PMID: 

PLoS One. 2015 ;10(11):e0142259. Epub 2015 Nov 11. PMID: 26559811

Abstract Title: 

Genotoxicity Induced by Foetal and Infant Exposure to Magnetic Fields and Modulation of Ionising Radiation Effects.

Abstract: 

BACKGROUND: Few studies have investigated the toxicity and genotoxicity of extremely low frequency magnetic fields (ELF-MF) during prenatal and neonatal development. These phases of life are characterized by cell proliferation and differentiation, which might make them sensitive to environmental stressors. Although in vitro evidences suggest that ELF-MF may modify the effects of ionizing radiation, no research has been conducted so far in vivo on the genotoxic effects of ELF-MF combined with X-rays.AIM AND METHODS: Aim of this study was to investigate in somatic and germ cells the effects of chronic ELF-MF exposure from mid gestation until weaning, and any possible modulation produced by ELF-MF exposure on ionizing radiation-induced damage. Mice were exposed to 50 Hz, 65μT magnetic field, 24 hours/day, for a total of 30 days, starting from 12 days post-conception. Another group was irradiated with 1 Gy X-rays immediately before ELF-MF exposure, other groups were only X-irradiated or sham-exposed. Micronucleus test on blood erythrocytes was performed at multiple times from 1 to 140 days after birth. Additionally, 42 days after birth, genotoxic and cytotoxic effects on male germ cells were assessed by comet assay and flow cytometric analysis.RESULTS: ELF-MF exposure had no teratogenic effect and did not affect survival, growth and development. The micronucleus test indicated that ELF-MF induced a slight genotoxic damage only after the maximum exposure time and that this effect faded away in the months following the end of exposure. ELF-MF had no effects on ionizing radiation (IR)-induced genotoxicity in erythrocytes. Differently, ELF-MF appeared to modulate the response of male germ cells to X-rays with an impact on proliferation/differentiation processes. These results point to the importance of tissue specificity and development on the impact of ELF-MF on the early stages of life and indicate the need of further research on the molecular mechanisms underlying ELF-MF biological effects.

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PMID: 

Molecules. 2019 Jun 25 ;24(12). Epub 2019 Jun 25. PMID: 31242627

Abstract Title: 

Piperlongumine Induces Apoptosis and Synergizes with Doxorubicin by Inhibiting the JAK2-STAT3 Pathway in Triple-Negative Breast Cancer.

Abstract: 

Triple-negative breast cancer (TNBC) lacks major effective target molecules and chemotherapy remains the current main treatment. However, traditional chemotherapy drugs, such as doxorubicin (DOX), cause serious side effects and have a poor prognosis. Piperlongumine (PL), a natural alkaloid, has showed selective anticancer effects and is expected to become a new strategy against TNBC. In our research, cell viability, colony formation, flow cytometry, Western blot, and tumor xenograft model assays were established to evaluate the suppression effect of PL and DOX alone and in combination. Data showed that PL could effectively inhibit cell growth and induce apoptosis in two TNBC cell lines. We also demonstrated for the first time that the combination treatment of PL and DOX synergistically inhibited cell growth and induced apoptosis in TNBC cells. The suppression of STAT3 activation was indicated to be a mechanism of the anticancer effect. Moreover, the effectiveness of this combination was confirmed in a tumor xenograft model. These results revealed that inhibition of the JAK2-STAT3 pathway was a key anticancer mechanism when treated with PL alone or combined with DOX, suggesting that the combination of PL and chemotherapy drugs may be a potential strategy for the clinical treatment of TNBC.

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PMID: 

Cell Death Dis. 2019 Aug 8 ;10(8):600. Epub 2019 Aug 8. PMID: 31395855

Abstract Title: 

The synergistic effects of oxaliplatin and piperlongumine on colorectal cancer are mediated by oxidative stress.

