[Excretion of three alkaloids from Simiao Pills in urine, feces, and bile between normal and type 2 diabetic rats].

This study investigated the differences in excretion kinetics of three alkaloids and their four metabolites from Simiao Pills in normal and type 2 diabetic rats. The diabetes model was established in rats by injection of streptozotocin, and the alkaloids in urine, feces, and bile of normal and diabetic rats were detected by LC-MS/MS to explore the effect of diabetes on alkaloid excretion of Simiao Pills. The results showed that 72 h after intragastric administration of the extract of Simiao Pills, feces were the main excretion route of alkaloids from Simiao Pills. The total excretion rates of magnoflorine and berberine in normal rats were 4.87% and 56.54%, which decreased to 2.35% and 35.53% in diabetic rats, which had statistical significance(P<0.05). The total excretion rates of phellodendrine, magnoflorine, and berberine in the urine of diabetic rats decreased significantly, which were 53.57%, 60.84%, and 52.78% of those in normal rats, respectively. After 12 h of intragastric administration, the excretion rate of berberine in the bile of diabetic rats increased significantly, which was 253.33% of that of normal rats. In the condition of diabetes, the excretion rate of berberine metabolite, thalifendine significantly decreased in urine and feces, but significantly increased in bile. The total excretion rates of jateorrhizine and palmatine in the urine increased significantly, and t_(1/2) and K_e changed significantly. The results showed that diabetes affected the in vivo process of alkaloids from Simiao Pills, reducing their excretion in the form of prototype drug, affecting the biotransformation of berberine, and ultimately increasing the exposure of alkaloids in vivo, which would be conducive to the hypoglycemic effect of alkaloids. This study provides references for the clinical application and drug development of Simiao Pills in diabetes.

Shared and specific patterns of dynamic functional connectivity variability of striato-cortical circuitry in unmedicated bipolar and major depressive disorders.

BACKGROUND: Accumulating studies have found structural and functional abnormalities of the striatum in bipolar disorder (BD) and major depressive disorder (MDD). However, changes in intrinsic brain functional connectivity dynamics of striato-cortical circuitry have not been investigated in BD and MDD. This study aimed to investigate the shared and specific patterns of dynamic functional connectivity (dFC) variability of striato-cortical circuitry in BD and MDD. METHODS: Brain resting-state functional magnetic resonance imaging data were acquired from 128 patients with unmedicated BD II (current episode depressed), 140 patients with unmedicated MDD, and 132 healthy controls (HCs). Six pairs of striatum seed regions were selected: the ventral striatum inferior (VSi) and the ventral striatum superior (VSs), the dorsal-caudal putamen (DCP), the dorsal-rostral putamen (DRP), and the dorsal caudate and the ventral-rostral putamen (VRP). The sliding-window analysis was used to evaluate dFC for each seed. RESULTS: Both BD II and MDD exhibited increased dFC variability between the left DRP and the left supplementary motor area, and between the right VRP and the right inferior parietal lobule. The BD II had specific increased dFC variability between the right DCP and the left precentral gyrus compared with MDD and HCs. The MDD had increased dFC variability between the left VSi and the left medial prefrontal cortex compared with BD II and HCs. CONCLUSIONS: The patients with BD and MDD shared common dFC alteration in the dorsal striatal-sensorimotor and ventral striatal-cognitive circuitries. The patients with MDD had specific dFC alteration in the ventral striatal-affective circuitry.

Comparative pharmacokinetics, intestinal absorption and urinary excretion of six alkaloids from herb pair Phellodendri Chinensis cortex-Atractylodis Rhizoma.

Phellodendri Chinensis Cortex (PCC) and Atractylodis Rhizoma (AR) are frequently used as herb pair to treat eczema and gout owing to their synergistic effects. Alkaloids are the major ingredients from PCC and the effect of their combination on the in vivo processing of alkaloids remains unclear. In this study, a simple and reliable UPLC-MS/MS method for simultaneous determination of six alkaloids in rat plasma was developed. This method was applied to a comparative pharmacokinetic study between PCC and PCC-AR in rats. Effect of AR on absorption of alkaloids was investigated by a single-pass intestinal perfusion study. The effect of AR on urinary excretion of alkaloids was studied. Pharmacokinetic studies showed that the values of rea under the concentration-time curve of phellodendrine, magnoflorine and palmatine were greater in the PCC-AR group than in the PCC group. The intestinal absorptive parameters absorption rate constant and effective permeability of phellodendrine and jatrorrhizine in PCC-AR groups were higher than those in the PCC group. Urinary excretion studies revealed that the excreted amount of alkaloids in the PCC-AR group was lower than that in the PCC group. The results revealed that the combination of PCC and AR improves intestinal absorption of alkaloids and reduces their urinary excretion, which enhances their systemic exposure. This study may explain the synergetic effects of PCC and AR in clinical applications.

