The interplay of semantic and syntactic processing across hemispheres.

The current study investigated the hemispheric dynamics underlying semantic and syntactic priming in lexical decision tasks. Utilizing primed-lateralized paradigms, we observed a distinct pattern of semantic priming contingent on the priming hemisphere. The right hemisphere (RH) exhibited robust semantic priming irrespective of syntactic congruency between prime and target, underscoring its proclivity for semantic processing. Conversely, the left hemisphere (LH) demonstrated slower response times for semantically congruent yet syntactically incongruent word pairs, highlighting its syntactic processing specialization. Additionally, nonword data revealed a hemispheric divergence in syntactic processing, with the LH showing significant intrahemispheric syntactic priming. These findings illuminate the intrinsic hemispheric specializations for semantic and syntactic processing, offering empirical support for serial processing models. The study advances our understanding of the complex interplay between semantic and syntactic factors in hemispheric interactions.

2-Deoxyglucose and hydroxychloroquine HPLC-MS-MS analytical methods and pharmacokinetic interactions after oral co-administration in male rats.

Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2-addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) analytical methods for 2-DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples. Using a jugular vein-cannulated male rat model with serial blood collection before and after a single gavage dose of each drug alone or in combination, we examined their PK metrics for drug-drug interactions. The data demonstrated a rapid and complete separation of 2-DG from common monosaccharides by HPLC-MS-MS multi-reaction monitoring. Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of nine rats showed a peak time (Tmax ) for 2-DG of 0.5 h after 2-DG alone or with HCQ and identical post-peak half-life of approximately 1 h. With a seemingly bi-modal time course for HCQ, the Tmax for HCQ alone (1.2 h) was faster than that for the combination (2 h; p = .017). After combination dosing, the peak concentration (Cmax ) and area under the curve (AUC0-4h ) of 2-DG were decreased by 53.8% (p = .0004) and 53.7% (p = .0001), whereas AUC0-8h for HCQ was decreased by 30.8% (p = .0279) from the respective single dosing. Without changing the mean residence time (MRT0-∞ ) of each drug, the combination affected the apparent volume of distribution (Vd ) and clearance (CL) of 2-DG, and CL for HCQ without affecting its Vd . We observed significant negative PK interactions, probably at the intestinal absorption level, between 2-DG and HCQ taken simultaneously by mouth. Future optimization efforts are warranted for their combination regimen for clinical translation.

Decoding foveal word recognition: the role of interhemispheric inhibition in bilateral hemispheric processing.

Extant research has largely favored the Split Fovea Theory (SFT) over the Bilateral Projection Theory (BPT) in the context of foveal word recognition. SFT posits that during foveal fixation, letters in the left and right visual fields are projected to their respective contralateral hemispheres, thereby facilitating a division of labor across the bilateral hemispheres. This division may serve as a regulatory mechanism to mitigate redundant processing in both hemispheres. The present investigation conducted two experiments utilizing Korean visual words to explore whether this hemispheric division in foveal word recognition is a strategy to circumvent potential interhemispheric inhibition arising from duplicated processing. Experiment 1 established the suitability of Korean visual words for studies involving both unilateral and bilateral presentations. Experiment 2 revealed that the split presentation of a word elicited greater accuracy compared to its identical presentation in the bilateral visual fields. These findings lend credence to the notion that interhemispheric inhibition may drive the hemispheres to engage in divided labor, thereby reducing processing redundancy in foveal word recognition.

The pattern of intra-/inter-hemispheric interactions of left and right hemispheres in visual word processing.

