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BACKGROUND: Facet joint osteoarthritis (FJOA) is a prevalent condition contributing to low back pain, particularly in the elderly population. This study aimed to investigate the potential role of Cytokine Receptor-like Factor 1 (CRLF1) in FJOA pathogenesis and its therapeutic implications. METHODS: Bioinformatics analysis was utilized to identify CRLF1 as the target gene, followed by quantification of CRLF1 expression levels and joint degeneration degree using immunohistochemistry (IHC). In primary chondrocytes, the inhibition of CRLF1 expression by siRNA was performed, and Western blot analysis was conducted to evaluate the involvement of the extracellular matrix and MAPK/ERK signaling pathway. Flow cytometry was employed to assess the apoptosis rate of chondrocytes, while immunofluorescence (IF) was utilized to evaluate the localization of CRLF1, cleaved-caspase3, MMP13, COL2A1, and ERK. RESULTS: The expression of CRLF1 was found to be significantly elevated in FJOA tissues compared to normal tissues. Through the use of loss-of-function assays, it was determined that CRLF1 not only enhanced the rate of apoptosis in chondrocytes, but also facilitated the degradation of the extracellular matrix in vitro. Furthermore, CRLF1 was found to activate the ERK1/2 pathways. The pro-arthritic effects elicited by CRLF1 were mitigated by treatment with the MEK inhibitor U0126 in chondrocytes. CONCLUSION: These results suggest that CRLF1 enhances chondrocytes apoptosis and extracellular matrix degration in FJOA and thus may therefore be a potential therapeutic target for FJOA.
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Aspergillus fumigatus is the predominant pathogen responsible for aspergillosis infections, with emerging drug-resistant strains complicating treatment strategies. The role of mitochondrial functionality in fungal resistance to antifungal agents is well-documented yet not fully understood. In this study, the mitochondrial protein Bcs1A, a homolog of yeast Bcs1, was found to regulate colony growth, ion homeostasis, and the response to antifungal drugs in A. fumigatus. Microscopic observations revealed substantial colocalization of Bcs1A-GFP fusion protein fluorescence with mitochondria. Bcs1A deletion compromised colony growth and the utilization of non-fermentable carbon sources, alongside causing abnormal mitochondrial membrane potential and reduced reactive oxygen species production. These findings underscore Bcs1A's vital role in maintaining mitochondrial integrity. Phenotypic analysis and determinations of minimum inhibitory concentrations indicated that the Δbcs1A mutant was more resistant to various antifungal agents, such as azoles, terbinafine, and simvastatin, compared to wild-type strain. RNA sequencing and RT-qPCR analysis highlighted an upregulation of multiple efflux pumps in the Δbcs1A mutant. Furthermore, loss of the principal drug efflux pump, mdr1, decreased azole tolerance in the Δbcs1A mutant, suggesting that Bcs1A's modulated of azoles response via efflux pump expression. Collectively, these results establish Bcs1A as essential for growth and antifungal drug responsiveness in A. fumigatus mediated through mitochondrial regulation.IMPORTANCEDrug resistance presents a formidable obstacle in the clinical management of aspergillosis. Mitochondria are integral to various biochemical pathways, including those involved in fungi drug response, making mitochondrial proteins promising therapeutic targets for drug therapy. This study confirms that Bcs1A, a mitochondrial respiratory chain protein, is indispensable for mitochondrial functionality and multidrug tolerance in Aspergillus fumigatus. Mutation of Bcs1A not only leads to a series of drug efflux pumps upregulated but also shows that loss of the primary efflux pump, mdr1, partial reduction in drug tolerance in the Bcs1A mutant, highlighting that Bcs1A's significant influence on mitochondria-mediated drug resistance.
