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Background: For Rheumatoid Arthritis (RA), a long-term chronic illness, it is essential to identify and describe patient subtypes with comparable goal status and molecular biomarkers. This study aims to develop and validate a new subtyping scheme that integrates genome-scale transcriptomic profiles of RA peripheral blood genes, providing a fresh perspective for stratified treatments. Methods: We utilized independent microarray datasets of RA peripheral blood mononuclear cells (PBMCs). Up-regulated differentially expressed genes (DEGs) were subjected to functional enrichment analysis. Unsupervised cluster analysis was then employed to identify RA peripheral blood gene expression-driven subtypes. We defined three distinct clustering subtypes based on the identified 404 up-regulated DEGs. Results: Subtype A, named NE-driving, was enriched in pathways related to neutrophil activation and responses to bacteria. Subtype B, termed interferon-driving (IFN-driving), exhibited abundant B cells and showed increased expression of transcripts involved in IFN signaling and defense responses to viruses. In Subtype C, an enrichment of CD8+ T-cells was found, ultimately defining it as CD8+ T-cells-driving. The RA subtyping scheme was validated using the XGBoost machine learning algorithm. We also evaluated the therapeutic outcomes of biological disease-modifying anti-rheumatic drugs. Conclusions: The findings provide valuable insights for deep stratification, enabling the design of molecular diagnosis and serving as a reference for stratified therapy in RA patients in the future.
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Artrite Reumatoide , Perfilação da Expressão Gênica , Transcriptoma , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/diagnóstico , Humanos , Antirreumáticos/uso terapêutico , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Biomarcadores , Linfócitos T CD8-Positivos/imunologiaRESUMO
Background: Insomnia is one of the most common symptoms among breast cancer patients, which can be present throughout all stages of breast cancer. As a non-pharmacological alternative treatment, acupuncture has been suggested to improve sleep situations in patients with cancer suffering from insomnia. However, there is a lack of well-designed, high-quality clinical evidence regarding the efficacy of acupuncture in the treatment of breast cancer-related insomnia. This study is conducted to evaluate the efficacy and safety of acupuncture treatment for breast cancer-related insomnia. Methods: This study was designed as a multicenter, randomized, sham-controlled clinical trial. A total of 264 eligible patients with breast cancer-related insomnia will be randomized into an acupuncture group and a sham acupuncture group in a 1:1 ratio. In the trial, patients in the acupuncture and sham acupuncture groups will receive 12 sessions over a consecutive 4-week period. The primary outcome will be the treatment response rate of Insomnia Severity Index (ISI) at week 4; secondary outcomes include treatment remission rate of ISI, Sleep Efficiency (SE) obtained by the use of Sleep diary, treatment response rate of ISI at 8th and 16th weeks of follow-up, the mean changes of ISI, Generalized Anxiety Disorder Scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Quality of Life Questionnaire - Core 30 (QLQ-C30), sleep parameters recorded in Actigraphy and weekly usage of remedial drugs. Adverse events will be recorded throughout the study. All analyses will be based on the ITT principle and performed with SAS 9.4 statistical software. Discussion: This trial will evaluate the clinical efficacy and safety of acupuncture for breast cancer-related insomnia. If proven effective, acupuncture will provide an effective option for patients with breast cancer-related insomnia, which will play a positive role in helping patients reduce their use of sleeping medications. Clinical trial registration: ClinicalTrials.gov, identifier NCT05510700.
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Metal halide perovskite materials inherently possess imperfections, particularly under nonequilibrium conditions, such as exposure to light or heat. To tackle this challenge, we introduced stearate ligand-capped nickel oxide (NiOx), a redox-sensitive metal oxide with variable valence, into perovskite intermediate films. The integration of NiOx improved the efficiency and stability of perovskite solar cells (PSCs) by offering multifunctional roles: (1) chemical passivation for ongoing defect repair, (2) energetic passivation to bolster defect tolerance, and (3) field-effect passivation to mitigate charge accumulation. Employing a synergistic approach that tailored these three passivation mechanisms led to a substantial increase in the devices' efficiencies. The target cell (0.12 cm2) and module (18 cm2) exhibited efficiencies of 24.0 and 22.9%, respectively. Notably, the encapsulated modules maintained almost 100 and 87% of the initial efficiencies after operating for 1100 h at the maximum power point (60 °C, 50% RH) and 2000 h of damp-heat testing (85 °C, 85% RH), respectively. Outdoor real-time tests further validated the commercial viability of the NiOx-assisted PSMs. The proposed passivation strategy provides a practical and uncomplicated approach for fabricating high-efficiency and stable photovoltaics.
