RESUMEN

Protein kinases, mediating their biological function via their catalytic activity, play important role in cell development, including cell proliferation, migration, angiogenesis and survival. Over the years, protein kinase inhibitors have been developed as an important class of anticancer agents clinically. However, the off-targeting and drug resistance of protein kinase inhibitors limit their efficiency. Anticancer peptides derived from marine organisms represent a novel class of bioactive substances, and some of the peptides exhibit anticancer effect via inhibiting protein kinases. In this mini review, the recent progress of anticancer peptides targeting protein kinases from marine sources are presented. Marine peptides inhibiting resistant cancer cells by targeting novel domains of protein kinases are highlighted. The challenges and prospects of developing marine peptides as anticancer agents are also discussed.

RESUMEN

BACKGROUND: Diabetic wounds present significant challenges, specifically in terms of bacterial infection and delayed healing. Therefore, it is crucial to address local bacterial issues and promote accelerated wound healing. In this investigation, we utilized electrospinning to fabricate microgel/nanofiber membranes encapsulating MXene-encapsulated microgels and chitosan/gelatin polymers. RESULTS: The film dressing facilitates programmed photothermal therapy (PPT) and mild photothermal therapy (MPTT) under near-infrared (NIR), showcasing swift and extensive antibacterial and biofilm-disrupting capabilities. The PPT effect achieves prompt sterilization within 5 min at 52 °C and disperses mature biofilm within 10 min. Concurrently, by adjusting the NIR power to induce local mild heating (42 °C), the dressing stimulates fibroblast proliferation and migration, significantly enhancing vascularization. Moreover, in vivo experimentation successfully validates the film dressing, underscoring its immense potential in addressing the intricacies of diabetic wounds. CONCLUSIONS: The MXene microgel-loaded nanofiber dressing employs temperature-coordinated photothermal therapy, effectively amalgamating the advantageous features of high-temperature sterilization and low-temperature promotion of wound healing. It exhibits rapid, broad-spectrum antibacterial and biofilm-disrupting capabilities, exceptional biocompatibility, and noteworthy effects on promoting cell proliferation and vascularization. These results affirm the efficacy of our nanofiber dressing, highlighting its significant potential in addressing the challenge of diabetic wounds struggling to heal due to infection.

Asunto(s)

Antibacterianos , Vendajes , Nanofibras , Terapia Fototérmica , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Nanofibras/química , Terapia Fototérmica/métodos , Animales , Antibacterianos/farmacología , Antibacterianos/química , Ratones , Biopelículas/efectos de los fármacos , Quitosano/química , Masculino , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Experimental/complicaciones , Temperatura , Ratas , Rayos Infrarrojos , Proliferación Celular/efectos de los fármacos , Ratas Sprague-Dawley , Humanos , Infección de Heridas/terapia

RESUMEN

Microbial contamination has profoundly impacted human health, and the effective eradication of widespread microbial issues is essential for addressing serious hygiene concerns. Taking polystyrene (PS) membrane as an example, we herein developed report a robust strategy for the in situ preparation of chlorine-regenerable antimicrobial polymer molecular sieve membranes through combining post-crosslinking and nucleophilic substitution reaction. The cross-linking PS membranes underwent a reaction with 5,5-dimethylhydantoin (DMH), leading to the formation of polymeric N-halamine precursors (PS-DMH). These hydantoinyl groups within PS-DMH were then efficiently converted into biocidal N-halamine structures (PS-DMH-Cl) via a simple chlorination process. ATR-FTIR and XPS spectra were recorded to confirm the chemical composition of the as-prepared PS-DMH-Cl membranes. SEM analyses revealed that the chlorinated PS-DMH-Cl membranes displayed a rough surface with a multitude of humps. The effect of chlorination temperature and time on the oxidative chlorine content in the PS-DMH-Cl membranes was systematically studied. The antimicrobial assays demonstrated that the PS-DMH-Cl membranes could achieve a 6-log inactivation of E. coli and S. aureus within just 4 min of contact time. Additionally, the resulting PS-DMH-Cl membranes exhibited excellent stability and regenerability of the oxidative chlorine content.

