Altered Brain Structural Reorganization and Hierarchical Integrated Processing in Obesity.

The brain receives sensory information about food, evaluates its desirability and value, and responds with approach or withdrawal. The evaluation process of food in the brain with obesity may involve a variety of neurocircuit abnormalities in the integration of internal and external information processing. There is a lack of consistency of the results extant reported for aberrant changes in the brain with obesity that prohibits key brain alterations to be identified. Moreover, most studies focus on the observation of neural plasticity of function or structure, and the evidence for functional and structural correlations in the neuronal plasticity process of obesity is still insufficient. The aims of this article are to explore the key neural structural regions and the hierarchical activity pattern of key structural nodes and evaluate the correlation between changes in functional modulation and eating behavior. Forty-two participants with obesity and 33 normal-weight volunteers were recruited. Gray matter volume (GMV) and Granger causality analysis (GCA) were performed using the DPARSF, CAT12, and DynamicBC toolbox. Compared with the normal weight group, the obesity group exhibited significantly increased GMV in the left parahippocampal gyrus (PG). The obesity group showed decreased causal inflow to the left PG from the left orbitofrontal cortex (OFC), right calcarine, and bilateral supplementary motor area (SMA). Decreased causal outflow to the left OFC, right precuneus, and right SMA from the left PG, as well as increased causal outflow to the left middle occipital gyrus (MOG) were observed in the obesity group. Negative correlations were found between DEBQ-External scores and causal outflow from the left PG to the left OFC, and DEBQ-Restraint scores and causal inflow from the left OFC to the left PG in the obesity group. Positive correlation was found between DEBQ-External scores and causal outflow from the left PG to the left MOG. These results show that the increased GMV in the PG may play an important role in obesity, which may be related to devalued reward system, altered behavioral inhibition, and the disengagement of attentional and visual function for external signals. These findings have important implications for understanding neural mechanisms in obesity and developing individual-tailored strategies for obesity prevention.

Hierarchical integrated processing of reward-related regions in obese males: A graph-theoretical-based study.

Abnormal activities in reward-related regions are associated with overeating or obesity. Preliminary studies have shown that changes in neural activity in obesity include not only regional reward regions abnormalities but also impairments in the communication between reward-related regions and multiple functional areas. A recent study has shown that the transitions between different neural networks are nonrandom and hierarchical, and that activation of particular brain networks is more likely to occur after other brain networks. The aims of this study were to investigate the key nodes of reward-related regions in obese males and explore the hierarchical integrated processing of key nodes. Twenty-four obese males and 24 normal-weight male controls of similar ages were recruited. The fMRI data were acquired using 3.0 T MRI. The fMRI data preprocessing was performed in DPABI and SPM 12. Degree centrality analyses were conducted using GRETNA toolkit, and Granger causality analyses were calculated using DynamicBC toolbox. Decreased degree centrality was observed in left ventral medial prefrontal cortex (vmPFC) and right parahippocampal/hippocampal gyrus in group with obesity. The group with obesity demonstrated increased effective connectivity between left vmPFC and several regions (left inferior temporal gyrus, left supplementary motor area, right insular cortex, right postcentral gyrus, right paracentral lobule and bilateral fusiform gyrus). Increased effective connectivity was observed between right parahippocampal/hippocampal gyrus and left precentral/postcentral gyrus. Decreased effective connectivity was found between right parahippocampal/hippocampal gyrus and left inferior parietal lobule. This study identified the features of hierarchical interactions between the key reward nodes and multiple function networks. These findings may provide more evidence for the existing view of hierarchical organization in reward processing.

Abnormal Regional Neural Activity and Reorganized Neural Network in Obesity: Evidence from Resting-State fMRI.