Daidzein Protects Caco-2 Cells against Lipopolysaccharide-Induced Intestinal Epithelial Barrier Injury by Suppressing PI3K/AKT and P38 Pathways.

The intestinal epithelium provides an important barrier against bacterial endotoxin translocation, which can regulate the absorption of water and ions. The disruption of epithelial barrier function can result in water transport and tight junction damage, or further cause diarrhea. Therefore, reducing intestinal epithelial barrier injury plays an important role in diarrhea. Inflammatory response is an important cause of intestinal barrier defects. Daidzein improving the barrier integrity has been reported, but the effect on tight junction proteins and aquaporins is not well-described yet, and the underlying mechanism remains indistinct in the human intestinal epithelium. This study aimed to investigate the effects and mechanisms of daidzein on intestinal epithelial barrier injury induced by LPS, and a barrier injury model induced by LPS was established with human colorectal epithelial adenocarcinoma cell line Caco-2 cells. We found that daidzein protected the integrity of Caco-2 cell monolayers, reversed LPS-induced downregulation of ZO-1, occludin, claudin-1, and AQP3 expression, maintained intercellular junction of ZO-1, and suppressed NF-κB and the expression of inflammatory factors (TNF-α, IL-6). Furthermore, we found that daidzein suppressed the phosphorylation of the PI3K/AKT and P38 pathway-related proteins and the level of the related genes, and the PI3K/AKT and P38 pathway inhibitors increased ZO-1, occludin, claudin-1, and AQP3 expression. The study showed that daidzein could resist LPS-induced intestinal epithelial barrier injury, and the mechanism is related to suppressing the PI3K/AKT and P38 pathways. Therefore, daidzein could be a candidate as a dietary supplementation or drug to prevent or cure diarrhea.

Inflammation is correlated with abnormal functional connectivity in unmedicated bipolar depression: an independent component analysis study of resting-state fMRI.

BACKGROUND: Inflammation might play a role in bipolar disorder (BD), but it remains unclear the relationship between inflammation and brain structural and functional abnormalities in patients with BD. In this study, we focused on the alterations of functional connectivity (FC), peripheral pro-inflammatory cytokines and their correlations to investigate the role of inflammation in FC in BD depression. METHODS: In this study, 42 unmedicated patients with BD II depression and 62 healthy controls (HCs) were enrolled. Resting-state-functional magnetic resonance imaging was performed in all participants and independent component analysis was used. Serum levels of Interleukin-6 (IL-6) and Interleukin-8 (IL-8) were measured in all participants. Correlation between FC values and IL-6 and IL-8 levels in BD was calculated. RESULTS: Compared with the HCs, BD II patients showed decreased FC in the left orbitofrontal cortex (OFC) implicating the limbic network and the right precentral gyrus implicating the somatomotor network. BD II showed increased IL-6 (p = 0.039), IL-8 (p = 0.002) levels. Moreover, abnormal FC in the right precentral gyrus were inversely correlated with the IL-8 (r = -0.458, p = 0.004) levels in BD II. No significant correlation was found between FC in the left OFC and cytokines levels. CONCLUSIONS: Our findings that serum IL-8 levels are associated with impaired FC in the right precentral gyrus in BD II patients suggest that inflammation might play a crucial role in brain functional abnormalities in BD.

[Comparative analysis of pharmacokinetics and intestinal absorption of six alkaloids between Sanmiao Pills and Simiao Pills in rats].

The present study investigated the differences in pharmacokinetics and intestinal absorption of six alkaloids in Sanmiao Pills and Simiao Pills in rats and explored the different efficacies of the two formulae. After oral administration of Sanmiao Pills and Simiao Pills in rats, blood samples were collected at different time points. Samples were prepared for the determination of six alkaloids in plasma by UPLC-MS/MS. The chromatography was performed on an ACE Excel 3 C_(18 )column with acetonitrile-0.1% formic acid in water as the mobile phase for gradient elution. Analytes were detected in the positive ion mode. Plasma concentrations and pharmacokinetic parameters were calculated. Intestinal absorption of alkaloids was investigated by single-pass intestinal perfusion and absorption parameters of ingredients were calculated. The results showed that the UPLC-MS/MS method for simultaneous determination of concentrations of six alkaloids in plasma was developed and validated by methodological investigations, such as specificity, calibration curves, precision, accuracy, recovery, matrix effect, and stability. The results of the pharmacokinetic assay revealed that C_(max) and AUC values of phellodendrine, berberine, magnoflorine, berberrubine, and jatrorrhizine in Simiao Pills were significantly increased, and CL/F values were reduced as compared with those in Sanmiao Pills, which indicated the increase in plasma concentrations of alkaloids. The intestinal absorption parameters K_(a )and P_(eff) values of phellodendrine, berberine, and jatrorrhizine in Simiao Pills were higher than those in Sanmiao Pills. The intestinal absorption and plasma concentrations of alkaloids in Simiao Pills were significantly higher than those in Sanmiao Pills, suggesting that the composition of Simiao Pills was more conducive to the alkaloids into the blood to resist inflammation and lower uric acid.

