RESUMO
OBJECTIVE: Interstitial fibrosis and tubular atrophy (IFTA) were frequent histologic features of lupus nephritis (LN), and LN patients with IFTA have poor renal outcomes. In this study, we aimed to construct prediction models for the IFTA in LN patients. METHODS: This retrospective study included 303 patients with biopsy proven LN at the Affiliated Hospital of Qingdao University and Union Hospital of Fujian Medical University. The participants were randomly divided into development and validation cohorts. They were further divided into IFTA and non-IFTA groups. The least absolute shrinkage and selection operator (LASSO) regression model with laboratory test results collected at the time of kidney biopsy was used to optimize feature selection for the risk model. Multivariable logistic regression analysis was applied to build a predicting model incorporating the feature selected in the LASSO regression model. Discrimination, calibration, and clinical usefulness of the predicting model were assessed using the C-index, calibration plot, and ROC curve analysis. Internal validation was assessed using the bootstrapping validation. A nomogram for individual assessment was constructed based on the preferable model. RESULTS: Predictors contained in the prediction nomogram included age, body mass index (BMI), mean arterial pressure (MAP), logANA, C3, eGFR and serum uric acid. The model displayed good discrimination with a C-index of 0.794 (95% CI 0.734-0.854) and good calibration. High C-index value of 0.857 (95% CI 0.776-0.938) could still be reached in the interval validation. A nomogram model based on the LASSO model was created for producing a probability score of IFTA in LN patients. CONCLUSION: With excellent predictive abilities, the nomogram may provide a simple and reliable tool to distinguish LN patients with IFTA and helps physicians make clinical decisions in their comprehensive assessment.
RESUMO
Stroke is a major cause of adult disability worldwide, often involving disruption of the blood-brain barrier (BBB). Repairing the BBB is crucial for stroke recovery, and pericytes, essential components of the BBB, are potential intervention targets. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for functional impairments after stroke, with potential effects on BBB integrity. However, the underlying mechanisms remain unclear. In this study using a transient middle cerebral artery occlusion (tMCAO) rat model, we investigated the impact of rTMS on post-stroke BBB. Through single-cell sequencing (ScRNAs), we observed developmental relationships among pericytes, endothelial cells, and vascular smooth muscle cells, suggesting the differentiation potential of pericytes. A distinct subcluster of pericytes emerged as a potential therapeutic target for stroke. Additionally, our results revealed enhanced cellular communication among these cell types, enriching signaling pathways such as IGF, TNF, NOTCH, and ICAM. Analysis of differentially expressed genes highlighted processes related to stress, differentiation, and development. Notably, rTMS intervention upregulated Reck in vascular smooth muscle cells, implicating its role in the classical Wnt signaling pathway. Overall, our bioinformatics findings suggest that rTMS may modulate BBB permeability and promote vascular regeneration following stroke. This might happen through 20 Hz rTMS promoting pericyte differentiation into vascular smooth muscle cells, upregulating Reck, then activating the classical Wnt signaling pathway, and facilitating vascular regeneration and BBB stability.
RESUMO
BACKGROUND: To produce jasmine tea of excellent quality, it is crucial to select jasmine flowers at their optimal growth stage during harvesting. However, achieving this goal remains a challenge due to environmental and manual factors. This study addresses this issue by classifying different jasmine flowers based on visual attributes using the YOLOv7 algorithm, one of the most advanced algorithms in convolutional neural networks. RESULTS: The mean average precision (mAP value) for detecting jasmine flowers using this model is 0.948, and the accuracy for five different degrees of openness of jasmine flowers, namely small buds, buds, half-open, full-open and wiltered, is 87.7%, 90.3%, 89%, 93.9% and 86.4%, respectively. Meanwhile, other ways of processing the images in the dataset, such as blurring and changing the brightness, also increased the credibility of the algorithm. CONCLUSION: This study shows that it is feasible to use deep learning algorithms for distinguishing jasmine flowers at different growth stages. This study can provide a reference for jasmine production estimation and for the development of intelligent and precise flower-picking applications to reduce flower waste and production costs. © 2024 Society of Chemical Industry.
