INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2023
·Vol. 52
·期 6
·1-11
·
IF 5.4
Su-Ji Jeon,Eun-Young Choi,Eun-Ji Han,Sang-Woo Lee,Jun-Mo Moon,Soo-Hyun Jung,Ji-Youn Jung
Piperlongumine (PL) is an amide alkaloid with diverse pharmacological effects against cancer, bronchitis and asthma; however, research on its efficacy against melanoma is lacking. The present study investigated the anticancer effects of PL on A375SM and A375P human melanoma cells. PL decreased the survival rate of A375SM and A375P cells, as shown by MTT assay, increase of apoptotic cells by DAPI staining. And PL induced apoptosis by decreasing the expression of the anti‑apoptotic protein Bcl‑2 and increasing that of the pro‑apoptotic proteins cleaved‑PARP and Bax. PL also induced apoptosis in A375SM and A375P cells via the MAPK pathway, increasing expression of the MAPK pathway proteins, phosphorylated‑(p‑ERK), p‑JNK p‑p38. These proteins were confirmed by western blot. In addition, A375SM and A375P cells treated with PL showed an increased number of acidic vesicular organelles by acridine orange staining. Also, autophagy induced by the expression of 1A/1B‑light chain 3, Beclin 1and mTOR was investigated through western blot. When PL was applied following treatment with autophagy inhibitors 3‑methyladenine and hydroxychloroquine, autophagy exhibited a cytoprotective effect against apoptosis in MTT assay. Pretreatment of A375P cells with the ERK inhibitor PD98059 and the JNK inhibitor SP600125 followed by treatment with PL confirmed that apoptosis and autophagy were mediated via the MAPK/ERK pathway by western blot. In summary, the present study provided empirical evidence supporting the anticancer effects of PL on human melanoma cells and indicated the potential of PL as a treatment for melanoma.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2022
·
IF 8.786
Xiangyu Fan,Jini Qiu,Tianjie Yuan,Jing Zhang,Jianjiang Xu
Background Neovascularization and inflammatory response are two essential features of corneal allograft rejection. Here, we investigated the impact of Piperlongumine (PL) on alleviating corneal allograft rejection, primarily focusing on pathological angiogenesis and inflammation. Methods A murine corneal allograft transplantation model was utilized to investigate the role of PL in preventing corneal allograft rejection. PL (10 mg/kg) or vehicle was intraperitoneally injected daily into BALB/c recipients from day -3 to day 14. The clinical signs of the corneal grafts were monitored for 30 days. Corneal neovascularization and inflammatory cell infiltration were detected by immunofluorescence staining and immunohistochemistry. The proportion of CD4 + T cells and macrophages in the draining lymph nodes (DLNs) was examined by flow cytometry. In vitro , HUVECs were cultured under hypoxia or incubated with TNF-α to mimic the hypoxic and inflammatory microenvironment favoring neovascularization in corneal allograft rejection. Multiple angiogenic processes including proliferation, migration, invasion and tube formation of HUVECs in hypoxia with or without PL treatment were routinely evaluated. The influence of PL treatment on TNF-α-induced pro-inflammation in HUVECs was investigated by real-time PCR and ELISA. Results In vivo , PL treatment effectively attenuated corneal allograft rejection, paralleled by coincident suppression of neovascularization and alleviation of inflammatory response. In vitro , PL distinctively inhibited hypoxia-induced angiogenic processes in HUVECs. Two key players in hypoxia-induced angiogenesis, HIF-1α and VEGF-A were significantly suppressed by PL treatment. Also, TNF-α-induced pro-inflammation in HUVECs was hampered by PL treatment, along with a pronounced reduction in ICAM-1, VCAM-1, CCL2, and CXCL5 expression. Conclusions The current study demonstrated that PL could exhibit both anti-angiogenic and anti-inflammatory effects in preventing corneal allograft rejection, highlighting the potential therapeutic applications of PL in clinical strategy.
