Invasive Exploitation and the Multiplicative Hypothesis: Polyvictimization and Adolescent Depression Symptoms in Nepal.

Adverse effects of childhood maltreatment experience and adolescent depression symptoms are theorized to be more profound for adolescents who have suffered multiple maltreatments (polyvictimization). New theoretical insights into the study of polyvictimization suggest that it must be studied using a multiplicative logic, particularly when maltreatment is characterized by invasive exploitation. This study, for the first time, examined the concept of invasive exploitation in the context of polyvictimization and its association with adolescent depression symptoms. The study used a random, three stage probability proportional to size (PPS) cluster sample of 565 mother-adolescent dyads in Kathmandu, Nepal, and also examined the protective effects of maternal empathy. We hypothesized that (a) singly, the empirical categories of maltreatment (neglect, physical abuse, and child sexual abuse) would associate positively with adolescent depressive symptoms and (b) main effects held constant, the interaction effects of a child sexual abuse X neglect and a child sexual abuse X physical abuse would be positive. Regression with clustering corrections found that neglect (B = 3.17, p < .01) and sexual abuse (B = 3.48, p < .05) positively associated with adolescent depression symptoms. Results support the multiplicative invasive exploitation polyvictimization hypothesis (child sexual abuse X neglect interaction; B = 6.14, p < .05). The positive neglect X sexual abuse interaction is consistent with the theory that sexual abuse is distinct as invasive exploitation, and demonstrates that the multiplicative hypothesis can be fruitfully applied to the study of polyvictimization. Interventions targeting polyvictims with experience of invasive exploitation and studies aiming to provide deeper insights into sexual abuse as invasive exploitation are needed.

PERK activation by SB202190 ameliorates amyloidogenesis via the TFEB-induced autophagy-lysosomal pathway.

The protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), a key ER stress sensor of the unfolded protein response (UPR), can confer beneficial effects by facilitating the removal of cytosolic aggregates through the autophagy-lysosome pathway (ALP). In neurodegenerative diseases, the ALP ameliorates the accumulation of intracellular protein aggregates in the brain. Transcription factor-EB (TFEB), a master regulator of the ALP, positively regulates key genes involved in the cellular degradative pathway. However, in neurons, the role of PERK activation in mitigating amyloidogenesis by ALP remains unclear. In this study, we found that SB202190 selectively activates PERK independently of its inhibition of p38 mitogen-activated protein kinase, but not inositol-requiring transmembrane kinase/endoribonuclease-1α (IRE1α) or activating transcription factor 6 (ATF6), in human neuroblastoma cells. PERK activation by SB202190 was dependent on mitochondrial ROS production and promoted Ca2+-calcineurin activation. The activation of the PERK-Ca2+-calcineurin axis by SB202190 positively affects TFEB activity to increase ALP in neuroblastoma cells. Collectively, our study reveals a novel physiological mechanism underlying ALP activation, dependent on PERK activation, for ameliorating amyloidogenesis in neurodegenerative diseases.

Survivin protects fused cancer cells from cell death.

Tetraploidy, a potential precursor of cancer-associated aneuploidy, is produced either by cell fusion or failure of cytokinesis. In this study, low p53-expressing HeLa cells were used to address the fate of cancer cells after fusion. We found that massive cell death or growth arrest occurred a few days after fusion. Interestingly, cells with larger nuclei preferentially died after fusion, suggesting that a larger deviation of DNA content is a strong inducer of apoptosis. Notably, a fraction of cells escaped cell death. Also, the stability of survivin increased, and its localization changed preferentially to the cytosol in fused cells. Knockdown of survivin decreased the survival of fused cells, more than observed in unfused cells, showing increased dependency of fused cells on survivin. Collectively, after cancer cell fusion, some fused cells avoid the apoptotic crisis partly owing to survivin, and continue to proliferate, a process that contributes to human cancer progression. [BMB Reports 2017; 50(7): 361-366].

The p90 ribosomal S6 kinase 2 specifically affects mitotic progression by regulating the basal level, distribution and stability of mitotic spindles.

