Heterogeneously elevated branched-chain/aromatic amino acids among new-onset type-2 diabetes mellitus patients are potentially skewed diabetes predictors.

BACKGROUND: The lack of specific predictors for type-2 diabetes mellitus (T2DM) severely impacts early intervention/prevention efforts. Elevated branched-chain amino acids (BCAAs: Isoleucine, leucine, valine) and aromatic amino acids (AAAs: Tyrosine, tryptophan, phenylalanine)) show high sensitivity and specificity in predicting diabetes in animals and predict T2DM 10-19 years before T2DM onset in clinical studies. However, improvement is needed to support its clinical utility. AIM: To evaluate the effects of body mass index (BMI) and sex on BCAAs/AAAs in new-onset T2DM individuals with varying body weight. METHODS: Ninety-seven new-onset T2DM patients (< 12 mo) differing in BMI [normal weight (NW), n = 33, BMI = 22.23 ± 1.60; overweight, n = 42, BMI = 25.9 ± 1.07; obesity (OB), n = 22, BMI = 31.23 ± 2.31] from the First People's Hospital of Yunnan Province, Kunming, China, were studied. One-way and 2-way ANOVAs were conducted to determine the effects of BMI and sex on BCAAs/AAAs. RESULTS: Fasting serum AAAs, BCAAs, glutamate, and alanine were greater and high-density lipoprotein (HDL) was lower (P < 0.05, each) in OB-T2DM patients than in NW-T2DM patients, especially in male OB-T2DM patients. Arginine, histidine, leucine, methionine, and lysine were greater in male patients than in female patients. Moreover, histidine, alanine, glutamate, lysine, valine, methionine, leucine, isoleucine, tyrosine, phenylalanine, and tryptophan were significantly correlated with abdominal adiposity, body weight and BMI, whereas isoleucine, leucine and phenylalanine were negatively correlated with HDL. CONCLUSION: Heterogeneously elevated amino acids, especially BCAAs/AAAs, across new-onset T2DM patients in differing BMI categories revealed a potentially skewed prediction of T2DM development. The higher BCAA/AAA levels in obese T2DM patients would support T2DM prediction in obese individuals, whereas the lower levels of BCAAs/AAAs in NW-T2DM individuals may underestimate T2DM risk in NW individuals. This potentially skewed T2DM prediction should be considered when BCAAs/AAAs are to be used as the T2DM predictor.

miR-212 as potential biomarker suppresses the proliferation of gastric cancer via targeting SOX4.

BACKGROUND: Circulating microRNAs that post-transcriptionally regulate gene expressions have been reported as promising biomarkers in cancer monitoring. This study was to identify the potential role of circulating miR-212 in gastric cancer and whether it could serve as a novel biomarker for gastric cancer. METHODS: We detected the serum levels of miR-212 in 100 health people and 110 gastric cancer patients and analyzed the relationships of the serum level of miR-212 with gastric cancer. We detected the expression of miR-212 in human gastric mucosal epithelial cell line (GES-1) and human gastric cancer cell lines (NCI-N87 and SNU-16) using qRT-PCR. Then, we detected the role of 5-aza-deoxycytidine on the epigenetic regulation of miR-212 in human gastric cancer cell lines. Furthermore, luciferase reporter assay was used to detect binding activity of miR-212 on SOX4 mRNA, and their functions on the cell proliferation and apoptosis. RESULTS: The expression of miR-212 was higher in health people than that in gastric cancer patients, higher in gastric mucosal epithelial cell line than that in gastric cancer cells. miR-212 can be a circulating biomarker and an independent prognostic factor of gastric cancer. Moreover, miR-212 can directly regulate the 3'UTR of SOX4 mRNA to suppress p53 and Bax, resulting gastric cancer cells proliferation inhibition and apoptosis induction. CONCLUSION: Our study demonstrated that miR-212 was epigenetically downregulated in gastric cancer, and resulting low level of miR-212 can be a potential circulating biomarker and poor prognosis predicator of gastric cancer.

miR-519d-3p Inhibits Cell Proliferation and Invasion of Gastric Cancer by Downregulating B-Cell Lymphoma 6.

miR-519d inhibits cell growth, migration, and invasion, but its role in gastric cancer (GC) cells is obscure. We showed that miR-519d-3p was lowly expressed in GC tissues and was associated with the clinical stage and lymph node metastasis of GC tissues. We found that miR-519d-3p repressed cell proliferation and invasion of MGC803 cells and delayed the G1/S phase transition, resulting in decreased cyclin B1 and MMP2 and increased E-cadherin levels. Furthermore, miR-519d-3p targeted and downregulated B-cell lymphoma 6 (BCL6) expression. BCL6 overexpression partially abrogated the suppressive function of miR-519d in MGC803 cells. In conclusion, our study demonstrated that miR-519d-3p functions as a tumor suppressor by targeting and downregulating the expression of BCL6 in GC cells.

