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The genotoxic and clastogenic/aneugeneic potentials of four α,ß-unsaturated aldehydes, 2-phenyl-2-butenal, nona-2-trans-6-cis-dienal, 2-methyl-2-pentenal, and p-methoxy cinnamaldehyde, which are used as fragrance materials, were assessed using the Chicken Egg Genotoxicity Assay (CEGA) and the Hen's egg micronucleus (HET-MN) assay, respectively. Selection of materials was based on their chemical structures and the results of their previous assessment in the regulatory in vitro and/or in vivo genotoxicity test battery. Three tested materials, 2-phenyl-2-butenal, nona-2-trans-6-cis-dienal, and 2-methyl-2-pentenal, were negative in both, CEGA and HET-MN assays. These findings were congruent with the results of regulatory in vivo genotoxicity assays. In contrast, p-methoxy cinnamaldehyde, which was also negative in the in vivo genotoxicity assays, produced evidence of DNA damage, including DNA strand breaks and DNA adducts in CEGA. However, no increase in the micronucleus formation in blood was reported in the HET-MN study. Such variation in responses between the CEGA and HET-MN assay can be attributed to differences in the dosing protocols. Pretreatment with a glutathione precursor, N-acetyl cysteine, negated positive outcomes produced by p-methoxy cinnamaldehyde in CEGA, indicating that difference in response observed in the chicken egg and rodent models can be attributed to rapid glutathione depletion. Overall, our findings support the conclusion that CEGA and/or HET-MN can be considered as a potential alternative to animal testing as follow-up strategies for assessment of genotoxic potential of fragrance materials with evidence of genotoxicity in vitro.

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OBJECTIVE: To investigate the clinical significance of using 3D printing guides in modified unilateral puncture percutaneous vertebroplasty (PVP) for the treatment of osteoporotic vertebral compression fractures (OVCF), and to explore a new method for preventing paravertebral vein leakage during PVP in conjunction with a previous study of the optimal puncture-side bone cement/vertebral volume ratio(PSBCV/VV%). METHODS: This retrospective study analyzed 99 patients who underwent unilateral puncture PVP between January 2023 and December 2023. Patients were divided into a guide plate group (46 patients) and a conventional group (53 patients). The guide plate group underwent modified unilateral puncture PVP with the guidance of 3D printing guides, while the conventional group underwent unilateral puncture PVP using the conventional pedicle approach. The distribution of bone cement, surgical outcomes, and the occurrence of cement leakage into paravertebral veins were observed in both groups. RESULTS: The guide plate group had significantly shorter operating time and required fewer fluoroscopies compared to the conventional group. The amount of bone cement volume (BCV) used in the guide plate group was higher, but the amount of bone cement volume on the puncture side(PSBCV), the PSBCV/VV%, and the rate of paravertebral vein leakage were lower in the guide plate group compared to the conventional group (P < 0.05). Within each group, significant improvements in anterior vertebral margin height, Cobb angle, visual analog scale (VAS) score, and Oswestry Disability Index (ODI) were observed at 1 day and 1 month postoperatively compared to preoperative values (P < 0.05). CONCLUSION: Using 3D printing guides in modified unilateral puncture PVP is a safe and effective method for treating OVCF. And it has the advantages of short operation time, less fluoroscopy, even distribution of bone cement, and a low rate of paravertebral vein leakage.

Asunto(s)

Cementos para Huesos , Fracturas por Compresión , Fracturas Osteoporóticas , Impresión Tridimensional , Fracturas de la Columna Vertebral , Vertebroplastia , Humanos , Estudios Retrospectivos , Fracturas por Compresión/cirugía , Fracturas por Compresión/diagnóstico por imagen , Femenino , Vertebroplastia/métodos , Masculino , Anciano , Fracturas Osteoporóticas/cirugía , Fracturas de la Columna Vertebral/cirugía , Fracturas de la Columna Vertebral/diagnóstico por imagen , Persona de Mediana Edad , Anciano de 80 o más Años , Cementos para Huesos/uso terapéutico , Resultado del Tratamiento , Punciones/métodos , Relevancia Clínica

