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Tetrahydroisoquinoline (THIQ) derivatives stand out as a promising class of compounds due to their diverse range of biological activities, making them particularly valuable in drug discovery. To enhance their structural diversity, an Rh-catalyzed denitrogenative annulation method has been introduced for synthesizing these derivatives. An intriguing aspect of this method is the ability of the Brønsted acid to prevent further annulation while facilitating the production of the desired THIQ derivatives, achieving impressive yields of up to 86%. This synthetic approach was subsequently leveraged to create an analogue of cyclocelabenzine, a compound showing potential as an anti-inflammatory agent.
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Background: Ferroptosis is an iron-driven cell-death mechanism that plays a central role in various diseases. Recent studies have suggested that baicalein inhibits ferroptosis, making it a promising therapeutic candidate. Materials and Methods: Fibroblast cultures were treated with different agents to determine the effects of baicalein on ferroptosis. Ferroptosis-related gene expression, lipid peroxidation, and post-treatment cellular structural changes were measured using real-time quantitative polymerase chain reaction, C11-BODIPY dye, and transmission electron microscopy, respectively. Results: Baicalein significantly inhibited rat sarcoma virus selective lethal 3-induced ferroptosis in fibroblasts. Moreover, in baicalein-treated groups, reduced ferroptosis-related gene expression, decreased lipid peroxidation, and maintained cell structure was observed when compared with those of the controls. Discussion: The ability of baicalein to counteract RSL3-induced ferroptosis underscores its potential protective effects, especially in diseases characterized by oxidative stress and iron overload in fibroblasts. Conclusion: Baicalein may serve as a potent therapeutic agent against conditions in which ferroptosis is harmful. The compound's efficacy in halting RSL3-triggered ferroptosis in fibroblasts paves the way for further in vivo experiments and clinical trials.
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Ferroptose , Fibroblastos , Flavanonas , Peroxidação de Lipídeos , Ferroptose/efeitos dos fármacos , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Humanos , Animais , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ferro/metabolismo , CarbolinasRESUMO
Background: Hyperopia is a significant refractive error in children, often leading to vision impairment. This study aimed to investigate whether partial or full spectacle correction is benefit for hyperopia in preschool-aged children. Methods: A retrospective study was conducted on hyperopic children visited to teaching medical center outpatient clinic between October 2011 and October 2018, and were categorized into three groups: full correction, overcorrection, and undercorrection. The study was approved by the institutional ethical committee of Tri-Service General Hospital. Results: Following a minimum of one-year follow-up period, no statistically significant differences were observed in best-corrected visual acuity (BCVA) among children receiving full, over, or under spectacle correction. Notably, the overcorrection group exhibited a significant reduction in spherical equivalent (SE) compared to both the full and under correction groups, indicating a better SE with spectacle overcorrection. Conclusions: Spectacle overcorrection may offer potential benefits for enhancing SE in preschool children with hyperopia. Nevertheless, further investigation through randomized controlled trials is warranted to establish the validity of this approach and its impact on visual outcomes in this hyperopic pediatric population.
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Óculos , Hiperopia , Acuidade Visual , Humanos , Hiperopia/terapia , Hiperopia/fisiopatologia , Estudos Retrospectivos , Pré-Escolar , Feminino , Masculino , Refração Ocular/fisiologia , Criança , Resultado do Tratamento , SeguimentosRESUMO
CONTEXT: Chronic ankle instability (CAI) is a common injury in athletes. Different forms of physical therapy have been applied to the population with CAI to assess their impact on spinal excitability. OBJECTIVE: The purpose of this systematic review and meta-analysis was to investigate the effectiveness of various physical therapy interventions on the alteration of spinal excitability in patients with CAI. DATA SOURCES: Four databases (EMBASE, MEDLINE, Cochrane CENTRAL, and Scopus) were searched from inception to November 2022. STUDY SELECTION: A total of 253 studies were obtained and screened; 11 studies on the effects of physical therapy intervention on the alteration of spinal excitability in patients with CAI were identified for meta-analysis. STUDY DESIGN: Systematic review and meta-analysis. LEVEL OF EVIDENCE: Level 3a. DATA EXTRACTION: A total of 11 studies that included the maximal Hoffmann reflex normalized by the maximal muscle response (H/M ratio) in the peroneus longus and soleus muscles were extracted and summarized. The quality of the studies was assessed using the PEDro scale. RESULTS: The extracted studies had an average PEDro score of 4.7 ± 1.4, indicating that most of them had fair-to-good quality. The physical therapy interventions included cryotherapy, taping, mobilization, proprioceptive training, and dry needling. The overall effects showed that the H/M ratios of the peroneus longus (P = 0.44, I2 = 0%) and soleus (P = 0.56,I2 = 22%) muscles were not changed by physical therapy in patients with CAI. CONCLUSION: The meta-analysis indicated that physical therapy interventions such as cryotherapy, taping, mobilization, proprioceptive training, and dry needling do not alter the spinal excitability in patients with CAI. Given that only 1 study reported ineffective changes in spinal excitability with dry needling, more research is essential to establish and validate its efficacy. PROSPERO REGISTRATION: CRD42022372998.
