The association between dietary inflammatory index and cognitive function in adults with/without chronic kidney disease

Background and aimsCognitive impairment (CI) is a prevalent condition in patients with chronic kidney disease (CKD), who face an elevated risk of developing cognitive decline. The fundamental mechanism underlying CI is linked to chronic inflammation, which can be gauged by the Dietary Inflammatory Index (DII). The DII is categorized into anti-inflammatory diets with lower scores and pro-inflammatory diets with higher scores. Specifically, pro-inflammatory diets may contribute to chronic inflammation. However, the correlation between the inflammatory potential of diet and cognitive function in patients with CKD has not been explored. This study aims to investigate the connection between the inflammatory potential of diet and cognitive function in individuals with or without chronic kidney disease.MethodsData from the 2011–2012 and 2013–2014 National Health and Nutrition Examination Survey (NHANES) were utilized. Participants under the age of 60 or lacking DII, CI, CKD, and other essential data were excluded. DII was computed based on a 24-h dietary recall interview for each participant. Cognitive performance was evaluated using three cognitive tests: the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test, the Animal Fluency Test (AFT), and the Digital Symbol Substitution Test (DSST). Logistic regression analysis and subgroup analysis were conducted to assess the independent relationship between DII score and CI in the CKD and non-CKD populations.ResultsThe study included a total of 2069 subjects, with CI prevalence ranging from 21.4 to 23.5%. Multiple regression models showed that after adjusting for all covariates of the three cognitive function tests, higher DII scores were significantly associated with increased risk of CI (CERAD OR = 1.18, 95% CI: 1.1 ~ 1.26, AFT OR = 1.15, 95% CI: 1.08 ~ 1.23, DSST OR = 1.19, 95% CI: 1.11 ~ 1.28). Subgroup analysis indicated that the effect of DII score on CI remained consistent in all subgroups (p > 0.05).ConclusionHigher DII scores were associated with an increased risk of cognitive impairment in people with or without CKD, suggesting that consuming a pro-inflammatory diet may contribute to the impairment of the cognitive function

Imaging-guided synergistic targeting-promoted photo-chemotherapy against cancers by methotrexate-conjugated hyaluronic acid nanoparticles

Abstract(#br)A combination of chemotherapy and photothermal therapy (PTT) against cancer, overcoming the intrinsic limitations of single-modal chemotherapy or PTT, has emerged as a promising strategy to achieve synergistic therapeutic effect. However, the lack of precise drug delivery and intelligent drug release based on photo-chemotherapy at specific tumor sites remained a challenge. Hence, the both tumor-specific targeting molecule (methotrexate) and ligand (hyaluronic acid)-introduced, glutathione-responsive amphiphiles (deoxycholic acid-hyaluronic acid-methotrexate, DA-SS-HA-MTX) were developed for synchronous delivery of indocyanine green (ICG) and doxorubicin (DOX). The as-synthesized DOX/ICG@DSHM remarkably improved the intracellular drug uptake and accumulation owing to both the CD44/folate receptors-mediated synergistic targeting and the glutathione-triggered rapid drug release. Moreover, DOX/ICG@DSHM efficiently accumulated at the tumor sites, realizing the notable tumor ablation under the guidance of dual-modal optical imaging. Taken together, this study provided a promising nanotheranostic agent for imaging-guided chemo-photothermal combination therapy

Leflunomide Inhibits rat-to-Mouse Cardiac Xenograft Rejection by Suppressing Adaptive Immune Cell Response and NF-κB Signaling Activation

Xenotransplantation is a potential solution for the severe shortage of human donor organs and tissues. The generation of humanized animal models attenuates strong innate immune responses, such as complement-mediated hyperacute rejection. However, acute vascular rejection and cell mediated rejection remain primary barriers to xenotransplantation, which limits its clinical application. In this study, we systematically investigated the immunosuppressive effect of LEF using a rat-to-mouse heart xenotransplantation model. SD rat xenogeneic hearts were transplanted into C57BL/6 mice, and survived 34.5 days after LEF treatment. In contrast, BALB/c allogeneic hearts were transplanted into C57BL/6 mice, and survived 31 days after LEF treatment. Compared to normal saline treatment, LEF treatment decreased xenoreactive T cells and CD19+ B cells in recipient splenocytes. Most importantly, LEF treatment protected myocardial cells by decreasing xenoreactive T and B cell infiltration, inflammatory gene expression, and IgM deposition in grafts. In vivo assays revealed that LEF treatment eliminated xenoreactive and alloreactive T and B lymphocytes by suppressing the activation of the NF-κB signaling pathway. Taken together, these observations complement the evidence supporting the potential use of LEF in xenotransplantation