This study aimed to investigate the intra-/inter-hemispheric interactions during visual word processing, by manipulating stimulus onset asynchrony (SOA) in a primed-lateralized lexical decision task. To assess intra-/inter-hemispheric priming effects, identical prime-target pairs were presented in the same or opposite unilateral visual fields. The study found that the right visual field advantage (RVFA) was observed when Korean words were presented sequentially within hemispheres, indicating that the inherent characteristics of the two hemispheres, rather than differences in memory or linguistic aspects of lexical processing, contributed to the hemispheric asymmetry. Additionally, intra-hemispheric priming effects were symmetrical in both hemispheres, with similar increases in priming for words and nonwords from SOA 120 ms to SOA 600 ms. Furthermore, inter-hemispheric priming effects were asymmetrical, with stronger priming when stimuli were presented in a sequence of LH→RH than in RH→LH. These findings suggest that the intrinsic differences in lexical processing between the two hemispheres may be related to the asymmetric pattern of hemispheric interactions in visual word processing.

Left-superiority in lexical processing was maintained in sequential presentation.Recency memory of lexical processing does not lead to hemispheric asymmetry.Symmetrical pattern in intra-hemispheric repetition primings was shown.Asymmetry pattern in inter-hemispheric repetition primings was observed.Hemispheric asymmetry of lexical processing have relevance to these patterns.

Asymmetry in hemispheric strategies for visual recognition of homonyms.

The primary objective of this investigation was to explore the strategic asymmetry exhibited by the two hemispheres during semantic processing, specifically focusing on the visual recognition of homonyms. By utilizing balanced and unbalanced homonyms, we sought to ascertain whether foveal processing adheres to a specific hemisphere's strategy. In Experiment 1, we employed a visual half-field presentation paradigm to elucidate the unihemispheric strategy employed for homonym recognition. Notably, our results revealed a significant type effect, whereby responses were more accurate for unbalanced homonyms compared to balanced homonyms, particularly in the LVF/RH. This outcome suggests that the RH exhibits a stronger activation of the dominant meaning, primarily driven by frequency, while the LH concurrently activates all candidate meanings of homonyms with comparable intensity. Building upon these insights, Experiment 2 involved the presentation of both homonym types within the foveal vision, leading to the identification of a significant type effect and providing evidence for the robust utilization of the RH strategy during foveal homonym recognition. Collectively, these findings delineate an asymmetric strategy employed during semantic processing across the hemispheres, with the RH assuming a dominant role in the semantic processing of foveal words.

Examining interhemispheric processing and task demand in lexical decision-making: insights from lateralized visual field paradigm.

This study aimed to investigate the influence of task demand on the uni-/bi-hemispheric processing of lexical decision-making. Two types of nonwords were used in parafoveal and foveal lexical decision tasks (LDTs) to manipulate task demand. In Experiment 1, a visual half-field paradigm was utilized to evaluate the unihemispheric strategy in lexical decision, which revealed a significant response bias toward "word" at the RVF/LH in the pseudoword LDT in contrast with the nonword LDT, indicating the strategic use of orthographical legality in LH for word-pseudoword lexical decision. In Experiment 2, the study evaluated whether foveal lexical decision follows the orthographical legality strategy of LH in pseudoword LDT relative to the nonword LDT. The results showed a response bias toward "word" in the foveal pseudoword LDT in contrast with the foveal nonword LDT, suggesting the recruitment of LH in foveal pseudoword LDT. These findings support the left-dominant bihemispheric processing in foveal lexical decision and contribute to our understanding of the mechanisms underlying lexical decision-making.

Electrophysiological Evidence Reveals the Asymmetric Transfer from the Right to Left Hemisphere as Key to Reading Proficiency.

The present investigation aimed to explore the interhemispheric interactions that contribute to changes in reading proficiency by examining the processing of visual word recognition in relation to word familiarity. A lexical decision task was administered to 25 participants, and their electrophysiological activity was recorded. A behavioral analysis showed the faster and more accurate processing of highly familiar words compared to less familiar ones. An event-related potential analysis uncovered an asymmetric familiarity effect over the N100 and N400 components across the two hemispheres, indicating an asymmetrical word familiarity processing. Granger causality analyses demonstrated a stronger transfer of information from the right hemisphere (RH) to the left hemisphere (LH) during the N100 processing and a weaker transfer from the LH to the RH during the N400 processing for highly familiar word recognition. These findings suggest that the asymmetric coordination between the RH and LH occurs early in visual word recognition and highlight the importance of interhemispheric interactions in efficient visual word recognition and proficient reading.

