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Immunodeficiency can disrupt normal physiological activity and function. In this study, donkey bone collagen peptide (DP) and its iron chelate (DPI) were evaluated their potential as immunomodulators in cyclophosphamide (Cytoxan®, CTX)-induced Balb/c mice. The femoral tissue, lymphocytes, and serum from groups of mice were subjected to hematoxylin and eosin (H&E) staining, methylthiazolyldiphenyl-tetrazolium bromide (MTT) cell proliferation assays, and enzyme-linked immunosorbent assay (ELISA), respectively. Furthermore, a non-targeted metabolomics analysis based on UPLC-MS/MS and a reverse transcription polymerase chain reaction (RT-qPCR) technology were used to explore the specific metabolic pathways of DPI regulating immunocompromise. The results showed that CTX was able to significantly reduce the proliferative activity of mouse splenic lymphocytes and led to abnormal cytokine expression. After DP and DPI interventions, bone marrow tissue damage was significantly improved. In particular, DPI showed the ability to regulate the levels of immune factors more effectively than Fe2+ and DP. Furthermore, metabolomic analysis in both positive and negative ion modes showed that DPI and DP jointly regulated the levels of 20 plasma differential metabolites, while DPI and Fe2+ jointly regulated 14, and all 3 jointly regulated 10. Fe2+ and DP regulated energy metabolism and pyrimidine metabolism pathways, respectively. In contrast, DPI mainly modulated the purine salvage pathway and the JAK/STAT signaling pathway, which are the key to immune function. Therefore, DPI shows more effective immune regulation than Fe2+ and DP alone, and has good application potential in improving immunosuppression.
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Colágeno , Ciclofosfamida , Equidae , Quelantes de Ferro , Camundongos Endogâmicos BALB C , Animais , Colágeno/metabolismo , Quelantes de Ferro/farmacologia , Camundongos , Proliferação de Células/efeitos dos fármacos , Peptídeos/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Imunossupressores/farmacologia , Metabolômica , Citocinas/metabolismo , Masculino , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Terapia de ImunossupressãoRESUMO
Six new phenylpropanoid glycosides (1-6), two new phenylethanol glycosides (7 and 8), one new phenylmethanol glycoside (9), three new phenylpropanoid dimers (10-12), two new phenylpropanoid-flavan-3-ol heterodimers (13 and 14), and six known relevant compounds (15-20) were isolated and identified from the well-liked edible and medicinal substance (the bark of Cinnamomum cassia (L.) J.Presl). The structures of these isolates were determined by using spectroscopic analyses, chemical methods, and quantum chemical calculations. Notably, compounds 4-9 were rare apiuronyl-containing glycosides, and compounds 13 and 14 were heterodimers of phenylpropanoids and flavan-3-ols linked through C-9â³-C-8 bonds. The antioxidant and α-glucosidase inhibitory activities of all isolates were evaluated. Compounds 10 and 12 exhibited DPPH radical scavenging capacities with IC50 values of 20.1 and 13.0 µM, respectively (vitamin C IC50 value of 14.3 µM). In the ORAC experiment, all these compounds exhibited different levels of capacity for scavenging free radicals, and compound 10 displayed extraordinary free radical scavenging capacity with the ORAC value of 6.42 ± 0.01 µM TE/µM (EGCG ORAC value of 1.54 ± 0.02 µM TE/µM). Compound 12 also showed significant α-glucosidase inhibitory activity with an IC50 of 56.3 µM (acarbose IC50 of 519.4 µM).