Asunto(s)

Cloro , Escherichia coli , Membranas Artificiales , Staphylococcus aureus , Cloro/química , Escherichia coli/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Antiinfecciosos/farmacología , Antiinfecciosos/química , Halogenación , Polímeros/química , Poliestirenos/química , Hidantoínas/química , Hidantoínas/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Aminas

RESUMEN

Background: No intervention definitively extends transplant-free survival in primary sclerosing cholangitis (PSC). Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), may enhance PSC prognosis, but their efficacy is debated. Methods: We analyzed HMGCR single-nucleotide polymorphisms from published genome-wide association studies using Mendelian randomization to assess the causal relationship between HMGCR and PSC risk. Effects of HMGCR were compared with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, common lipid-lowering drugs, using coronary heart disease risk as a positive control. The inverse-variance weighted (IVW) method was the primary analysis, complemented by the weighted median method. Heterogeneity analysis, examination of horizontal pleiotropy, and leave-one-out sensitivity analysis were conducted for result robustness. Results: Genetically predicted HMGCR exhibited a pronounced detrimental effect on PSC in both the IVW method (odds ratio [OR] [95%] = 2.43 [1.23-4.78], P = 0.010) and the weighted median method (OR [95%] = 2.36 [1.02-5.45], P = 0.044). However, PCSK9 did not reach statistical significance. Moreover, all analyses passed through heterogeneity analysis, horizontal pleiotropy analysis, and leave-one-out sensitivity analysis. Conclusion: This study has confirmed a causal relationship between HMGCR and PSC risk, suggesting statins targeting HMGCR could enhance PSC patient outcomes.

RESUMEN

Since the migrasome concept was first proposed in 2015, extensive research has been conducted on these novel organelles, which grow on retracted fibers at the posterior end of migrating cells. Recently, molecular markers, biological functions, and clinical values based on the initial formation mechanism of migrasomes have emerged. Additionally, researchers are recognizing the significant role that migrasomes play in the pathological and diagnostic processes of clinical diseases. In this review, we summarize recent advances in the biology and clinical application of migrasomes and provide a comprehensive view of the prospective challenges surrounding their clinical application.

Asunto(s)

Movimiento Celular , Orgánulos , Humanos , Orgánulos/metabolismo , Animales

RESUMEN

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia, however no effective treatments are available. Here, based on magnetic resonance imaging studies of patients with white matter damage, we found that this damage is associated with disorganized cortical structure. In a mouse model, optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell (OPC) proliferation, remyelination in the corpus callosum, and recovery of cognitive ability after cerebral hypoperfusion. The therapeutic effect of such stimulation was restricted to the upper layers of the cortex, but also spanned a wide time window after ischemia. Mechanistically, enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons. Additionally, skin stroking, an easier method to translate into clinical practice, activated the somatosensory cortex, thereby promoting OPC proliferation, remyelination and cognitive recovery following cerebral hypoperfusion. In summary, we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion. It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

