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Cholesterol is a component of cell membranes and a precursor of hormones, and excess levels are associated with disease development; therefore, it must be maintained within the normal range. Silkworm cocoons are known to contain bioactive substances. Therefore, we compared the bioactivities of pigmented and white silkworm cocoons. Sericin extract of the Yeonnokjam (YN) variety, which contained a high flavonoid content, showed the highest antioxidant activity and inhibited cholesterol biosynthetic enzyme activity. YN-fed mice showed a 26% reduction in serum low-density lipoprotein cholesterol level. In addition, a 27% decrease in cholesterol accumulation in the liver was observed. Mechanistically, YN reduced the expression of 3-hydroxy-3-methylglutaryl-CoA reductase and acetyl-CoA acetyltransferase 2 proteins by 34 and 13%, respectively. In conclusion, YN suppresses cholesterol synthesis in the liver and stimulates bile acid secretion, which contributes to reduction in cholesterol levels, suggesting its potential as a cholesterol-lowering agent.
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Objectives: Although mandibular advancement device (MAD) treatment is effective in patients with obstructive sleep apnea (OSA), there are still some concerns about its potential therapeutic and side effects. Thus, we developed a novel MAD that auto-titrates depending on its position in patients with OSA. Therefore, we conducted a clinical trial to determine the efficacy of an auto-titrating mandibular advancement device (AMAD) for treating OSA. Methods: Fourteen patients with OSA were enrolled in this study. Polysomnography (PSG) was conducted at the start of the clinical trial, and PSG with AMAD in situ was performed after three months of treatment. Results: The mean Epworth Sleepiness Scale (ESS) and STOP-Bang scores were 8.21 ± 4.21 and 5.00 ± 1.00, respectively. After 3 months of treating AMAD, STOP-Bang scores improved to 3.75 ± 1.06; however, there was no significant change in ESS scores. Additionally, we found statistically significant improvements in several respiratory parameters in the PSG data after AMAD treatment. The AHI (32.85 ± 21.71 to 12.93 ± 10.70), supine AHI (45.91 ± 23.58 to 15.59 ± 12.76), lateral AHI (13.94 ± 10.95 to .49 ± 7.40), lowest O2 saturation (79.71 ± 6.22 to 84.00 ± 5.71), total arousal number (191.14 ± 112.07 to 86.57 ± 48.80), and arousal index (33.76 ± 21.00 to 15.05 ± 8.42) were recorded. However, there were no significant changes in total sleep time, sleep efficiency, or mean oxygen saturation. Additionally, we did not observe any major side effects during treatment, specifically related to tooth or jaw pain. Conclusion: Our clinical trial revealed that AMAD improved PSG parameters and reduced the incidence of common side effects. Therefore, AMAD may be an effective alternative treatment for OSA.
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BACKGROUND: A set of criteria for severity classification is essential in alopecia areata (AA). Currently, no guidelines are universally accepted for defining AA severity. OBJECTIVE: This study aimed to establish a set of consensus criteria for classifying the severity of and identifying treatment refractoriness in AA. METHODS: A preliminary draft of the definition for moderate-to-severe AA was crafted based on available evidence, and members of the Korean Hair Research Society (KHRS) subsequently endorsed the recommendation through an online survey. RESULTS: In the first Delphi round, consensus was attained on 15 questions. After refining certain items in the second round, consensus was achieved on 23 out of 26 questions. The KHRS first defined AA severity using the severity of alopecia tool (SALT). SALT ≥50 was defined as severe, 20≤ SALT <50 as moderate, and SALT <20 as mild. Moderate AA was considered severe if it meets one or more of the following criteria: dermatology life quality index >10, presence of accompanying eyebrow or eyelash loss, positive hair loss activity, or treatment-refractory AA. CONCLUSION: These consensus criteria can help clinicians accurately diagnose AA, provide appropriate treatment, and monitor its progression.
