Previous research has shown that type 2 diabetes mellitus (T2DM) is associated with an increased risk of cognitive impairment. Patients with impaired cognition often show decreased spontaneous brain activity on resting-state functional magnetic resonance imaging (rs-fMRI). This study used rs-fMRI to investigate changes in spontaneous brain activity among patients with T2DM and to determine the relationship of these changes with cognitive impairment. T2DM patients (n = 29) and age-, sex-, and education-matched healthy control subjects (n = 27) were included in this study. Amplitude of lowfrequency fluctuation (ALFF) and regional homogeneity (ReHo) values were calculated to represent spontaneous brain activity. Brain volume and cognition were also evaluated among these participants. Compared with healthy control subjects, patients with T2DM had significantly decreased ALFF and ReHo values in the occipital lobe and postcentral gyrus. Patients performed worse on several cognitive tests; this impaired cognitive performance was correlated with decreased activity in the cuneus and lingual gyrus in the occipital lobe. Brain volume did not differ between the two groups. The abnormalities of spontaneous brain activity reflected by ALFF and ReHo measurements in the absence of structural changes in T2DM patients may provide insights into the neurological pathophysiology underlying diabetes-associated cognitive decline.
OBJECTIVEType 2 diabetes is characterized by insulin resistance, which is involved in the development of Alzheimer disease. This study aims to investigate the relationship between abnormal resting-state brain functional connectivity and insulin resistance in type 2 diabetes. RESEARCH DESIGN AND METHODSA total of 30 patients with type 2 diabetes and 31 healthy well-matched volunteers were prospectively examined. Resting-state brain functional connectivity analysis was used to examine the correlation between the posterior cingulate cortex (PCC) and whole-brain regions. The possible relationships between functional connectivity measures and insulin resistance were evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTSCompared with healthy controls, we observed significantly decreased functional connectivity of the PCC within some selected regions, including the right middle temporal gyrus (MTG), left lingual gyrus, left middle occipital gyrus, and left precentral gyrus; increased functional connectivity of the PCC was detected in the left cerebellum posterior lobe, right superior frontal gyrus, and right middle frontal gyrus. A significant negative correlation was found between the PCC-right MTG connectivity and HOMA-IR in type 2 diabetic patients (P = 0.014; r = 20.446). CONCLUSIONSType 2 diabetic patients develop aberrant functional connectivity of the PCC, which is associated with insulin resistance in selected brain regions. Resting-state connectivity disturbance of PCC-MTG may be a central role for evaluating the cognitive dysfunction in type 2 diabetes.Type 2 diabetes is characterized by insulin resistance, as indicated by chronically increased peripheral insulin levels and concomitantly reduced brain insulin activity (1,2). Insulin modulates numerous metabolic pathways, including those associated with brain cognitive function, such as glucose metabolism, synaptic maintenance, vascular function, tau phosphorylation, and b-amyloid regulation (3-5). Recent longitudinal studies have shown that insulin resistance is associated with an increasing risk of developing into Alzheimer disease (AD) from healthy individuals or type 2 diabetic patients (6,7). Due to the distribution of insulin receptors in
It is found that Prussian Blue nanoparticles (PBNPs) possess a catalase‐like activity to catalyse the breakdown of H2O2 into oxygen (O2) molecules under the neutral conditions (pH = 7.4). Based on this finding, we have developed a new strategy in which PBNPs can be excellent ultrasound (US) and magnetic‐resonance (MR) dual modality imaging contrast agents for H2O2 diagnostics in vitro and in vivo.
