Circ_0028826 Promotes Growth and Metastasis of NSCLC via Acting as a Sponge of miR-758-3p to Derepress IDH2 Expression.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the cancers with the highest mortality and morbidity in the world. Circular RNAs (circRNAs) are newly identified players in carcinogenesis and development of various cancers. This study is aimed at exploring the functional effects and mechanism of circ_0028826 in the development of NSCLC. METHODS: Real-time quantitative PCR (RT-qPCR) was used to detect the expression levels of circ_0028826, IDH2 mRNA, and miR-758-3p. IDH2, Bcl2, Bax, and E-cadherin protein levels were detected using a western blot. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, wound healing, and transwell assays were used to assess the capacities of proliferation, apoptosis, migration, and invasion. Interaction between miR-758-3p and circ_0028826 or IDH2 was validated using a dual-luciferase reporter assay. The role of circ_0028826 in vivo was checked based on a xenograft tumor model. RESULTS: Circ_0028826 was elevated in NSCLC, and its absence inhibited NSCLC cell proliferation, migration, invasion, and induced apoptosis. In terms of mechanism, circ_0028826 increased IDH2 expression by targeting miR-758-3p. In addition, circ_0028826 knockdown also regulated IDH2 by targeting miR-758-3p to inhibit tumor growth in vivo. CONCLUSION: Circ_0028826 promoted the development of NSCLC via regulation of the miR-758-3p/IDH2 axis, providing a new strategy for NSCLC treatment.

IGF-1 and myostatin-mediated co-regulation in skeletal muscle and bone of Daurian ground squirrels (Spermophilus dauricus) during different hibernation stages.

Muscle and bone are cooperatively preserved in Daurian ground squirrels (Spermophilus dauricus) during hibernation. As such, we hypothesized that IGF-1 and myostatin may contribute to musculoskeletal maintenance during this period. Thus, we systematically assessed changes in the protein expression levels of IGF-1 and myostatin, as well as their corresponding downstream targets, in the vastus medialis (VM) muscle and femur in Daurian ground squirrels during different stages. Group differences were determined using one-way analysis of variance (ANOVA). Results indicated that the co-localization levels of IGF-1 and its receptor (IGF-1R) increased by 50% during the pre-hibernation period (PRE) and by 35% during re-entry into torpor (RET) compared to the summer active period (SA). The phosphorylation level of FOXO1 in the VM muscle increased by 50% in the torpor (TOR) group and by 82% in the inter-bout arousal (IBA) group compared to the PRE group. The phosphorylation level of SGK-1 increased by 54% in the IBA group and by 62% in the RET group compared to the SA group. In contrast, the protein expression of IGF-1 and phosphorylation levels of PI3K, Akt, mTOR, and GSK3ß in the VM muscle showed no obvious differences among the different groups. ß-catenin protein expression was up-regulated by 84% in the RET group compared to the SA group, while the content of IGF-1 protein, correlation coefficients of IGF-1 and IGF-1R, and phosphorylation levels of PI3K, Akt, and GSK3ß in the femur showed no significant differences among groups. Regarding myostatin and its downstream targets, myostatin protein expression decreased by 70% in the RET group compared to the SA group, whereas ActRIIB protein expression and Smad2/3 phosphorylation in the VM muscle showed no obvious differences among groups. Furthermore, Smad2/3 phosphorylation decreased by 58% in the TOR group and 53% in the RET group compared to the SA group, whereas ActRIIB protein expression in the femur showed no obvious differences among groups. Overall, the observed changes in IGF-1 and myostatin expression and their downstream targets may be involved in musculoskeletal preservation during hibernation in Daurian ground squirrels.

MIL-88A(Al)/chitosan/graphene oxide composite aerogel with hierarchical porosity for enhanced radioactive iodine adsorption.