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Antioxidantes , Cinnamomum aromaticum , Inibidores de Glicosídeo Hidrolases , Glicosídeos , Casca de Planta , Extratos Vegetais , Casca de Planta/química , Glicosídeos/química , Glicosídeos/farmacologia , Cinnamomum aromaticum/química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo , DimerizaçãoRESUMO
STUDY OBJECTIVE: To assess the association of intraoperative hypotension with long-term survivals in older patients after major noncardiac surgery mainly for cancer. DESIGN: A secondary analysis of databases from three randomized trials with long-term follow-up. SETTING: The underlying trials were conducted in 17 tertiary hospitals in China. PATIENTS: Patients aged 60 to 90 years who underwent major noncardiac thoracic or abdominal surgeries (≥ 2 h) in a single center were included in this analysis. EXPOSURES: Restricted cubic spline models were employed to determine the lowest mean arterial pressure (MAP) threshold that was potentially harmful for long-term survivals. Patients were arbitrarily divided into three groups according to the cumulative duration or area under the MAP threshold. The association between intraoperative hypotension exposure and long-term survivals were analyzed with the Cox proportional hazard regression models. MEASUREMENTS: Our primary endpoint was overall survival. Secondary endpoints included recurrence-free and event-free survivals. MAIN RESULTS: A total of 2664 patients (mean age 69.0 years, 34.9% female sex, 92.5% cancer surgery) were included in the final analysis. MAP < 60 mmHg was adopted as the threshold of intraoperative hypotension. Patients were divided into three groups according to duration under MAP < 60 mmHg (<1 min, 1-10 min, and > 10 min) or area under MAP <60 mmHg (< 1 mmHgâ min, 1-30 mmHgâ min, and > 30 mmHgâ min). After adjusting confounders, duration under MAP < 60 mmHg for > 10 min was associated with a shortened overall survival when compared with the < 1 min patients (adjusted hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.09 to 1.57, P = 0.004); area under MAP < 60 mmHg for > 30 mmHgâ min was associated with a shortened overall survival when compared with the < 1 mmHgâ min patients (adjusted HR 1.40, 95% CI 1.16 to 1.68, P < 0.001). Similar associations exist between duration under MAP < 60 mmHg for > 10 min or area under MAP < 60 mmHg for > 30 mmHgâ min and recurrence-free or event-free survivals. CONCLUSIONS: In older patients who underwent major noncardiac surgery mainly for cancer, intraoperative hypotension was associated with worse overall, recurrence-free, and event-free survivals.
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The global incidence and prevalence of inflammatory bowel disease (IBD) are gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and murine colitis models is observed. A HFD induces a significant decrease in indole-3-acetic acid (IAA) and leads to intestinal barrier damage. Furthermore, IAA supplementation enhances intestinal mucin sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin sulfation, including 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (Papss2) and solute carrier family 35 member B3 (Slc35b3), the synthesis enzyme and the transferase of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), via the aryl hydrocarbon receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fail to exhibit such effects. Overall, IAA enhances intestinal mucin sulfation through the AHR-Papss2-Slc35b3 pathway, contributing to the protection of intestinal homfeostasis.
A HFD can lead to the development of colitis by disrupting tryptophan metabolism in the gut microbiome and lowering levels of IAA. Supplementation with IAA has been shown to alleviate colitis in mice and improve intestinal barrier function. It is believed that IAA may activate the AHR to upregulate the expression of Papss2 and Slc35b3, promoting sulfation modification of mucins and protecting the intestinal barrier. HFD, high-fat diet; AHR, aryl hydrocarbon receptor; IAA, indole-3-acetic acid; Papss2, 3'-phosphoadenosine 5'-phosphosulfate synthase 2; Slc35b3, solute carrier family 35 member B3.
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Microbioma Gastrointestinal , Homeostase , Ácidos Indolacéticos , Mucosa Intestinal , Mucinas , Animais , Humanos , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Mucinas/metabolismo , Ácidos Indolacéticos/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos Endogâmicos C57BL , Colite/microbiologia , Colite/metabolismo , Colite/induzido quimicamente , Limosilactobacillus reuteri/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Masculino , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Modelos Animais de DoençasRESUMO
Background: HIF1A-AS1, an antisense transcript of HIF1α gene, is a 652-bp LncRNA that is globally expressed in multiple tissues of animals. Recent evidence indicated that HIF1A-AS1 was involved in tumorigenesis of several types of cancer. However, the role of lncRNA in PC has not been reported, and the molecular mechanism remains elusive. Results: In order to investigate the role of HIF1A-AS1 in PC, it was overexpressed in some PC cell lines (PANC-1, PATU8988 and SW1990), and a series of experiments including cell viability detection, flow cytometry, transwell migration, clone formation and wound healing were performed. Functionally, the results indicated that overexpression of HIF1A-AS1 could greatly inhibit proliferation and migration and promote apoptosis of PC cells. Moreover, the isobaric tags for relative and absolute quantification (iTRAQ) quantitative proteomics analysis was implemented to explore the underlying mechanism and the results indicated that OE of HIF1A-AS1 globally affected the expression levels of multiple proteins associated with metabolism of cancer. At last, the network analysis revealed that most of these differentially expressed proteins (DEPs) were integrated and severed essential roles in regulatory function. In view of this, we guessed HIF1A-AS1 overexpression induced the dysfunction of metabolism and disordered proteins' translation, which may account for its excellent tumour suppressor effect. Conclusions: HIF1A-AS1 altered the cell function of PC cell lines via affecting the expression of numerous proteins. In summary, HIF1A-AS1 may exhibit a potential therapeutic effect on PC, and our study provided useful information in this filed.