Inflammation is associated with decreased functional connectivity of insula in unmedicated bipolar disorder.

BACKGROUND: Systemic inflammation and immune dysregulation have been considered as risk factors in the pathophysiology of mood disorders including bipolar disorder (BD). Previous neuroimaging studies have demonstrated metabolic, structural and functional abnormalities in the insula in BD, proposed that the insula played an important role in BD. We herein aimed to explore neural mechanisms underlying inflammation-induced in the insular subregions functional connectivity (FC) in patients with BD. METHODS: Brain resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 41 patients with unmedicated BD II (current episode depressed), 68 healthy controls (HCs). Three pairs of insular seed regions were selected: the bilateral anterior insula (AI), the bilateral middle insula (MI) and the bilateral posterior insula (PI), and calculated the whole-brain FC for each subregion. Additionally, the serum levels of pro-inflammatory cytokines in patients and HCs, including IL-6 and TNF-α, were detected. Then the partial correlation coefficients between the abnormal insular subregions FC values and pro-inflammatory cytokines levels in patients with BD II depression were calculated. RESULTS: The BD II depression group exhibited decreased FC between the right PI and the left postcentral gyrus, and increased FC between the left AI and the bilateral insula (extended to the right putamen) when compared with the HC group. Moreover, the patients with BD II depression showed higher IL-6 and TNF-α levels than HCs, and IL-6 level was negatively correlated with FC of the right PI to the left postcentral gyrus. CONCLUSIONS: Our results demonstrated that abnormal FC between the bilateral insula, and between the insula and sensorimotor areas in BD. Moreover, disrupted FC between the insula and sensorimotor areas was associated with elevated pro-inflammatory cytokine levels of IL-6 in BD.

Characteristics of temporal dynamics of intrinsic brain activity in unmedicated bipolar disorder with suicidality.

BACKGROUND: Bipolar disorder is associated with a high risk of suicide. Routine neuroimaging examination exhibited that bipolar disorder with suicidality was associated with brain structural and functional changes. However, the alterations of brain dynamics have still remained elusive. PURPOSE: To investigate the alterations of brain dynamics in unmedicated bipolar disorder II depression with suicidality and predict the severity of suicidality. MATERIALS AND METHODS: This prospective study included 106 bipolar disorder II participants (20 with suicidal attempt, 35 with suicidal ideation, 51 without suicidal ideation) and 50 healthy controls who underwent resting-state functional magnetic resonance imaging between February 2016 and December 2017. We first used sliding window analysis to evaluate the dynamic amplitude of low-frequency fluctuations. Then, we predicted the severity of suicidality using a multivariate regression model. RESULTS: One-way analysis of covariance revealed that the dynamic amplitude of low-frequency fluctuations in the right temporal pole, inferior temporal gyrus, superior temporal gyrus and the bilateral precuneus/posterior cingulate cortex was significantly different among the four groups. Post hoc pairwise comparisons revealed that dynamic amplitude of low-frequency fluctuations was remarkably decreased in the bilateral precuneus/posterior cingulate cortex in the three bipolar disorder II groups compared with that in healthy controls group. Increased dynamic amplitude of low-frequency fluctuations was found in the right superior temporal gyrus and inferior temporal gyrus in the suicidal attempt group compared with that in the other groups, and in the right temporal pole in the suicidal attempt group compared with that in the suicidal ideation and healthy controls groups. Importantly, these temporal variabilities could be used to predict the severity of suicidality (r = 0.330, p = 0.036), whereas static amplitude of low-frequency fluctuations couldn't (r = -0.050, p = 0.532). CONCLUSION: Our findings indicated that alterations of temporal variability in the precuneus/posterior cingulate cortex are such a common feature of bipolar disorder patients. Besides, the severity of suicidality could be predicted by the dynamic amplitude of low-frequency fluctuations abnormalities rather than static amplitude of low-frequency fluctuations abnormalities, which is the first evidence of dynamic brain alterations in bipolar disorder patients with suicidality. The proposed predictive model may be advantageous for clinical applications.

