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Purpose: To investigate the predictors for poor outcomes (including disease exacerbation, hospitalization and myasthenic crisis) in patients with pre-existing myasthenia gravis (MG) following Coronavirus disease 2019 (COVID-19), and to explore the potential effects of COVID-19 on inflammatory and immune responses in MG patients. Patients and Methods: This retrospective cohort study analyzed medical records of 845 MG patients who were diagnosed with COVID-19 between January 2020 to March 2023 at a single medical center. Results: Generalized MG at onset and comorbidities (chronic kidney disease and malignancy) were independent risk factors of poor outcomes. Patients achieving minimal manifestation or better status before COVID-19 had a significantly reduced risk for poor outcomes. Furthermore, patients with older onset age or anti-acetylcholine receptor antibody had a higher risk of exacerbation and hospitalization than those without. Prednisone or immunosuppressant treatment had the potential to reduce the occurrence of poor outcomes, while the duration of prednisone or immunosuppressant usage was associated with a higher risk of poor outcomes. Of the 376 MG patients with blood results available, patients with COVID-19 tended to have higher levels of leukocyte counts, neutrophil-lymphocyte-ratio, hypersensitive C-reactive protein, and Interleukin-6, as well as lower percentages of lymphocytes and regulatory T cells compared to patients without COVID-19. Conclusion: Disease severity at onset, comorbidities, and unsatisfactory control of myasthenic symptoms predicted the occurrence of poor outcomes in MG patients following COVID-19. The risk of poor outcomes was reduced in patients controlled by short-term immunosuppressive therapy. Novel coronavirus might affect inflammatory and immune responses in MG patients, particularly in altering interleukin-6 and regulatory T cell levels.

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De novo lipogenesis (DNL), a hallmark of cancer, facilitates tumor growth and metastasis. Therapeutic drugs targeting DNL are being developed. However, how DNL is directly regulated in cancer remains largely unknown. Here, transcription factor sine oculis homeobox 1 (SIX1) is shown to directly increase the expression of DNL-related genes, including ATP citrate lyase (ACLY), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1), via histone acetyltransferases amplified in breast cancer 1 (AIB1) and lysine acetyltransferase 7 （HBO1/KAT7）, thus promoting lipogenesis. SIX1 expression is regulated by insulin/lncRNA DGUOK-AS1/microRNA-145-5p axis, which also modulates DNL-related gene expression as well as DNL. The DGUOK-AS1/microRNA-145-5p/SIX1 axis regulates liver cancer cell proliferation, invasion, and metastasis in vitro and in vivo. In patients with liver cancer, SIX1 expression is positively correlated with DGUOK-AS1 and SCD1 expression and is negatively correlated with microRNA-145-5p expression. DGUOK-AS1 is a good predictor of prognosis. Thus, the DGUOK-AS1/microRNA-145-5p/SIX1 axis strongly links DNL to tumor growth and metastasis and may become an avenue for liver cancer therapeutic intervention.

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Pancreatic cancer (PC) is a challenging and heterogeneous disease with a high mortality rate. Despite advancements in treatment, the prognosis for PC patients remains poor, with a high chance of disease recurrence. Biomarkers are crucial for diagnosing cancer, predicting patient prognosis and selecting treatments. However, the current lack of effective biomarkers for PC could contribute to the insufficiency of existing treatments. These findings underscore the urgent need to develop novel strategies to fight this disease. This study utilized multiple comprehensive bioinformatic analyses to identify potential therapeutic target genes in PC, focusing on histone lysine demethylases (KDMs). We found that high expression levels of KDM family genes, particularly KDM1A, KDM5A and KDM5B, were associated with improved overall survival in the cohort. Furthermore, the infiltration of various immune cells, including B cells, neutrophils, CD8+ T cells, dendritic cells, and macrophages, was positively correlated with KDM1A, KDM5A, and KDM5B expression. Moreover, MetaCore pathway analysis revealed interesting connections between KDM1A and the cell cycle and proliferation, between KDM5A and DNA damage and double-strand break repair through homologous recombination, and between KDM5B and WNT/ß-catenin signaling. These findings suggest that KDM1A, KDM5A and KDM5B may serve as promising biomarkers and therapeutic targets for PC, a disease of high importance due to its aggressive nature and urgent need for novel biomarkers to improve diagnosis and treatment.

