Pterostilbene suppresses gastric cancer proliferation and metastasis by inhibiting oncogenic JAK2/STAT3 signaling: In vitro and in vivo therapeutic intervention.

BACKGROUND: Gastric cancer (GC) represents a significant health burden with dire prognostic implications upon metastasis and recurrence. Pterostilbene (PTE) has been proven to have a strong ability to inhibit proliferation and metastasis in other cancers, while whether PTE exhibits anti-GC activity and its potential mechanism remain unclear. PURPOSE: To explore the efficacy and potential mechanism of PTE in treating GC. METHODS: We employed a comprehensive set of assays, including CCK-8, EdU staining, colony formation, flow cytometry, cell migration, and invasion assays, to detect the effect of PTE on the biological function of GC cells in vitro. The xenograft tumor model was established to evaluate the in vivo anti-GC activity of PTE. Network pharmacology was employed to predict PTE's potential targets and pathways within GC. Subsequently, Western blotting, immunofluorescence, and immunohistochemistry were utilized to analyze protein levels related to the cell cycle, EMT, and the JAK2/STAT3 pathway. RESULTS: Our study demonstrated strong inhibitory effects of PTE on GC cells both in vitro and in vivo. In vitro, PTE significantly induced cell cycle arrest at G0/G1 and S phases and suppressed proliferation, migration, and invasion of GC cells. In vivo, PTE led to a dose-dependent reduction in tumor volume and weight. Importantly, PTE exhibited notable safety, leaving mouse weight, liver function, and kidney function unaffected. The involvement of the JAK2/STAT3 pathway in PTE's anti-GC effect was predicted utilizing network pharmacology. PTE suppressed JAK2 kinase activity by binding to the JH1 kinase structural domain and inhibited the downstream STAT3 signaling pathway. Western blotting confirmed PTE's inhibition of the JAK2/STAT3 pathway and EMT-associated protein levels. The anti-GC effect was partially reversed upon STAT3 activation, validating the pivotal role of the JAK2/STAT3 signaling pathway in PTE's activity. CONCLUSION: Our investigation validates the potent inhibitory effects of PTE on the proliferation and metastasis of GC cells. Importantly, we present novel evidence implicating the JAK2/STAT3 pathway as the key mechanism through which PTE exerts its anti-GC activity. These findings not only establish the basis for considering PTE as a promising lead compound for GC therapeutics but also contribute significantly to our comprehension of the intricate molecular mechanisms underlying its exceptional anti-cancer properties.

Paeoniflorin Protects against Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Paeoniflorin, a natural product and active ingredient of Paeonia lactiflora, has been demonstrated to have many pharmacological effects including antiinflammatory and antihyperglycemic activity. We investigated the effects of paeoniflorin on NAFLD in mice and its underlying mechanisms. We examined this hypothesis using a well-established animal model of NAFLD. The effects of paeoniflorin on inflammation and glucolipid metabolism disorder were evaluated. The corresponding signaling pathways were measured using real-time polymerase chain reaction (PCR). We demonstrated that the mice developed obesity, dyslipidemia, and fatty liver, which formed the NAFLD model. Paeoniflorin attenuated NAFLD and exhibited potential cardiovascular protective effects in vivo by lowering body weight, hyperlipidemia, and insulin resistance; blocking inflammation; and inhibiting lipid ectopic deposition. Further investigation revealed that the antagonistic effect on hyperlipidemia and lipid ectopic deposition was related to lowering the lipid synthesis pathway (de novo pathway, 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoAR)), promoting fatty acid oxidation [peroxisome proliferator-activated receptor-alpha (PPARα), carnitine palmitoyltransferase-1, etc.] and increasing cholesterol output (PPARγ-liver X receptor-α-ATP-binding cassette transporter-1); the inhibitory effects on inflammation and hyperglycemia were mediated by blocking inflammatory genes activation and reducing gluconeogenic genes expression (phosphoenolpyruvate carboxykinase and G6Pase). These results suggest that paeoniflorin prevents the development of NAFLD and reduces the risks of atherosclerosis through multiple intracellular signaling pathways. It may therefore be a potential therapeutic compound for NAFLD.