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Modern medicine has unveiled that essential oil made from Aquilaria possesses sedative and hypnotic effects. Among the chemical components in Aquilaria, nerolidol, a natural sesquiterpene alcohol, has shown promising effects. This study aimed to unravel the potential of nerolidol in treating depression. Chronic unpredictable mild stress (CUMS) was utilized to induce depression-like behavior in mice, and open field test, sucrose preference, and tail suspension test was conducted. The impacts of nerolidol on the inflammatory response, microglial activation, and DNA methyltransferase 1 (DNMT1) were assessed. To study the regulatory role of DNMT1, lipopolysaccharide (LPS) was used to treat BV2 cells, followed by the evaluation of cell viability and DNMT1 level. Additionally, the influence of DNMT1 overexpression on BV2 cell activation was determined. Behavioral analysis revealed that nerolidol reduced depression-like behavior in mice. Nerolidol reduced the levels of inflammatory factors and microglial activation caused by CUMS. Nerolidol treatment was found to reduce DNMT1 levels in mouse brain tissue and it also decrease the LPS-induced increase in DNMT1 levels in BV2 cells. DNMT1 overexpression reversed the impacts of nerolidol on the inflammation response and cell activation. This study underscores the potential of nerolidol in reducing CUMS-induced depressive-like behavior and inhibiting microglial activation by downregulating DNMT1. These findings offer valuable insights into the potential of nerolidol as a therapeutic option for depression.
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Depressão , Sesquiterpenos , Animais , Camundongos , Comportamento Animal , Depressão/tratamento farmacológico , Depressão/etiologia , Modelos Animais de Doenças , Hipocampo , Lipopolissacarídeos , Metiltransferases/metabolismo , Microglia , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Estresse Psicológico/complicaçõesRESUMO
BACKGROUND: Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer's disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. OBJECTIVE: This study aims to investigate the causal effects of the mTOR signaling targets on AD. METHODS: We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer's Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. RESULTS: The elevated levels of AKT (ORâ=â0.910, 95% CI=0.840-0.986, pâ=â0.02) and RP-S6K (ORâ=â0.910, 95% CI=0.840-0.986, pâ=â0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (ORâ=â1.805, 95% CI=1.002-1.174, pâ=â0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (pâ>â0.05). CONCLUSION: There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação Eucariótico 4G/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR/genéticaRESUMO
Electroacupuncture (EA) has been widely applied for overactive bladder, but the mechanism of its action remains to be clarified. This study was aimed to investigate EA regulating the effect of purinergic signaling in the OAB of rats. Electroacupuncture (continuous wave, 30 Hz, 1 mA) was applied to stimulate the Ciliao point (BL32) and the Huiyang point (BL35) of rats. Results showed that when the P2X3 receptor in bladder peripheral level and the spinal cord central level was involved in the bladder micturition reflex of the afferent signaling, intravenous administration P2X3 antagonist AF-353 can significantly inhibit urination in naive rats and OAB of rats and increase bladder volume and micturition pressure. EA stimulation alleviated bladder overactivity significantly and after the P2X3 receptor was blocked, the EA effect was weakened. EA stimulation can effectively reduce the P2X3 mRNA and protein expression in OAB of rats, spinal cord (L6-S1), and DRG (L6-S1) and can significantly reduce the number of positive P2X3 cells in OAB of rats, spinal cord (L6-S1), and DRG (L6-S1). These findings suggest that EA stimulation could alleviate bladder overactivity, and the function is closely related to the inhabited P2X3 receptor in the bladder.
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OBJECTIVE: To analyze the effects of glutamine and valsartan on the brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) of patients with chronic heart failure (CHF). METHODS: A total of 140 CHF patients were divided into a treatment group and a control group by random drawing, and were subjected to standard anti-heart failure treatment and administered with valsartan. Besides, the treatment group was also intravenously transfused glutamine. The treatment lasted eight weeks. RESULTS: The overall efficacy of treatment group and control group were 98.6% and 90.0% respectively, with a statistically significant difference (P<0.05). The two groups had significantly increased left ventricular ejection fractions as well as significantly decreased left ventricular end-diastolic volumes and left ventricular end-diastolic dimensions after treatments (P<0.05) compared with those before. There were also inter-group differences between these values (P<0.05). After treatment, the levels of BNP, NT-proBNP and CD8(+) in both groups significantly decreased (P<0.05), whereas those of CD4(+) significantly increased (P<0.05). The two groups also had significantly different values (P<0.05). CONCLUSION: Glutamine in combination with valsartan enhanced the therapeutic effects by improving cardiac function, which may be associated with decreased expressions of BNP and NT-proBNP and beneficial effects of glutamine on immune function.
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It is well known that acupuncture treatment has an effect on patients with an overactive bladder, but the mechanism of its action remains to be clarified. This study was aimed to investigate the effects of acupuncture on bladder overactivity, and the excitability of interstitial cells of Cajal of the bladder in a rat model of partial bladder outlet obstruction. Electroacupuncture (continuous wave, 30 Hz, 1 mA) was applied to stimulate the Ciliao point (BL32) and the Huiyang point (BL35) of rats for 20 min, 3 days. Results showed that acupuncture suppressed detrusor unstable contraction frequency and decreased detrusor maximum pressure in the bladder filling period. Compared with the normal control rats, HCN2 mRNA and protein expression within the bladder were upregulated and were reversed by electroacupuncture in overactive bladder rats as determined by RT-PCR, western blotting and immunohistochemistry. Moreover, in-vitro cell-cultured OAB rats bladder interstitial cells of Cajal intracellular Ca(2+) concentration were higher than normal control rats, which were lowered after acupuncture treatment. These findings suggest that acupuncture stimulation can suppress bladder overactivity, and regulate the excitability of bladder interstitial cells of Cajal in treatment of overactive bladder myogenic mechanism.