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PMID: 

J Nutr Biochem. 2020 Jan ;75:108261. Epub 2019 Oct 27. PMID: 31710934

Abstract Title: 

Piperine regulates glycogen synthase kinase-3β-related signaling and attenuates cognitive decline in D-galactose-induced aging mouse model.

Abstract: 

Aging-related cholinergic dysfunction, extensive neuroinflammation and oxidative stress in brain are predominant pathogenic factors for dementia. In the present study, we aimed to evaluate the protective effects of piperine, an alkaloid nutrient component of Piper nigrum, against cognitive impairment in a senescent mouse model induced by D-galactose (D-Gal) and to explore the underlying mechanisms. Senescent mouse model was established by repeated subcutaneous injection of D-Gal (150 mg/kg, once daily for 42 days). Fourteen days after the first D-Gal exposure, piperine (2.5, 5, 10 mg/kg) or vehicle was intraperitoneally administered once daily for 28 days. The cognitive function of mice was evaluated by Morris water maze test (MWM). Twenty-four hours after behavioral test, the cholinergic function and oxidative stress level in mouse hippocampus were measured by spectrophotometric assays. In addition, the hippocampal levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β and interleukin-6, were quantified using enzyme-linked immunosorbent assay. Expressions of glycogen synthase kinase-3β (GSK-3β) and its upstream or downstream molecules including phosphatidylinositol 3-kinase (PI3K)，protein kinase B (AKT), protein kinase C (PKC), NF-E2-related factor 2, nuclear factor-κB and microtubule-associated protein tau in hippocampus were determined by western blotting, immunohistochemical or immunofluorescent staining. Our data revealed that chronic D-Gal exposure in mice led to cognitive impairment in MWM, along with cholinergic malfunction, extensive oxidative stress and neuroinflammation, as well as hyperphosphorylation of tau protein in hippocampus. All these neurochemical, neuroinflammatory and cognitive alterations could be ameliorated by 4-week repeated piperine administration. Moreover, piperine also reversed D-Gal-induced GSK-3βactivation through modulating PKC and PI3K/AKT pathways in senescent mouse hippocampus, suggesting GSK-3β-related signaling might be involved in the benefits of piperine against D-Gal-induced cognitive decline in mice.

PMID: 

J Agric Food Chem. 2020 Feb 7. Epub 2020 Feb 7. PMID: 32031370

Abstract Title: 

Alkaloids from Black Pepper (Piper nigrum L.) Exhibit Anti-inflammatory Activity in Murine Macrophages by Inhibiting Activation of NF-κB Pathway.

Abstract: 

Black Pepper (Piper nigrum L.) has been commonly utilized in food preparation as well as traditional medicine in several countries. Seven new amide alkaloids, pipernigramides A-G (3, 10, 38, and 41-44), a new piperic ester, pipernigrester A (48), along with forty-seven known compounds were isolated from the EtOH extract of Piper nigrum. The inhibitory effects on nitric oxide (NO) of all compounds was then evaluated. Among the tested compounds, three of them (42-44) significantly inhibited iNOS-mediated NO (IC50 =4.74± 0.18, 4.08 ± 0.19 and 3.71 ± 0.32 μM, respectively), and IL-1β, IL-6, TNF-α, as well as PGE2 release in RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Moreover, 42-44 suppressed IκB degradation and further inhibited the of p65 subunit cytosol-nucleus translocation by targeting IKK-β. In the carrageenan-induced paw edema test, 42-44 demonstrated anti-inflammatory effects as well. These results indicate that all three compounds from Piper nigrum have the potential anti-inflammatory effects.

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PMID: 

Cell Immunol. 2019 Dec 30:104035. Epub 2019 Dec 30. PMID: 32051090

Abstract Title: 

Piper Nigrum extract improves OVA-induced nasal epithelial barrier dysfunction via activating Nrf2/HO-1 signaling.