RESUMO
As a common consequence of various neurogenic disorders, dysphagia has a significant impact on the quality of life for patients. To promote the development the field of swallowing, it will be helpful to clarify the pathological and therapeutic mechanisms of dysphagia. Through visual analysis of related papers from 1993 to 2023 in the Web of Science Core Collection (WoSCC) database, the research status and development trend of the pathogenesis of dysphagia were discussed. The co-occurrence study was finished using CiteSpace 6.2 R4 software, including keywords, countries, institutions, and authors. Finally, 1,184 studies satisfied the inclusion requirements. The findings of the visualization analysis suggested that aspiration and gastroesophageal reflux disease would be the areas of greatest interest for researchers studying the mechanism of dysphagia. As for the latest occurred research trends, fMRI, signals and machine learning emerging into the field of view of researchers. Based on an analysis of country co-occurrence, United States, Japan and China rank the top three, in terms of the number of publications on dysphagia. University System of Ohio is the organization that has published the most amount of articles regarding the mechanism of dysphagia. Other highly published schools in the top three include State University System of Florida and Northwestern University. For the prolific authors, German, Rebecca Z published the most articles at present, whose own research team working closely together. Several closely cooperating research teams have been formed at present, including the teams centered around German, Rebecca Z, Warnecke, Tobias and Hamdy Shaheen. This study intuitively analyzed the current research status of the mechanism of dysphagia, provided researchers with research hotspots in this field.
RESUMO
Pharyngeal electrical stimulation (PES), a novel noninvasive peripheral nerve stimulation technique, can effectively improve neurogenic dysphagia and increase the safety and effectiveness of swallowing in the clinic. However, the lack of animal models for dysphagia has limited the mechanistic research on PES, which affects its wide application. Therefore, determining optimal parameters for PES in rats is needed to enable mechanistic studies. Modified PES (mPES), which has different waves and pulse widths from PES, was used; in previous studies mPES was found to have a neurological mechanism like that of PES. A poststroke dysphagia (PSD) model was established, and rats with dysphagia were grouped into three different intensities (0.1 mA, 0.5 mA, and 1 mA) for the selection of optimal intensity and three different frequencies (1 Hz, 2 Hz, and 5 Hz) for the selection of optimal frequency based on a stimulation duration of 10 min in the clinic. A Videofluroscopic Swallow Screen (VFSS) was used to assess swallowing function in rats before and after mPES treatment. The results showed that the 1 mA group had better swallowing function (p < 0.05) than the model group. Compared with the model group, the 1 Hz and 5 Hz groups had the same improvement in swallowing function (p < 0.05). However, the increase in excitatory signals in the sensorimotor cortex was more pronounced in the 5 Hz group than in the other frequency stimulation groups (p < 0.05). Combining the clinical findings with the above results, we concluded that the optimal stimulation parameter for mPES in rats is "frequency: 5 Hz, current intensity: 1 mA for 10 min/day", which provides a basis for future basic experimental studies of mPES in animals.
Assuntos
Transtornos de Deglutição , Terapia por Estimulação Elétrica , Faringe , Ratos Sprague-Dawley , Acidente Vascular Cerebral , Animais , Ratos , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , Masculino , Terapia por Estimulação Elétrica/métodos , Faringe/fisiopatologia , Modelos Animais de Doenças , Deglutição/fisiologiaRESUMO
Abundant evidence has shown the protective effect of aerobic exercise on central neuronal system, however, research about resistance exercise remains limited. To evaluate the effect and potential molecular mechanisms of resistance exercise in improving cognition and mental health, three-month-old male C57BL/6J mice underwent resistance training for five weeks. Body parameters, cognitive performance and synaptic plasticity were then assessed. In both groups, total RNA from the frontal cortex, hippocampus and gastrocnemius was isolated and sequenced, GO term and KEGG analysis were performed to identify molecular mechanisms. The results from RNA sequencing were then verified by RT-PCR. Our data found that mice in training group showed reduced anxiety-like behavior and better spatial memory. Accordingly, resistance exercise specifically increased the number of thin spines without affecting the number of other kind of spines. mRNA sequence analysis showed that resistance exercise induced differential expression of hundreds of genes in the above three tissues. KEGG analysis indicated the FoxO signaling pathway the most significant changed pathway throughout the brain and muscle. GO terms analysis showed that Sgk1 was enriched in the three key cognition related BP, including long-term memory, learning or memory and memory, and the expression level of Sgk1 was positive related with cognitive performance in the water maze. In conclusion, resistance exercise improved the mental health, cognition and synaptic plasticity of mice. Integrating analysis of mRNA expression profiles in frontal cortex, hippocampus and muscle reveals Sgk1 as the key mediator in brain-muscle crosstalk.