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Ultrasound (US)-triggered microbubbles (MBs) drug delivery is a promising tool for noninvasive and localized therapy. Several studies have shown the potential of drug-loaded MBs to boost the delivery of therapeutic substances to target tissue effectively. Nevertheless, little is known about the surface payload distribution affecting the cavitation activity and drug release behavior of the drug-loaded MBs. In this study, we designed a common chemodrug (Doxorubicin, Dox)-loaded MB (Dox-MBs) and regulated the payload distribution as uniform or cluster onto the outer surface of MBs. The Dox distribution on the MB shells was assessed by confocal fluorescence microscopic imaging. The acoustic properties of the Dox-MBs with different Dox distributions were evaluated by their acoustic stability and cavitation activities. The payload release and the fragments from Dox-MBs in response to different US parameters were measured and visualized by column chromatography and cryo-electron microscopy, respectively. By amalgamating these methodologies, we found that stable cavitation was sufficient for triggering uniform-loaded MBs to release their payload, but stable cavitation and inertial cavitation were required for cluster-loaded MBs. The released substances included free Dox and Dox-containing micelle/liposome; their portions depended on the payload distribution, acoustic pressure, cycle number, and sonication duration. Furthermore, we also revealed that the Dox-containing micelle/liposome in cluster-loaded MBs had the potential for multiple drug releases upon US sonication. This study compared uniform-loaded MBs and cluster-loaded MBs to enhance our comprehension of drug-loaded MBs mediated drug delivery.
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Lipossomos , Micelas , Lipossomos/química , Liberação Controlada de Fármacos , Microbolhas , Microscopia Crioeletrônica , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodosRESUMO
The linkages of disulfide bond (DSB) play important roles in protein stability and activity. Mass spectrometry-based (MS-based) techniques become accepted tools for DSB analysis in the recent decade. In the bottom-up approach, after enzyme digestion, the neighbouring amino acids of cysteines have great impacts on the physicochemical properties of resulting disulfide bond peptides, determining their retention behaviour on liquid chromatography (LC) and their MS ionization efficiency. In this study, the addition of supercharging reagent in LC mobile phase was used to examine the impact of supercharging reagent on the charge states of disulfide-bond peptides. The results showed that 0.1 % m-nitrobenzyl alcohol (m-NBA) in LC mobile phase increased the sensitivity and charge states of DSB peptides from our model protein, equine Interleukin-5 (eIL5), as well as the resolution of reversed-phase chromatography. Notably, also the sensitivity of C-terminal peptide with His-tag significantly improved. Our findings highlight the effectiveness of employing m-NBA as a supercharging reagent when investigating disulfide-linked peptides and the C-terminal peptide with a His-tag through nano-liquid chromatography mass spectrometry.