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OBJECTIVE: The objective of this study is to assess and compare the efficacy of oXiris with conventional continuous renal replacement therapy (CRRT) in managing severe abdominal infections. METHODS: A retrospective analysis encompassing cases from 2017 to 2023 was conducted at the Department of Critical Care Medicine within the First Affiliated Hospital of Fujian Medical University. Parameters including heart rate (HR), mean arterial pressure (MAP), oxygenation index (OI), lactate (Lac), platelet count (PLT), neutrophil ratio (N%), procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), norepinephrine (NE) dosage, acute physiology and chronic health evaluation II (APACHE II), and sequential organ failure assessment (SOFA) were recorded prior to treatment initiation, at 24 hours, and 72 hours post-treatment for both the oXiris and conventional CRRT groups. Additionally, the duration of respiratory support, CRRT treatment, length of stay in the intensive care unit (ICU), total hospitalization period, as well as mortality rates at 14 and 28 days for both groups were recorded. RESULTS: 1) Within the conventional CRRT group, notable enhancement was observed solely in Lac levels at 24 hours post-treatment compared to pre-treatment levels. Also, at 72 hours post-treatment, improvements were evident in HR, Lac, CRP, and IL-6 levels. 2) Conversely, the oXiris group exhibited improvements in HR, MAP, Lac, OI, N%, and IL-6 at 24 hours post-treatment when compared to baseline values. Additionally, reductions were observed in APACHE II and SOFA scores. At 72 hours post-treatment, all parameters demonstrated enhancement except for PLT. 3) Analysis of the changes in the indexes (Δ) between the two groups at 24 hours post-treatment revealed variances in HR, MAP, Lac, NE dosage, CRP levels, IL-6 levels, APACHE II scores, and SOFA scores. 4) The Δ indexes at 72 hours post-treatment indicated more significant improvements following oXiris treatment for both groups, except for PCT. 5) The 14-day mortality rate (24.4%) exhibited a significant reduction in the oXiris group when compared to the conventional group (43.6%). However, no significant difference was observed in the 28-day mortality rate between the two groups. 6) Subsequent to multifactorial logistic regression analysis, the results indicated that oXiris treatment correlated with a noteworthy decrease in the 14-day and 28-day mortality rates associated with severe abdominal infections, by 71.3% and 67.6%, respectively. CONCLUSION: oXiris demonstrates clear advantages over conventional CRRT in the management of severe abdominal infections. Notably, it reduces the fatality rates, thereby establishing itself as a promising and potent therapeutic option.

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BACKGROUND: Persistent infection with high-risk human papillomavirus (HR-HPV) plays a key role in the onset of cervical cancer. This study was designed to examine the epidemiological trends and genotype distribution of HPV from 2014 to 2023 in the plateau region of Southwest China. METHODS: The findings could offer valuable insights for clinical screening of cervical cancer and the formulation of HPV vaccination policies. This retrospective study analyzed 66,000 women who received HPV-DNA testing at the First People's Hospital of Qujing, Yunnan, China, between 2014 and 2023. The cohort consisted of 33,512 outpatients, 3,816 inpatients, and 28,672 individuals undergoing health examinations. Cervical cells were collected for DNA extraction, and PCR amplification along with Luminex xMAP technology were used to detect 27 HPV genotypes. The data analysis was conducted using GraphPad Prism and IBM SPSS Statistics 27 software. RESULTS: The overall HPV infection rate at the First People's Hospital of Qujing declined from 24.92% in 2014 to 16.29% in 2023, averaging 16.02%. Specific infection rates were 18.50% among outpatients, 12.97% among inpatients, and 13.53% for health examination attendees. The predominant high-risk HPV genotypes identified were HPV52 (2.61%), HPV16 (2.06%), HPV58 (1.81%), HPV53 (1.55%), and HPV39 (1.09%). Meanwhile, the most frequent low-risk HPV genotypes were HPV6 (1.30%), HPV61 (1.21%), and HPV11 (0.85%). In HPV-positive cases, the distribution of single, double, triple, and quadruple or more infections were 79.90%, 15.17%, 3.59%, and 1.33%, respectively. The proportions of pure LR-HPV, pure HR-HPV, and mixed infections were 22.16%, 67.82%, and 10.02%, respectively. Age-specific analysis revealed a bimodal distribution of HPV infection, with the infection rate rapidly decreasing from 44.02% in the ≤ 19 age group to 19.55% in the 20-29 age group and 13.84% in the 30-39 age group, followed by a gradual increase to 14.64% in the 40-49 age group, 16.65% in the 50-59 age group, and 22.98% in the ≥ 60 age group. The coverage rates of the three available vaccines are all below 50%. The results of this study indicated a declining trend in HPV prevalence in the plateau region of Southwest China over the period from 2014 to 2023, especially in the reduction of genotypes targeted by vaccines. CONCLUSION: There were significant variations in the genotypes prevalent among different age groups, years, and patient sources within the same region. The underwhelming vaccination rates emphasize the critical need for developing either a multivalent vaccine or a personalized vaccine that targets the HPV genotypes common in the Chinese population. Furthermore, vaccinating adolescents to curb HPV infection and ensuring regular cervical cancer screenings for postmenopausal women are crucial steps.