Decreased expression of mineralocorticoid receptor mRNA in the prefrontal cortex in schizophrenia and bipolar disorder.

Abnormal prefrontal cortical activity, activation of the hypothalamic-pituitary-adrenal (HPA) axis, and deficits in slow-wave sleep (SWS) have been extensively reported in patients with affective disorders and schizophrenia, yet the underlying pathophysiological mechanisms have not been completely elucidated. Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) are two nuclear hormone receptors of primary importance in the control of stress-related and circadian HPA activity. A recent study showed that blocking brain MR activity not only enhances CRF-induced ACTH and cortisol release, but also significantly reduces SWS in humans. We hypothesized that the expression of MR would be deficient in the prefrontal cortex of patients with schizophrenia and affective disorders. The MR mRNA expression in the post-mortem prefrontal cortex of patients with major depression (MD), bipolar (BP), and schizophrenic (SZ) disorders and non-psychiatric controls (n=15 for each patient group, and n=14 for controls) was determined by in-situ hybridization. In the dorsolateral prefrontal cortex Brodmann's area 9 (BA 9), MR mRNA was significantly lower (p<0.05) in all laminae (I-VI) in BP, and in laminae I, III, IV and VI in SZ than in the controls. MR mRNA in BA 9 was negatively correlated with the duration of psychiatric illnesses. In BA 46, MR mRNA was not significantly different among groups, but was positively correlated with brain pH. These results provide the first evidence of deficient prefrontal MR mRNA expression in BP and SZ. Whether these findings may be linked to the abnormal prefrontal function, HPA axis activation, or the deficits in SWS found in these major psychiatric illnesses remains to be further explored.

Unidirectional cross-tolerance from levetiracetam to carbamazepine in amygdala-kindled seizures.

PURPOSE: Tolerance is a potential problem in long-term anticonvulsant therapy of epilepsy, bipolar disorder, and neuropathic pain. The present study was designed to determine whether cross-tolerance occurs between levetiracetam (LEV) and carbamazepine (CBZ) in amygdala-kindled rats. METHODS: Male Sprague-Dawley rats were implanted with an electrode into the left amygdala. While kindling stimulation was started, animals received repeated treatment (i.p.) with saline (n = 7) or LEV (150 mg/kg, n = 8). Saline-injected rats were subsequently challenged with a single dose of 150 mg/kg LEV when full kindling developed (stage > or =4). Both groups of rats were then administered long-term CBZ (5 mg/kg) until rats developed complete tolerance. All CBZ-tolerant rats were subsequently re-exposed to LEV (150 mg/kg) for an additional 10 consecutive days. RESULTS: Repeated LEV treatment significantly suppressed the increase in seizure stage, seizure duration, and afterdischarge duration induced by amygdala stimulation, markedly increasing the number of stimulations to achieve a kindling major motor seizure. The LEV challenge produced a more robust suppression of seizure stage in saline-injected rats compared with LEV-treated animals. CBZ treatment markedly suppressed fully kindled seizures in rats initially injected with saline, and then anticonvulsant tolerance rapidly developed after 3-4 days of repeated treatment. In contrast, rats that had initially received repeated LEV treatment did not show a response to treatment with CBZ (5 mg/kg). When CBZ-tolerant rats were subsequently exposed to LEV (150 mg/kg), noticeable anticonvulsant effects were observed; but these were gradually lost with increasing numbers of LEV exposures. CONCLUSIONS: Whereas LEV shows potent antiepileptogenic and anticonvulsant effects in amygdala-kindled rats, its repeated treatment induces anticonvulsant tolerance and unidirectional cross-tolerance to CBZ. In contrast, anticonvulsant tolerance to CBZ does not transfer to LEV. The mechanistic implications of the present results for clinical therapeutics remain to be evaluated.