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Álcoois Benzílicos , Dissulfetos , Peptídeos , Dissulfetos/química , Álcoois Benzílicos/química , Álcoois Benzílicos/isolamento & purificação , Peptídeos/química , Peptídeos/isolamento & purificação , Animais , Cavalos , Histidina/química , Cromatografia Líquida/métodos , Cromatografia de Fase Reversa/métodos , Cromatografia Líquida de Alta Pressão/métodosRESUMO
Methamphetamine (MA) use disorder poses significant challenges to both the affected individuals and society. Current non-drug therapies like transcranial direct-current stimulation and transcranial magnetic stimulation have limitations due to their invasive nature and limited reach to deeper brain areas. Transcranial focused ultrasound (FUS) is gaining attention as a noninvasive option with precise spatial targeting, able to affect deeper areas of the brain. This research focused on assessing the effectiveness of FUS in influencing the infralimbic cortex (IL) to prevent the recurrence of MA-seeking behavior, using the conditioned place preference (CPP) method in rats. The study involved twenty male Sprague-Dawley rats. Neuronal activation by FUS was first examined via electromyography (EMG). Rats received alternately with MA or saline, and confined to one of two distinctive compartments in a three compartment apparatus over a 4-day period. After CPP test, extinction, the first reinstatement, and extinction again, FUS was applied to IL prior to the second MA priming-induced reinstatement. Safety assessments were conducted through locomotor and histological function examinations. EMG data confirmed the effectiveness of FUS in activating neurons. Significant attenuation of reinstatement of MA CPP was found, along with successful targeting of the IL region, confirmed through acoustic field scanning, c-Fos immunohistochemistry, and Evans blue dye staining. No damage to brain tissue or impaired locomotor activity was observed. The results of the study indicate that applying FUS to the IL markedly reduced the recurrence of MA seeking behavior, without harming brain tissue or impairing motor skills. This suggests that FUS could be a promising method for treating MA use disorder, with the infralimbic cortex being an effective target for FUS in preventing MA relapse.
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Extinção Psicológica , Metanfetamina , Ratos Sprague-Dawley , Animais , Masculino , Metanfetamina/farmacologia , Ratos , Extinção Psicológica/efeitos dos fármacos , Terapia por Ultrassom/métodos , Estimulantes do Sistema Nervoso Central/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
This study aimed to investigate posterior chain muscle function and the influence of pointe shoes in ballet dancers with and without low back pain (LBP) in the Arabesque. Twenty-nine young professional ballet dancers (17 with LBP and 12 healthy controls) were recruited. Muscle strength and mechanical properties of the erector spinae and hamstrings were assessed. The displacement of centre of mass (COM) during Arabesque under different shoe conditions (R-class, Chacott, and own shoes) was measured with a motion capture system. The LBP group exhibited greater dynamic stiffness and decreased mechanical stress relaxation time in the lateral hamstring compared to the control group. During Arabesque, the LBP group demonstrated significantly greater anterior-posterior displacement of the COM and a larger percentage of time to achieve maximal trunk extension angle. The COM displacement in vertical and medial-lateral directions was smaller in the R-class than in their own shoes. LBP impacts muscle mechanical properties, particularly in the lateral hamstring. The compromised muscle function resulted in a longer time to spinal extension during Arabesque, signifying that reduced trunk control contributed to greater COM displacement. Hence, it is essential to emphasise that evaluating muscle properties and dynamic postural control is imperative for dancers experiencing LBP.
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The escalating menace of multidrug-resistant (MDR) pathogens necessitates a paradigm shift from conventional antibiotics to innovative alternatives. Antimicrobial peptides (AMPs) emerge as a compelling contender in this arena. Employing in silico methodologies, we can usher in a new era of AMP discovery, streamlining the identification process from vast candidate sequences, thereby optimizing laboratory screening expenditures. Here, we unveil cutting-edge machine learning (ML) models that are both predictive and interpretable, tailored for the identification of potent AMPs targeting World Health Organization's (WHO) high-priority pathogens. Furthermore, we have developed ML models that consider the hemolysis of human erythrocytes, emphasizing their therapeutic potential. Anchored in the nuanced physical-chemical attributes gleaned from the three-dimensional (3D) helical conformations of AMPs, our optimized models have demonstrated commendable performance-boasting an accuracy exceeding 75% when evaluated against both low-sequence-identified peptides and recently unveiled AMPs. As a testament to their efficacy, we deployed these models to prioritize peptide sequences stemming from PEM-2 and subsequently probed the bioactivity of our algorithm-predicted peptides vis-à-vis WHO's priority pathogens. Intriguingly, several of these new AMPs outperformed the native PEM-2 in their antimicrobial prowess, thereby underscoring the robustness of our modeling approach. To elucidate ML model outcomes, we probe via Shapley Additive exPlanations (SHAP) values, uncovering intricate mechanisms guiding diverse actions against bacteria. Our state-of-the-art predictive models expedite the design of new AMPs, offering a robust countermeasure to antibiotic resistance. Our prediction tool is available to the public at https://ai-meta.chem.ncu.edu.tw/amp-meta.