OBJECTIVE: This study aimed to investigate regional neural activity and regulation of patterns in the reorganized neural network of obesity and explore the correlation between brain activities and eating behavior. METHODS: A total of 23 individuals with obesity and 23 controls with normal weight were enrolled. Functional magnetic resonance imaging (fMRI) data were acquired using 3.0-T MRI. Amplitude of low-frequency fluctuation and functional connectivity (FC) analyses were conducted using Data Processing Assistant for resting-state fMRI and Resting-State fMRI Data Analysis Toolkit (REST). RESULTS: The group with obesity showed increased amplitude of low-frequency values in left fusiform gyrus/amygdala, inferior temporal gyrus (ITG), hippocampus/parahippocampal gyrus, and bilateral caudate but decreased values in right superior temporal gyrus. The group with obesity showed increased FC between left caudate and right superior temporal gyrus, left fusiform gyrus/amygdala and left ITG, right caudate and left fusiform gyrus/amygdala, and right caudate and left hippocampus/parahippocampal gyrus. Dutch Eating Behavior Questionnaire-Emotional scores were positively correlated with FC between left hippocampus/parahippocampal gyrus and right caudate but negatively correlated with FC between left fusiform gyrus/amygdala and left ITG. CONCLUSIONS: The study indicated the reorganized neural network presented as a bilateral cross-regulation pattern across hemispheres between reward and various appetite-related functional processing, thus affecting emotional and external eating behavior. These results could provide further evidence for neuropsychological underpinnings of food intake and their neuromodulatory therapeutic potential in obesity.

Precise Detection of Gene Mutations in Fine-Needle Aspiration Specimens of the Papillary Thyroid Microcarcinoma Using Next-Generation Sequencing.

PURPOSE: To assess the feasibility of next-generation sequencing (NGS) to detect mutations in BRAF, RAS, TERT promoter, and TP53 genes in ultrasound-guided fine-needle aspiration (FNA) biopsy samples of the papillary thyroid microcarcinoma (PTMC). METHODS: A total of 135 FNA samples out of 135 patients with suspected PTMC were submitted for mutation testing using NGS. NGS was successfully performed in 114 specimens, while the remaining 21 samples were excluded due to insufficient amount/poor quality of DNA and sequencing failure. Of those 114 samples, 72 who were confirmed as having PTMC by postoperative histopathology were enrolled in our study, and the other 42 who had a follow-up with ultrasound were excluded. Mutations of genes including BRAF, NRAS, HRAS, KRAS, TERT promoter, and TP53 were evaluated using NGS. The associations of gene mutations and clinicopathological characteristics of PTMC were analyzed. RESULTS: BRAF mutation was observed in 59 (81.94%) of 72 specimens. This mutation detected in BRAF was p.V600E (c.1799T>A) in exon 15 of all 59 specimens. NRAS mutation was identified in 1 (1.39%) specimen classified as Bethesda III and pathologically confirmed as a follicular variant PTMC. There were no mutations found in TERT promoter or TP53. The tumor with a maximum diameter (D max) larger than 5 mm was shown to be significantly correlated with the BRAF mutation in a multivariate analysis (OR 5.52, 95% CI 1.51-26.42, P = 0.033). But the BRAF mutation was not found to be significantly associated with the gender or age of patients with PTMC (P > 0.05). CONCLUSIONS: This study demonstrated that gene mutations in FNA specimens of PTMC could be successfully analyzed with a higher sensitivity using NGS compared to conventional methods for mutation detection. BRAF mutation of p.V600E was statistically associated with PTMC with a D max larger than 5 mm.

Integration of Neural Reward Processing and Appetite-Related Signaling in Obese Females: Evidence From Resting-State fMRI.

BACKGROUND: The reward-related regions have been considered a crucial component in the regulation of eating behavior. Furthermore, appetite-related regions associated with reward can influence eating behaviors through altered functional activity related to food in brain areas associated with emotion, memory, sensory processing, motor function, and cognitive control. PURPOSE: To investigate the key nodes in obese females of reward-related regions and, based on key nodes, to evaluate the directionality of functional connectivity between key nodes and appetite-related regions. STUDY TYPE: Prospective. POPULATION: Twenty-eight obese and 28 normal-weight female controls of similar age. FIELD STRENGTH/SEQUENCE: 3.0 T MRI and echo planar imaging (EPI) sequence, 3D BRAVO sequence. ASSESSMENT: The fMRI data preprocessing was based on the Data Processing & Analysis of Brain Imaging and Statistical Parametric Mapping 12. Degree centrality calculation was based on the GRETNA toolkit and granger causality analysis were based on the DynamicBC toolbox. Statistical Tests: Independent two-sample t-tests were used to assess the differences in demographic and clinical data between two groups. Two-sample t-tests were conducted to test the difference in degree centrality and effective connectivity of key nodes between two groups. RESULTS: Compared with normal-weight controls, obese females showed an increased degree centrality in the left ventral striatum/caudate (t = 2.96808, P < 0.05) and decreased degree centrality in right orbitofrontal cortex (OFC) (t = -3.3558, P < 0.05). The obese females showed directional effective connectivity between left ventral striatum/caudate and several regions (left inferior temporal gyrus, fusiform gyrus, postcentral gyrus, and right precentral gyrus) (P < 0.05). Directional effective connectivity was also observed between the right OFC and several regions (left middle temporal gyrus, cuneus, OFC, superior temporal gyrus, middle frontal gyrus, and right inferior parietal lobule) (P < 0.05). DATA CONCLUSION: The left ventral striatum/caudate and right OFC are key nodes in reward-related regions. The key nodes with reward processing mainly enhance visual processing of information and further participate in cognitive, attention, and sensorimotor processing. LEVEL OF EVIDENCE: 1. Technical Efficacy: Stage 4. J. Magn. Reson. Imaging 2019;50:541-551.

