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1.
Int J Surg Case Rep ; 121: 109965, 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38981294

RESUMEN

INTRODUCTION AND IMPORTANCE: Spontaneous ovarian luteal hyperfunction after pregnancy is associated with activating mutations in the follicle-stimulating hormone receptor gene, and clarification of the etiology can help with subsequent treatment. PRESENTATION OF CASE: A 32-year-old woman presented with enlarged ovaries and bilateral ovarian polycystic echoes at 12 weeks of both pregnancies. The first pregnancy underwent transabdominal bilateral ovarian aspiration at 17 weeks and was spontaneously aborted 4 days after the procedure. After the discovery of bilateral ovarian polycystic echoes in the second pregnancy, genetic testing suggested the presence of activating mutations in the follicle-stimulating hormone receptor (FSHR) gene, resulting in ovarian luteinization, and the patient's condition was stabilized after conservative treatment. CLINICAL DISCUSSION: Ovarian luteal hyperfunction may be associated with hyperandrogenemia, thyroid-stimulating hormone abnormalities, abnormal testosterone levels, and genetic mutations. When ovarian luteal hyperfunction occurs, it is recommended to search for the etiology and treat the symptoms. CONCLUSION: Patients presenting with spontaneous ovarian hyperlutealization should be operated on cautiously, treated conservatively, closely observed, and managed for complications, and genetic testing should be performed to clarify the etiology if necessary.

2.
Commun Biol ; 7(1): 848, 2024 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-38992164

RESUMEN

Filamentous fungi produce polysaccharide-degrading enzymes, which is controlled by poorly understood transcriptional circuits. Here we show that a circuit comprising RsrC-RsrA-RsrB (Rsr: production of raw-starch-degrading enzyme regulator) that positively regulates production of raw starch-degrading enzymes in Penicillium oxalicum. Transcription factor (TF) RsrA is essential for biosynthesis of raw starch-degrading enzymes. RsrB and RsrC containing Zn2Cys6- and C2H2-zinc finger domains, act downstream and upstream of RsrA, respectively. RsrA activates rsrB transcription, and three nucleotides (G-286, G-287 and G-292) of rsrB promoter region are required for RsrA, in terms of TF, for binding. RsrB165-271 binds to DNA sequence 5'-TCGATCAGGCACGCC-3' in the promoter region of the gene encoding key raw-starch-degrading enzyme PoxGA15A. RsrC specifically binds rsrA promoter, but not amylase genes, to positively regulate the expression of rsrA and the production of raw starch-degrading enzymes. These findings expand complex regulatory network of fungal raw starch-degrading enzyme biosynthesis.


Asunto(s)
Proteínas Fúngicas , Regulación Fúngica de la Expresión Génica , Penicillium , Factores de Transcripción , Penicillium/genética , Penicillium/metabolismo , Penicillium/enzimología , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Regiones Promotoras Genéticas , Polisacáridos/metabolismo , Polisacáridos/biosíntesis , Redes Reguladoras de Genes
3.
World J Surg Oncol ; 22(1): 187, 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39039538

RESUMEN

BACKGROUND: The cranial-caudal-medial approach (CCMA) has been proposed for laparoscopic right hemicolectomy nowadays. This study aimed to investigate the safety and oncological efficacy of CCMA in the treatment of right-sided colon cancer compared to the medial-lateral approach (MLA). METHODS: Patients diagnosed with right-sided colon cancer were included from February 2015 to June 2018, retrospectively, dividing into the CCMA group and the MLA group. We compared the basic characteristics and the short-term and long-term outcomes in two groups. RESULTS: Two hundred and ninety-six patients were included in this study. The baseline characteristics were similar in two groups. Compared with MLA group, CCMA group exhibited shorter operation time (136.3 ± 25.3 min vs. 151.6 ± 21.5 min, P < 0.001), lower estimated blood loss (44.1 ± 15.2 ml vs. 51.4 ± 26.9 min, P = 0.010), and more harvested lymph nodes (18.5 ± 7.1 vs. 16.5 ± 5.7, P = 0.021). The 5-year overall survival (OS) rate for the CCMA group was 76.5%, and the 5-year disease-free survival (DFS) rate was 72.3%, both of which were not inferior to the MLA group. No significant difference was found between two groups in terms of other clinical parameters. CONCLUSION: The CCMA in laparoscopic right hemicolectomy is safe and feasible, making the anatomical plane clearer. This approach can shorten the operation time, reduce intraoperative blood loss, harvest more lymph nodes, and yield satisfactory oncological outcomes.