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The aim of the study was to compare the efficacy and safety of robot-assisted (RA) percutaneous hollow screw fixation with traditional open reduction internal fixation (ORIF) for the treatment of calcaneal fractures through a systematic review and meta-analysis. An extensive search was conducted in the following databases-PubMed, CNKI, Embase, and the Cochrane Library-to gather research on patients with calcaneal fractures published up to July 2024. This search focuses on studies comparing the effectiveness of robot-assisted percutaneous cannulated screw fixation versus ORIF. We will include studies published in both English and Chinese. Our screening process adhered strictly to predefined inclusion and exclusion criteria, emphasizing randomized controlled trials (RCTs) and cohort studies. The ROBINS-I tool was utilized to evaluate the risk of bias in non-randomized studies. Meta-analysis was conducted using Review Manager 5.4.1. The final analysis incorporated six retrospective cohort studies comprising 247 patients-122 treated with robotic-assisted percutaneous cannulated screw fixation and 125 with conventional open reduction and internal fixation. The findings indicated that patients undergoing robotic-assisted percutaneous cannulated screw fixation experienced advantages over those receiving conventional treatment in terms of reduced hospital stay, lower estimated blood loss, and higher AOFAS scores at both 3 and 6 months. No statistically significant differences were observed between the two methods concerning operative time, fracture healing duration, or the frequency of intraoperative fluoroscopies. Robotic-assisted percutaneous cannulated screw fixation is a safe and viable treatment approach for patients with calcaneal fractures. When compared to ORIF methods, this robotic-assisted technique demonstrated significant benefits, including reduced hospital stay, lower estimated blood loss, and improved AOFAS scores at both 3 and 6 months.
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Calcáneo , Fijación Interna de Fracturas , Fracturas Óseas , Reducción Abierta , Procedimientos Quirúrgicos Robotizados , Humanos , Calcáneo/cirugía , Calcáneo/lesiones , Fijación Interna de Fracturas/métodos , Fijación Interna de Fracturas/instrumentación , Procedimientos Quirúrgicos Robotizados/métodos , Fracturas Óseas/cirugía , Reducción Abierta/métodos , Tornillos Óseos , Resultado del Tratamiento , Tiempo de Internación , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Masculino , Tempo OperativoRESUMEN
OBJECTIVE: This study aimed to distinguish tuberculous spondylodiscitis (TS) from pyogenic spondylodiscitis (PS) based on laboratory, magnetic resonance imaging (MRI) and computed tomography (CT) findings. Further, a novel diagnostic model for differential diagnosis was developed. METHODS: We obtained MRI, CT and laboratory data from TS and PS patients. Predictive models were built using binary logistic regression analysis. The receiver operating characteristic curve was analyzed. Both internal and external validation was performed. RESULTS: A total of 81 patients with PS (n = 46) or TS (n = 35) were enrolled. All patients had etiological evidence from the focal lesion. Disc signal or height preservation, skip lesion or multi segment (involved segments ≥ 3) involvement, paravertebral calcification, massive sequestra formation, subligamentous bone destruction, bone erosion with osteosclerotic margin, higher White Blood Cell Count (WBC) and positive result of tuberculosis infection T cell spot test (T-SPOT.TB) were more prevalent in the TS group. A diagnostic model was developed and included four predictors: WBC<7.265 * (10^9/L), skip lesion or involved segments ≥ 3, massive sequestra formation and subligamentous bone destruction. The model showed good sensitivity, specificity, and total accuracy (91.4%, 95.7%, and 93.8%, respectively); the area under the receiver operating characteristic curve (AUC) was 0.981, similar to the results of internal validation using bootstrap resampling (1000 replicates) and external validation set, indicating good clinical predictive ability. CONCLUSIONS: This study develop a good diagnostic model based on both CT and MRI, as well as laboratory findings, which may help clinicians distinguish between TS and PS.
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Introduction: Alzheimer's disease (AD) represents a critical global health challenge with limited therapeutic options, prompting the exploration of alternative strategies. A key pathology in AD involves amyloid beta (Aß) aggregation, and targeting both Aß aggregation and oxidative stress is crucial for effective intervention. Natural compounds from medicinal and food sources have emerged as potential preventive and therapeutic agents, with Nelumbo nucifera leaf extract (NLE) showing promising properties. Methods: In this study, we utilized transgenic Caenorhabditis elegans (C. elegans) models to investigate the potential of NLE in countering AD and to elucidate the underlying mechanisms. Various assays were employed to assess paralysis rates, food-searching capabilities, Aß aggregate accumulation, oxidative stress, lifespan under stress conditions, and the expression of stress-resistance-related proteins. Additionally, autophagy induction was evaluated by measuring P62 levels and the formation of LGG-1+ structures, with RNAi-mediated inhibition of autophagy-related genes to confirm the mechanisms involved. Results: The results demonstrated that NLE significantly reduced paralysis rates in CL4176 and CL2006 worms while enhancing food-searching capabilities in CL2355 worms. NLE also attenuated Aß aggregate accumulation and mitigated Aß-induced oxidative stress in C. elegans. Furthermore, NLE extended the lifespan of worms under oxidative and thermal stress conditions, while concurrently increasing the expression of stress-resistance-related proteins, including SOD-3, GST-4, HSP-4, and HSP-6. Moreover, NLE induced autophagy in C. elegans, as evidenced by reduced P62 levels in BC12921 worms and the formation of LGG-1+ structures in DA2123 worms. The RNAi-mediated inhibition of autophagy-related genes, such as bec-1 and vps-34, negated the protective effects of NLE against Aß-induced paralysis and aggregate accumulation. Discussion: These findings suggest that NLE ameliorates Aß-induced toxicity by activating autophagy in C. elegans. The study underscores the potential of NLE as a promising candidate for further investigation in AD management, offering multifaceted approaches to mitigate AD-related pathology and stress-related challenges.