RESUMEN

Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been implicated in PSC pathogenesis with the emergence of the "microbiota" and "gut lymphocyte homing" hypotheses, albeit their identities remain controversial. The first genome-wide association analysis leveraged nonoverlapping data from 3757 Europeans to evaluate 731 immunophenotypes. A genome-wide association analysis comprising 2871 cases and 12,019 controls yielded summary statistics for PSC. An inverse-variance weighted (IVW) analysis was performed to identify immunophenotypes causally related to PSC, and the results were validated using weighted mode, MR-Egger, and weighted median methods. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. IVW analysis revealed 26 immune traits exhibiting causal associations with PSC. CD3 on HLA-DR+ CD4+ (IVW odds ratio [OR]: 0.904; 95% confidence interval [CI]: 0.828-0.986, P = .023) and CD3 on secreting Treg (IVW OR: 0.893; 95% CI: 0.823-0.969, P = .007) were negatively associated with PSC susceptibility and demonstrated high consistency across the 3 validation methods. Moreover, 7 other immune traits, including CD39+ resting Treg absolute cell (IVW OR = 1.083, 95% CI: 1.013-1.157, P = .019), CD39+ secreting Treg absolute cell (IVW OR = 1.063, 95% CI: 1.012-1.118, P = .015), CD3 on naive CD8br (IVW OR = 0.907, 95% CI: 0.835-0.986, P = .022), CD3 on CD39+ activated Treg (IVW OR = 0.927, 95% CI: 0.864-0.994, P = .034), CD28 on resting Treg (IVW OR = 0.724, 95% CI: 0.630-0.833, P = 5.95E-06), and CD39 on CD39+ CD4+ (IVW OR = 1.055, 95% CI: 1.001-1.112, P = .044) exhibited consistent results in the Weighted Median and Weighted Mode validation methods. Moreover, no significant heterogeneity or horizontal pleiotropy was observed across the single nucleotide polymorphisms. The leave-one-out results revealed that sequentially eliminating each single nucleotide polymorphism had no significant influence on model effect estimates or qualitative inference. This study evaluated potential causal links between 731 immune traits and PSC susceptibility. Twenty-six immune traits were identified using the IVW method. Verification across multiple methods revealed 9 immune traits with a plausible causal connection to PSC. These findings may uncover mechanistic pathways and novel therapeutic approaches.

Asunto(s)

Colangitis Esclerosante , Estudio de Asociación del Genoma Completo , Inmunofenotipificación , Análisis de la Aleatorización Mendeliana , Colangitis Esclerosante/genética , Colangitis Esclerosante/inmunología , Humanos , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple

RESUMEN

The development of metallic joint prostheses has been ongoing for more than a century alongside advancements in hip and knee arthroplasty. Among the materials utilized, the Cobalt-Chromium-Molybdenum (Co-Cr-Mo) and Titanium-Aluminum-Vanadium (Ti-Al-V) alloys are predominant in joint prosthesis construction, predominantly due to their commendable biocompatibility, mechanical strength, and corrosion resistance. Nonetheless, over time, the physical wear, electrochemical corrosion, and inflammation induced by these alloys that occur post-implantation can cause the release of various metallic components. The released metals can then flow and metabolize in vivo, subsequently causing potential local or systemic harm. This review first details joint prosthesis development and acknowledges the release of prosthetic metals. Second, we outline the metallic concentration, biodistribution, and elimination pathways of the released prosthetic metals. Lastly, we discuss the possible organ, cellular, critical biomolecules, and significant signaling pathway toxicities and adverse effects that arise from exposure to these metals.

Asunto(s)

Metales , Humanos , Animales , Metales/química , Metales/farmacocinética , Prótesis Articulares de Metal sobre Metal/efectos adversos , Distribución Tisular , Titanio/química , Titanio/farmacocinética , Titanio/toxicidad , Titanio/efectos adversos , Prótesis Articulares/efectos adversos , Diseño de Prótesis , Aleaciones/farmacocinética , Aleaciones/química , Aleaciones/toxicidad

RESUMEN

Background: Interleukin-25 (IL-25) has been proved to play a role in the pathogenesis and metastasis of Hepatocellular carcinoma (HCC), but the relationship between the level of IL-25 and the metastasis and prognosis of HCC is still not clear. This study aimed to investigate the expression of IL-25 and other potential biochemical indicators among healthy people, HBV-associated HCC patients without lung metastasis and HBV-associated HCC patients with lung metastasis. Methods: From September 2019 to November 2021, 33 HCC patients without lung metastasis, 37 HCC patients with lung metastasis and 29 healthy controls were included in the study. IL-25 and other commonly used biochemical markers were measured to establish predictors of overall survival (OS) and progression-free survival (PFS) after treatment. Results: The serum level of IL-25 was increased in HCC patients than healthy controls (p < 0.001) and HCC patients with lung metastasis had higher IL-25 level than HCC patients without metastasis (p = 0.035). Lung metastasis also indicated higher death rate (p < 0.001) by chi-square test, higher GGT level (p = 0.024) and higher AFP level (p = 0.049) by non-parametric test. Kaplan-Meier analysis demonstrated that IL-25 was negatively associated with PFS (p = 0.024). Multivariate Cox-regression analysis indicated IL-25 (p = 0.030) and GGT (p = 0.020) to be independent predictors of poorer PFS, while IL-25 showed no significant association with OS. Conclusion: The level of IL-25 was significantly associated with disease progression and lung metastasis of HBV-associated HCC. The high expression of IL-25 predicted high recurrence rate and death probability of HCC patients after treatment. Therefore, IL-25 may be an effective predictor of prognosis in HCC.