Asunto(s)
Colectomía , Neoplasias del Colon , Laparoscopía , Puntaje de Propensión , Humanos , Colectomía/métodos , Femenino , Masculino , Laparoscopía/métodos , Estudios Retrospectivos , Neoplasias del Colon/cirugía , Neoplasias del Colon/patología , Persona de Mediana Edad , Tasa de Supervivencia , Estudios de Seguimiento , Anciano , Tempo Operativo , Pronóstico
4.
Obes Surg ; 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39042305

RESUMEN

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has emerged as the predominant metabolic bariatric surgery. With a growing number of studies evaluating the feasibility of robotic sleeve gastrectomy (RSG), it becomes imperative to ascertain whether the outcomes of both techniques are comparable. This study endeavors to synthesize existing evidence and juxtapose the surgical outcomes of LSG and RSG. METHODS: We collected articles comparing LSG and RSG published between 2011 and 2024. The compiled data included author names, study duration, sample size, average age, gender distribution, geographical location, preoperative body mass index (BMI), bougie diameter, duration of hospitalization, surgical duration, readmission rates, conversion rates, costs, postoperative percentage of excess weight loss (%EWL), postoperative BMI, mortality rates, and complications. RESULTS: We incorporated 21 articles. Both the RSG and LSG cohorts exhibited comparable rates of readmission, conversion, mortality, and incidence of complications (p > 0.05). Moreover, the efficacy of weight loss was similar between RSG and LSG. Nonetheless, RSG was linked to longer operative duration (WMD, -27.50 minutes; 95% confidence interval [CI], -28.82 to -26.18; p < 0.0001), prolonged hospitalization (WMD, -0.15 days; 95% CI, -0.25 to -0.04; p = 0.006), and elevated expenses (WMD, -5830.9 dollars; 95% CI, -8075.98 to -3585.81; p < 0.0001). CONCLUSIONS: While both RSG and LSG demonstrated positive postoperative clinical outcomes, RSG patients experienced extended hospital stays, longer operative times, and increased hospitalization costs compared to LSG patients. Using the robotic platform for sleeve gastrectomy (SG) in patients with obesity did not appear to offer any clear benefits.

