Correlation between body composition and disease severity in patients with chronic obstructive pulmonary disease.

Background: Body composition changes are important extrapulmonary manifestations in chronic obstructive pulmonary disease (COPD) patients. This study aimed to investigate the characteristics of body composition in patients with COPD, and its correlation with disease severity. Methods: A total of 105 COPD patients admitted to Zhongshan Hospital affiliated to Dalian University, from May 1, 2021 to January 31, 2023, were included as the COPD group, and 105 subjects without COPD were enrolled as the control group during the same period. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) comprehensive assessment indicators, COPD patients were divided into groups: the degree of pulmonary function airflow limitation was grouped according to FEV1%pred; clinical symptoms were grouped according to mMRC scores and CAT scores; the risk of acute exacerbation was divided into low risk and high risk groups. Body composition was measured by bioelectrical impedance analysis (BIA). Results: (1) Concerning body composition, the body mass index (BMI), fat-free mass index (FFMI), and angle of phase (PhA) of COPD patients were lower than those of the control group. Extracellular water-to-total body water ratio (ECW/TBW) and extra-to-intracellular water ratio (ECW/ICW) were higher than those of the control group, and the difference was statistically significant (p < 0.05). (2) There were differences in body composition among COPD patients with different severity of disease: FFMI and PhA in the mild/moderate airflow limitation group were higher than those in the severe/very severe airflow limitation group. According to mMRC scores classification, the FFMI and PhA of the less symptomatic group were higher than those of the more symptomatic group, and ECW/TBW and ECW/ICW were lower than those of the more symptomatic group. According to CAT scores classification, FFMI and PhA in the mild/moderate disease group were higher than those in the severe/very severe disease group. The FFMI of the low-risk group was higher than that of the high-risk group, and ECW/TBW was lower than that of the high risk group. (3) Correlation analysis between body composition and disease severity indicators showed that FFMI and PhA were negatively correlated with mMRC scores and CAT scores, and positively correlated with FEV1%pred. ECW/TBW ratio and ECW/ICW ratio were positively correlated with mMRC scores and CAT scores, and negatively correlated with FEV1%pred, and the difference was statistically significant (p < 0.05). Conclusion: There are significant differences in body composition between COPD patients and the control group, and there are significant differences in body composition between COPD patients with different severity of disease, with correlations between body composition and severity of disease.

Fungal communities associated with early immature tubers of wild Gastrodia elata.

Full myco-heterotrophic orchid Gastrodia elata Bl. is widely distributed in Northeast Asia, and previous research has not fully investigated the symbiotic fungal community of its early immature tubers. This study utilized Illumina sequencing to compare symbiotic fungal communities in natural G. elata immature tubers and their habitats. LEfSe (Linear Discriminant Analysis Effect Size) was used to screen for Biomarkers that could explain variations among different fungal communities, and correlation analyses were performed among Biomarkers and other common orchid mycorrhizal fungi. Our results illustrate that the symbiotic fungal communities of immature G. elata tubers cannot be simply interpreted as subsets of the environmental fungal communities because some key members cannot be traced back to the environment. The early growth of G. elata was related to a small group of fungi, such as Sebacina, Thelephora, and Inocybe, which were also common mycorrhizal fungi from other orchids. In addition, Mycena, Auricularia, and Cryptococcus were unique fungal partners of G. elata, and many new species have yet to be discovered. Possible symbiotic Mycena should be M. plumipes and its sibling species in this case. Our results provide insight into the symbiotic partner switch and trophic pattern change during the development and maturation of G. elata.

Foxo1 Drives the TGFß1-Dependent Dichotomy of Th17 Cell Fates.