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Objective: To investigate the impact of diaphragmatic breathing combined with limb training on lower limb lymphedema following surgery for gynecological cancer. Methods: From January 2022 to May 2022, 60 patients with lower limb lymphedema post-gynecologic cancer surgery were chosen. They were split into a control group (n = 30) and a treatment group (n = 30). The control group underwent complex decongestive therapy (CDT) for managing lower limb lymphedema after gynecologic cancer surgery, while the treatment group received diaphragmatic breathing combined with limb coordination training alongside CDT. Both groups completed a 4-week treatment regimen. The lower limb lymphedema symptoms were evaluated using the genital, lower limb, buttock, and abdomen (GCLQ) scores; bilateral lower limb circumference measurements; and anxiety and depression scores. Results: Compared to sole CDT administration, individuals undergoing diaphragmatic breathing coupled with limb coordination training experienced notable reductions in scores for the self-perceived symptom assessment questionnaire (GCLQ), bilateral lower limb circumference, as well as anxiety and depression scores. Conclusion: The incorporation of diaphragmatic breathing combined withalongside limb coordination training can accelerate and augment the efficacy of treating lower limb lymphedema post-gynecologic cancer surgery.
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Nucleoside triphosphates (NTPs) are essential in various biological processes. Cellular or even organismal controlled delivery of NTPs would be highly desirable, yet in cellulo and in vivo applications are hampered owing to their negative charge leading to cell impermeability. NTP transporters or NTP prodrugs have been developed, but a spatial and temporal control of the release of the investigated molecules remains challenging with these strategies. Herein, we describe a general approach to enable intracellular delivery of NTPs using covalently bound dendritic polycations, which are derived from PAMAM dendrons and their guanidinium derivatives. By design, these modifications are fully removable through attachment on a photocage, ready to deliver the native NTP upon irradiation enabling spatiotemporal control over nucleotide release. We study the intracellular distribution of the compounds depending on the linker and dendron generation as well as side chain modifications. Importantly, as the polycation is bound covalently, these molecules can also penetrate deeply into the tissue of living organisms, such as zebrafish.
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Gliomas, the most prevalent primary brain tumors, pose considerable challenges due to their heterogeneity, intricate tumor microenvironment (TME), and blood-brain barrier (BBB), which restrict the effectiveness of traditional treatments like surgery and chemotherapy. This review provides an overview of engineered cell membrane technologies in glioma therapy, with a specific emphasis on targeted drug delivery and modulation of the immune microenvironment. This study investigates the progress in engineered cell membranes, encompassing physical, chemical, and genetic alterations, to improve drug delivery across the BBB and effectively target gliomas. The examination focuses on the interaction of engineered cell membrane-coated nanoparticles (ECM-NPs) with the TME in gliomas, emphasizing their potential to modulate glioma cell behavior and TME to enhance therapeutic efficacy. The review further explores the involvement of ECM-NPs in immunomodulation techniques, highlighting their impact on immune reactions. While facing obstacles related to membrane stability and manufacturing scalability, the review outlines forthcoming research directions focused on enhancing membrane performance. This review underscores the promise of ECM-NPs in surpassing conventional therapeutic constraints, proposing novel approaches for efficacious glioma treatment.
