Disrupted Resting-State Functional Connectivity between the Dorsal Attention, Default Mode, and Frontoparietal Networks in Nonorganic Gastrointestinal Disorder Patients with Spleen Deficiency Syndrome

Introduction. Spleen deficiency syndrome (SDS), a common clinical syndrome of traditional Chinese medicine, is manifested with digestive symptoms and cognitive impairments. However, the cognitive neural mechanism in brain networks of SDS still remained unclear. Our aim was to investigate the changes between the default mode, dorsal attention, and frontoparietal networks in SDS. Methods. Twenty nonorganic gastrointestinal disorder (NOGD) patients with SDS and eighteen healthy controls were enrolled to attend functional magnetic resonance imaging scan and participated a continuous performance test (CPT) before scanning. Results. Compared with healthy controls, NOGD patients with SDS showed the significantly increased functional connectivity (FC) between dorsal attention network (DAN) and left frontal-parietal control network (LFPN) and significantly decreased FC between LFPN and default mode network (DMN). The functional network connectivity analysis showed positive correlation coefficients between the DAN and LFPN and DAN and DMN as well as negative correlation between LFPN and DMN in NOGD patients with SDS compared with healthy controls. Correlation analysis revealed that the increased FC between LFPN and DAN was positively correlated with 4-digitnumber reaction time mean (RTM) and 3-digitnumber RTM. Conclusion. Our study may provide novel insights into the relationship among the DMN, DAN, and FPN in NOGD patients with SDS to deepen our understanding of the neuropsychological mechanisms of SDS.

Patient Reported Traditional Chinese Medicine Spleen Deficiency Syndrome (TCM-SDS) Scale for Colorectal Cancer: Development and Validation in China

Introduction: Spleen Deficiency Syndrome (SDS) is recognized as one of the most common Traditional Chinse Medicine (TCM) syndromes in patients with colorectal cancer (CRC). However so far there is no existing patient-reported outcome (PRO) to evaluate SDS. Our study aimed to develop and validate a PRO TCM-SDS scale for CRC in China. Methods: We developed an initial 8-item TCM-SDS scale for CRC based on literature review and consultation with experts. We then pilot tested the scale ( n = 40) and performed item revision. We conducted a survey study among CRC patients from oncology clinics at a TCM Hospital to further determine the reliability and validity of the scale. Results: Among 100 patients finally enrolled and analyzed in the survey study, 46% were female with median age of 60 years old, 77% had left side tumors and 23% had stage IV disease. Factor loading indicated that there were three domains within TCM-SDS scale. The final TCM-SDS scale involves 5 items including “I feel loss of appetite,” “I feel abdomen fullness,” “I feel my arms and legs lack strength,” “I feel short of breath when talking,” and “My stool is formless” (Cronbach’s alpha coefficient 0.76). We calculated the total score of the scale by summing the 5 individual items and normalizing them to a value maximum of 10, with higher scores indicating greater burden of spleen deficiency syndrome. The average spleen deficiency score for all patients was 3.55 ± 1.54. Among them, those who had stage IV disease had higher scores than stage I-III patients (4.30 vs 3.38, P = .015). Test-retest reliability after 2 weeks showed Pearson coefficient of 0.67 and all items were highly related ( P < .001). Compared with healthy controls, CRC patients had significantly higher spleen deficiency scores (3.55 vs 3.23, P = .045). Conclusion: The patient-reported TCM-SDS scale for CRC showed adequate initial reliability and validity. The development of the scale provided an outcome measurement tool, which could facilitate future studies to better evaluate the role of TCM in treating CRC.

Treatment of Spleen-Deficiency Syndrome With Atractyloside A From Bran-Processed Atractylodes lancea by Protection of the Intestinal Mucosal Barrier

Atractylodes lancea (Thunb.) DC. (AL) is used in traditional Chinese medicine for the treatment of spleen-deficiency syndrome (SDS). Bran-processed Atractylodes lancea (BAL) has been found to be more effective than unprocessed AL. However, the compound in BAL active against SDS remains unclear. The pharmacological efficacy of BAL and its mechanism of action against SDS were investigated by HPLC-ELSD. Candidate compound AA (atractyloside A) in AL and BAL extracts was identified by HPLC-MS analysis. AA was tested in a rat model of SDS in which body weight, gastric residual rate, and intestinal propulsion were measured, and motilin (MTL), gastrin (GAS), and c-Kit were quantified by enzyme-linked immunosorbent assay. Potential targets and associated pathways were identified based on network pharmacology analysis. mRNA expression levels were measured by qRT-PCR and protein expression levels were measured by Western blot analysis and immunohistochemistry. AA increased body weight, intestinal propulsion, MTL, GAS, and c-Kit levels, while decreasing gastric residual volume and intestinal tissue damage, as same as Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen levels. Seventy-one potential pharmacologic targets were identified. Analysis of protein interaction, Gene Ontology (GO) functional analysis, pathway enrichment analysis, and docking and molecular interactions highlighted MAPK signaling as the potential signal transduction pathway. Validation experiments indicated that treatment with AA increased MTL, GAS, ZO-1, and OCLN levels, while reducing AQP1, AQP3, and FGF2 levels. In addition, phosphorylation of p38 and myosin light-chain kinase (MLCK) expression were inhibited. AA improved gastrointestinal function by protecting the intestinal mucosal barrier via inhibition of the p38 MAPK pathway. The results have clinical implications for the therapy of SDS.

Development of A Novel Anti-Liver Fibrosis Formula with luteolin, licochalcone A, aloe-emodin and acacetin by network pharmacology and transcriptomics analysis

Background: Liver fibrosis leads to loss of liver function. Xiaoyaosan decoction (XYS) as a classical Traditional Chinese Medicine (TCM) formula is used to treatment liver fibrosis in clinical and alleviated CCl4-induced liver fibrosis in our previous study.Xiaoyaosan decoction was composed of many ingredients, and the active ingredients is not clear. The Aim of this study is to explore the clarified compounds or compound combinations to treat liver fibrosis.Methods: Network pharmacology combined with transcriptomics analysis were used to analyze the Xiaoyaosan decoction (XYS) and liver depression and spleen deficiency syndrome liver fibrosis. This consisted constructed XYS-Syndrome-liver fibrosis network, the predict formula named LLAAF was develop from the network by topological analysis according to network stability. The anti-fibrosis effect was evaluated by in vitro and in vivo study.Results: According to the network XYS-Syndrome-liver fibrosis network, luteolin, licochalcone A, aloe-emodin, and acacetin formula (LLAAF) was predicted from 8 key compounds and 255 combinations in XYS, and LLAAF had a synergistic effect on the proliferation inhibition of hepatic stellate cells (HSCs) compared to each individual compound alone. The treatment of XYS and LLAAF showed a similar anti-liver fibrotic effect that reduced histopathological changes of liver fibrosis, Hyp content and levels of α-SMA and collagen I in CCl4-induced liver fibrosis in rat. Transcriptomics analysis revealed LLAAF regulated PI3K-Akt, AMPK, FoxO, Jak-STAT3, P53, cell cycle, focal adhesion, and PPAR signaling. Furthermore, LLAAF was confirmed to regulate Jak-STAT and PI3K-Akt-FoxO signaling in vitro and in vivo.Conclusions: This study developed a novel anti-liver formula, LLAAF from XYS demonstrated the anti-liver fibrotic activity may be involved in the regulation of Jak-STAT and PI3K-Akt-FoxO signaling.