Complanatuside A ameliorates 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice by regulating the Th17/Treg balance via the JAK2/STAT3 signaling pathway.

Immunity imbalance of T helper 17 (Th17)/regulatory T (Treg) cells is involved in the pathogenesis of Crohn's disease (CD). Complanatuside A (CA), a flavonol glycoside, exerts anti-inflammatory activities and our study aimed to identify its effect on TNBS-induced colitis and the possible mechanisms. We found that CA alleviated the symptoms of colitis in TNBS mice, as demonstrated by prevented weight loss and colon length shortening, as well as decreased disease activity index scores, inflammatory scores, and levels of proinflammatory factors. Flow cytometry analysis showed that CA markedly reduced the percentage of Th17 cells while increasing the percentage of Treg cells in TNBS mice. Under Th17 cell polarizing conditions, CA inhibited the differentiation of Th17 cells while the Treg cell differentiation was elevated under Treg cell polarizing conditions. Furthermore, it was observed that JAK2 interacted with CA through six hydrogen bonds via molecular docking. The phosphorylation of JAK2/STAT3 was reduced by CA, which might be correlated with the protective effect of CA on colitis. In conclusion, CA reduced the imbalance of Th17/Treg cells by inhibiting the JAK2/STAT3 signaling pathway in TNBS-induced colitis, which may provide novel strategies for CD treatment.

Sclareol protected against intestinal barrier dysfunction ameliorating Crohn's disease-like colitis via Nrf2/NF-B/MLCK signalling.

BACKGROUND: Inflammation-induced intestinal barrier dysfunction is not only a pathological feature of Crohn's disease (CD) but also an important therapeutic target. Sclareol (SCL) is a nontoxic natural plant compound with anti-inflammatory effect, but its role in CD has not been established. METHODS: In vivo studies of mice with TNBS-induced colitis were carried out to evaluate the effects of SCL on CD-like colitis and intestinal barrier function. In vitro, a TNF-α-induced colonic organoid model was established to test the direct effect of SCL on inflammation-induced intestinal barrier injure and inflammatory response. The Nrf2/NF-κB/MLCK signalling was analysed to explore the mechanism of SCL. RESULTS: In vivo, SCL largely alleviated the colitis in TNBS mice, as evidenced by improvements in the weight loss, colitis symptoms, endoscopic score, macroscopic histological score, and histological inflammation score. Moreover, SCL significantly improved intestinal barrier dysfunction, manifested as reduced intestinal permeability and decreased intestinal bacterial translocation in TNBS mice. Importantly, SCL antagonised the intestinal mucosal inflammation while protecting tight junctions in TNBS mice. In vitro, SCL largely depressed pro-inflammatory cytokines levels and improved intestinal epithelial permeability in a TNF-α-induced colonic organoid model. In the context of CD, the protective effects of SCL against inflammation and intestinal barrier damage are at least partially results from the Nrf2 signalling activation and the NF-κB/MLCK signalling inhibition. CONCLUSIONS: SCL improved intestinal barrier dysfunction and alleviated CD-like colitis, possibly through modulation of Nrf2/NF-κB/MLCK signalling. In view of SCL's safety profile, there is hope that it will be useful in the clinic.

Intestinal adipocytes transdifferentiate into myofibroblast-like cells and contribute to fibrosis in Crohn's disease.

BACKGROUND AND AIMS: Intestinal fibrotic stenosis is a major reason for surgery in Crohn's disease [CD], but the mechanism is unknown. Thus, we asked whether intestinal adipocytes contribute to intestinal fibrosis. Adipocytes were found to transdifferentiate into myofibroblasts and confirmed to be involved in mesenteric fibrosis in our recent study. Here, we investigated the role and possible mechanisms of intestinal adipocytes in intestinal fibrosis in CD. METHODS: The intestinal tissue of patients with CD with or without fibrotic stenosis [CDS or CDN] and normal intestinal tissue from individuals without CD were obtained to assess alterations in submucosal adipocytes in CDS and whether these cells transdifferentiated into myofibroblasts and participated in the fibrotic process. Human primary adipocytes and adipose organoids were used to evaluate whether adipocytes could be induced to transdifferentiate into myofibroblasts and to investigate the fibrotic behaviour of adipocytes. LPS/TLR4/TGF-ß signalling was also studied to explore the underlying mechanism. RESULTS: Submucosal adipocytes were reduced in number or even absent in CDS tissue, and the extent of the reduction correlated negatively with the degree of submucosal fibrosis. Interestingly, submucosal adipocytes in CDS tissue transdifferentiated into myofibroblast-like cells and expressed collagenous components, possibly due to stimulation by submucosally translocated bacteria. LPS-stimulated human primary adipocytes and adipose organoids also exhibited transdifferentiation and profibrotic behaviour. Mechanistically, TLR4-mediated TGF-ß signalling was associated with the transdifferentiation and profibrotic behaviour of intestinal adipocytes in CDS tissue. CONCLUSIONS: Intestinal adipocytes transdifferentiate into myofibroblasts and participate in the intestinal fibrosis process in CD, possibly through LPS/TLR4/TGF-ß signalling.

Two-Dimensional MFI-Type Zeolite Flow Battery Membranes.