Asunto(s)

Genotipo , Papillomaviridae , Infecciones por Papillomavirus , Humanos , Femenino , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , China/epidemiología , Adulto , Prevalencia , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven , Papillomaviridae/genética , Papillomaviridae/clasificación , Papillomaviridae/aislamiento & purificación , Adolescente , Anciano , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/epidemiología , ADN Viral/genética , Cuello del Útero/virología

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The five-year survival rate for patients with hepatocellular carcinoma (HCC) is only 20 %, highlighting the urgent need to identify new therapeutic targets and develop potential therapeutic options to improve patient prognosis. One promising approach is inhibiting autophagy as a strategy for HCC treatment. In this study, we established a virtual docking conformation of the autophagy promoter ULK1 binding XST-14 derivatives. Based on this conformation, we designed and synthesized four series of derivatives. By evaluating their affinity and anti-HCC effects, we confirmed that these compounds exert anti-HCC activity by inhibiting ULK1. The structure-activity relationship was summarized, with derivative A4 showing 10 times higher activity than XST-14 and superior efficacy to sorafenib against HCC. A4 has excellent effect on reducing tumor growth and enhancing sorafenib activity in HepG2 and HCCLM3 cells. Moreover, we verified the therapeutic effect of A4 in sorafenib-resistant HCC cells both in vivo and in vitro. These results suggest that inhibiting ULK1 to regulate autophagy may become a new treatment method for HCC and that A4 will be used as a lead drug for HCC in further research. Overall, A4 shows good drug safety and efficacy, offering hope for prolonging the survival of HCC patients.

Asunto(s)

Antineoplásicos , Carcinoma Hepatocelular , Diseño de Fármacos , Indoles , Neoplasias Hepáticas , Inhibidores de Proteínas Quinasas , Sorafenib , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Autofagia/efectos de los fármacos , Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Indoles/farmacología , Indoles/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Sorafenib/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Developing an effective Staphylococcus aureus (S. aureus) vaccine has been a challenging endeavor, as demonstrated by numerous failed clinical trials over the years. In this study, we formulated a vaccine containing a highly conserved moonlighting protein, the pyruvate dehydrogenase complex E2 subunit (PDHC), and showed that it induced strong protective immunity against epidemiologically relevant staphylococcal strains in various murine disease models. While antibody responses contributed to bacterial control, they were not essential for protective immunity in the bloodstream infection model. Conversely, vaccine-induced systemic immunity relied on γδ T cells. It has been suggested that prior S. aureus exposure may contribute to the reduction of vaccine efficacy. However, PDHC-induced protective immunity still facilitated bacterial clearance in mice previously exposed to S. aureus. Collectively, our findings indicate that PDHC is a promising serotype-independent vaccine candidate effective against both methicillin-sensitive and methicillin-resistant S. aureus isolates.