Assuntos

Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases com o Domínio Jumonji , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Biologia Computacional , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Histona Desmetilases/metabolismo , Histona Desmetilases/genética , Terapia de Alvo Molecular/métodos , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Proteína 2 de Ligação ao Retinoblastoma/genética , Via de Sinalização Wnt/genética , Proliferação de Células/genética , Proteínas Nucleares , Proteínas Repressoras

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BACKGROUND: Numerous reports indicate that both obesity and type 2 diabetes mellitus (T2DM) are factors associated with cognitive impairment (CI). The objective was to assess the relationship between abdominal obesity as measured by waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and CI in middle-aged and elderly patients with T2DM. METHODS: A cross-sectional study was conducted, in which a total of 1154 patients with T2DM aged ≥ 40 years were included. WHRadjBMI was calculated based on anthropometric measurements and CI was assessed utilizing the Montreal Cognitive Assessment (MoCA). Participants were divided into CI group (n = 509) and normal cognition group (n = 645). Correlation analysis and binary logistic regression were used to explore the relationship between obesity-related indicators including WHRadjBMI, BMI as well as waist circumference (WC) and CI. Meanwhile, the predictive power of these indicators for CI was estimated by receiver operating characteristic (ROC) curves. RESULTS: WHRadjBMI was positively correlated with MoCA scores, independent of sex. The Area Under the Curve (AUC) for WHRadjBMI, BMI and WC were 0.639, 0.521 and 0.533 respectively, and WHRadjBMI had the highest predictive power for CI. Whether or not covariates were adjusted, one-SD increase in WHRadjBMI was significantly related to an increased risk of CI with an adjusted OR of 1.451 (95% CI: 1.261-1.671). After multivariate adjustment, the risk of CI increased with rising WHRadjBMI quartiles (Q4 vs. Q1 OR: 2.980, 95%CI: 2.032-4.371, P for trend < 0.001). CONCLUSIONS: Our study illustrated that higher WHRadjBMI is likely to be associated with an increased risk of CI among patients with T2DM. These findings support the detrimental effects of excess visceral fat accumulation on cognitive function in middle-aged and elderly T2DM patients.

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Índice de Massa Corporal , Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Relação Cintura-Quadril , Humanos , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/epidemiologia , Obesidade Abdominal/epidemiologia , Obesidade Abdominal/complicações , Fatores de Risco , Adulto , China/epidemiologia

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OBJECTIVE: To explore the ultrasonographic features and influencing factors of free-floating thrombus (FFT) detachment in the lower extremity deep veins (LEDVs) of patients with fractures. METHODS: Clinical data of patients diagnosed with FFT in the LEDVs and implanted with an inferior vena cava filter (IVCF) in our hospital between July 2021 and August 2023 were retrospectively analysed. The patients were divided into the thrombus detachment group (the experimental group, n = 92) and the non-thrombus detachment group (the control group, n = 103) based on the presence of detached thrombus in the IVCF. The effects of thrombus echogenicity, floating degree, thrombus location, thrombin time, D-dimer and fibrinogen on thrombus shedding were analysed. The nomogram method was used to establish the model and predict the probability of delayed postoperative recovery. RESULTS: The proportions of patients with extremely hypoechoic thrombus and medium and high floating degrees increased in the experimental group compared with those in the control group, and the differences between the two groups were statistically significant (P < 0.05). Extremely hypoechoic thrombus (P = 0.021, 95 % CI: 1.109-13.748) and high (P = 0.001, 95 % CI: 3.854-28.573) and medium floating degrees (P = 0.004, 95 % CI: 1.792-13.453) were risk factors for deep veins FFT (DV FFT) detachment. The results of receiver operating characteristic curve analysis showed that the area under the curve of the model was 0.893, with a 95 % CI of 0.856-0.937, indicating a high prediction accuracy. CONCLUSION: Ultrasonographic parameters, including thrombus echogenicity and floating degree, are valuable in predicting DV FFT detachment in patients with traumatic fractures, providing references for IVCF implantation.