2-Deoxyglucose and hydroxychloroquine HPLC-MS-MS analytical methods and pharmacokinetic interactions after oral co-administration in male rats.

Our previous work has shown a synergistic tumoricidal action of the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) on HK2-addicted prostate cancers in animal models through intraperitoneal injections. Here we developed high performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) methods for 2-DG and clinically favored drug hydroxychloroquine (HCQ) and explored PK interaction of the orally administered drugs in a jugular vein cannulated male rat model, which allowed serial blood collection before and 0.5, 1, 2, 4 and 8 h after a single gavage dose of each drug alone or simultaneously after appropriate washout periods between the drugs. The results demonstrated a rapid and satisfactory separation of 2-DG standard from common monosaccharides by HPLC-MS-MS multi-reaction monitoring (MRM) and the presence of endogenous "2-DG". Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of 9 evaluable rats showed a peak time (Tmax) of 2-DG of 0.5 h after 2-DG dosing alone or with HCQ and glucose-like PK behavior. With a seemingly bi-modal time course for HCQ, the Tmax for HCQ dosing alone (1.2 h) was faster than that for the combination (2 h; p = 0.013, 2-tailed t-test). After combination dosing, the peak concentration (Cmax) and area under the curve (AUC) of 2-DG were decreased by 54% (p < 0.0001) and 52%, whereas those for HCQ were decreased by 40% (p = 0.026) and 35%, respectively, compared to single dosing. The data suggest significant negative PK interactions between the two oral drugs taken simultaneously and warrant optimization efforts for the combination regimen.

Seleno-aspirin compound AS-10 promotes histone acetylation ahead of suppressing androgen receptor transcription, G1 arrest, and apoptosis of prostate cancer cells.

BACKGROUND: The novel selenium-aspirin compound AS-10 was recently reported by us with a cancer cell killing potency three orders of magnitude greater than aspirin in pancreatic cancer cell lines with caspase-mediated apoptosis and a reasonable selectivity against malignant cells. Although we also observed its cytocidal activity against PC-3 and DU145 androgen receptor (AR)-negative and P53-null/mutant aggressive human prostate cancer (PCa) cell lines in NCI-60 screen, the potential involvement and targeting of AR and P53 pathways that are intact in early-stage prostate carcinogenesis has not been examined, nor its primary molecular signaling after exposure. METHODS: Human LNCaP PCa cells with functional AR and intact P53 were used to examine their cell cycle and cell fate responses to AS-10 exposure and upstream molecular signaling events including histone acetylation as a known aspirin effect. The AR-positive 22Rv1 human PCa cells were used to validate key findings. RESULTS: In addition to confirming AS-10's superior cytocidal potency than aspirin against all four PCa cell lines, we report a rapid (within 5 min) promotion of histone acetylation several hours ahead of the suppression of AR and prostate-specific antigen (PSA, coded by KLK3 gene) in LNCaP and 22Rv1 cells. AS-10 decreased AR and KLK3 mRNA levels without impacting pre-existing AR protein degradation or nuclear translocation in LNCaP cells. Sustained exposure to AS-10 arrested cells predominantly in G1 , and induced caspase-mediated apoptosis without necrosis. The death induced by AS-10 in LNCaP cells was attenuated by nontranscriptional activation of P53 protein or Jun N-terminal Kinase cellular stress signaling and was mitigated modestly by glutathione-boosting antioxidant N-acetylcysteine. AS-10 synergized with histone deacetylase inhibitor SAHA to suppress AR/PSA abundance and kill LNCaP cells. RNA-seq confirmed AR suppression at the transcriptional level and suggested multiple oncogene, cyclin, and CDK/CKI transcriptional actions to contribute to the cellular consequences. CONCLUSIONS: AS-10 promotes histone acetylation as its probable primary mechanism of action to induce PCa cell-cycle arrest and apoptosis, regardless of AR and P53 status. Nevertheless, the inhibition of AR signaling through mechanisms distinct from canonical AR antagonists may hold promise for combinatorial use with androgen deprivation therapy regimens or AR-axis targeting drugs.