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Infecciones Estafilocócicas , Vacunas Estafilocócicas , Staphylococcus aureus , Animales , Infecciones Estafilocócicas/prevención & control , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Ratones , Staphylococcus aureus/inmunología , Staphylococcus aureus/enzimología , Vacunas Estafilocócicas/inmunología , Complejo Piruvato Deshidrogenasa/metabolismo , Complejo Piruvato Deshidrogenasa/inmunología , Femenino , Anticuerpos Antibacterianos/inmunología , Modelos Animales de Enfermedad , Humanos , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/metabolismo , Ratones Endogámicos C57BL , Staphylococcus aureus Resistente a Meticilina/inmunología , Piruvato Deshidrogenasa (Lipoamida)/inmunología , Piruvato Deshidrogenasa (Lipoamida)/metabolismo , Piruvato Deshidrogenasa (Lipoamida)/genética

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BACKGROUND: Stroke frequently results in oropharyngeal dysfunction (OD), leading to difficulties in swallowing and eating, as well as triggering negative emotions, malnutrition, and aspiration pneumonia, which can be detrimental to patients. However, routine nursing interventions often fail to address these issues adequately. Systemic and psychological interventions can improve dysphagia symptoms, relieve negative emotions, and improve quality of life. However, there are few clinical reports of systemic interventions combined with psychological interventions for stroke patients with OD. AIM: To explore the effects of combining systemic and psychological interventions in stroke patients with OD. METHODS: This retrospective study included 90 stroke patients with OD, admitted to the Second Affiliated Hospital of Qiqihar Medical College (January 2022-December 2023), who were divided into two groups: regular and coalition. Swallowing function grading (using a water swallow test), swallowing function [using the standardized swallowing assessment (SSA)], negative emotions [using the self-rating anxiety scale (SAS) and self-rating depression scale (SDS)], and quality of life (SWAL-QOL) were compared between groups before and after the intervention; aspiration pneumonia incidence was recorded. RESULTS: Post-intervention, the coalition group had a greater number of patients with grade 1 swallowing function compared to the regular group, while the number of patients with grade 5 swallowing function was lower than that in the regular group (P < 0.05). Post-intervention, the SSA, SAS, and SDS scores of both groups decreased, with a more significant decrease observed in the coalition group (P < 0.05). Additionally, the total SWAL-QOL score in both groups increased, with a more significant increase observed in the coalition group (P < 0.05). During the intervention period, the total incidence of aspiration and aspiration pneumonia in the coalition group was lower than that in the control group (4.44% vs 20.00%; P < 0.05). CONCLUSION: Systemic intervention combined with psychological intervention can improve dysphagia symptoms, alleviate negative emotions, enhance quality of life, and reduce the incidence of aspiration pneumonia in patients with OD.

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BACKGROUND: Silicosis is an irreversible fibrotic disease of the lung caused by chronic exposure to silica dust, which manifests as infiltration of inflammatory cells, excessive secretion of pro-inflammatory cytokines, and pulmonary diffuse fibrosis. As the disease progresses, lung function further deteriorates, leading to poorer quality of life of patients. Currently, few effective drugs are available for the treatment of silicosis. Bicyclol (BIC) is a compound widely employed to treat chronic viral hepatitis and drug-induced liver injury. While recent studies have demonstrated anti-fibrosis effects of BIC on multiple organs, including liver, lung, and kidney, its therapeutic benefit against silicosis remains unclear. In this study, we established a rat model of silicosis, with the aim of evaluating the potential therapeutic effects of BIC. METHODS: We constructed a silicotic rat model and administered BIC after injury. The FlexiVent instrument with a forced oscillation system was used to detect the pulmonary function of rats. HE and Masson staining were used to assess the effect of BIC on silica-induced rats. Macrophages-inflammatory model of RAW264.7 cells, fibroblast-myofibroblast transition (FMT) model of NIH-3T3 cells, and epithelial-mesenchymal transition (EMT) model of TC-1 cells were established in vitro. And the levels of inflammatory mediators and fibrosis-related proteins were evaluated in vivo and in vitro after BIC treatment by Western Blot analysis, RT-PCR, ELISA, and flow cytometry experiments. RESULTS: BIC significantly improved static compliance of lung and expiratory and inspiratory capacity of silica-induced rats. Moreover, BIC reduced number of inflammatory cells and cytokines as well as collagen deposition in lungs, leading to delayed fibrosis progression in the silicosis rat model. Further exploration of the underlying molecular mechanisms revealed that BIC suppressed the activation, polarization, and apoptosis of RAW264.7 macrophages induced by SiO2. Additionally, BIC inhibited SiO2-mediated secretion of the inflammatory cytokines IL-1ß, IL-6, TNF-α, and TGF-ß1 in macrophages. BIC inhibited FMT of NIH-3T3 as well as EMT of TC-1 in the in vitro silicosis model, resulting in reduced proliferation and migration capability of NIH-3T3 cells. Further investigation of the cytokines secreted by macrophages revealed suppression of both FMT and EMT by BIC through targeting of TGF-ß1. Notably, BIC blocked the activation of JAK2/STAT3 in NIH-3T3 cells required for FMT while preventing both phosphorylation and nuclear translocation of SMAD2/3 in TC-1 cells necessary for the EMT process. CONCLUSION: The collective data suggest that BIC prevents both FMT and EMT processes, in turn, reducing aberrant collagen deposition. Our findings demonstrate for the first time that BIC ameliorates inflammatory cytokine secretion, in particular, TGF-ß1, and consequently inhibits FMT and EMT via TGF-ß1 canonical and non-canonical pathways, ultimately resulting in reduction of aberrant collagen deposition and slower progression of silicosis, supporting its potential as a novel therapeutic agent.