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BACKGROUND: While ambient air pollution has been associated with fetal growth in singletons, its correlation among twins is not well-established due to limited research in this area. METHODS: The effects of exposure to PM2.5 particulate matter and its main components during pregnancy on birth weight and the incidence of large for gestational age (LGA) were investigated in 6177 twins born after in vitro fertilization at the Center for Reproductive Medicine of Shanghai Ninth People's Hospital (Shanghai, China) between 2007 and 2021. Other birth weight-related outcomes included macrosomia, low birth weight, very low birth weight, and small for gestational age (SGA). The associations of PM2.5 exposure with birth weight outcomes were analyzed using linear mixed-effect models and random-effect logistic regression models. Distributed lag models were incorporated to estimate the time-varying associations. RESULTS: The findings revealed that an interquartile range (IQR) increase (18 µg/m3) in PM2.5 exposure over the entire pregnancy was associated with a significant increase (57.06 g, 95 % confidence interval [CI]: 30.91, 83.22) in the total birth weight of twins. The effect was more pronounced in larger fetuses (34.93 g, 95 % CI: 21.13, 48.72) compared to smaller fetuses (21.77 g, 95 % CI: 6.94, 36.60) within twin pregnancies. Additionally, an IQR increase in PM2.5 exposure over the entire pregnancy was associated with a 34 % increase in the risk of LGA (95 % CI: 11 %, 63 %). Furthermore, specific chemical components of PM2.5, such as sulfate (SO42-), exhibited effect estimates comparable to the PM2.5 total mass. CONCLUSION: Overall, the findings indicate that exposures to PM2.5 and its specific components are associated with fetal overgrowth in twins.

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Poluentes Atmosféricos , Peso ao Nascer , Fertilização in vitro , Desenvolvimento Fetal , Exposição Materna , Material Particulado , Feminino , Humanos , Exposição Materna/estatística & dados numéricos , Gravidez , China , Desenvolvimento Fetal/efeitos dos fármacos , Poluentes Atmosféricos/toxicidade , Peso ao Nascer/efeitos dos fármacos , Adulto , Gêmeos , Poluição do Ar/estatística & dados numéricos , Recém-Nascido

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BACKGROUND: Microwave ablation (MWA) is widely used to eliminate colorectal liver metastases (CRLM). However, the risk of tumor recurrence is difficult to predict due to lack of reliable clinical and biological markers. Elevation of gamma-glutamyl transferase (GGT) and aspartate transaminase (AST) provides signals for liver inflammation and cancer progression. The present study evaluated the association between pre-ablation GGT to AST ratio index (GSR) and hepatic recurrence in patients with CRLM after MWA. METHODS: A retrospectively analyzed 192 CRLM patients who underwent MWA from January 2013 to December 2017. Pre-ablation GSR was classified into high (≤ 2.34) or low (> 2.34) using the upper quartile value. The prognostic value of GSR and other risk factors for liver progression-free survival (LPFS) and cancer-specific survival (CSS) were evaluated by univariate and multivariate analyses. RESULTS: High GSR was significantly associated with males (P = 0.041), the presence of cholelithiasis (P = 0.012), but not pre-ablation chemotherapy (P = 0.355), which caused significantly increased levels of GGT (P = 0.015) and AST (P = 0.008). GSR showed a significant association with LPFS and CSS through univariate analysis (P = 0.002 and 0.006) and multivariate analysis (P = 0.043 and 0.037). The subgroup analysis demonstrated no interaction between GSR and all variables except for distribution in the sub-analysis of LPFS. CONCLUSIONS: Our findings suggest that the pre-ablation GSR can be considered as a promising prognostic indicator for poor prognosis of patients with CRLM underwent MWA. TRIAL REGISTRATION: Not applicable.