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Neoplasias Encefálicas , Membrana Celular , Glioma , Nanopartículas , Microambiente Tumoral , Glioma/tratamento farmacológico , Glioma/terapia , Glioma/metabolismo , Glioma/imunologia , Glioma/patologia , Humanos , Nanopartículas/química , Membrana Celular/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/imunologia , Animais , Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Imunomodulação/efeitos dos fármacosRESUMO
STUDY OBJECTIVE: We compared the analgesic effects of erector spinae plane block versus quadratus lumborum block following laparoscopic nephrectomy. DESIGN: A randomized controlled trial. SETTING: A tertiary hospital in Beijing, China. PATIENTS: Patients scheduled for elective laparoscopic nephrectomy. INTERVENTIONS: A total of 110 patients were enrolled and randomized to receive either erector spinae plane block (n = 55) or quadratus lumborum block (n = 55) under ultrasound guidance. Patient-controlled sufentanil analgesia was provided after surgery. MEASUREMENTS: Our primary outcome was cumulative opioid consumption within 24 h after surgery. Secondary outcomes included postoperative pain intensity, subjective sleep quality, and quality of recovery. MAIN RESULTS: All 110 patients (mean 53 years, 57.3% female) were included in the intention-to-treat analysis. Cumulative sufentanil equivalent within 24 h was lower in patients given erector spinae plane block (median 13 µg, interquartile range 4 to 33) than in those given quadratus lumborum block (median 25 µg, interquartile range 13 to 39; median difference - 8 µg, 95% CI -15 to 0, P = 0.041). Pain intensity (0-10 range where 0 = no pain and 10 = the worst pain) at 2, 6, 12, and 24 h after surgery was lower with erector spinae plane block (at rest: median differences -1 point, all P ≤ 0.009; with movement: median differences -2 to -1 points, all P < 0.001). Subjective sleep quality on the night of surgery (the Richards-Campbell Sleep Questionnaire: 0-100 range, higher score better; median difference 12, 95% CI 2 to 23, P = 0.018) and quality of recovery at 24 h (the Quality of Recovery-15: 0-150 range, higher score better; median difference 8, 95% CI 2 to 15, P = 0.012) were better with erector spinae plane block. No procedure-related adverse events occurred. CONCLUSIONS: Compared with quadratus lumborum block, erector spinae plane block provided better analgesia as manifested by lower opioid consumption and pain intensity for up to 24 h after laparoscopic nephrectomy.
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Músculos Abdominais , Analgésicos Opioides , Laparoscopia , Nefrectomia , Bloqueio Nervoso , Dor Pós-Operatória , Sufentanil , Ultrassonografia de Intervenção , Humanos , Feminino , Bloqueio Nervoso/métodos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/etiologia , Nefrectomia/efeitos adversos , Nefrectomia/métodos , Analgésicos Opioides/administração & dosagem , Adulto , Sufentanil/administração & dosagem , Músculos Abdominais/inervação , Medição da Dor , Analgesia Controlada pelo Paciente/métodos , Músculos Paraespinais/inervação , Idoso , Resultado do Tratamento , Qualidade do Sono , Anestésicos Locais/administração & dosagemRESUMO
Gut microbial homeostasis is crucial for the health of cognition in elderly. Previous study revealed that polysorbate 80 (P80) as a widely used emulsifier in food industries and pharmaceutical formulations could directly alter the human gut microbiota compositions. However, whether long-term exposure to P80 could accelerate age-related cognitive decline via gut-brain axis is still unknown. Accordingly, in this study, we used the senescence accelerated mouse prone 8 (SAMP8) mouse model to investigate the effects of the emulsifier P80 intake (1 % P80 in drinking water for 12 weeks) on gut microbiota and cognitive function. Our results indicated that P80 intake significantly exacerbated cognitive decline in SAMP8 mice, along with increased brain pathological proteins deposition, disruption of the blood-brain barrier and activation of microglia and neurotoxic astrocytes. Besides, P80 intake could also induce gut microbiota dysbiosis, especially the increased abundance of secondary bile acids producing bacteria, such as Ruminococcaceae, Lachnospiraceae, and Clostridium scindens. Moreover, fecal microbiota transplantation from P80 mice into 16-week-old SAMP8 mice could also exacerbated cognitive decline, microglia activation and intestinal barrier impairment. Intriguingly, the alterations of gut microbial composition significantly affected bile acid metabolism profiles after P80 exposure, with markedly elevated levels of deoxycholic acid (DCA) in serum and brain tissue. Mechanically, DCA could activate microglial and promote senescence-associated secretory phenotype production through adenosine triphosphate-binding cassette transporter A1 (ABCA1) importing lysosomal cholesterol. Altogether, the emulsifier P80 accelerated cognitive decline of aging mice by inducing gut dysbiosis, bile acid metabolism alteration, intestinal barrier and blood brain barrier disruption as well as neuroinflammation. This study provides strong evidence that dietary-induced gut microbiota dysbiosis may be a risk factor for age-related cognitive decline.
