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Accumulating evidence suggests that the passenger strands microRNAs (miRNAs) derived from pre-miRNAs are closely involved in cancer pathogenesis. Analysis of our miRNA expression signature of lung adenocarcinoma (LUAD) and The Cancer Genome Atlas (TCGA) data revealed that miR-144-5p (the passenger strand derived from pre-miR-144) was significantly downregulated in LUAD tissues. The aim of this study was to identify therapeutic target molecules controlled by miR-144-5p in LUAD cells. Ectopic expression assays demonstrated that miR-144-5p attenuated LUAD cell aggressiveness, e.g., inhibited cell proliferation, migration and invasion abilities, and induced cell cycle arrest and apoptotic cells. A total of 18 genes were identified as putative cancer-promoting genes controlled by miR-144-5p in LUAD cells based on our in silico analysis. We focused on a family with sequence similarity 111 member B (FAM111B) and investigated its cancer-promoting functions in LUAD cells. Luciferase reporter assay showed that expression of FAM111B was directly regulated by miR-144-5p in LUAD cells. FAM111B knockdown assays showed that LUAD cells significantly suppressed malignant phenotypes, e.g., inhibited cell proliferation, migration and invasion abilities, and induced cell cycle arrest and apoptotic cells. Furthermore, we investigated the FAM111B-mediated molecular networks in LUAD cells. Identifying target genes regulated by passenger strands of miRNAs may aid in the discovery of diagnostic markers and therapeutic targets for LUAD. [ABSTRACT FROM AUTHOR]

Synaptic zinc ions (Zn2+) play an important role in the development of vascular dementia (VD) and Parkinson's disease (PD). In this article, we reviewed the current comprehension of the Zn2+-induced neurotoxicity that leads to the pathogenesis of these neuronal diseases. Zn2+-induced neurotoxicity was investigated by using immortalised hypothalamic neurons (GT1-7 cells). This cell line is useful for the development of a rapid and convenient screening system for investigating Zn2+-induced neurotoxicity. GT1-7 cells were also used to search for substances that prevent Zn2+-induced neurotoxicity. Among the tested substances was a protective substance in the extract of Japanese eel (Anguilla japonica), and we determined its structure to be like carnosine (β-alanylhistidine). Carnosine may be a therapeutic drug for VD and PD. Furthermore, we reviewed the molecular mechanisms that involve the role of carnosine as an endogenous protector and its protective effect against Zn2+-induced cytotoxicity and discussed the prospects for the future therapeutic applications of this dipeptide for neurodegenerative diseases and dementia. [ABSTRACT FROM AUTHOR]

Simple Summary: Based on the miRNA expression signature of LUAD, we focused on miR-139-3p, a passenger strand, and clarified its tumor-suppressive function in lung adenocarcinoma (LUAD) cells. A total of the 21 target genes (KRT80, CENPM, SPC24, ORC1, MYEOV, TRIP13, GPX8, ARHGEF39, MKI67, KIF18B, CHAF1B, CP, GPRIN1, UCK2, CHEK1, HELLS, CTSV, FAM111B, SLC16A3, MELK, and CENPF) were identified as miR-139-3p targets in LUAD, and the expression of these genes was as independent prognostic factor for patient survival. Moreover, inhibition of TRIP13 using a specific inhibitor (DCZ0415) enhanced the sensitivity of LUAD cells to anticancer drugs. Analyses of our microRNA (miRNA) expression signature combined with The Cancer Genome Atlas (TCGA) data revealed that both strands of pre-miR-139 (miR-139-5p, the guide strand, and miR-139-3p, the passenger strand) are significantly downregulated in lung adenocarcinoma (LUAD) clinical specimens. Functional analyses of LUAD cells ectopically expressing miR-139-3p showed significant suppression of their aggressiveness (e.g., cancer cell proliferation, migration, and invasion). The involvement of the passenger strand, miR-139-3p, in LUAD pathogenesis, is an interesting finding contributing to the elucidation of unknown molecular networks in LUAD. Of 1108 genes identified as miR-139-3p targets in LUAD cells, 21 were significantly upregulated in LUAD tissues according to TCGA analysis, and their high expression negatively affected the prognosis of LUAD patients. We focused on thyroid hormone receptor interactor 13 (TRIP13) and investigated its cancer-promoting functions in LUAD cells. Luciferase assays showed that miR-139-3p directly regulated TRIP13. siRNA-mediated TRIP13 knockdown and TRIP13 inhibition by a specific inhibitor (DCZ0415) attenuated the malignant transformation of LUAD cells. Interestingly, when used in combination with anticancer drugs (cisplatin and carboplatin), DCZ0415 exerted synergistic effects on cell proliferation suppression. Identifying the molecular pathways regulated by tumor-suppressive miRNAs (including passenger strands) may aid in the discovery of diagnostic markers and therapeutic targets for LUAD. [ABSTRACT FROM AUTHOR]

Simple Summary: Two microRNAs (miRNAs) (miR-486-5p and miR-486-3p) derived from pre-miR-486 acted as tumor-suppressive miRNAs in lung adenocarcinoma (LUAD). We identified seven genes (MKI67, GINS4, RRM2, HELLS, MELK, TIMELESS, and SAPCD2) involved in the malignant phenotype of LUAD cells coordinately regulated by these miRNAs. It is possible to suppress the malignant transformation of LUAD by controlling these genes. The involvement of passenger strands of miRNAs in the molecular pathogenesis of human cancers is a recent concept in miRNA research, and it will broaden our understanding of the molecular mechanisms of miRNA-mediated cancer. The analysis of our miRNA signature of LUAD revealed that both strands of pre-miR-486 (miR-486-5p and miR-486-3p) were downregulated in LUAD tissues. Ectopic expression of both miRNAs induced cell cycle arrest in LUAD cells, suggesting both strands of miRNAs derived from pre-miR-486 were tumor suppressive. Our in silico analysis showed a total of 99 genes may be under the control of both miRNAs in LUAD cells. Importantly, among these targets, the high expression of seven genes (MKI67, GINS4, RRM2, HELLS, MELK, TIMELESS, and SAPCD2) predicted a poorer prognosis of LUAD patients (p < 0.05). We focused on GINS4, a DNA replication complex GINS protein that plays an essential role in the initiation of DNA replication. Our functional assays showed that GINS4 was directly controlled by both strands of pre-miR-486, and its aberrant expression facilitated the aggressive behavior of LUAD cells. GINS4 is attractive as a therapeutic target for this disease. MiRNA analysis, including passenger strands, will further improve our understanding of the molecular pathogenesis of LUAD. [ABSTRACT FROM AUTHOR]

Thallium (Tl), is a highly toxic heavy metal that exists in monovalent (Tl(I)) and trivalent (Tl(III)) ionic states. This study aimed to compare the toxicities of Tl(I) and Tl(III) in a mouse hypothalamic GT1-7 neuronal cell line. Decreased viability and increased cytotoxicity were observed in the GT1-7 cells 16 h after Tl(I) or Tl(III) treatment. Tl(III) was more cytotoxic, than Tl(I), as indicated by extracellular lactate dehydrogenase levels. Both treatments induced caspase 3 activity, DNA fragmentation, malondialdehyde (MDA) production, and superoxide dismutase activity in the cells. MDA production was higher after Tl(III) than after Tl(I) treatment. Moreover, co-treatment with antioxidants, such as mannitol, ascorbic acid, or tocopherol, significantly attenuated the Tl-induced decrease in GT1-7 cell numbers. Therefore, both treatments induced oxidative stress-related apoptosis. Furthermore, Tl(III) reduced the cell viability more subtly than Tl(I) after 1 and 3 h of treatment. This effect was enhanced by co-treatment with maltol or citric acid, which promoted the influx of metallic elements into the cells. Thus, Tl(III) entered GT1-7 cells later than Tl(I) and had a delayed onset of toxicity. However, Tl(III) likely produces more extracellular lipid peroxides, which may explain its stronger cytotoxicity. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous disease characterized by chronic airway inflammation. Group 2 innate lymphoid cells (ILC2) play an important role in the pathogenesis of asthma. ILC2s lack antigen-specific receptors and respond to epithelial-derived cytokines, leading to the induction of airway eosinophilic inflammation in an antigen-independent manner. Additionally, ILC2s might be involved in the mechanism of steroid resistance. Numerous studies in both mice and humans have shown that ILC2s induce airway inflammation through inflammatory signals, including cytokines and other mediators derived from immune or non-immune cells. ILC2s and T helper type 2 (Th2) cells collaborate through direct and indirect interactions to organize type 2 immune responses. Interestingly, the frequencies or numbers of ILC2 are increased in the blood and bronchoalveolar lavage fluid of asthma patients, and the numbers of ILC2s in the blood and sputum of severe asthmatics are significantly larger than those of mild asthmatics. These findings may contribute to the regulation of the immune response in asthma. This review article highlights our current understanding of the functional role of ILC2s in asthma. [ABSTRACT FROM AUTHOR]