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The emergence of drug-resistant bacteria poses a significant threat to people's lives and health as bacterial infections continue to persist. Currently, antibiotic therapy remains the primary approach for tackling bacterial infections. However, the escalating rates of drug resistance coupled with the lag in the development of novel drugs have led to diminishing effectiveness of conventional treatments. Therefore, the development of nonantibiotic-dependent therapeutic strategies has become imperative to impede the rise of bacterial resistance. The emergence of chemodynamic therapy (CDT) has opened up a new possibility due to the CDT can convert H2O2 into â¢OH via Fenton/Fenton-like reaction for drug-resistant bacterial treatment. However, the efficacy of CDT is limited by a variety of practical factors. To overcome this limitation, the sterilization efficiency of CDT can be enhanced by introducing the therapeutics with inherent antimicrobial capability. In addition, researchers have explored CDT-based combined therapies to augment its antimicrobial effects and mitigate its potential toxic side effects toward normal tissues. This review examines the research progress of CDT in the antimicrobial field, explores various strategies to enhance CDT efficacy and presents the synergistic effects of CDT in combination with other modalities. And last, the current challenges faced by CDT and the future research directions are discussed.
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The aim of this study was to evaluate the influence factors of metagenomic next-generation sequencing (mNGS) negative results in the diagnosed patients with spinal infection. mNGS test was applied in a cohort of 114 patients with suspected spinal infection, among which 56 patients had a final diagnosis of spinal infection. mNGS achieved a sensitivity of 75.0% (95% CI, 61.6% to 85.6%) and a specificity of 84.5% (95% CI, 72.6% to 92.7%), using histopathology and culture results as reference. Diagnosed patients with a negative culture result had lower white blood cell account, percentage of neutrophilic granulocyte, C-reactive protein (all P<0.05) and relatively higher rate of prior antimicrobial treatment history (P=0.059). However, diagnosed patients with a negative mNGS result did not have such difference with mNGS-positive patients, suggesting that mNGS was not strictly limited by the above indicators, which presented the advantages of this technique from another point of view.
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Secuenciación de Nucleótidos de Alto Rendimiento , Metagenómica , Sensibilidad y Especificidad , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Masculino , Femenino , Metagenómica/métodos , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Adulto Joven , Enfermedades de la Columna Vertebral/microbiología , Enfermedades de la Columna Vertebral/diagnósticoRESUMEN
Background: Rheumatoid arthritis (RA), a systemic autoimmune disease with approximately 1% prevalent population worldwide, which the etiology is still unclear. RA cannot be completely cured at present, which seriously affects the quality of life of patients. This study is to compare the peripheral blood α-L-fucosidase (AFU) between RA and healthy persons. Methods: A cross-sectional study was performed using total of 96 patients with RA served as case group and another 94 age-matched healthy volunteers served as a control group. AFU assay is detected by continuous monitoring method using Toshiba TBA-120FR (Tokyo, Japan) fully automatic biochemical analyzer in Japan, and the reagent is purchased from Zhejiang Quark Biological Company (Zhejiang, China). Statistical analysis was performed using SPSS 24.0 (SPSS, Inc., Chicago, IL, USA). Results: AFU activity in peripheral blood of RA patients were lower than healthy controls. The higher AFU activity, the shorter the course of disease (r=-0.2790, P=0.0065). The activity of lactate dehydrogenase in patients with RA is higher than that of healthy control, but the activity of acetylcholinesterase is lower than that of normal people. Finally, AFU activity was negatively correlated with the activity of lactate dehydrogenase (r=-0.2381, P=0.0208) and positively correlated with the activity of acetylcholinesterase (r=0.2985, P=0.0035). Conclusions: Changes of peripheral blood AFU activity might be associated with progression of disease in RA patients. The changes of AFU activity may lead to disturbances in glucose and lipid metabolism.