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BACKGROUND: Disease susceptibility and progression of Mycobacterium avium complex pulmonary disease (MAC-PD) is associated with multiple factors, including low body mass index (BMI). However, the specific impact of low BMI on MAC-PD progression remains poorly understood. This study aims to examine the progression of MAC-PD in the context of low BMI, utilising a disease-resistant mouse model. METHODS: We employed a MAC infection-resistant female A/J mouse model to compare the progression of MAC-PD under two dietary conditions: one group was fed a standard protein diet, representing protein-energy unrestricted conditions, and the other was fed a low protein diet (LPD), representing protein-energy restriction. FINDINGS: Our results reveal that protein-energy restriction significantly exacerbates MAC-PD progression by disrupting lipid metabolism. Mice fed an LPD showed elevated fatty acid levels and related gene expressions in lung tissues, similar to findings of increased fatty acids in the serum of patients who exhibited the MAC-PD progression. These mice also exhibited increased CD36 expression and lipid accumulation in macrophages upon MAC infection. In vitro experiments emphasised the crucial role of CD36-mediated palmitic acid uptake in bacterial proliferation. Importantly, in vivo studies demonstrated that administering anti-CD36 antibody to LPD-fed A/J mice reduced macrophage lipid accumulation and impeded bacterial growth, resulting in remarkable slowing disease progression. INTERPRETATION: Our findings indicate that the metabolic status of host immune cells critically influences MAC-PD progression. This study highlights the potential of adequate nutrient intake in preventing MAC-PD progression, suggesting that targeting CD36-mediated pathways might be a host-directed therapeutic strategy to managing MAC infection. FUNDING: This research was funded by the National Research Foundation of Korea, the Korea Research Institute of Bioscience and Biotechnology, and the Korea National Institute of Health.
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Modelos Animales de Enfermedad , Progresión de la Enfermedad , Metabolismo de los Lípidos , Infección por Mycobacterium avium-intracellulare , Animales , Femenino , Ratones , Infección por Mycobacterium avium-intracellulare/microbiología , Infección por Mycobacterium avium-intracellulare/metabolismo , Antígenos CD36/metabolismo , Antígenos CD36/genética , Macrófagos/metabolismo , Humanos , Complejo Mycobacterium avium , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Ácidos Grasos/metabolismo , Mycobacterium avium , Susceptibilidad a EnfermedadesRESUMEN
Radiation therapy is a clinically proven, localized preventive measure for heterotopic ossification (HO). Despite its efficacy, there is a lack of standardization of radiation prescription dosing and fractionation, and the mechanism of the impact of radiation in HO prevention remains unknown. Here, using an established mouse model of traumatic HO induced by burn and tenotomy, we demonstrate that 7Gy in one fraction delivered to the injury site within 72 hours postoperatively significantly decreases HO formation and improves hindlimb range of motion. In-depth single-cell transcriptomic analyses, in combination with immunofluorescent staining, demonstrate decreased cellular numbers as well as aberrant endochondral differentiation and downregulation of associated upstream signaling pathways in irradiated mesenchymal progenitor cells. Our study provides the framework for future mechanistic and clinically relevant studies exploring radiation efficacy in preventing HO formation.
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BACKGROUND: Robust risk assessment is crucial for the growing repaired tetralogy of Fallot population at risk of major adverse clinical outcomes; however, current tools are hindered by lack of validation. This study aims to develop and validate a risk prediction model for death in the repaired tetralogy of Fallot population. METHODS AND RESULTS: Patients with repaired tetralogy of Fallot enrolled in the INDICATOR (International Multicenter Tetralogy of Fallot Registry) cohort with clinical, arrhythmia, cardiac magnetic resonance, and outcome data were included. Patients from London, Amsterdam, and Boston sites were placed in the development cohort; patients from the Toronto site were used for external validation. Multivariable Cox regression was used to evaluate factors associated with time from cardiac magnetic resonance until the primary outcome: all-cause death. Of 1552 eligible patients (n=1221 in development, n=331 in validation; median age at cardiac magnetic resonance 23.4 [interquartile range, 15.6-35.6] years; median follow up 9.5 years), 102 (6.6%) experienced the primary outcome. The multivariable Cox model performed similarly during development (concordance index, 0.83 [95% CI, 0.78-0.88]) and external validation (concordance index, 0.80 [95% CI, 0.71-0.90]) and identified older age at cardiac magnetic resonance, obesity, type of tetralogy of Fallot repair, higher right ventricular end-systolic volume index, and lower biventricular global function index as independent predictors of death. A risk-scoring algorithm dividing patients into low-risk (score ≤4) versus high-risk (score >4) groups was validated to effectively discriminate risk of death (15-year survival of 95% versus 74%, respectively; P<0.001). CONCLUSIONS: This externally validated mortality risk prediction algorithm can help identify vulnerable patients with repaired tetralogy of Fallot who may benefit from targeted interventions.