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Background: Clinical practice guidelines recommend adjuvant therapy for patients with early non-small cell lung cancer (eNSCLC), especially those with lymph node metastasis. This study evaluated the prevalence of lymph node examination and its association with adjuvant treatment rates, overall survival (OS), and healthcare costs among United States (US) Medicare patients with resected eNSCLC. Methods: This retrospective observational cohort study used Surveillance, Epidemiology, and End Results cancer registry data linked with Medicare claims data. Eligible patients were aged ≥65 years with newly diagnosed non-small cell lung cancer (NSCLC) stages IA to IIIB [the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th edition] between January 2010 and December 2017 with surgery ≤1 month prior to or ≤12 months after diagnosis. Patients were grouped by lymph node examination status: no examination (pNX), examination and no metastasis (pN0), or metastasis staging in N1 (pN1) or N2 (pN2). OS and costs were evaluated by examination status and number of lymph node examined. OS was analyzed using extended Cox proportional hazards models for specific time periods and time interaction with examination status, and adjusted for patient characteristics. Adjusted post-surgical healthcare costs per patient per month (PPPM) were analyzed using gamma-log regression models. Results: Among the 14,648 patients included in the study, approximately 11% were pNX, whereas most were pN0 (68%), followed by pN1 (11%) and pN2 (10%). Adjuvant treatment rates were higher for pNX (35%) than pN0 (18%), but lower than pN1 (68%) and pN2 (74%) patients (P<0.001). Unadjusted OS for pNX patients was nearly identical to pN2, and significantly worse compared to pN0 and pN1 (P<0.0001). After adjusting for patient characteristics, pNX patients had higher risk of death relative to pN0 patients (P<0.001). Marginal mean adjusted total costs were comparable across pNX ($15,827 PPPM), pN0 ($12,712 PPPM) and pN1 ($17,089 PPPM), but significantly less for pN0 compared to pN2 ($23,566 PPPM) (P=0.002). Conclusions: Inadequate lymph node examination is associated with underutilization of adjuvant treatment and poor OS in resected NSCLC. In the current era of targeted and immunotherapies, lymph node examination is more important than ever, implicating the need for Quality Improvement practices and multidisciplinary coordination.
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Circulating exosomes derived from polymicrobial sepsis contain various non-coding RNAs and proteins. Isobaric tags for a relative or absolute quantitation proteomic analysis of the exosomal content revealed 70 dysregulated proteins in the circulating exosomes from septic mice. Next-generation sequencing was used to profile the long non-coding RNA expression in primary cultured macrophages treated with exosomes obtained from the blood of septic C57BL/6 mice, and it was discovered that the nuclear factor-kappa B (NF-κB)/miR-17-92a-1 cluster host gene (MIR17HG) pathways were activated in the macrophages. The inhibition of MIR17HG expression by RNA interference resulted in significantly decreased cell viability. RNA pull-down assays of MIR17HG revealed that ten protein targets bind to MIR17HG. Interaction networks of proteins pulled down by MIR17HG were constructed using GeneMANIA, and their functions were mainly involved in ribonucleoprotein granules, type I interferons, the regulation of organelle assembly, the biosynthesis of acetyl coenzyme A, as a signal transducer and activator of transcription (STAT) protein phosphorylation, and mRNA splicing. Furthermore, RNA interference inhibited MIR17HG expression, resulting in significantly decreased cell survival. In conclusion, this work discovered considerable MIR17HG overexpression in macrophages treated with circulating exosomes from sepsis-affected animals. This study's findings assist us in comprehending the role of exosomes in modulating inflammatory responses and mediating pathogenic pathways in macrophages during sepsis.
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The overexpression of sialic acids on glycans, called hypersialylation, is a common alteration found in cancer cells. Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells (MDSCs). We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated. In murine cancer models of emergency myelopoiesis, Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential. We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs. Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.