T-helper 17 (Th17) cells play a dual role in immunological responses, serving as essential components in tissue homeostasis and host defense against microbial pathogens while also contributing to pro-inflammatory conditions and autoimmunity. While Transforming Growth Factor-beta 1 (TGFß1) is pivotal for the differentiation of non-pathogenic Th17 cells, the role of TGFß3 and Activin in steering Th17 cells toward a pathogenic phenotype has been acknowledged. However, the molecular mechanisms governing this dichotomy remain elusive. In this study, we demonstrate that the transcription factor Foxo1 is upregulated in a TGFß1 dose-dependent manner, serving as a critical regulator that specifically modulates the fate of pathogenic Th17 cells. Analyses in both uveitis patients and an Experimental Autoimmune Uveitis (EAU) mouse model reveal a strong correlation between disease severity and diminished Foxo1 expression levels. Ectopic expression of Foxo1 selectively attenuates IL-17A production under pathogenic Th17-inducing conditions. Moreover, enhanced Foxo1 expression, triggered by TGFß1 signaling, is implicated in fatty acid metabolism pathways that favor non-pathogenic Th17 differentiation. Our drug screening identifies several FDA-approved compounds can upregulate Foxo1. Collectively, our findings offer evidence that Foxo1 serves as a molecular switch to specifically control pathogenic versus non-pathogenic Th17 differentiation in a TGFß1-dependent manner. Suggest that targeting Foxo1 could be a promising therapeutic strategy for autoimmune diseases.

Advances in reparative materials for infectious bone defects and their applications in maxillofacial regions.

Infectious bone defects are characterized by the partial loss or destruction of bone tissue resulting from bacterial contaminations subsequent to diseases or external injuries. Traditional bone transplantation and clinical methods are insufficient in meeting the treatment demands for such diseases. As a result, researchers have increasingly focused on the development of more sophisticated biomaterials for improved therapeutic outcomes in recent years. This review endeavors to investigate specific reparative materials utilized for the treatment of infectious bone defects, particularly those present in the maxillofacial region, with a focus on biomaterials capable of releasing therapeutic substances, functional contact biomaterials, and novel physical therapy materials. These biomaterials operate via heightened antibacterial or osteogenic properties in order to eliminate bacteria and/or stimulate bone cells regeneration in the defect, ultimately fostering the reconstitution of maxillofacial bone tissue. Based upon some successful applications of new concept materials in bone repair of other parts, we also explore their future prospects and potential uses in maxillofacial bone repair later in this review. We highlight that the exploration of advanced biomaterials holds promise in establishing a solid foundation for the development of more biocompatible, effective, and personalized treatments for reconstructing infectious maxillofacial defects.

The effect of enhanced structure in the posterior segment of clear aligners during anterior retraction: a three-dimensional finite element and experimental model analysis.

BACKGROUND: Mesial tipping of posterior teeth occurs frequently during space closure with clear aligners (CAs). In this study, we proposed a new modification of CA by localized thickening of the aligner to form the enhanced structure and investigate its biomechanical effect during anterior retraction. METHODS: Two methods were employed in this study. First, a finite element (FE) model was constructed, which included alveolar bone, the first premolars extracted maxillary dentition, periodontal ligaments (PDL), attachments and aligners. The second method involved an experimental model-a measuring device using multi-axis transducers and vacuum thermoforming aligners. Two groups were formed: (1) The control group used common CAs and (2) the enhanced structure group used partially thickened CAs. RESULTS: FE model revealed that the enhanced structure improved the biomechanics during anterior retraction. Specifically, the second premolar, which had a smaller PDL area, experienced a smaller protraction force and moment, making it less likely to tip mesially. In the same vein, the molars could resist movement due to their larger PDL area even though they were applied larger forces. The resultant force of the posterior tooth was closer to the center of resistance, reducing the tipping moment. The canine was applied a larger retraction force and moment, resulting in sufficient retraction of anterior teeth. The experimental model demonstrated a similar trend in force variation as the FE model. CONCLUSIONS: Enhanced structure allowed force distribution more in accordance with optimal principles of biomechanics during the extraction space closure while permitting less mesial tipping and anchorage loss of posterior teeth and better retraction of anterior teeth. Thus, enhanced structure alleviated the roller coaster effect associated with extraction cases and offered a new possibility for anchorage reinforcement in clear aligner therapy.

High-Efficiency Corrosion Inhibitor of Biomass-Derived High-Yield Carbon Quantum Dots for Q235 Carbon Steel in 1 M HCl Solution.

