaling is involved in the modulation of blood-brain barrier (BBB) permeability. The functional and structural integrity of the BBB is critical for maintaining the homeostasis of the brain microenvironment. BBB integrity is maintained primarily by endothelial cells and basement membrane but also be regulated by pericytes, neurons, astrocytes, microglia and oligodendrocytes. In this review, we summarized the purinergic receptors and nucleotidases expressed on BBB cells and focused on the regulation of BBB permeability by purinergic signaling. The permeability of BBB is regulated by a series of purinergic receptors classified as P2Y1, P2Y4, P2Y12, P2X4, P2X7, A1, A2A, A2B, and A3, which serve as targets for endogenous ATP, ADP, or adenosine. P2Y1 and P2Y4 antagonists could attenuate BBB damage. In contrast, P2Y12-mediated chemotaxis of microglial cell processes is necessary for rapid closure of the BBB after BBB breakdown. Antagonists of P2X4 and P2X7 inhibit the activation of these receptors, reduce the release of interleukin-1 beta (IL-1ß), and promote the function of BBB closure. In addition, the CD39/CD73 nucleotidase axis participates in extracellular adenosine metabolism and promotes BBB permeability through A1 and A2A on BBB cells. Furthermore, A2B and A3 receptor agonists protect BBB integrity. Thus, the regulation of the BBB by purinergic signaling is complex and affects the opening and closing of the BBB through different pathways. Appropriate selective agonists/antagonists of purinergic receptors and corresponding enzyme inhibitors could modulate the permeability of the BBB, effectively delivering therapeutic drugs/cells to the central nervous system (CNS) or limiting the entry of inflammatory immune cells into the brain and re-establishing CNS homeostasis.
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Accumulating evidence shows that the abnormal increase in the mortality of intestinal epithelial cells (IECs) caused by apoptosis, pyroptosis, and necroptosis is closely related to the function of mucous membrane immunity and barrier function in patients with ulcerative colitis (UC). As a procedural death path that integrates the above-mentioned many deaths, the role of PANoptosis in UC has not been clarified. This study aims to explore the characterization of PANoptosis patterns and determine the potential biomarkers and therapeutic targets. We constructed a PANoptosis gene set and revealed significant activation of PANoptosis in UC patients based on multiple transcriptome profiles of intestinal mucosal biopsies from the GEO database. Comprehensive bioinformatics analysis revealed five key genes (ZBP1, AIM2, CASP1/8, IRF1) of PANoptosome with good diagnostic value and were highly correlated with an increase in pro-inflammatory immune cells and factors. In addition, we established a reliable ceRNA regulatory network of PANoptosis and predicted three potential small-molecule drugs sharing calcium channel blockers that were identified, among which flunarizine exhibited the highest correlation with a high binding affinity to the targets. Finally, we used the DSS-induced colitis model to validate our findings. This study identifies key genes of PANoptosis associated with UC development and hypothesizes that IRF1 as a TF promotes PANoptosome multicomponent expression, activates PANoptosis, and then induces IECs excessive death.
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Colite Ulcerativa , Colite , Humanos , Colite Ulcerativa/genética , Apoptose , Biópsia , Bloqueadores dos Canais de CálcioRESUMO
Background: Aloe vera is a medically valuable plant with anti-epileptic activity; however, its mechanism of action remains unknown. In this study, network pharmacological, in vitro, and in vivo experiments were carried out to explore the potential anti-epileptic components and targets of Aloe vera. Methods: The main active components of Aloe vera were identified by searching the Traditional Chinese Medicine System Pharmacology database. Targets of Aloe vera were predicted using SwissTargetPrediction, whereas information about the epilepsy disease targets was obtained from Gene Cards. The protein-protein interaction network and core targets were screened according to the topological structure and CytoNCA plugin. The glutamate-induced HT22 cell line and pentylenetetrazol-induced seizure rats were used to confirm the effect of aloesone by detecting reactive oxygen species (ROS) and apoptosis, and predicting the targets. Results: A total of 14 core active components were selected based on the screening criteria of oral bioavailability ≥30% and drug-likeness ≥ 0.10. Four compounds, namely linoleic acid, aloesone, isoeleutherol glucosiden qt, and anthranol, demonstrated the potential ability of crossing the blood-brain barrier. A total of 153 targets associated with epilepsy were predicted for the four compounds. Moreover, after network analysis with CytoNCA, 10 targets, namely, MAPK1, SRC, MARK3, EGFR, ESR1, PTGS2, PTPN11, JAK2, PPKCA, and FYN, were selected as the core genes, and SRC, which has been predicted to be the target of aloesone and anthranol, exhibited the highest subgraph centrality value. In vitro experiments confirmed that aloesone treatment significantly inhibited the glutamate-induced neuronal injury by reducing the intracellular ROS content and the early phase of apoptosis. Additionally, treatment with 50 mg/kg aloesone resulted in anti-seizure effects by reducing the seizure score and prolonging the latent period in acute and chronic rats. Furthermore, aloesone treatment increased the phosphorylation of c-SRC at Y418 and reduced the phosphorylation at Y529, simultaneously activating c-SRC. Conclusion: Integrating network pharmacology with in vitro and in vivo experiments demonstrated that aloesone, which inhibited seizure by activating c-SRC, is a potential anti-seizure compound present in Aloe vera.
