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Importance: Chronic pelvic pain (CPP) is the main sequela of pelvic inflammatory disease (PID), with no established treatment. ZY5301 tablets, an effective part preparation extracted from Ajuga decumbens Thunb. (jingucao), are being tested as a treatment for CPP caused by PID. Objective: To evaluate whether ZY5301 tablets are effective and safe for CPP treatment in women with PID. Design, Setting, and Participants: This placebo-controlled double-blind, dose-parallel, phase 2 randomized clinical trial was conducted in 9 hospitals in China. Female participants with CPP after PID were enrolled between October 16, 2020, and August 31, 2021. The data analysis was performed between December 2021 and March 2022. Interventions: Participants were randomized 1:1:1 to receive ZY5301 300 mg/d, ZY5301 600 mg/d, or placebo orally 3 times a day for 12 weeks. Main Outcomes and Measures: Visual analog scale (VAS) scores were the main measure used to evaluate the efficacy of ZY5301 in reducing CPP. The evaluation end points for VAS score included changes in mean weekly VAS score from baseline, area under the VAS score-time curve, pain remission (VAS score of 0 and 1) rate, and median time to pain remission. Safety was evaluated by the occurrence of treatment-emergent and treatment-related adverse events. Results: In total, 180 women were randomly assigned, and 177 were included in the efficacy analysis; thus, the full analysis set included 60 participants in the ZY5301 mg/d group (mean [SD] age, 37.4 [8.1] years), 58 in the ZY5301 600 mg/d group (mean [SD] age, 37.1 [7.9] years), and 59 in the placebo group (mean [SD] age, 38.9 [7.3] years). Participant characteristics at baseline were similar among the groups. After 12 weeks of treatment, the mean (SD) change in VAS score from the baseline was -2.1 (1.7) points, -3.5 (1.5) points, and -3.8 (1.7) points in the placebo, ZY5301 300 mg/d, and ZY5301 600 mg/d groups, respectively (P < .001). The pain remission rates at week 12 were 43.3% and 53.5% in the ZY5301 300 mg/d and ZY5301 600 mg/d groups, respectively, a significant difference compared with the placebo group (11.9%; P < .001). All the other end points showed similar improvements. The ZY5301 600 mg/d group had better efficacy than the ZY5301 300 mg/d group, but the difference was not significant. The safety analysis revealed no significant differences among groups. Conclusions and Relevance: These findings show that ZY5301 tablet is efficacious for the relief of CPP with acceptable tolerability. Trial Registration: ClinicalTrials.gov Identifier: NCT05460546.
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Doença Inflamatória Pélvica , Dor Pélvica , Humanos , Feminino , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Adulto , Doença Inflamatória Pélvica/tratamento farmacológico , Método Duplo-Cego , Comprimidos , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Pessoa de Meia-Idade , Resultado do Tratamento , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Medição da Dor , ChinaRESUMO
BACKGROUND: Human hepatocellular carcinoma (HCC) acquired resistance to anti-cancer agents due to the presence of immunosuppressive tumour microenvironment (TME) established by the interaction between tumour cells and immune populations. New treatment targeting the interaction is urgently needed and clinically beneficial to patients with HCC. This study aims to explore the anti-tumour effect of a Traditional Chinese Medicine formula Siwu Decoction (SWD) and its potential mechanism. MATERIALS AND METHODS: The chemical profile of SWD was determined by high-performance liquid chromatography coupled with mass spectrometry. In vitro and in vivo effects of SWD in regressing HCC were assessed. The role of myeloid-derived suppressor cells (MDSCs) in mediating SWD-induced HCC inhibition was determined by adoptive transfer assay. The regulation of SWD-induced interaction between HCC cells and MDSCs was also confirmed both in vitro and in vivo. RESULTS: SWD dose-dependent inhibited the HCC growth and lung metastasis in an orthotopic growth tumour in mice, without significant toxicity and adverse side effect. SWD induced necroptosis in HCC cells, but did not directly inhibit in vitro culture of MDSCs, instead, SWD-treated HCC cell culture supernatant suppressed MDSCs by inducing its cell apoptosis. The necroptotic response of HCC cells can also suppress the MDSCs population in the TME without reducing circulating MDSCs infiltration into the tumours. Adoptive transfer of MDSCs recovered tumour growth and lung metastasis of HCC in SWD-treated mice. In HCC cells, SWD induced a necroptotic response, and blockade of necroptotic response in HCC cells recovered the MDSCs population in vitro and in vivo, and restored tumour growth and lung metastasis in SWD-treated mice. A combination of SWD improves the anti-HCC efficacy of sorafenib without inducing adverse side effects. Albiflorin, the effective compound of SWD, its anti-HCC manner has been verified to be consistent with that of SWD. CONCLUSION: Our study observed for the first time that SWD can suppress HCC by regulating MDSCs through necroptosis of tumour cells in the TME. The main effective compound of SWD, albiflorin can be a potential adjuvant therapy in the clinical management of human HCC.