Assuntos
Encéfalo , Proteínas Imediatamente Precoces , Camundongos Endogâmicos C57BL , Músculo Esquelético , Condicionamento Físico Animal , Proteínas Serina-Treonina Quinases , RNA Mensageiro , Animais , Masculino , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Encéfalo/metabolismo , Camundongos , Músculo Esquelético/metabolismo , Treinamento Resistido , Cognição/fisiologia , Transcriptoma , Plasticidade Neuronal/genética , Hipocampo/metabolismo , Ansiedade/genética , Ansiedade/metabolismoRESUMO
Idiopathic nephrotic syndrome (NS) is a heterogeneous group of glomerular disorders which includes two major phenotypes: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). MCD and FSGS are classic types of primary podocytopathies. We aimed to explore the molecular mechanisms in NS triggered by primary podocytopathies and evaluate diagnostic value of the selected proteomic signatures by analyzing blood proteome profiling. Totally, we recruited 90 participants in two cohorts. The first cohort was analyzed using label-free quantitative (LFQ) proteomics to discover differential expressed proteins and identify enriched biological process in NS which were further studied in relation to clinical markers of kidney injury. The second cohort was analyzed using parallel reaction monitoring-based quantitative proteomics to verify the data of LFQ proteomics and assess the diagnostic performance of the selected proteins using receiver-operating characteristic curve analysis. Several biological processes (such as immune response, cell adhesion, and response to hypoxia) were found to be associated with kidney injury during MCD and FSGS. Moreover, three proteins (CSF1, APOC3, and LDLR) had over 90% sensitivity and specificity in detecting adult NS triggered by primary podocytopathies. The identified biological processes may play a crucial role in MCD and FSGS pathogenesis. The three blood protein markers are promising for diagnosing adult NS triggered by primary podocytopathies.
Assuntos
Biomarcadores , Glomerulosclerose Segmentar e Focal , Nefrose Lipoide , Síndrome Nefrótica , Podócitos , Proteômica , Humanos , Síndrome Nefrótica/sangue , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/metabolismo , Proteômica/métodos , Adulto , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/sangue , Glomerulosclerose Segmentar e Focal/patologia , Feminino , Nefrose Lipoide/diagnóstico , Nefrose Lipoide/metabolismo , Masculino , Podócitos/metabolismo , Podócitos/patologia , Biomarcadores/sangue , Proteoma/análise , Pessoa de Meia-Idade , Estudos de Coortes , Curva ROCRESUMO
Electroacupuncture (EA) stimulation has been shown to be beneficial in stroke rehabilitation; however, little is known about the neurological mechanism by which this peripheral stimulation approach treats for stroke. This study showed that both pyramidal and parvalbumin (PV) neuronal activity increased in the contralesional primary motor cortex forelimb motor area (M1FL) after ischemic stroke induced by focal unilateral occlusion in the M1FL. EA stimulation reduced pyramidal neuronal activity and increased PV neuronal activity. These results were obtained by a combination of fiber photometry recordings, in vivo and in vitro electrophysiological recordings, and immunofluorescence. Moreover, EA was found to regulate the expression/function of N-methyl-D-aspartate receptors (NMDARs) altered by stroke pathology. In summary, our findings suggest that EA could restore disturbed neuronal activity through the regulation of the activity of pyramidal and PV neurons. Furthermore, NMDARs we shown to play an important role in EA-mediated improvements in sensorimotor ability during stroke rehabilitation.
RESUMO
Background: The mechanism by which high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) improves swallowing function by regulating intestinal flora remains unexplored. We aimed to evaluate this using fecal metabolomics and 16S rRNA sequencing. Methods: A Post-stroke dysphagia (PSD) rat model was established by middle cerebral artery occlusion. The magnetic stimulation group received HF-rTMS from the 7th day post-operation up to 14th day post-surgery. Swallowing function was assessed using a videofluoroscopic swallowing study (VFSS). Hematoxylin-eosin (H&E) staining was used to assess histopathological changes in the intestinal tissue. Intestinal flora levels were evaluated by sequencing the 16S rRNA V3-V4 region. Metabolite changes within the intestinal flora were evaluated by fecal metabolomics using liquid chromatography-tandem mass spectrometry. Results: VFSS showed that the bolus area and pharyngeal bolus speed were significantly decreased in PSD rats, while the bolus area increased and pharyngeal transit time decreased after HF-rTMS administration (p < 0.05). In the PSD groups, H&E staining revealed damaged surface epithelial cells and disrupted cryptal glands, whereas HF-rTMS reinforced the integrity of the intestinal epithelial cells. 16S rRNA sequencing indicated that PSD can disturb the intestinal flora and its associated metabolites, whereas HF-rTMS can significantly regulate the composition of the intestinal microflora. Firmicutes and Lactobacillus abundances were lower in the PSD group than in the baseline group at the phylum and genus levels, respectively; however, both increased after HF-rTMS administration. Levels of ceramides (Cer), free fatty acids (FA), phosphatidylethanolamine (PE), triacylglycerol (TAG), and sulfoquinovosyl diacylglycerol were increased in the PSD group. The Cer, FA, and DG levels decreased after HF-rTMS treatment, whereas the TAG levels increased. Peptococcaceae was negatively correlated with Cer, Streptococcus was negatively correlated with DG, and Acutalibacter was positively correlated with FA and Cer. However, these changes were effectively restored by HF-rTMS, resulting in recovery from dysphagia. Conclusion: These findings suggest a synergistic role for the gut microbiota and fecal metabolites in the development of PSD and the therapeutic mechanisms underlying HF-rTMS.