To ensure the sustainable development of the nuclear industry, the effective capture of radioiodine from nuclear wastewater has attracted much attention. Herein, a novel MIL-88A(Al)/chitosan/graphene oxide (MCG) composite aerogel was prepared by using crosslinked chitosan and graphene oxide as the 3D network skeleton, and MIL-88A(Al) nanocrystalline particles were introduced into the skeleton by freeze-drying method. MIL-88A(Al) adsorption capacities for volatile and soluble iodine were 2.02 g g-1 and 850.00 mg g-1, respectively. Owing to the synergistic effect of MIL-88A(Al), GO, CS, and the hierarchically porous structures of the MCG aerogel, the adsorption capacities for volatile and soluble iodine by the MCG aerogel were increased to 2.62 g g-1 and 1072.60 mg g-1, respectively. Furthermore, the adsorption performance of the MCG aerogel for volatile and soluble iodine could be maintained at 83 % and 82 % after 5 cycles, suggesting excellent recoverability. Meanwhile, the adsorption mechanism studies showed the interactions between iodine and NH, AlO, and CO in MCG aerogel. Furthermore, the adsorption process is consistent with the Elovich kinetic and Sips isotherm models. MCG aerogels are potential candidates for enhanced radioiodine adsorption due to their high radioiodine capture performance and excellent recyclability.

Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer's disease.

Asymptomatic Alzheimer's disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology (i.e., beta-amyloid (Aß) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aß, preserving brain health, and slowing AD pathology progression.

Discovery of novel penetrating peptides able to target human leukemia and lymphoma for enhanced PROTAC delivery.

Proteolysis targeting chimeras (PROTAC) are bifunctional chimeric molecules capable of directly degrading binding proteins through the ubiquitin-proteasome pathway. PROTACs have demonstrated significant potential in overcoming drug resistance and targeting previously untreatable targets. However, several limitations still need to be addressed, including their high molecular weight resulting in poor membrane permeability and bioavailability. In this study, we proposed that cancer-targeted penetrating peptides could enhance the cell permeability of PROTACs. We developed 26 novel targeted penetrating peptides for leukemia and lymphoma cells, among which C9C-f(3Bta) and Cyclo-C9C-R exhibited superior membrane permeability, targetability, and stability. By combining C9C-f(3Bta) and Cyclo-C9C-R with IMA-PROTAC, we effectively enhanced the anti-proliferative activity of IMA-PROTAC, facilitated degradation of Bcr-Abl protein in K562 cells, and reduced downstream STAT5 phosphorylation. Furthermore, the combined application promoted cell apoptosis while blocking G1 phase progression. HPLC-MRM-MS revealed that the combination of C9C-f(3Bta) or Cyclo-C9C-R with IMA-PROTAC significantly enhanced intracellular IMA-PROTAC content. In summary, our proof-of-concept study validated the hypothesis that combining PROTACs with targeted penetrating peptides can improve protein degradation efficiency as well as anti-proliferative capabilities.

Discovery of novel amide derivatives against VEGFR-2/tubulin with potent antitumor and antiangiogenic activity.

Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.

Diagnostic Value of Hepcidin in Sepsis: A Systematic Review and Meta-Analysis.

Objectives: To investigate the diagnostic value of hepcidin for sepsis diagnosis. Methods: The relevant literature on hepcidin for sepsis diagnosis published up to October 20, 2023, was systematically searched in the Web of Science, PubMed, Embase, and China Knowledge Network databases. Two researchers screened the literature and extracted relevant data according to the inclusion and exclusion criteria. Study quality was evaluated using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis and calculation of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were performed using State16 and Review Manager 5.3 software. Furthermore, receiver operating characteristic curve (ROC) was plotted, and the respective area under the curve (AUC) was calculated to assess the accuracy of hepcidin. Publication bias was evaluated using Deeks' funnel plot asymmetry test. Results: Overall, 1047 patients from 8 studies were included (625 patients with sepsis and 422 controls). The quality of the literature was relatively moderate. Meta-analysis demonstrated the presence of heterogeneity in the data (I2 > 50%, P < .05), and a randomized model was employed to combine the diagnostic indicators. Regarding its accuracy for sepsis diagnosis, hepcidin demonstrated a pooled sensitivity of 0.88 (95% confidence interval [CI]: 0.76-0.94) and specificity of 0.91 (95% CI: 0.76-0.97). The diagnostic odds ratio was 69.00 (95% CI: 19.00-253.00), and the ROC curve revealed an AUC of 0.95. Additionally, Deeks' funnel plot asymmetry test demonstrated absence of publication bias. Conclusions: Our meta-analysis suggested that hepcidin has a high diagnostic value in sepsis and may be a valuable diagnostic tool.