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Sistema de Registros , Tetralogía de Fallot , Humanos , Tetralogía de Fallot/cirugía , Tetralogía de Fallot/mortalidad , Masculino , Femenino , Medición de Riesgo/métodos , Adulto , Adolescente , Adulto Joven , Factores de Riesgo , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/mortalidad , Reproducibilidad de los Resultados , Factores de Tiempo , Valor Predictivo de las Pruebas , Causas de MuerteRESUMEN
In this study, we investigated the anti-hypertensive properties of mulberry products by modulating the renin-angiotensin system (RAS). Comparative analysis showed that the ethyl acetate fractions, particularly from the Cheongil and Daeshim cultivars, contained the highest levels of polyphenols and flavonoids, with concentrations reaching 110 mg gallic acid equivalent (GE)/g and 471 mg catechin equivalent (CE)/g of extract, respectively. The ethyl acetate fraction showed superior angiotensin-converting enzyme (ACE) inhibitory activity, mainly because of the presence of the prenylated flavonoids kuwanon G and H. UPLC/Q-TOF-MS analysis identified kuwanon G and H as the primary active components, which significantly contributed to the pharmacological efficacy of the extract. In vivo testing of mice fed a high-salt diet showed that the ethyl acetate fraction substantially reduced the heart weight and lowered the serum renin and angiotensinogen levels by 34% and 25%, respectively, highlighting its potential to modulate the RAS. These results suggested that the ethyl acetate fraction of mulberry root bark is a promising candidate for the development of natural ACE inhibitors. This finding has significant implications for the management of hypertension through RAS regulation and the promotion of cardiovascular health in the functional food industry.
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Bispecific T cell engagers (TCEs) show promising clinical efficacy in blood tumors, but their application to solid tumors remains challenging. Here, we show that Fc-fused IL-7 (rhIL-7-hyFc) changes the intratumoral CD8 T cell landscape, enhancing the efficacy of TCE immunotherapy. rhIL-7-hyFc induces a dramatic increase in CD8 tumor-infiltrating lymphocytes (TILs) in various solid tumors, but the majority of these cells are PD-1-negative tumor non-responsive bystander T cells. However, they are non-exhausted and central memory-phenotype CD8 T cells with high T cell receptor (TCR)-recall capacity that can be triggered by tumor antigen-specific TCEs to acquire tumoricidal activity. Single-cell transcriptome analysis reveals that rhIL-7-hyFc-induced bystander CD8 TILs transform into cycling transitional T cells by TCE redirection with decreased memory markers and increased cytotoxic molecules. Notably, TCE treatment has no major effect on tumor-reactive CD8 TILs. Our results suggest that rhIL-7-hyFc treatment promotes the antitumor efficacy of TCE immunotherapy by increasing TCE-sensitive bystander CD8 TILs in solid tumors.
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Linfocitos T CD8-positivos , Inmunoterapia , Interleucina-7 , Linfocitos Infiltrantes de Tumor , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Interleucina-7/inmunología , Interleucina-7/metabolismo , Humanos , Animales , Inmunoterapia/métodos , Ratones , Neoplasias/inmunología , Neoplasias/terapia , Línea Celular Tumoral , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Efecto Espectador/inmunologíaRESUMEN
A 59-year-old previously healthy woman presented with a six-month history of fever, nonproductive cough, and weight loss. The cause of these symptoms remained obscure despite a thorough, month-long hospitalization. On presentation, she was normotensive with a pulse of 98 beats/minute, respiratory rate of 20 breaths/minute, and a temperature of 39.4C. She was emaciated. Physical examination was notable for faint bibasilar crackles on lung auscultation. Initial laboratory testing revealed pancytopenia. Peripheral smear demonstrated normocytic, normochromic anemia without immature cells or schistocytes. Other notable laboratory findings included elevated levels of lactate dehydrogenase, elevated ferritin, and elevated levels of fasting serum triglycerides. A comprehensive laboratory evaluation for connective tissue disease was negative. Plain chest radiography was normal while computed tomography (CT) of the chest demonstrated sub-centimeter nodules in a branching centrilobular pattern as well as in a peri-lymphatic distribution without associated lymphadenopathy or organomegaly. The above constellation of laboratory abnormalities raised concern for hemophagocytic lymphohistiocytosis (HLH). Soluble IL-2 (CD25) receptor levels were markedly elevated. Bronchoscopy with transbronchial biopsies of the right lower lobe was performed, revealing intravascular lymphoma associated with HLH. Our case emphasizes the need for clinicians to consider vascular causes of tree - in-bud nodules in addition to the conventional bronchiolar causes. The case also is a reminder of the need to conduct an exhaustive search for malignancy, in patients with HLH.