Assuntos
Transtornos de Deglutição , Modelos Animais de Doenças , Fezes , Microbioma Gastrointestinal , Metabolômica , RNA Ribossômico 16S , Acidente Vascular Cerebral , Animais , RNA Ribossômico 16S/genética , Fezes/microbiologia , Fezes/química , Ratos , Metabolômica/métodos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , Transtornos de Deglutição/terapia , Masculino , Estimulação Magnética Transcraniana/métodos , Ratos Sprague-Dawley , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/genética , Bactérias/metabolismoRESUMO
BACKGROUND: Observational studies have suggested a link between panic disorder (PD) and Alzheimer disease (AD). This study aimed to identify the underlying association of PD with the risk of AD using Mendelian randomization. METHODS: Genetic instrumental variables (IVs) were retrieved in the genome-wide association study between PD and AD. Then, five different models, namely inverse variance weighting (IVW), weighted median, weighted mode, MR-Egger and MR-robust adjusted profile scores (MR-RAPS), were used for MR Analysis. Finally, the heterogeneity and pleiotropy of identified IVs were verified by multiple sensitivity tests. RESULTS: The Cochran's Q test based on MR Egger and IVW showed that no evidence of heterogeneity was found in the effects of instrumental variables, so a fixed-effect model was used. IVW analysis (OR 1.000479, 95% CI [1.000147056, 1.000811539], p = 0.005) indicated that PD was associated with an increased risk of AD, and a causal association existed between them. Meanwhile, weighted median (OR 1.000513373, 95% CI [1.000052145, 1.000974814], p = 0.029) and MR-RAPS (OR 1.000510118, 95% CI [1.000148046, 1.00087232], p = 0.006) also showed the similar findings. In addition, extensive sensitivity analyses confirmed the robustness and accuracy of these results. CONCLUSION: This investigation provides evidence of a potential causal relationship between PD and the increased risk of AD. Based on our MR results, when diagnosing and treating patients with PD, clinicians should pay more attention to their AD-related symptoms to choose therapeutic measures or minimize comorbidities. Furthermore, the development of drugs that improve both PD and AD may better treat patients with these comorbidities.
Assuntos
Doença de Alzheimer , Transtorno de Pânico , Humanos , Análise da Randomização Mendeliana , Transtorno de Pânico/genética , Doença de Alzheimer/genética , Estudo de Associação Genômica Ampla , Análise de VariânciaRESUMO
BACKGROUND: Post-stroke dysphagia (PSD) is a common symptom of stroke. Clinical complications of PSD include malnutrition and pneumonia. Clinical studies have shown that high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) can improve the swallowing function in stroke patients. However, few studies have elucidated the underlying molecular mechanisms. METHODS: A PSD rat model was established using transient middle cerebral artery occlusion (tMCAO). Rats were randomly divided into sham-operated groups, PSD groups, PSD + sham-rTMS groups, PSD + 5 Hz-rTMS groups, PSD + 10 Hz-rTMS groups and PSD + 20 Hz-rTMS groups. Rats were weighed and videofluoroscopic swallowing studies were conducted. Pulmonary inflammation, levels of substance P (SP) and calcitonin gene-related peptide (CGRP) in the serum, lung, and nucleus tractus solitarius (NTS), brain-derived neurotrophic factor (BDNF) and 5-hydroxytryptamine (5HT) in NTS were evaluated. RESULTS: Rats in the PSD group experienced weight loss, reduced bolus area and pharyngeal bolus speed, and increased pharyngeal transit time (PTT) and inter-swallow interval (ISI) on day 7 and day 14 after operation. Moreover, PSD rats showed pulmonary inflammation, reduced levels of SP in the lung and serum, increased levels of CGRP in the lung and NTS, reduced levels of BDNF and 5HT in the NTS. There was no significant difference between the PSD group and the PSD + sham-rTMS group in the results of weight and VFSS. Comparing with the PSD group, there significant increases in the bolus area, decreases in PTT of rats following 5 Hz rTMS intervention. HF-rTMS at 10 Hz significantly increased the weight, bolus area, pharyngeal bolus speed and decreased the PTT and ISI of rats. There were also significant increases in the bolus area (p < 0.01) and pharyngeal bolus speed, decreases in PTT and ISI of rats following 20 Hz rTMS intervention. Furthermore, compared with the PSD + 5 Hz-rTMS group, there were significant increases in the bolus area and pharyngeal bolus speed, decreases in ISI in the