Tracking the extensive three-dimensional motion of single ions by an engineered point-spread function.

Three-dimensional (3D) imaging of individual atoms is a critical tool for discovering new physical phenomena and developing new technologies in microscopic systems. However, the current single-atom-resolved 3D imaging methods are limited to static circumstances or a shallow detection range. Here, we demonstrate a generic dynamic 3D imaging method to track the extensive motion of single ions by exploiting the engineered point-spread function (PSF). We show that the image of a single ion can be engineered into a helical PSF, thus enabling single-snapshot acquisition of the position information of the ion in the trap. A preliminary application of this technique is demonstrated by recording the 3D motion trajectory of a single trapped ion and reconstructing the 3D dynamical configuration transition between the zig and zag structures of a 5-ion crystal. This work opens the path for studies on single-atom-resolved dynamics in both trapped-ion and neutral-atom systems.

A multicenter cross-sectional study in China revealing the intrinsic relationship between medical students' grade and their perceptions of the learning environment.

BACKGROUND: Medical school learning environment (MSLE) has a holistic impact on students' psychosomatic health, academic achievements, and personal development. Students in different grades perceive MSLE in different ways. Thus, it is essential to investigate the specific role of student's grade in the perception of MSLE. METHODS: Using the Johns Hopkins Learning Environment Scale (JHLES) as a quantification instrument for the perception level of MSLE, 10,901 medical students in 12 universities in China were categorized into low or high JHLES group according to their questionnaires. We investigated the relationship between student's grade and JHLES category by univariate analysis employing Pearson Chi-square test and Welch's ANOVA. Then multivariable logistic regression analysis confirmed the predictive efficacy of student's grade. A nomogram concerning the prediction of low JHLES score probability in medical students was also constructed. RESULTS: A significant difference between two JHLES categories among students in different grades was observed (p < 0.001), with the proportion of the high JHLES group dominating in grade 1, 5, and the graduate subgroups (p < 0.001). The mean JHLES score declined especially in the third and fourth graders compared to freshmen (p < 0.001), while the mean score among the fifth graders had a remarkable rebound from the third graders (p < 0.001). Most imperatively, identified by multivariable logistic regression analysis, students in grade 3 (OR = 1.470, 95% CI = 1.265-1.709, p < 0.001) and 4 (OR = 1.578, 95% CI = 1.326-1.878, p < 0.001) perceived more negatively than freshmen. The constructed nomogram provided a promising prediction model for student's low JHLES score probability, with accuracy, accordance, and discrimination (area under the curve (AUC) = 0.627). CONCLUSION: The student's grade was a significant influencing factor in medical students' perception of MSLE. The perceptions among the third and fourth graders got worse, probably due to the worrying changes in various aspects of MSLE during that period. The relevant and appropriate interventions to improve medical students' perceptions are urgently needed.

The impact of high-order features on performance of radiomics studies in CT non-small cell lung cancer.

High-order radiomic features have been shown to produce high performance models in a variety of scenarios. However, models trained without high-order features have shown similar performance, raising the question of whether high-order features are worth including given their increased computational burden. This comparative study investigates the impact of high-order features on model performance in CT-based Non-Small Cell Lung Cancer (NSCLC) and the potential uncertainty regarding their application in machine learning. Three categories of features were retrospectively retrieved from CT images of 347 NSCLC patients: first- and second-order statistical features, morphological features and transform (high-order) features. From these, three datasets were constructed: a "low-order" dataset (Lo) which included the first-order, second-order, and morphological features, a high-order dataset (Hi), and a combined dataset (Combo). A diverse selection of datasets, feature selection methods, and predictive models were included for the uncertainty analysis, with two-year survival as the study endpoint. AUC values were calculated for comparisons and Kruskal-Wallis testing was performed to determine significant differences. The Hi (AUC: 0.41-0.62) and Combo (AUC: 0.41-0.62) datasets generate significantly (P < 0.01) higher model performance than the Lo dataset (AUC: 0.42-0.58). High-order features are selected more often than low-order features for model training, comprising 87 % of selected features in the Combo dataset. High-order features are a source of data that can improve machine learning model performance. However, its impact strongly depends on various factors that may lead to inconsistent results. A clear approach to incorporate high-order features in radiomic studies requires further investigation.