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Diseases that occur in silkworms include soft rot, hardening disease, digestive diseases, and sepsis. However, research on the causes of bacterial diseases occurring in silkworms and the resulting changes in the microbial community is lacking. Therefore, we examined the morphological characteristics of sepsis and changes in the microbial community between silkworms that exhibit a unique odor and healthy silkworms; thus, we established a relationship between disease-causing microorganisms and sepsis. After producing a 16S rRNA amplicon library for samples showing sepsis, we obtained information on the microbial community present in silkworms using next-generation sequencing. Compared to that in healthy silkworms, in silkworms with sepsis, the abundance of the Firmicutes phylum was significantly reduced, while that of Proteobacteria was increased. Serratia sp. was dominant in silkworms with sepsis. After bacterial isolation, identification, and reinfection through the oral cavity, we confirmed this organism as the disease-causing agent; its mortality rate was 1.8 times higher than that caused by Serratia marcescens. In summary, we identified a new causative bacterium of silkworm sepsis through microbial community analysis and confirmed that the microbial community balance was disrupted by the aberrant proliferation of certain bacteria.
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Bombyx , Microbiota , Sepsis , Animales , Serratia/genética , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: General anesthesia is inevitable for pediatric patients undergoing surgery, though volatile anesthetic agents may cause neuroinflammation and neurodevelopmental impairment; however, the underlying pathophysiology remains unclear. We aimed to investigate the neuroinflammation mechanism in developing rat brains associated with sevoflurane exposure time, by identifying the specific damage-associated molecular patterns (DAMPs) pathway and evaluating the effects of non-steroidal anti-inflammatory drugs (NSAIDs) in alleviating neuroinflammation. METHODS: A three-step experiment was conducted to investigate neuroinflammation induced by sevoflurane. First, the exposure time required for sevoflurane to cause neuroinflammation was determined. Next, the specific pathways of DAMPs involved in neuroinflammation by sevoflurane were identified. Finally, the effects of NSAIDs on sevoflurane-induced neuroinflammation were investigated. The expression of various molecules in the rat brain were assessed using immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, western blot analysis, and enzyme-linked immunosorbent assay. RESULTS: In total, 112 rats (aged 7 days) were used, of which six rats expired during the experiment (mortality rate, 5.3%). Expression of CD68, HMGB-1, galectin-3, TLR4, TLR9, and phosphorylated NF-κB was significantly increased upon 6 h of sevoflurane exposure. Conversely, transcriptional levels of TNF-α and IL-6 significantly increased and IFN-γ significantly decreased after 6 h of sevoflurane exposure. Co-administration of NSAIDs with sevoflurane anesthesia significantly attenuated TNF-α and IL-6 levels and restored IFN-γ levels. CONCLUSIONS: In conclusion, 6 h of sevoflurane exposure induces neuroinflammation through the DAMPs pathway, HMGB-1, and galectin-3. Co-administration of ibuprofen reduced sevoflurane-induced neuroinflammation.