Abstract: 

Oxaliplatin-based chemotherapy is recommended as the first-line therapeutic regimen for metastatic colorectal cancer. However, long-term and repeated oxaliplatin therapy leads to drug resistance and severe adverse events, which hamper its clinical application. Thus, chemosensitizers are urgently required for overcoming oxaliplatin resistance and toxicity. Here, the anticancer effects of oxaliplatin combined with piperlongumine (PL), a molecule promoting reactive oxygen species (ROS) generation, in colorectal cancer, were assessed. We demonstrated that oxaliplatin elevated cellular ROS amounts and showed synergistic anticancer effects with PL in colorectal cancer cells. These anticancer effects were mediated by mitochondrial dysfunction and endoplasmic reticulum (ER) stress apoptotic-associated networks. Meanwhile, blockage of ROS production prevented apoptosis and fully reversed mitochondrial dysfunction and ER stress associated with the oxaliplatin/PL combination. Moreover, xenograft assays in mouse models highly corroborated in vitro data. In conclusion, this study provides a novel combination therapy for colorectal cancer, and reveals that manipulating ROS production might constitute an effective tool for developing novel treatments in colorectal cancer.

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PMID: 

Int J Mol Med. 2019 Aug 23. Epub 2019 Aug 23. PMID: 31485612

Abstract Title: 

Piperlongumine induces autophagy in biliary cancer cells via reactive oxygen species-activated Erk signaling pathway.

Abstract: 

Biliary cancer (BC) is an aggressive neoplasm with high mortality. BC can be categorized into three groups: Intrahepatic cholangiocarcinoma (CCA; also known as bile duct cancer), extrahepatic cholangiocarcinoma and gallbladder cancer. Due to its heterogeneity and aggressiveness, the response to current chemotherapy and radiotherapy methods in patients with BC is poor. Therefore, there is an urgent requirement to develop drugs to treat BC. Piperlongumine (PL), a naturally occurring small molecule isolated from Piper longum L., exhibits anticancer activity by inducing reactive oxygen species (ROS) production. In the present study, the effects of PL on cell proliferation, cell cycle, apoptosis and autophagy in BC cells were investigated. PL induced BC cell death in a concentration‑ and time‑dependent mannerby inducing ROS production. PL induced cell cycle arrest in CCA cells (HuCCT‑1) and gallbladder cancer cells (OCUG‑1) cells, but with distinct cell cycle distribution profiles. PL caused G2/M cell cycle arrest in HuCCT‑1 cells, and G0/G1 cell cycle arrest in OCUG‑1 cells. PL induced apoptosis and autophagy; PL treatment induced accumulation of LC3‑II in a concentration‑ and time‑dependent manner. The Erk signaling pathway appeared to be involved in autophagy induction. Application of the ROS scavenger, N‑acetyl‑l‑cysteine, to BC cells attenuated the cell death, cell cyclearrest, apoptosis and autophagy induced by PL treatment. These findings indicated that PL may be a potential agent for BC treatment in the future.

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PMID: 

Int J Mol Med. 2019 Aug 21. Epub 2019 Aug 21. PMID: 31485644

Abstract Title: 

Piperlongumine reduces ovalbumin‑induced asthma and airway inflammation by regulating nuclear factor‑κB activation.

Abstract: 

Asthma is a common chronic airway inflammatory disease, characterized by airway inflammation and remodeling. Piperlongumine (PL) has a number of physiological and pharmacological properties. However, the anti‑asthmatic effect of PL has not been reported to date. In the present study, ovalbumin (OVA) was used to sensitize and challenge mice to induce asthma. The results revealed that PL pretreatment reduced OVA‑induced airway inflammatory cell infiltration, reduced Th2 cytokine expression, both in the bronchoalveolar lavage fluid and in lung tissues, reduced the serum IgE level, pro‑inflammatory cytokine [tumor necrosis factor (TNF)‑α and interleukin (IL)‑6] and intercellular adhesion molecule expression, as well as nuclear factor (NF)‑κB activation. In addition, PL also mitigated OVA‑induced goblet cell metaplasia, inhibited mucus protein secretion, mitigated airway fibrosis and downregulated fibrosis marker expression. It was also demonstrated that PL inhibited TNF‑α induced inflammatory cytokine expression and NF‑κB activation in vitro. Taken together, the findings of the present study indicated that PL can reduce OVA‑induced airway inflammation and remodeling in asthmatic mice, and that these effects may be mediated by inhibiting NF‑κB signaling.