研究领域:
眼科学
·
免疫学
·
药理学
·
移植学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Yelin Tang,Wenxin Zhang,Liqin Wu,Bin Bai,Bin Zheng,Mengying Li,Yue Tang,Xiaona Zhu,Yali Zhang,Yi Wang,Bing Zhang
Purpose Acute lung injury (ALI) is a fatal acute inflammatory illness with restricted therapeutic choices clinically. Piperlongumine (PL) is recognized as an alkaloid separated from Piper longum L, which was suggested to exhibit multiple pharmacological activities (e.g., anti-inflammatory activity). However, the effects of PL on LPS-triggered ALI and its anti-inflammatory target remain unclear. This paper intended to assess the roles of PL in LPS-triggered ALI, as well as its underlying mechanism and target. Methods In vivo, ALI was induced by intratracheal injection of LPS to evaluate protective effects of PL and assessed by the changes of histopathological. In vitro, the anti-inflammatory activity and mechanism of PL were investigated by ELISA, RT-qPCR, transcription factor enrichment analysis, Western blotting and Immunofluorescence assay. The binding affinity of PL to MD2 was analyzed using computer docking, surface plasmon resonance , ELISA and immunoprecipitation assay. Results It was reported here that PL treatment alleviated LPS-induced pulmonary damage, inflammatory cells infiltration and inflammatory response in mice. In culture cells, PCR array showed that PL significantly inhibited LPS-induced inflammatory cytokines, chemokines , and type I IFNs genetic expression, along with the inhibition of TAK1 and TBK1 pathway. It is noteworthy that PL is capable of straightly binding to MD2 and inhibiting MD2/TLR4 complex formation and TLR4 dimerization . Conclusions As revealed from this study, PL directly binding to MD2 to block cytokines expression by inhibiting the activation of TAK1 and TBK1 pathway, which then exerted its pulmonary protective activity. Accordingly, PL may act as an underlying candidate for treating LPS-triggered ALI.
研究领域:
药理学
·
免疫学
·
肺医学
✓ 已验证
DOI
PubMed
高影响因子
Current Pharmaceutical Analysis
·
2026
·
IF 3.6
Li Shan,Ye Lu,Xiaoli Zhu,Xu Cheng
Background Radiotherapy has been applied for the treatment of cervical cancer (CC), and our current study aims to reveal the mechanism of Piperlongumine on strengthening radiotherapy sensitization in CC. Methods The cell counting kit-8 assay was applied to explore the inhibitory effects of Piperlongumine on the viability of CC cells HeLa and SiHa, and the mechanism of action of Piperlongumine on strengthening radiotherapy sensitization in CC cells. The generation of reactive oxygen species in CC cells after the treatment of different concentrations of Piperlongumine, meanwhile, was observed under a fluorescence microscope, while the assay of flow cytometry was adopted to determine the cell cycle. Further, the content of oxidative stress indicators glutathione (GSH) and thioredoxin reductase (TrxR) and the protein level of DNA damage indicator H2AX was quantified using the enzyme-linked immunosorbent assay (ELISA) and western blotting, respectively. Results The intervention of Piperlongumine evidently reduced the proliferation and survival fraction of CC cells following irradiation at different radiation dosages. Meanwhile, the intervention of Piperlongumine led to increased reactive oxygen species production, while inducing DNA damage (as evidenced by increased H2AX levels), disrupting redox homeostasis (reduced GSH, increased TrxR), and promoting G2/M phase arrest in CC cells. Due to the lack of in vivo validation and the incomplete elucidation of certain mechanisms in this study, future work is needed. Conclusion The current study elucidates the mechanisms of Piperlongumine on strengthening radiotherapy sensitization in CC.
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DOI
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
·
2017
·
IF 2.713
Qi Liu,Di Zhao,Xiaojie Zhu,Huili Chen,Yue Yang,Jiaqiu Xu,Qing Zhang,Ali Fan,Ning Li,Chaorui Guo,Ying Kong,Yang Lu,Xijing Chen
The purpose of this study was to develop a nanocarrier system for codelivery of paclitaxel (PTX) and piperlongumine (PL) and investigate the therapeutic potential of improving efficacy and reducing toxicity. PTX and PL were formulated into poly lactic-co-glycolic acid and D-α-tocopheryl polyethylene glycol succinate via organic solvent evaporation method. The average diameter was 117.1 ± 1.9 nm , and the zeta potential was −43.25 ± 2.76 mV. PL facilitated the cellular uptake of PTX, and the increased cytotoxicity was similarly displayed. The formulation with the PTX/PL concentration ratio at 1:200 showed the best antitumor activity , the IC 50 of PTX were 5.10 ± 0.08 nM in HepG2 cells, and 3.79 ± 1.01 nM in Michigan Cancer Foundation–7 cells. Correspondingly, the combination index was 0.79 and 0.76. Furthermore, intracellular uptake of PTX toward HepG2 cells in coencapsulated nanoparticles was significantly more than free solution. In addition, the antitumor effect of PTX/PL-PTNPs in the HepG2 xenograft tumor model suggested that the nanoparticles showed a higher antitumor efficacy with reduced toxicity to other tissues compared with free PTX. In summary, the results indicated that PTX/PL-PTNPs processed well characteristics and enhanced its therapeutic efficacy; thus, this delivery system could be clinically effective for treatment of cancers.