Asunto(s)

Fibrosis Pulmonar , Transducción de Señal , Silicosis , Factor de Crecimiento Transformador beta1 , Animales , Silicosis/tratamiento farmacológico , Silicosis/patología , Silicosis/metabolismo , Silicosis/complicaciones , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/complicaciones , Ratones , Transducción de Señal/efectos de los fármacos , Células RAW 264.7 , Masculino , Factor de Crecimiento Transformador beta1/metabolismo , Células 3T3 NIH , Ratas , Transición Epitelial-Mesenquimal/efectos de los fármacos , Pulmón/patología , Pulmón/efectos de los fármacos , Citocinas/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Inflamación/patología , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Compuestos de Bifenilo

RESUMEN

Pregabalin is a medication primarily used in the treatment of neuropathic pain and anxiety disorders, owing to its gabapentinoid properties. Pregabalin monotherapy faces limitations due to its variable efficacy and dose-dependent adverse reactions. In this study, we conducted a comprehensive investigation into the potentiation of pregabalin's analgesic effects by dexborneol, a neuroprotective bicyclic monoterpenoid compound. We performed animal experiments where pain models were induced using two methods: peripheral nerve injury, involving axotomy and ligation of the tibial and common peroneal nerves, and incisional pain through a longitudinal incision in the hind paw, while employing a multifaceted methodology that integrates behavioral pharmacology, molecular biology, neuromorphology, and lipidomics to delve into the mechanisms behind this potentiation. Dexborneol was found to enhance pregabalin's efficacy by promoting its transportation to the central nervous system, disrupting self-amplifying vicious cycles via the reduction of HMGB1 and ATP release, and exerting significant anti-oxidative effects through modulation of central lipid metabolism. This combination therapy not only boosted pregabalin's analgesic property but also notably decreased its side effects. Moreover, this therapeutic cocktail exceeded basic pain relief, effectively reducing neuroinflammation and glial cell activation-key factors contributing to persistent and chronic pain. This study paves the way for more tolerable and effective analgesic options, highlighting the potential of dexborneol as an adjuvant to pregabalin therapy.