Abstract: 

BACKGROUND: Piper nigrum L. (Piperaceae) is commonly used as a spice and traditional medicine in many countries. It has been reported to have anti-oxidant, anti-bacterial, anti-tumor, anti-mutagenic, anti-diabetic, and anti-inflammatory properties. However, the protective role of P. nigrum on epithelial function of upper respiratory tract injury in an allergic rhinitis (AR) mouse model has been unclear. This study aims to investigate the effects of P. nigrum fruit extract (PNE) on the nasal epithelial barrier function of the upper respiratory tract in an ovalbumin (OVA)-induced AR model.METHODS: AR mouse model was established by intraperitoneal injection with 200 µL saline containing 50 µg OVA adsorbed to 1 mg aluminum hydroxide, and intranasal challenge with 20 µL per nostril of 1 mg/ml OVA. Besides, mice were orally administrated once daily with PNE and dexamethasone (Dex) in 13 days. The nasal symptoms, inflammatory cells, OVA-specific immunoglobulins, cytokines, nasal histopathology, and immunohistochemistry were evaluated.RESULTS: The PNE oral administrations inhibited allergic responses via reduction of OVA-specific antibodies levels and mast cells histamine release, accordingly, the nasal symptoms in the early-phase reaction were also clearly ameliorated. In both nasal lavage fluid and nasal tissue, PNE suppressed the inflammatory cells accumulation, specifically with eosinophils. The intravenous Evans blue injection illustrated the epithelial permeability reduction of nasal mucosa layer in PNE-treated mice. Also; PNE treatments protected the epithelium integrity by preventing the epithelial shedding from nasal mucosa; as a result of enhancing the strong expression of the E-cadherin tight junction protein in cell-to-cell junctions, as well as inhibiting the degraded levels of zonula occludens-1 (ZO-1) and occludin into the nasal cavity. Additionally, PNE protected against nasal epithelial barrier dysfunction via enhancing the expression of Nrf2 activated form which led to increasing synthesis of the anti-inflammation enzyme HO-1.CONCLUSIONS: These obtained results suggest that PNE has a promising strategy for epithelial barrier stabilization in allergic rhinitis treatment.

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PMID: 

Food Chem. 2020 Jan 23 ;316:126280. Epub 2020 Jan 23. PMID: 32058192

Abstract Title: 

Antioxidant and anti-glycation potential of green pepper (Piper nigrum): Optimization ofβ-cyclodextrin-based extraction by response surface methodology.

Abstract: 

Green pepper (Piper nigrum) presents high levels of functional compounds, with antioxidant and anti-glycation properties. Thus, the optimization of theβ-cyclodextrin-based extraction of functional compounds from green pepper through Response Surface Methodology was performed. The optimum extraction conditions were assessed by optimizing total polyphenolic content (TPC) and antioxidant activity (DPPH• and FRAP methods). 15 mM for β-CD solution, 5 min of ultrasonication and 41 °C were the optimum extraction conditions, with the TPC of 24.9 mg GAE/mL and the anti-radical activities were 3.1 mg GAE/mL (DPPH• assay) and 0.45 mg GAE/mL (FRAP method). This natural extract obtained through eco-friendly techniques proved to be effectiveto reduce the formation of hydroxymethylfurfural, a glycation marker, at 70 and 80 °C. GPE presented higher TPC than black and white pepper. The relationship between the antioxidant and anti-glycation properties was confirmed and green pepper and can be proposed as a natural potential anti-glycation agent.

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PMID: 

Cancer Lett. 2019 Sep 28 ;460:119-127. Epub 2019 Jun 14. PMID: 31207322

Abstract Title: 

Piplartine suppresses proliferation and invasion of hepatocellular carcinoma by LINC01391-modulated Wnt/β-catenin pathway inactivation through ICAT.

Abstract: 

Although piplartine is regarded as an anticancer agent, the relationship between long noncoding RNAs (lncRNAs), which are involved in various diseases (e.g., tumors) and piplartine in hepatocellular carcinoma (HCC) remains unclear. We identified LINC01391 using microarray analysis and validated its expression by qRT-PCR. Functional assays were applied to evaluate the biological effects of LINC01391 and inhibitory ofβ-catenin and T-cell factor (ICAT) on HepG2 and SMMC-7721 cells. The binding relationship between LINC01391 and ICAT was determined by RNA pull-down and RNA immunoprecipitation (RIP). Results showed that piplartine attenuated cell proliferation and invasion but promoted cell apoptosis. Upregulation of LINC01391 induced by piplartine inhibited HCC cell proliferation, invasion in vitro, and tumor growth in vivo. LINC01391 interacted with ICAT and promoted its inhibitory effect on the Wnt/β-catenin pathway, as enhanced interaction between β-catenin and ICAT, and dampened interaction of β-catenin and TCF/LEF were induced by overexpression of LINC01391. Knockdown of ICAT also promoted cell proliferation in vitro and tumor growth in vivo. Our study supported a role for piplartine and LINC01391 in HCC treatment. We found that LINC01391 inhibited the Wnt/β-catenin pathway and suppressed tumor growth via ICAT.