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PMID: 

Cell Oncol (Dordr). 2019 Sep 6. Epub 2019 Sep 6. PMID: 31493144

Abstract Title: 

Piperlongumine potentiates the antitumor efficacy of oxaliplatin through ROS induction in gastric cancer cells.

Abstract: 

PURPOSE: Oxaliplatin is one of the most commonly used chemotherapeutic agents in the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Therefore, there is a pressing need to develop novel therapies to potentiate the efficacy and reduce the toxicity of oxaliplatin. Piperlongumine (PL), an alkaloid isolated from Piper longum L., has recently been identified as a potent agent against cancer cells in vitro and in vivo. In the present study, we investigated whether PL can potentiate the antitumor effect of oxaliplatin in gastric cancer cells.METHODS: Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells or tumor tissues was determined using an endpoint insulin reduction assay. Western blotting was used to analyze the expression levels of the indicated proteins. Nude mice xenograft models were used to test the effects of PL and oxaliplatin combinations on gastric cancer cell growth in vivo.RESULTS: We found that PL significantly enhanced oxaliplatin-induced growth inhibition in both gastric and colon cancer cells. Moreover, we found that PL potentiated the antitumor effect of oxaliplatin by inhibiting TrxR1 activity. PL combined with oxaliplatin markedly suppressed the activity of TrxR1, resulting in the accumulation of ROS and, thereby, DNA damage induction and p38 and JNK signaling pathway activation. Pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly abrogated the combined treatment-induced ROS generation, DNA damage and apoptosis. Importantly, we found that activation of the p38 and JNK signaling pathways prompted by PL and oxaliplatin was also reversed by NAC pretreatment. In vivo, we found that PL combined with oxaliplatin significantly suppressed tumor growth in a gastric cancer xenograft model, and effectively reduced the activity of TrxR1 in tumor tissues. Remarkably, we found that PL attenuated body weight loss evoked by oxaliplatin treatment.CONCLUSIONS: Our data support a synergistic effect of PL and oxaliplatin and suggest that application of its combination may be more effective for the treatment of gastric cancer than oxaliplatin alone.

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PMID: 

Behav Pharmacol. 2019 Sep 9. Epub 2019 Sep 9. PMID: 31503069

Abstract Title: 

Piperlongumine produces antidepressant-like effects in rats exposed to chronic unpredictable stress.

Abstract: 

Piperlongumine, an alkaloid compound extracted from Peper longum L, has been reported to produce neuroprotective effects in the brain and exert various pharmacological activities such as antitumor, antiangiogenic, anti-inflammatory and analgesic properties. The aim of this study was to investigate the antidepressant-like effects and the possible mechanism of action of piperlongumine in a chronic unpredictable stress (CUS) model. We found that, with venlafaxine as a positive control, orally administered piperlongumine (12.5 and 25 mg/kg) for 7 days, not a single dose, significantly reduced immobility time in the forced swimming test, but did not alter locomotor activity in the open field test, indicating that piperlongumine has antidepressant-like effects without nonspecific motor changes. Then, using the CUS model of depression, piperlongumine was administrated orally for 4 weeks, followed by sucrose preference and forced swimming tests to evaluate the depressive-like behaviors. We found that piperlongumine reversed both the decreased sucrose preference and increased immobility time in rats exposed to CUS. In addition, piperlongumine also reversed the increase in proinflammatory cytokine levels in the hippocampus of rats in the CUS model. Altogether, the present study demonstrated that piperlongumine exhibits the antidepressant-like effects in rats, which may be mediated by the inhibition of the neuronal inflammation in the hippocampus.