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Barreira Hematoencefálica , Disfunção Cognitiva , Disbiose , Emulsificantes , Microbioma Gastrointestinal , Polissorbatos , Animais , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Polissorbatos/farmacologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/induzido quimicamente , Emulsificantes/metabolismo , Emulsificantes/farmacologia , Disbiose/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Envelhecimento/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Masculino , Microglia/metabolismo , Microglia/efeitos dos fármacos , Eixo Encéfalo-Intestino/efeitos dos fármacos , Cognição/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismoRESUMO
Rapid ascent to high-altitude areas above 2500 m often leads to acute high altitude illness (AHAI), posing significant health risks. Current models for AHAI research are limited in their ability to accurately simulate the high-altitude environment for drug screening. Addressing this gap, a novel static self-assembled water vacuum transparent chamber was developed to induce AHAI in zebrafish. This study identified 6000 m for 2 h as the optimal condition for AHAI induction in zebrafish. Under these conditions, notable behavioral changes including slow movement, abnormal exploration behavior and static behavior in the Novel tank test. Furthermore, this model demonstrated changes in oxidative stress-related markers included increased levels of malondialdehyde, decreased levels of glutathione, decreased activities of superoxide dismutase and catalase, and increased levels of inflammatory markers IL-6, IL-1ß and TNF-α, and inflammatory cell infiltration and mild edema in the gill tissue, mirroring the clinical pathophysiology observed in AHAI patients. This innovative zebrafish model not only offers a more accurate representation of the high-altitude environment but also provides a high-throughput platform for AHAI drug discovery and pathogenesis research.
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Common tyrosinase (TYR) inhibitors used in cosmetics, such as hydroquinone, kojic acid, and arbutin, can cause side effects including erythema, skin peeling, and dryness. Therefore, the development of natural whitening agents that offer excellent permeability, minimal irritation, and high safety has become a primary focus in the field of TYR inhibitors. In this study, we demonstrate that White birch sap (WBS), within a safe concentration range, effectively reduces TYR activity and melanin content in both B16F10 mouse melanoma cells and zebrafish larvae. Importantly, WBS exhibits minimal irritation to neutrophils in fluorescent zebrafish and does not affect the behavior of adult zebrafish. Furthermore, WBS downregulates the gene expression levels of microphthalmia-associated transcription factor, TYR, tyrosinase-related protein-1, and tyrosinase-related protein-2 in B16F10 cells. In conclusion, our research confirms that WBS, a naturally derived substance, offers high safety and mild effects, making it a promising candidate for a skin-whitening agent.
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Purpose: To investigate the impact of vergence dysfunction on myopia progression in children with Defocus incorporated multiple segments (DIMS) spectacle lenses. Patients and Methods: We retrospectively enrolled children prescribed DIMS spectacle lenses to slow myopic progression. Baseline vergence dysfunction was determined according to phoria at distance and near. Axial length (AL) measurement and cycloplegic subjective refraction were performed before fitting the lenses and at six-month and one-year follow-ups. The six-month and one-year AL and spherical equivalent (SE) change from baseline were calculated and compared in subgroups stratified with the type of vergence dysfunction. Results: Two hundred and ninety-two myopic children were included. Significant AL elongation and SE progression were observed at six months and one year (P < 0.05 for all comparisons). Multiple regression demonstrated that AL elongation at six months (P < 0.001) and one year (P < 0.001) was negatively correlated with age, and SE progression at six months was associated with age (P = 0.002). The AL elongation at six months in children with convergence excess was significantly greater than in normal myopic subjects (P = 0.011) and subjects with convergence insufficiency (P = 0.008), divergence excess (P = 0.007), divergence insufficiency (P = 0.024) and basic esophoria (P = 0.048) at six months. Conclusion: The present research demonstrated that vergence dysfunction influences myopia progression for myopic children with DIMS, and the children with convergence excess suffer from the greatest myopia progression among different types of vergence dysfunction.
