Brief Report: Adenosine A2A receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function

Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A_2A receptor (A_2AR) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A_2AR inhibition by the Food and Drug Administration–approved A_2AR antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin’s antitumor activity. Collectively, our study identifies A_2AR signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.     

Impact of interim progression during the surgery-to-radiotherapy interval and its predictors in glioblastoma treated with temozolomide-based radiochemotherapy

This study was designed to investigate the impact of interim progression of disease (PD) during the surgery-to-radiotherapy interval (SRI) and its predictors in glioblastoma based on MRIs. A total of 222 patients were planned for radiotherapy (RT) and 166 of them were evaluable for the presence of interim PD by 2 separate MRIs. The size criteria from the updated Response Assessment in Neuro-Oncology criteria was adopted to determine interim PD. 32 (19.3%) patients experienced interim PD, and their median survival (MS) was shorter than patients without PD in univariate (11.3 vs. 19.6 months, p?<?0.001) and multivariate analysis (HR 2.237, 95% CI 1.367–3.660, p?=?0.002). The volume of residual enhancing tumor (p?=?0.003) and prolongation of the SRI (p?=?0.004) were significant predictors of interim PD. Every 1-cc increase in residual enhancing tumor and every 1-day prolongation of the SRI significantly increased the risk of interim PD by 3.9% (p?=?0.003) and 8.1% (p?=?0.004), respectively. A significant portion of patients demonstrate interim PD during SRI and these patients have poor prognosis. The presence of interim PD should be concerned as a significant confounding factor for stratification in future clinical trials. A baseline pre-RT MRI is essential for accurate disease evaluation and RT-target delineation, especially in patients with larger residual disease after surgery and prolonged SRI due to the high risk of interim PD.     

Characterization of degradation behavior for PLGA in various pH condition by simple liquid chromatography method

The aim of this study was to detect the amount of lactic acid (LA) and glycolic acid (GA) in poly(D,L-lactide-co-glycolide) (PLGA) by development a simple HPLC method and to determine the pH of media, which can influence on degradation of PLGA and drug release. Analysis of in vitro degradation behavior of PLGA with two different molecular weights as 8000 and 33,000 g/mol were performed in various media conditions (pH 3.0, 5.0, 7.0, and 9.0 of PBS and distilled water (approx. pH 5.8)). Also, effect of some additives on PLGA degradation was also investigated in pH 7.0 of PBS. GA and LA were easily detected by a simple HPLC method (retention time: 6.5 min and 10.2 min, respectively). The result showed that GA was released larger amount than that of LA considering the initial sample weight of polymers, due to the higher hydrophilic property. In the lower pH of media conditions, the PLGA was faster degraded generally. The presence of various additives, moreover, affected decrease of pH and slight acceleration of LA and GA detection.     

The Alleviation of Gut Microbiota-Induced Depression and Colitis in Mice by Anti-Inflammatory Probiotics NK151, NK173, and NK175

Gut microbiota dysbiosis is strongly associated with psychiatric disorders and inflammatory bowel disease (IBD). Herein, we examined whether the fecal microbiota of IBD patients with depression (IBDD) and their gut microbiota culture (iGm) could cause depression and colitis in mice and anti-inflammatory probiotics could mitigate depression in iGm-transplanted or immobilization stress (IS)-exposed mice. Fecal microbiota transplantation (FMT) from IBDD patients, which exhibited Enterobacteriaceae-rich gut microbiota, and its gut microbiota culture (iGm) increased depression-like behaviors in mice. Their treatments heightened the blood lipopolysaccharide (LPS) level and colonic IL-1β and IL-6 expression. However, FMT from healthy volunteers or sulfasalazine treatment alleviated cGm-induced depressive-like behaviors and hippocampal and colonic inflammation in mice. Moreover, oral administration of Lactobacillus plantarum NK151, Bifidobacterium longum NK173, and Bifidobacterium bifidum NK175, which inhibited LPS-induced IL-6 expression in macrophages, alleviated cGm-induced depression-like behaviors, hippocampal NF-κB⁺Iba1⁺ cell numbers and IL-1β and IL-6 expression, blood LPS, IL-6, and creatinine levels, and colonic NF-κB⁺CD11c⁺ number and IL-1β and IL-6 expression in mice. Treatment with NK151, NK173, or NK175 mitigated immobilization stress (IS)-induced depressive-like behaviors, neuroinflammation, and gut inflammation in mice. NK151, NK173, or NK175 also decreased IS-induced blood LPS, IL-6, and creatinine levels. The transplantation of Enterobacteriaceae-rich gut microbiota can cause depression and colitis, as IS exposure, and anti-inflammatory NK151, NK173, and NK175, may alleviate stress-induced fatigue, depression, and colitis by regulating the expression of proinflammatory and anti-inflammatory cytokines through the suppression of gut bacterial LPS.     

Fimasartan Ameliorates Deteriorations in Glucose Metabolism in a High Glucose State by Regulating Skeletal Muscle and Liver Cells

PurposeSince diabetes and hypertension frequently occur together, it is thought that these conditions may have a common pathogenesis. This study was designed to evaluate the anti-diabetic function of the anti-hypertensive drug fimasartan on C2C12 mouse skeletal muscle and HepG2 human liver cells in a high glucose state.Materials and MethodsThe anti-diabetic effects and mechanism of fimasartan were identified using Western blot, glucose uptake tests, oxygen consumption rate (OCR) analysis, adenosine 5′-triphosphate (ATP) enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining for diabetic biomarkers in C2C12 cells. Protein biomarkers for glycogenolysis and glycogenesis were evaluated by Western blotting and ELISA in HepG2 cells.ResultsThe protein levels of phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK), p-AKT, insulin receptor substrate-1 (IRS-1), and glucose transporter type 4 (Glut4) were elevated in C2C12 cells treated with fimasartan. These increases were reversed by peroxisome proliferator-activated receptor delta (PPARδ) antagonist. ATP, OCR, and glucose uptake were increased in cells treated with 200 µM fimasartan. Protein levels of glycogen phosphorylase, glucose synthase, phosphorylated glycogen synthase, and glycogen synthase kinase-3 (GSK-3) were decreased in HepG2 cells treated with fimasartan. However, these effects were reversed following the addition of the PPARδ antagonist GSK0660.ConclusionIn conclusion, fimasartan ameliorates deteriorations in glucose metabolism as a result of a high glucose state by regulating PPARδ in skeletal muscle and liver cells.     