Therapeutic Interaction of Apatinib and Chidamide in T-Cell Acute Lymphoblastic Leukemia through Interference with Mitochondria Associated Biogenesis and Intrinsic Apoptosis

T-cell acute lymphoblastic leukemia (T-ALL) shows poor clinical outcome and has limited therapeutic options, indicating that new treatment approaches for this disease are urgently required. Our previous study demonstrated that apatinib, an orally selective VEGFR-2 antagonist, is highly effective in T-ALL. Additionally, chidamide, a histone deacetylase inhibitor, has proven to be cytotoxic against T-ALL in preclinical and clinical settings. However, whether the therapeutic interaction of apatinib and chidamide in T-ALL remains unknown. In this study, apatinib and chidamide acted additively to decrease cell viability and induce apoptosis in T-ALL in vitro. Notably, compared with apatinib or chidamide alone, the combinational regimen was more efficient in abrogating the leukemia burden in the spleen and bone marrow of T-ALL patient-derived xenograft (PDX) models. Mechanistically, the additive antileukemia effect of apatinib and chidamide was associated with suppression of mitochondrial respiration and downregulation of the abundance levels of several rate-limiting enzymes that are involved in the citric acid cycle and oxidative phosphorylation (OXPHOS). In addition, apatinib enhanced the antileukemia effect of chidamide on T-ALL via activation of the mitochondria-mediated apoptosis pathway and impediment of mitochondrial biogenesis. Taken together, the study provides a potential role for apatinib in combination with chidamide in the management of T-ALL and warrants further clinical evaluations of this combination in patients with T-ALL

Risk of fall in patients with chronic kidney disease: results from the China health and retirement longitudinal study (CHARLS)

Abstract Background Chronic kidney disease (CKD), often coexisting with various systemic disorders, may increase the risk of falls. Our study aimed to assess the prevalence and risk of falls among patients with CKD in China. Methods We included patients with/without CKD from China Health and Retirement Longitudinal Study (CHARLS). Our primary outcome was the occurrence of fall accidents within the past 2 years. To enhance the robustness of our findings, we employed a multivariable logistic regression model, conducted propensity score analysis, and applied an inverse probability-weighting model. Results A total of 12,658 participants were included, the prevalence of fall accident rates were 17.1% (2,028/11,837) among participants without CKD and 24.7% (203/821) among those with CKD. In the inverse probability-weighting model, participants with CKD exhibited higher fall accident rates (OR = 1.28, 95% CI: 1.08–1.53, p = 0.005 ). Sensitivity and subgroup analysis showed the results still stable. Conclusions The population in China afflicted with CKD has a significantly heightened risk of experiencing falls, underscoring the crucial importance of intensifying efforts in assessing and preventing fall risks

Soluble Flt-1 in AMI Patients Serum Inhibits Angiogenesis of Endothelial Progenitor Cells by Suppressing Akt and Erk’s Activity

In acute myocardial infarction (AMI), endothelial progenitor cells (EPCs) are essential for the recovery of collateral circulation via angiogenesis. Clinical research has shown that the poor prognosis of the patients with AMI is closely associated with the cell quantity and function of EPCs. Whether there are differences in the biological features of EPCs from AMI patients and healthy subjects is worth exploring. In this study, EPCs were isolated from human peripheral blood and identified as late-stage EPCs by flow cytometry, immunofluorescence, and blood vessel formation assay. Compared to healthy subjects, AMI patients had more EPCs in the peripheral blood compared to healthy subjects. In addition, EPCs from AMI patients exhibited higher migration ability in the transwell assay compared to EPCs from healthy subjects. However, no difference in the angiogenesis of EPCs was observed between AMI patients and healthy subjects. Further studies revealed that soluble vascular endothelial growth factor receptor 1 (sFlt-1) in the serum of AMI patients was involved in the inhibition of EPCs angiogenesis by suppressing the Akt and Erk pathways. In conclusion, this study demonstrated that elevated serum sFlt-1 inhibits angiogenesis of EPC in AMI patients. Our findings uncover a pathogenic role of sFlt-1 in AMI

Dimerization and Structural Stability of Amyloid Precursor Proteins Affected by the Membrane Microenvironments