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PURPOSE: Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression. METHODS: Apcmin/+ mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC. RESULTS: TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/ß-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/ß-catenin pathway activation. CONCLUSION: The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.
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Carcinogênese , Microbioma Gastrointestinal , Metilaminas , Receptores Citoplasmáticos e Nucleares , Transdução de Sinais , Via de Sinalização Wnt , Metilaminas/metabolismo , Metilaminas/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Células HCT116 , Proliferação de Células/efeitos dos fármacos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Neoplasias Intestinais/induzido quimicamente , Neoplasias Intestinais/microbiologia , Masculino , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/induzido quimicamente , Apoptose/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/metabolismoRESUMO
An innovative energy-absorbing and bearing structure was proposed, which incorporated the coupling of glass microspheres with a metal tube. Glass microsphere-filled steel tube (GMFST) column, consisting of external steel tube and inner glass microspheres, was expected to give full play to the energy-absorbing and load-bearing capacities of the particle while restricting particle flow from collapsing, thereby enhancing the overall structural strength. Four groups of steel tubes and the GMFST specimens were designed and subjected to axial compression tests at four different loading rates to investigate the performance of the structure. These tests aimed to analyze the deformation mode, mechanical response, and energy absorption capacity of the GMFST columns under quasi-static to low-speed compression conditions. The results indicated that the deformation process and failure mode of GMFST columns were similar to those of hollow steel tubes, albeit with a different post-buckling mode. Filling the steel tubes with glass microspheres reduced the load fluctuation range, moderated load-displacement curves, and exhibited a strain rate strengthening effect. The GMFST columns demonstrated superior energy absorption capacity, with significant increases in crush force efficiency, the averaged crush force, and the total absorbed energy, particularly in terms of subsequent support capacity. The load-increasing reinforcement properties enabled GMFST columns to overcome the limitations associated with the unstable post-buckling path of energyabsorbing damping structure, exhibiting outstanding load-bearing performance and stability in the later stages. The results provided valuable guidelines for designing and engineering high-performance GMFST columns, serving as a new type of energy-absorbing and supporting structure.
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Purpose: Cough during emergence from anesthesia is a common problem and may cause adverse events. Monotherapy faces uncertainty in preventing emergence cough due to individual differences. We aimed to evaluate the efficacy and safety of multimodal intervention for preventing emergence cough in patients following nasal endoscopic surgery. Methods: In this double-blind randomized trial, 150 adult patients undergoing nasal endoscopic surgery were randomly allocated into three groups. For the control group (n = 50), anesthesia was performed according to clinical routine, no intervention was provided. For the double intervention group (n = 50), normal saline 3 mL was sprayed endotracheally before intubation, 0.4 µg/kg dexmedetomidine was infused over 10 min after intubation, and target-controlled remifentanil infusion was maintained at an effect-site concentration of 1.5 ng/mL before extubation after surgery. For the multimodal intervention group (n = 50), 0.5% ropivacaine 3 mL was sprayed endotracheally before intubation, dexmedetomidine and remifentanil were administered as those in the double intervention group. The primary endpoint was the incidence of emergence cough, defined as single cough or more from end of surgery to 5 min after extubation. Results: The incidences of emergence cough were 98% (49/50) in the control group, 90% (45/50) in the double group, and 70% (35/50) in the multimodal group, respectively. The incidence was significantly lower in the multimodal group than those in the control (relative risk 0.71; 95% CI 0.59 to 0.86; p < 0.001) and double (relative risk 0.78; 95% CI 0.63 to 0.95; p = 0.012) groups; the difference between the double and control groups was not statistically significant (relative risk 0.92; 95% CI 0.83 to 1.02; p = 0.20). The severity of sore throat was significantly lower in the multimodal group than that in the control group (median difference-1; 95% CI -2 to 0; p = 0.016). Adverse events did not differ among the three groups. Conclusion: For adult patients undergoing endonasal surgery, multimodal intervention including ropivacaine topical anesthesia before intubation, dexmedetomidine administration after intubation, and remifentanil infusion before extubation after surgery significantly reduced emergence cough and was safe.