Achyranthes bidentata polysaccharide ameliorates type 2 diabetes mellitus by gut microbiota-derived short-chain fatty acids-induced activation of the GLP-1/GLP-1R/cAMP/PKA/CREB/INS pathway.

Gut microbiota variances reflecting the severity type 2 diabetes mellitus (T2DM). Achyranthes bidentata polysaccharide (ABP) can regulate gut microbiota. However, the hypoglycemic effect and underlying mechanism of ABP remain unclear. Herein, we characterized the structure of ABP and revealed the hypoglycemic effect of ABP in mice with T2DM. ABP repaired the intestinal barrier in T2DM mice and regulated the composition and abundance of gut microbiota, especially increasing bacteria which producing short-chain fatty acids (SCFAs), then increasing glucagon-like peptide-1 (GLP-1) level. The abundance of these bacteria was positively correlated with blood lipid and INS levels, negatively correlated with FBG levels. Colon transcriptome data and immunohistochemistry demonstrated that the alleviating T2DM effect of ABP was related to activation of the GLP-1/GLP-1 receptor (GLP-1R)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB)/INS pathway. Fecal microbiota transplantation (FMT) confirmed the transmissible efficacy of ABP through gut microbiota. Overall, our research shows that ABP plays a hypoglycemic role by increasing gut microbiota-derived SCFAs levels, and activating the GLP-1/GLP-1R/cAMP/PKA/CREB/INS pathway, emphasizing ABP as promising T2DM therapeutic candidates.

Xianglian pill modulates gut microbial production of succinate and induces regulatory T cells to alleviate ulcerative colitis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Xianglian pill (XLP), a traditional Chinese formula, is widely used as treatment for ulcerative colitis (UC) in China. However, the mechanism of its therapeutic effect is still unclear. AIM OF THE STUDY: Our previous studies showed a low oral bioavailability and a predominant distribution of major XLP ingredients in the gut. In the present study, we aimed to explore the mechanism of action of XLP on UC with respect to the regulation of gut microecology. MATERIALS AND METHODS: UC model rats established using 5% dextran sulfate sodium were treated with XLP. After the treatment period, bodyweight, colon length, histopathology, and inflammatory changes were evaluated. Further, changes in gut microbiota structure were detected via 16S rRNA sequencing, and microbial metabolites in feces were analyzed via a metabolomic assay. Antibiotic intervention and fecal microbiota transplantation were also employed to explore the involvement of gut microbiota, while the level of regulatory T cells (Tregs) in mesenteric lymph nodes was determined via flow cytometry. Transcriptome sequencing was also performed to determine colonic gene changes. RESULTS: XLP alleviated colonic injury, inflammation, and gut microbial dysbiosis in UC model rats and also changed microbial metabolite levels. Particularly, it significantly decreased succinate level in the tyrosine pathway. We also observed that fecal microbiota derived from XLP-treated rats conferred resilience to UC model rats. However, this therapeutic effect of XLP on UC was inhibited by succinate. Moreover, XLP increased the level of anti-inflammatory cellular Tregs via gut microbiota. However, this beneficial effect was counteracted by succinate supplementation. Further, XLP induced the differentiation of Treg possibly by the regulation of the PHD2/HIF-1α pathway via decreasing microbial succinate production. CONCLUSIONS: Our findings indicated that XLP exerts its therapeutic effects on UC mainly via the gut microbiota-succinate-Treg differentiation axis.

Coptidis Rhizoma processed with Evodia Rutaecarpa improves the effect on ulcerative colitis by increasing intestinal energy metabolites alpha-ketoglutarate and Lactobacillus reuteri.

