
Three sesquiterpene lactones suppress lung adenocarcinoma by blocking TMEM16A-mediated Ca2+-activated Cl− channels
Abstract : Cornuside is a secoiridoid glucoside compound extracted from the fruits of Cornus officinalis. Cornuside has immunomodulatory and anti-inflammatory properties; however, its potential therapeutic effects on diabetic nephropathy (DN) have not been completely explored. In this study, we established an in vitro model of DN through treating mesangial cells (MMCs) with glucose. MMCs were then treated with different concentrations of cornuside (0, 5, 10, and 30 μM). Cell viability was determined using cell counting kit-8 and 5-ethynyl-2′-deoxyuridine assays. Levels of proinflammatory cytokines, including interleukin (IL)-6, tumor necrosis factor-α, and IL-1β were examined using enzyme-linked immunosorbent assay. Reverse transcription quantitative real-time polymerase chain reaction and Western blotting were performed to detect the expression of AKT and nuclear factor-kappa B (NF-κB)-associated genes. We found that cornuside treatment significantly reduced glucose-induced increase in MMC viability and expression of pro-inflammatory cytokines. Moreover, cornuside inhibited glucose-induced phosphorylation of AKT and NF-κB inhibitor alpha, decreased the expression of proliferating cell nuclear antigen and cyclin D1, and increased the expression of p21. Our study indicates that the anti-inflammatory properties of cornuside in DN are due to AKT and NF-κB inactivation in MMCs.
Abstract : Transmembrane protein TMEM16A, which encodes calcium-activated chloride channel has been implicated in tumorigenesis. Overexpression of TMEM16A is associated with poor prognosis and low overall survival in multiple cancers including lung adenocarcinoma, making it a promising biomarker and therapeutic target. In this study, three structure-related sesquiterpene lactones (mecheliolide, costunolide and dehydrocostus lactone) were extracted from the traditional Chinese medicine Aucklandiae Radix and identified as novel TMEM16A inhibitors with comparable inhibitory effects. Their effects on the proliferation and migration of lung adenocarcinoma cells were examined. Whole-cell patch clamp experiments showed that these sesquiterpene lactones potently inhibited recombinant TMEM16A currents in a concentration-dependent manner. The half-maximal concentration (IC50) values for three tested sesquiterpene lactones were 29.9 ± 1.1 μM, 19.7 ± 0.4 μM, and 24.5 ± 2.1 μM, while the maximal effect (Emax) values were 100.0% ± 2.8%, 85.8% ± 0.9%, and 88.3% ± 4.6%, respectively. These sesquiterpene lactones also significantly inhibited the endogenous TMEM16A currents and proliferation, and migration of LA795 lung cancer cells. These results demonstrate that mecheliolide, costunolide and dehydrocostus lactone are novel TMEM16A inhibitors and potential candidates for lung adenocarcinoma therapy.
Abstract : Sweroside is a natural monoterpene derived from Swertia pseudochinensis Hara. Recently, studies have shown that sweroside exhibits a variety of biological activities, such as anti-inflammatory, antioxidant, and hypoglycemic effects. However, its role and mechanisms in high glucose (HG)-induced renal injury remain unclear. Herein, we established a renal injury model in vitro by inducing human renal tubular epithelial cell (HK-2 cells) injury by HG. Then, the effects of sweroside on HK-2 cell activity, inflammation, reactive oxygen species (ROS) production, and epithelial mesenchymal transition (EMT) were observed. As a result, sweroside treatment ameliorated the viability, inhibited the secretion of inflammatory cytokines (TNF-α, IL-1β, and VCAM-1), reduced the generation of ROS, and inhibited EMT in HK-2 cells. Moreover, the protein expression of SIRT1 was increased and the acetylation of p65 NF-kB was decreased in HK-2 cells with sweroside treatment. More importantly, EX527, an inhibitor of SIRT1, that inactivated SIRT1, abolished the improvement effects of sweroside on HK-2 cells. Our findings suggested that sweroside may mitigate HG-caused injury in HK-2 cells by promoting SIRT1-mediated deacetylation of p65 NF-kB.