5.
Appl Environ Microbiol ; : e0039024, 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39023351

RESUMEN

Filamentous fungi can produce raw-starch-degrading enzyme, however, regulation of production of raw-starch-degrading enzyme remains poorly understood thus far. Here, two novel transcription factors raw-starch-degrading enzyme regulator D (RsrD) and raw-starch-degrading enzyme regulator E (RsrE) were identified to participate in the production of raw-starch-degrading enzyme in Penicillium oxalicum. Individual knockout of rsrD and rsrE in the parental strain Δku70 resulted in 31.1%-92.9% reduced activity of raw-starch-degrading enzyme when cultivated in the presence of commercial starch from corn. RsrD and RsrE contained a basic leucine zipper and a Zn2Cys6-type DNA-binding domain, respectively, but with unknown functions. RsrD and RsrE dynamically regulated the expression of genes encoding major amylases over time, including raw-starch-degrading glucoamylase gene PoxGA15A and α-amylase gene amy13A. Interestingly, RsrD and RsrE regulated each other at transcriptional level, through binding to their own promoter regions; nevertheless, both failed to bind to the promoter regions of PoxGA15A and amy13A, as well as the known regulatory genes for regulation of amylase gene expression. RsrD appears to play an epistatic role in the module RsrD-RsrE on regulation of amylase gene expression. This study reveals a novel regulatory pathway of fungal production of raw-starch-degrading enzyme.IMPORTANCETo survive via combating with complex extracellular environment, filamentous fungi can secrete plant polysaccharide-degrading enzymes that can efficiently hydrolyze plant polysaccharide into glucose or other mono- and disaccharides, for their nutrients. Among the plant polysaccharide-degrading enzymes, raw-starch-degrading enzymes directly degrade and convert hetero-polymeric starch into glucose and oligosaccharides below starch gelatinization temperature, which can be applied in industrial biorefinery to save cost. However, the regulatory mechanism of production of raw-starch-degrading enzyme in fungi remains unknown thus far. Here, we showed that two novel transcription factors raw-starch-degrading enzyme regulator D (RsrD) and raw-starch-degrading enzyme regulator E (RsrE) positively regulate the production of raw-starch-degrading enzyme by Penicillium oxalicum. RsrD and RsrE indirectly control the expression of genes encoding enzymes with amylase activity but directly regulate each other at transcriptional level. These findings expand diversity of gene expression regulation in fungi.

6.
Oncotarget ; 15: 424-438, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38953895

RESUMEN

Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.


Asunto(s)
Combinación de Medicamentos , Sinergismo Farmacológico , Neoplasias Gastrointestinales , Mutación , Células Madre Neoplásicas , Neovascularización Patológica , Compuestos de Fenilurea , Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas p21(ras) , Piridinas , Pirrolidinas , Factor de Transcripción STAT3 , Timina , Trifluridina , Uracilo , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Trifluridina/farmacología , Compuestos de Fenilurea/farmacología , Animales , Piridinas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/metabolismo , Uracilo/farmacología , Uracilo/análogos & derivados , Ratones , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Timina/farmacología , Línea Celular Tumoral , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Angiogénesis
7.
World J Psychiatry ; 14(6): 938-944, 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38984341

RESUMEN

BACKGROUND: The generalized tonic-clonic seizure (GTCS) is the most usual variety of epileptic seizure. It is mainly characterized by strong body muscle rigidity, loss of consciousness, a disorder of plant neurofunction, and significant damage to cognitive function. The effect of antiepileptic drugs on cognition should also be considered. At present, there is no effective treatment for patients with epilepsy, but traditional Chinese medicine has shown a significant effect on chronic disease with fewer harmful side effects and should, therefore, be considered for the therapy means of epilepsy with cognitive dysfunction. AIM: To investigate the clinical efficacy of Baijin pills for treating GTCS patients with cognitive impairment. METHODS: This prospective study enrolled patients diagnosed with GTCS between January 2020 and December 2023 and separate them into two groups (experimental and control) using random number table method. The control group was treated with sodium valproate, and the experimental group was Baijin pills and sodium valproate for three months. The frequency and duration of each seizure, the Montreal Cognitive Assessment Scale (MoCA), and the Quality of Life Rating Scale (QOLIE-31) were recorded before and after treatment. RESULTS: There were 85 patients included (42 in the control group and 43 in the experimental group). After treatment, the seizure frequency in the experimental group was significantly reduced (P < 0.05), and seizure duration was shortened (P < 0.01). The total MoCA score in the experimental group significantly increased compared to before treatment (P < 0.01), and the sub-item scores, except naming and abstract generalization ability, significantly increased (P < 0.05), whereas the total MoCA score in the control group significantly decreased after treatment (P < 0.05). The QOLIE-31 score of the experimental group increased significantly after treatment compared to before treatment (P < 0.01). CONCLUSION: Baijin pills have a good clinical effect on epilepsy with cognitive dysfunction.