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Protein aggregation caused by the disruption of proteostasis will lead to cellular cytotoxicity and even cell death, which is implicated in multiple neurodegenerative diseases. The elimination of aggregated proteins is mediated by selective macroautophagy receptors, which is termed aggrephagy. However, the identity and redundancy of aggrephagy receptors in recognizing substrates remain largely unexplored. Here, we find that CCDC50, a highly expressed autophagy receptor in brain, is recruited to proteotoxic stresses-induced polyubiquitinated protein aggregates and ectopically expressed aggregation-prone proteins. CCDC50 recognizes and further clears these cytotoxic aggregates through autophagy. The ectopic expression of CCDC50 increases the tolerance to stress-induced proteotoxicity and hence improved cell survival in neuron cells, whereas CCDC50 deficiency caused accumulation of lipid deposits and polyubiquitinated protein conjugates in the brain of one-year-old mice. Our study illustrates how aggrephagy receptor CCDC50 combats proteotoxic stress for the benefit of neuronal cell survival, thus suggesting a protective role in neurotoxic proteinopathy.Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; ATG5: autophagy related 5; BODIPY: boron-dipyrromethene; CASP3: caspase 3; CCDC50: coiled-coil domain containing 50; CCT2: chaperonin containing TCP1 subunit 2; CHX: cycloheximide; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; Cas9: CRISPR-associated system 9; DAPI: 4',6-diamidino-2-phenylindole; FK2: Anti-ubiquitinylated proteins antibody, clone FK2; FUS: FUS RNA binding protein; GFP: green fluorescent protein; HD: Huntington disease; HTT: huntingtin; KEGG: Kyoto Encyclopedia of Genes and Genomes; LDS: LIR-docking site; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MIU: motif interacting with ubiquitin; NBR1: NBR1, autophagy cargo receptor; OPTN: optineurin; PD: Parkinson disease; PI: propidium iodide; ROS: reactive oxygen species; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; Ub: ubiquitin; UDS: UIM-docking site; UIM: ubiquitin interacting motif; UPS: ubiquitin-proteasome system.
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Background: Type 2 diabetes mellitus (T2DM) and hearing loss (HL) constitute significant public health challenges worldwide. Recently, the association between T2DM and HL has aroused attention. However, possible residual confounding factors and other biases inherent to observational study designs make this association undetermined. In this study, we performed univariate and multivariable Mendelian Randomization (MR) analysis to elucidate the causal association between T2DM and common hearing disorders that lead to HL. Methods: Our study employed univariate and multivariable MR analyses, with the Inverse Variance Weighted method as the primary approach to assessing the potential causal association between T2DM and hearing disorders. We selected 164 and 9 genetic variants representing T2DM from the NHGRI-EBI and DIAGRAM consortium, respectively. Summary-level data for 10 hearing disorders were obtained from over 500,000 participants in the FinnGen consortium and MRC-IEU. Sensitivity analysis revealed no significant heterogeneity of instrumental variables or pleiotropy was detected. Results: In univariate MR analysis, genetically predicted T2DM from both sources was associated with an increased risk of acute suppurative otitis media (ASOM) (In NHGRI-EBI: OR = 1.07, 95% CI: 1.02-1.13, P = 0.012; In DIAGRAM: OR = 1.14, 95% CI: 1.02-1.26, P = 0.016). Multivariable MR analysis, adjusting for genetically predicted sleep duration, alcohol consumption, body mass index, and smoking, either individually or collectively, maintained these associations. Sensitivity analyses confirmed the robustness of the results. Conclusion: T2DM was associated with an increased risk of ASOM. Strict glycemic control is essential for the minimization of the effects of T2DM on ASOM.
