Four-dimensional mapping of dynamic longitudinal brain subcortical development and early learning functions in infants.

Brain subcortical structures are paramount in many cognitive functions and their aberrations during infancy are predisposed to various neurodevelopmental and neuropsychiatric disorders, making it highly essential to characterize the early subcortical normative growth patterns. This study investigates the volumetric development and surface area expansion of six subcortical structures and their associations with Mullen scales of early learning by leveraging 513 high-resolution longitudinal MRI scans within the first two postnatal years. Results show that (1) each subcortical structure (except for the amygdala with an approximately linear increase) undergoes rapid nonlinear volumetric growth after birth, which slows down at a structure-specific age with bilaterally similar developmental patterns; (2) Subcortical local area expansion reveals structure-specific and spatiotemporally heterogeneous patterns; (3) Positive associations between thalamus and both receptive and expressive languages and between caudate and putamen and fine motor are revealed. This study advances our understanding of the dynamic early subcortical developmental patterns.

The Ameliorative Effects of Saikosaponin in Thioacetamide-Induced Liver Injury and Non-Alcoholic Fatty Liver Disease in Mice.

Liver disorders are a major health concern. Saikosaponin-d (SSd) is an effective active ingredient extracted from Bupleurum falcatum, a traditional Chinese medicinal plant, with anti-inflammatory and antioxidant properties. However, its hepatoprotective properties and underlying mechanisms are unknown. We investigated the effects and underlying mechanisms of SSd treatment for thioacetamide (TAA)-induced liver injury and high-fat-diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in male C57BL/6 mice. The SSd group showed significantly higher food intake, body weight, and hepatic antioxidative enzymes (catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) and lower hepatic cyclooxygenase-2 (COX-2), serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and fibroblast growth factor-21 (FGF21) compared with controls, as well as reduced expression of inflammation-related genes (nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS)) messenger RNA (mRNA). In NAFLD mice, SSd reduced serum ALT, AST, triglycerides, fatty acid-binding protein 4 (FABP4) and sterol regulatory element-binding protein 1 (SREBP1) mRNA, and endoplasmic reticulum (ER)-stress-related proteins (phosphorylated eukaryotic initiation factor 2α subunit (p-eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). SSd has a hepatoprotective effect in liver injury by suppressing inflammatory responses and acting as an antioxidant.

Early-Life Nutrition and Cognitive Development: Imaging Approaches.

Brain development in the first years of life is the most dynamic and perhaps the most important phase of brain maturation. While it is widely recognized that nutrition plays a key role in early brain development, particular nutrients will most likely differentially affect distinct aspects of brain development. The critical dosage windows and time frames for various nutrients at different stages of brain development are likely dissimilar. Therefore, efforts have been devoted to identifying potential associations between nutrients and early brain development. However, behavioral assessments are typically employed as the outcome measures, which are known to suffer from low sensitivity and the inability to provide neural substrates underlying brain functional maturation. In contrast, magnetic resonance imaging is capable of providing detailed anatomical and functional information - an ideal tool to characterize brain functional development and nutrition. Our team has developed strategies that enable imaging of typically developing children from birth to teens without sedation. Quantitative assessments of brain structural and functional development during the first years of life have been accomplished, which reveal important features of early brain development. These developed tools will most likely substantially enhance our ability to rigorously characterize the interplay between nutrients and early brain development.

Antiapoptosis and Antifibrosis Effects of Qishen Granules on Heart Failure Rats via Hippo Pathway.

Qishen granules (QSG) are a famous formula with cardioprotective properties to heart failure (HF). The aim of this study was to investigate the underlying mechanism of QSG on apoptosis and fibrosis in the treatment of HF. HF model was induced by left anterior descending artery ligation on Sprague-Dawley rats. Transcriptome analysis was used to investigate the regulatory pathways of QSG on HF. Interestingly, downregulated genes of QSG were significantly enriched in Hippo pathway which plays a crucial role in regulating cell apoptosis and proliferation. We found that QSG inhibited the expressions of proapoptotic key proteins P-53 and fibrosis-related proteins TGF-ß1, SMAD3, and CTGF. Further, we conducted research on the key proteins in the Hippo pathway upstream of CTGF and P-53. The results showed that MST1, P-MST1, P-LATS1, and RASSF1A that exert proapoptotic function were downregulated after QSG intervention. Similarly, P-YAP and P-TAZ, mediating self-degradation and apoptosis, were both observably decreased after QSG administration. Taken together, QSG are shown to be likely to exert cardioprotective effects by inhibiting the progression of apoptosis and fibrosis through Hippo pathway.

Decomposing the Mechanism of Qishen Granules in the Treatment of Heart Failure by a Quantitative Pathway Analysis Method.