APOD: A biomarker associated with oxidative stress in acute rejection of kidney transplants based on multiple machine learning algorithms and animal experimental validation.

BACKGROUND: Oxidative stress is an unavoidable process in kidney transplantation and is closely related to the development of acute rejection after kidney transplantation. This study aimed to investigate the biomarkers associated with oxidative stress and their potential biological functions during acute rejection of kidney transplants. METHODS: We identified Hub genes using five machine learning algorithms based on differentially expressed genes (DEGs) in the kidney transplant acute rejection dataset GSE50058 and oxidative stress-related genes (OS) obtained from the MSigDB database, and validated them with the datasets GSE1563 and GSE9493, as well as with animal experiments; Subsequently, we explored the potential biological functions of Hub genes using single-gene GSEA enrichment analysis; The Cibersort algorithm was used to explore the altered levels of infiltration of 22 immune cells during acute rejection of renal transplantation, and a correlation analysis between Hub genes and immune cells was performed; Finally, we also explored transcription factors (TFs), miRNAs, and potential drugs that regulate Hub genes. RESULTS: We obtained a total of 57 genes, which we defined as oxidative stress-associated differential genes (DEOSGs), after intersecting DEGs during acute rejection of kidney transplants with OSs obtained from the MSigDB database; The results of enrichment analysis revealed that DEOSGs were mainly enriched in response to oxidative stress, response to reactive oxygen species, and regulation of oxidative stress and reactive oxygen species; Subsequently, we identified one Hub gene as APOD using five machine learning algorithms, which were validated by validation sets and animal experiments; The results of single-gene GSEA enrichment analysis revealed that APOD was closely associated with the regulation of immune signaling pathways during acute rejection of kidney transplants; The Cibersort algorithm found that the infiltration levels of a total of 10 immune cells were altered in acute rejection, while APOD was found to correlate with the expression of multiple immune cells; Finally, we also identified 154 TFs, 12 miRNAs, and 12 drugs or compounds associated with APOD regulation. CONCLUSION: In this study, APOD was identified as a biomarker associated with oxidative stress during acute rejection of kidney transplants using multiple machine learning algorithms, which provides a potential therapeutic target for mitigating oxidative stress injury and reducing the incidence of acute rejection in kidney transplantation.

MDSCs promote pathological angiogenesis in ocular neovascular disease.

BACKGROUND: Ocular neovascular diseases, which contribute significantly to vision loss, lack effective preventive treatments. Recent studies have highlighted the significant involvement of immune cells in neovascular retinopathy. Myeloid-derived suppressor cells (MDSCs) promote the development of neovascularization, but it is unknown whether they participate in pathological neovascularization and whether they are expected to be a therapeutic target. METHOD: We investigated the role of MDSCs in promoting pathological angiogenesis using an oxygen-induced retinopathy (OIR) model, employing flow cytometry, immunofluorescence, and smart-seq analysis. Then, we evaluated the proportion of MDSCs in patient blood samples using flow cytometry. Additionally, we assessed the effect of MDSC depletion using an anti-Gr-1 monoclonal antibody on retinal vasculopathy and alterations in retinal microglia. RESULTS: In the OIR model, an elevated ratio of MDSCs was observed in both blood and retinal tissue during phase II (Neovascularization). The depletion of MDSCs resulted in reduced retinal neovascularization and vaso-obliteration, along with a decrease in microglia within the neovascularization area. Furthermore, analysis of gene transcripts associated with MDSCs indicated activation of vascular endothelial growth factor (VEGF) regulation and inflammation. Importantly, infants with ROP exhibited a higher proportion of MDSCs in their blood samples. CONCLUSION: Our results suggested that excessive MDSCs represent an unrecognized feature of ocular neovascular diseases and be responsible for the retinal vascular inflammation and angiogenesis, providing opportunities for new therapeutic approaches to ocular neovascular disease.