Asunto(s)

Biomarcadores de Tumor , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Pulmonares , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/sangre , Estudios de Casos y Controles , China/epidemiología , Pueblos del Este de Asia , Hepatitis B/complicaciones , Hepatitis B/virología , Interleucina-17/sangre , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/virología , Pronóstico

RESUMEN

Objective: The objective of this study was to provide a multi-modal deep learning framework for forecasting the survival of rectal cancer patients by utilizing both digital pathological images data and non-imaging clinical data. Materials and methods: The research included patients diagnosed with rectal cancer by pathological confirmation from January 2015 to December 2016. Patients were allocated to training and testing sets in a randomized manner, with a ratio of 4:1. The tissue microarrays (TMAs) and clinical indicators were obtained. Subsequently, we selected distinct deep learning models to individually forecast patient survival. We conducted a scanning procedure on the TMAs in order to transform them into digital pathology pictures. Additionally, we performed pre-processing on the clinical data of the patients. Subsequently, we selected distinct deep learning algorithms to conduct survival prediction analysis using patients' pathological images and clinical data, respectively. Results: A total of 292 patients with rectal cancer were randomly allocated into two groups: a training set consisting of 234 cases, and a testing set consisting of 58 instances. Initially, we make direct predictions about the survival status by using pre-processed Hematoxylin and Eosin (H&E) pathological images of rectal cancer. We utilized the ResNest model to extract data from histopathological images of patients, resulting in a survival status prediction with an AUC (Area Under the Curve) of 0.797. Furthermore, we employ a multi-head attention fusion (MHAF) model to combine image features and clinical features in order to accurately forecast the survival rate of rectal cancer patients. The findings of our experiment show that the multi-modal structure works better than directly predicting from histopathological images. It achieves an AUC of 0.837 in predicting overall survival (OS). Conclusions: Our study highlights the potential of multi-modal deep learning models in predicting survival status from histopathological images and clinical information, thus offering valuable insights for clinical applications.

RESUMEN

Diabetic wounds pose a challenge to healing due to increased bacterial susceptibility and poor vascularization. Effective healing requires simultaneous bacterial and biofilm elimination and angiogenesis stimulation. In this study, we incorporated polyaniline (PANI) and S-Nitrosoglutathione (GSNO) into a polyvinyl alcohol, chitosan, and hydroxypropyltrimethyl ammonium chloride chitosan (PVA/CS/HTCC) matrix, creating a versatile wound dressing membrane through electrospinning. The dressing combines the advantages of photothermal antibacterial therapy and nitric oxide gas therapy, exhibiting enduring and effective bactericidal activity and biofilm disruption against methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Escherichia coli. Furthermore, the membrane's PTT effect and NO release exhibit significant synergistic activation, enabling a nanodetonator-like burst release of NO through NIR irradiation to disintegrate biofilms. Importantly, the nanofiber sustained a uniform release of nitric oxide, thereby catalyzing angiogenesis and advancing cellular migration. Ultimately, the employment of this membrane dressing culminated in the efficacious amelioration of diabetic-infected wounds in Sprague-Dawley rats, achieving wound closure within a concise duration of 14 days. Upon applying NIR irradiation to the PVA-CS-HTCC-PANI-GSNO nanofiber membrane, it swiftly eradicates bacteria and biofilm within 5 min, enhancing its inherent antibacterial and anti-biofilm properties through the powerful synergistic action of PTT and NO therapy. It also promotes angiogenesis, exhibits excellent biocompatibility, and is easy to use, highlighting its potential in treating diabetic wounds.