Qishen granules (QSG) have beneficial therapeutic effects for heart failure, but the effects of decomposed recipes, including Wenyang Yiqi Huoxue (WYH) and Qingre Jiedu (QJ), are not clear. In this study, the efficacy of WYH and QJ on heart failure is evaluated by using transverse aortic constriction (TAC) induced mice and the significantly changed genes in heart tissues were screened with a DNA array. Furthermore, a new quantitative pathway analysis tool is developed to evaluate the differences of pathways in different groups and to identify the pharmacological contributions of the decomposed recipes. Finally, the related genes in the significantly changed pathways are verified by a real-time polymerase chain reaction and a Western blot. Our data show that both QJ and WYH improve the left ventricular ejection fraction, which explain their contributions to protect against heart failure. In the energy metabolism, QJ achieves the therapeutic effects of QSG through nicotinamide nucleotide transhydrogenase (Nnt)-mediated mechanisms. In ventricular remodeling and inflammation reactions, QJ and WYH undertake the therapeutic effects through 5'-nucleotidase ecto (Nt5e)-mediated mechanisms. Together, QJ and WYH constitute the therapeutic effects of QSG and play important roles in myocardial energy metabolism and inflammation, which can exert therapeutic effects for heart failure.

Multipronged Therapeutic Effects of Chinese Herbal Medicine Qishenyiqi in the Treatment of Acute Myocardial Infarction.

Background: Based on global gene expression profile, therapeutic effects of Qishenyiqi (QSYQ) on acute myocardial infarction (AMI) were investigated by integrated analysis at multiple levels including gene expression, pathways involved and functional group. Methods: Sprague-Dawley (SD) rats were randomly divided into 3 groups: Sham-operated, AMI model (left anterior descending coronary artery ligation) and QSYQ-treated group. Cardiac tissues were obtained for analysing digital gene expression. Sequencing and transcriptome analyses were performed collaboratively, including analyses of differential gene expression, gene co-expression network, targeted attack on network and functional grouping. In this study, a new strategy known as keystone gene-based group significance analysis was also developed. Results: Analysis of top keystone QSYQ-regulated genes indicated that QSYQ ameliorated ventricular remodeling (VR), which is an irreversible process in the pathophysiology of AMI. At pathway level, both well-known cardiovascular diseases and cardiac signaling pathways were enriched. The most remarkable finding was the novel therapeutic effects identified from functional group analysis. This included anti-inflammatory effects mediated via suppression of arachidonic acid lipoxygenase (LOX) pathway and elevation of nitric oxide (NO); and amelioration of dyslipidaemia mediated via fatty acid oxidation. The regulatory patterns of QSYQ on key genes were confirmed by western blot, immunohistochemistry analysis and measurement of plasma lipids, which further validated the therapeutic effects of QSYQ proposed in this study. Conclusions: QSYQ exerts multipronged therapeutic effects on AMI, by concurrently alleviating VR progression, attenuating inflammation induced by arachidonic acid LOX pathway and NO production; and ameliorating dyslipidaemia.

Lingguizhugan Decoction Protects against High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease by Alleviating Oxidative Stress and Activating Cholesterol Secretion.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become a leading cause of liver transplantation. Lingguizhugan decoction (LGZG), a classical Chinese herbal formula, has beneficial effects on NAFLD animal models. Our study examined the impact of LGZG on hepatic global transcriptome of high-fat-diet-induced NAFLD rats. METHODS: Three groups of Wistar rats were included: normal, NAFLD model, and LGZG-treated NAFLD groups. Four weeks for the treatment, liver tissues were harvested for RNA sequencing. Differentially expressed genes (DEGs) and enriched pathways were detected on hepatic global transcriptome profile. Real-time PCR validated the regulatory patterns of LGZG on NAFLD rats. RESULTS: DEGs between the NAFLD model and normal groups indicated the elevated peroxisome proliferator-activated receptor (PPAR) and hedgehog signaling pathways in NAFLD rats. In bile secretion pathway, genes involved in cholesterol secretion were activated by LGZG treatment. Increased expression of antioxidant OSIGN1 and decreased expression of genes (AHR, IRF2BP2, and RASGEF1B) that induce oxidative stress and inflammation were observed in NAFLD rats treated with LGZG. The regulatory patterns of LGZG treatment on these oxidative stress-related genes were confirmed by real-time PCR. CONCLUSION: Our study revealed a "two-hits-targeting" mechanism of LGZG in the treatment for NAFLD: alleviating oxidative stress and activating cholesterol secretion.

Development of thalamocortical connectivity during infancy and its cognitive correlations.

Although commonly viewed as a sensory information relay center, the thalamus has been increasingly recognized as an essential node in various higher-order cognitive circuits, and the underlying thalamocortical interaction mechanism has attracted increasing scientific interest. However, the development of thalamocortical connections and how such development relates to cognitive processes during the earliest stages of life remain largely unknown. Leveraging a large human pediatric sample (N = 143) with longitudinal resting-state fMRI scans and cognitive data collected during the first 2 years of life, we aimed to characterize the age-dependent development of thalamocortical connectivity patterns by examining the functional relationship between the thalamus and nine cortical functional networks and determine the correlation between thalamocortical connectivity and cognitive performance at ages 1 and 2 years. Our results revealed that the thalamus-sensorimotor and thalamus-salience connectivity networks were already present in neonates, whereas the thalamus-medial visual and thalamus-default mode network connectivity emerged later, at 1 year of age. More importantly, brain-behavior analyses based on the Mullen Early Learning Composite Score and visual-spatial working memory performance measured at 1 and 2 years of age highlighted significant correlations with the thalamus-salience network connectivity. These results provide new insights into the understudied early functional brain development process and shed light on the behavioral importance of the emerging thalamocortical connectivity during infancy.