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Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.
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Trombocitopenia , Clorhidrato de Vilazodona , Ratones , Animales , Clorhidrato de Vilazodona/efectos adversos , Clorhidrato de Vilazodona/metabolismo , Pez Cebra , Receptor de Serotonina 5-HT1A/metabolismo , Plaquetas/metabolismo , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/metabolismo , Megacariocitos/metabolismo , TrombopoyesisRESUMEN
BACKGROUND: Ferroptosis, a unique type of cell death triggered by iron-dependent lipid peroxidation, plays a critical role in the pathogenesis of Alzheimer's disease (AD), a debilitating condition marked by memory loss and cognitive impairment due to the accumulation of beta-amyloid (Aß) and hyperphosphorylated Tau protein. Increasing evidence suggests that inhibitors of ferroptosis could be groundbreaking in the treatment of AD. METHOD: In this study, we established in vitro ferroptosis using erastin-, RSL-3-, hemin-, and iFSP1-induced PC-12 cells. Using MTT along with Hoechst/PI staining, we assessed cell viability and death. To determine various aspects of ferroptosis, we employed fluorescence probes, including DCFDA, JC-1, C11 BODIPY, Mito-Tracker, and PGSK, to measure ROS production, mitochondrial membrane potential, lipid peroxidation, mitochondrial morphology, and intracellular iron levels. Additionally, Western blotting, biolayer interferometry technology, and shRNA were utilized to investigate the underlying molecular mechanisms. Furthermore, p-CAX APP Swe/Ind- and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, along with Caenorhabditis elegans (C. elegans) strains CL4176, CL2331, and BR5270, were employed to examine ferroptosis in AD models. RESULTS: Here, we conducted a screening of our natural medicine libraries and identified the ethanol extract of Penthorum chinense Pursh (PEE), particularly its ethyl acetate fraction (PEF), displayed inhibitory effects on ferroptosis in cells. Specifically, PEF inhibited the generation of ROS, lipid peroxidation, and intracellular iron levels. Furthermore, PEF demonstrated protective effects against H2O2-induced cell death, ROS production, and mitochondrial damage. Mechanistic investigations unveiled PEF's modulation of intracellular iron accumulation, GPX4 expression and activity, and FSP1 expression. In p-CAX APP Swe/Ind and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, PEF significantly reduced cell death, as well as ROS and lipid peroxidase production. Moreover, PEF ameliorated paralysis and slowing rate in Aß and Tau transgenic C. elegans models, while inhibiting ferroptosis, as evidenced by decreased DHE intensity, lipid peroxidation levels, iron accumulation, and expression of SOD-3 and gst-4. CONCLUSION: Our findings highlight the suppressive effects of PEF on ferroptosis in AD cellular and C. elegans models. This study helps us better understand how ferroptosis affects AD and emphasizes the potential of PCP as a candidate for AD intervention.
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Enfermedad de Alzheimer , Ferroptosis , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Caenorhabditis elegans , Especies Reactivas de Oxígeno/metabolismo , Peróxido de Hidrógeno/farmacología , Hierro/metabolismoRESUMEN
JOURNAL/nrgr/04.03/01300535-202419110-00027/figure1/v/2024-03-08T184507Z/r/image-tiff Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer's disease. Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases, including Parkinson's and Huntington's diseases, however, the effect of Citri Reticulatae Semen on Alzheimer's disease remains unelucidated. In the current study, the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated. Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy. In addition, Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro, and suppress amyloid-beta-induced pathology such as paralysis, in a transgenic Caenorhabditis elegans in vivo model. Moreover, genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent. Most importantly, Citri Reticulatae Semen extract was confirmed to improve cognitive impairment, neuronal injury and amyloid-beta burden in 3×Tg Alzheimer's disease mice. As revealed by both in vitro and in vivo models, these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer's disease via its neuroprotective autophagic effects.