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Diabetes Mellitus Tipo 2 , Análise da Randomização Mendeliana , Otite Média Supurativa , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Otite Média Supurativa/genética , Otite Média Supurativa/complicações , Otite Média Supurativa/epidemiologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Doença Aguda , Perda Auditiva/genética , Perda Auditiva/epidemiologia , Perda Auditiva/etiologia , Feminino , Masculino , Predisposição Genética para DoençaRESUMO
Background: Amid the backdrop of global aging, the increasing prevalence of cognitive decline among the elderly, particularly within the female demographic, represents a considerable public health concern. Physical activity (PA) is recognized as an effective non-pharmacological intervention for mitigating cognitive decline in older adults. However, the relationship between different PA patterns and cognitive function (CF) in elderly women remains unclear. Methods: This study utilized data from National Health and Nutrition Examination Survey (NHANES) 2011-2014 to investigate the relationships between PA, PA patterns [inactive, Weekend Warrior (WW), and Regular Exercise (RE)], and PA intensity with CF in elderly women. Multivariate regression analysis served as the primary analytical method. Results: There was a significant positive correlation between PA and CF among elderly women (ß-PA: 0.003, 95% CI: 0.000-0.006, P = 0.03143). Additionally, WW and RE activity patterns were associated with markedly better cognitive performance compared to the inactive group (ß-WW: 0.451, 95% CI: 0.216-0.685, P = 0.00017; ß-RE: 0.153, 95% CI: 0.085-0.221, P = 0.00001). Furthermore, our results indicate a progressive increase in CF with increasing PA intensity (ß-MPA- dominated: 0.16, 95% CI: 0.02-0.09, P = 0.0208; ß-VPA-dominated: 0.21, 95% CI: 0.09-0.34, P = 0.0011; ß-Total VPA: 0.31, 95% CI: -0.01-0.63, P = 0.0566). Conclusion: Our study confirms a positive association between PA and CF in elderly women, with even intermittent but intensive PA models like WW being correlated with improved CF. These findings underscore the significant role that varying intensities and patterns of PA play in promoting cognitive health among older age groups, highlighting the need for adaptable PA strategies in public health initiatives targeting this population.
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INTRODUCTION: Adipogenesis, the process of white adipose tissue expansion, plays a critical role in the development of obesity. Osteoprotegerin (OPG), known for its role in bone metabolism regulation, emerges as a potential regulator in mediating adipogenesis during obesity onset. OBJECTIVES: This study aims to elucidate the involvement of OPG in adipogenesis during the early phases of diet-induced obesity and explore its therapeutic potential in obesity management. METHODS: Using a diet-induced obesity model, we investigated OPG expression patterns in adipocytes and explored the mechanisms underlying its involvement in adipogenesis. We also assessed the effects of targeted silencing of OPG and recombinant OPG administration on obesity progression and insulin resistance. Additionally, the impact of electroacupuncture treatment on OPG levels and obesity management was evaluated in both animal models and human participants. RESULTS: OPG expression was prominently activated in adipocytes of white adipose tissues during the early phase of diet-induced obesity. Hyperlipidemia induced Cbfa1-dependent OPG transcription, initiating and promoting adipogenesis, leading to cell-size expansion and lipid storage. Intracellular OPG physically bound to RAR and released the PPARɤ/RXR complex, activating adipogenesis-associated gene expression. Targeted silencing of OPG suppressed obesity development, while recombinant OPG administration promoted disease progression and insulin resistance in obese mice. Electroacupuncture treatment suppressed obesity development in an OPG-dependent manner and improved obesity parameters in obese human participants. CONCLUSION: OPG emerges as a key regulator in mediating adipogenesis during obesity development. Targeting OPG holds promise for the prevention and treatment of obesity, as evidenced by the efficacy of electroacupuncture treatment in modulating OPG levels and managing obesity-related outcomes.
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Adipócitos , Adipogenia , Obesidade , Osteoprotegerina , Obesidade/metabolismo , Animais , Humanos , Osteoprotegerina/metabolismo , Camundongos , Masculino , Adipócitos/metabolismo , Resistência à Insulina , Camundongos Endogâmicos C57BL , Tecido Adiposo Branco/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , AdultoRESUMO
Vestibular compensation is a physiological response of the vestibular organs within the inner ear. This adaptation manifests during consistent exposure to acceleration or deceleration, with the vestibular organs incrementally adjusting to such changes. The molecular underpinnings of vestibular compensation remain to be fully elucidated, yet emerging studies implicate associations with neuroplasticity and signal transduction pathways. Throughout the compensation process, the vestibular sensory neurons maintain signal transmission to the central equilibrium system, facilitating adaptability through alterations in synaptic transmission and neuronal excitability. Notable molecular candidates implicated in this process include variations in ion channels and neurotransmitter profiles, as well as neuronal and synaptic plasticity, metabolic processes, and electrophysiological modifications. This study consolidates the current understanding of the molecular events in vestibular compensation, augments the existing research landscape, and evaluates contemporary therapeutic strategies. Furthermore, this review posits potential avenues for future research that could enhance our comprehension of vestibular compensation mechanisms.