研究领域:
药学
·
肿瘤学
·
纳米技术
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2026
·
IF 5.8
Xiulong Deng,Xueqin Mu,Xiaoliang Li,Zhiming Shen,Chengyong Zhong,Hong Yang,Jintao Yi,Dong Peng,Dongliang Lu,Xun Li,Yiping Qian
Abstract The therapeutic potential of piperlongumine (PL) against schistosomiasis and hepatic injury is limited by its poor water solubility. Herein, well-defined, monodisperse, surface glucose-functionalized, and PL-encapsulated nanoparticles (PL-NPs) with uniform size (hydrodynamic diameter: ∼264 nm) were synthesized via a nanoprecipitation protocol. These PL-NPs possessed excellent stability in various media (>120 h) and controlled-release profiles in vitro in Roswell Park Memorial Institute 1640 (t1/2 = 2.4 h) and phosphate-buffered saline (t1/2 = 12 h). Cytocompatibility assessments and organ toxicity studies confirmed that PL-NPs possessed excellent biocompatibility. In vivo and ex vivo fluorescence imaging revealed the perfect schistosoma-targeting capability of PL-NPs via the specific recognition and binding property of tegumental schistosome glucose transporter protein 4 toward the glucose molecule. PL-NPs (containing 10 μM PL) achieved an in vitro worm mortality of ∼95%, which was approximately 2.7-fold higher than that of PL alone (∼35%) with the same dosage. The enhanced worm-killing activity of PL-NPs compared to that of PL alone was attributed to a greater ability to disrupt the schistosomal tegument and a more pronounced impairment of the worm’s internal antioxidant capacity. After PL-NPs treatment, in vivo worm burden and hepatic and intestinal egg burden were significantly decreased by approximately 56%, 44%, and 37%, respectively, representing 1.9-, 2.0-, and 2.1-fold greater reductions than those observed with the PL group. Concurrently, PL-NPs obviously attenuated hepatic liver function impairment and fibrosis progression by decreasing the intrahepatic number of granulomas (∼75%, 1.7-fold lower than PL), granuloma size (∼50%, 3.6-fold lower than PL), and lipid peroxidation and restoring intrahepatic antioxidant capacity to near-normal levels. Thus, these PL-NPs, which were characterized by controlled release, specific schistosoma-targeting, potent anti-schistosomal efficacy, and hepatoprotective activity, offer a promising therapeutic strategy for schistosomiasis.
✓ 已验证
DOI
高影响因子
ACS Chemical Neuroscience
·
2019
·
IF 3.861
Ge Li,Yuantie Zheng,Jiali Yao,Linya Hu,Qunpeng Liu,Furong Ke,Weixiao Feng,Ya Zhao,Pencheng Yan,Wenfei He,Hui Deng,Peihong Qiu,Wulan Li,Jianzhang Wu
The supplementation of exogenous antioxidants to scavenge excessive reactive oxygen species (ROS) is an effective treatment for cerebral ischemia-reperfusion injury (CIRI) in stroke. Piperlongumine (PL), a natural alkaloid, has a great potential as a neuroprotective agent, but it also has obvious toxicity. Moreover, its neuroprotective effects remain to be improved. In this study, we designed a series of novel PL analogs by hybridizing the screened low-toxicity diketene skeleton with antioxidant effect and the 3,4,5-trimethoxyphenyl group, which may increase the antioxidant activity of PL. The intermediate was synthesized by a novel green synthesis method, and 34 compounds were obtained. The compounds without obvious cytotoxicity have remarkable antioxidant effects, especially compared with diketene skeletons and PL. The cytoprotection of the active compound decreased significantly by reduction of the carbon–carbon double bonds of the Michael acceptor in the diketene skeleton. More importantly, further study revealed that compound A9, which has the best activity, can confer protection for cells against oxidative stress and attenuate brain injury in vivo. Overall, this study provided a promising drug candidate for the treatment of CIRI and guided the further development of drug research in oxidative stress-mediated diseases.