BACKGROUND: Evodia Rutaecarpa-processed Coptidis Rhizoma (ECR) is a traditional Chinese medicine for the treatment of ulcerative colitis (UC) in China. However, the mechanisms underlying the ECR processing are not elucidated. PURPOSE: Coptidis Rhizoma (CR) regulates the gut microbiota in the treatment of gastrointestinal diseases. This study explored the mechanism of action of ECR before and after processing in UC in view of the regulation of gut microecology. STUDY DESIGN: A preclinical experimental investigation was performed using a mouse model of UC to examine the regulatory effect of ECR and its mechanisms through gut microbiota analysis and metabolomic assays. METHODS: Mice received 4% dextran sulfate sodium to establish a UC model and treated with ECR and CR. Colonic histopathology and inflammatory changes were observed. Gut microbiota was analyzed using 16 s rRNA sequencing. Transplants of Lactobacillus reuteri were used to explore the correlation between ECR processing and the gut microbiota. The expression of mucin-2, Lgr5, and PCNA in colonic epithelial cells was measured using immunofluorescence. Wnt3a and ß-catenin levels were detected by western blotting. The metabolites in the colon tissue were analyzed using a targeted energy metabolomic assay. The effect of energy metabolite α-ketoglutarate (α-KG) on L. reuteri growth and UC were verified in mice. RESULTS: ECR improved the effects on UC in mice compared to CR, including alleviating colonic injury and inflammation, and modulating gut microbiota by increasing L. reuteri level. L. reuteri dose-dependently alleviated colonic injury, increased mucin-2 level, and promoted colonic epithelial regeneration by increasing Lgr5 and PCNA expression. This was consistent with the results before and after ECR processing. L. reuteri promoted epithelial regeneration by upregulating Wnt/ß-catenin pathway. Moreover, ECR increased metabolites levels (especially α-KG) to promote energy metabolism in the colon tissue compared to CR. α-KG treatment increased L. reuteri level and alleviated mucosal damage in UC mice. It promoted L. reuteri growth by increasing the energy metabolic status by enhancing α-KG dehydrogenase activity. CONCLUSION: ECR processing improves the therapeutic effects of UC via the α-KG-L. reuteri-epithelial regeneration axis.

Gegen Qinlian pills alleviate carrageenan-induced thrombosis in mice model by regulating the HMGB1/NF-κB/NLRP3 signaling.

BACKGROUND: The high incidence of thrombotic events is one of the clinical characteristics of coronavirus disease of 2019 (COVID-19), due to a hyperinflammatory response caused by the virus. Gegen Qinlian Pills (GQP) is a Traditional Chinese Medicine that is included in the Chinese Pharmacopoeia and played an important role in the clinical fight against COVID-19. Although GQP has shown the potential to treat thrombosis, there is no relevant research on its treatment of thrombosis so far. HYPOTHESIS: We hypothesized that GQP may be capable inhibit inflammation-induced thrombosis. STUDY DESIGN: We tested our hypothesis in a carrageenan-induced thrombosis mouse model in vivo and lipopolysaccharide (LPS)-induced human endothelial cells (HUVECs) in vitro. METHODS: We used a carrageenan-induced mouse thrombus model to confirm the inhibitory effect of GQP on inflammation-induced thrombus. In vitro, studies in human umbilical vein endothelial cells (HUVECs) and in silico network pharmacology analyses were performed to reveal the underlying mechanisms of GQP and determine the main components, targets, and pathways of GQP, respectively. RESULTS: Oral administration of 227.5 mg/kg, 445 mg/kg and 910 mg/kg of GQP significantly inhibited thrombi in the lung, liver, and tail and augmented tail blood flow of carrageenan-induced mice with reduced plasma tumor necrosis factor α (TNF-α) and diminished expression of high mobility group box 1 (HMGB1) in lung tissues. GQP ethanol extract (1, 2, or 5 µg/ml) also reduced the adhesion of platelets to LPS stimulated HUVECs. The TNF-α and the expression of HMGB1, nuclear factor kappa B (NF-κB), and NLR family pyrin domain containing 3 (NLRP3) in LPS stimulated HUVECs were also attenuated. Moreover, we analyzed the components of GQP and inferred the main targets, biological processes, and pathways of GQP in the treatment of inflammation-induced thrombosis through network pharmacology. CONCLUSION: Overall, we demonstrated that GQP could reduce inflammation-induced thrombosis by inhibiting HMGB1/NFκB/NLRP3 signaling and provided an accurate explanation for the multi-target, multi-function mechanism of GQP in the treatment of thromboinflammation, and provides a reference for the clinical usage of GQP.

Network Pharmacology Integrated with Transcriptomics Analysis Reveals Ermiao Wan Alleviates Atopic Dermatitis via Suppressing MAPK and Activating the EGFR/AKT Signaling.