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BACKGROUND AND AIMS: Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. MATERIALS AND METHODS: A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. RESULTS: CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. CONCLUSION: Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Camundongos , Animais , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , RNA Longo não Codificante/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , RNA Guia de Sistemas CRISPR-Cas , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR alfa/uso terapêutico , Proteômica , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Background: Cognitive-Motor Dual Task (CMDT) training has been widely utilized in rehabilitation and sports practice. However, whether CMDT training can better enhance athletes' cognitive-motor performance compared to traditional single-task (ST) training remains unclear. Method: A systematic review that complied with PRISMA was carried out (Prospero registration number: CRD42023443594). The electronic databases used for the systematic literature search from the beginning through 13 June 2023, included Web of Science, Embase, PubMed, and the Cochrane Library. After obtaining the initial literature, two researchers independently assessed it based on inclusion and exclusion criteria. Finally, the included literature was analyzed to compare the differences between ST training and CMDT training. Results: After screening 2,094 articles, we included 10 acute studies and 7 chronic studies. Conclusion: This systematic review shows that athletes typically show a degradation of performance in CMDT situations as opposed to ST when evaluated transversally. However, this performance decline is notably reduced following longitudinal training in CMDT, indicating the effectiveness of sustained CMDT training in enhancing cognitive-motor performance under dual-task conditions. Our study provides new insights into the application of CMDT in the field of sports training. Practitioners can utilize CMDT to assess athletic skill levels or optimize cognitive-motor performance of athletes, taking into account the specific needs of each sport. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023443594.
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BACKGROUND: Par-3 Family Cell Polarity Regulator (PARD3) is a cellular protein essential for asymmetric cell division and polarized growth. This study aimed to study the role of PARD3 in hepatic tumorigenesis. METHODS: The essential role of PARD3 in mediating hepatic tumorigenesis was assessed in diet-induced spontaneous liver tumour and syngeneic tumour models. The mechanism of PARD3 was delineated by bulk and single-cell RNA sequencing. The clinical significance of PARD3 was identified by tissue array analysis. RESULTS: PARD3 was overexpressed in tumour tissues and PARD3 overexpression was positively correlated with high tumour stage as well as the poor prognosis in patients. In models of spontaneous liver cancer induced by choline-deficient, amino acid-defined (CDAA) and methionine-choline-deficient (MCD) diets, upregulation of PARD3 was induced specifically at the tumorigenesis stage rather than other early stages of liver disease progression. Site-directed knockout of PARD3 using an adeno-associated virus 8 (AAV8)-delivered CRISPR/Cas9 single-guide RNA (sgRNA) plasmid blocked hepatic tumorigenesis, while PARD3 overexpression accelerated liver tumour progression. In particular, single-cell sequencing analysis suggested that PARD3 was enriched in primitive tumour cells and its overexpression enhanced tumour-initiating cell (TICs). Overexpression of PARD3 maintained the self-renewal ability of the CD133+ TIC population within hepatocellular carcinoma (HCC) cells and promoted the in vitro and in vivo tumorigenicity of CD133+ TICs. Transcriptome analysis revealed that Sonic Hedgehog (SHH) signalling was activated in PARD3-overexpressing CD133+ TICs. Mechanistically, PARD3 interacted with aPKC to further activate SHH signalling and downstream stemness-related genes. Suppression of SHH signalling and aPKC expression attenuated the in vitro and in vivo tumorigenicity of PARD3-overexpressing CD133+ TICs. Tissue array analysis revealed that PARD3 expression was positively associated with the phosphorylation of aPKC, SOX2 and Gli1 and that the combination of these markers could be used to stratify HCC patients into two clusters with different clinicopathological characteristics and overall survival prognoses. The natural compound berberine was selected as a potent suppressor of PARD3 expression and could be used as a preventive agent for liver cancer that completely blocks diet-induced hepatic tumorigenesis in a PARD3-dependent manner. CONCLUSION: This study revealed PARD3 as a potential preventive target of liver tumorigenesis via TIC regulation.