研究领域:
药化化学
·
神经科学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Ziqing Wang,Wenwen Mu,Zhaotang Gong,Guoyun Liu,Jie Yang
Piperlongumine (PL) has been showed to have multiple pharmacological activities. In this study, we reported the synthesis of three series of PL derivatives, and evaluation of their anti-inflammatory effects in both lipopolysaccharide (LPS)-induced Raw264.7 macrophages and a dextran sulfate sodium (DSS)-induced mouse model of colitis. Our results presented that two meta -substituent containing derivatives 1 – 3 and 1 – 6 , in which γ-butyrolactam replaced α,β-unsaturated δ-valerolactam ring of PL, displayed low cytotoxicity and effective anti-inflammatory activity. Molecular docking also showed that the meta -substituted derivative, compared with the corresponding ortho - or para -substituted derivative, had significant interactions with the amino acid residues of CD14, which was the core receptors recognizing LPS. In vitro and in vivo studies, 1 – 3 and 1 – 6 could inhibit the expression of pro-inflammatory cytokines, and the excessive production of reactive nitrogen species and reactive oxygen species. Oral administration of 100 mg/kg/day of 1 – 3 or 1 – 6 alleviated the severity of clinical symptoms of colitis in mice, and significantly reduced the colonic tissue damage to protect the colonic tissue from the DSS-induced colitis. These results suggested that meta -substituted derivatives 1 – 3 and 1 – 6 were potential anti-inflammatory agents, which may lead to future pharmaceutical development.
研究领域:
药理学
·
炎症
·
药物开发
✓ 已验证
DOI
PubMed
高影响因子
ANTICANCER RESEARCH
·
2025
·Vol. 45
·期 12
·5423-5434
·
IF 1.7
YUN-SEO JANG,SU-JI JEON,SANG-WOO LEE,SU-A LEE,HUI-JIN JANG,SOO-HYUN JUNG,MYEON-SIK YANG,SANG-KI KIM,BYUNG-KWON PARK,YOUNG-SEOK PARK,BYEONG-SOO KIM,JI-YOUN JUNG
Background/Aim: Piperlongumine, a major alkaloid compound found in long pepper (Piper longum L.), is used to treat tumors, malaria, bronchitis, and asthma. This study aimed to investigate the anticancer effects of piperlongumine on SK-BR-3 and T47D human breast cancer cell lines, focusing on its potential to induce apoptosis and autophagy.
Materials and Methods: Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to determine whether piperlongumine reduced breast cancer cell survival. Apoptosis was evaluated through 4′,6-diamidino-2-phenylindole staining for morphological changes and flow cytometry was conducted for quantitative analysis. Acridine orange staining was performed to examine autophagy induction. Western blotting was used to analyze the expression of proteins associated with apoptosis, the mitogen-activated protein kinase (MAPK)/NF-κB pathway, and autophagy.
Results: We observed an increase in the apoptosis-related proteins Bax and cleaved poly (ADP-ribose) polymerase, while apoptosis was associated with decreased Bcl-2. Among the MAPK-related proteins, the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) decreased, whereas that of phosphorylated c-Jun N-terminal kinase (p-JNK) and phosphorylated p38 (p-p38) increased. The autophagy-related protein phosphorylated mammalian target of rapamycin (p-mTOR) was decreased, whereas Beclin 1 and LC3-II expression levels increased, indicating autophagy induction.
Conclusion: In SK-BR-3 and T47D breast cancer cell lines, piperlongumine induces apoptosis via the MAPK/NF-κB pathway and promotes autophagy. These findings suggests that piperlongumine may serve as a potential therapeutic agent against human breast cancer cells.