Vanadium flow battery (VFB) is one of the most reliable stationary electrochemical energy-storage technologies, and a membrane with high vanadium resistance and proton conductivity is essential for manufacturing high-performance VFBs. In this study, a two-dimensional (2D) MFI-type zeolite membrane was fabricated from zeolite nanosheet modules, which displayed excellent vanadium resistance (0.07 mmol L-1 h-1 ) and proton conductivity (0.16 S cm-1 ), yielding a coulombic efficiency of 93.9 %, a voltage efficiency of 87.6 %, and an energy efficiency of 82.3 % at 40 mA cm-2 . The self-discharge period of a VFB equipped with 2D MFI-type zeolite membrane increased up to 116.2 h, which was significantly longer than that of the commercial perfluorinated sulfonate membrane (45.9 h). Furthermore, the corresponding battery performance remained stable over 1000 cycles (>1500 h) at 80 mA cm-2 . These findings demonstrate that 2D MFI-type membranes are promising ion-conductive membranes applicable for stationary electrochemical energy-storage devices.

High-Efficiency CO2 /N2 Separation Enabled by Rotation of Electrostatically Anchored Flexible Ligands in Metal-Organic Framework.

Metal organic frameworks (MOF) are of great potential for molecular separation, but the ligand rotation flexibility makes them remain challenging in the construction of fixed nanochannels for precise sieving. Here we report an electrostatic-anchoring strategy to fix the rotation of 2-methylimidazole (2-MIM) ligand in ZIF-8. Electrostatic inducer trifluoroacetate anchored at and blocked the six-membered windows of ZIF-8, and meanwhile induced the positive 2-MIM rotated from initial 49° to 68°, thus opening neighbored four-membered windows with a constant size of 3.4 Å. The obtained ZIF-8 significantly enhanced the CO2 /N2 adsorption selectivity from 14.02 to 332.86. Further membrane-based separation exhibited an outstanding CO2 /N2 selectivity of up to 137 with a desired permeability of 286 Barrer, which exceeded the 2019 upper bound. This strategy provides a new inspiration for fixing the ligand rotation in soft MOF for desired precise molecular sieving.

Ultrafast Water Transport in Two-Dimensional Channels Enabled by Spherical Polyelectrolyte Brushes with Controllable Flexibility.

Fast water transport channels are crucial for water-related membrane separation processes. However, overcoming the trade-off between flux and selectivity is still a major challenge. To address this, we constructed spherical polyelectrolyte brush (SPB) structures with a highly hydrophilic polyelectrolyte brush layer, and introduced them into GO laminates, which increased both the flux and the separation factor. At 70 °C, the flux reached 5.23 kg m-2 h-1 , and the separation factor of butanol/water increased to ≈8000, which places it among the most selective separation membranes reported to date. Interestingly, further studies demonstrated that the enhancement of water transport was not only dependent on the hydrophilicity of the polyelectrolyte chains, but also influenced by their flexibility in the solvent. Quartz crystal microbalance with dissipation and molecular dynamics simulations revealed the structure-performance correlations between water molecule migration and the flexibility of the ordered polymer chains in the 2D confined space.

Identification and validation of PSAT1 as a potential prognostic factor for predicting clinical outcomes in patients with colorectal carcinoma.

The aim of the present study was to explore the existence of known or candidate drug-target genes that are upregulated in colorectal cancer (CRC) and may serve as novel prognostic factors or therapeutic targets for this type of malignancy. An in silico analysis was conducted using the Oncomine tool to compare the expression levels of a list of drug-target genes between cancerous and normal tissues in 6 independent CRC cohorts retrieved from the Oncomine database. Phosphoserine aminotransferase 1 (PSAT1) was identified as the top-ranked upregulated gene in CRC tumors, and was highly expressed in patients with chemoresistant disease. Subsequently, the expression of PSAT1 was further experimentally validated using immunohistochemistry in an independent cohort of CRC specimens. The immunohistochemistry results demonstrated that PSAT1 was overexpressed in the CRC tissues compared with the normal colorectal tissues, which was consistent with the previous in silico analysis. Furthermore, PSAT1 overexpression was associated with response to irinotecan, 5-fluorouracil and leucovorin chemotherapy, and with shorter survival time, and retained significance as an independent prognostic factor for CRC when subjected to the multivariate analysis with a Cox's proportional hazards model. Therefore, the present results implicate PSAT1 as a potential prognostic biomarker and a promising therapeutic target for CRC. Targeted PSAT1 inhibition in the treatment of CRC warrants further investigation.

Sodium tanshinone IIA sulfonate attenuates hemorrhagic shock-induced organ damages by nuclear factor-kappa B pathway.

BACKGROUND: Trauma resulted hemorrhagic shock (HS) leads to increased oxidative stress and inflammatory responses, which contributes greatly to organ failure or dysfunction. Tanshinone IIA sulfonate (TSA), as an antioxidant, may potentially be used in fluid resuscitation to prevent HS-induced organ damages. METHODS: In this study, a rat HS model was constructed. HS rats received TSA or vehicle drug during resuscitation. Mean arterial pressure and factors associated with organ failure or dysfunction, oxidative stress, and inflammatory response were investigated to evaluate treatment responses. Expression of proteins in NF-кB pathway was evaluated to elucidate the mechanism of TSA in preventing HS-induced organ damage. RESULTS: Although HS induced organ damage and upregulated oxidative stress and inflammatory response, TSA treatment ameliorated organ dysfunction, reduced oxidative stress, and suppressed inflammatory responses. We also showed that TSA treatment attenuated HS-induced activation in NF-кB pathway. CONCLUSIONS: TSA can potentially serve as an antioxidant for ameliorating HS-induced organ failure or function. Its mechanism of action may be through inhibiting NF-кB pathway.