Follow-up study of high-dose praziquantel therapy for cerebral sparganosis.

BACKGROUND: Cerebral sparganosis is the most serious complication of human sparganosis. Currently, there is no standard for the treatment of inoperable patients. Conventional-dose praziquantel therapy is the most reported treatment. However, the therapeutic outcomes are not very effective. High-dose praziquantel therapy is a useful therapeutic choice for many parasitic diseases that is well tolerated by patients, but it has not been sufficiently evaluated for cerebral sparganosis. This study aims to observe the prognoses following high-dose praziquantel therapy in inoperable patients and the roles of MRI and peripheral eosinophil absolute counts during follow-up. METHODOLOGY: Baseline and follow-up epidemiological, clinical, radiological and therapeutic data related to 10 inoperable patients with cerebral sparganosis that were treated with repeated courses of high-dose praziquantel therapy, with each course consisting of 25 mg/kg thrice daily for 10 days were assessed, followed by analyses of the prognoses, MRI findings and peripheral eosinophil absolute counts. PRINCIPAL FINDINGS: Baseline clinical data: the clinical symptoms recorded included seizures, hemiparesis, headache, vomiting and altered mental status. Peripheral blood eosinophilia was found in 3 patients. The baseline radiological findings were as follows. Motile lesions were observed in 10 patients, including aggregated ring-like enhancements, tunnel signs, serpiginous and irregular enhancements. Nine of the 10 patients had varying degrees of white matter degeneration, cortical atrophy and ipsilateral ventricle dilation. The follow-up clinical data were as follows. Clinical symptom relief was found in 8 patients, symptoms were eliminated in 1 patient, and symptoms showed no change from baseline in 1 patient. Peripheral blood eosinophilia was found in 2 patients. The follow-up radiological findings were as follows. Motile lesions that were transformed into stable, chronic lesions were found in 8 patients, and motile lesions that were eliminated completely were found in 2 patients. CONCLUSIONS: High-dose praziquantel therapy for cerebral sparganosis is effective. The radiological outcomes of motile lesions are an important indicator during the treatment process, especially during follow-ups after clinical symptoms have improved. Peripheral eosinophil absolute counts cannot be used as an effective prognostic indicator.

The clinical presentation and collateral pathway development of congenital absence of the internal carotid artery.

OBJECTIVE: The objective of this study was to investigate the clinical presentation, risks, and collateral pathway development of the congenital absence of the internal carotid artery (ICA). METHODS: Sixty-four patients (10 new patients and 54 patients from the relevant literature) were studied. Data on demographic, clinical, and radiologic features were collected, followed by an analysis of the risks associated with ICA agenesis. RESULTS: There were 31 male and 33 female patients whose ages ranged from 5 months to 75 years, with a mean age of 31.1 years. The range of clinical symptoms recorded included transient ischemic attack (17 patients), subarachnoid hemorrhage (12 patients), developmental delay (13 patients), asymptomatic (8 patients), and other symptoms (15 patients). All 64 patients presented with absence of unilateral or bilateral ICAs, as measured by cervical computed tomography angiography or magnetic resonance angiography. The carotid canal was absent in all patients on computed tomography of the base of the skull, and abnormal development of collateral circulation pathways was observed. Five patients presented with basilar artery dilation on angiography. Aneurysms were observed in the angiography results from 16 patients. Ten patients presented with variations in the ophthalmic artery origin (the ophthalmic artery originated from the ipsilateral middle meningeal artery in six patients and from the ipsilateral middle cerebral artery in four patients). CONCLUSIONS: From analysis of our 10 cases of ICA agenesis and our review of the relevant literature, we conclude that young patients with ICA agenesis may present with developmental delay, subarachnoid hemorrhage, or other developmental abnormalities, whereas older patients most commonly present with transient neurologic events. Complications of carotid agenesis are related to specific anatomic subtypes and the resulting collateral circulation development.