Asunto(s)

Antibacterianos , Vendajes , Biopelículas , Óxido Nítrico , Terapia Fototérmica , Ratas Sprague-Dawley , Cicatrización de Heridas , Animales , Cicatrización de Heridas/efectos de los fármacos , Óxido Nítrico/farmacología , Óxido Nítrico/metabolismo , Ratas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/uso terapéutico , Biopelículas/efectos de los fármacos , Terapia Fototérmica/métodos , Masculino , Quitosano/química , Quitosano/farmacología , Nanofibras/química , Escherichia coli/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Diabetes Mellitus Experimental/complicaciones , Staphylococcus aureus/efectos de los fármacos , Alcohol Polivinílico/química , Alcohol Polivinílico/farmacología , S-Nitrosoglutatión/farmacología , S-Nitrosoglutatión/química

RESUMEN

BACKGROUND: Primary sclerosing cholangitis (PSC) is a complex disease with pathogenic mechanisms that remain to be elucidated. Previous observational studies with small sample sizes have reported associations between PSC, dyslipidemia, and gut microbiota dysbiosis. However, the causality of these associations is uncertain, and there has been no systematic analysis to date. METHODS: The datasets comprise data on PSC, 179 lipid species, and 412 gut microbiota species. PSC data (n = 14,890) were sourced from the International PSC Study Group, while the dataset pertaining to plasma lipidomics originated from a study involving 7174 Finnish individuals. Data on gut microbiota species were derived from the Dutch Microbiome Project study, which conducted a genome-wide association study involving 7738 participants. Furthermore, we employed a two-step Mendelian randomization (MR) analysis to quantify the proportion of the effect of gut microbiota-mediated lipidomics on PSC. RESULTS: Following a rigorous screening process, our MR analysis revealed a causal relationship between higher levels of gene-predicted Phosphatidylcholine (O-16:1_18:1) (PC O-16:1_18:1) and an increased risk of developing PSC (inverse variance-weighted method, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.03-1.63). There is insufficient evidence to suggest that gene-predicted PSC impacts the levels of PC O-16:1_18:1 (OR 1.01, 95% CI 0.98-1.05). When incorporating gut microbiota data into the analysis, we found that Eubacterium rectale-mediated genetic prediction explains 17.59% of the variance in PC O-16:1_18:1 levels. CONCLUSION: Our study revealed a causal association between PC O-16:1_18:1 levels and PSC, with a minor portion of the effect mediated by Eubacterium rectale. This study aims to further explore the pathogenesis of PSC and identify promising therapeutic targets. For patients with PSC who lack effective treatment options, the results are encouraging.

Asunto(s)

Colangitis Esclerosante , Microbioma Gastrointestinal , Lipidómica , Análisis de la Aleatorización Mendeliana , Humanos , Colangitis Esclerosante/sangre , Colangitis Esclerosante/microbiología , Colangitis Esclerosante/genética , Microbioma Gastrointestinal/genética , Masculino , Estudio de Asociación del Genoma Completo , Femenino , Fosfatidilcolinas/sangre , Disbiosis/sangre , Persona de Mediana Edad , Adulto