swallowing function of rats in the PSD + 10 Hz-rTMS group. Besides, compared with the PSD + 5 Hz-rTMS group, there were significant decreases in ISI in the swallowing function of rats in the PSD + 20 Hz-rTMS group. HF-rTMS at 10 Hz alleviated pulmonary inflammation, increased the levels of SP in the lung, serum, and NTS, CGRP in the serum and NTS, 5HT in the NTS of PSD rats. CONCLUSION: Compared with 5 Hz and 20 Hz rTMS, 10 Hz rTMS more effectively improved the swallowing function of rats with PSD. HF-rTMS at 10 Hz improved the swallowing function and alleviated pneumonia in PSD rats. The mechanism may be related to increased levels of SP in the lung, serum and NTS, levels of CGRP in the serum and NTS, 5HT in the NTS after HF-rTMS treatment.
Assuntos
Transtornos de Deglutição , Pneumonia , Acidente Vascular Cerebral , Humanos , Animais , Ratos , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Deglutição/fisiologia , Estimulação Magnética Transcraniana/métodos , Fator Neurotrófico Derivado do Encéfalo , Peptídeo Relacionado com Gene de Calcitonina , Pneumonia/terapia , Pneumonia/complicaçõesRESUMO
BACKGROUND: Post-stroke dysphagia (PSD), a common and serious disease, affects the quality of life of many patients and their families. Electroacupuncture (EA) has been commonly used effectively in the treatment of PSD, but the therapeutic mechanism is still under exploration at present. We aim to investigate the effect of the nucleus tractus solitarus (NTS) on the treatment of PSD by EA at Lianquan (CV23) through the primary motor cortex (M1). METHODS: C57 male mice were used to construct a PSD mouse model using photothrombotic technique, and the swallowing function was evaluated by electromyography (EMG) recording. C-Fos-positive neurons and types of neurons in the NTS were detected by immunofluorescence. Optogenetics and chemical genetics were used to regulate the NTS, and the firing rate of neurons was recorded via multichannel recording. RESULTS: The results showed that most of the activated neurons in the NTS were excitatory neurons, and multichannel recording indicated that the activity levels of both pyramidal neurons and interneurons in the NTS were regulated by M1. This process was involved in the EA treatment. Furthermore, while chemogenetic inhibition of the NTS reduced the EMG signal associated with the swallowing response induced by activation of M1 in PSD mice, EA rescued this signal. CONCLUSION: Overall, the NTS was shown to participate in the regulation of PSD by EA at CV23 through M1.
Assuntos
Transtornos de Deglutição , Eletroacupuntura , Córtex Motor , Humanos , Ratos , Masculino , Camundongos , Animais , Núcleo Solitário , Eletroacupuntura/métodos , Ratos Sprague-Dawley , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Qualidade de VidaRESUMO
AIMS: Electroacupuncture (EA) at the Lianquan (CV23) could alleviate swallowing dysfunction. However, current knowledge of its neural modulation focused on the brain, with little evidence from the periphery. Transient receptor potential channel vanilloid subfamily 1 (TRPV1) is an ion channel predominantly expressed in sensory neurons, and acupuncture can trigger calcium ion (Ca2+ ) wave propagation through active TRPV1 to deliver signals. The present study aimed to investigate whether TRPV1 mediated the signal of EA to the primary sensory cortex (S1) during regulation of swallowing function. METHODS: Blood perfusion was evaluated by laser speckle contrast imaging (LSCI), and neuronal activity was evaluated by fiber calcium recording and c-Fos staining. The expression of TRPV1 was detected by RNA-seq analysis, immunofluorescence, and ELISA. In addition, the swallowing function was assessed by in vivo EMG recording and water consumption test. RESULTS: EA treatment potentiated blood perfusion and neuronal activity in the S1, and this potentiation was absent after injecting lidocaine near CV23. TRPV1 near CV23 was upregulated by EA-CV23. The blood perfusion at CV23 was decreased in the TRPV1 hypofunction mice, while the blood perfusion and the neuronal activity of the S1 showed no obvious change. These findings were also present in post-stroke dysphagia (PSD) mice. CONCLUSION: The TRPV1 at CV23 after EA treatment might play a key role in mediating local blood perfusion but was not involved in transferring EA signals to the central nervous system (CNS). These findings collectively suggested that TRPV1 may be one of the important regulators involved in the mechanism of EA treatment for improving swallowing function in PSD.