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Proteínas Adaptadoras de Transdução de Sinal , Carcinoma Hepatocelular , Proteínas de Ciclo Celular , Neoplasias Hepáticas , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinogênese/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Colina/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/metabolismo , RNA Guia de Sistemas CRISPR-CasRESUMO
BACKGROUND: The growth and development of rice (Oryza sativa L.) are affected by multiple factors, such as ROS homeostasis and utilization of iron. Here, we demonstrate that OsUGE2, a gene encoding a UDP-glucose 4-epimerase, controls growth and development by regulating reactive oxygen species (ROS) and iron (Fe) level in rice. Knockout of this gene resulted in impaired growth, such as dwarf phenotype, weakened root growth and pale yellow leaves. Biochemical analysis showed that loss of function of OsUGE2 significantly altered the proportion and content of UDP-Glucose (UDP-Glc) and UDP-Galactose (UDP-Gal). Cellular observation indicates that the impaired growth may result from decreased cell length. More importantly, RNA-sequencing analysis showed that knockout of OsUGE2 significantly influenced the expression of genes related to oxidoreductase process and iron ion homeostasis. Consistently, the content of ROS and Fe are significantly decreased in OsUGE2 knockout mutant. Furthermore, knockout mutants of OsUGE2 are insensitive to both Fe deficiency and hydrogen peroxide (H2O2) treatment, which further confirmed that OsUGE2 control rice growth possibly through Fe and H2O2 signal. Collectively, these results reveal a new pathway that OsUGE2 could affect growth and development via influencing ROS homeostasis and Fe level in rice.
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Root hairs are crucial in the uptake of essential nutrients and water in plants. This study showed that a zinc finger protein, GIS3 is involved in root hair growth in Arabidopsis. The loss-of-function gis3 and GIS3 RNAi transgenic line exhibited a significant reduction in root hairs compared to the wild type. The application of 1-aminocyclopropane-1-carboxylic acid (ACC), an exogenous ethylene precursor, and 6-benzyl amino purine (BA), a synthetic cytokinin, significantly restored the percentage of hair cells in the epidermis in gis3 and induced GIS3 expression in the wild type. More importantly, molecular and genetic studies revealed that GIS3 acts upstream of ROOT HAIR DEFECTIVE 2 (RHD2) and RHD4 by binding to their promoters. Furthermore, exogenous ACC and BA application significantly induced the expression of RHD2 and RHD4, while root hair phenotype of rhd2-1, rhd4-1, and rhd4-3 was insensitive to ACC and BA treatment. We can therefore conclude that GIS3 modulates root hair development by directly regulating RHD2 and RHD4 expression through ethylene and cytokinin signals in Arabidopsis.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Inflorescência/metabolismo , Etilenos/metabolismo , Citocininas/metabolismo , Raízes de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , MutaçãoRESUMO
Radiation-induced damage to the blood-brain barrier (BBB) is the recognized pathological basis of radiation-induced brain injury (RBI), a side effect of head and neck cancer treatments. There is currently a lack of therapeutic approaches for RBI due to the ambiguity of its underlying mechanisms. Therefore, it is essential to identify these mechanisms in order to prevent RBI or provide early interventions. One crucial factor contributing to BBB disruption is the radiation-induced activation of astrocytes and oversecretion of vascular endothelial growth factor (VEGF). Mechanistically, the PI3K-AKT pathway can inhibit cellular autophagy, leading to pathological cell aggregation. Moreover, it acts as an upstream pathway of VEGF. In this study, we observed the upregulation of the PI3K-AKT pathway in irradiated cultured astrocytes through bioinformatics analysis, we then validated these findings in animal brains and in vitro astrocytes following radiation exposure. Additionally, we also found the inhibition of autophagy and the oversecretion of VEGF in irradiated astrocytes. By inhibiting the PI3K-AKT pathway or promoting cellular autophagy, we observed a significant amelioration of the inhibitory effect on autophagy, leading to reductions in VEGF oversecretion and BBB disruption. In conclusion, our study suggests that radiation can inhibit autophagy and promote VEGF oversecretion by upregulating the PI3K-AKT pathway in astrocytes. Blocking the PI3K pathway can alleviate both of these effects, thereby mitigating damage to the BBB in patients undergoing radiation treatment.