8.
Langenbecks Arch Surg ; 409(1): 216, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-39008130

RESUMEN

PURPOSE: The percentage of retroperitoneal sarcomas (RPS) among all soft tissue sarcomas ranges from 10 to 15%. Surgery remains the gold standard for RPS. In this study, we analyzed the impact of surgical treatment for primary RPS on recurrence and overall mortality at a Chinese institution and identified and evaluated prognostic variables. METHODS: Data from patients with RPS who underwent surgical treatment were retrospectively analyzed. The patients were treated at a single center from January 2000 to June 2018. Retrospectively collected demographic, clinicopathological, and surgical factors were examined. Overall survival (OS) and disease-free survival (DSF) were used as the primary endpoints. Predicted 5-year survival rates, encompassing both DFS and OS, were derived from the Sarculator prognostic nomogram. RESULTS: A total of 110 patients met the inclusion criteria. The median follow-up time after surgery for patients with primary RPS was 5.3 years. During this period, 59 patients died. The 5-year OS and DFS estimates were 63.5% and 35.3%, respectively. In a multivariate analysis, poor OS following surgical treatment of primary RPS was independently correlated with FNCLCC grade (p < 0.001) and surgical margin status (p = 0.016). FNCLCC grade (p = 0.001) and surgical margin status (p = 0.002) were also independently associated with poor DFS. The C-indices for 5-year OS and DFS survival utilizing the Sarculator prognostic nomogram were 0.71 and 0.73 respectively. CONCLUSION: The overall mortality rate of patients with RPS was considered acceptable. OS and DFS prognostic markers were established for primary RPS. Tumor grade and intraregional margins are other factors that affect survival and recurrence.


Asunto(s)
Neoplasias Retroperitoneales , Sarcoma , Humanos , Neoplasias Retroperitoneales/cirugía , Neoplasias Retroperitoneales/mortalidad , Neoplasias Retroperitoneales/patología , Masculino , Femenino , Persona de Mediana Edad , Sarcoma/cirugía , Sarcoma/mortalidad , Sarcoma/patología , Estudios Retrospectivos , Pronóstico , Adulto , Anciano , Tasa de Supervivencia , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Supervivencia sin Enfermedad , Márgenes de Escisión , Adulto Joven
9.
J Clin Invest ; 134(14)2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-39007268

RESUMEN

Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.


Asunto(s)
Apoptosis , Neoplasias , Transducción de Señal , Proteína p53 Supresora de Tumor , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Neoplasias/genética , Apoptosis/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética
11.
Aging Dis ; 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38913043

RESUMEN

Cellular senescence, characterized by irreversible cell cycle arrest, not only exists in age-related physiological states, but has been found to exist in various diseases. It plays a crucial role in both physiological and pathological processes and has become a trending topic in global research in recent years. Acute liver injury (ALI) has a high incidence worldwide, and recent studies have shown that hepatic senescence can be induced following ALI. Therefore, we reviewed the significance of cellular senescence in ALI. To minimize the potential confounding effects of aging on cellular senescence and ALI outcomes, we selected studies involving young individuals to identify the characteristics of senescent cells, the value of cellular senescence in liver repair, its regulation mechanisms in ALI, its potential as a biomarker for ALI, the prospect of treatment, and future research directions.