Assuntos
Terapia por Acupuntura , Eletroacupuntura , Acidente Vascular Cerebral , Camundongos , Animais , Eletroacupuntura/métodos , Deglutição/fisiologia , Cálcio/metabolismo , Sistema Nervoso Central/metabolismo , Canais de Cátion TRPV/metabolismo , Pontos de AcupunturaRESUMO
As one of the commonly used therapies for pain-related diseases in clinical practice, electroacupuncture (EA) has been proven to be effective. In chronic pain, neurons in the anterior cingulate cortex (ACC) have been reported to be hyperactive, while the mechanism by which cannabinoid type 1 receptors (CB1Rs) in the ACC are involved in EA-mediated analgesic mechanisms remains to be elucidated. In this study, we investigated the potential central mechanism of EA analgesia. A combination of techniques was used to detect the expression and function of CB1R, including quantitative real-time PCR (q-PCR), western blot (WB), immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and in vivo multichannel optical fibre recording, and neuronal activity was examined by in vivo two-photon imaging and in vivo electrophysiological recording. We found that the hyperactivity of pyramidal neurons in the ACC during chronic inflammatory pain is associated with impairment of the endocannabinoid system. EA at the Zusanli acupoint (ST36) can reduce the hyperactivity of pyramidal neurons and exert analgesic effects by increasing the endocannabinoid ligands anandamide (AEA), 2-arachidonoylglycerol (2-AG) and CB1R. More importantly, CB1R in the ACC is one of the necessary conditions for the EA-mediated analgesia effect, which may be related to the negative regulation of the N-methyl-D-aspartate receptor (NMDAR) by the activation of CB1R downregulating NR1 subunits of NMDAR (NR1) via histidine triad nucleotide-binding protein 1 (HINT1). Our study suggested that the endocannabinoid system in the ACC plays an important role in acupuncture analgesia and provides evidence for a central mechanism of EA-mediated analgesia.
RESUMO
DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response pathway, plays an instrumental role in repairing double-strand breaks (DSB) induced by DNA-damaging poisons. We evaluate ZL-2201, an orally bioavailable, highly potent, and selective pharmacologic inhibitor of DNA-PK activity, for the treatment of human cancerous malignancies. ZL-2201 demonstrated greater selectivity for DNA-PK and effectively inhibited DNA-PK autophosphorylation in a concentration- and time-dependent manner. Initial data suggested a potential correlation between ataxia-telangiectasia mutated (ATM) deficiency and ZL-2201 sensitivity. More so, ZL-2201 showed strong synergy with topoisomerase II inhibitors independent of ATM status in vitro. In vivo oral administration of ZL-2201 demonstrated dose-dependent antitumor activity in the NCI-H1703 xenograft model and significantly enhanced the activity of approved DNA-damaging agents in A549 and FaDu models. From a phosphoproteomic mass spectrometry screen, we identified and validated that ZL-2201 and PRKDC siRNA decreased Ser108 phosphorylation of MCM2, a key DNA replication factor. Collectively, we have characterized a potent and selective DNA-PK inhibitor with promising monotherapy and combinatory therapeutic potential with approved DNA-damaging agents. More importantly, we identified phospho-MCM2 (Ser108) as a potential proximal biomarker of DNA-PK inhibition that warrants further preclinical and clinical evaluation. Significance: ZL-2201, a potent and selective DNA-PK inhibitor, can target tumor models in combination with DNA DSB-inducing agents such as radiation or doxorubicin, with potential to improve recurrent therapies in the clinic.