RESUMEN

Injectable hydrogels, offering adaptable drug delivery of growth factors (GFs), hold promise for treating bone defects. To optimize osteogenic efficacy, the release of GFs should mirror the natural bone healing. We developed an injectable thermo-responsive hydrogel/microgels platform for dual GF delivery for bone regeneration. Stromal cell-derived factor-1 alpha (SDF-1a) and the Methacrylate Gelatin (GelMA) microgels which encapsulated insulin-like growth factor-1 (IGF-1) loaded liposomes (Ls) were introduced into Poloxamer 407 (P407) hydrogel matrix. This system achieved the biomimetic release profile of SDF-1a and IGF-1, which covered the early stage from day 1 to 7 and the continuous stage from day 5 to 21, respectively. In vitro study confirmed the enhanced migration, osteogenic biomarker expression, and matrix mineralization of the bone marrow mesenchymal stem cells (BMSCs) co-cultivated with the dual GFs delivering hydrogel/microgels. Transcriptome sequencing revealed that the potential mechanism was associated with mitogen-activated protein kinase (MAPK) signaling activation and its downstream ribosomal protein S6 kinase 2 (RSK2) upregulation. In a critical-sized calvarial defect model in Sprague-Dawley (SD) rats, the injectable hydrogel/microgels system promoted significant bone regeneration. Collectively, our study suggested the current hydrogel/microgels system with the biomimetic release of SDF-1a and IGF-1 efficiently promoted bone regeneration, informing the future development of GF delivery systems intended for bone regeneration therapies.

Asunto(s)

Regeneración Ósea , Quimiocina CXCL12 , Gelatina , Hidrogeles , Factor I del Crecimiento Similar a la Insulina , Poloxámero , Animales , Regeneración Ósea/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Quimiocina CXCL12/farmacología , Quimiocina CXCL12/administración & dosificación , Gelatina/química , Hidrogeles/química , Poloxámero/química , Ratas , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratas Sprague-Dawley , Metacrilatos/química , Osteogénesis/efectos de los fármacos , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Liberación de Fármacos , Inyecciones , Masculino

RESUMEN

BACKGROUND: The widespread use of sodium propionate as a preservative in food may affect public health. We aimed to assess the effects of sodium propionate on circadian rhythms and pancreatic development in zebrafish and the possible underlying mechanisms. RESULTS: In this experiment, we analyzed the relationship between circadian rhythms and pancreatic development and then revealed the role of the thyroid endocrine system in zebrafish. The results showed that sodium propionate interfered with the rhythmic behavior of zebrafish, and altered the expression of important rhythmic genes. Experimental data revealed that pancreatic morphology and developmental genes were altered after sodium propionate exposure. Additionally, thyroid hormone levels and key gene expression associated with the hypothalamic-pituitary-thyroid axis were significantly altered. Melatonin at a concentration of 1 µmol L-1, with a mild effect on zebrafish, observably alleviated sodium propionate-induced disturbances in circadian rhythms and pancreatic development, as well as regulating the thyroid system. CONCLUSION: Melatonin, while modulating the thyroid system, significantly alleviates sodium propionate-induced circadian rhythm disturbances and pancreatic developmental disorders. We further revealed the deleterious effects of sodium propionate as well as the potential therapeutic effects of melatonin on circadian rhythm, pancreatic development and the thyroid system. © 2024 Society of Chemical Industry.

Asunto(s)

Ritmo Circadiano , Sistema Hipotálamo-Hipofisario , Melatonina , Páncreas , Propionatos , Glándula Tiroides , Pez Cebra , Animales , Melatonina/farmacología , Pez Cebra/crecimiento & desarrollo , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Ritmo Circadiano/efectos de los fármacos , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/crecimiento & desarrollo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/crecimiento & desarrollo , Hormonas Tiroideas/metabolismo

RESUMEN

RATIONALE: Bilateral vestibulopathy is an important cause of imbalance. There are multiple etiologies of bilateral vestibulopathy (BVP), but reports of BVP due to otosyphilis are rare. PATIENT CONCERNS: A 39-year-old male was referred to our medical center due to vertigo, persistent dizziness and gait disturbance for 2 months. DIAGNOSES: Bilateral vestibulopathy due to otosyphilis was considered in this case, as confirmed through analyses of vestibular function, laboratory tests, and penicillin treatment. INTERVENTIONS: The patient was was treated with a high dose of penicillin G (24 × 106 IU/d) for 14 days. OUTCOMES: The patient's symptoms had improved greatly following treatment, with dizziness and gait disturbance having completely resolved at 3 months following hospital discharge. LESSONS: Bilateral vestibulopathy should be considered when evaluating patients with acute or subacute persistent dizziness. Clinicians should also be aware of the potential for otosyphilis among patients who report BVP.