Eco-friendly self-doped carbon quantum dots (ZCQDs) with excellent corrosion inhibition ability were prepared via solid-phase pyrolysis only using Zanthoxylum bungeanum leaves as the raw material. Compared with the relevant research, a simpler and higher yield (25%) preparation process for carbon quantum dots was proposed. ZCQDs were characterized by transmission electron microscopy and X-ray photoelectron spectroscopy, and the average size of ZCQDs with multitudes of O- and N-containing functional groups was about 2.53 nm. The prepared ZCQDs were used to inhibit the corrosion of Q235 steel in HCl solution, and the inhibition behavior was investigated through weight loss, electrochemical test, surface analysis, and adsorption thermodynamic analyses. The results showed that the ZCQDs, acted as a mixed corrosion inhibitor, have an effective corrosion inhibition for Q235, the corrosion inhibition efficiency reached 95.98% at 200 mg/L, and at this concentration, effective protection of at least 132h (IE > 90%) is provided. Moreover, the adsorption mechanism of ZCQDs was consistent with that of Redlich-Peterson adsorption, including chemisorption and physisorption. A new corrosion inhibition mechanism of ZCQDs has been thoroughly studied and proposed; ZCQDs have functional groups containing O and N, which can form a protective barrier through physical adsorption and chemisorption, but the coverage of the protective film is low at low concentrations. With the increase of concentration, the protective film formed by ZCQDs on the metal surface will first increase the coverage and then adsorb more ZCQDs on the protective film to form a thicker and denser protective film to protect the metal. The carbon quantum dots prepared in this paper have advantages including a green, renewable precursor, a fast method, high yield, and excellent corrosion inhibition. Therefore, this work can inspire and facilitate, to a certain extent, the future application of doped carbon quantum dots as efficient corrosion inhibitors in HCl solutions.

Separate and Joint Associations of Remnant Cholesterol Accumulation and Variability With Carotid Atherosclerosis: A Prospective Cohort Study.

Background We aimed to examine separate and joint associations of remnant cholesterol (RC) accumulation and variability with the risk of carotid atherosclerosis (CAS) in the general population. Methods and Results A total of 6213 participants who underwent 3 sequential health examinations during 2010 to 2015 were enrolled and were followed up until December 31, 2021. Cumulative RC (cumRC) and RC variability among the 3 visits were the exposure of interest in our study. Adjusted Cox models were performed to calculate the hazard ratio (HR) and 95% CI. C-statistics, integrated discrimination improvement, and the net reclassification index were used to estimate the incremental predictive ability. During a median follow-up of 4.00 years, 2613 participants developed CAS. Higher cumRC (HR, 1.33 [95% CI, 1.17-1.52]) and greater RC variability (HR, 1.22 [95% CI, 1.08-1.39]) were significantly associated with elevated risk of CAS, independent of traditional cardiovascular risk factors and low-density lipoprotein cholesterol. Participants were divided into 4 groups according to the median of cumRC and RC variability to assess their joint associations. Compared with "low cumRC and low variability," "high cumRC and high variability" had the highest risk of CAS, followed by "high cumRC and low variability" and "low cumRC and high variability." Finally, joint assessment of RC accumulation and variability had the significantly highest incremental effect on the predictive value of CAS versus single-time-point measures of RC. Conclusions Excessive cumRC levels and greater RC variability were each independently associated with higher incidence of CAS, and their coexistence could further yield significantly higher risks.

The Effects of Cinobufagin on Hepatocellular Carcinoma Cells Enhanced by MRT68921, an Autophagy Inhibitor.

Cinobufagin, a cardiotonic steroid derived from toad venom extracts, exhibits significant anticancer properties by inhibiting Na[Formula: see text]/K[Formula: see text]-ATPase in cancer cells. It is frequently used in clinical settings to treat advanced-stage cancer patients, improving their quality of life and survival time. However, its long-term use can result in multidrug resistance to other chemotherapy drugs, and the exact mechanism underlying this effect remains unknown. Therefore, this study explores the molecular mechanism underlying the anticancer effects of cinobufagin in hepatocellular carcinomas (HCCs), specifically in HepG2 and Huh-7 cells. As determined using transcriptome analysis, cinobufagin-triggered protective autophagy suppressed cell apoptosis in liver cancer HepG2 and Huh-7 cells by inhibiting the phosphoinositide-3-Kinase (PI3K)-AKT serine/threonine kinase (AKT)-mammalian target of rapamycin (mTOR) pathway. Cinobufagin-inhibited cell proliferation, induced apoptosis, and generated cell autophagy by upregulating the expression of MAP1 light chain 3 protein II, Beclin1, and autophagy-related protein 12-5. In addition, the autophagy inhibitor MRT68921 improved the antiproliferative and proapoptotic effects of cinobufagin in the studied cell lines. Overall, this study suggests that combining cinobufagin with an autophagy inhibitor can effectively treat HCC, providing a potential strategy for cancer therapy.