研究领域:
肿瘤学
·
分子生物学
·
药理学
·
细胞生物学
·
信号转导
·
转化医学
✓ 已验证
DOI
PubMed
高影响因子
Biomedicines
·
2023
·Vol. 11
·期 9
·2442
·
IF 4.7
Eun-Young Choi,Eun-Ji Han,Su-Ji Jeon,Sang-Woo Lee,Jun-Mo Moon,Soo-Hyun Jung,Ji-Youn Jung
Oral cancer is a malignant tumor that primarily affects areas such as the lips, tongue, buccal mucosa, salivary gland, and gingiva and has a very high malignancy. Piperlongumine (PL), isolated from long pepper (Piper longumL.), is a natural alkaloid with pharmacological effects, such as anti-inflammatory and anti-atherosclerotic effects. The effect and mechanism of PL in oral cancer cell lines has not been explored. Therefore, this study aimed to investigate the mechanism of anticancer effects of PL in the human oral cancer cell lines MC-3 and HSC-4 in vitro. This study demonstrated that PL inhibits cell proliferation by inducing apoptosis and autophagy in human oral cancer cell lines, which was confirmed by the levels of apoptosis- and autophagy-related proteins through Western blotting. Moreover, the pharmacological blockade of autophagy activation by hydroxychloroquine (HCQ), an autophagy inhibitor, significantly improved PL-induced apoptosis in MC-3 cells, suggesting a cytoprotective effect. In addition, activation of the mitogen-activated protein kinase (MAPK) signaling pathway contributed to PL-induced apoptosis. Collectively, the study suggested that combining an autophagy inhibitor with PL treatment can exert effective anticancer properties in oral cancer cells by inducing apoptosis and cytoprotective autophagy via the JNK-mediated MAPK pathway.Keywords:piperlongumine;oral cancer;apoptosis;autophagy;MAPK pathway;anti-cancer agent
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Eun-Ji Han,Eun-Young Choi,Su-Ji Jeon,Sang-Woo Lee,Jun-Mo Moon,Soo-Hyun Jung,Bumseok Kim,Sung-Dae Cho,Jeong-Seok Nam,Changsun Choi,Jeong-Hwan Che,Ji-Youn Jung
Natural products are continuously being researched to develop safe and effective treatment options for cervical cancer , the fourth most common cancer in women. Piperlongumine (PL), an amide alkaloid mainly present in long pepper , exhibits neuroprotective and anti-cancer properties. However, the specific effect of PL in cervical cancer and the relationship between the anti-cancer pathway and autophagy remain unclear. Therefore, we aimed to investigate PL-induced apoptosis in KB human cervical cancer cells and the relationship between apoptosis and autophagy therein. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and wound-healing assays showed that PL treatment suppressed KB cell viability and proliferation. Apoptosis was identified through 4′,6-diamidino-2-phenylindole and annexin V-propidium iodide staining, increased cleaved-poly (ADP-ribose) polymerase and Bcl-2 associated X levels, and decreased B cell lymphoma 2 levels. Acridine orange staining and increased microtubule-associated protein 1A/1B-light chain 3-II and Beclin-1 levels confirmed autophagy. We determined that KB cell-related autophagy exerted cytoprotective effects using the autophagy inhibitors 3-methyladenine and hydroxychloroquine . PL treatment promoted apoptosis by inhibiting the phosphatidylinositol-3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin pathway in KB cells; inhibiting the pathway using PI3K inhibitors increased autophagy. We suggest that PL is a potential natural anticancer agent for cervical cancer treatment.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
天然产物化学
✓ 已验证
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2022
·
IF 10.334
Liyun Zheng,Shiji Fang,Aifang Chen,Weiqian Chen,Enqi Qiao,Minjiang Chen,Gaofeng Shu,Dengke Zhang,Chunli Kong,Qiaoyou Weng,Suqin Xu,Zhongwei Zhao,Jiansong Ji
Sorafenib , a multikinase inhibitor, is the first-line agent for advanced liver cancer. Sorafenib strongly inhibits both cell proliferation and tumour angiogenesis. However, the development of drug resistance hampers its anticancer efficacy. To improve the antitumour activity of sorafenib, we demonstrate that piperlongumine (PL), an alkaloid isolated from the fruits and roots of Piper longum L ., enhances the cytotoxicity of sorafenib in HCCLM3 and SMMC7721 cells using the cell counting kit-8 test. Flow cytometry analysis indicated that PL and sorafenib cotreatment induced robust reactive oxygen species (ROS) generation and mitochondrial dysfunction, thereby increasing the number of apoptotic cells and the ratio of G2/M phase cells in both HCCLM3 and SMMC7721 cells. Furthermore, AMP-protein kinase (AMPK) signalling was activated by excess ROS accumulation and mediated growth inhibition in response to PL and sorafenib cotreatment. RNA-sequencing analysis indicated that PL treatment disrupted RNA processing in HCCLM3 cells. In particular, PL treatment decreased the expression of cleavage and polyadenylation specificity factor 7 (CPSF7), a subunit of cleavage factor I , in a time- and concentration-dependent manner in HCCLM3 and SMMC7721 cells. CPSF7 knockdown using a gene interference strategy promoted growth inhibition of PL or sorafenib monotherapy , whereas CPSF7 overexpression alleviated the cytotoxicity of sorafenib in cultured liver cancer cells. Finally, PL and sorafenib coadministration significantly reduced the weight and volume of HCCLM3 cell xenografts in vivo. Taken together, our data indicate that PL displays potential synergistic antitumour activity in combination with sorafenib in liver cancer.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）