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Astrócitos , Barreira Hematoencefálica , Animais , Humanos , Barreira Hematoencefálica/patologia , Astrócitos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , AutofagiaRESUMO
Radiation-induced brain injury (RBI) poses a significant challenge in the context of radiotherapy for intracranial tumors, necessitating a comprehensive understanding of the cellular and molecular mechanisms involved. While prior investigations have underscored the role of astrocyte activation and excessive vascular endothelial growth factor production in microvascular damage associated with RBI, there remains a scarcity of studies examining the impact of radiation on astrocytes, particularly regarding organelles such as mitochondria. Thus, our study aimed to elucidate alterations in astrocyte and mitochondrial functionality following radiation exposure, with a specific focus on evaluating the potential ameliorative effects of translocator protein 18 kDa(TSPO) ligands. In this study, cultured astrocytes were subjected to X-ray irradiation, and their cellular states and mitochondrial functions were examined and compared to control cells. Our findings revealed that radiation-induced astrocytic hyperactivation, transforming them into the neurotoxic A1-type, concomitant with reduced cell proliferation. Additionally, radiation triggered mitochondrial hyperfunction, heightened the mitochondrial membrane potential, and increased oxidative metabolite production. However, following treatment with FGIN-1-27, a TSPO ligand, we observed a restoration of mitochondrial function and a reduction in oxidative metabolite production. Moreover, this intervention mitigated astrocyte hyperactivity, decreased the number of A1-type astrocytes, and restored cell proliferative capacity. In conclusion, our study has unveiled additional manifestations of radiation-induced astrocyte dysfunction and validated that TSPO ligands may serve as a promising therapeutic strategy to mitigate this dysfunction. It has potential clinical implications for the treatment of RBI.
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Astrócitos , Fator A de Crescimento do Endotélio Vascular , Astrócitos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Mitocôndrias/metabolismo , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacologia , Células Cultivadas , Proteínas de Transporte/metabolismoRESUMO
A high postoperative tumour recurrence rate has significantly rendered a poorer prognosis in hepatocellular carcinoma (HCC) patients. The aim of this study is to identify a natural compound genipin as a potential and effective candidate to suppress the postoperative recurrence of HCC. Clinical analysis revealed that infiltration of macrophage into the adjacent tissue but not HCC predicted patients' poor prognosis on recurrence-free survival. Genipin intervention suppressed the Ly6C+CD11b+F4/80+ pro-inflammatory macrophage infiltration in the postoperative liver of mice. Adoptive transfer of pro-inflammatory monocytic cells completely abolished the inhibitory effect of genipin on HCC recurrence. Transcriptomic analysis on FACs-sorted macrophages from the postoperative livers of mice revealed that PPARγ signalling was involved in the regulatory effect of genipin. Genipin is directly bound to PPARγ, causing PPARγ-induced p65 degradation, which in turn suppressed the transcriptional activation of CCR2 signalling. PPARγ antagonist GW9662 abrogated the effects of genipin on CCR2-medaited macrophage infiltration as well as HCC recurrence. Cytokine array analysis identified that genipin intervention potently suppressed the secretion of CCL2 further partially contributed to the pro-inflammatory macrophage infiltration into the postoperative liver. Multiplex immunostaining on tissue array of human HCC revealed that PPARγ expression was inversely associated with CCL2 and the macrophage infiltration in the adjacent liver of HCC patients. Our works provide scientific evidence for the therapeutic potential of genipin as a PPARγ agonist in preventing postoperative recurrence of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , PPAR gama/genética , Recidiva Local de Neoplasia , Macrófagos , Receptores CCR2/genéticaRESUMO
AIMS: Therapeutic outcome of sorafenib in hepatocellular carcinoma (HCC) is undermined by the development of drug resistance. This study aimed to identify the critical microRNA (miRNA) which is responsible for sorafenib resistance at the genomic level. METHODS: CRISPR/Cas9 screen followed by gain- and loss-of-function assays both in vitro and in vivo were applied to identify the role of miR-3689a-3p in mediating sorafenib response in HCC. The upstream and downstream molecules of miR-3689a-3p and their mechanism of action were investigated. RESULTS: CRISPR/Cas9 screening identified miR-3689a-3p was the most up-regulated miRNA in sorafenib sensitive HCC. Knockdown of miR-3689a-3p significantly increased sorafenib resistance, while its overexpression sensitized HCC response to sorafenib treatment. Proteomic analysis revealed that the effect of miR-3689a-3p was related to the copper-dependent mitochondrial superoxide dismutase type 1 (SOD1) activity. Mechanistically, miR-3689a-3p targeted the 3'UTR of the intracellular copper chaperone for superoxide dismutase (CCS) and suppressed its expression. As a result, miR-3689a-3p disrupted the intracellular copper trafficking and reduced SOD1-mediated scavenge of mitochondrial oxidative stress that eventually caused HCC cell death in response to sorafenib treatment. CCS overexpression blunted sorafenib response in HCC. Clinically, miR-3689a-3p was down-regulated in HCC and predicted favorable prognosis for HCC patients. CONCLUSION: Our findings provide comprehensive evidence for miR-3689a-3p as a positive regulator and potential druggable target for improving sorafenib treatment in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Superóxido Dismutase-1 , Sistemas CRISPR-Cas , Cobre , Proteômica , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , MicroRNAs/genética , Superóxido Dismutase/genética , Estresse Oxidativo/genéticaRESUMO