Background: Ermiao Wan (EMW) is commonly used to treat atopic dermatitis (AD) in China. However, the pharmacological mechanisms underlying the action of EMW against AD remain unclear. Purpose: We aimed to determine the mechanisms underlying the effectiveness of EMW in the treatment of AD. Methods: We evaluated the effect of EMW on AD induced by dinitrochlorobenzene (DNCB) in BALB/C mice. To clarify the key components of EMW in AD treatment, the main components of EMW were identified using HPLC. Serum pharmacochemistry was used to analyze the absorbed ingredients from blood. Based on the phytochemical results, network pharmacology and molecular docking were used to predict the action of EMW. Skin transcriptomic analysis was used to validate the network pharmacology results. RT-qPCR,ELISA, and immunohistochemical were performed to validate the results of skin transcriptomics. Results: EMW improved the symptoms of AD, with less rashes, less spontaneous scratching, less inflammatory cell infiltration, and fewer allergic reactions. The established HPLC method is simple and reliable. Chlorogenic acid, phellodendrine, magnoflorine, jatrorrhizine, palmatine, berberine, and atractylodin were the key effective ingredients with a high blood concentration. Fifty-seven primary causal targets of EMW against AD were identified. These targets are mainly involved in ErbB signaling pathways including EGFR, AKT1, MAPK8, JUN, MAPK1. Molecular docking showed that EGFR, AKT1, MAPK8, JUN, MAPK1 had good binding force with EMW. In AD mice, EMW regulated the EGFR/AKT signaling through upregulation of Grb2, GAB1, Raf-1, EGFR, and AKT, and downregulation of MAPK1 and JUN, compared to that in the MD group. Conclusion: EMW could alleviate AD through activating EGFR/AKT signaling and suppressing MAPK. This study provides a theoretical basis for the clinical use of EMW.

Gegen Qinlian decoction restores the intestinal barrier in bacterial diarrhea piglets by promoting Lactobacillus growth and inhibiting the TLR2/MyD88/NF-κB pathway.

Acute bacterial diarrhea is a severe global problem with a particularly high incidence rate in children. The microecology inhabiting the intestinal mucosa is the key factor leading to diarrhea. Gegen Qinlian decoction (GQD) is used to treat bacterial diarrhea, however, its underlying mechanism remains unclear. Thus, this study aimed to clarify the restorative effect of GQD on the intestinal barrier from the perspective of gut microbiota. A Tibetan piglet model with bacterial diarrhea was established through orally administered Escherichia coli, and diarrheal piglets were treated with GQD for three days. After treatment, GQD significantly ameliorated the diarrheal symptoms. GQD decreased the levels of IL-6, LPS, and DAO, and increased SIgA, ZO-1, and occludin levels in intestinal mucosa, indicating the restoration of intestinal barrier. GQD modulated the microbial compositions inhabited on the intestinal mucosa, especially an increase of the Lactobacillus. Spearman analysis showed that Lactobacillus was the key genus of intestinal barrier-related bacteria. Bacterial culture in vitro validated that GQD directly promoted Lactobacillus growth and inhibited E. coli proliferation. Moreover, the expressions of TLR2, MyD88, and NF-κB in the colon decreased after GQD treatment. In conclusion, GQD may treat diarrhea and restore the intestinal mucosal barrier by facilitating Lactobacillus growth and inhibiting the TLR2/MyD88/NF-κB signaling pathway.

Simiao Wan and its ingredients alleviate type 2 diabetes mellitus via IRS1/AKT2/FOXO1/GLUT2 signaling.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disease. Simiao Wan (SMW) is a commonly used clinical drug for hyperuricemia treatment. SMW has been confirmed to improve insulin resistance and is expected to be a novel hypoglycemic agent. However, the hypoglycemic bioactive ingredients and mechanisms of action of SMW are unclear. Objective: To explore the hypoglycemic effects and reveal the mechanisms of SMW and bioactive ingredients (SMW-BI). Study design and methods: The hypoglycemic effects of SMW and SMW-BI were verified in a mouse model of T2DM induced by streptozotocin (STZ) and a high-fat and high-sugar diet (HFSD). Network pharmacology was used to predict the mechanisms of SMW and SMW-BI. Histological analysis and real-time quantitative polymerase chain reaction (RT-qPCR) verified network pharmacology results. RT-qPCR results were further verified by immunofluorescence (IFC) and molecular docking. The correlation between proteins and biochemical indicators was analyzed by Spearman's correlation. Results: Chlorogenic acid, phellodendrine, magnoflorine, jateorhizine, palmatine, berberine, and atractydin were identified as SMW-BI. After 8 weeks of treatment, SMW and SMW-BI decreased the levels of fasting blood glucose (FBG), total cholesterol (TC), triacylglycerols (TG) and low-density lipoprotein cholesterol (LDL-C), increased the level of high-density lipoprotein cholesterol (HDL-C), alleviated weight loss, and increased serum insulin levels in T2DM mice. In addition, SMW and SMW-BI improved hepatocyte morphology in T2DM mice, decreased the number of adipocytes, and increased liver glycogen. Network pharmacological analysis indicated that SMW and SMW-BI may exert hypoglycemic by regulating insulin receptor substrate 1 (IRS1)/RAC-beta serine/threonine-protein kinase (AKT2)/forkhead box protein O1 (FOXO1)/glucose transporter type 2 (GLUT2) signaling. Moreover, correlation analysis showed that SMW and SMW-BI were associated with activation of IRS1, AKT2, and GLUT2, and inhibiting FOXO1. RT-qPCR revealed that SMW and SMW-BI could increase levels of IRS1, AKT2, and GLUT2 in the livers of T2DM mice and lower the level of FOXO1. Furthermore, immunofluorescence analysis showed that FOXO1 expression in the livers of T2DM mice decreased after oral administration of SMW and SMW-BI. Furthermore, molecular docking showed that SMW-BI could bind directly to IRS1 and AKT2. Conclusion: SMW and SMW-BI are potential hypoglycemic drugs that alleviate T2DM by regulating IRS1/AKT2/FOXO1 signaling. Our study provides a research idea for screening the bioactive ingredients in traditional Chinese medicine (TCM).