12.
J Environ Manage ; 364: 121311, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38875977

RESUMEN

Soil salinization and sodification, the primary causes of land degradation and desertification in arid and semi-arid regions, demand effective monitoring for sustainable land management. This study explores the utility of partial least square (PLS) latent variables (LVs) derived from visible and near-infrared (Vis-NIR) spectroscopy, combined with remote sensing (RS) and auxiliary variables, to predict electrical conductivity (EC) and sodium absorption ratio (SAR) in northern Xinjiang, China. Using 90 soil samples from the Karamay district, machine learning models (Random Forest, Support Vector Regression, Cubist) were tested in four scenarios. Modeling results showed that RS and Land use alone were unreliable predictors, but the addition of topographic attributes significantly improved the prediction accuracy for both EC and SAR. The incorporation of PLS LVs derived from Vis-NIR spectroscopy led to the highest performance by the Random Forest model for EC (CCC = 0.83, R2 = 0.80, nRMSE = 0.48, RPD = 2.12) and SAR (CCC = 0.78, R2 = 0.74, nRMSE = 0.58, RPD = 2.25). The variable importance analysis identified PLS LVs, certain topographic attributes (e.g., valley depth, elevation, channel network base level, diffuse insolation), and specific RS data (i.e., polarization index of VV + VH) as the most influential predictors in the study area. This study affirms the efficiency of Vis-NIR data for digital soil mapping, offering a cost-effective solution. In conclusion, the integration of proximal soil sensing techniques and highly relevant topographic attributes with the RF model has the potential to yield a reliable spatial model for mapping soil EC and SAR. This integrated approach allows for the delineation of hazardous zones, which in turn enables the consideration of best management practices and contributes to the reduction of the risk of degradation in salt-affected and sodicity-affected soils.


Asunto(s)
Salinidad , Suelo , Suelo/química , China , Monitoreo del Ambiente/métodos , Tecnología de Sensores Remotos , Análisis de los Mínimos Cuadrados
13.
BMC Infect Dis ; 24(1): 567, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38844850

RESUMEN

This study investigates the longitudinal dynamic changes in immune cells in COVID-19 patients over an extended period after recovery, as well as the interplay between immune cells and antibodies. Leveraging single-cell mass spectrometry, we selected six COVID-19 patients and four healthy controls, dissecting the evolving landscape within six months post-viral RNA clearance, alongside the levels of anti-spike protein antibodies. The T cell immunophenotype ascertained via single-cell mass spectrometry underwent validation through flow cytometry in 37 samples. Our findings illuminate that CD8 + T cells, gamma-delta (gd) T cells, and NK cells witnessed an increase, in contrast to the reduction observed in monocytes, B cells, and double-negative T (DNT) cells over time. The proportion of monocytes remained significantly elevated in COVID-19 patients compared to controls even after six-month. Subpopulation-wise, an upsurge manifested within various T effector memory subsets, CD45RA + T effector memory, gdT, and NK cells, whereas declines marked the populations of DNT, naive and memory B cells, and classical as well as non-classical monocytes. Noteworthy associations surfaced between DNT, gdT, CD4 + T, NK cells, and the anti-S antibody titer. This study reveals the changes in peripheral blood mononuclear cells of COVID-19 patients within 6 months after viral RNA clearance and sheds light on the interactions between immune cells and antibodies. The findings from this research contribute to a better understanding of immune transformations during the recovery from COVID-19 and offer guidance for protective measures against reinfection in the context of viral variants.


Asunto(s)
COVID-19 , Citometría de Flujo , Leucocitos Mononucleares , ARN Viral , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/sangre , COVID-19/virología , Leucocitos Mononucleares/virología , Leucocitos Mononucleares/inmunología , SARS-CoV-2/inmunología , Masculino , Femenino , Persona de Mediana Edad , ARN Viral/sangre , Adulto , Estudios Longitudinales , Análisis de la Célula Individual/métodos , Células Asesinas Naturales/inmunología , Anticuerpos Antivirales/sangre , Inmunofenotipificación , Anciano
14.
Bioorg Med Chem ; 108: 117787, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38838580

RESUMEN

19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides (H1-H19) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides (J1-J5) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the ß2-adrenergic receptor (ß2AR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at ß2AR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against ß2AR than Cmpd-15, the first reported ß2AR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for ß2AR. Furthermore, the active pyrazole derivatives have relative better drug-like profiles than Cmpd-15. Taken together, we discovered a series of derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides as a novel scaffold of ß2AR NAM.