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Introduction: Clinical trials investigating the safety and efficacy of experimental drugs and devices are the cornerstone of medicinal advancement. Enrolling sufficient participants in these trials is vital to ensure adequate statistical power and generalizability. Clinical trial participation is particularly low among certain populations, including medically underserved communities (i.e., rural areas) and Black, Indigenous, and People of Color (BIPOC). Methods: A retrospective study design was used to understand patient outcomes and access/barriers to clinical trial participation in the rural northwest United States. A quantitatively focused retrospective chart review was conducted for adult participants enrolled in at least one clinical trial in a single northwest health system between 1999 and 2022. Descriptive and inferential statistical analyses were performed to assess trial outcomes at a significance level 0.05. Results: The retrospective chart review yielded 833 clinical trial records with 753 individual enrolled participants. The all-cause relative frequency of death at last known follow-up amongst clinical trial participants was 8.90% (n = 67). Based on logistic regression, the death was significantly associated with the participants' age at initial trial screening (ß = 0.09, p-value <0.001), those that resided in non-metro areas (ß = -0.86, p-value = 0.045), and those that lived in Northeastern Montana (ß = 1.27, p-value = 0.025). Additionally, death at last known follow-up was significantly associated with enrollment in 2021-2022 (ß = -1.52, p-value <0.001), enrolled in more than one study (ß = 0.84, p-value = 0.023), in internationally sponsored trials (ß = -2.08, p-value <0.001), in Phase I (ß = 5.34, p-value <0.001), in Phase II trials (ß = 1.37, p-value = 0.013), diabetes as a primary trial target (ß = -2.04, p-value = 0.003). Conclusion: As decentralized trial design and remote or virtual elements of traditional trials become normative, representation of rural and frontier populations is imperative to support the generalizability of trial data encouraged by the FDA.
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Cooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell-like cluster with tumor cell-initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell-like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11ß1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFß and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11ß1 axis inhibited fibroblast TGFß production, enhanced CD8+ T cell-mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11ß1 axis is a potential strategy to inhibit osteosarcoma lung metastasis. SIGNIFICANCE: Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11ß1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.
Assuntos
Quimiocinas CXC , Integrinas , Neoplasias Pulmonares , Osteossarcoma , Microambiente Tumoral , Humanos , Linhagem Celular Tumoral , Quimiocinas CXC/metabolismo , Fibroblastos/metabolismo , Integrinas/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Osteossarcoma/patologia , Receptores de Colágeno , Fator de Crescimento Transformador beta/metabolismoRESUMO
Micro- and nanoplastics (MNPs), emerging as pervasive environmental pollutants, present multifaceted threats to diverse ecosystems. This review critically examines the ability of MNPs to traverse biological barriers in fish, leading to their accumulation in gonadal tissues and subsequent reproductive toxicity. A focal concern is the potential transgenerational harm, where offspring not directly exposed to MNPs exhibit toxic effects. Characterized by extensive specific surface areas and marked surface hydrophobicity, MNPs readily adsorb and concentrate other environmental contaminants, potentially intensifying reproductive and transgenerational toxicity. This comprehensive analysis aims to provide profound insights into the repercussions of MNPs on fish reproductive health and progeny, highlighting the intricate interplay between MNPs and other pollutants. We delve into the mechanisms of MNPs-induced reproductive toxicity, including gonadal histopathologic alterations, oxidative stress, and disruptions in the hypothalamic-pituitary-gonadal axis. The review also underscores the urgency for future research to explore the size-specific toxic dynamics of MNPs and the long-term implications of chronic exposure. Understanding these aspects is crucial for assessing the ecological risks posed by MNPs and formulating strategies to safeguard aquatic life.