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Anestésicos por Inhalación , Animales Recién Nacidos , Antiinflamatorios no Esteroideos , Enfermedades Neuroinflamatorias , Ratas Sprague-Dawley , Sevoflurano , Sevoflurano/toxicidad , Sevoflurano/farmacología , Sevoflurano/administración & dosificación , Animales , Anestésicos por Inhalación/toxicidad , Anestésicos por Inhalación/administración & dosificación , Ratas , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Éteres Metílicos/toxicidad , Masculino , Encéfalo/efectos de los fármacos , Encéfalo/metabolismoRESUMEN
Sterol regulatory element-binding protein (SREBP)-1c is involved in cellular lipid homeostasis and cholesterol biosynthesis and is highly increased in nonalcoholic steatohepatitis (NASH). However, the molecular mechanism by which SREBP-1c regulates hepatic stellate cells (HSCs) activation in NASH animal models and patients have not been fully elucidated. In this study, we examined the role of SREBP-1c in NASH and the regulation of LCN2 gene expression. Wild-type and SREBP-1c knockout (1cKO) mice were fed a high-fat/high-sucrose diet, treated with carbon tetrachloride (CCl4), and subjected to lipocalin-2 (LCN2) overexpression. The role of LCN2 in NASH progression was assessed using mouse primary hepatocytes, Kupffer cells, and HSCs. LCN2 expression was examined in samples from normal patients and those with NASH. LCN2 gene expression and secretion increased in CCl4-induced liver fibrosis mice model, and SREBP-1c regulated LCN2 gene transcription. Moreover, treatment with holo-LCN2 stimulated intracellular iron accumulation and fibrosis-related gene expression in mouse primary HSCs, but these effects were not observed in 1cKO HSCs, indicating that SREBP-1c-induced LCN2 expression and secretion could stimulate HSCs activation through iron accumulation. Furthermore, LCN2 expression was strongly correlated with inflammation and fibrosis in patients with NASH. Our findings indicate that SREBP-1c regulates Lcn2 gene expression, contributing to diet-induced NASH. Reduced Lcn2 expression in 1cKO mice protects against NASH development. Therefore, the activation of Lcn2 by SREBP-1c establishes a new connection between iron and lipid metabolism, affecting inflammation and HSCs activation. These findings may lead to new therapeutic strategies for NASH.
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Hierro , Lipocalina 2 , Cirrosis Hepática , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Animales , Humanos , Masculino , Ratones , Tetracloruro de Carbono/farmacología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Hepatocitos/metabolismo , Hepatocitos/patología , Hierro/metabolismo , Lipocalina 2/metabolismo , Lipocalina 2/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/genética , Cirrosis Hepática/inducido químicamente , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
Backgrounds/Aims: Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Methods: Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. Results: In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. Conclusions: The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.
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Background: Eosinophilic esophagitis (EoE) is a disease that has been subcategorized into two endoscopic phenotypes: inflammatory and fibrostenotic. Moreover, studies have shown a link between EoE and immunoglobulin G4 (IgG4), a subclass of the immunoglobulin G (IgG) antibody. In this study, we aimed to evaluate the relationship between histologic IgG4 expression and endoscopic phenotypes in patients with EoE. Methods: This case-control study included patients diagnosed with EoE (n = 19) and patients with non-obstructive dysphagia without abnormal findings as controls (NOD; n = 12). The EoE group was further divided into three subgroups based on endoscopic phenotype: inflammatory, fibrostenotic, or combined. Retrospective examination of endoscopic findings and pathological slides was performed to analyze IgG4 staining. Results: Histological analysis revealed a significant difference in IgG4 cell count (15.00 vs. 0.58, p = 0.003) and eosinophil cell count (84.67 vs. 0.08, p < 0.001) between the EoE and NOD groups. Symptom manifestation and blood test results were similar across all three endoscopic EoE phenotypes. However, histological analysis revealed a significant difference in IgG4 cell count between the inflammatory, fibrostenotic, and combined phenotypes (4.13 vs. 17.6 vs. 59.7, p = 0.030). Conclusions: IgG4 expression was higher in EoE patients than in those with NOD, the highest being in the combined phenotype subgroup. These findings emphasize the important role of endoscopic and histological examination in diagnosing EoE and the need for further research in this area.
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Imbalances in gut microbiota reportedly contribute to the development of autoimmune diseases, but the association between the etiopathogenesis of alopecia areata (AA) and gut microbial dysbiosis remains unclear. This cross-sectional study was conducted to identify and compare the composition of the gut microbiome in patients affected by AA and those in a healthy control (HC) group, and to investigate possible bacterial biomarkers for the disease. Fecal samples were collected from 19 AA patients and 20 HCs to analyze the relationship with fecal bacteria. The three major genera constituting the gut microbiome of AA patients were Bacteroides, Blautia, and Faecalibacterium. The alpha diversity of the AA group was not statistically significant different from that of the HC group. However, bacterial community composition in the AA group was significantly different from that of HC group according to Jensen-Shannon dissimilarities. In patients with AA, we found an enriched presence of the genera Blautia and Eubacterium_g5 compared to the HC group (p < 0.05), whereas Bacteroides were less prevalent (p < 0.05). The gut microbiota of AA patients was distinct from those of the HC group. Our findings suggest a possible involvement of gut microbiota in in the as-yet-undefined pathogenesis of AA.