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Aspartato Aminotransferases , Neoplasias Colorretais , Neoplasias Hepáticas , Micro-Ondas , gama-Glutamiltransferase , Humanos , Masculino , Feminino , gama-Glutamiltransferase/sangue , Neoplasias Colorretais/patologia , Neoplasias Colorretais/sangue , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Estudos Retrospectivos , Micro-Ondas/uso terapêutico , Pessoa de Meia-Idade , Aspartato Aminotransferases/sangue , Idoso , Prognóstico , Recidiva Local de Neoplasia/sangue , Biomarcadores Tumorais/sangue , Fatores de Risco , Adulto , Idoso de 80 Anos ou mais , Técnicas de Ablação

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Fungal keratitis (FK) is a blinding corneal infectious disease. The prognosis is frequently unfavorable due to fungal invasion and an excessive host inflammatory response. Licochalcone A (Lico A) exhibits a broad spectrum of pharmacological activities, encompassing antifungal, anti-inflammatory, antioxidation, and antitumor properties. However, the role of Lico A has not yet been studied in FK. In this study, we discovered that Lico A could disrupt Aspergillus fumigatus (A. fumigatus) biofilms, inhibit fungal growth and adhesion to host cells, induce alterations of hyphal morphology, and impair the cell membrane and cell wall integrity and mitochondrial structure of A. fumigatus. Lico A can alleviate the severity of FK in mice, reduce neutrophil infiltration and fungal load, and significantly decrease the pro-inflammatory cytokines in mouse corneas infected with A. fumigatus. In vitro, we also demonstrated that Lico A increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) around the nucleus in human corneal epithelial cells (HCECs) stimulated with A. fumigatus. We verified that the anti-inflammatory effect of Lico A is associated with the activation of the Nrf2/HO-1 axis. These results indicated that Lico A could provide a protective role in A. fumigatus keratitis through its anti-inflammatory and antifungal activities.

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Introduction: NK cells are dysfunctional in myasthenia gravis (MG), but the mechanism is unclear. This study aims to measure associations and underlying mechanisms between the NK cells and the development of MG. Methods: Twenty healthy controls (HCs) and 53 MG patients who did not receive glucocorticoids and immunosuppressants were collected. According to the Myasthenia Gravis Foundation of America (MGFA) classification, MG patients were categorized into MGFA I group (n = 18) and MGFA II-IV group (n = 35). Flow cytometry, cell sorting, ELISA, mRNA-sequencing, RT-qPCR, western blot, and cell culture experiments were performed to evaluate the regulatory mechanism of exhausted NK cells. Results: Peripheral NK cells in MGFA II-IV patients exhibit exhausted phenotypes than HCs, marked by the dramatic loss of total NK cells, CD56dimCD16- NK cells, elevated PD1 expression, reduced NKG2D expression, impaired cytotoxic activity (perforin, granzyme B, CD107a) and cytokine secretion (IFN-γ). Plasma IL-6 and IL-21 are elevated in MG patients and mainly derived from the aberrant expansion of monocytes and Tfh cells, respectively. IL-6/IL-21 cooperatively induced NK-cell exhausted signature via upregulating SOCS2 and inhibiting the phosphorylation of STAT5. SOCS2 siRNA and IL-2 supplement attenuated the IL-6/IL-21-mediated alteration of NK-cell phenotypes and function. Discussion: Inhibition of IL-6/IL-21/SOCS2/STAT5 pathway and recovery of NK-cell ability to inhibit autoimmunity may be a new direction in the treatment of MG.