Hsa_circ_0057105 modulates a balance of epithelial-mesenchymal transition and ferroptosis vulnerability in renal cell carcinoma.

BACKGROUND: The incidence of renal cell carcinoma (RCC) has increased in recent years. Metastatic RCC is common and remains a major cause of mortality. A regulatory role for circular RNAs (circRNAs) in the occurrence and progression of RCC has been identified, but their function, molecular mechanisms, and potential clinical applications remain poorly understood. METHODS: High-throughput RNA sequencing was used to explore the differential expression of circRNAs and their related pathways in RCC patients. Transwell and CCK-8 assays were used to assess the function of hsa_circ_0057105 in RCC cells. The clinical relevance of hsa_circ_0057105 was evaluated in a cohort of RCC patients. The hsa_circ_0057105 regulatory axis was defined using RNA pull-down, luciferase reporter assays, and fluorescence in situ hybridization assays, and the in vivo effect of hsa_circ_0057105 was validated using animal experiments. RESULTS: Single-sample gene set enrichment analysis and correlation analysis of RNA-seq data showed that hsa_circ_0057105 was potentially oncogenic and may serve to regulate epithelial-mesenchymal transition (EMT) activation in RCC. Hsa_circ_0057105 expression was associated with advanced TNM stages and was an independent prognostic factor for poor RCC patient survival. Phenotypic studies show that hsa_circ_0057105 can enhance the migration and invasion abilities of RCC cells. Further, hsa_circ_0057105 was shown to inhibit the expression of miR-577, a miRNA that regulated the expression of both COL1A1, which induced EMT activation, and VDAC2, which modulated ferroptosis sensitivity. The dual regulatory roles of hsa_circ_0057105 on EMT and ferroptosis sensitivity were verified using rescue experiments. Animal studies confirmed that hsa_circ_0057105 increased the metastatic ability and ferroptosis sensitivity of RCC cells in vivo. CONCLUSIONS: In RCC, hsa_circ_0057105 regulates COL1A1 and VDAC2 expression through its sponge effect on miR-577, acting like a 'double-edged sword'. These findings provide new insight into the relationship between EMT and ferroptosis in RCC and provide potential biomarkers for RCC surveillance and treatment.

PHB promotes bladder cancer cell epithelial-mesenchymal transition via the Wnt/ß-catenin signaling pathway.

As a member of PHB (prohibitin1) family, PHB plays important roles in many cancers, but its property in bladder carcinoma aggressiveness is unknown. This research was to explore the function and potential mechanism of PHB in bladder carcinoma in vivo and in vitro. The invasive abilities of cancer cell were determined by transwell and wound-healing assays. The function of PHB was confirmed by gene knockdown and overexpression methods. Further in vivo confirmation was performed in a nude mouse model with lung metastasis. The relationship of PHB and ß-catenin was confirmed by immunoprecipitation and immunofluorescence staining assays. The protein expression of epithelial-mescenchymal transition (EMT) and Wnt/ß-catenin signaling pathway was tested by immunofluorescence staining and western blotting assay. The depletion of PHB prevented bladder cancer cell invasiveness and inhibited EMT. Contrarily，the abilities of bladder carcinoma cells migration and invasion in vitro as well as metastasis in vivo were enhanced when the PHB overexpressed unnormally. Importantly, the ß-catenin was identified to be bound by PHB and ß-catenin knockdown reduced the cancer cell migration, invasion and EMT in PHB overexpressing cells. In addition, PHB stabilized ß-catenin by inhibiting its ubiqutin-mediated degradation thus leading to increased Wnt/ß-catenin signaling. These observations indicate that PHB could promote bladder cancer aggressiveness by binding with ß-catenin to prevent the degradation of ß-catenin and the localized invasive bladder cancer patients with PHB overexpression should take more aggressive postsurgical adjuvant anticancer therapies.

LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway.

LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients' tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.

EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1.

High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC). There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN-γ-induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain-binding protein 1-like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN-γ/JAK1/STAT1/PD-L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8+ T cell-mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD-L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient-derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy.

Bidirectional Associations between Daytime Napping Duration and Metabolic Syndrome: A Nationally Representative Cohort Study.

BACKGROUND: We aimed to examine the bidirectional associations between daytime napping duration and metabolic syndrome (MetS). METHODS: Using data from the China Health and Retirement Longitudinal Study from 2011 to 2015, modified Poisson regression models were performed to explore the longitudinal associations of baseline napping duration with the occurrence and remission of MetS. Generalized estimating equation was conducted to explore the association between baseline MetS status with subsequent changes in daytime napping duration. Cross-lagged panel analysis was performed to further verify their bidirectional relationships. RESULTS: During the four-year follow-up, among 5041 participants without MetS at baseline, extended naps were significantly associated with MetS occurrence, compared with non-napping. This association was only significant in individuals with adequate night-time sleep duration or good sleep quality of the 2898 participants with MetS at baseline. Excessive napping duration may be not favorable for MetS remission especially for adequate night-time sleepers. With respect to reverse associations, baseline MetS status significantly increased the napping duration during the subsequent follow-up period. Finally, there were significant bidirectional cross-lagged associations between napping duration and MetS severity score after adjusting for all covariates. CONCLUSIONS: Our study indicates bidirectional relationships exist between daytime napping duration and MetS. Interestingly, longer napping duration was detrimental to cardiometabolic health only in those with sufficient night-time sleep duration or good sleep quality.

Up-regulation of miR-133a-3p promotes ovary insulin resistance on granulosa cells of obese PCOS patients via inhibiting PI3K/AKT signaling.

BACKGROUND: MicroRNAs are a type of non-coding single-stranded RNA, which is involved in the regulation of ovary insulin resistance (IR). This study aims to explore the underlying mechanisms of miR-133a-3p regulating ovary IR in obese polycystic ovary syndrome (PCOS). METHODS: Granulosa cells (GCs) were extracted from follicular fluids of PCOS patients (obese PCOS group and non-obese PCOS group) and healthy women (control group). The expression of miR-133a-3p in GCs was detected by qRT-PCR. The targets and pathways of miR-133a-3p were predicted by bioinformatics analyses. The protein levels of PI3K, p-AKT, GLUT4, p-GSK-3ß, and p-FOXO1 were measured by Western blotting. RESULTS: MiR-133a-3p was highly expressed in GCs from PCOS patients, especially in obese PCOS patients. The protein levels of PI3K and p-AKT was downregulated in GCs from PCOS patients. There were 11 target genes of miR-133a-3p enriching in PI3K/AKT signaling pathway. miR-133a-3p mimic downregulated the expression of PI3K, p-AKT, and GLUT4, and upregulated the protein levels of p-GSK-3ß and p-FOXO1. miR-133a-3p inhibitor presented the opposite effect of miR-133a-3p mimic. CONCLUSION: MiR-133a-3p promotes ovary IR on GCs of obese PCOS patients via inhibiting PI3K/AKT signaling pathway. This study lays a foundation for further research on the mechanism of ovary IR in obese PCOS patients.

Glucose-6-phosphate dehydrogenase exerts antistress effects independently of its enzymatic activity.