Decursinol-mediated antinociception and anti-allodynia in acute and neuropathic pain models in male mice: Tolerance and receptor profiling.

Korean scientists have shown that oral administration of Angelica gigas Nakai (AGN) root alcoholic extract and the metabolite of its pyranocoumarins, decursinol, have antinociceptive properties across various thermal and acute inflammatory pain models. The objectives of this study were 1) to assess whether tolerance develops to the antinociceptive effects of once-daily intraperitoneally administered decursinol (50 mg/kg) in acute thermal pain models, 2) to establish its anti-allodynic efficacy and potential tolerance development in a model of chemotherapy-evoked neuropathic pain (CENP) and 3) to probe the involvement of select receptors in mediating the pain-relieving effects with antagonists. The results show that decursinol induced antinociception in both the hot plate and tail-flick assays and reversed mechanical allodynia in mice with cisplatin-evoked neuropathic pain. Tolerance was detected to the antinociceptive effects of decursinol in the hot plate and tail-flick assays and to the anti-allodynic effects of decursinol in neuropathic mice. Pretreatment with either the 5-HT2 antagonist methysergide, the 5-HT2A antagonist volinanserin, or the 5-HT2C antagonist SB-242084 failed to attenuate decursinol-induced antinociception in the tail-flick assay. While pretreatment with the cannabinoid inverse agonists rimonabant and SR144528 failed to modify decursinol-induced anti-allodynia, pretreatment with the opioid antagonist naloxone partially attenuated the anti-allodynic effects of decursinol. In conclusion, our data support decursinol as an active phytochemical of AGN having both antinociceptive and anti-allodynic properties. Future work warrants a more critical investigation of potential receptor mechanisms as they are likely more complicated than initially reported.

Familiarity with words modulates interhemispheric interactions in visual word recognition.

Bilateral redundancy gain (BRG) indicates superior performance in bilaterally presented word recognition in the left and right visual fields (RVFs) relative to word recognition given in either the left or the RVF. The BRG may be modulated by participants' subjective familiarity with words as previous studies found smaller regional activations in the brain as they become proficient. It can be assumed that visual recognition of words with high subjective familiarity indicates skilled performance in visual recognition. Thus, this study examined the subjective familiarity effect of visual words on the BRG during lateralized lexical decision performances. It showed that the significant BRG of response times was only observed in the most familiar word condition (F4 level); on the other hand, accuracy results revealed the significant BRGs in all the subjective familiarity levels (F1, F2, F3, and F4 levels). These results suggest that the bilateral presentation of identical words with higher subjective familiarity facilitates the recognition led by cooperative interactions between cerebral hemispheres. Therefore, the subjective familiarity with visual words modulates the efficiency of hemispheric interactions in visual word recognition.

The examination of the visual-perceptual locus in hemispheric laterality of the word length effect using Korean visual word.

Greater word length effects have been reported when a word was presented in the left visual field (LVF) than when presented in the right visual field (RVF). The current study employed 2 experiments to examine the visual-perceptual loci of asymmetric word length effect while testing the physical and linguistic length effects and the effect of visual angle increase at the RVF. Experiment 1 showed significant effects on the number of strokes in both VHFs (visual half fields) with the added significance of the number of syllables in the LVF, suggesting both parafoveal fields were affected by the physical length factors in contrast with the linguistic length factors, inducing asymmetric word length effects in the symmetrically presented word recognition in parafoveal vision. Experiment 2 widened the visual angle of the RVF presentation to test the differential effects of the visual-perceptual difficulty across the VHFs. It showed successful interruption at the RVF word recognition and comparable word length effects between the LVF and RVF. Therefore, this study suggests that the asymmetric word length effects in the parafoveal word recognition are attributable to the greater visual-perceptual difficulty at the LVF than at the RVF.