Asunto(s)

Vestibulopatía Bilateral , Humanos , Masculino , Adulto , Vestibulopatía Bilateral/diagnóstico , Vestibulopatía Bilateral/complicaciones , Sífilis/complicaciones , Sífilis/diagnóstico , Sífilis/tratamiento farmacológico , Mareo/etiología , Mareo/diagnóstico , Antibacterianos/uso terapéutico , Penicilina G/uso terapéutico , Penicilina G/administración & dosificación , Vértigo/etiología , Vértigo/diagnóstico

RESUMEN

Peripheral nerve block is performed for precise pain control and lesser side effects after surgery by reducing opioid consumption. Injectable hydrogel delivery systems with high biosafety and moisture content have good clinical application prospects for local anesthetic delivery. However, how to achieve high drug loading and long-term controlled release of water-soluble narcotic drugs remains a big challenge. In this study, heterogeneous microspheres and an injectable gel-matrix composite drug delivery system are designed in two steps. First, heterogeneous hydrogel microspheres loaded with ropivacaine (HMS-ROP) are prepared using a microfluidic chip and in situ alkalization. An injectable self-healing hydrogel matrix (Gel) is then prepared from modified carboxymethylcellulose (CMC-ADH) and oxidized hyaluronic acid (OHA). A local anesthetic delivery system, Gel/HMS-ROP/dexmedetomidine (DEX), with long-term retention and drug release in vivo is prepared by combining HMS-ROP and Gel/DEX. The drug loading of HMS-ROP reached 41.1%, with a drug release time of over 160 h in vitro, and sensory and motor blockade times in vivo of 48 and 36 h, respectively. In summary, the sequential release and synergistic analgesic effects of the two anesthetics are realized using core-shell microspheres, DEX, and an injectable gel, providing a promising strategy for long-acting postoperative pain management.

Asunto(s)

Anestesia Local , Anestésicos Locales , Sistemas de Liberación de Medicamentos , Hidrogeles , Ropivacaína , Hidrogeles/química , Anestésicos Locales/administración & dosificación , Animales , Sistemas de Liberación de Medicamentos/métodos , Ropivacaína/administración & dosificación , Anestesia Local/métodos , Microesferas , Ratones , Modelos Animales de Enfermedad , Ratas , Ácido Hialurónico/química , Ácido Hialurónico/administración & dosificación , Bloqueo Nervioso/métodos , Masculino

RESUMEN

The presence of bacteria in tumor results in chemotherapeutic drug resistance and weakens the immune response in colorectal cancer. To overcome bacterium-induced chemotherapeutic drug resistance and potentiate antitumor immunity, herein a novel molecule Biotin-Lys(SA-Cip-OH)-Lys(SA-CPT)-Phe-Phe-Nap (Biotin-Cip-CPT-Nap) is rationally designed containing four functional motifs (i.e., a biotin motif for targeting, Phe-Phe(-Nap) motif for self-assembly, ciprofloxacin derivative (Cip-OH) motif for antibacterial effect, and camptothecin (CPT) motif for chemotherapy). Using the designed molecule, a novel strategy of intracellular enzymatic nanofiber formation and synergistic antibacterium-enhanced chemotherapy and immunotherapy is achieved. Under endocytosis mediated by highly expressed biotin receptor in colorectal cancer cell membrane and the catalysis of highly expressed carboxylesterase in the cytoplasm, this novel molecule can be transformed into Biotin-Nap, which self-assembled into nanofibers. Meanwhile, antibiotic Cip-OH and chemotherapeutic drug CPT are released, overcoming bacterium-induced drug resistance and enhancing the therapeutic efficacy of immunotherapy towards colorectal cancer. This work offers a feasible strategy for the design of novel multifunctional prodrugs to improve the efficiency of colorectal cancer treatment.