Shared and specific characteristics of regional cerebral blood flow and functional connectivity in unmedicated bipolar and major depressive disorders.

BACKGROUND: Identifying brain similarities and differences between bipolar disorder (BD) and major depressive disorder (MDD) can help us better understand their pathophysiological mechanisms and develop more effective treatments. However, the features of whole-brain regional cerebral blood flow (CBF) and intrinsic functional connectivity (FC) underlying BD and MDD have not been directly compared. METHODS: Eighty-eight unmedicated BD II depression patients, 95 unmedicated MDD patients, and 96 healthy controls (HCs) underwent three-dimensional arterial spin labeling (3D ASL) and resting-state functional MRI (rs-fMRI). The functional properties of whole brain CBF and seed-based resting-state FC further performed based on those regions with changed CBF were analyzed between the three groups. RESULTS: The patients with BD and MDD showed commonly increased CBF in the left posterior lobe of the cerebellum and the left middle temporal gyrus (MTG) compared with HCs. The CBF of the left MTG was positively associated with 24-items Hamilton Depression Rating Scale scores in MDD patients. Decreased FC between the left posterior lobe of the cerebellum and the left inferior frontal gyrus (IFG) was observed only in patients with BD compared with HCs. CONCLUSION: Patients with BD and those with MDD shared common features of CBF in the posterior lobe of the cerebellum and the MTG. The altered posterior lobe of the cerebellum-IFG FC can be considered as a potential biomarker for the differentiation of patients with BD from those with MDD.

Association between resting-state functional connectivity of amygdala subregions and peripheral pro-inflammation cytokines levels in bipolar disorder.

The pathophysiological mechanisms of bipolar disorder (BD) are not completely known, and systemic inflammation and immune dysregulation are considered as risk factors. Previous neuroimaging studies have proved metabolic, structural and functional abnormalities of the amygdala in BD, suggesting the vital role of amygdala in BD patients. This study aimed to test the underlying neural mechanism of inflammation-induced functional connectivity (FC) in the amygdala subregions of BD patients. Resting-state functional MRI (rs-fMRI) was used to delineate the amygdala FC from two pairs of amygdala seed regions (the bilateral lateral and medial amygdala) in 51 unmedicated BD patients and 69 healthy controls (HCs). The levels of pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α were measured in the serum. The correlation between abnormal levels of pro-inflammatory cytokines and FC values were calculated in BD patients. The BD group exhibited decreased FC between the right medial amygdala and bilateral medial frontal cortex (MFC), and decreased FC between the left medial amygdala and the left temporal pole (TP), right orbital inferior frontal gyrus compared with HCs. The BD patients had higher levels of TNF-α than HCs. Correlation analysis showed negative correlation between the TNF-α level and abnormal FC of the right medial amygdala-bilateral MFC; and negative correlation between TNF-α levels and abnormal FC of the left medial amygdala-left TP in BD group. These findings suggest that dysfunctional and immune dysregulation between the amygdala and the frontotemporal circuitry might play a critical role in the pathogenesis of BD.

Reduced myelin density in unmedicated major depressive disorder: An inhomogeneous magnetization transfer MRI study.

OBJECTIVES: To detect the whole-brain reduced myelin density in unmedicated patients with major depressive disorder (MDD) using the inhomogeneous magnetization transfer (ihMT) imaging technology. Compared to other technologies, the ihMT provides high specificity and sensitivity to detect myelin. METHOD: In this prospective study, fifty unmedicated patients (mean age 25.36 years, 40% men) with MDD and 57 age- and sex-matched healthy controls (HCs) (mean age 25.02 years, 53% men) were recruited between January 2019 and December 2019. All participants underwent ihMT imaging, and pseudo-quantitative ihMT (qihMT) and ihMT ratio (ihMTR) were obtained. The mean values of qihMT and ihMTR extracted from the 50 WM masks (extracted from the International Consortium for Brain Mapping, ICBM-152) in each participant were compared between participants in the MDD and HCs groups. The symptoms of patients were evaluated using the 24-item Hamilton Depression Rating scale (HDRS). RESULTS: Compared with the HC group, the MDD group showed significantly decreased qihMT and ihMTR values in the left inferior fronto-occipital fasciculus (IFOF) (t = -4.057, p < 0.001; t = -3.662, p < 0.001) and the left uncinate fasciculus (UF) (t = -4.776, p < 0.001; t = -3.800, p < 0.001) after Bonferroni correction. The correlation analysis displayed a significant negative correlation between qihMT values of the left IFOF and HDRS total scores in patients with MDD (r = -0.390, p = 0.012). LIMITATIONS: This was a cross-sectional study with a relative small sample. CONCLUSIONS: These findings suggest the reduced myelin density in the IFOF and UF in patients with MDD, which might be associated with the pathophysiology of MDD.

