S-ketamine administration in pregnant mice induces ADHD- and depression-like behaviors in offspring mice.

BACKGROUND: Anesthesia and psychotropic drugs in pregnant women may cause long-term effects on the brain development of unborn babies. The authors set out to investigate the neurotoxicity of S-ketamine, which possesses anesthetic and antidepressant effects and may cause attention deficit hyperactivity disorder (ADHD)- and depression-like behaviors in offspring mice. METHODS: Pregnant mice were administered with low-, medium-, and high-dose S-ketamine (15, 30, and 60 mg/kg) by intraperitoneal injection for 5 days from gestational day 14-18. At 21 days after birth, an elevated plus-maze test, fear conditioning, open field test, and forced swimming test were used to assess ADHD- and depression-like behaviors. Neuronal amount, glial activation, synaptic function indicated by ki67, and inhibitory presynaptic proteins revealed by GAD2 in the hippocampus, amygdala, habenula nucleus, and lateral hypothalamus (LHA) were determined by immunofluorescence assay. RESULTS: All the pregnant mice exposed to high-dose S-ketamine administration had miscarriage after the first injection. Both low-dose and medium-dose S-ketamine administration significantly increased the open-arm time and attenuated frozen time in the fear conditioning, which indicates impulsivity and memory dysfunction-like behaviors. Medium-dose S-ketamine administration reduced locomotor activity in the open field and increased immobility time in the forced swimming test, indicating depression-like behaviors. Changes in astrocytic activation, synaptic dysfunction, and decreased inhibitory presynaptic proteins were found in the hippocampus, amygdala, and habenula nucleus. CONCLUSIONS: These results demonstrate that S-ketamine may lead to detrimental effects, including ADHD-and depression-like behaviors in offspring mice. More studies should be promoted to determine the neurotoxicity of S-ketamine in the developing brain.

Exosomal DNMT1 mediates cisplatin resistance in ovarian cancer.

Ovarian cancer is the most common malignancy in women. Owing to late syndromic presentation and lack of efficient early detection, most cases are diagnosed at advanced stages. Surgery and platinum-based chemotherapy are still the standard care currently. However, resistance invoked often compromises the clinical value of the latter. Expression of DNA methyltransferase 1 (DNMT1) was analysed by gene array. Protein was determined by immunoblotting. Exosome was isolated with commercial kit. Cell proliferation was measured by CCK8 method. Annexin V-PI double staining was performed for apoptosis evaluation. Xenograft model was established and administrated with exosome. Tumour growth and overall survival were monitored. We demonstrated the upregulation of DNMT1 in both tumour and derived cell line. DNMT1 transcripts were highly enriched in exosomes from conditioned medium of ovarian cells. Co-incubation with exosomes stimulated endogenous expression and rendered host cell the resistance to cytotoxicity of cisplatin. In vivo administration of DNMT1-containing exosomes exacerbated xenograft progression and reduced overall survival significantly. Moreover, treatment with exosome inhibitor GW4869 almost completely restored sensitivity in resistant cells. Our data elucidated an unappreciated mechanism of exosomal DNMT1 in cisplatin resistance in ovarian cancer, also indicating the potential of the combination of exosome inhibitor with cisplatin in resistant patients.

Plasma microRNA-16-5p, -17-5p and -20a-5p: Novel diagnostic biomarkers for gestational diabetes mellitus.

AIM: To explore whether plasma microRNA-16-5p, -17-5p and -20a-5p can be used as diagnostic biomarkers in gestational diabetes mellitus (GDM) and to investigate the relationship between those microRNAs and the risk factors of GDM (body mass index [BMI], insulin resistance [IR] and tumor necrosis factor-α (TNF-α)). METHODS: A total of 85 pregnant women with GDM and 72 pregnant women without GDM were enrolled in this study. The plasma concentration of microRNAs (microRNA-16-5p, -17-5p, -19a-3p, -19b-3p, -20a-5p) was measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Spearman's correlation analysis was used to evaluate the correlation between those microRNAs and the risk factors of GDM, and receiver operating characteristic curve analysis was used to evaluate diagnostic sensitivity and specificity. RESULTS: Compared with non-GDM women, the relative and absolute expression of plasma microRNA-16-5p, -17-5p, -20a-5p from GDM women were significantly upregulated, when those women were diagnosed as GDM. During pregnancy, the expression of those microRNAs from GDM women also were significantly upregulated. The expression of those microRNAs was also positively correlated with IR, a risk factor of GDM. Plasma microRNA-16-5p, -17-5p, -20a-5p reflected an obvious separation between GDM women and non-GDM women, with areas under the curve of 0.92 (95%CI: 0.871-0.984), 0.88 (95%CI: 0.798-0.962), and 0.74 (95%CI: 0.618-0.870), respectively, cut-offs >2554, 1820, 3886 copies/µL, respectively; sensitivity 41.6%, 21.4% and 17.8%, respectively; and specificity 95.8%, 95.4% and 95.4%, respectively. CONCLUSION: Plasma microRNA-16-5p, -17-5p and -20a-5p are potential diagnostic biomarkers in GDM.

Naringenin enhances the efficacy of human embryonic stem cell-derived pancreatic endoderm in treating gestational diabetes mellitus mice.

Gestational diabetes mellitus (GDM) is a disease commonly occurs during mid to late pregnancy with pathologies such as hyperglycemia, hyperinsulinemia and mal-development of fetus. We have previously demonstrated that pancreatic endoderm (PE) derived from human embryonic stem cells (hESCs) effectively alleviated diabetic symptoms in a mouse model of GDM, although the clinical efficacy was limited due to oxidative stress. In this study, using the anti-oxidant agent naringenin, we aimed to further enhance the efficacy of hESC-derived PE transplant. Insulin-secreting PE was differentiated from hESCs, which were then transplanted into GDM mice. Naringenin was administered to mice receiving the PE transplant, with sham operated mice serving as negative control, to assess its effect on alleviation of GDM symptoms. We found that naringenin supplement further improved insulin response, glucose metabolism and reproductive outcome of the PE-transplanted female mice. Our new findings further potentiates the feasibility of using differentiated hESCs to treat GDM, in which anti-oxidative agent such as naringenin could greatly enhance the clinical efficacy of stem cell based therapies.