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BACKGROUND: Advanced gastric cancer is a common malignancy that is often diagnosed at an advanced stage and is still at risk of recurrence after radical surgical treatment. Chemoradiotherapy, as one of the important treatment methods for gastric cancer, is of great significance for improving the survival rate of patients. However, the tumor recurrence and survival prognosis of gastric cancer patients after radiotherapy and chemotherapy are still uncertain. AIM: To analyze the tumor recurrence after radical radiotherapy and chemotherapy for advanced gastric cancer and provide more in-depth guidance for clinicians. METHODS: A retrospective analysis was performed on 171 patients with gastric cancer who received postoperative adjuvant radiotherapy and chemotherapy in our hospital from 2021 to 2023. The Kaplan-Meier method was used to calculate the recurrence rate and survival rate; the log-rank method was used to analyze the single-factor prognosis; and the Cox model was used to analyze the prognosis associated with multiple factors. RESULTS: The median follow-up time of the whole group was 63 months, and the follow-up rate was 93.6%. Stage II and III patients accounted for 31.0% and 66.7%, respectively. The incidences of Grade 3 and above acute gastrointestinal reactions and hematological adverse reactions were 8.8% and 9.9%, respectively. A total of 166 patients completed the entire chemoradiotherapy regimen, during which no adverse reaction-related deaths occurred. In terms of the recurrence pattern, 17 patients had local recurrence, 29 patients had distant metastasis, and 12 patients had peritoneal implantation metastasis. The 1-year, 3-year, and 5-year overall survival (OS) rates were 83.7%, 66.3%, and 60.0%, respectively. The 1-year, 3-year, and 5-year disease-free survival rates were 75.5%, 62.7%, and 56.5%, respectively. Multivariate analysis revealed that T stage, peripheral nerve invasion, and the lymph node metastasis rate (LNR) were independent prognostic factors for OS. CONCLUSION: Postoperative intensity-modulated radiotherapy combined with chemotherapy for gastric cancer treatment is well tolerated and has acceptable adverse effects, which is beneficial for local tumor control and can improve the long-term survival of patients. The LNR was an independent prognostic factor for OS. For patients with a high risk of local recurrence, postoperative adjuvant chemoradiation should be considered.

RESUMEN

Programmed cell death ligand 2 (PD-L2), a ligand for the receptor programmed cell death 1 (PD-1), has an identity of 34% with its twin ligand PD-L1 and exhibits higher binding affinity with PD-1 than PD-L1. However, the role of PD-L2 in non-small cell lung cancer (NSCLC) progression, especially tobacco-induced cancer progression, has not been fully understood. Here, we found that PD-L2 promoted tumor growth in murine models with recruitment of regulatory T cells (Tregs). In patients with NSCLC, PD-L2 expression level in tumor samples was higher than in counterpart normal controls and was positively associated with patients' response to anti-PD-1 treatment. Mechanismly, PD-L2 bound its receptor Repulsive guidance molecule B (RGMB) on cancer cells and activated extracellular signal-regulated kinase (Erk) and nuclear factor κB (NFκB), leading to increased production of chemokine CCL20, which recruited Tregs and contributed to NSCLC progression. Consistently, knockdown of RGMB or NFκB p65 inhibited PD-L2-induced CCL20 production, and silencing of PD-L2 repressed Treg recruitment by NSCLC cells. Furthermore, cigarette smoke and carcinogen benzo(a)pyrene (BaP) upregulated PD-L2 in lung epithelial cells via aryl hydrocarbon receptor (AhR)-mediated transcription activation, whose deficiency markedly suppressed BaP-induced PD-L2 upregulation. These results suggest that PD-L2 mediates tobacco-induced recruitment of Tregs via the RGMB/NFκB/CCL20 cascade, and targeting this pathway might have therapeutic potentials in NSCLC.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Quimiocina CCL20 , Neoplasias Pulmonares , FN-kappa B , Proteína 2 Ligando de Muerte Celular Programada 1 , Linfocitos T Reguladores , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Humanos , FN-kappa B/metabolismo , Animales , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Quimiocina CCL20/metabolismo , Quimiocina CCL20/genética , Ratones , Fumar Tabaco/efectos adversos , Transducción de Señal , Línea Celular Tumoral , Masculino , Femenino