Assuntos

Células Matadoras Naturais , Miastenia Gravis , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Miastenia Gravis/imunologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Interleucinas/metabolismo , Interleucina-6/metabolismo , Interleucina-6/sangue , Transdução de Sinais , Estudos de Casos e Controles

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BACKGROUND: Renal fibrosis is a hallmark of chronic kidney disease (CKD). Smad3 serves as the principal transcription factor mediating the pro-fibrosis effects of TGF-ß signaling in renal fibrosis. Biochanin A (BCA), a natural isoflavone, has been shown to attenuate renal fibrosis by inhibiting TGF-ß signaling but the detailed mechanisms remain unresolved. This study aimed to elucidate the specific mechanisms by which BCA modulates TGF-ß signaling. METHODS: Renal fibrosis models were established both in vitro, using TGF-ß1-stimulated mouse renal tubular TCMK1 cells, and in vivo, employing mice with unilateral ureter obstruction (UUO). RNA-seq was conducted to identify BCA-regulated genes. The AnimalTFDB4.0 database was utilized to predict transcription factors with potential binding to Smad3 promoter. The activities of TGF-ß signaling and the cloned mouse Smad3 promoter were assessed using luciferase reporter assays. Plasmid transfection was performed using polyethylenimine in TCMK1 cells or ultrasound microbubbles in UUO kidneys. Gene expression was analyzed by RT-PCR, western blot, and immunohistochemistry assays. RESULTS: BCA significantly inhibited TGF-ß signaling activity and suppressed TGF-ß1-induced fibrotic gene expression in TCMK1 cells. RNA-seq and in silico analyses identified Smad3 as the key gene downregulated by BCA, while leaving Smad2 unaffected. This selective transcriptional suppression of Smad3 by BCA was validated by luciferase reporter assays using the cloned Smad3 promoter. Furthermore, transcription factor binding prediction identified that Klf6, a transcription factor downregulated by BCA, has binding potential to the Smad3 promoter and promotes Smad3 transcription. Klf6 expression was induced in TGF-ß1-stimulated TCMK1 cells and UUO kidneys, but this induction was abolished upon BCA treatment. Importantly, Klf6 overexpression restored Smad3 expression and counteracted the anti-fibrosis effects of BCA in both TGF-ß1-stimulated TCMK1 cells and UUO kidneys. CONCLUSION: TGF-ß-responsive Klf6 transcriptionally transactivates Smad3 expression. BCA exerts anti-renal fibrosis effects by inhibiting the Klf6-Smad3 signaling axis, underscoring its therapeutic potential in the treatment of CKD.

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Oncogene amplification is a significant factor contributing to poor prognosis and limited treatment in patients with advanced gastric cancer. Therefore, identifying amplified oncogenes and elucidating their oncogenic mechanisms will provide reliable therapeutic targets for the clinical treatment of gastric cancer. In this study, we identify a high amplification of 17q12, which includes five oncogenes that are co-amplified and co-overexpressed with ERBB2 using array comparative genomic hybridization, with migration and invasion enhancer 1 (MIEN1) being particularly highlighted for its clinical significance, function, and role in gastric cancer progression. By detecting MIEN1 copy number and expression level across eight gastric cancer cell lines and in tissue microarrays from 543 primary gastric cancer tissues, we found that MIEN1 amplification and overexpression correlated with sex and Lauren's intestinal type classification of gastric cancer. Besides that, elevated MIEN1 expression was associated with poorer patient survival. In vitro experiments have shown that MIEN1 overexpression enhanced cell proliferation, invasion, and migration, whereas MIEN1 knockdown reversed these malignant phenotypes in vitro. Furthermore, MIEN1 knockdown inhibited tumorigenesis and metastasis of gastric cancer cells in nude mice. Mechanistically, MIEN1 activates the IL-6/JAK2/STAT3 signaling pathway, which drives the proliferation, invasion, and migration of gastric cancer cells. This study demonstrates that MIEN1 contributes to the malignant behavior of gastric cancer through the IL-6/JAK2/STAT3 pathway, suggesting that MIEN1 could serve as a valuable therapeutic target for gastric cancer.

