Phloretin-induced STAT3 inhibition suppresses pancreatic cancer growth and progression via enhancing Nrf2 activity.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a malignant pancreatic tumor charactered by a rapid progression and high lethal rate. Hyperactivation of STAT3 signaling exerts a vital effect on the growth and progression of PDAC. While dietary flavonoid phloretin has anti-inflammatory and antioxidant activities, it remains unclear whether phloretin has anti-tumor effects on PDAC. PURPOSE: The focus of the present study is to elucidate the effects of phloretin on PDAC and investigate its underlying molecular mechanisms. STUDY DESIGN AND METHODS: Effect of phloretin were assessed in the pancreatic cancer cells (PCCs) by colony formation assay, real-time cell analysis, flow cytometry, Immunofluorescence staining, and cell migration assay. The expressions of mRNA and protein were respectively analyzed by quantitative PCR and Western blotting. A xenograft model was used to appraise the antitumor efficacy of phloretin. RESULTS: Phloretin treatment significantly restrained cell viability and metastasis, induced DNA injury and ROS accumulation, and triggered mitochondrial-dependent apoptosis in PCCs. Mechanistically, phloretin exhibits anti-tumor potential via inactivating STAT3 signaling and enhancing Nrf2 activity. STAT3 overexpression and Nrf2 silencing partially relieved phloretin-induced inhibition on cell growth and metastasis in PCCs. Phloretin remarkably blocked pancreatic tumor growth and metastasis in vivo. CONCLUSIONS: Phloretin suppresses pancreatic cancer growth and progression through inhibition of STAT3 mediated by enhancing Nrf2 activity. Phloretin may serve as a promising therapeutic agent for PDAC.

Corynoxine suppresses pancreatic cancer growth primarily via ROS-p38 mediated cytostatic effects.

BACKGROUND: Pancreatic cancer is among the most common malignant tumours, and effective therapeutic strategies are still lacking. While Corynoxine (Cory) can induce autophagy in neuronal cells, it remains unclear whether Cory has anti-tumour activities against pancreatic cancer. METHODS: Two pancreatic cancer cell lines, Patu-8988 and Panc-1, were used. Effects of Cory were evaluated by cell viability analysis, EdU staining, TUNEL assay, colony formation assay, and flow cytometry. Quantitative PCR and Western blot were performed to analyse mRNA and protein levels, respectively. In vivo anti-tumour efficacy of Cory was determined by a xenograft model. RESULTS: Cory treatment inhibited cell proliferation, induced endoplasmic reticulum (ER) stress, and triggered apoptosis in the pancreatic cancer cell lines. CHOP knockdown-mediated inhibition of ER stress alleviated the Cory-induced apoptosis but showed a limited effect on cell viability. Cory induced cell death partially via promoting reactive oxygen species (ROS) production and activating p38 signalling. Pretreatment with ROS scavenger N-acetylcysteine and p38 inhibitor SB203580 relieved the Cory-induced inhibition on cell growth. Cory remarkably blocked pancreatic tumour growth in vivo. CONCLUSIONS: Cory exerts an anti-tumour effect on pancreatic cancer primarily via ROS-p38-mediated cytostatic effects. Cory may serve as a promising therapeutic agent for pancreatic cancer.

Rosmarinic Acid Decreases the Malignancy of Pancreatic Cancer Through Inhibiting Gli1 Signaling.