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Quimiocina CCL2 , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides , Polissacarídeos , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Animais , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Polissacarídeos/metabolismo , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Humanos , Quimiocina CCL2/metabolismo , Camundongos , Camundongos Knockout , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linhagem Celular Tumoral , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Ácido N-Acetilneuramínico/metabolismoRESUMO
OBJECTIVE: Age-related macular degeneration (AMD), particularly its exudative form, is a primary cause of vision impairment in older adults. As diabetes becomes increasingly prevalent in aging, it is crucial to explore the potential relationship between diabetic retinopathy (DR) and AMD. This study aimed to assess the risk of developing overall, non-exudative, and exudative AMD in individuals with DR compared to those without retinopathy (non-DR) based on a nationwide population study in Taiwan. METHODS: A retrospective cohort study was conducted using the Taiwan National Health Insurance Database (NHIRD) (2000-2013). A total of 3413 patients were placed in the study group (DR) and 13,652 in the control group (non-DR) for analysis. Kaplan-Meier analysis and the Cox proportional hazards model were used to calculate the hazard ratios (HRs) and adjusted hazard ratios (aHRs) for the development of AMD, adjusting for confounding factors, such as age, sex, and comorbid conditions. RESULTS: Kaplan-Meier survival analysis indicated a significantly higher cumulative incidence of AMD in the DR group compared to the non-DR group (log-rank test, p < 0.001). Adjusted analyses revealed that individuals with DR faced a greater risk of overall AMD, with an aHR of 3.50 (95% CI = 3.10-3.95). For senile (unspecified) AMD, the aHR was 3.45 (95% CI = 3.04-3.92); for non-exudative senile AMD, it was 2.92 (95% CI = 2.08-4.09); and for exudative AMD, the aHR was 3.92 (95% CI = 2.51-6.14). CONCLUSION: DR is a significant risk factor for both overall, senile, exudative, and non-exudative AMD, even after adjusting for demographic and comorbid conditions. DR patients tend to have a higher prevalence of vascular comorbidities; however, our findings indicate that the ocular pathologies inherent to DR might have a more significant impact on the progression to AMD. Early detection and appropriate treatment of AMD is critically important among DR patients.
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Virus-like particles (VLPs) are emerging as nanoscaffolds in a variety of biomedical applications including delivery of vaccine antigens and cargo such as mRNA to mucosal surfaces. These soft, colloidal, and proteinaceous structures (capsids) are nevertheless susceptible to mucosal environmental stress factors. We cross-linked multiple capsid surface amino acid residues using homobifunctional polyethylene glycol tethers to improve the persistence and survival of the capsid to model mucosal stressors. Surface cross-linking enhanced the stability of VLPs assembled from Acinetobacter phage AP205 coat proteins in low pH (down to pH 4.0) and high protease concentration conditions (namely, in pig and mouse gastric fluids). Additionally, it increased the stiffness of VLPs under local mechanical indentation applied using an atomic force microscopy cantilever tip. Small angle X-ray scattering revealed an increase in capsid diameter after cross-linking and an increase in capsid shell thickness with the length of the PEG cross-linkers. Moreover, surface cross-linking had no effect on the VLPs' mucus translocation and accumulation on the epithelium of in vitro 3D human nasal epithelial tissues with mucociliary clearance. Finally, it did not compromise VLPs' function as vaccines in mouse subcutaneous vaccination models. Compared to PEGylation without cross-linking, the stiffness of surface cross-linked VLPs were higher for the same length of the PEG molecule, and also the lifetimes of surface cross-linked VLPs were longer in the gastric fluids. Surface cross-linking using macromolecular tethers, but not simple conjugation of these molecules, thus offers a viable means to enhance the resilience and survival of VLPs for mucosal applications.
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Resiliência Psicológica , Vacinas de Partículas Semelhantes a Vírus , Humanos , Animais , Camundongos , Suínos , Proteínas do Capsídeo/química , Capsídeo/metabolismo , Vacinas de Partículas Semelhantes a Vírus/genéticaRESUMO
BACKGROUND: This study investigated the use of ultrasound-guided extracorporeal shock wave lithotripsy (ESWL) to break stones in the genitourinary tract and prevent genitourinary injury. Our goals were to achieve accurate focusing and minimal X-ray exposure for the benefit of the patients. METHODS: The LiteMed LM-9200 lithotripter with ultrasonography and fluoroscopy was used for two different procedures: autoaimed and autoperiodical. These procedures enabled dual focusing on stone localization and tracking. RESULTS: Out of 108 patients who underwent autoperiodical procedures, 29 had no gross hematuria. Among the 335 patients who received autoaimed procedures, 194 had no gross hematuria. The average duration of X-ray exposure during autoperiodical and autoaimed procedures was 120 and 50â s, respectively. CONCLUSION: The ultrasound-guided ESWL with minimal X-ray exposure was found to be useful in treating genitourinary upper-tract urolithiasis in the autoaimed procedure. Patients who underwent the autoaimed procedure experienced less gross hematuria compared to those who underwent the autoperiodical procedure.