Abstract : Retinal prostheses have shown some clinical success in restoring vision in patients with retinitis pigmentosa. However, the post-implantation visual acuity does not exceed that of legal blindness. The reason for the poor visual acuity might be that (1) degenerate retinal ganglion cells (RGCs) are less responsive to electrical stimulation than normal RGCs, and (2) electrically-evoked RGC spikes show a more widespread not focal response. The single-biphasic pulse electrical stimulation, commonly used in artificial vision, has limitations in addressing these issues. In this study, we propose the benefit of multiple consecutive-biphasic pulse stimulation. We used C57BL/6J mice and C3H/HeJ (rd1) mice for the normal retina and retinal degeneration model. An 8 × 8 multi-electrode array was used to record electrically-evoked RGC spikes. We compared RGC responses when increasing the amplitude of a single biphasic pulse versus increasing the number of consecutive biphasic pulses at the same stimulus charge. Increasing the amplitude of a single biphasic pulse induced more RGC spike firing while the spatial resolution of RGC populations decreased. For multiple consecutive-biphasic pulse stimulation, RGC firing increased as the number of pulses increased, and the spatial resolution of RGC populations was well preserved even up to 5 pulses. Multiple consecutive-biphasic pulse stimulation using two or three pulses in degenerate retinas induced as much RGC spike firing as in normal retinas. These findings suggest that the newly proposed multiple consecutive-biphasic pulse stimulation can improve the visual acuity in prosthesis-implanted patients.
Xiong Song1,#, Liangui Nie1,#, Junrong Long2, Junxiong Zhao1, Xing Liu1, Liuyang Wang1, Da Liu1, Sen Wang1, Shengquan Liu1,*, and Jun Yang1,*
2023; 27(1): 1-8
https://doi.org/10.4196/kjpp.2023.27.1.1
Eu-Gene Kim1,#, Wonseok Chang2,#, SangYep Shin2,3, Anjana Silwal Adhikari2, Geun Hee Seol4, Dae-Yong Song1,*, and Sun Seek Min2,*
2023; 27(1): 113-125
https://doi.org/10.4196/kjpp.2023.27.1.113
Ri Zhe Zhu#, Bing Si Li#, Shang Shang Gao, Jae Ho Seo*, and Byung-Min Choi*
2021; 25(4): 297-305
https://doi.org/10.4196/kjpp.2021.25.4.297
Zhi-Qing Chen1, You Zhou1, Jun-Wen Huang1, Feng Chen2, Jing Zheng1, Hao-Liang Li1, Tao Li1, and Lang Li1,*
2021; 25(2): 147-157
https://doi.org/10.4196/kjpp.2021.25.2.147
Hualei Bai1, Shize Chen1, Tiezheng Yuan1, Dongyuan Xu1, Songbiao Cui2,*, and Xiangdan Li1,*
2021; 25(3): 217-225
https://doi.org/10.4196/kjpp.2021.25.3.217
Phan Thi Lam Hong1,2,#, Hyun Jong Kim2,#, Woo Kyung Kim2,3,*, and Joo Hyun Nam1,2,*
2021; 25(3): 251-258
https://doi.org/10.4196/kjpp.2021.25.3.251
Haixia Wang1,2, Xin Shi2, Longlong Cheng3, Jie Han2, and Jianjun Mu1,*
2021; 25(3): 239-249
https://doi.org/10.4196/kjpp.2021.25.3.239
Myeongjoo Son1,2,#, Seyeon Oh2,#, Hye Sun Lee2, Junwon Choi1,2, Bae-Jin Lee3, Joung-Hyun Park3, Chul Hyun Park4, Kuk Hui Son4,*, and Kyunghee Byun1,2,*
2021; 25(1): 27-38
https://doi.org/10.4196/kjpp.2021.25.1.27
Yoonhee Bae1,2, Jell Lee3, Changwon Kho2, Joon Sig Choi3, and Jin Han1,*
2021; 25(5): 467-478
https://doi.org/10.4196/kjpp.2021.25.5.467
Promise M. Emeka1,*, Sahibzada T. Rasool2, Mohamed A. Morsy1,3, Mohamed I. Hairul Islam4, and Muhammad S. Chohan2
2021; 25(4): 321-331
https://doi.org/10.4196/kjpp.2021.25.4.321
Hyemi Bae1, Taeho Kim2, and Inja Lim1,*
2021; 25(3): 227-237
https://doi.org/10.4196/kjpp.2021.25.3.227
Jing Cheng1, Chaoyang Ren2, Renli Cheng3, Yunning Li4, Ping Liu1, Wei Wang1,*, and Li Liu1,*
2021; 25(2): 131-137
https://doi.org/10.4196/kjpp.2021.25.2.131
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