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Alopecia Areata , Heces , Microbioma Gastrointestinal , Humanos , Alopecia Areata/microbiología , Femenino , Masculino , Adulto , Heces/microbiología , Estudios Transversales , Disbiosis/microbiología , Persona de Mediana Edad , Adulto Joven , Estudios de Casos y Controles , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , ARN Ribosómico 16S/genética , Bacteroides/aislamiento & purificaciónRESUMEN
Lidocaine exerts potential anti-tumor effects on various cancer cell lines, and its intravesical instillation is considered safer than intravenous administration for bladder cancer. However, the mechanisms underlying its anti-tumor effects have not been fully elucidated. Here, we aimed to elucidate the anti-tumor molecular mechanisms of lidocaine in bladder cancer cells and a xenograft model to substantiate the efficacy of its intravesical administration. We investigated the anti-proliferative and autophagyinducing activities of lidocaine in Nara Bladder Tumor No. 2 (NBT-II) rat bladder carcinoma cells using cell viability, flow cytometry, a wound healing assay, and western blotting. We also established a xenograft mouse model of bladder cancer, and cancer growth was examined using in vivo bioluminescence imaging. Lidocaine decreased cell viability, induced G0/G1 phase cell cycle arrest, and inhibited cell migration partially via glycogen synthase kinase (GSK) 3ß phosphorylation. Moreover, a combination of lidocaine and SB216763 (a GSK3ß inhibitor) suppressed autophagy-related protein expression. Bafilomycin-A1 with lidocaine significantly enhanced microtubule-associated protein 1A/1B-light chain (LC3B) expression; however, it decreased LC3B expression in combination with 3-methyladenine compared to lidocaine alone. In the xenograft mouse model, the bladder cancer volume was reduced by lidocaine. Overall, lidocaine exerts anti-proliferative effects on bladder cancer via an autophagy-inducing mechanism.
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Heterotopic ossification (HO) is a debilitating pathology where ectopic bone develops in areas of soft tissue. HO can develop as a consequence of traumatic insult or as a result of dysregulated osteogenic signaling, as in the case of the orphan disease fibrodysplasia ossificans progressiva (FOP). Traumatic HO (tHO) formation is mediated by the complex interplay of signaling between progenitor, inflammatory, and nerve cells, among others, making it a challenging process to understand. Research into the pathogenesis of genetically mediated HO (gHO) in FOP has established a pathway involving uninhibited activin-like kinase 2 receptor (ALK2) signaling that leads to downstream osteogenesis. Current methods of diagnosis and treatment lag behind pre-mature HO detection and progressive HO accumulation, resulting in irreversible decreases in range of motion and chronic pain for patients. As such, it is necessary to draw on advancements made in the study of tHO and gHO to better diagnose, comprehend, prevent, and treat both.
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Miositis Osificante , Osificación Heterotópica , Humanos , Miositis Osificante/diagnóstico , Miositis Osificante/genética , Miositis Osificante/complicaciones , Osificación Heterotópica/etiología , Osificación Heterotópica/metabolismo , Osificación Heterotópica/patología , Osteogénesis , Huesos/metabolismoRESUMEN
While hypoxic signaling has been shown to play a role in many cellular processes, its role in metabolism-linked extracellular matrix (ECM) organization and downstream processes of cell fate after musculoskeletal injury remains to be determined. Heterotopic ossification (HO) is a debilitating condition where abnormal bone formation occurs within extra-skeletal tissues. Hypoxia and hypoxia-inducible factor 1α (HIF-1α) activation have been shown to promote HO. However, the underlying molecular mechanisms by which the HIF-1α pathway in mesenchymal progenitor cells (MPCs) contributes to pathologic bone formation remain to be elucidated. Here, we used a proven mouse injury-induced HO model to investigate the role of HIF-1α on aberrant cell fate. Using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analyses of the HO site, we found that collagen ECM organization is the most highly up-regulated biological process in MPCs. Zeugopod mesenchymal cell-specific deletion of Hif1α (Hoxa11-CreERT2; Hif1afl/fl) significantly mitigated HO in vivo. ScRNA-seq analysis of these Hoxa11-CreERT2; Hif1afl/fl mice identified the PLOD2/LOX pathway for collagen cross-linking as downstream of the HIF-1α regulation of HO. Importantly, our scRNA-seq data and mechanistic studies further uncovered that glucose metabolism in MPCs is most highly impacted by HIF-1α deletion. From a translational aspect, a pan-LOX inhibitor significantly decreased HO. A newly screened compound revealed that the inhibition of PLOD2 activity in MPCs significantly decreased osteogenic differentiation and glycolytic metabolism. This suggests that the HIF-1α/PLOD2/LOX axis linked to metabolism regulates HO-forming MPC fate. These results suggest that the HIF-1α/PLOD2/LOX pathway represents a promising strategy to mitigate HO formation.