G6PD (glucose-6-phosphate dehydrogenase) is the rate-limiting enzyme in the oxidative pentose phosphate pathway that can generate cytosolic NADPH for biosynthesis and oxidative defense. Since cytosolic NADPH can be compensatively produced by other sources, the enzymatic activity deficiency alleles of G6PD are well tolerated in somatic cells but the effect of null mutations is unclear. Herein, we show that G6PD KO sensitizes cells to the stresses induced by hydrogen peroxide, superoxide, hypoxia, and the inhibition of the electron transport chain. This effect can be completely reversed by the expressions of natural mutants associated with G6PD deficiency, even without dehydrogenase activity, exactly like the WT G6PD. Furthermore, we demonstrate that G6PD can physically interact with AMPK (AMPK-activated protein kinase) to facilitate its activity and directly bind to NAMPT (nicotinamide phosphoribosyltransferase) to promote its activity and maintain the NAD(P)H/NAD(P)+ homeostasis. These functions are necessary to the antistress ability of cells but independent of the dehydrogenase activity of G6PD. In addition, the WT G6PD and naturally inactive mutant also can similarly regulate the metabolism of glucose, glutamine, fatty acid synthesis, and GSH and interact with the involved enzymes. Therefore, our findings reveal the previously unidentified functions of G6PD that can act as the important physiological neutralizer of stresses independently of its enzymatic activity.

Moderate increase of serum uric acid within a normal range is associated with improved cognitive function in a non-normotensive population: A nationally representative cohort study.

Background: Associations between serum uric acid (SUA) and changes in cognitive function are understudied in non-normotensive populations, and many previous studies only considered the baseline SUA at a single time point. We aimed to examine the effects of baseline SUA and 4-year changes in SUA on cognitive changes in the non-normotensive population. Materials and methods: In the China Health and Retirement Longitudinal Study (CHARLS), cognitive function was measured based on executive function and episodic memory in four visits (years: 2011, 2013, 2015, and 2018). We identified two study cohorts from CHARLS. The first cohort included 3,905 non-normotensive participants. Group-based single-trajectory and multi-trajectory models were applied to identify 7-year cognitive trajectories. Adjusted ordinal logistics models were performed to assess the association between baseline SUA and 7-year cognitive trajectories, and subgroup analyses were conducted according to the presence of hyperuricemia or SUA levels. The second cohort included 2,077 eligible participants. Multiple linear regression was used to explore the effect of a 4-year change in SUA on cognitive change during the subsequent 3-year follow-up. Results: Four distinct single-trajectories of global cognitive performance and four multi-trajectories of executive function and episodic memory were identified. Higher baseline SUA levels were significantly associated with more favorable cognitive single-trajectories (OR Q4 vs. Q1: 0.755; 95% CI: 0.643, 0.900) and multi-trajectories (OR Q4 vs. Q1: 0.784; 95% CI: 0.659, 0.933). Subgroup analyses revealed that the protective effect of SUA was significant in the non-hyperuricemia groups or the low-level SUA groups. Additionally, changes in SUA could influence future cognitive changes. Compared with non-hyperuricemia participants with elevated SUA, non-hyperuricemia participants with decreased SUA and patients with persistent hyperuricemia had a higher risk for cognitive decline. Furthermore, only the Q3 group of changes in SUA could enhance global cognitive function compared with the Q1 group (ß: 0.449; 95% CI: 0.073, 0.826). Conclusion: Our study indicates that the maintenance of normal SUA levels and a moderate increase of SUA were advantageous in improving cognitive function or trajectories in a non-normotensive population. Conversely, SUA may impair cognitive function in patients with persistent hyperuricemia.

KLF16 enhances stress tolerance of colorectal carcinomas by modulating nucleolar homeostasis and translational reprogramming.

Translational reprogramming is part of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, which acts to the advantage of cancer growth and development in different stress conditions, but the mechanism of ER stress-related translational reprogramming in colorectal carcinoma (CRC) progression remains unclear. Here, we identified that Krüppel-like factor 16 (KLF16) can promote CRC progression and stress tolerance through translational reprogramming. The expression of KLF16 was upregulated in CRC tissues and associated with poor prognosis for CRC patients. We found that ER stress inducers can recruit KLF16 to the nucleolus and increase its interaction with two essential proteins for nucleolar homeostasis: nucleophosmin1 (NPM1) and fibrillarin (FBL). Moreover, knockdown of KLF16 can dysregulate nucleolar homeostasis in CRC cells. Translation-reporter system and polysome profiling assays further showed that KLF16 can effectively promote cap-independent translation of ATF4, which can enhance ER-phagy and the proliferation of CRC cells. Overall, our study unveils a previously unrecognized role for KLF16 as an ER stress regulator through mediating translational reprogramming to enhance the stress tolerance of CRC cells and provides a potential therapeutic vulnerability.