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PMID: 

Cell Death Dis. 2020 Jan 10 ;11(1):21. Epub 2020 Jan 10. PMID: 31924750

Abstract Title: 

Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation.

Abstract: 

Psoriasis is an autoimmune skin disease, where chronic immune responses due to exaggerated cytokine signaling, abnormal differentiation, and evasion of keratinocytes apoptosis plays a crucial role in mediating abnormal keratinocytes hyperproliferation. From the therapeutic perspective, the molecules with strong anti-proliferative and anti-inflammatory properties could have tremendous relevance. In this study, we demonstrated that piperlongumine (PPL) treatment effectively abrogated the hyperproliferation and differentiation of keratinocytes by inducing ROS-mediated late apoptosis with loss of mitochondrial membrane potential. Besides, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation. Molecularly, inhibition of STAT3 and Akt signaling was observed with a decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression. Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly. Furthermore, prominent anti-inflammatory effects were observed by inhibition of lipopolysaccharide (LPS)/Imiquimod (IMQ)-induced p65 NF-κB signaling cascade and strongly inhibited the production of cytokine storm involved in psoriasis-like skin inflammation, thus led to the restoration of normal epidermal architecture with reduction of epidermal hyperplasia and splenomegaly. In addition, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1-4) and class II (HDAC6) evaluated by immunoblotting and HDAC enzyme assay kit. In addition, our results show that PPL effectively inhibits the nuclear translocation of p65 and a histone modulator HDAC3, thus sequestered in thecytoplasm of macrophages. Furthermore, PPL effectively enhanced the protein-protein interactions of HDAC3 and p65 with IκBα, which was disrupted by LPS stimulation and were evaluated by Co-IP and molecular modeling. Collectively, our findings indicate that piperlongumine may serve as an anti-proliferative and anti-inflammatory agent and could serve as a potential therapeutic option in treating psoriasis.

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PMID: 

Acta Trop. 2020 Jan 18:105350. Epub 2020 Jan 18. PMID: 31962096

Abstract Title: 

Antiparasitic activity of piplartine (piperlongumine) in a mouse model of schistosomiasis.

Abstract: 

Schistosomiasis is one of the most important parasitic infections in terms of its negative effects on public health and economics. Since praziquantel is currently the only drug available to treat schistosomiasis, there is an urgent need to identify new anthelmintic agents. Piplartine, also known as piperlongumine, is a biologically active alkaloid/amide from peppers that can be detected in high amounts in the roots of Piper tuberculatum. Previously, it has been shown to have in vitro schistosomicidal effects. However, its anthelmintic activity in an animal host has not been reported. In the present work, in vivo antischistosomal properties of isolated piplartine were evaluated in a mouse model of schistosomiasis infected with either adult (patent infection) or juvenile (pre-patent infection) stages of Schistosoma mansoni. A single dose of piplartine (100, 200 or 400 mg/kg) or daily doses for five consecutive days (100 mg/kg/day) administered orally to mice infected with schistosomes resulted in a reduction in worm burden and egg production. Treatment with the highest piplartine dose (400 mg/kg) caused a significant reduction in a total worm burden of 60.4% (P

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PMID: 

Toxicol In Vitro. 2020 Jan 24 ;65:104775. Epub 2020 Jan 24. PMID: 31987842

Abstract Title: 

Piperlongumine induces apoptosis and G/M phase arrest in human osteosarcoma cells by regulating ROS/PI3K/Akt pathway.

Abstract: 

Previous research has reported that piperlongumine exerts antitumor properties on several types of tumor cells. However, its effect on osteosarcoma cells remains unknown. This study aimed to investigate the antitumor effects of piperlongumine on osteosarcoma cells (MG63 and U2OS cells) in vitro and determined the underlying mechanism. Cell viability was measured using MTT assay. Cell apoptosis was assessed via AO/EB staining and flow cytometry apoptosis as well as western blot analysis. Cell cycle distribution was detected by flow cytometric cell cycle and western blot analysis. In our research, we found that piperlongumine induced apoptosis and G/M phase arrest of MG63 cells. Western blot analysis not only confirmed the above results, but also demonstrated that piperlongumine induced apoptosis of osteosarcoma cells by activating Caspase-9-dependent apoptotic pathway. Furthermore, we also found that piperlongumine significantly induced apoptosis and cell cycle arrest of osteosarcoma cells by regulating ROS/PI3K/Akt signaling pathway. In summary, our findings suggested that piperlongumine inhibited osteosarcoma progression by promoting apoptosis of osteosarcoma cells. In addition, the underlying mechanism demonstrated that piperlongumine produced potent antitumor properties in osteosarcoma cells by regulating ROS/PI3K/Akt signaling pathway.