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Developing multifunctional flexible composites with high-performance electromagnetic interference (EMI) shielding, thermal management, and sensing capacity is urgently required but challenging for next-generation smart electronic devices. Herein, novel nacre-like aramid nanofibers (ANFs)-based composite films with an anisotropic layered microstructure were prepared via vacuum-assisted filtration and hot-pressing. The formed 3D conductive skeleton enabled fast electron and phonon transport pathways in the composite films. As a result, the composite films showed a high electrical conductivity of 71.53 S/cm and an outstanding thermal conductivity of 6.4 W/m·K when the mass ratio of ANFs to MXene/AgNWs was 10:8. The excellent electrical properties and multi-layered structure endowed the composite films with superior EMI shielding performance and remarkable Joule heating performance, with a surface temperature of 78.3 °C at a voltage of 2.5 V. Additionally, it was found that the composite films also exhibited excellent mechanical properties and outstanding flame resistance. Moreover, the composite films could be further designed as strain sensors, which show great promise in monitoring real-time signals for human motion. These satisfactory results may open up a new opportunity for EMI shielding, thermal management, and sensing applications in wearable electronic devices.

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Atomic-scale doping strategies and structure design play pivotal roles in tailoring the electronic structure and physicochemical property of electromagnetic wave absorption (EMWA) materials. However, the relationship between configuration and electromagnetic (EM) loss mechanism has remained elusive. Herein, drawing inspiration from the DNA transcription process, we report the successful synthesis of novel in situ Mn/N co-doped helical carbon nanotubes with ultrabroad EMWA capability. Theoretical calculation and EM simulation confirm that the orbital coupling and spin polarization of the Mn-N4-C configuration, along with cross polarization generated by the helical structure, endow the helical converters with enhanced EM loss. As a result, HMC-8 demonstrates outstanding EMWA performance, achieving a minimum reflection loss of -63.13 dB at an ultralow thickness of 1.29 mm. Through precise tuning of the graphite domain size, HMC-7 achieves an effective absorption bandwidth (EAB) of 6.08 GHz at 2.02 mm thickness. Furthermore, constructing macroscale gradient metamaterials enables an ultrabroadband EAB of 12.16 GHz at a thickness of only 5.00 mm, with the maximum radar cross section reduction value reaching 36.4 dB m2. This innovative approach not only advances the understanding of metal-nonmetal co-doping but also realizes broadband EMWA, thus contributing to the development of EMWA mechanisms and applications.

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This study was aimed to investigate the effects of dietary calcitriol or quercetin supplementation on eggshell and bone quality of laying hens. In trial 1, 72 Hy-Line Brown layers (80-week-old) with weak-shelled strength (25 to 30 N) were assigned into 4 dietary treatments with 6 replicates of 3 birds and fed a basal diet (4% calcium level) or basal diets supplemented with 0.5% calcium, 5 µg/kg calcitriol or 500 mg/kg quercetin for 4 weeks. In trial 2, 360 Hy-Line Brown layers (60-week-old) were divided into 3 groups with 8 replicates of 15 birds: control group (basal diet), calcitriol group (basal diet + 5 µg/kg calcitriol), and quercetin group (basal diet + 500 mg/kg quercetin). This trial lasted for 12 weeks. The results showed that dietary calcitriol or quercetin improved eggshell quality in both trials (P < 0.05). In trial 2, compared with the control group, both calcitriol and quercetin supplementations improved femoral bone quality, calcium retention of hens and calcium content in uterine fluid at 18.5 h post-oviposition (PO) (P < 0.05), along with enhancing uterine morphology. Compared to the control group, supplemental calcitriol or quercetin up-regulated the relative mRNA expression levels of uterine transient receptor potential cation channel, subfamily V, member 6 (TRPV6) at 8.5 h PO and plasma membrane calcium-ATPase (PMCA), vitamin D receptor (VDR), estrogen receptor alpha (ERα) at 18.5 h PO (P < 0.05), but down-regulated the uterine caspase 3 (CASP3) relative mRNA expression level at 8.5 h PO (P < 0.05). Meanwhile, the femoral relative mRNA expression levels of tartrate-resistant acid phosphatase (TRAP) (up-regulated at 8.5 and 18.5 h PO) and alkaline phosphatase (ALP) (up-regulated at 8.5 h PO but down-regulated at 18.5 h PO) were also affected by calcitriol or quercetin supplementation (P < 0.05). Compared to the calcitriol, quercetin increased hen-day egg production and femoral medullary bone volume/bone tissue volume but reduced femoral stiffness (P < 0.05), which were accompanied by increased relative mRNA expression levels of uterine TRPV6, estrogen receptor beta (ERß) at 18.5 h PO (P < 0.05). Overall, both dietary calcitriol and quercetin could improve eggshell and bone quality by modulating calcium metabolism of aged layers. Compared to calcitriol, dietary quercetin up-regulated the expression of uterine calcium transporters, without affecting eggshell quality.