Asunto(s)
Receptores Adrenérgicos beta 2 , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 2/química , Regulación Alostérica/efectos de los fármacos , Humanos , Relación Estructura-Actividad , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Estructura Molecular , Antagonistas de Receptores Adrenérgicos beta 2/farmacología , Antagonistas de Receptores Adrenérgicos beta 2/química , Antagonistas de Receptores Adrenérgicos beta 2/síntesis química
15.
Biochem Pharmacol ; 226: 116360, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38871334

RESUMEN

NLRP3 inflammasome plays an important role in autoimmunity and the dysregulation of NLRP3 inflammasome can lead to various human diseases. Natural products are an important source for the discovery of safe and effective inflammatory inhibitors. Chloranthalactone B (CTB), a lindenane sesquiterpenoid (LS) from a common traditional Chinese medicine (TCM) (Sarcandra glabra), could significantly inhibit the level of IL-1ß. This study aims to investigate the anti-inflammatory mechanism and target of CTB and its therapeutic effects on inflammatory diseases. CTB significantly inhibited IL-1ß secretion induced by different agonists. Co-IP and flow cytometry results showed that CTB inhibited NLRP3-NEK7 interactions, but had no significant effect on upstream events. Pull-down, DARTS, CETSA, biolayer interferometry assay (BLI), and LC/MS/MS results showed that CTB could covalently bind to cysteine 279 (Cys279) in the NACHT domain of NLRP3. The result of the chemical modification indicated that the epoxide motif was the key group of CTB for its anti-inflammatory effect of CTB. Further animal studies showed that CTB significantly reduced the symptoms and inflammation levels of gout, peritonitis, and acute lung injury. However, the protective effect of CTB against peritonitis and gout was abolished in NLRP3-knocked out (NLRP3 KO) mice. Overall, our research revealed that CTB was a specific NLRP3 covalent inhibitor, and epoxide motif was an active pharmacophore that covalently binds to NLRP3, which provided new insights in designing new NLRP3 inhibitors for treating NLRP3-driven diseases.

16.
Front Vet Sci ; 11: 1406576, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38840635

RESUMEN

Introduction: Dehorning calves is necessary to minimize injury because intensive raising circumstances make horned cows more aggressive. However, acute pain is commonly perceived by farm animals when undergoing painful practices such as dehorning, affecting their health status and quality of life. By quantifying the magnitude of pain and discomfort associated with dehorning, we aim to contribute to a more humane and sustainable cattle farming industry. Methods: The objective of this study was to evaluate the behavioral, physiological, and emotional effects of acute dehorning pain in calves using two methods: dehorning cream and dehorning hot-iron.30 Holstein calves aged 4 days were selected for the study. These calves were randomly assigned to two experimental groups based on the method of disbudding: dehorning cream (n = 15) and hot-iron dehorning (n = 15). Before and after dehorning, we evaluated their physiological indicators of infrared eye temperature, concentrations of substance P, IL-6, cortisol, haptoglobin, as well as emotional state, and pain-related behavioral reactions. Results: Post-dehorning, the duration of lying down decreased significantly in both groups (DI and DC: 0-4 h) after dehorning (p < 0.05). Both groups exhibited increased frequencies of pain-related behaviors such as head shaking (DI: 1-7 h, DC: 1-6 h), ear flicking (DI: 2-7 h, DC: 2-7 h), head scratching (DI: 2-3 h, DC: 1-7 h), and top scuffing (DI: 2 h, DC: 2-7 h) compared to pre-dehorning (p < 0.05). The DC group demonstrated a higher frequency of head-shaking, ear-flicking, head-scratching, and top-rubbing behaviors, along with a longer duration of lying down (0-4 h), compared to the DI group (p < 0.05). Post-dehorning, play behavior reduced significantly in both groups (6-8 h) (p < 0.05), whereas judgment bias and fear levels showed no significant change (p > 0.05). Physiological measures including eye temperature, and blood levels of substance P and IL-6, did not differ significantly between the groups before and after dehorning (p > 0.05). However, 48 h after dehorning, calves in the DC group had significantly higher haptoglobin levels compared to the DI group (p = 0.015). Additionally, salivary cortisol levels in the DC group increased significantly at 3.5 h and 7 h post-dehorning (p = 0.018, p = 0.043). Discussion: Both hot-iron and cream dehorning induced pain in calves, as evidenced by increased pain-related behaviors, elevated salivary cortisol, and higher haptoglobin levels, alongside reduced positive behaviors. Notably, these effects were more pronounced in the DC group than in the DI group, suggesting that dehorning hot-iron may be a comparatively less stressful dehorning method for young calves. Moreover, the brief duration of pain response and weaker response to dehorning observed in 13-day-age calves in this study suggests that dehorning at younger ages may be more advisable and warrants further research.