Breaking Barriers in Pharmaceutical Analysis: Streamlined UV Spectrometric Quantification and Stability Profiling of Haloperidol and Methylparaben in Liquid Formulations.

This study aims to quantify haloperidol and methylparaben in a liquid pharmaceutical formulation (2 mg/ml) using UV spectrometry and the simultaneous equations method. Additionally, we explored the stability of haloperidol under various stress conditions. The UV analysis revealed maximum absorption peaks at 248 nm for haloperidol and 256 nm for methylparaben, using a 1% (v/v) lactic acid solution as the solvent. Method validation, conducted according to ICH guidelines, affirmed the method's reliability, showing excellent results in terms of linearity, precision, accuracy, and sensitivity. The method allows direct application to finished products, enabling simultaneous quantification without extractions. Its simplicity, speed, and cost-effectiveness make it ideal for routine controls in pharmaceutical industry haloperidol solution analyses. The method extends to monitoring forced degradation, indicating photolytic and hydrolytic degradation under acidic and basic conditions, while affirming thermal and oxidative stability. This proposed UV spectrometric method serves as a compelling alternative to pharmacopeia-recommended techniques, simplifying simultaneous determination of the active ingredient and preservative. This streamlines analysis, reducing time and costs. Additionally, it proves valuable in small industries lacking sophisticated instrumentation, offering insights into active ingredient behavior during forced degradation.

Sequence and phylogenetic analysis of FMD virus isolated from two outbreaks in Egypt.

Despite intensive control efforts, Foot and mouth disease (FMD) outbreaks continue to occur regularly in Egypt and resulting in dramatic economic losses to the livestock industry. During 2018 and 2022, FMD was clinically suspected among previously vaccinated cattle in Beheira and Kafr El-Sheikh provinces, Egypt. FMDV RNA was detected in 18 (45%) out of 40 epithelial tissue samples using real-time RT-PCR based on a pan-FMDV primers set. The 2018 outbreak isolates (n = 8) included the FMDV serotypes A and SAT2, whereas all isolates (n = 10) from the 2022 outbreak belonged to the FMDV serotype A. Four selected isolates, designated FMDV/SAT2/EGY/Beheira/2018, FMDV/A/EGY/Kafr El-Sheikh/2018, FMDV/A/EGY/Kafr El-Sheikh/2022 and FMDV/A/EGY/Behiera/2022, were characterized on the basis of partial VP1 gene sequence analysis. The FMDV/SAT2/EGY/Beheira/2018 strain was clustered within the Lib-12 lineage of the topotype VII and shared 79.2-98.4% nucleotide identity with other Egyptian SAT2 strains available in Genbank database. On the other hand, the three FMDV serotype A sequences shared 74.4-99.1% nucleotide identity with each other. Also, they were phylogenetically classified within two distinct topotypes. The FMDV/A/Egy/Kafr El-Sheikh/2018 strain was grouped within the Asian topotype, meanwhile the FMDV/A/EGY/Kafr El-Sheikh/2022 and FMDV/A/EGY/Behiera/2022 strains were grouped together within the genotype IV of the African topotype. Interestingly, the deduced amino acid sequences of the four strains displayed numerous variations in comparison to the vaccine strains currently used in Egypt. In addition, most of these variations were present in prominent antigenic positions in the VP1 protein. These findings raise a crucial need to validate the protective potential of the vaccine strains against the newly emerging FMDV field strains and to update the vaccination strategy accordingly.

Assessing and harnessing updated polyketide synthase modules through combinatorial engineering.

The modular nature of polyketide assembly lines and the significance of their products make them prime targets for combinatorial engineering. The recently updated module boundary has been successful for engineering short synthases, yet larger synthases constructed using the updated boundary have not been investigated. Here we describe our design and implementation of a BioBricks-like platform to rapidly construct 5 triketide, 25 tetraketide, and 125 pentaketide synthases to test every module combination of the pikromycin synthase. Anticipated products are detected from 60% of the triketide synthases, 32% of the tetraketide synthases, and 6.4% of the pentaketide synthases. We determine ketosynthase gatekeeping and module-skipping are the principal impediments to obtaining functional synthases. The platform is also employed to construct active hybrid synthases by incorporating modules from the erythromycin, spinosyn, and rapamycin assembly lines. The relaxed gatekeeping of a ketosynthase in the rapamycin synthase is especially encouraging in the quest to produce designer polyketides.