The Effects of Self-Perceived Parenting Attitudes on Visuo-Spatial Attention and Mental Rotation Abilities among Adolescents.

The present study aimed to investigate the effect of adolescents' perceived negative evaluation of parenting on their visuo-spatial attention and mental rotation abilities. The useful field of view (UFOV) and mental rotation tasks were used to measure visuo-spatial attention and mental rotation abilities among adolescents. The experimental groups were divided into the negatively evaluating group (MAge = 18.44, SD = 0.87, 20.7% girls) and positively evaluating group (MAge = 18.40, SD = 0.81, 23.3% girls) based on their scores on the self-perceived parenting attitude scales. The UFOV task showed lesser accuracy of the negatively evaluating group when compared to the positively evaluating one in target perception presented in 20° visual angle, indicating a deteriorated visuo-spatial attention ability in the negatively evaluating group. In the mental rotation task, the negatively evaluating group exhibited a small trade-off effect between response times and rotation angles, which implied an impatient strategy was employed to perform the task, whereas such a trade-off was not observed in the positively evaluating group. Thus, both experimental groups differed in terms of their visual attention and mental spatial abilities. This study suggests that the reduced visuo-spatial attention and mental rotation abilities may act as precursors for serious psychological symptoms caused by the negative self-evaluation of their parents' parenting attitudes.

Aqueous metabolome of tissue-specific conditional Pten-knockout mouse prostate cancer and TRAMP neuroendocrine carcinoma.

BACKGROUND: Metabolic reprograming is now a recognized hallmark of cancer. The prostate-specific phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene-conditional knockout (KO) mouse carcinogenesis model is highly desirable for studying prostate cancer biology and prevention due to its close resemblance of primary molecular defects and histopathological features of human prostate cancer. We have recently published macromolecular profiling of this model by proteomics and transcriptomics, denoting a preeminence of inflammation and myeloid suppressive immune cell features. Here, we performed metabolomic analyses of Pten-KO prostate versus wild type (WT) counterpart for discernable changes in the aqueous metabolites and contrasted to those in the TRAMP neuroendocrine carcinoma (NECa). METHODS: Three matched pairs of tissue-specific conditional Pten-KO mouse prostate and WT prostate of litter/cage-mates at 20-22 weeks of age and three pairs of TRAMP NECa versus WT (28-31 weeks) were profiled for their global aqueous metabolite changes, using hydrophilic interaction liquid chromatography-tandem mass spectrometry. RESULTS: The Pten-KO prostate increased purine nucleotide pools, cystathionine, and both reduced and oxidized glutathione (GSH, GSSG), and gluconate/glucuronate species in addition to cholesteryl sulfate and polyamine precursor ornithine. On the contrary, Pten-KO prostate contained diminished pools of glycolytic intermediates and phosphorylcholine derivatives, select amino acids, and their metabolites. Bioinformatic integration revealed a significant shunting of glucose away from glycolysis-citrate cycle and glycerol-lipid genesis to pentose phosphate cycle for NADPH/GSH/GSSG redox and pentose moieties for purine and pyrimidine nucleotides, and glycosylation/glucuronidation. Implicit arginine catabolism to ornithine was consistent with immunosuppression in Pten-KO model. While also increased in cystathionine-GSH/GSSG, purine, and pyrimidine nucleotide pools and glucuronidation at the expense of glycolysis-citrate cycle, the TRAMP NECa increased abundance of many amino acids, methyl donor S-adenosyl-methionine, and intermediates for phospholipids without increasing cholesteryl sulfate or ornithine. CONCLUSIONS: The aqueous metabolomic patterns in Pten-KO prostate and TRAMP NECa shared similarities in the greater pools of cystathionine, GSH/GSSG redox pair, and nucleotides and shunting away from glycolysis-citrate cycle in both models. Remarkable metabolic distinctions between them included metabolisms of many amino acids (protein synthesis; arginine-ornithine/immune suppression) and cholesteryl sulfate and methylation donor for epigenetic regulations.