17.
Pract Lab Med ; 40: e00409, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38846326

RESUMEN

Objective: This study aimed to establish the reference intervals of Cyfra21-1 and CEA for the local screening populations using a chemiluminescence method. Methods: A total of 4845 healthy adults and 190 lung cancer patients were included from the First Hospital of Hebei Medical University. The levels of Cyfra21-1 and CEA were measured to establish the local reference intervals. Results: The upper limit reference intervals for Cyfra21-1 and CEA were determined as 3.19 ng/ml and 3.13 ng/ml, respectively. Notably, both Cyfra21-1 and CEA levels were found to be higher in males than in females. Additionally, both biomarkers showed an increasing trend with age.In terms of diagnostic efficacy, the receiver operating characteristic (ROC) curve areas for Cyfra21-1, CEA, and their combination in lung cancer were 0.86, 0.73, and 0.91, respectively. Conclusion: Our study revealed that the reference intervals of Cyfra21-1 and CEA in the local population differed from the established reference intervals. Furthermore, both biomarkers exhibited gender-dependent variations and demonstrated a positive correlation with age. Combining the two biomarkers showed potential for improving the diagnosis rate of lung cancer.

18.
Front Pharmacol ; 15: 1394936, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38895632

RESUMEN

Background: Ischemic stroke is a serious and sudden cerebrovascular condition that significantly affects individual's health and imposes a substantial economic burden on medical management. Despite its widespread use in China, there is still a lack of reliable evidence regarding the efficacy of Shenmai injection (SMI) in acute ischemic stroke (AIS). We aimed to comprehensively assess the effectiveness and safety of SMI in treating AIS through a systematic review and meta-analysis. Methods: Randomized controlled studies (RCTs) investigating the efficacy of SMI in treating AIS were searched for in eight databases from the inception of each database till January 2024. We utilized the ROB 2.0 to assess the risk of bias. A meta-analysis was conducted using Review Manager 5.4, while sensitivity analyses and publication bias assessments were conducted using Stata 16.1. Results: A total of 17 studies involving 1,603 AIS patients were included in our meta-analysis. Our results showed that SMI plus conventional treatments (CTs) was more effective than CTs alone in improving the total effective rate (RR 1.22, 95% CI: 1.14 to 1.30, p < 0.00001), the Barthel index (BI) (MD 12.18, 95% CI: 10.30 to 14.06, p < 0.00001), and reducing the National Institute of Health Stroke Scale Score (NIHSS) score (MD -3.05, 95% CI: 3.85 to -2.24, p < 0.00001) and Modified Rankin Scale (mRS) (MD -0.68, 95% CI: 0.86 to-0.49, p < 0.00001). In addition, SMI combination therapy was better than CTs alone in decreasing the levels of IL-6, IL-18, and hs-CRP. SMI therapy also enhanced the cerebral hemorheology of patients by reducing levels of fibrinogen and plasma viscosity. However, there was no significant difference in the incidence of adverse events, including elevated transaminase, rash, nausea, bleeding, urticaria, headache, vomiting, chest tightness, and facial flushes. Moreover, no serious adverse effects or life-threatening events were reported. Conclusion: Our study shows that combining SMI with CTs effectively enhances the neurological function of patients with acute cerebral infarction. However, our findings should be interpreted considering the significant heterogeneity and suboptimal quality of the analyzed trials. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024504675, Identifier PROSPERO, CRD42024504675.