A practical and effective strategy for synthesizing PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) is established. In this strategy, poly(acrylic acid) (PAA) is combined with SPIONs via multiple coordination between the carboxylic groups of PAA and SPIONs, which introduces abundant carboxylic groups, then, α,ω‐diamino PEG is linked to SPIONs via the amidation of the carboxylic groups. The synthesized PEGylated SPIONs exhibit no cytotoxicity and high resistance to phagocytosis by macrophages in vitro as well as low uptake by the liver and spleen in vivo, which makes the SPIONs highly efficient in tumor imaging by magnetic resonance imaging (MRI) at a relatively low dose of SPIONs. These outstanding properties are largely due to the significant shielding effect of the dense PEG coating as well as the net neutral surface of the PEGylated SPIONs in physiological conditions. In summary, the PEGylated SPIONs prepared by this strategy exhibit great application potential in tumor imaging as MRI contrast agents targeting through enhanced permeability and retention (EPR) effect.
Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and -negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs. The glycolytic CAFs feed the extra pyruvate and lactate to tumor cells for augmentation of mitochondrial activity, and this energy metabolically coupled in a 'host-parasite relationship' between catabolic CAFs and anabolic cancer cells confers the tumor cells with multiple drug resistance to several conventional clinical treatments including endocrine therapy (tamoxifen), Her-2-targeted therapy (herceptin) and chemotherapy (epirubicin). Moreover, the clinical data from F-fluorodeoxyglucose positron emission tomography/computed tomography further present a strong association between the GPER/cAMP/PKA/CREB pathway of stromal fibroblasts with tumor metabolic activity and clinical treatment, suggesting that targeting cytoplasmic GPER in CAFs may rescue the drug sensitivity in patients with breast cancer. Thus, our data define novel insights into the stromal GPER-mediated multiple drug resistance from the point of reprogramming of tumor energy metabolism and provide the rationale for CAFs as a promising target for clinical therapy.
Objectives To demonstrate the feasibility of using chemical exchange saturation transfer (CEST) imaging to detect Parkinson’s disease (PD) in patients at 3 Tesla. Methods Twenty-seven PD patients (17 men and 10 women; age range, 54–77 years) and 22 age-matched normal controls (13 men and 9 women; age range, 55–73 years) were examined on a 3-Tesla MRI system. Magnetization transfer spectra with 31 different frequency offsets (−6 to 6 ppm) were acquired at two transverse slices of the head, including the basal ganglia and midbrain. One-way analysis of variance tests was used to compare the differences in CEST imaging signals between PD patients and normal controls. Results Total CEST signal between the offsets of 0 and 4 ppm in the substantia nigra was significantly lower in PD patients than in normal controls (P=0.006), which could be associated with the loss of dopaminergic neurons. Protein-based CEST imaging signals at the offset of 3.5 ppm in the globus pallidus, putamen and caudate were significantly increased in PD patients, compared to normal controls (P<0.001, P=0.003, P<0.001, respectively). Conclusions CEST imaging signals could potentially serve as imaging biomarkers to aid in the non-invasive molecular diagnosis of PD.
Gasdermin D (GSDMD) has been proven to be a key protein in the activation of pyroptosis. Pyroptosis of renal tubular epithelial cells contributes to the progression of tubular injury in kidney diseases. However, it remains elusive whether and how GSDMD is involved in the regulation of diabetic kidney disease (DKD). In this study, we found that tubular injury is accompanied by the up-regulation of Toll-like receptor 4 (TLR4) and GSDMD in patients with diabetic kidney disease. In addition, we discovered that the expressions of cleaved Caspase-1, active N-terminal fragments of GSDMD (GSDMD-NT), IL-18, and the secretion of IL-1β also increased in the kidneys of db/db mice. These changes were partially ameliorated following intraperitoneal injection of TAK-242, an inhibitor of TLR4. Similar results were observed in human tubular cells (HK-2) subjected to high-glucose (HG) conditions and treated with TAK-242 or parthenolide (inhibitor of NF-κB) by Western blot, Enzyme-linked immunosorbent assay (ELISA), and flow cytometry. These results indicated that TLR4/NF-κB signaling could induce GSDMD-mediated pyroptosis in tubular cells in DKD.
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