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Dendrobium nobile is a traditional Chinese herb with anti-inflammatory, antioxidant, and neuroprotective properties. However, its antiaging effects are unclear. Herein, we studied the aging-related functions and the mechanism of action of the alcohol extract of Dendrobium nobile (DnAE) in the model organism Caenorhabditis elegans. The results indicated that 1 mg/mL DnAE slowed lipofuscin accumulation, decreased the levels of reactive oxygen species, elevated superoxide dismutase activity, enhanced oxidative and heat stress resistance, extended the lifespan of nematodes, protected their dopamine neurons from 6-hydroxydopamine-induced neurodegeneration, and reduced Aß-induced neurotoxicity. DnAE upregulated the mRNA expression of the transcription factors DAF-16 and HSF-1, promoted the nuclear localization of DAF-16, and enhanced the fluorescence intensity of HSP-16.2. However, it had no effect on the lifespan of DAF-16 mutants. Thus, DnAE can significantly extend lifespan, enhance heat stress tolerance, and delay age-related diseases through a DAF-16-dependent pathway.
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Proteínas de Caenorhabditis elegans , Dendrobium , Animales , Longevidad , Caenorhabditis elegans , Dendrobium/metabolismo , Estrés Oxidativo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción del Choque Térmico/metabolismo , Etanol/metabolismo , Factores de Transcripción Forkhead/metabolismoRESUMEN
Pharmacological strategies to delay aging and combat age-related diseases are increasingly promising. This study explores the anti-aging and therapeutic effects of two novel 18-norspirostane steroidal saponins from Trillium tschonoskii Maxim, namely deoxytrillenoside CA (DTCA) and epitrillenoside CA (ETCA), using Caenorhabditis elegans (C. elegans). Both DTCA and ETCA significantly extended the lifespan of wild-type N2 worms and improved various age-related phenotypes, including muscle health, motility, pumping rate, and lipofuscin accumulation. Furthermore, these compounds exhibited notable alleviation of pathology associated with Parkinson's disease (PD) and Huntington's disease (HD), such as the reduction of α-synuclein and poly40 aggregates, improvement in motor deficits, and mitigation of neuronal damage. Meanwhile, DTCA and ETCA improved the lifespan and healthspan of PD- and HD-like C. elegans models. Additionally, DTCA and ETCA enhanced the resilience of C. elegans against heat and oxidative stress challenges. Mechanistic studies elucidated that DTCA and ETCA induced mitophagy and promoted mitochondrial biogenesis in C. elegans, while genetic mutations or RNAi knockdown affecting mitophagy and mitochondrial biogenesis effectively eliminated their capacity to extend lifespan and reduce pathological protein aggregates. Together, these compelling findings highlight the potential of DTCA and ETCA as promising therapeutic interventions for delaying aging and preventing age-related diseases.
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Proteínas de Caenorhabditis elegans , Enfermedad de Parkinson , Saponinas , Animales , Caenorhabditis elegans/metabolismo , Longevidad , Mitofagia , Biogénesis de Organelos , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Saponinas/farmacologíaRESUMEN
OBJECTIVE: Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Despite extensive research, no definitive cure or effective disease-modifying treatment for PD exists to date. Therefore, the identification of novel therapeutic agents with neuroprotective properties is of utmost importance. Here, we aimed to investigate the potential neuroprotective effects of Carpesii fructus extract (CFE) in both cellular and Caenorhabditis elegans (C. elegans) models of PD. METHODS: The neuroprotective effect of CFE in H2O2- or 6-OHDA-induced PC-12 cells and α-synuclein-overexpressing PC-12 cells were investigated by determining the cell viability, mitochondrial damage, reactive oxygen species (ROS) production, apoptosis, and α-synuclein expression. In NL5901, BZ555, and N2 worms, the expression of α-synuclein, motive ability, the viability of dopaminergic neurons, lifespan, and aging-related phenotypes were investigated. The signaling pathway was detected by Western blotting and validated by employing small inhibitors and RNAi bacteria. RESULTS: In cellular models of PD, CFE significantly attenuated H2O2- or 6-OHDA-induced toxicity, as evidenced by increased cell viability and reduced apoptosis rate. In addition, CFE treatment suppressed ROS generation and restored mitochondrial membrane potential, highlighting its potential as a mitochondrial protective agent. Furthermore, CFE reduced the expression of α-synuclein in wide type (WT)-, A53T-, A30P-, or E46K-α-synuclein-overexpressing PC-12 cells. Our further findings reveal that CFE administration reduced α-synuclein expression and improved its induced locomotor deficits in NL5901 worms, protected dopaminergic neurons against 6-OHDA-induced degeneration in BZ555 worms, extended lifespan, delayed aging-related phenotypes, and enhanced the ability of stress resistance in N2 worms. Mechanistic studies suggest that the neuroprotective effects of CFE may involve the modulation of the MAPK signaling pathway, including ERK, JNK, and p38, whereas the interference of these pathways attenuated the neuroprotective effect of CFE in vitro and in vivo. CONCLUSION: Overall, our study highlights the potential therapeutic value of CFE as a neuroprotective agent in the context of PD. Furthermore, elucidation of the active compounds of CFE will provide valuable insights for the development of novel therapeutic strategies for PD.