RESUMEN

BACKGROUND: Accumulating evidence has shown that the NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in the inflammatory cascades involved in the development of acute pancreatitis (AP). However, the specific agonist responsible for activating the NLRP3 inflammasome in this process has not yet been identified. The purpose of this study is to clarify whether heparan sulfate (HS) works as an NLRP3 inflammasome activator to evoke inflammatory cascades in the progression of AP. METHODS: Two experimental mouse models of AP were utilized to investigate the pro-inflammatory activity of HS in the development of AP by measuring the secretion of inflammatory cytokines and the neutrophil infiltration in pancreatic tissue. The ability of HS to activate the NLRP3 inflammasome was evaluated both in vitro and in vivo. The nuclear factor kappa B (NF-κB)-mediated expression of NLRP3 inflammasome components in response to HS treatment was determined to decipher the role of HS in transcriptional priming of NLRP3 inflammasome. Furthermore, HS-triggered deubiquitination of NLRP3 was analyzed to reveal the promoting effect of HS on the NLRP3 inflammasome priming via a non-transcriptional pathway. RESULTS: High plasma level of HS was observed with a positive correlation to that of inflammatory cytokines in AP mice. Administration of HS to mice resulted in an exacerbated inflammatory profile, while reducing HS production by an inhibitor of heparanase significantly attenuated inflammatory response. Pharmacological inhibition or genetic deletion of NLRP3 substantially suppressed the HS-stimulated elevation of IL-1ß levels in AP mice. The in vitro data demonstrated that HS primarily serves as a priming signal for the activation of the NLRP3 inflammasome. HS possesses the ability to increase the transcriptional activity of NF-κB and TLR4/NF-κB-driven transcriptional pathway is employed for NLRP3 inflammasome priming. Moreover, HS-induced deubiquitination of NLRP3 is another pathway responsible for non-transcriptional priming of NLRP3 inflammasome. CONCLUSIONS: Our current work has unveiled HS as a new activator of the NLRP3 inflammasome responsible for the secondary inflammatory cascades during the development of AP, highlighting the HS-NLRP3 pathway as a potential target for future preventive and therapeutic approaches of AP.

Asunto(s)

Modelos Animales de Enfermedad , Heparitina Sulfato , Inflamasomas , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Pancreatitis , Animales , Masculino , Ratones , Enfermedad Aguda , Citocinas/metabolismo , Heparitina Sulfato/metabolismo , Inflamasomas/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL , Infiltración Neutrófila/efectos de los fármacos , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Pancreatitis/metabolismo

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The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral activity. Here, we show that carrimycin, a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials, decreases the efficiency of programmed -1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum fashion. Carrimycin binds directly to the coronaviral frameshift-stimulatory element (FSE) RNA pseudoknot, interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription complexes. Combined carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on coronaviruses. Because the FSE mechanism is essential in all coronaviruses, carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE RNA. This finding may open a new direction in antiviral drug discovery for coronavirus variants.

RESUMEN

Aim: To assess the therapeutic potential of human umbilical cord mesenchymal stem cells (hUCMSCs) combined with porcine small intestinal submucosa (SIS) on full-thickness skin injuries in rats. Methods: We established full-thickness skin injury models in Sprague-Dawley rats, dividing them into blank control, SIS, hUCMSCs and hUCMSCs combined with SIS. We monitored wound healing, scores and area, and analyzed inflammatory cells, microvessel density and collagen fibers after 12 days. Results: The blank group showed no healing, forming a scar of 0.6 × 0.5 cm2, while SIS and hUCMSCs groups exhibited incomplete healing with 0.4 × 0.5 cm2 scabs. Wound healing was significantly better in the hUCMSCs combined with the SIS group. Conclusion: Local application of hUCMSCs combined with SIS enhances full-thickness skin injury wound healing in rats.

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Our skin protects us from infections and injuries, but severe damage can lead to health problems. In this study, we explored a promising new treatment to enhance skin healing. We used mesenchymal stem cells derived from umbilical cords in combination with a biological material called porcine small intestinal submucosa (SIS) to conduct experiemnts on rats with skin wounds. This treatment led to much better healing in rats with deep skin wounds compared with standard approaches. This approach is promising for treating severe skin injuries, offering hope for quicker recovery and better outcome, including faster recovery, reduced pain and inflammation and less scarring.

Asunto(s)

COVID-19 , Secuenciación de Nucleótidos de Alto Rendimiento , Metagenómica , Humanos , Beijing/epidemiología , COVID-19/epidemiología , Metagenómica/métodos , Masculino , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/virología , Persona de Mediana Edad , Femenino , Gripe Humana/epidemiología , Gripe Humana/virología , Monitoreo Epidemiológico , Adulto , SARS-CoV-2/genética , Anciano , Adolescente , Adulto Joven , Estaciones del Año , Niño , Preescolar

RESUMEN

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.