A novel role of the tumor suppressor GNMT in cellular defense against DNA damage.

Glycine N-methyltransferase (GNMT) is a folate binding protein commonly diminished in human hepatoma yet its role in tumor development remains to be established. GNMT binds to methylfolate but is also inhibited by it; how such interactions affect human carcinogenesis is unclear. We postulated that GNMT plays a role in folate-dependent methyl group homeostasis and helps maintain genome integrity by promoting nucleotide biosynthesis and DNA repair. To test the hypothesis, GNMT was over-expressed in GNMT-null cell lines cultured in conditions of folate abundance or restriction. The partitioning of folate dependent 1-carbon groups was investigated using stable isotopic tracers and GC/MS. DNA damage was assessed as uracil content in cell models, as well as in Gnmt wildtype (Gnmt(+/+)), heterozygote (Gnmt(+/-)) and knockout (Gnmt(-/-)) mice under folate deplete, replete, or supplementation conditions. Our study demonstrated that GMMT 1) supports methylene-folate dependent pyrimidine synthesis; 2) supports formylfolate dependent purine syntheses; 3) minimizes uracil incorporation into DNA when cells and animals were exposed to folate depletion; 4) translocates into nuclei during prolonged folate depletion. In conclusion, loss of GNMT impairs nucleotide biosynthesis. Over-expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. To our best knowledge, the role of GNMT in folate dependent 1-carbon transfer in nucleotide biosynthesis has never been investigated. The present study gives new insights into the underlying mechanism by which GNMT can participate in tumor prevention/suppression in humans.

Ameliorative effects of Vaccaria segetalis extract on osteopenia in ovariectomized rats.

The purpose of this study was to determine the ameliorative effects of a crude extract of Vaccaria segetalis (Neck.) Garcke (Caryophyllaceae) (VSE) on osteopenia in ovariectomized (OVX) rats over 12 weeks. Rats were divided into the sham and OVX groups. The OVX rats were allowed to lose bone for 6 weeks. At 6 weeks post-OVX, the OVX rats were divided into four groups treated with water, 17beta-estradiol (30 microg/kg, daily subcutaneous injection), or VSE (0.5 or 1.0 g/kg, daily, orally) for 6 weeks. In OVX rats, the increases of serum total cholesterol were significantly decreased by VSE or 17beta-estradiol treatment. There were decreases in bone density and calcium content, including the left femur and the fourth lumbar vertebra, when compared with the sham control rats. Treatment with 17beta-estradiol or VSE ameliorated these changes induced by OVX. In addition, ovariectomy increased urinary deoxypyridinoline (DPD) amounts (P < 0.001). The increases were suppressed by 17beta-estradiol and 0.5 or 1.0 g/kg VSE (P < 0.01, P < 0.05, P < 0.01, respectively). Our results demonstrated that VSE ameliorates ovariectomy-induced osteopenia by inhibition of bone resorption.

Momordica charantia extract on insulin resistance and the skeletal muscle GLUT4 protein in fructose-fed rats.

AIM OF THE STUDY: We investigated the preventive effect of Momordica charantia Linn. (Cucurbitaceae) fruit, commonly known as bitter melon, on hyperglycemia and insulin resistance in rats fed with a fructose-enriched diet. MATERIALS AND METHODS: First, rats were divided randomly into two groups: the control group was fed with control diet, whereas the experimental group was fed with a 60% high-fructose diet for 8 weeks. After the first 6 weeks, the fructose-treated rats were further subdivided into six groups and were orally fed with or without Momordica charantia L. or rosiglitazone (ROS) for 2 weeks while rats were still on fructose diet. RESULTS: We demonstrated that bitter melon was effective in ameliorating the fructose diet-induced hyperglycemia, hyperleptinemia, hyperinsulinemia, and hypertriglyceridemia as well as in decreasing the levels of free fatty acid (FFA) (P<0.001, P<0.05, P<0.05, P<0.05, P<0.05, respectively). Bitter melon reversed fructose diet-induced hypoadiponectinemia (P<0.05), which provides a therapeutic advantage to insulin resistance in improving insulin sensitivity. Additionally, bitter melon decreased the weights of epididymal (P<0.05) and retroperitoneal white adipose tissue (WAT) (P<0.05). Bitter melon increased the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma) in white adipose tissue (WAT). Conversely, bitter melon decreased the expression of leptin in WAT. Furthermore, we demonstrate that bitter melon significantly increases the mRNA expression and protein of glucose transporter 4 (GLUT4) in skeletal muscle. CONCLUSIONS: This study demonstrates, for the first time, the beneficial effects of two different extracts of bitter melon on insulin resistance in rats fed a high-fructose diet thereby producing evidence of the role of changes in expression of PPAR gamma and GLUT4.