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) currently ranks as the third leading cause of mortality worldwide, imposing substantial burdens on societal and individual health. Amongst health research tools, walking pace (WP) and hand grip strength (HGS) are cornerstones, extensively associated with diverse health conditions. However, the intricate interplay between these factors and COPD risk remains ambiguous. This study aims to elucidate the causal association of WP, HGS, with COPD risk through a bidirectional Mendelian randomization (MR) approach. METHODS: Bidirectional MR analysis was performed using Genome-wide association study (GWAS) data of European individuals for WP, HGS, and COPD. Inverse Variance Weighted (IVW) served as the primary MR analysis approach. To supplement the IVW findings, four additional MR methods [MR-Egger, weighted median, maximum likelihood, simple median] were used. To assess heterogeneity and pleiotropy, sensitivity analyses were performed. In addition, multivariate MR (MVMR) analysis was used to assess causality after adjustment for potential confounders. RESULTS: IVW method results show a significant negative association between WP and COPD risk in both initial (genome-wide threshold, odds ratio (OR) = 0.21, 95% confidence interval (CI) 0.09-0.51, P = 5.06 × 10- 4) and secondary (locus-wide threshold, OR = 0.27, 95%CI: 0.18-0.41, P = 4.88 × 10- 10) MR analysis. The reverse MR analysis suggested that COPD also diminishes WP. Additionally, a causal risk reduction for COPD with right HGS (OR = 0.74, 95% CI: 0.58-0.94, P = 1.44 × 10- 2) was only found in secondary MR analysis. The outcomes of the four additional MR methods also suggested similar causal relationships, and sensitivity analyses endorsed their robustness. Lastly, the MVMR analysis demonstrated that the WP's effect on reducing COPD risk persisted independently of potential confounding variables. CONCLUSION: A bidirectional causal relationship exists between typical WP and COPD risk. Conversely, a decrease in right HGS is unidirectionally associated with an increased risk of COPD. The study suggests that WP may serve as a predictive factor for COPD or as a simple evaluative indicator for prognosis.
Assuntos
Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica , Humanos , Força da Mão , Análise da Randomização Mendeliana , Velocidade de Caminhada , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genéticaRESUMO
Background: Osteoarthritis (OA) is one of the most common joint diseases worldwide, imposing a substantial burden on individuals and society. Numerous pieces of evidence suggest that walking pace (WP) can serve as a predictive indicator for the risk of various diseases, and observational studies have also found a potential link between WP and the risk of OA. However, the causal relationship between WP and the risk of OA remains unclear. Methods: We conducted a mendelian randomization (MR) study using data from the European Genome-wide Association Study, which included WP (including 459,915 participants), OA (including 10,083 cases and 40,425 controls), knee OA (including 24,955 cases and 378,169 controls), and hip OA (including 15,704 cases and 378,169 controls). Single nucleotide polymorphisms (SNPs) associated with WP were utilized to infer causal associations with OA and its subtypes. The Inverse Variance Weighted (IVW) technique served as the primary causal analysis method. Three auxiliary MR methods - MR-Egger, weighted median, and maximum likelihood - were used to substantiate the IVW results. Sensitivity analyses were performed to examine heterogeneity and pleiotropy. In addition, multivariate MR (MVMR) analysis was used to assess causality after adjustment for three potential confounders. Results: According to the results of the IVW method, every 1 standard deviation increased in genetic WP corresponds to an 89% reduction in the risk of OA (odds ratio (OR) = 0.11; 95% confidence interval (CI), 0. 06-0.19; p = 1.57 × 10-13), an 83% reduction in the risk of knee OA (OR = 0.17; 95% CI, 0.11-0.28; p = 2.78 × 10-13), and a 76% reduction in the risk of hip OA (OR = 0.24; 95% CI, 0.14-0.43; p = 1.51 × 10-6). These results were confirmed by the three additional MR methods and validated by the sensitivity analysis. Ultimately, the MVMR analysis confirmed that the role of WP in reducing the risk of OA and its subtypes remains consistent regardless of potential confounders. Conclusion: The results of our MR study highlight a significant causal association between WP and the susceptibility to OA, including its knee and hip subtypes. These findings propose that WP could be utilized as a potential prognostic factor for OA risk.