The lipid raft microenvironment is implicated in the generation of the pathological amyloid-β (Aβ) species in amyloid precursor protein (APP) that is associated with neurodegenerative diseases. Evidence shows that APP forms a transmembrane homodimer with changeable structures as a function of the membrane compositions. However, the molecular responsibility of the dimerization and structural alteration for the amyloidogenic process in segregated membranes remains largely unclear. Here, we performed multiple coarse grained (CG) simulations to explore the behavioral preference of the transmembrane domain of APP (called C99) that is affected by the lipid raft microenvironment. The results showed that C99 was anchored at the boundary of the lipid raft relying on the conserved hydrophobic motif of V₇₁₀xxA₇₁₃xxxV₇₁₇xxxV₇₂₁. Moreover, the dimerization of C99 was greatly destabilized by the lipid raft, which led to a susceptible switching packing conformation. The molecular driving forces were derived from the combined regulation of the saturated lipids and cholesterols rather than from the simple binding competition of cholesterol in the C99 dimerization. The molecular details of the differential dimerization in the raft-forming and bulk fluid bilayer environments were compared, and the structural information was helpful for further understanding the enzymolysis responsiveness of APP

Preclinical Studies of Chiauranib Show It Inhibits Transformed Follicular Lymphoma through the VEGFR2/ERK/STAT3 Signaling Pathway

Transformed follicular lymphoma (t-FL), for which there is no efficient treatment strategy, has a rapid progression, treatment resistance, and poor prognosis, which are the main reasons for FL treatment failure. In this study, we identified a promising therapeutic approach with chiauranib, a novel orally developed multitarget inhibitor targeting VEGFR/Aurora B/CSF-1R. We first determined the cytotoxicity of chiauranib in t-FL cell lines through CCK-8, EdU staining, flow cytometry, and transwell assays. We also determined the killing effect of chiauranib in a xenograft model. More importantly, we identified the underlying mechanism of chiauranib in t-FL tumorigenesis by immunofluorescence and Western blotting. Treatment with chiauranib significantly inhibited cell growth and migration, promoted apoptosis, induced cell cycle arrest in G2/M phase, and resulted in significant killing in vivo. Mechanistically, chiauranib suppresses the phosphorylation level of VEGFR2, which has an anti-t-FL effect by inhibiting the downstream MEK/ERK/STAT3 signaling cascade. In conclusion, chiauranib may be a potential therapy to treat t-FL, since it inhibits tumor growth and migration and induces apoptosis by altering the VEGFR2/ERK/STAT3 signaling pathway

Blood-brain barrier-penetrative fluorescent anticancer agents triggering paraptosis and ferroptosis for glioblastoma therapy

Currently used drugs for glioblastoma (GBM) treatments are ineffective, primarily due to the significant challenges posed by strong drug resistance, poor blood-brain barrier (BBB) permeability, and the lack of tumor specificity. Here, we report two cationic fluorescent anticancer agents (TriPEX-ClO4 and TriPEX-PF6) capable of BBB penetration for efficient GBM therapy via paraptosis and ferroptosis induction. These aggregation-induced emission (AIE)-active agents specifically target mitochondria, effectively triggering ATF4/JNK/Alix-regulated paraptosis and GPX4-mediated ferroptosis. Specifically, they rapidly induce substantial cytoplasmic vacuolation, accompanied by reactive oxygen species generation and intracellular Ca2+ overload, thereby disrupting metabolisms and inducing non-apoptotic cell death. In vivo imaging revealed that TriPEX-ClO4 and TriPEX-PF6 successfully traversed the BBB to target orthotopic glioma and initiated effective synergistic therapy post-intravenous injection. Our AIE drugs emerged as the pioneering paraptosis inducers against drug-resistant GBM, significantly extending survival up to 40 days compared to temozolomide (20 days) in drug-resistant GBM-bearing mice. These compelling results open up new venues for the development of fluorescent anticancer drugs and innovative treatments for brain diseases

A one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer’s disease

Abstract Toxic amyloid-beta (Aβ) plaque and harmful inflammation are two leading symptoms of Alzheimer’s disease (AD). However, precise AD therapy is unrealizable due to the lack of dual-targeting therapy function, poor BBB penetration, and low imaging sensitivity. Here, we design a near-infrared-II aggregation-induced emission (AIE) nanotheranostic for precise AD therapy. The anti-quenching emission at 1350 nm accurately monitors the in vivo BBB penetration and specifically binding of nanotheranostic with plaques. Triggered by reactive oxygen species (ROS), two encapsulated therapeutic-type AIE molecules are controllably released to activate a self-enhanced therapy program. One specifically inhibits the Aβ fibrils formation, degrades Aβ fibrils, and prevents the reaggregation via multi-competitive interactions that are verified by computational analysis, which further alleviates the inflammation. Another effectively scavenges ROS and inflammation to remodel the cerebral redox balance and enhances the therapy effect, together reversing the neurotoxicity and achieving effective behavioral and cognitive improvements in the female AD mice model