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AIMS: ß3-AR (ß3-adrenergic receptor) is essential for cardiovascular homeostasis through regulating adipose tissue function. Perivascular adipose tissue (PVAT) has been implicated in the pathogenesis of aortic dissection and aneurysm (AD/AA). Here, we aim to investigate ß3-AR activation-mediated PVAT function in AD/AA. METHODS AND RESULTS: Aortas from patients with thoracic aortic dissection (TAD) were collected to detect ß3-AR expression in PVAT. ApoE-/- and ß-aminopropionitrile monofumarate (BAPN)-treated C57BL/6 mice were induced with Angiotensin II (AngII) to simulate AD/AA, and subsequently received either placebo or mirabegron, a ß3-AR agonist. The results demonstrated an up-regulation of ß3-AR in PVAT of TAD patients and AD/AA mice. Moreover, activation of ß3-AR by mirabegron significantly prevented AngII-induced AD/AA formation in mice. RNA-sequencing analysis of adipocytes from PVAT revealed a notable increase of the lymphangiogenic factor VEGF-C in mirabegron-treated mice. Consistently, enhanced lymphangiogenesis was found in PVAT with mirabegron treatment. Mechanistically, the number of CD4+/CD8+ T cells and CD11c+ cells was reduced in PVAT but increased in adjacent draining lymph nodes (LNs) of mirabegron-treated mice, indicating the improved draining and clearance of inflammatory cells in PVAT by lymphangiogenesis. Importantly, adipocyte-specific VEGF-C knockdown by the adeno-associated virus system restrained lymphangiogenesis and exacerbated inflammatory cell infiltration in PVAT, which ultimately abolished the protection of mirabegron on AD/AA. In addition, the conditional medium derived from mirabegron-treated adipocytes activated the proliferation and tube formation of lymphatic endothelial cells (LECs), which was abrogated by the silencing of VEGF-C in adipocytes. CONCLUSIONS: Our findings illustrated the therapeutic potential of ß3-AR activation by mirabegron on AD/AA, which promoted lymphangiogenesis by increasing adipocyte-derived VEGF-C and, therefore, ameliorated PVAT inflammation.

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BACKGROUND: Overweight women undergoing IVF treatment have lower success rates. Letrozole, an aromatase inhibitor, has been used as an adjunct for IVF treatment, but its specific effects in overweight women have not been investigated. This study was to explore the effects of letrozole co-treatment in an antagonist protocol for overweight infertile women undergoing IVF treatment. METHODS: This retrospective cohort study included overweight infertile women who underwent IVF/ICSI treatment and fresh embryo transfer (ET), with or without letrozole co-treatment in an antagonist protocol, from 2007 to 2021 at Shanghai Ninth People's Hospital (Shanghai, China). A total of 704 overweight infertile women were included: 585 women were in the antagonist group, and 119 women were in the letrozole co-treatment group. The primary outcome was the live birth rate after fresh ET. Propensity score-based patient-matching was employed to balance the covariates between the groups. Multivariate logistic regression analysis was also performed to estimate odds ratio (OR) and 95% confidence interval (CI) for association of letrozole co-treatment and the live birth outcome. RESULTS: Letrozole co-treatment induced significant changes in hormonal profile on the trigger day. The letrozole group exhibited a decrease in the total number of follicles compared to the antagonist group, but a higher proportion of large follicles at oocyte retrieval (P < 0.05). The quantity and quality of embryos were comparable between the two groups (P > 0.05). The letrozole co-treatment group had a significantly higher live birth rate than the control group (38.7% vs. 22.6%, P = 0.026). With multivariate logistic regression analysis, letrozole co-treatment was associated with higher odds of live birth after adjusting for potential confounding factors (adjusted OR = 2.00, 95% CI = 1.17-3.39, P = 0.011). Letrozole presented no significant associations with obstetrical or neonatal complications (P > 0.05). CONCLUSION: Letrozole co-treatment in an antagonist protocol may offer potential benefits for overweight infertile women undergoing IVF treatment. Further research is warranted to validate these findings and explore the broader implications for letrozole co-treatment.