Research progress on variations of endogenous metabolites and intestinal bacteria in ulcerative colitis / 中国药理学与毒理学杂志

Ulcerative colitis(UC)is a common chronic intestinal inflammation and one of the modern diseases that are difficult to cure effectively.Increasing attention is paid on UC based on metabonomic and microbe analysis. In this article, we review the recent advances in endogenous metabolites including amino acid, energy metabolism and lipid metabolism, intestinal bacteria including Firmicutes, Bacte-roidetes, Proteobacteria and Actinobacteria as well as covariation between metabolites and intestinal bacteria in UC.Short chain fatty acid and tryptophan are used as examples to ecaborate on the important functions of metabolism of nutrients and intestinal bacteria in diseases and illustrate the contributions of intestinal bacteria to diseases.

Comparative pharmacokinetics of bergenin, a main active constituent of Saxifraga stolonifera Curt., in normal and hepatic injury rats after oral administration / 中国天然药物

Bergenin, isolated from the herb of Saxifrage stolonifera Curt. (Hu-Er-Cao) has hepatoprotective, anti-inflammatory, antitussive, and neuroprotective activities. The aim of the present study was to establish a simple, rapid, and sensitive RP-HPLC method for determination of bergenin in rat plasma and compare its oral pharmacokinetic behaviors in normal and CCl-induced hepatic injury rats. With norisoboldine as an internal standard, chromatographic separation was performed on a C analytical column with acetonitrile and water (11 : 89, V/V) containing 0.1% formic acid as the mobile phase. A good linearity was obtained over the range of 100-10 000 ng·mL. The lower limit of quantification was 50 ng·mL. The developed method was successfully applied to a study of the pharmacokinetic difference of bergenin (100 mg·kg) between normal and hepatic injury rats after oral administration. Marked alterations of pharmacokinetic parameters in hepatic injury rats were observed. Compared to normal rats, the AUC of bergenin in hepatic injury rats was elevated to 2.11-fold and C was increased by 130%, whereas CL value was only 55% of the normal rats, suggesting that the systemic exposure of bergenin was significantly increased under hepatic injury status.

Tetrandrine inhibits migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes through down-regulating the expressions of Rac1, Cdc42, and RhoA GTPases and activation of the PI3K/Akt and JNK signaling pathways / 中国天然药物

Tetrandrine (Tet), the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet (0.3, 1 μmol·L(-1)) was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC (against PI3K, Akt, JNK, ERK, p38 MAPK and NF-κB-p65, respectively) were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Rac1, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK.

In vitro evidence of baicalein's inhibition of the metabolism of zidovudine (AZT).

BACKGROUND: Herb-drug interaction (HDI) has been regarded as a key factor limiting the clinical application of herbs and drugs. AIMS: Potential baicalein-zidovudine (AZT) interaction was predicted in the present study. METHODS: In vitro evaluation of baicalein's inhibition towards human liver microsomes (HLMs)-catalyzed metabolism of zidovudine (AZT) was performed. Dixon and Lineweaver-Burk plots were used to determine the inhibition kinetic type, and second plot with the slopes from Lineweaver-Burk plot versus the concentrations of baicalein was employed to calculate the inhibition parameter (Ki). In combination with the in vivo concentration of baicalein, in vitro-in vivo extrapolation (IVIVE) was carried out to predict in vivo baicalein-AZT interaction. RESULTS: Competitive inhibition of baicalein towards AZT metabolism was demonstrated, and the Ki value was calculated to be 101.2 µM. The value of AUCi/AUC was calculated to be 2. CONCLUSION: Potential baicalein-AZT interaction was indicated in the present study, indicating the need for monitoring when AZT is co-administrated with baicalein or baicalein-containing herbs.