Assuntos
Proteína Quinase Ativada por DNA , Humanos , Administração Oral , Fosforilação , Animais , Proteína Quinase Ativada por DNA/antagonistas & inibidoresRESUMO
Background: S-ketamine (the S-isomer of ketamine) is twice as potent as the racemic mixture of this agent and carries fewer side effects when administered to humans. Information regarding the use of S-ketamine for the prevention of emergence delirium (ED) is limited. Thus, we evaluated the effect of S-ketamine administered at the end of anesthesia on ED in preschool children undergoing tonsillectomy and/or adenoidectomy. Methods: We investigated 108 children aged 3-7 years, who were scheduled for elective tonsillectomy and/or adenoidectomy under general anesthesia. They were randomly assigned to receive either S-ketamine 0.2 mg/kg or an equal volume of normal saline at the end of anesthesia. The primary outcome was the highest score on the pediatric anesthesia ED (PAED) scale during the first 30 min post-surgery. The secondary outcomes included the incidence of ED (defined as a score of ≥ 3 on Aono scale), pain score, time to extubation, and incidences of adverse events. Multivariate analyses were also performed using logistic regression to evaluate the independent factors predictive of ED. Results: The median (interquartile range) PAED score of the S-ketamine group (0 [0, 3]) was significantly lower than that in the control group (1 [0, 7]) (estimate median difference = 0, 95% confidence interval -2 to 0, p = 0.040). Significantly fewer patients in the S-ketamine group had an Aono scale score ≥ 3 (4 [7%] vs. 12 [22%], p = 0.030). Patients in the S-ketamine group also had a lower median pain score than did control subjects (4 [4, 6] vs. 6 [5, 8], p = 0.002). The time to extubation and incidences of adverse events were comparable between the two groups. However, multivariate analyses indicated that except S-ketamine use, pain scores, age and duration of anesthesia were independent factors predictive of ED. Conclusion: S-ketamine (0.2 mg/kg) administered at the end of anesthesia effectively reduced the incidence and severity of ED in preschool children undergoing tonsillectomy and/or adenoidectomy without prolonging the time to extubation or increasing adverse events. However, S-ketamine use was not an independent factor predictive of ED.
RESUMO
As a traditional medical therapy, stimulation at the Lianquan (CV23) acupoint, located at the depression superior to the hyoid bone, has been shown to be beneficial in dysphagia. However, little is known about the neurological mechanism by which this peripheral stimulation approach treats for dysphagia. Here, we first identified a cluster of excitatory neurons in layer 5 (L5) of the primary motor cortex (M1) that can regulate swallowing function in male mice by modulating mylohyoid activity. Moreover, we found that focal ischemia in the M1 mimicked the post-stroke dysphagia (PSD) pathology, as indicated by impaired water consumption and electromyographic responses in the mylohyoid. This dysfunction could be rescued by electroacupuncture (EA) stimulation at the CV23 acupoint (EA-CV23) in a manner dependent on the excitatory neurons in the contralateral M1 L5. Furthermore, neuronal activation in both the parabrachial nuclei (PBN) and nucleus tractus solitarii (NTS), which was modulated by the M1, was required for the ability of EA-CV23 treatment to improve swallowing function in male PSD model mice. Together, these results uncover the importance of the M1-PBN-NTS neural circuit in driving the protective effect of EA-CV23 against swallowing dysfunction and thus reveal a potential strategy for dysphagia intervention.