Ferroptosis and inflammation are modulated by the NFIL3-ACSL4 axis in sepsis associated-acute kidney injury.

Sepsis-associated acute kidney injury (SA-AKI) increases the risk of death in patients with sepsis, and its major pathological change is the death of renal tubular cells. However, the mechanism of its occurrence remains unclear. Sepsis can lead to circadian dysregulation, and the rhythm gene NFIL3 has been reported to regulate lipid metabolism. There is compelling evidence that has demonstrated that lipid peroxidation can cause cellular ferroptosis. In this study, we established the in vitro and in vivo models of SA-AKI and confirmed the presence of ferroptosis of the renal tubular epithelial cells in SA-AKI. In addition, analysis of the GEO database showed that NFIL3 was highly expressed in sepsis patients and was highly correlated with the key molecule of ferroptosis, ACSL4. The in vitro and in vivo data suggested that NFIL3 was involved in ferroptosis and inflammation in SA-AKI. Subsequently, loss-of-function experiments revealed that NFIL3 knockdown attenuated ferroptosis and inflammation in renal tubular epithelial cells by downregulating ACSL4 expression, thus protecting SA-AKI. In conclusion, this study is the first to illustrate the involvement of the rhythm gene NFIL3 in SA-AKI, providing new insights and potential therapeutic targets for SA-AKI.

Remnant cholesterol and all-cause mortality risk: findings from the National Health and Nutrition Examination Survey, 2003-2015.

Aims: Cholesterol carried in triglyceride-rich lipoproteins, also called remnant cholesterol, is increasingly acknowledged as an important causal risk factor for atherosclerosis. Elevated remnant cholesterol, marked by elevated plasma triglycerides, is associated causally with an increased risk of atherosclerotic cardiovascular disease. However, the association with all-cause mortality and cause-specific mortality is inconclusive. This study aimed to test the hypothesis that remnant cholesterol levels and plasma triglycerides are associated with increased all-cause mortality and mortality from cardiovascular disease, cancer, and other causes. Methods and results: Using a contemporary population-based cohort, 7,962 individuals from the National Health and Nutrition Examination Survey (NHANES) aged over 40 years at baseline in 2003-2015 were included. During up to 109.2 (± 1.44) months of follow-up, 1,323 individuals died: 385 individuals died from cardiovascular disease, 290 from cancer, 80 from cerebrovascular disease, and 568 from other causes. Compared with the middle tertile remnant cholesterol level, multivariable-adjusted mortality hazard ratios were 1.20 (95% confidence interval 1.02-1.40) for all-cause mortality. For the highest tertile remnant cholesterol level, multivariable-adjusted mortality hazard ratios were 1.21 (95% confidence interval 1.05,1.40). Our conclusions remained stable in subgroup analyses. Exploratory analysis of the cause of death subcategories showed corresponding hazard ratios of 1.25 (1.13-1.38) for Non-cardiovascular and Non-cerebrovascular Death for lower remnant cholesterol individuals, 1.47 (1.01-2.15) for cancer death for lower remnant cholesterol (RC) individuals, and 1.80 (1.36-2.38) for cancer death for higher RC individuals. Conclusion: RC levels were associated with U-shaped all-cause mortality. RC was associated with mortality from non-cardiovascular, non-cerebrovascular, and cancer, but not from cardiovascular causes. This novel finding should be confirmed in other cohorts.

Luteolin Alleviates Diabetic Nephropathy Fibrosis Involving AMPK/NLRP3/TGF-ß Pathway.