Novel Seleno-Aspirinyl Compound AS-10 Induces Apoptosis, G1 Arrest of Pancreatic Ductal Adenocarcinoma Cells, Inhibits Their NF-κB Signaling, and Synergizes with Gemcitabine Cytotoxicity.

Current available therapies for pancreatic ductal adenocarcinoma (PDAC) provide minimal overall survival benefits and cause severe adverse effects. We have identified a novel molecule AS-10, a selenazolidine-bis-aspirinyl derivative, that was two to three orders of magnitude more potent than aspirin and at least one to two orders of magnitude more potent than gemcitabine in inhibiting PDAC cancer cell growth/viability against three PDAC cell lines while sparing mouse embryonic fibroblasts in the same exposure range. In Panc-1 cells, AS-10 induced apoptosis without necrosis, principally through caspase-3/7 cascade and reactive oxygen species, in addition to an induction of G1 cell cycle block. Transcriptomic profiling with RNA-seq indicated the top responses to AS-10 exposure as CDKN1A (P21Cip1), CCND1, and nuclear transcription factor-kappa B (NF-κB) complex and the top functions as cell cycle, cell death, and survival without inducing the DNA damage gene signature. AS-10 pretreatment (6 h) decreased cytokine tumor necrosis factor-alpha (TNF-α)-stimulated NF-κB nuclear translocation, DNA binding activity, and degradation of cytosolic inhibitor of κB (IκB) protein. As NF-κB activation in PDAC cells confers resistance to gemcitabine, the AS-10 combination with gemcitabine increased the in vitro cytotoxicity more than the additivity of both compounds. Overall, our results suggest AS-10 may be a promising drug lead for PDAC, both as a single agent and in combination therapy.

Interception Targets of Angelica Gigas Nakai Root Extract versus Pyranocoumarins in Prostate Early Lesions and Neuroendocrine Carcinomas in TRAMP Mice.

We reported efficacy of Angelica gigas Nakai (AGN) root ethanol extract and equimolar decursin (D)/decursinol angelate (DA) through daily gavage starting at 8 weeks of age (WOA) to male transgenic adenocarcinoma of mouse prostate (TRAMP) mice such that these modalities suppressed precancerous epithelial lesions in their dorsolateral prostate (DLP) to similar extent, but AGN extract was better than the D/DA mixture at promoting the survival of mice bearing prostate neuroendocrine carcinomas to 28 WOA. Here, we compared by microarray hybridization the mRNA levels in pooled DLP tissues and individual neuroendocrine carcinomas to characterize potential molecular targets of AGN extract and D/DA. Clustering and principal component analyses supported distinct gene expression profiles of TRAMP DLP versus neuroendocrine carcinomas. Pathway Enrichment, Gene Ontology, and Ingenuity Pathway Analyses of differential genes indicated that AGN and D/DA affected chiefly processes of lipid and mitochondrial energy metabolism and oxidation-reduction in TRAMP DLP, while AGN affected neuronal signaling, immune systems and cell cycling in neuroendocrine carcinomas. Protein-Protein Interaction Network analysis predicted and reverse transcription-PCR verified multiple hub genes common in the DLP of AGN- and D/DA-treated TRAMP mice at 28 WOA and select hub genes attributable to the non-D/DA AGN components. The vast majority of hub genes in the AGN-treated neuroendocrine carcinomas differed from those in TRAMP DLP. In summary, the transcriptomic approach illuminated vastly different signaling pathways and networks, cellular processes, and hub genes of two TRAMP prostate malignancy lineages and their associations with the interception efficacy of AGN and D/DA. PREVENTION RELEVANCE: This study explores potential molecular targets associated with in vivo activity of AGN root alcoholic extract and its major pyranocoumarins to intercept precancerous epithelial lesions and early malignancies of the prostate. Without an ethically-acceptable, clearly defined cancer initiation risk reduction strategy available for the prostate, using natural products like AGN to delay formation of malignant tumors could be a plausible approach for prostate cancer prevention.