RESUMO
The treatment of patients with balance disorders is an urgent problem to be solved by the medical community. The causes of balance disorders are diverse. An aging population, traffic accidents, stroke, genetic diseases and so on are all possible factors. It has brought great pain and inconvenience to patients and their families. At present, there are two main types of assisted rehabilitation training robots for patients with balance disorders: exoskeleton robots and end robots. The exoskeleton robot is generally installed on the outside of the patient's body to follow their movement, which can support the weight of the body and provide power support to help the patient train and recover lower limb ability. The use of end robots is usually to secure the patient's foot to the motion platform and control the pedal to drive the lower limbs to conduct gait training. Such passive training is more suitable for patients with severe disorders. The patient has low awareness of active participation. This paper focuses on research on end rehabilitation training robots for balance disorders. In this paper, a robotic system for rehabilitation training of patients with balance disorders is invented. The robot body is a 9 degree of freedom (DOF) redundant series-parallel hybrid motion platform. Two sets of motion platforms with symmetrical mirror images are used together to simulate different motion modes of the human body and drive the human body to move. Each set of motion platforms is composed of a 6-DOF vestibular parallel device and a 3-DOF proprioception parallel device. It has the advantages of DOF decoupling and fast response, proposing a new structural form for the design of proprioceptive and vestibular simulation platforms. The robot's functional level can be divided into a vestibular sense module and a proprioception module according to the structure. The two modules can work independently to achieve different functions or work together to achieve complex motion and multisensory fusion. This robot is a redundant mechanism device with 9 DOFs. Through a reasonable distribution of DOF and motion, the robot's working space can be increased, and the robot's flexibility and motion performance can be improved. In this paper, a trajectory tracking control algorithm for vestibular and proprioceptive simulation is proposed, which can provide unlimited body sense training for patients within the robot's limited motion range.
Assuntos
Doenças do Sistema Nervoso , Robótica , Reabilitação do Acidente Vascular Cerebral , Humanos , Idoso , Doenças do Sistema Nervoso/reabilitação , Extremidade Inferior , Terapia por Exercício , MovimentoRESUMO
Generative approaches to molecular design are an area of intense study in recent years as a method to generate new pharmaceuticals with desired properties. Often though, these types of efforts are constrained by limited experimental activity data, resulting in either models that generate molecules with poor performance or models that are overfit and produce close analogs of known molecules. In this paper, we reduce this data dependency for the generation of new chemotypes by incorporating docking scores of known and de novo molecules to expand the applicability domain of the reward function and diversify the compounds generated during reinforcement learning. Our approach employs a deep generative model initially trained using a combination of limited known drug activity and an approximate docking score provided by a second machine learned Bayes regression model, with final evaluation of high scoring compounds by a full docking simulation. This strategy results in molecules with docking scores improved by 10-20% compared to molecules of similar size, while being 130 × faster than a docking only approach on a typical GPU workstation. We also show that the increased docking scores correlate with (1) docking poses with interactions similar to known inhibitors and (2) result in higher MM-GBSA binding energies comparable to the energies of known DDR1 inhibitors, demonstrating that the Bayesian model contains sufficient information for the network to learn to efficiently interact with the binding pocket during reinforcement learning. This outcome shows that the combination of the learned latent molecular representation along with the feature-based docking regression is sufficient for reinforcement learning to infer the relationship between the molecules and the receptor binding site, which suggest that our method can be a powerful tool for the discovery of new chemotypes with potential therapeutic applications.