Thyroid hormones disturbances, cognitive deficits and abnormal dynamic functional connectivity variability of the amygdala in unmedicated bipolar disorder.

OBJECTIVE: Accumulating evidence suggests that hypothalamus-pituitary-thyroid (HPT) axis dysfunction is relevant to the neuropsychological and pathophysiology functions of bipolar disorder (BD). However, no research has investigated the inter-relationships among thyroid hormones disturbance, neurocognitive deficits, and aberrant brain function (particularly in the amygdala) in patients with BD. MATERIALS AND METHODS: Data of dynamic resting-state functional connectivity (rs-dFC) were gathered from 59 patients with unmedicated BD II during depressive episodes and 52 healthy controls (HCs). Four seeds were selected (the bilateral lateral amygdala and the bilateral medial amygdala). The sliding-window analysis was applied to investigate dynamic functional connectivity (dFC). Additionally, the serum thyroid hormone (free tri-iodothyronine (FT3), total tri-iodothyronine (TT3), free thyroxin (FT4), total thyroxin (TT4) and thyroid-stimulating hormone (TSH)) levels, and cognitive scores on the MATRICS Consensus Cognitive Battery (MCCB) in patients and HCs were detected. RESULTS: The BD group exhibited increased dFC variability between the left medial amygdala and right medial prefrontal cortex (mPFC) when compared with the HC group. Additionally, the BD group showed lower FT3, TT3, and TSH level, higher FT4 level, and poorer cognitive score. Moreover, a significant negative correlation was observed between the dFC variability of the left medial amygdala-right mPFC and TSH level, or reasoning and problem solving of MCCB score in BD group. Multiple regression analysis showed that the TSH level × dFC variability of the medial amygdala-mPFC was an independent predictor for cognitive processing speed in BD group. CONCLUSIONS: This study revealed patients with BD II depression had excessive variability in dFC between the medial amygdala and mPFC. Moreover, both HPT axis dysfunction and abnormal dFC of the amygdala-mPFC might be implicated in cognitive impairment in the early stages of BD.

Large-scale network abnormality in bipolar disorder: A multimodal meta-analysis of resting-state functional and structural magnetic resonance imaging studies.

BACKGROUND: Bipolar disorder (BD) has been linked to abnormalities in the communication and gray matter volume (GMV) of large-scale brain networks, as reflected by impaired resting-state functional connectivity (rs-FC) and aberrant voxel-based morphometry (VBM). However, identifying patterns of large-scale network abnormality in BD has been elusive. METHODS: Whole-brain seed-based rs-FC and VBM studies comparing individuals with BD and healthy controls (HCs) were retrieved from multiple databases. Multilevel kernel density analysis was used to identify brain networks in which BD was linked to hyper-connectivity or hypo-connectivity with each prior network and the overlap between dysconnectivity and GMV changes. RESULTS: Thirty-six seed-based rs-FC publications (1526 individuals with BD and 1578 HCs) and 70 VBM publications (2715 BD and 3044 HCs) were included in the meta-analysis. Our results showed that BD was characterized by hypo-connectivity within the default network (DN), hyper-connectivity within the affective network (AN), and ventral attention network (VAN) and hypo- and hyper-connectivity within the frontoparietal network (FN). Hyper-connectivity between-network of AN-DN, AN-FN, AN-VAN, AN-thalamus network (TN), VAN-TN, VAN-DN, VAN-FN, and TN-sensorimotor network were found. Hypo-connectivity between-network of FN and DN was observed. Decreased GMV was found in the insula, inferior frontal gyrus, and anterior cingulate cortex. LIMITATIONS: Differential weights in the number of included studies and sample size of FC and VBM might have a disproportionate influence on the meta-analytic results. CONCLUSIONS: These results suggest that BD is characterized by both structural and functional abnormalities of large-scale neurocognitive networks, especially in the DN, AN, VAN, FN, and TN.