RSK2, also known as RPS6KA3 (ribosomal protein S6 kinase, 90 kDa, polypeptide 3), is a downstream kinase of the mitogen-activated protein kinase (MAPK) pathway, which is important in regulating survival, transcription, growth and proliferation. However, its biological role in mitotic progression is not well understood. In this study, we examined the potential involvement of RSK2 in the regulation of mitotic progression. Interestingly, depletion of RSK2, but not RSK1, caused the accumulation of mitotic cells. Time-lapse analysis revealed that mitotic duration, particularly the duration for metaphase-to-anaphase transition was prolonged in RSK2-depleted cells, suggesting activation of spindle assembly checkpoint (SAC). Indeed, more BubR1 (Bub1-related kinase) was present on metaphase plate kinetochores in RSK2-depleted cells, and depletion of BubR1 abolished the mitotic accumulation caused by RSK2 depletion, confirming BubR1-dependent SAC activation. Along with the shortening of inter-kinetochore distance, these data suggested that weakening of the tension across sister kinetochores by RSK2 depletion led to the activation of SAC. To test this, we analyzed the RSK2 effects on the stability of kinetochore-microtubule interactions, and found that RSK2-depleted cells formed less kinetochore-microtubule fibers. Moreover, RSK2 depletion resulted in the decrease of basal level of microtubule as well as an irregular distribution of mitotic spindles, which might lead to observed several mitotic progression defects such as increase in unaligned chromosomes, defects in chromosome congression and a decrease in pole-to-pole distance in these cells. Taken together, our data reveal that RSK2 affects mitotic progression by regulating the distribution, basal level and the stability of mitotic spindles.

Fenofibrate Reduces Age-related Hypercholesterolemia in Normal Rats on a Standard Diet.

Plasma cholesterol is increased in normal aging in both rodents and humans. This is associated with reduced elimination of cholesterol and decreased receptor-mediated clearance of plasma low-density lipoprotein (LDL) cholesterol. The aims of this study were: (1) to determine age-related changes in plasma lipid profiles, and (2) to determine the effect of fenofibrate, an activator of peroxisome proliferator activated receptor alpha (PPAR alpha), on plasma lipid profiles in normal rats on a standard diet. Male Sprague-Dawley (SD) rats (n=15) were fed standard chow and water from 10 to 25 weeks of age. During that period, we measured daily food intake, body weight, fasting and random blood glucose levels, plasma total cholesterol (TC), triglycerides (TG), and free fatty acid (FFA) levels. At 20 weeks of age, all rats were randomly divided into two groups: a fenofibrate group (in which rats were gavaged with 300 mg/kg/day of fenofibrate) and a control group (gavaged with water). Fenofibrate treatment lasted 5 weeks. There were no significant changes in daily food intake, blood glucose, and plasma TG level with age. Body weight, plasma TC, and FFA levels were significantly increased with age. Fenofibrate significantly decreased plasma concentrations of TC and FFA, which had been increased with age. However, fenofibrate did not influence the plasma concentration of TG, which had not increased with age. These results suggest that fenofibrate might have a novel role in preventing age-related hypercholesterolemia in SD rats on a normal diet.

Fenofibrate antagonizes Chk2 activation by inducing Wip1 expression: implications for cell proliferation and tumorigenesis.

AIMS: Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist that has been widely used to treat dyslipidemia. Previous studies have suggested that fenofibrate plays a role in cell proliferation and the development of hepatocarcinoma, but the underlying mechanism has not been fully characterized. In this report, we investigated whether fenofibrate treatment affected on the machinery of cell cycle checkpoint using nocodazole-induced cell cycle arrest. MAIN METHODS: The human normal liver cell line, CCL13 cells were treated with nocodazole and fenofibrate. Flow cytometry was performed for cell cycle analysis, and checkpoint kinase 2 (Chk2) and phosphatase Wip1 were analyzed by Western blot. KEY FINDINGS: Fenofibrate treatment overrode nocodazole-induced G2/M cell cycle arrest in a PPARalpha-independent manner. Mechanistically, fenofibrate treatment inhibited phosphorylation of checkpoint kinase Chk2 induced by nocodazole, and increased the expression of Wip1, a negative regulator of Chk2, suggesting that fenofibrate suppressed the nocodazole-induced G2/M cell cycle checkpoint through Wip1-mediated inhibition of Chk2 activation. SIGNIFICANCE: These results reveal a novel role of fenofibrate in cell cycle checkpoint control and provide a possible mechanistic explanation for how fenofibrate promotes cell proliferation and carcinogenesis.

Potential role of Homer-2a on cutaneous vascular anomaly.

Homer protein was identified based on its rapid induction in rat hippocampal granule cell neurons following excitatory synaptic activity. Although the presence of the Homer gene in the peripheral tissues has been observed in previous reports, the physiological function of the Homer protein in these tissues has not been noted. In this experiment, a Homer-2a cDNA fragment was successfully amplified by RTPCR in the involuting phase of human hemangioma but not in the human vascular malformation and normal vessel. After isolation of full Homer cDNA in a mouse liver cDNA library, E1-deleted recombinant adenovirus expressing the Homer protein (Adv.CMV.mHomer-2a) was constructed to determine its physiological function in peripheral tissues. Adv.CMV.mHomer2a, but not Adv.CMV.LacZ (recombinant adenovirus expressing Beta-galactosidase), strongly inhibited the growth rate of HUVECs (human umbilical vein endothelial cells) probably via inducing apoptosis determined by acridine orange/ethidium bromide (AO/EB) staining methods. This study suggests that the Homer gene is present in human specimens in the involuting phase of hemangioma, and it might be involved in the growth control.