19.
Artículo en Inglés | MEDLINE | ID: mdl-38895649

RESUMEN

Objective: To analyze the diagnostic value of quantitative features in multimodal magnetic resonance imaging (MRI) images to construct a radio-omics model for breast cancer. Methods: Ninety-five patients with breast-related diseases from January 2020 to January 2021 were grouped into the benign group (n=57) and malignant group (n=38) according to the pathological findings. All cases were randomized as the training group (n=66) and validation group (n=29) in a 7:3 ratio based on the examination time. All subjects were examined by T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), dynamic contrast enhancement (DCE), and apparent diffusion coefficient (ADC) multimodality MRI. The MRI findings were analyzed against pathological findings. A diagnostic breast cancer radiomics model was constructed. The diagnostic efficacy of the model in the validation group was analyzed, and the diagnostic efficacy was analyzed via the ROC curve. Results: Fibroadenoma accounted for 49.12% of benign breast diseases, and invasive ductal carcinoma accounted for 73.68% of malignant breast diseases. The sensitivity of T1WI, T2WI, DWI, ADC, and DCE in diagnosing breast cancer was 61.14%, 66.67%, 73.30%, 78.95%, and 85.96%, using the four-fold table method. The area under the curves (AUCs) of T1WI, T2WI, DWI, ADC, and DCE for diagnosing breast cancer were 0.715, 0.769, 0.785, 0.835, and 0.792, respectively. The AUCs of plain scan, diffuse, enhanced, plain scan + diffuse, plain scan + enhanced, enhanced + diffuse, and plain scan + enhanced + diffuse for diagnosing breast cancer were 0.746, 0.798, 0.816, 0.839, 0.890, 0.906, and 0.927, respectively. Conclusion: The construction of a radio-omics model by quantitative features in multimodal MRI images was valuable in the diagnosis of breast cancer. The value of radio-omics models such as plain scan + enhanced + diffuse was higher than the other models in diagnosing breast cancer and could be widely applied in clinical practice.

20.
JOR Spine ; 7(2): e1343, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38911099

RESUMEN

Objective: We analyzed the influence of the location of the upper and lower cement on the sandwich vertebrae (SV) by computer finite element analysis. Materials and Methods: A finite element model of the spinal segment of T11-L1 was constructed and 6 mL of cement was built into T11 and L1 simultaneously. According to the various distributions of bone cement at T11 and L1, the following four groups were formed: (i) Group B-B: bilateral bone cement reinforcement in both T11 and L1 vertebral bodies; (ii) Group L-B: left unilateral reinforcement in T11 and bilateral reinforcement in L1; (iii) Group L-R: unilateral cement reinforcement in both T11 and L1 (cross); (iv) Group L-L: unilateral cement reinforcement in both T11 and L1 (ipsilateral side). The maximum von Mises stress (VMS) and maximum displacement of the SV and intervertebral discs were compared and analyzed. Results: The maximum VMS of T12 was in the order of size: group B-B < L-B < L-R < L-L. Group B-B showed the lowest maximum VMS values for T12: 19.13, 18.86, 25.17, 25.01, 19.24, and 20.08 MPa in six directions of load flexion, extension, left and right lateral bending, and left and right rotation, respectively, while group L-L was the largest VMS in each group, with the maximum VMS in six directions of 21.55, 21.54, 30.17, 28.33, 19.88, and 25.27 MPa, respectively. Conclusion: Compared with the uneven distribution of bone cement in the upper and lower adjacent vertebrae (ULAV), the uniform distribution of bone cement in the ULAV reduced and uniformed the stress load on the SV and intervertebral disc. Theoretically, it can lead to the lowest incidence of sandwich vertebral fracture and the slowest rate of intervertebral disc degeneration.

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