Mutational Analysis of Triple-Negative Breast Cancer Using Targeted Kinome Sequencing

PurposeTriple-negative breast cancer (TNBC) does not have defined therapeutic targets and is currently treated with chemotherapy only. Kinase dysregulation triggers cancer cell proliferation and metastasis and is a crucial therapeutic target for cancer. In this study, targeted kinome sequencing of TNBC tumors was performed to assess the association between kinome gene alterations and disease outcomes in TNBC.MethodsA kinome gene panel consisting of 612 genes was used for the targeted sequencing of 166 TNBC samples and matched normal tissues. Analyses of the significantly mutated genes were performed. Genomic differences between Asian and non-Asian patients with TNBC were evaluated using two Asian TNBC datasets (from Seoul National University Hospital [SNUH] and Fudan University Shanghai Cancer Center [FUSCC]) and three non-Asian TNBC datasets (The Cancer Genome Atlas [TCGA], METABRIC, and Gustave Roussy). The prognostic value of kinome gene mutations was evaluated using tumor mutational burden (TMB) and oncogenic pathway analyses. Mutational profiles from the TCGA were used for validation.ResultsThe significantly mutated genes included TP53 (60% of patients), PIK3CA (21%), BRCA2 (8%), and ATM (8%). Compared with data from non-Asian public databases, the mutation rates of PIK3CA p.H1047R/Q were significantly higher in the SNUH cohort (p = 0.003, 0.048, and 0.032, respectively). This was verified using the FUSCC dataset (p = 0.003, 0.078, and 0.05, respectively). The TMB-high group showed a trend toward longer progression-free survival in our cohort and the TCGA TNBC cohort (p = 0.041 and 0.195, respectively). Kinome gene alterations in the Wnt pathway in patients with TNBC were associated with poor survival in both datasets (p = 0.002 and 0.003, respectively).ConclusionComprehensive analyses of kinome gene alterations in TNBC revealed genomic alterations that offer therapeutic targets and should help identify high-risk patients more precisely in future studies.     

Advanced parental age is an independent risk factor for term low birth weight and macrosomia

We aimed to investigate association between parental age and the risks of term low birth weight and macrosomia.This was a retrospective cohort study using a national database including 2,245,785 term singleton live births with complete parental age data. Old parental age was defined as 35 years or older. Odd ratios (OR) for term low birth weight and macrosomia were analyzed using univariate and multivariate logistic regression analysis.Neonatal sex, maternal occupation, parity, nationality, age, and paternal age were significant factors of term low birth weight and macrosomia, in univariate analysis. In multivariate analysis, old maternal age (≥35 years old) showed increased odds of term low birth weight and macrosomia (aOR = 1.122, 95% CI: 1.083 –1.162; and aOR = 1.166, 95% CI: 1.143 – 1.189, respectively). Similarly, old paternal age (≥35 years old) showed increased odds of term low birth weight and macrosomia (aOR = 1.090, 95% CI: 1.058 –1.122; and aOR = 1.101, 95% CI: 1.083 – 1.119, respectively). Maternal education that lasted more than 12 years had reduced odds of term low birth weight and macrosomia (OR = 0.817, 95% CI: 0.792 –0.842; and OR = 0.894, 95% CI: 0.879 – 0.91, respectively). Paternal education that lasted more than 12 years also had reduced odds of term low birth weight and macrosomia (OR = 0.865, 95% CI: 0.84 –0.892; and OR = 0.897, 95% CI: 0.881 – 0.913, respectively).This study suggests that not only maternal age but also paternal age are significantly associated with term low birth weight and macrosomia. In addition, parental education levels are also associated with term low birth weight and macrosomia.     

Friction Properties of Solid Lubricants with Different Multiwalled Carbon Nanotube Contents

Bushes are circular bearings that surround a shaft and help it rotate smoothly. In heavy equipment, bushes are coated with solid lubricants to reduce friction. Although the coating layer of the lubricant has a stable coefficient of friction (CoF), it is important that this should last for a long time. In this study, multiwalled carbon nanotubes (MWCNTs), which have a low CoF, were added to the lubricant to improve its performance. When 2.3 wt% MWCNTs were added to the polymer resin, the dynamic CoF (under a 29 N external load) decreased by 78% in relation to that of the resin without MWCNTs. As the MWCNT content increased, the roughness of the coating decreased, which reduced the CoF. Moreover, MWCNT addition increased the overall tensile strength owing to an increase in the bonding force between the resins. Under a high load of 20 tonnes (t), the MWCNT-based solid lubricant had a CoF of 0.05, lower than commercial MoS₂-based solid lubricants; this was maintained for more than 10,000 cycles in a bush and shaft test. With the MWCNT-based solid lubricant, a lubricating polymer film formed, even on worn bush surfaces. The CoF of the solid lubricant was reduced and the number of cycles with a constant CoF increased when MWCNTs were added owing to the formation of the lubricating polymer film.