BACKGROUND: Rosmarinic acid (RA) has been shown to exert anti-tumor effects on various types of cancer. However, its roles in the treatment of pancreatic ductal adenocarcinoma (PDAC) and the underlying mechanisms remain elusive. PURPOSE: The present study aimed to investigate the therapeutic effects of RA on PDAC as well as the underlying mechanisms. STUDY DESIGN: Evaluation of the effects of RA on PDAC malignancy both in vitro and in vivo. METHODS: Cell counting kit 8 (CCK8) assay, colony formation assay, 5-Ethynyl-2'-deoxyuridine (EDU) incorporation assay, cell cycle analysis, and apoptosis assay were conducted to assess the inhibitory effect of RA on PDAC cell proliferation. Meanwhile, western blotting and RT-qPCR assay were performed to detect the target gene expression at protein and mRNA levels, respectively. Moreover, the in vivo anti-tumor activities of RA were assayed in an xenograft mouse model of PDAC. RESULTS: RA dramatically down-regulated Gli1 and its downstream targets. Further studies showed that RA prevents the nuclear translocation of Gli1, while promoting the degradation of cytosolic Gli1 via the proteasome pathway. Moreover, we observed that RA induced G1/S cell cycle arrest and apoptosis in the PDAC cells through regulating the expression of P21, P27, CDK2, Cyclin E, Bax, and Bcl-2, it inhibited the PDAC cell migration and invasion via E-cadherin and MMP-9. Notably, Gli1 overexpression markedly reversed the above RA-induced effects on PDAC cells, whereas Gli1 knockdown enhanced the effects. Additionally, the in vivo assays demonstrated that RA suppresses the tumor growth of PDAC presumably by inhibiting Gli1. CONCLUSION: We provided evidence that RA restrained the nuclear translocation of Gli1 and facilitates Gli1 degradation via proteasome pathway, reducing the malignancy of PDAC cells. These findings implicated RA as a therapeutic agent for PDAC.

RUNX2 and LAMC2: promising pancreatic cancer biomarkers identified by an integrative data mining of pancreatic adenocarcinoma tissues.

Pancreatic carcinoma (PC) is a severe disease associated with high mortality. Although strategies for cancer therapy have made great progress, outcomes of pancreatic carcinoma patients remain extremely poor. Therefore, it is urgent to find novel biomarkers and therapeutic targets. To identify biomarkers for early diagnosis and therapy, three mRNA microarray datasets and two miRNA datasets were selected, and combinative analysis was performed by GEO2R. Functional and pathway enrichment analysis were performed using DAVID database. MiRTarBase, miRWalk and Diana Tools were used to get key genes. TCGA, HPA and western blotting were used to verify diagnostic and prognostic value of key genes. By integrating mRNA and miRNA expression profiles, we identified 114 differentially expressed genes and 114 differentially expressed miRNAs, respectively. Then, three overlapping key genes, RUNX2, LAMC2 and FBXO32, were found. Their protein levels in pancreatic tissue from PC patients and normal people were analyzed by immunohistochemical staining and western blotting. RUNX2 showed a potential property to identify PC. Aberrant over-expression of LAMC2 was associated with poor prognosis of PC patients, tumor status and subtypes. In summary, our current study identified that RUNX2 and LAMC2 may be promising targets for early diagnosis and therapy of PC patients.

Preparation and antioxidant activity of phosphorylated polysaccharide from purple sweet potato.

Purple sweet potato polysaccharide was extracted via hot water, and it was chemically modified by phosphorus oxychloride-pyridine to obtain phosphorylated polysaccharide from purple sweet potato (P-PPSP) with certain degrees of substitution. Furthermore, the structure and antioxidant activity in vitro of PPSP and phosphorylated derivative were compared. The result indicated that the phosphorylation modification product of polysaccharide from purple sweet potato could improve the scavenging effect on hydroxyl radical and superoxide anion of PPSP, significantly. It also could improve the anti-lipid peroxidation ability while fail to improve the reducing ability of PPSP.

A network-regulative pattern in the pathogenesis of kidney injury following severe acute pancreatitis.

Severe acute pancreatitis (SAP), a critical inflammatory pathological disease of the pancreas, is crucial for the manifestation of lethal multiple organ dysfunction syndrome and systemic inflammatory response syndrome. Acute kidney injury (AKI) is one of the most severe complications of severe acute pancreatitis. Yet, the specific pathogenesis of AKI following SAP is defectively understood, and involves in multiple pathological processes in a "network-regulative" pattern, including dysfunction of the intestinal barrier, prolonged activation of coagulation, elevated discharge of damage-associated molecular patterns, complication of abdominal compartment syndrome, excessive release of inflammatory mediators, overexpression of procalcitonin, and incitement of chronic metabolic diseases. Therefore, in this review, we summarize the current knowledge on the pathogenesis of kidney injury following SAP to provide a better understanding of the interactions involved and to encourage the identification of novel targeted therapies to treat SAP and associated AKI.

Anti-Inflammatory Efficacy of Fabricated Rhein Micelles.

