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1.
Phytomedicine ; 126: 155283, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38422652

ABSTRACT

BACKGROUND: Portulacae Herba and Granati Pericarpium pair (PGP) is a traditional Chinese herbal medicine treatment for colitis, clinically demonstrating a relatively favorable effect on relieving diarrhea and abnormal stools. However, the underlying mechanism remain uncertain. PURPOSE: The present study intends to evaluate the efficacy of PGP in treating colitis in mice and investigate its underlying mechanism. METHODS: The protective effect of PGP against colitis was determined by monitoring body weight, colon length, colon weight, and survival rate in mice. Colonic inflammation was assessed by serum cytokine levels, colonic H&E staining, and local neutrophil infiltration. The reversal of intestinal epithelial barrier damage by PGP was subsequently analyzed with Western blot and histological staining. Furthermore, RNA-seq analysis and molecular docking were performed to identify potential pathways recruited by PGP. Following the hints of the transcriptomic results, the role of PGP through the IL-6/STAT3/SOCS3 pathway in DSS-induced colitis mice was verified by Western blot. RESULTS: DSS-induced colitis in mice was significantly curbed by PGP treatment. PGP treatment significantly mitigated DSS-induced colitis in mice, as evidenced by improvements in body weight, DAI severity, survival rate, and inflammatory cytokines levels in serum and colon. Moreover, PGP treatment up-regulated the level of Slc26a3, thereby increasing the expressions of the tight junction/adherens junction proteins ZO-1, occludin and E-cadherin in the colon. RNA-seq analysis revealed that PGP inhibits the IL-6/STAT3/SOCS3 pathway at the transcriptional level. Molecular docking indicated that the major components of PGP could bind tightly to the proteins of IL-6 and SOCS3. Meanwhile, the result of Western blot revealed that the IL-6/STAT3/SOCS3 pathway was inhibited at the protein level after PGP administration. CONCLUSION: PGP could alleviate colonic inflammation and reverse damage to the intestinal epithelial barrier in DSS-induced colitis mice. The underlying mechanism involves the inhibition of the IL-6/STAT3/SOCS3 pathway.


Subject(s)
Colitis, Ulcerative , Colitis , Plant Extracts , Pomegranate , Animals , Mice , Interleukin-6/metabolism , Molecular Docking Simulation , Colitis/chemically induced , Colitis/drug therapy , Colitis/metabolism , Inflammation/metabolism , Colon/pathology , Cytokines/metabolism , Body Weight , Dextran Sulfate/adverse effects , Mice, Inbred C57BL , Disease Models, Animal , Colitis, Ulcerative/drug therapy , Sulfate Transporters/metabolism , Sulfate Transporters/pharmacology , Sulfate Transporters/therapeutic use , Antiporters/adverse effects , Antiporters/metabolism
2.
J Steroid Biochem Mol Biol ; 227: 106231, 2023 03.
Article in English | MEDLINE | ID: mdl-36462760

ABSTRACT

BACKGROUND: Vitamin D receptor (VDR) and SLC26A3 (DRA) have been identified as pivotal protective factors in maintaining gut homeostasis in IBD patients. However, the specific mechanism underlying the increased intestinal susceptibility to inflammation induced by the loss of VDR and whether DRA participates in the role of VDR regulating intestinal epithelial barrier function are undefined. AIM: The current study is undertaken to elucidate the regulatory effects of VDR on DRA and VDR prevents intestinal epithelial barrier dysfunction via up-regulating the expression of DRA. METHODS: WT and VDR-/- mice are used as models for intestinal epithelial response. Paracellular permeability is measured by TEER and FD-4 assays. Immunohistochemistry, immunofluorescence, qPCR and immunoblotting are performed to determine the effects of VDR and DRA on gut epithelial barrier function. RESULTS: VDR-/- mice exhibits significant hyperpermeability of intestine with greatly decreased levels of ZO-1 and Claudin1 proteins. DRA is located on the intestinal epithelial apical membrane and is tightly modulated by VDR in vivo and in vitro via activating ERK1/2 MAPK signaling pathway. Notably, the current study for the first time demonstrates that VDR maintains intestinal epithelial barrier integrity via up-regulating DRA expression and the lack of DRA induced by VDR knockdown leads to a more susceptive condition for intestine to DSS-induced colitis. CONCLUSION: Our study provides evidence and deep comprehension regarding the role of VDR in modulating DRA expression in gut homeostasis and makes novel contributions to better generally understanding the links between VDR, DRA and intestinal epithelial barrier function.


Subject(s)
Antiporters , Colitis , Receptors, Calcitriol , Sulfate Transporters , Animals , Humans , Mice , Antiporters/adverse effects , Antiporters/metabolism , Caco-2 Cells , Chloride-Bicarbonate Antiporters/metabolism , Chloride-Bicarbonate Antiporters/pharmacology , Epithelial Cells/metabolism , Intestinal Mucosa/metabolism , Mice, Inbred C57BL , Receptors, Calcitriol/metabolism , Sulfate Transporters/genetics , Sulfate Transporters/metabolism
3.
Kidney Int ; 88(2): 404-11, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25651363

ABSTRACT

Hyperkalemia contributes to significant mortality and limits the use of cardioprotective and renoprotective renin-angiotensin-aldosterone blockers. Current therapies are poorly tolerated and not always effective. Here we conducted a phase 2 randomized, double-blind, placebo-controlled dose-escalation study to assess safety and efficacy of ZS-9. This oral selective cation exchanger that preferentially entraps potassium in the gastrointestinal tract was given to patients with stable Stage 3 chronic kidney disease and hyperkalemia (5.0 to 6.0 mEq/l) during a 2-day period. Of 90 eligible patients with mean baseline serum potassium of 5.1 mEq/l, 30 were randomized to placebo, 12-0.3 g, 24-3 g, or 24 to 10 g of ZS-9 three times daily for 2 days with regular meals. None withdrew and ZS-9 dose-dependently reduced serum potassium. The primary efficacy end point (rate of serum potassium decline in the first 48 h) was met with significance in the 3- and 10-g cohorts. From baseline, mean serum potassium was significantly decreased by 0.92±0.52 mEq/l at 38 h. Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/- 21.8 vs. +8.9 +/- 22.9 mEq per 24h) from placebo at day 2. In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment. Thus, ZS-9 was well-tolerated in patients with stable chronic kidney disease and hyperkalemia leading to a rapid, sustained reduction in serum potassium.


Subject(s)
Antiporters/administration & dosage , Hyperkalemia/drug therapy , Potassium/blood , Renal Insufficiency, Chronic/complications , Silicates/administration & dosage , Aged , Aged, 80 and over , Antiporters/adverse effects , Constipation/chemically induced , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Hyperkalemia/blood , Hyperkalemia/etiology , Male , Middle Aged , Potassium/urine , Silicates/adverse effects
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