Asunto(s)

Antineoplásicos , Neoplasias Colorrectales , Profármacos , Profármacos/química , Profármacos/farmacología , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Animales , Inmunoterapia , Péptidos/química , Péptidos/farmacología , Camptotecina/farmacología , Camptotecina/química , Antibacterianos/farmacología , Antibacterianos/química , Ratones , Nanofibras/química , Ciprofloxacina/farmacología , Ciprofloxacina/química , Liberación de Fármacos , Biotina/química

RESUMEN

Background: Pituitary adenomas (PAs) are prevalent intracranial tumors necessitating a comprehensive exploration of their molecular intricacies. This study delved into the molecular interactions among HES1 (hairy and enhancer of split 1), ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1), and autophagy to elucidate their contributions to PA progression. Methods: Our in-depth bioinformatics analysis identified ITPR1 as a central hub gene in the PA-associated dataset. It exhibited reduced expression in PA and held significant clinical diagnostic relevance. Motivated by this discovery, we investigated the consequences of ITPR1 overexpression, as well as the use of autophagy inhibitors 3-Methyladenine (3-MA) and Baf A1, while considering the transcriptional influence of HES1. Results: In vitro experiments utilizing PA cell lines revealed that ITPR1 overexpression significantly hindered tumorigenic activities. In contrast, both 3-MA and Baf A1 exacerbated these tumorigenic properties, confirmed by a decreased LC3 II/LC3 I ratio, indicative of autophagy inhibition. Intriguingly, the concurrent introduction of ITPR1 and these inhibitors mitigated these intensified effects, implying a tumor-suppressive role for ITPR1. Further investigations pinpoint HES1 as a potential upstream regulator of ITPR1 transcription. Silencing HES1 lead to reduced ITPR1 promoter activity, weakening the impact of ITPR1 overexpression on autophagy. This neutralized the ITPR1-mediated suppressions on PA cell activities, including proliferation, invasion, and migration. Conclusions: In summary, our research uncovered a complex regulatory interplay among HES1, ITPR1, and autophagy in the context of PA progression. These findings opened up promising avenues for novel therapeutic interventions targeting this intricate network to enhance PA treatment.

RESUMEN

BACKGROUND: Long noncoding RNAs (lncRNAs) have emerged as key players in tumorigenesis and tumour progression. However, the biological functions and potential mechanisms of lncRNAs in colorectal cancer (CRC) are unclear. METHODS: The novel lncRNA POU6F2-AS1 was identified through bioinformatics analysis, and its expression in CRC patients was verified via qRT-PCR and FISH. In vitro and in vivo experiments, such as BODIPY staining, Oil Red O staining, triglyceride (TAG) assays, and liquid chromatography mass spectrometry (LC-MS) were subsequently performed with CRC specimens and cells to determine the clinical significance, and functional roles of POU6F2-AS1. Biotinylated RNA pull-down, RIP, Me-RIP, ChIP, and patient-derived organoid (PDO) culture assays were performed to confirm the underlying mechanism of POU6F2-AS1. RESULTS: The lncRNA POU6F2-AS1 is markedly upregulated in CRC and associated with adverse clinicopathological features and poor overall survival in CRC patients. Functionally, POU6F2-AS1 promotes the growth and lipogenesis of CRC cells both in vitro and in vivo. Mechanistically, METTL3-induced m6A modification is involved in the upregulation of POU6F2-AS1. Furthermore, upregulated POU6F2-AS1 could tether YBX1 to the FASN promoter to induce transcriptional activation, thus facilitating the growth and lipogenesis of CRC cells. CONCLUSIONS: Our data revealed that the upregulation of POU6F2-AS1 plays a critical role in CRC fatty acid metabolism and might provide a novel promising biomarker and therapeutic target for CRC.

Asunto(s)

Neoplasias Colorrectales , MicroARNs , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Regulación hacia Arriba , Línea Celular Tumoral , Proliferación Celular/genética , MicroARNs/genética , Neoplasias Colorrectales/patología , Ácidos Grasos , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Factores del Dominio POU/genética , Factores del Dominio POU/metabolismo , Metiltransferasas/metabolismo , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo