Aims: Chronic stress and glucocorticoid exposure are risk factors for depression. Oxytocin (OT) has been shown to have antistress and antidepressant‐like effects in male rodents. However, depression is twice as common in women than in men, and it remains unclear whether OT exerts antidepressant‐like effects in women with depression. Therefore, in this study, we investigated the therapeutic effect of chronic OT administration in a female mouse model of dexamethasone (DEX)‐induced depression.Methods: Female C57BL/6J mice were administered saline (vehicle, s.c.), DEX (s.c.), or OT (i.p.) + DEX (s.c.) daily for 8 weeks, and then assessed for anxiety‐ and depression‐like behaviors. We also examined the hippocampal levels of phosphorylated cAMP response element‐binding protein (p‐CREB) and brain‐derived neurotrophic factor (BDNF), which are important mediators of the response to antidepressants.Results: Simultaneous OT treatment blocked the adverse effects of DEX on emotional behaviors. Furthermore, it upregulated p‐CREB and BDNF in the hippocampus.Conclusion: OT may exert antidepressant‐like effects by activating hippocampal CREB‐BDNF signaling in a female mouse model of depression.

The 5′ splice site mutation (IVS20+6T>C) of theinhibitor of κ light polypeptide gene enhancer in B cells, kinase complex-associated protein(IKBKAP) gene in familial dysautonomia (FD) is at the sixth intronic nucleotide of the 5′ splice site. It is known to weaken U1 snRNP recognition and result in an aberrantly spliced mRNA product in neuronal tissue, but normally spliced mRNA in other tissues. Aberrantly splicedIKBKAPmRNA abrogates IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1) expression and results in a defect of neuronal cell development in FD. To elucidate the tissue-dependent regulatory mechanism, we screened an expression library of major RNA-binding proteins (RBPs) with our mammalian dual-color splicing reporter system and identified RBM24 as a regulator. RBM24 functioned as a cryptic intronic splicing enhancer binding to an element (IVS20+13–29) downstream from the intronic 5′ splice site mutation in theIKBKAPgene and promoted U1 snRNP recognition only to the mutated 5′ splice site (and not the wild-type 5′ splice site). Our results show that tissue-specific expression of RBM24 can explain the neuron-specific aberrant splicing ofIKBKAPexon 20 in familial dysautonomia, and that ectopic expression of RBM24 in neuronal tissue could be a novel therapeutic target of the disease.

Nivolumab, an anti-programmed cell death-1 monoclonal antibody, has improved the survival of patients with malignant melanoma. Despite its efficacy, nivolumab inconsistently induces thyroid dysfunction as an immune-related adverse event (irAE). This study aimed to evaluate nivolumab-induced thyroid dysfunction to determine the risks and mechanisms of thyroid irAEs. After excluding 10 patients, data of 24 patients with malignant melanoma (aged 17–85 years; 54% female) were retrospectively analyzed. Thyroid irAEs were observed in seven patients (29%). Three patients had hypothyroidism after preceding transient thyrotoxicosis, and the other four patients had hypothyroidism without thyrotoxicosis. Levothyroxine-Na replacement was required in three patients. Antithyroid antibody (ATA) titer was elevated in one of four assessable patients. The average (±SD) time to onset of thyroid irAE was 33.6 (±21.9) weeks. The administration period of nivolumab was longer in patients with thyroid irAEs than in those without thyroid irAEs (P < 0.01). There were no significant differences between patients with and without thyroid irAEs regarding age, sex, tumor stage, response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab). Thyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced thyroid dysfunction. A conventional ATA-independent mechanism might be involved in thyroid irAEs. Further studies are required to clarify the mechanism and identify the predictive factors of thyroid irAEs.

Objectives: The high-mobility group A protein 1a (HMGA1a) protein is known as a transcription factor that binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. We were prompted to decipher the mechanism of HMGA1a-induced alternative splicing of the estrogen receptor alpha (ERα) that we recently reported would alter tamoxifen sensitivity in MCF-7 TAMR1 cells. Methods: Endogenous expression of full length ERα66 and its isoform ERα46 were evaluated in MCF-7 breast cancer cells by transient expression of HMGA1a and an RNA decoy (2′-O-methylated RNA of the HMGA1a RNA-binding site) that binds to HMGA1a. RNA-binding of HMGA1a was checked by RNA-EMSA. In vitro splicing assay was performed to check the direct involvement of HMGA1a in splicing regulation. RNA-EMSA assay in the presence of purified U1 snRNP was performed with psoralen UV crosslinking to check complex formation of HMGA1a-U1 snRNP at the upstream pseudo-5′ splice site of exon 1. Results: HMGA1a induced exon skipping of a shortened exon 1 of ERα in in vitro splicing assays that was blocked by the HMGA1a RNA decoy and sequence-specific RNA-binding was confirmed by RNA-EMSA. RNA-EMSA combined with psoralen UV crosslinking showed that HMGA1a trapped purified U1 snRNP at the upstream pseudo-5′ splice site. Conclusions: Regulation of ERα alternative splicing by an HMGA1a-trapped U1 snRNP complex at the upstream 5′ splice site of exon 1 offers novel insight on 5′ splice site regulation by U1 snRNP as well as a promising target in breast cancer therapy where alternative splicing of ERα is involved.

To prevent and treat hypertension, it is important to restrict salt in one's diet since adolescence. However, an effective salt‐reduction education system has yet to be established. Besides accurate evaluation, we believe that the frequent usage of a measurement device may motivate individuals to avoid high salt intake. The present study evaluated the use of a urinary salt excretion measurement device for salt‐reduction education in a parallel randomized trial of two groups. The sample comprised 100 university students who provided consent to participate. A survey with 24‐hour home urine collection and blood pressure measurement was conducted. Participants in the self‐monitoring group measured their own urinary salt excretion level for 4 weeks, using the self‐measurement device. Analyses were conducted on 51 participants in the control group and 49 in the self‐monitoring group. At baseline, there was no significant difference between the two groups in terms of their characteristics and 24‐hour urinary salt excretion levels. After intervention, 24‐hour urinary sodium/potassium ratio showed no change in the control group [baseline score: 4.1 ± 1.5; endline score: 4.2 ± 2.0; P = 0.723], but it decreased significantly in the self‐monitoring group [baseline score: 4.0 ± 1.7; endline score: 3.5 ± 1.4; P = 0.044]. This change was significant even after adjusting for baseline and endline differences between groups using analysis of covariance (P = 0.045). The self‐monitoring urinary salt excretion measurement device improved the 24‐hour urinary sodium/potassium ratio. The device is a useful and practical tool for educating young individuals about dietary salt reduction.