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Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Oxidopamina/toxicidad , Peróxido de Hidrógeno/toxicidad , Peróxido de Hidrógeno/metabolismo , Neuronas Dopaminérgicas/metabolismo , Modelos Animales de EnfermedadRESUMEN
THE ETHNOPHARMACOLOGICAL SIGNIFICANCE: Diabetic chronic foot ulcers pose a significant therapeutic challenge as a result of the oxidative stress caused by hyperglycemia. Which impairs angiogenesis and delays wound healing, potentially leading to amputation. Gynura divaricata (L.) DC. (GD), a traditional Chinese herbal medicine with hypoglycemic effects, has been proposed as a potential therapeutic agent for diabetic wound healing. However, the underlying mechanisms of its effects remain unclear. AIM OF THE STUDY: In this study, we aimed to reveal the effect and potential mechanisms of GD on accelerating diabetic wound healing in vitro and in vivo. MATERIALS AND METHODS: The effects of GD on cell proliferation, apoptosis, reactive oxygen species (ROS) production, migration, mitochondrial membrane potential (MMP), and potential molecular mechanisms were investigated in high glucose (HG) stimulated human umbilical vein endothelial cells (HUVECs) using CCK-8, flow cytometry assay, wound healing assay, immunofluorescence, DCFH-DA staining, JC-1 staining, and Western blot. Full-thickness skin defects were created in STZ-induced diabetic rats, and wound healing rate was tracked by photographing them every day. HE staining, immunohistochemistry, and Western blot were employed to investigate the effect and molecular mechanism of GD on wound healing in diabetic rats. RESULTS: GD significantly improved HUVEC survival, decreased apoptosis, lowered ROS production, restored MMP, improved migration ability, and raised VEGF expression. The use of Nrf2-siRNA completely abrogated these effects. Topical application of GD promoted angiogenesis and granulation tissue growth, resulting in faster healing of diabetic wounds. The expression of VEGF, CD31, and VEGFR was elevated in the skin tissue of diabetic rats after GD treatment, which upregulated HO-1, NQO-1, and Bcl-2 expression while downregulating Bax expression via activation of the Nrf2 signaling pathway. CONCLUSION: The findings of this study indicate that GD has the potential to serve as a viable alternative treatment for diabetic wounds. This potential arises from its ability to mitigate the negative effects of oxidative stress on angiogenesis, which is regulated by the Nrf2 signaling pathway. The results of our study offer valuable insights into the therapeutic efficacy of GD in the treatment of diabetic wounds, emphasizing the significance of directing interventions towards the Nrf2 signaling pathway to mitigate oxidative stress and facilitate the process of angiogenesis.