Ameliorative effects of sodium ferulate on experimental colitis and their mechanisms in rats.

AIM: To investigate the ameliorative effects of sodium ferulate (SF) on acetic acid-induced colitis and their mechanisms in rats. METHODS: The colitis model of Sprague-Dawley rats was induced by intracolon enema with 8% (V/V) of acetic acid. The experimental animals were randomly divided into model control, 5-aminosalicylic acid therapy group and three dose of SF therapy groups. The 5 groups were treated intracolonically with normal saline, 5-aminosalicylic acid (100 mg x kg(-1)), and SF at the doses of 200, 400 and 800 mg x kg(-1) respectively and daily (8:00 am) for 7 days 24 h following the induction of colitis. A normal control group of rats clystered with normal saline instead of acetic acid was also included in the study. Pathological changes of the colonic mucosa were evaluated by the colon mucosa damage index (CMDI) and the histopathological score (HS). The insulted colonic mucosa was sampled for a variety of determinations at the end of experiment when the animals were sacrificed by decapitation. Colonic activities of myeloperoxidase (MPO) and superoxide dismutase (SOD), and levels of malondialdehyde (MDA) and nitric oxide (NO) were assayed with ultraviolet spectrophotometry. Colonic contents of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) were determined by radioimmunoassay. The expressions of inducible nitric oxide synthase (iNOS), cyclo-oxygenase-2 (COX-2) and nuclear factor kappa B (NF-kappaB) p65 proteins in the colonic tissue were detected with immunohistochemistry. RESULTS: Enhanced colonic mucosal injury, inflammatory response and oxidative stress were observed in the animals clystered with acetic acid, which manifested as the significant increase of CMDI, HS, MPO activities, MDA and NO levels, PGE2 and TXB2 contents, as well as the expressions of iNOS, COX-2 and NF-kappaB p65 proteins in the colonic mucosa, although the colonic SOD activity was significantly decreased compared with the normal control (CMDI: 2.9+/-0.6 vs 0.0+/-0.0; HS: 4.3+/-0.9 vs 0.7+/-1.1; MPO: 98.1+/-26.9 vs 24.8+/-11.5; MDA: 57.53+/-12.36 vs 9.21+/-3.85; NO: 0.331+/-0.092 vs 0.176+/-0.045; PGE2: 186.2+/-96.2 vs 42.8+/-32.8; TXB2: 34.26+/-13.51 vs 8.83+/-3.75; iNOS: 0.365+/-0.026 vs 0.053+/-0.015; COX-2: 0.296+/-0.028 vs 0.034+/-0.013; NF-kappaB p65: 0.314+/-0.026 vs 0.039+/-0.012; SOD: 28.33+/-1.17 vs 36.14+/-1.91; P<0.01). However, these parameters were found to be significantly ameliorated in rats treated locally with SF at the given dose protocols, especially at 400 mg x kg(-1) and 800 mg x kg(-1) doses (CMDI: 1.8+/-0.8, 1.6+/-0.9; HS: 3.3+/-0.9, 3.1+/-1.0; MPO: 63.8+/-30.5, 36.2+/-14.2; MDA: 41.84+/-10.62, 37.34+/-8.58; NO: 0.247+/-0.042; 0.216+/-0.033; PGE2: 77.2+/-26.9, 58.4+/-23.9; TXB2: 18.07+/-14.83; 15.52+/-8.62; iNOS:0.175+/-0.018, 0.106+/-0.019; COX-2: 0.064+/-0.018, 0.056+/-0.014; NF-kappaBp65: 0.215+/-0.019,0.189+/-0.016; SOD: 32.15+/-4.26, 33.24+/-3.69; P<0.05-0.01). Moreover, a therapeutic dose protocol of 800 mg x kg(-1) SF was observed as effective as 100 mg x kg(-1) of 5-ASA in the amelioration of colonic mucosal injury as evaluated by CMDI and HS. CONCLUSION: Administration of SF intracolonically may have significant therapeutic effects on the rat model of colitis induced by acetic acid enema, which was probably due to the mechanism of antioxidation, inhibition of arachidonic acid metabolism and NF-kappaB expression.