A LC-ESI-MS method for the simultaneous determination of madecassoside and its metabolite madecassic acid in rat plasma: comparison pharmacokinetics in normal and collagen-induced arthritic rats / 中国天然药物

To develop a simple and highly sensitive high performance liquid chromatography with electrospray ionization mass spectrometric (LC-ESI-MS) method for the simultaneous determination of madecassoside and its major metabolite madecassic acid in rat plasma, and compare the pharmacokinetics of the two compounds in normal and collagen-induced arthritis (CIA) rats. Glycyrrhetinic acid was used as the internal standard (IS). Chromatographic separation was accomplished on an Inertsil ODS-3 column, using a gradient elution with the mobile phase composed of acetonitrile and water acidified with 0.1% (V/V) formic acid. Detection was achieved by ESI-MS under the negative selected ion monitoring (SIM) mode. In normal and CIA rats, madecassoside (30 mg·kg(-1)) was orally administered for 21 consecutive days from the day of arthritis onset. For madecassoside, the linear range was 10-1 000 ng·mL(-1) with the square regression coefficient (r) of 0.998 9, while for madecassic acid, the linear range was 10-500 ng·mL(-1) with the square regression coefficient (r) of 0.996 1. The lower limit of quantification was 10 ng·mL(-1) for both analytes. The intra- and inter-day precision ranged from 1.78% to 13.42% for madecassoside and 2.30% to 14.90% for madecassic acid, and the accuracy was between -0.95% and 6.30% for madecassoside and between -1.48% and 5.34% for madecassic acid. The average recoveries of madecassoside, madecassic acid and IS from spiked plasma samples were > 81%. The developed method was successfully applied to the pharmacokinetic study of madecassoside and madecassic acid in rats after an oral administration of madecassoside. During initial 7 days of dosing, the cmax and AUC of madecassoside were greatly decreased and Vd/F was markedly increased in CIA rats, and no significant difference was observed on the first day of dosing. In contrast, the T1/2, cmax and AUC of madecassic acid were significantly increased, and Ke of madecassic acid was greatly decreased in CIA rats compared with normal rats. Along with repeated administration of madecassoside, the differences of pharmacokinetic parameters of both madecassoside and madecassic acid between CIA and normal rats gradually subsided. The pharmacokinetic characteristics of both madecassoside and madecassic acid in rats were significantly altered by arthritis status, and the differences of pharmacokinetic parameters between arthritis and normal rats coincide with the severity of arthritis.

Studies on absorption kinetics of scopoletin in rat stomachs and intestines / 中国中药杂志

<p><b>OBJECTIVE</b>To study absorption kinetics of scopoletin in rat stomachs and intestines.</p><p><b>METHOD</b>Rats was cannulated for in situ recirculation. UV and HPLC methods were used to determine the concentrations of phenolsulfonphthalein and scopoletin, respectively.</p><p><b>RESULT</b>The absorption rates in rat stomachs at 2 h after administration was 76.31%; The absorption rates at colon, duodenum, ileum and jejunum were 46.25%, 40.54%, 38.21%, 32.77%, respectively. The absorption rate constant (Ka) at concentrations of 10.0144, 20.0288-40.0576 mg x L(-1) in intestine were 0.6434, 0.6137, 0.5970 h(-1), respectively. The Ka of scopoletin at pH of 6.0, 6.8 and 7.4 in intestine were 0.6217, 0.6033, 0.6137 h(-1), respectively.</p><p><b>CONCLUSION</b>The concentrations and pH values of scopoletin solution had no distinctive effect on the absorption kinetics. The absorption of scopoletin was a first-order process with passive diffusion mechanism. Scopoletin was well absorbed at stomachs and intestines in rats. Colon was the best absorption site of scopoletin, which suggest that a sustained-release preparation should be suitable for this compound.</p>

Determination of the content of saponin in Kochia scoparia fruits from different producing areas / 中国中药杂志

<p><b>OBJECTIVE</b>To compare the content of momordin Ic and total saponin in K. scoparia fruits from eleven producing areas.</p><p><b>METHOD</b>HPLC-ELSD and colorimetric method were used to determine the content of momordin Ic and total saponin, respectively.</p><p><b>RESULT</b>The content of momordin Ic in K. scoparia fruits was related to that of total saponin. In the eleven kinds of K. scoparia fruits tested, those produced in Bozhou, Baoding Anguo and Heilongjiang contained more saponins.</p><p><b>CONCLUSION</b>The content of saponin in K. scoparia fruits from various areas is different, and attention must be paid to the effects of environment on the quality of herbs.</p>