The role of microRNA-33 as a key regulator in hepatic lipogenesis signaling and a potential serological biomarker for NAFLD with excessive dietary fructose consumption in C57BL/6N mice.

Limited studies reported mechanisms by which microRNAs (miRNA) are interlinked in the etiology of fructose-induced non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the significance of miRNAs in fructose-induced NAFLD pathogenesis through unbiased approaches. In experiment I, C57BL/6N mice were fed either water or 34% fructose for six weeks ad libitum. In experiment II, time course effects of fructose intervention were monitored using the same conditions; mice were killed at the baseline, fourth, and sixth weeks. Bioinformatic analyses for hepatic proteomics revealed that SREBP1 is the most significant upstream regulator influenced by fructose; miR-33-5p (miR-33) was identified as the key miRNA responsible for SREBP1 regulation upon fructose intake, which was validated by in vitro transfection assay. In experiment II, we confirmed that the longer mice consumed fructose, the more severe liver injury markers (e.g., serum AST) appeared. Moreover, hepatic Srebp1 mRNA expression was increased depending upon the duration of fructose consumption. Hepatic miR-33 was time-dependently decreased by fructose while serum miR-33 expression was increased; these observations indicated that miR-33 from the liver might be released upon cell damage. Finally we observed that fructose-induced ferroptosis might be a cause of liver toxicity, resulting from oxidative damage. Collectively, our findings suggest that fructose-induced oxidative damage induces ferroptosis, and miR-33 could be used as a serological biomarker of fructose-induced NAFLD.

Colon Transcriptomics Reveals Sex-Dependent Metabolic Signatures in Response to 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Treatment in C57BL/6N Mice.

Diets high in red meats, particularly meats cooked at high temperature, increase the risk of colon cancer due to a production of heterocyclic aromatic amines (HAAs). Of the identified HAAs, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most mass abundant colon carcinogen in charred meat or fish. Here, we comprehensively examined sex-dependent colon transcriptome signatures in response to PhIP treatment to identify biological discrepancies. Eight-week-old male and female C57BL/6N mice were intraperitoneally injected with PhIP (10 mg/kg of body weight) and colon tissues were harvested 24 h after PhIP injection, followed by colon transcriptomics analysis. A list of differentially expressed genes (DEGs) was utilized for computational bioinformatic analyses. Specifically, overrepresentation test using the Protein Analysis Through Evolutionary Relationships tool was carried out to annotate sex-dependent changes in transcriptome signatures after PhIP treatment. Additionally, the most significantly affected canonical pathways by PhIP treatment were predicted using the Ingenuity Pathway Analysis. As results, male and female mice presented different metabolic signatures in the colon transcriptome. In the male mice, oxidative phosphorylation in the mitochondrial respiratory chain was the pathway impacted the most; this might be due to a shortage of ATP for DNA repair. On the other hand, the female mice showed concurrent activation of lipolysis and adipogenesis. The present study provides the foundational information for future studies of PhIP effects on underlying sex-dependent mechanisms.

Proteomic and transcriptomic profiling of Pten gene-knockout mouse model of prostate cancer.