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PMID: 

Fitoterapia. 2019 Aug 6 ;138:104290. Epub 2019 Aug 6. PMID: 31398448

Abstract Title: 

Monoterpene glycosides with anti-inflammatory activity from Paeoniae Radix.

Abstract: 

Six new monoterpene glycosides, named 6'-O-nicotinoylalbiflorin (1), 4'-O-vanillylalbiflorin (2), paeonidanin L (3), paeoniflorigenin-1-O-β-d-xyloside (4), 6'-(2-hydroxypropanoyl)-paeoniflorin (5), oxylactiflorin (6), together with 16known ones (7-22) were isolated from the 70% ethanol extract of Paeoniae Radix. Their structures were elucidated based on spectroscopic analysis (1D and 2D NMR, HRESIMS, IR and UV), chemical evidences and comparison with literatures. The inhibitory effects of all the isolates were evaluated against lipopolysaccharide (LPS) stimulated PGEproduction in RAW 264.7 macrophages.

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PMID: 

Inflammation. 2019 Aug 31. Epub 2019 Aug 31. PMID: 31473900

Abstract Title: 

Paeoniflorin Prevents Intestinal Barrier Disruption and Inhibits Lipopolysaccharide (LPS)-Induced Inflammation in Caco-2 Cell Monolayers.

Abstract: 

Inflammatory bowel disease (IBD) in humans is closely related to bacterial infection and the disruption of the intestinal barrier. Paeoniflorin (PF), a bioactive compound from Paeonia lactiflora Pallas plants, exerts a potential effect of anti-inflammatory reported in various researches. However, the effect of PF on intestinal barrier function and its related mechanisms has not been identified. Here, we investigate the PF potential anti-inflammatory effect on lipopolysaccharide (LPS)-stimulated human Caco-2 cell monolayers and explore its underlying key molecular mechanism. In this context, PF significantly increased TEER value, decreased intestinal epithelium FITC-dextran flux permeability, and restored the expressions of occludin, ZO-1, and claudin5 in LPS-induced Caco-2 cell. In vitro, treatment of PF significantly inhibited LPS-induced expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9). In addition, we found that PF suppressed nuclear factor kappa B (NF-κB) signaling via activating the Nrf2/HO-1 signaling pathways in ILPS-stimulated Caco-2 cells. Our findings indicate that PF has an inhibitory effect on endothelial injury. Our findings suggested that PF has an anti-inflammatory effect in ILPS-stimulated Caco-2 cells, which might be a potential therapeutic agent against IBD and intestinal inflammation.

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PMID: 

Nutr Cancer. 2019 Aug 7:1-14. Epub 2019 Aug 7. PMID: 31387393

Abstract Title: 

Multi-Targeting by-Elemene and Its Anticancer Properties: A Good Choice for Oncotherapy and Radiochemotherapy Sensitization.

Abstract: 

Several studies have focused on chemical agents, tailored from natural edible products, used to prevent and treat various diseases.β-elemene is a well-known compound derived fromthat possesses a wide spectrum of anticancer properties under preclinical and clinical conditions. Several studies have demonstrated its inhibitory effect both in humans and animals with cancers. Numerousandexperimental models have revealed thatβ-elemene can modulate multiple molecular pathways involved in carcinogenesis. In general, (1) β-elemene itself can inhibit and kill tumor cells through a variety of mechanisms, and (2) can synergistically enhance the effect of radiotherapy and/or chemotherapy, (3) also can regulate autoimmune inthe treatment of tumors. In this article, we critically focused on the available scientific evidence discussing the use of β-elemene in cancer prevention, and its molecular targets and mechanisms of action in different types of cancer. In addition, we have discussed its sources, chemistry, bioavailability, and future research directions.

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