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Osificación Heterotópica , Osteogénesis , Animales , Ratones , Colágeno/metabolismo , Modelos Animales de Enfermedad , Matriz Extracelular/genética , Hipoxia/metabolismo , Osificación Heterotópica/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Acute kidney injury frequently occurs after cardiac surgery, and is primarily attributed to renal ischemia-reperfusion (I/R) injury and inflammation from surgery and cardiopulmonary bypass. Vitamin C, an antioxidant that is often depleted in critically ill patients, could potentially mitigate I/R-induced oxidative stress at high doses. We investigated the effectiveness of high-dose vitamin C in preventing I/R-induced renal injury. The ideal time and optimal dosage for administration were determined in a two-phase experiment on Sprague-Dawley rats. The rats were assigned to four groups: sham, IRC (I/R + saline), and pre- and post-vitC (vitamin C before and after I/R, respectively), with vitamin C administered at 200â¯mg/kg. Additional groups were examined for dose modification based on the optimal timing determined: V100, V200, and V300 (100, 200, and 300â¯mg/kg, respectively). Renal I/R was achieved through 45â¯min of ischemia followed by 24â¯h of reperfusion. Vitamin C administration during reperfusion significantly reduced renal dysfunction and tubular damage, more than pre-ischemic administration. Doses of 100 and 200â¯mg/kg during reperfusion reduced oxidative stress markers, including myeloperoxidase and inflammatory responses by decreasing high mobility group box 1 release and nucleotide-binding and oligomerization domain-like receptor 3 inflammasome. Overall beneficial effect was most prominent with 200â¯mg/kg. The 300â¯mg/kg dose, however, showed no additional benefits over the IRC group regarding serum blood urea nitrogen and creatinine levels and histological evaluation. During reperfusion, high-dose vitamin C administration (200â¯mg/kg) significantly decreased renal I/R injury by effectively attenuating the major triggers of oxidative stress and inflammation.
Asunto(s)
Lesión Renal Aguda , Antineoplásicos , Daño por Reperfusión , Humanos , Ratas , Animales , Ratas Sprague-Dawley , Riñón , Estrés Oxidativo , Lesión Renal Aguda/metabolismo , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Ácido Ascórbico/metabolismo , Daño por Reperfusión/patología , Antineoplásicos/farmacología , Inflamación/metabolismo , Isquemia/metabolismo , CreatininaRESUMEN
OBJECTIVE: To determine how the use of United States Medical Licensing Examination (USMLE) score cutoffs during the screening process of the Urology Residency Match Program may affect recruitment of applicants who are underrepresented in medicine (URM). MATERIALS AND METHODS: Deidentified data from the Association of American Medical Colleges' (AAMC) Electronic Residency Application Service (ERAS) system was reviewed, representing all applicants to our institution's urology residency program from 2018 to 2022. We analyzed self-reported demographic variables including race/ethnicity, age, sex/gender, as well as USMLE Step 1 and Step 2 scores. Chi-square tests and ANOVA were used to determine the association between race/ethnicity and other sociodemographic factors and academic metrics. Applicants were stratified according to USMLE Step 1 cutoff scores and the distribution of applicants by race/ethnicity was assessed using a Gaussian nonlinear regression fit. RESULTS: A total of 1258 applicants submitted applications to our program during the 5-year period, including 872 males (69.3%) and 386 females (30.7%). Most applicants were White (43.5%), followed by Asian (28.3%), Hispanic/Latino (11.7%), and Black (7.0%). There was an association between race/ethnicity and USMLE scores. Median USMLE Step 1 scores for White, Asian, Hispanic/Latino, and Black applicants were 242, 242, 237, and 232, respectively (P < .001). As cutoff score increases, percentage of URM applicants decreases. CONCLUSION: The use of cutoffs based on USMLE scores disproportionately affects URM applicants. Transitioning from numeric scores to pass/fail may enhance holistic review processes and increase the representation of URM applicants offered interviews at urology residency programs.