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PMID: 

Pulm Pharmacol Ther. 2020 Jan 24 ;61:101896. Epub 2020 Jan 24. PMID: 31988027

Abstract Title: 

Effect of piperlongumine during exposure to cigarette smoke reduces inflammation and lung injury.

Abstract: 

Chronic obstructive pulmonary disease (COPD) is related to smoking and anti-inflammatory therapy is indicated. Among the mediators with anti-inflammatory properties, we highlight piperlongumine (PL), an alkaloid/amide of Piper longum. Here we evaluated the PL administration on an experimental model of respiratory inflammation resulting from exposure to cigarette smoke. Male Balb/c mice were exposed to burning of 10 commercial cigarettes, 2x/day, for five weeks on specific equipment. PL efficacy was evaluated in control, exposed to smoke without treatment and PL treated (2.0 mg/kg, 3x/week) groups. Animals were weighed and plethysmographic analyses performed at the end of the exposure protocol. Inflammatory cells were evaluated in the bronchoalveolar lavage (BAL) and hemoglobin and glucose in the blood. Lung fragments were processed for histopathological studies and AnxA1, COX-2, NF-kB and neutrophil elastase expressions. Plethysmography revealed that PL maintained pulmonary frequency, volume and ventilation parameters similar to controls, with respiratory volume reduction compared to untreated animals. Final weight was reduced in both exposed groups. PL decreased hemoglobin concentration, attenuated the reduction of glucose levels and reduced influx of lymphocytes, neutrophils and macrophages in BAL. Histopathologically occured infiltration of inflammatory cells, increase of the interalveolar septa and intra-alveolar spaces in untreated animals. But, PL administration recovered lung tissues and, immunohistochemically, promoted increased expression of AnxA1 and reduction of COX-2, NF-kB and neutrophil elastase. Together the results indicate that PL attenuates systemic and pulmonary inflammatory changes, partially by modulating the expression the endogenous AnxA1, and may represent a promising therapy in preventing the inflammation induced by cigarette smoke.

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PMID: 

Cancer Sci. 2007 Nov ;98(11):1689-95. PMID: 17894552

Abstract Title: 

Inhibitory effect of nordihydroguaiaretic acid, a plant lignan, on Helicobacter pylori-associated gastric carcinogenesis in Mongolian gerbils.

Abstract: 

Recent epidemiological studies have demonstrated that consumption of certain natural products can lower cancer risk in humans. For example, plant-derived lignans have been shown to exert chemopreventive effects against cancer in vitro and in vivo. In the present study, the effects of three such lignans, termed arctiin, arctigenin, and nordihydroguaiaretic acid (NDGA), on the proliferation of Helicobacter pylori and the prevention of H. pylori-associated gastric cancer were investigated in Mongolian gerbils. To examine the effects of arctigenin and NDGA on stomach carcinogenesis, specific pathogen-free male, 5-week-old gerbils were infected with H. pylori, administered 10 p.p.m. N-methyl-N-nitrosourea in their drinking water and fed diets containing various concentrations of lignans until they were killed after 52 weeks. At a dietary level of 0.25%, NDGA significantly decreased the incidence of gastric adenocarcinomas. Arctigenin, in contrast, failed to attenuate neoplasia at a level of 0.1%. Both NDGA and arctigenin significantly reduced serum 8-hydroxy-2'-deoxyguanosine levels at doses of 0.25 and 0.05% (NDGA), and 0.1% (arctigenin). Administration of 0.25% NDGA significantly suppressed the formation of intestinal metaplasia both in the antrum and the corpus. Although all three lignans dose-dependently inhibited the in vitro proliferation of H. pylori, there were no differences in the titers of anti-H. pylori antibodies or the amount of the H. pylori-specific urease A gene among all H. pylori-infected groups. These results suggest that NDGA might be effective for prevention of gastric carcinogenesis. The possible mechanisms appear to be related to inhibitory effects on progression of gastritis and antioxidative activity rather than direct antimicrobial influence.

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