ITLN1 inhibits tumor neovascularization and myeloid derived suppressor cells accumulation in colorectal carcinoma.

Low levels of ITLN1 have been correlated with obesity-related colorectal carcinogenesis, however, the specific functions and underlying mechanisms remain unclear. Thus, we sought to explore the inhibitory role of ITLN1 in the tumor-permissive microenvironment that exists during the first occurrence and subsequent development of colorectal carcinoma (CRC). Results indicated that ITLN1 was frequently lost in CRC tissues and ITLN1 to be an independent prognostic predictor of CRC. Orthotopic and subcutaneous tumor xenograft approaches were then used to further confirm the protective role of ITLN1 during tumor progression. Increased ITLN1 expression in CRC cells significantly inhibited local pre-existing vessels sprouting, EPC recruitment and the infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) into tumor tissues without affecting the behavior of CRC cells in vitro. Comparatively, ITLN1-derived MDSCs had a lower suppressive effect on T cell proliferation, NOS2 expression, and ROS production. In addition, ITLN1 overexpression markedly suppressed bone marrow (BM)-derived hematopoietic progenitor cells (HPC) differentiation into MDSCs as well as NOS2 activity on MDSCs. Using H-2b+YFP + chimerism through bone marrow transplantation, increased ITLN1 in HCT116 significantly reduced the BM-derived EPCs and MDSCs in vivo mobilization. Mechanistically, results indicated ITLN1 inhibited tumor-derived IL-17D and CXCL2 (MIP2) through the KEAP1/Nrf2/ROS/IL-17D and p65 NF-ĸB/CXCL2 signaling cascades dependent on PI3K/AKT/GSK3ß. This effect was reversed by the PI3K selective inhibitor LY294002. Collectively, ITLN1 synergistically suppressed IL-17D and CXCL2-mediated tumor vascularization, bone marrow derived EPC recruitment, as well as MDSCs generation and trafficking. Thus, ITLN1 potentially serves as a critical prognostic and therapeutic target for CRC.

Simultaneous 3-Nitrophenylhydrazine Derivatization Strategy of Carbonyl, Carboxyl and Phosphoryl Submetabolome for LC-MS/MS-Based Targeted Metabolomics with Improved Sensitivity and Coverage.

Metabolomics is a powerful and essential technology for profiling metabolic phenotypes and exploring metabolic reprogramming, which enables the identification of biomarkers and provides mechanistic insights into physiology and disease. However, its applications are still limited by the technical challenges particularly in its detection sensitivity for the analysis of biological samples with limited amount, necessitating the development of highly sensitive approaches. Here, we developed a highly sensitive liquid chromatography tandem mass spectrometry method based on a 3-nitrophenylhydrazine (3-NPH) derivatization strategy that simultaneously targets carbonyl, carboxyl, and phosphoryl groups for targeted metabolomic analysis (HSDccp-TM) in biological samples. By testing 130 endogenous metabolites including organic acids, amino acids, carbohydrates, nucleotides, carnitines, and vitamins, we showed that the derivatization strategy resulted in significantly improved detection sensitivity and chromatographic separation capability. Metabolic profiling of merely 60 oocytes and 5000 hematopoietic stem cells primarily isolated from mice demonstrated that this method enabled routine metabolomic analysis in trace amounts of biospecimens. Moreover, the derivatization strategy bypassed the tediousness of inferring the MS fragmentation patterns and simplified the complexity of monitoring ion pairs of metabolites, which greatly facilitated the metabolic flux analysis (MFA) for glycolysis, the tricarboxylic acid (TCA) cycle, and pentose phosphate pathway (PPP) in cell cultures. In summary, the novel 3-NPH derivatization-based method with high sensitivity, good chromatographic separation, and broad coverage showed great potential in promoting metabolomics and MFA, especially in trace amounts of biospecimens.