Several recent studies have shown that both strands of certain miRNAs derived from miRNA duplexes are involved in cancer pathogenesis. Our own recent studies revealed that both strands of the miR-150 duplex act as tumor-suppressive miRNAs in lung adenocarcinoma (LUAD) through the targeting of several oncogenes. The aim of the study here was to further investigate the tumor-suppressive roles of miR-150-3p (the passenger strand) in lung squamous cell carcinoma (LUSQ) and its control of cancer-promoting genes in LUSQ cells. The downregulation of miR-150-3p in LUSQ tissues was confirmed by data in The Cancer Genome Atlas (TCGA). The ectopic expression of miR-150-3p attenuated cancer cell aggressive features, e.g., cell cycle arrest, migration and invasive abilities. Our target search strategy successfully identified a total of 49 putative targets that were listed as subjects of miR-150-3p regulation in LUSQ cells. Interestingly, among these targets, 17 genes were categorized as related to the "cell cycle" based on Gene Ontology (GO) classification, namely CENPA, CIT, CCNE1, CCNE2, TIMELESS, BUB1, MCM4, HELLS, SKA3, CDCA2, FANCD2, NUF2, E2F2, SUV39H2, CASC5, ZWILCH and CKAP2). Moreover, we show that the expression of HELLS (helicase, lymphoid specific) is directly controlled by miR-150-3p, and its expression promotes the malignant phenotype of LUSQ cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). We examined the relationship between the trough plasma concentrations of afatinib and adverse effects, including diarrhea, rash, stomatitis and mucositis. The dose reduction of afatinib was associated with the trough plasma concentration of afatinib in this paper. As a result, we clarified that a higher trough plasma concentration induced adverse events, and there was a threshold to reduce the dosage or not. Monitoring plasma concentrations of afatinib is useful to predict the adverse effects of afatinib and to support quality of life in patients with EGFR-mutated advanced NSCLC. Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Small cell lung cancer (SCLC) is a fatal malignant tumor with a poor prognosis for patients who relapse after first-line treatment. There are few effective treatments for SCLC patients with relapse. Elucidation of the molecular network related to treatment resistance is an important issue for this disease. In this study, the molecular signature of SCLC specimens after treatment failure was generated. Several pathways, e.g., "cell cycle", "homologous recombination", "DNA replication", and "p53 signaling" were identified as the enriched pathways in this signature. Aberrant expression of MCM2, MCM4, MCM6, and MCM7 were detected in SCLC clinical specimens after treatment failure. This signature contains molecules involved in treatment resistance and will contribute to the study of SCLC molecular pathogenesis. Small cell lung cancer (SCLC) is a highly aggressive cancer, and patients who become refractory to first-line treatment have a poor prognosis. The development of effective treatment regimens is urgently needed. In this study, we identified a gene expression signature of SCLC after treatment failure using SCLC clinical specimens (GEO accession number: GSE162102). A total of 1,136 genes were significantly upregulated in SCLC tissues. These upregulated genes were subjected to KEGG pathway analysis, and "cell cycle", "Fanconi anemia", "alcoholism", "systemic lupus erythematosus", "oocyte meiosis", "homologous recombination", "DNA replication", and "p53 signaling" were identified as the enriched pathways among the genes. We focused on the cell cycle pathway and investigated the clinical significance of four genes associated with this pathway: minichromosome maintenance (MCM) 2, MCM4, MCM6, and MCM7. The overexpression of these MCM genes was confirmed in SCLC clinical specimens. Knockdown assays using siRNAs targeting each of these four MCM genes showed significant attenuation of cancer cell proliferation. Moreover, siRNA-mediated knockdown of each MCM gene enhanced the cisplatin sensitivity of SCLC cells. Our SCLC molecular signature based on SCLC clinical specimens after treatment failure will provide useful information to identify novel molecular targets for this disease. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) is the most aggressive cancer and the prognosis of these patients is unfavorable. We revealed that the expression levels of both strands of miR-99a (miR-99a-5p and miR-99a-3p) were significantly suppressed in several cancer tissues. Analyses of large The Cancer Genome Atlas (TCGA) datasets showed that reduced miR-99a-5p or miR-99a-3p expression is associated with worse prognoses in LUAD patients (disease-free survival (DFS): p = 0.1264 and 0.0316; overall survival (OS): p = 0.0176 and 0.0756, respectively). Ectopic expression of these miRNAs attenuated LUAD cell proliferation, suggesting their tumor-suppressive roles. Our in silico analysis revealed 23 putative target genes of pre-miR-99a in LUAD cells. Among these targets, high expressions of 19 genes were associated with worse prognoses in LUAD patients (OS: p < 0.05). Notably, FAM64A was regulated by both miR-99a-5p and miR-99a-3p in LUAD cells, and its aberrant expression was significantly associated with poor prognosis in LUAD patients (OS: p = 0.0175; DFS: p = 0.0276). FAM64A knockdown using siRNAs suggested that elevated FAM64A expression contributes to cancer progression. Aberrant FAM64A expression was detected in LUAD tissues by immunostaining. Taken together, our miRNA-based analysis might be effective for identifying prognostic and therapeutic molecules in LUAD. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer's disease, dementia with Lewy bodies, and vascular dementia. In particular, synaptic Zn2+ is known to play critical roles in the pathogenesis of vascular dementia. In this article, we review the molecular pathways of Zn2+-induced neurotoxicity based on our and numerous other findings, and demonstrated the implications of the energy production pathway, the disruption of calcium homeostasis, the production of reactive oxygen species (ROS), the endoplasmic reticulum (ER)-stress pathway, and the stress-activated protein kinases/c-Jun amino-terminal kinases (SAPK/JNK) pathway. Furthermore, we have searched for substances that protect neurons from Zn2+-induced neurotoxicity among various agricultural products and determined carnosine (β-alanyl histidine) as a possible therapeutic agent for vascular dementia. [ABSTRACT FROM AUTHOR]

Our analyses of tumor-suppressive microRNAs (miRNAs) and their target oncogenes have identified novel molecular networks in lung adenocarcinoma (LUAD). Moreover, our recent studies revealed that some passenger strands of miRNAs contribute to cancer cell malignant transformation. Downregulation of both strands of the miR-143 duplex was observed in LUAD clinical specimens. Ectopic expression of these miRNAs suppressed malignant phenotypes in cancer cells, suggesting that these miRNAs have tumor-suppressive activities in LUAD cells. Here, we evaluated miR-143-5p molecular networks in LUAD using genome-wide gene expression and miRNA database analyses. Twenty-two genes were identified as potential miR-143-5p-controlled genes in LUAD cells. Interestingly, the expression of 11 genes (MCM4, RAD51, FAM111B, CLGN, KRT80, GPC1, MTL5, NETO2, FANCA, MTFR1, and TTLL12) was a prognostic factor for the patients with LUAD. Furthermore, knockdown assays using siRNAs showed that downregulation of MCM4 suppressed cell growth, migration, and invasion in LUAD cells. Aberrant expression of MCM4 was confirmed in the clinical specimens of LUAD. Thus, we showed that miR-143-5p and its target genes were involved in the molecular pathogenesis of LUAD. Identification of tumor-suppressive miRNAs and their target oncogenes may be an effective strategy for elucidation of the molecular oncogenic networks of this disease. [ABSTRACT FROM AUTHOR]

Based on our miRNA expression signatures, we focused on miR-150-5p (the guide strand) and miR-150-3p (the passenger strand) to investigate their functional significance in lung adenocarcinoma (LUAD). Downregulation of miR-150 duplex was confirmed in LUAD clinical specimens. In vitro assays revealed that ectopic expression of miR-150-5p and miR-150-3p inhibited cancer cell malignancy. We performed genome-wide gene expression analyses and in silico database searches to identify their oncogenic targets in LUAD cells. A total of 41 and 26 genes were identified as miR-150-5p and miR-150-3p targets, respectively, and they were closely involved in LUAD pathogenesis. Among the targets, we investigated the oncogenic roles of tensin 4 (TNS4) because high expression of TNS4 was strongly related to poorer prognosis of LUAD patients (disease-free survival: p = 0.0213 and overall survival: p = 0.0003). Expression of TNS4 was directly regulated by miR-150-3p in LUAD cells. Aberrant expression of TNS4 was detected in LUAD clinical specimens and its aberrant expression increased the aggressiveness of LUAD cells. Furthermore, we identified genes downstream from TNS4 that were associated with critical regulators of genomic stability. Our approach (discovery of anti-tumor miRNAs and their target RNAs for LUAD) will contribute to the elucidation of molecular networks involved in the malignant transformation of LUAD. [ABSTRACT FROM AUTHOR]

In the human genome, miR-451a is encoded close to the miR-144 on chromosome region 17q11.2. Our previous study showed that both strands of pre-miR-144 acted as antitumor miRNAs and were involved in lung squamous cell carcinoma (LUSQ) pathogenesis. Here, we aimed to investigate the functional significance of miR-451a and to identify its targeting of oncogenic genes in LUSQ cells. Downregulation of miR-451a was confirmed in LUSQ clinical specimens, and low expression of miR-451a was significantly associated with poor prognosis of LUSQ patients (overall survival: p = 0.035, disease-free survival: p = 0.029). Additionally, we showed that ectopic expression of miR-451a significantly blocked cancer cell aggressiveness. In total, 15 putative oncogenic genes were shown to be regulated by miR-451a in LUSQ cells. Among these targets, high kinesin family member 2A (KIF2A) expression was significantly associated with poor prognosis (overall survival: p = 0.043, disease-free survival: p = 0.028). Multivariate analysis showed that KIF2A expression was an independent prognostic factor in patients with LUSQ (hazard ratio = 1.493, p = 0.034). Aberrant KIF2A expression promoted the malignant transformation of this disease. Analytic strategies based on antitumor miRNAs and their target oncogenes are effective tools for identification of novel molecular pathogenesis of LUSQ. [ABSTRACT FROM AUTHOR]