Assuntos

Inibidores da Aromatase , Transferência Embrionária , Fertilização in vitro , Infertilidade Feminina , Letrozol , Sobrepeso , Taxa de Gravidez , Humanos , Letrozol/uso terapêutico , Feminino , Estudos Retrospectivos , Adulto , Gravidez , Inibidores da Aromatase/uso terapêutico , Fertilização in vitro/métodos , Infertilidade Feminina/terapia , Transferência Embrionária/métodos , Indução da Ovulação/métodos , Nascido Vivo , China , Injeções de Esperma Intracitoplásmicas

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Fungal keratitis (FK) is recognized as a stubborn ocular condition, caused by intense fungal invasiveness and heightened immune reaction. The glycosaminoglycan chondroitin sulfate exhibits properties of immunomodulation and tissue regeneration. In prior investigations, oxidized chondroitin sulfate (OCS) ameliorated the prognosis of FK in murine models. To further improve the curative efficacy, we used the antifungal drug natamycin to functionalize OCS and prepared oxidized chondroitin sulfate-natamycin (ON) eye drops. The structure of ON was characterized by FTIR, UV-vis, and XPS, revealing that the amino group of natamycin combined with the aldehyde group in OCS through Schiff base reaction. Antifungal experiments revealed that ON inhibited fungal growth and disrupted the mycelium structure. ON exhibited exceptional biocompatibility and promoted the proliferation of corneal epithelial cells. Pharmacokinetic analysis indicated that ON enhanced drug utilization by extending the mean residence time in tears. In murine FK, ON treatment reduced the clinical score and corneal fungal load, restored corneal stroma conformation, and facilitated epithelial repair. ON effectively inhibited neutrophil infiltration and decreased the expression of TLR-4, LOX-1, IL-1ß, and TNF-α. Our research demonstrated that ON eye drops achieved multifunctional treatment for FK, including inhibiting fungal growth, promoting corneal repair, enhancing drug bioavailability, and controlling inflammatory reactions.

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The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC.

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Background: Despite advancements in diabetes treatment, the management of Painful Diabetic Neuropathy (PDN) remains challenging. Our previous research indicated a significant correlation between the expression and distribution of Aquaporin-4 (AQP4) in the spinal glymphatic system and PDN. However, the potential role and mechanism of liquiritin in PDN treatment remain uncertain. Methods: This study established a rat model of PDN using a combination of low-dose Streptozotocin (STZ) and a high-fat, high-sugar diet. Rats were treated with liquiritin and MCC950 (an NLRP3 inhibitor). We monitored fasting blood glucose, body weight, and mechanical allodynia periodically. The glymphatic system's clearance function was evaluated using Magnetic Resonance Imaging (MRI), and changes in proteins including NLRP3, MMP-9, and AQP4 were detected through immunofluorescence and Western blot techniques. Results: The rats with painful diabetic neuropathy (PDN) demonstrated several physiological changes, including heightened mechanical allodynia, compromised clearance function within the spinal glymphatic system, altered distribution of AQP4, increased count of activated astrocytes, elevated expression levels of NLRP3 and MMP-9, and decreased expression of AQP4. However, following treatment with liquiritin and MCC950, these rats exhibited notable improvements. Conclusion: Liquiritin may promote the restoration of AQP4 polarity by inhibiting NLRP3 and MMP-9, thereby enhancing the clearance functions of the spinal cord glymphatic system in PDN rats, alleviating the progression of PDN.