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Background: Hyperglycaemia in pregnancy (HIP) is closely associated with short- and long-term adverse fetal and maternal outcomes. However, the screening and diagnostic strategies for pregnant women with risk factors for HIP are not set. This prospective study aimed to explore a screening strategy for women at high risk for HIP. Methods: A total of 610 pregnant women were divided into experimental (n=305) and control (n=305) groups. Pregnant women underwent a 75-g OGTT in early (<20 weeks), middle (24-28 weeks), and late pregnancy (32-34 weeks) in the experimental group and only in middle pregnancy in the control group. The general conditions, HIP diagnosis, and perinatal outcomes of the two groups were compared. Results: In the experimental group, HIP was diagnosed in 29.51% (90/305), 13.44% (41/305), and 10.49% (32/305) of patient in early, middle, and late pregnancy, respectively. The total HIP diagnosis rate was significantly higher in the experimental group (53.44% vs. 35.74%, P<0.001). Multivariate logistic regression analysis revealed that previous gestational diabetes mellitus (GDM) (odds ratio, OR=9.676, P<0.001), pre-pregnancy body mass index (BMI) ≥23 kg/m2 (OR=4.273, P<0.001), and maternal age ≥35 years (OR=2.377, P=0.010) were risk factors for HIP diagnosis in early pregnancy. Previous GDM (OR=8.713, P=0.002) was a risk factor for HIP diagnosis in late pregnancy. No significant differences in perinatal clinical data were observed between the experimental and control groups. The gestational age at delivery was significantly earlier in the experimental subgroup with early-HIP than in the experimental and control subgroups with normal blood glucose (NBG). The weight gain during pregnancy was lower in the experimental early-HIP, middle-HIP, and control NBG subgroups. Conclusions: We recommend sequential screening in early and middle pregnancy for high-risk pregnant women with maternal age ≥35 years or pre-pregnancy BMI ≥23 kg/m2, and in early, middle, and late pregnancy for high-risk pregnant women with a previous history of GDM. Trial Registration: This study was registered in the Chinese Clinical Trial Registry (no. ChiCTR2000041278).
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Diabetes Gestacional , Hiperglicemia , Adulto , Índice de Massa Corporal , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/epidemiologia , Feminino , Humanos , Hiperglicemia/diagnóstico , Gravidez , Estudos Prospectivos , Aumento de PesoRESUMO
AIM: A prenatal diagnosis of coarctation of the aorta (CoA) is challenging. This study aimed to develop a coarctation probability model incorporating prenatal cardiac sonographic markers to estimate the probability of an antenatal diagnosis of CoA. METHODS: We reviewed 89 fetuses as an investigation cohort with prenatal suspicion for CoA and categorized them into three subgroups: severe CoA: symptomatic CoA and surgery within the first 3 months; mild CoA: surgery within 4 months to 1 year (29); and false-positive CoA: not requiring surgery (45). Logistic regression was used to create a multiparametric model, and a validation cohort of 86 fetuses with suspected CoA was used to validate the model. RESULTS: The prediction model had an optimal criterion >0.25 (sensitivity of 97.7%; specificity of 59.1%), and the area under the receiver operator curve was 0.85. The parameters and their cut-off values were as follows: left common carotid artery to left subclavian artery distance/distal transverse arch (LCCA-LSCA)/DT Index >1.77 (sensitivity 62%, specificity 88%, 95% confidence interval [CI]: 0.6-0.8), and z-score of AAo peak Doppler > -1.7 (sensitivity 77%, specificity 56%, 95% CI: 0.6-0.8). The risk assessment demonstrated that fetuses with a model probability >60% should have inpatient observation for a high risk of CoA, whereas fetuses with a model probability <15% should not undergo clinical follow-up. CONCLUSION: The probability model performs well in predicting CoA outcomes postnatally and can also improve the accuracy of risk assessment. The objectivity of its parameters may allow its implementation in multicenter studies of fetal cardiology.
Assuntos
Coartação Aórtica , Feminino , Humanos , Recém-Nascido , Gravidez , Aorta Torácica/diagnóstico por imagem , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/cirurgia , Feto , Modelos Estatísticos , Prognóstico , Estudos Retrospectivos , Sensibilidade e Especificidade , Ultrassonografia Pré-NatalRESUMO
Skin temperature is an important physiological parameter that reflects human thermal sensation. However, it is uncertain whether it can evaluate overall thermal sensation in non-uniform thermal environments. This study aims to explore the feasibility of using skin temperature to predict overall thermal sensation in non-uniform environments. The overall thermal sensation votes and skin temperatures were obtained in a non-uniform thermal environment with local cooling on the chest in a climate chamber. The predictive power of the representative skin temperature (RST) estimated from five different methods was examined by analysing its sensitivity and the correlation between the overall thermal sensation and the RST. The RSTs estimated from the 7-point method with the measurement site of trunk assigned on the chest and the 1-point method with a measurement site at the centre of the chest had high sensitivity and coefficients of determination. They could reflect overall thermal sensation in the non-uniform environments with local cooling on the chest. The results imply that skin temperature could be used to evaluate overall thermal sensation in non-uniform environments. The overall thermal sensation in non-uniform environments can be evaluated by the RST if, when determining the RST, the measuring site exposed to local cooling is involved and given a high weight.