Asunto(s)

Proteínas de Unión a Ácidos Grasos , Hígado Graso , Glutatión Transferasa , Regulación hacia Arriba , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Animales , Humanos , Ratones , Proteínas de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Hígado Graso/metabolismo , Hígado Graso/tratamiento farmacológico , Regulación hacia Arriba/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones Endogámicos C57BL , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Ácido Oléico/metabolismo , Células Hep G2 , Triglicéridos/metabolismo , Isoenzimas

RESUMEN

In this study, we aimed to investigate the risk factors associated with in-hospital mortality in patients with cirrhosis and sepsis, establish and validate the nomogram. This retrospective study included patients diagnosed with liver cirrhosis and sepsis in the Medical Information Mart for Intensive Care IV (MIMIC-IV). Models were compared by the area under the curve (AUC), integrated discriminant improvement (IDI), net reclassification index (NRI) and decision curve analysis (DCA). A total of 1,696 patients with cirrhosis and sepsis were included in the final cohort. Our final model included the following 9 variables: age, heartrate, total bilirubin (TBIL), glucose, sodium, anion gap (AG), fungal infections, mechanical ventilation, and vasopressin. The nomogram were constructed based on these variables. The AUC values of the nomograms were 0.805 (95% CI 0.776-0.833), which provided significantly higher discrimination compared to that of SOFA score [0.684 (95% CI 0.647-0.720)], MELD-Na [0.672 (95% CI 0.636-0.709)] and ABIC [0.674(95% CI 0.638-0.710)]. We established the first nomogram for predicting in-hospital mortality in patients with liver cirrhosis and sepsis based on these factors. This nomogram can performs well and facilitates clinicians to identify people at high risk of in-hospital mortality.

Asunto(s)

Mortalidad Hospitalaria , Cirrosis Hepática , Nomogramas , Sepsis , Humanos , Cirrosis Hepática/mortalidad , Cirrosis Hepática/complicaciones , Sepsis/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Factores de Riesgo , Pronóstico , Curva ROC , Adulto , Área Bajo la Curva

RESUMEN

Intracerebral hemorrhage (ICH), for which there are currently no effective preventive or treatment methods, has a very high fatality rate. Statins, such as atorvastatin (ATV), are the first-line drugs for regulating blood lipids and treating hyperlipidemia-related cardiovascular diseases. However, ATV-associated ICH has been reported, although its incidence is rare. In this study, we aimed to investigate the protective action and mechanisms of berberine (BBR) against ATV-induced brain hemorrhage. We established an ICH model in zebrafish induced by ATV (2 µM) and demonstrated the effects of BBR (10, 50, and 100 µM) on ICH via protecting the vascular network using hemocyte staining and three transgenic zebrafish. BBR was found to reduce brain inflammation and locomotion injury in ICH-zebrafish. Mechanism research showed that ATV increased the levels of VE-cadherin and occludin proteins but disturbed their localization at the cell membrane by abnormal phosphorylation, which decreased the number of intercellular junctions between vascular endothelial cells (VECs), disrupting the integrity of vascular walls. BBR reversed the effects of ATV by promoting autophagic degradation of phosphorylated VE-cadherin and occludin in ATV-induced VECs examined by co-immunoprecipitation (co-IP). These findings provide crucial insights into understanding the BBR mechanisms involved in the maintenance of vascular integrity and in mitigating adverse reactions to ATV.

Asunto(s)

Atorvastatina , Berberina , Hemorragia Cerebral , Pez Cebra , Animales , Atorvastatina/farmacología , Hemorragia Cerebral/inducido químicamente , Berberina/farmacología , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos

RESUMEN

In this study, [1+2+2] cyclization of tryptamine-derived isocyanides with 3-ylideneoxindoles was systematically investigated. A series of structurally complex spiro-oxindole derivatives were obtained. Characteristic dynamic covalent chemistry was observed and confirmed by experiments and density functional theory calculation. Through the regulation of the solvent, temperature, and time, the precise and stereodivergent synthesis of spiro-oxindoles was achieved.