Rhein is a potential anti-inflammatory agent, but its poor water solubility significantly restricts its clinical application. In this study, rhein micelles (RMs) with improved water solubility were fabricated on Pluronic F127 (F-127). Transmission electron microscopy showed that the as-prepared RMs displayed a mean diameter of approximately 20 nm and a spherical morphology. The encapsulation efficiency of the micelles towards drugs varied from 81.38 ± 4.35% to 24.87 ± 4.32%. The RMs exhibited a burst release during the first 6 h and a following sustained release up to 96 h with a biphasic drug release pattern as suggested by the drug release assay. Cytotoxicity assessment showed that the RMs caused no change in cell viability at drug concentrations below 40 µM after 24 and 48 h of incubation. In RAW264.7 macrophages, the RMs inhibited the lipopolysaccharide-induced activation of p65/NF-κB, which in turn suppressed the transcription of its downstream inducible nitric oxide synthase, and cytokine genes such as interleukin-1ß and tumor necrosis factor-α . Simultaneously, the RMs led to reduced cytokine secretions, including cyclooxygenase-2, prostaglandin E2, nitric oxide, and interleukin-6 in a dose-dependent manner. The RMs reported herein may be a promising candidate for developing anti-inflammatory therapeutic formulations.

Quercetin ameliorates kidney injury and fibrosis by modulating M1/M2 macrophage polarization.

Interstitial inflammation is the main pathological feature in kidneys following injury, and the polarization of macrophages is involved in the process of inflammatory injury. Previous studies have shown that quercetin has a renal anti-inflammatory activity, but the potential molecular mechanism remains unknown. In obstructive kidneys, administration of quercetin inhibited tubulointerstitial injury and reduced the synthesis and release of inflammatory factors. Further study revealed that quercetin inhibited the infiltration of CD68+ macrophages in renal interstitium. Moreover, the decrease in levels of iNOS and IL-12, as well as the proportion of F4/80+/CD11b+/CD86+ macrophages, indicated quercetin-mediated inhibition of M1 macrophage polarization in the injured kidneys. In cultured macrophages, lipopolysaccharide-induced inflammatory polarization was suppressed by quercetin treatment, resulting in the reduction of the release of inflammatory factors. Notably, quercetin-induced inhibitory effects on inflammatory macrophage polarization were associated with down-regulated activities of NF-κB p65 and IRF5, and thus led to the inactivation of upstream signaling TLR4/Myd88. Interestingly, quercetin also inhibited the polarization of F4/80+/CD11b+/CD206+ M2 macrophages, and reduced excessive accumulation of extracellular matrix and interstitial fibrosis by antagonizing the TGF-ß1/Smad2/3 signaling. Thus, quercetin ameliorates kidney injury via modulating macrophage polarization, and may have therapeutic potential for patients with kidney injury.

Bright Light Suppresses Form-Deprivation Myopia Development With Activation of Dopamine D1 Receptor Signaling in the ON Pathway in Retina.

Purpose: To determine whether dopamine receptor D1 (D1R) signaling pathway activation by bright light (BL) in specific retinal neuronal cell types contributes to inhibiting form-deprivation myopia (FDM) in mice. Methods: Mice (3-weeks old) were raised under either normal light (NL: 100-200 lux) or BL (2500-5000 lux) conditions with or without form deprivation. Refraction changes were evaluated with an eccentric infrared photorefractor, and ocular axial components with optical coherence tomography. The D1R antagonist, SCH39166, was intraperitoneally injected daily to evaluate if BL mediates declines in FDM development through D1R activation. Six different biomarkers of retinal neuronal types delineated differential distribution of D1R expression. c-Fos and phosphorylated tyrosine hydroxylase (p-TH) immunofluorescent staining evaluated D1R receptor activation and dopamine synthesis, respectively. Results: Bright light exposure for 4 weeks (6 hours per day) inhibited FDM development by reducing ocular elongation and shifting refraction toward hyperopia compared with changes occurring in NL. SCH39166 injections completely reversed the inhibitory effects of BL on both refraction and ocular elongation. Bright light increased the number of cells expressing p-TH and c-fos. Increases in c-fos+ cells occurred mainly in D1R+ bipolar cells (BCs), especially D1R+ ON-BCs. Conclusions: Bright light increases D1R activity in the BCs of the ON pathway, which is associated with less myopic shift and ocular elongation than those occurring in NL. These declines suggest that increased D1R activity in the ON pathway contributes to the BL suppression of FDM development in mice.