Purpose: Luteolin is a promising candidate for diabetic nephropathy due to its potential anti-inflammatory and anti-fibrotic properties. This study explored the molecular mechanisms through which luteolin combats fibrosis in DN. Methods: Potential targets affected by luteolin and genes associated with DN were collected from databases. Overlapping targets between luteolin and diabetic nephropathy were identified through Venn analysis. A protein-protein interaction network was constructed using these common targets, and critical pathways and targets were elucidated through GO and KEGG analysis. These pathways and targets were confirmed using a streptozotocin-induced mouse model. Luteolin was administered at 45 mg/kg and 90 mg/kg. Various parameters were evaluated, including body weight, blood glucose levels, and histopathological examinations. Protein levels related to energy metabolism, inflammation, and fibrosis were quantified. Results: Fifty-three targets associated with luteolin and 36 genes related to diabetic nephropathy were extracted. The AGE-RAGE signaling pathway was the key pathway impacted by luteolin in diabetic nephropathy. Key molecular targets include TGF-ß, IL-1ß, and PPARG. Luteolin reduced body weight and blood glucose levels, lowered the left kidney index, and improved insulin and glucose tolerance. Furthermore, luteolin mitigated inflammatory cell infiltration, basement membrane thickening, and collagen deposition in the kidney. Luteolin up-regulated the protein expression of p-AMPKα (Th172) while simultaneously down-regulated the protein expression of p-NF-ĸB (p65), NLRP3, TGF-ß1, α-SMA, and Collagen I. Conclusion: Luteolin mitigated renal fibrosis by alleviating energy metabolism disruptions and inflammation by modulating the AMPK/NLRP3/TGF-ß signaling pathway.

Association between dietary intake of niacin and stroke in the US residents: evidence from national health and nutrition examination survey (NHANES) 1999-2018.

Objective: This study aims to explore the association between niacin intake and stroke within a diverse, multi-ethnic population. Methods: A stringent set of inclusion and exclusion criteria led to the enrollment of 39,721 participants from the National Health and Nutrition Examination Survey (NHANES). Two interviews were conducted to recall dietary intake, and the USDA's Food and Nutrient Database for Dietary Studies (FNDDS) was utilized to calculate niacin intake based on dietary recall results. Weighted multivariate logistic regression was employed to examine the correlation between niacin and stroke, with a simultaneous exploration of potential nonlinear relationships using restricted cubic spline (RCS) regression. Results: A comprehensive analysis of baseline data revealed that patients with stroke history had lower niacin intake levels. Both RCS analysis and multivariate logistic regression indicated a negative nonlinear association between niacin intake and stroke. The dose-response relationship exhibited a non-linear pattern within the range of dietary niacin intake. Prior to the inflection point (21.8 mg) in the non-linear correlation between niacin intake and stroke risk, there exists a marked decline in the risk of stroke as niacin intake increases. Following the inflection point, the deceleration in the decreasing trend of stroke risk with increasing niacin intake becomes evident. The inflection points exhibit variations across diverse populations. Conclusion: This investigation establishes a negative nonlinear association between niacin intake and stroke in the broader American population.

Treatments for pathogen infection rescued 2 patients with renal artery rupture after kidney transplantation: A case report.

RATIONALE: Renal artery rupture due to allograft infection, especially by fungi, is a serious clinical complication that can occur after kidney transplantation, and may lead to graft loss and death. PATIENT CONCERNS: Two kidney recipients from China who developed renal artery rupture at our hospital on 5 days (47-year-old female) and 45 days (39-year-old male) after surgery. DIAGNOSES: The male had immunoglobulin A nephropathy as a primary disease, and experienced a postoperative attack of vascular rejection and mixed infection by Mucor and bacteria. The female had chronic glomerulonephritis as a primary disease, and experienced renal artery rupture near the anastomosis site with infection by fungi and other pathogens. INTERVENTIONS: The male received resection of the implanted kidney and antibiotic therapy with intravenous vancomycin (0.5 g, 2 days) and amphotericin B (530 mg in 33 days). The female received replacing the segment of renal arterial and internal iliac artery by saphenous vein, as well as antibiotic therapy with amphotericin B (320 mg in 8 days). OUTCOMES: The male was recovered and received a second transplantation, while the female was discharged on postoperative day 19. LESSONS: In both patients, prompt surgery and aggressive treatment with an antifungal drug (amphotericin B) and antidrugs led to successful rescue.