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Diabetes Mellitus Experimental , Pie Diabético , Ratas , Humanos , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Diabetes Mellitus Experimental/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Cicatrización de Heridas , Células Endoteliales de la Vena Umbilical Humana , Transducción de SeñalRESUMEN
Objective: This retrospective analysis aims to assess the efficacy of transesophageal ultrasound-guided patent foramen ovale (PFO) closure in treating migraine in adolescents and compare the therapeutic outcomes of PFO closure for migraine with and without aura. Methods: We conducted a retrospective analysis of 86 cases of adolescents (12-20 years old) who underwent PFO closure for migraine at our institution over the past 3 years. The efficacy was evaluated using the visual analogue scale (VAS), headache impact test (HIT)-6, and pediatric migraine disability assessment (PedMIDAS) scores, as well as by assessing the monthly frequency of migraine attacks, duration of each attack, and overall migraine burden. The patients were divided into two groups: an aura group (55 cases) and a non-aura group (31 cases) to investigate difference in therapeutic efficacy between the groups. The effect of residual shunt on migraine burden was assessed. Results: Among the 86 patients, 46 (54%) experienced complete remission of migraine, while 71 (83%) achieved a >50% reduction in migraine burden during the one-year follow-up period. Patients in the aura group showed more significant improvements in VAS, HIT-6, and PedMIDAS scores, as well as in monthly migraine attack frequency, duration of each attack, and overall migraine burden, than patients in the non-aura group. Moreover, patients with residual shunt did not exhibit statistically significant differences in therapeutic efficacy compared to patients with complete closure. Conclusion: PFO closure can effectively alleviate migraine symptoms in adolescents with migraine with concomitant PFO. The therapeutic efficacy is particularly pronounced for migraine with aura. Furthermore, minor levels of residual shunt have no effect on the improvement in migraine symptoms.
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Background and Objective: Bullying is notably prevalent among children and adolescents, especially within the context of physical education (PE) environments. Understanding the underlying factors that trigger bullying behavior is essential in designing strategies to prevent bullying and formulating more effective interventions in PE. There is a lack of integrated findings regarding the wide range of correlates of bullying behavior among children and adolescents within the PE context. Therefore, this systematic review aimed to synthesize the correlates of bullying behavior among children and adolescents within the context of PE. Methods: We conducted a systematic search across four databases (EBSCOhost, PubMed, Scopus, Web of Science) for relevant studies published before August 2023. Two reviewers independently examined the articles, assessed their methodological quality, and performed data extraction. Results: A total of 23 articles met the inclusion criteria. It is found that demographic, physical movement, physical appearance, psycho-cognitive, teacher-related, and contextual factors emerged as six prominent influential factors affecting adolescent bullying behavior. Specifically, demographic factors mainly encompassed age and gender; physical movement factors primarily include physical activity, sedentary behavior, physical exercise, and sports competence; physical appearance factors primarily include being overweight, too thin, too tall, or too short; psycho-cognitive factors chiefly involved cognitive empathy, motivation, enjoyment of physical activity; teacher-related factors primarily comprised activity choices, teachers competence, controlling style, autonomy support; and contextual factors primarily cover desolate climate, perceived caring climate, strong sense of competition and winning setting. Conclusion: The results indicate that bullying is a complex and multifaced behavior primarily determined by demographic, physical movement, physical appearance, psycho-cognitive, teacher-related, and contextual factors. Future studies need to enhance the diversity of research samples and comparative studies on the factors influencing bullying behavior among children and adolescents in different countries. Additionally, a more extensive range of intervention studies addressing bullying behavior among children and adolescents is warranted.
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Innate and adaptive immunity is important for initiating and maintaining immune function. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome serves as a checkpoint in innate and adaptive immunity, promoting the secretion of pro-inflammatory cytokines and gasdermin D-mediated pyroptosis. As a highly inflammatory form of cell death distinct from apoptosis, pyroptosis can trigger immunogenic cell death and promote systemic immune responses in solid tumors. Previous studies proposed that NLRP3 was activated by translocation to the mitochondria. However, a recent authoritative study has challenged this model and proved that the Golgi apparatus might be a prerequisite for the activation of NLRP3. In this study, we first developed a Golgi apparatus-targeted photodynamic strategy to induce the activation of NLRP3 by precisely locating organelles. We found that Golgi apparatus-targeted photodynamic therapy could significantly upregulate NLRP3 expression to promote the subsequent release of intracellular proinflammatory contents such as IL-1ß or IL-18, creating an inflammatory storm to enhance innate immunity. Moreover, this acute NLRP3 upregulation also activated its downstream classical caspase-1-dependent pyroptosis to enhance tumor immunogenicity, triggering adaptive immunity. Pyroptosis eventually led to immunogenic cell death, promoted the maturation of dendritic cells, and effectively activated antitumor immunity and long-lived immune memory. Overall, this Golgi apparatus-targeted strategy provided molecular insights into the occurrence of immunogenic pyroptosis and offered a platform to remodel the tumor microenvironment.