BACKGROUND: The prostate-specific phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene-conditional knockout (KO) mouse carcinogenesis model is highly desirable for studies of prostate cancer biology and chemoprevention due to its close resemblance of primary molecular defect and many histopathological features of human prostate cancer including androgen response and disease progression from prostatic intraepithelial neoplasia to invasive adenocarcinoma. Here, we profiled the proteome and transcriptome of the Pten-KO mouse prostate tumors for global macromolecular expression alterations for signaling changes and biomarker signatures. METHODS: For proteomics, four pairs of whole prostates from tissue-specific conditional knockout Pten-KO mice (12-15 weeks of age) and their respective wild-type littermates housed in the same cages were analyzed by 8-plex isobaric tags for relative and absolute quantitation iTRAQ. For microarray transcriptomic analysis, three additional matched pairs of prostate/tumor specimens from respective mice at 20 to 22 weeks of age were used. Real-time quantitative reverse transcription-polymerase chain reaction was used to verify the trends of protein and RNA expression changes. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were carried out for bioinformatic characterizations of pathways and networks. RESULTS: At the macromolecular level, proteomic and transcriptomic analyses complement and cross-validate to reveal overexpression signatures including inflammation and immune alterations, in particular, neutrophil/myeloid lineage suppressor cell features, chromatin/histones, ion and nutrient transporters, and select glutathione peroxidases and transferases in Pten-KO prostate tumors. Suppressed expression patterns in the Pten-KO prostate tumors included glandular differentiation such as secretory proteins and androgen receptor targets, smooth muscle features, and endoplasmic reticulum stress proteins. Bioinformatic analyses identified immune and inflammation responses as the most profound macromolecular landscape changes, and the predicted key nodal activities through Akt, nuclear factor-kappaB, and P53 in the Pten-KO prostate tumor. Comparison with other genetically modified mouse prostate carcinogenesis models revealed notable molecular distinctions, especially the dominance of immune and inflammation features in the Pten-KO prostate tumors. CONCLUSIONS: Our work identified prominent macromolecular signatures and key nodal molecules that help to illuminate the patho- and immunobiology of Pten-loss driven prostate cancer and can facilitate the choice of biomarkers for chemoprevention and interception studies in this clinically relevant mouse prostate cancer model.

Effects of the 2018 heat wave on health in the elderly: implications for adaptation strategies to climate change.

There has been growing concern over the effects of heat waves on health. However, the effects of heat waves on the health of individuals in vulnerable groups have rarely been examined. We aimed to investigate the acute health effects of heat waves in elderly individuals living in rural areas and to survey their adaptation capacity. Repeated measurements of body temperature (BT), blood pressure, sleep disturbance, and indoor temperature were conducted up to six times for each of 104 elderly individuals living in rural areas of South Korea during the 2018 heat wave. Changes in BT, systolic blood pressure (SBP), and diastolic blood pressure (DBP) according to variations in indoor and outdoor temperature were analyzed using linear mixed effect models controlling for age, sex, smoking, and drug use. We also surveyed heat wave adaptation capacity, heat wave shelters, and self-reported health problems. The average indoor temperature measured during the study period was 30.5°C (range: 22.9-38.3°C) and that of ambient temperature was 30.6°C (range: 24.6-36.3°C). BT significantly increased with indoor and outdoor temperatures. The effect on BT was greater in elderly women and the elderly with hypertension. DBP generally decreased with increasing indoor temperature, though the correlation was only statistically significant among the elderly with hypertension. Only 22 (21.2%) individuals used air conditioners during the heat wave. Most did not use an air conditioner mainly to avoid high electricity costs. Of the participants, 58.7% reported experiencing sleep disturbance, which was the most frequent self-reported health problem. Elderly individuals living in rural areas are directly exposed to high temperatures during heat waves, and their vital signs are sensitive to increases in indoor temperature due to poor adaptation capacity. Well-designed strategies for alleviating health-related stress during heat waves are necessary.