Assuntos
Transtornos de Deglutição , Eletroacupuntura , Córtex Motor , Acidente Vascular Cerebral , Masculino , Camundongos , Animais , Núcleo Solitário , Deglutição/fisiologia , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Eletroacupuntura/métodos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapiaRESUMO
Background: Pneumonia is common in patients with tracheostomy and dysphagia. However, the influence of dysphagia and tracheostomy on pneumonia in patients with stroke remains unclear. The aim of this study was to explore the risk factors related to pneumonia, and the association between dysphagia, tracheostomy and pneumonia in patients with stroke was investigated. Methods: Patients with stroke who experienced tracheostomy and dysphagia were included and divided into two groups based on record of pneumonia at discharge. Clinical manifestations and physical examination were used to diagnose pneumonia, whereas clinical swallowing examination, and videofluoroscopy swallowing studies (VFSS) were used to evaluate swallowing function. Results: There were significant differences between the pneumonia group and the no pneumonia group in total tracheostomy time (6.3 ± 5.9 vs. 4.3 ± 1.7 months, p = 0.003), number of instances of ventilator support (0.41 ± 0.49 vs. 0.18 ± 0.38, p = 0.007), PAS score (5.2 ± 1.92 vs. 4.3 ± 1.79, p = 0.039), impaired or absent cough reflex (76.4 vs. 55.6%, p = 0.035), oropharyngeal phase dysfunction (60.6 vs. 40.8%, p = 0.047), length of hospital stay (36.0 ± 7.2 vs. 30.5 ± 11.7 days, p = 0.025) and direct medical costs (15,702.21 ± 14,244.61 vs. 10,923.99 ± 7250.14 United States dollar [USD], p = 0.042). Multivariate logistic regression showed that the total tracheostomy time (95% confidence interval [CI], 1.966−12.922, p = 0.001), impaired or absent cough reflex (95% CI, 0.084−0.695, p = 0.008), and oropharyngeal phase dysfunction (95% CI, 1.087−8.148, p = 0.034) were risk factors for pneumonia. Spearman's correlation analysis demonstrated that PAS scores were significantly correlated with cough reflex dysfunction (r = 0.277, p = 0.03), oropharyngeal phase dysfunction (r = 0.318, p < 0.01) and total tracheostomy time (r = 0.178, p = 0.045). The oropharyngeal phase dysfunction was significantly correlated with cough reflex (r = 0.549, p < 0.001) and UES opening (r = 0.643, p < 0.01). Conclusions: Tracheostomy and dysphagia increased the risk of pneumonia in patients with stroke. Total tracheostomy time, duration of ventilator support, degree of penetration and aspiration, and oropharyngeal phase dysfunction are risk factors. Given this, we also found that there may be a correlation between tracheostomy and dysphagia.
RESUMO
Objective: Aspiration is a common complication after tracheostomy in patients with acquired brain injury (ABI), resulting from impaired swallowing function, and which may lead to aspiration pneumonia. The Passy-Muir Tracheostomy and Ventilator Swallowing and Speaking Valve (PMV) has been used to enable voice and reduce aspiration; however, its mechanism is unclear. This study aimed to investigate the mechanisms underlying the beneficial effects of PMV intervention on the prevention of aspiration. Methods: A randomized, single-blinded, controlled study was designed in which 20 tracheostomized patients with aspiration following ABI were recruited and randomized into the PMV intervention and non-PMV intervention groups. Before and after the intervention, swallowing biomechanical characteristics were examined using video fluoroscopic swallowing study (VFSS) and high-resolution manometry (HRM). A three-dimensional (3D) upper airway anatomical reconstruction was made based on computed tomography scan data, followed by computational fluid dynamics (CFD) simulation analysis to detect subglottic pressure. Results: The results showed that compared with the non-PMV intervention group, the velopharynx maximal pressure (VP-Max) and upper esophageal sphincter relaxation duration (UES-RD) increased significantly (P < 0.05), while the Penetration-Aspiration Scale (PAS) score decreased in the PMV intervention group (P < 0.05). Additionally, the subglottic pressure was successfully detected by CFD simulation analysis, and increased significantly after 2 weeks in the PMV intervention group compared to the non-PMV intervention group (P < 0.001), indicating that the subglottic pressure could be remodeled through PMV intervention. Conclusion: Our findings demonstrated that PMV could improve VP-Max, UES-RD, and reduce aspiration in tracheostomized patients, and the putative mechanism may involve the subglottic pressure. Clinical trial registration: [http://www.chictr.org.cn], identifier [ChiCTR1800018686].
RESUMO
Objective: To investigate the relationship of lobar and deep brain regions with post-stroke dysphagia (PSD). Method: The databases of Medline, Embase, Web of Science, and Cochrane Library were searched from the establishment to May 2022. Studies that investigated the effects of lesions in lobar and deep brain regions on swallowing function after stroke were screened. The primary outcomes were PSD-related brain regions (including aspiration-related and oral transit time-related brain regions). The secondary outcomes were the incidence rate of PSD. The brain regions with the most overlap in the included studies were considered to be most relevant to PSD, and were presented as percentages. Data were compared utilizing the t-tests for continuous variables and χ2 for frequency-based variables. Result: A total of 24 studies and 2306 patients were included. The PSD-related lobar and deep brain regions included the insular cortex, frontal lobe, temporal gyrus, basal ganglia, postcentral, precentral, precuneus, corona radiate, etc. Among these brain regions, the insular cortex was most frequently reported (taking up 54.2%) in the included studies. Furthermore, the total incidence rate of PSD was around 40.4%, and the incidence of male was nearly 2.57 times as much as that of female (χ2 = 196.17, p < 0.001). Conclusions: In lobar and deep brain regions, the insular cortex may be most relevant to PSD and aspiration, which may be a potentially promising target in the treatment of PSD.