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Shelly A Cruz, Zhaohong Qin, Alexandre F R Stewart, Hsiao-Huei Chen
Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases (RIPK) associated with the tumor necrosis factor-alpha (TNF-α)/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and alleviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar concentrations...
February 2018: Neural Regeneration Research
Yingying Qian, Xiangjiang Guo, Lin Che, Xuejing Guan, Bei Wu, Renhua Lu, Mingli Zhu, Huihua Pang, Yucheng Yan, Zhaohui Ni, Leyi Gu
BACKGROUND/AIMS: Klotho is a multifunctional protein expressed predominantly in kidney tubular epithelium. Here, we investigated the protective effects of Klotho on necroptosis in renal ischemic-reperfusion injury (IRI) and the role of oxidative stress in this process. METHODS: Mice were subjected to bilateral renal pedicle clamping. Mouse renal tubular epithelial (TCMK-1) cells were exposed to hypoxia/reoxygenation (H/R) or H2O2. Kidney samples from acute kidney injury (AKI) patients and controls were examined by immunofluorescence...
March 10, 2018: Cellular Physiology and Biochemistry
Yanlan Li, Xiaodan Liu, Pengchao Gong, Xin Tian
Bufalin, a key active ingredient of the Chinese medicine Chan Su, inhibits breast cancer tumorigenesis in vitro and in vivo. Here we found that the pan-caspase inhibitor zVAD-fmk failed to inhibit bufalin-induced cell death in MCF-7 and MDA-MB-231 human breast cancer cells, confirming that the cell death induced by bufalin is caspase-independent. Instead, bufalin increased the expression of the necroptosis mediators RIP1 and RIP3. Bufalin-induced cell death was prevented by small molecule inhibitors of RIP1 and poly (ADP-ribose) polymerase-1 (PARP-1) or genetic knockdown of RIP3 by shRNA transfection...
March 13, 2018: Carcinogenesis
Su Hwan Lee, Ju Hye Shin, Joo Han Song, Ah Young Leem, Moo Suk Park, Young Sam Kim, Joon Chang, Kyung Soo Chung
Insulin-like growth factor-1 (IGF-1) levels are known to increase in the bronchoalveolar lavage fluid (BALF) of patients with acute respiratory distress syndrome. Herein, we investigated the role of IGF-1 in lipopolysaccharide (LPS)-induced lung injury. In LPS-treated cells, expressions of receptor-interacting protein 3 (RIP3) and phosphorylated mixed lineage kinase domain-like protein (MLKL) were decreased in IGF-1 receptor small interfering RNA (siRNA)-treated cells compared to control cells. The levels of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-10, tumour necrosis factor-α, and macrophage inflammatory protein 2/C-X-C motif chemokine ligand 2 in the supernatant were significantly reduced in IGF-1 receptor siRNA-treated cells compared to control cells...
March 12, 2018: Biochemical and Biophysical Research Communications
Felix Lauffer, Manja Jargosch, Linda Krause, Natalie Garzorz-Stark, Regina Franz, Sophie Roenneberg, Alexander Böhner, Nikola S Mueller, Fabian J Theis, Carsten B Schmidt-Weber, Tilo Biedermann, Stefanie Eyerich, Kilian Eyerich
Interface dermatitis (ID) is a characteristic histological pattern which occurs in autoimmune and chronic inflammatory skin diseases. It is unknown whether a common mechanism orchestrates this distinct type of skin inflammation. Here we investigated the overlap of two different ID positive skin diseases, lichen planus (LP) and lupus erythematosus (LE). The shared transcriptome signature pointed towards a strong type I immune response and biopsy derived T cells were dominated by IFN-γ and TNF-α positive cells...
March 8, 2018: Journal of Investigative Dermatology
Xingfeng Qiu, Yingying Zhang, Jiahuai Han
No abstract text is available yet for this article.
March 9, 2018: Cell Death and Differentiation
Kang Wang, Lei Hu, Jian-Kang Chen
Recent preclinical and clinical evidence suggests that hyperuricemia (HU) is an independent risk factor for metabolic syndrome, hypertension, cardiovascular disease and chronic kidney disease. Receptor-interacting protein 3 (RIP3) is an important contributor in inducing programmed necrosis, representing a newly identified mechanism of cell death combining features of both apoptosis and necrosis. In our study, RIP3 was strongly expressed in mice with hyperuricemia. RIP3 deficiency attenuated hyperuricemia in mice, evidenced by reduced serum uric acid and creatinine and enhanced urinary uric acid and creatinine, as well as the improved histological alterations in renal sections...
March 5, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Suoyuan Li, Tao Zhang, Weiguo Xu, Jianxun Ding, Fei Yin, Jing Xu, Wei Sun, Hongsheng Wang, Mengxiong Sun, Zhengdong Cai, Yingqi Hua
PURPOSE: Osteosarcoma is the most common primary bone cancer and is notorious for pulmonary metastasis, representing a major threat to pediatric patients. An effective drug targeting osteosarcoma and its lung metastasis is urgently needed. DESIGN: In this study, a sarcoma-targeting peptide-decorated disulfide-crosslinked polypeptide nanogel (STP-NG) was exploited for enhanced intracellular delivery of shikonin (SHK), an extract of a medicinal herb, to inhibit osteosarcoma progression with minimal systemic toxicity...
2018: Theranostics
Yanling Guo, Xiaxia Wu, Qin Wu, Yuanfu Lu, Jingshan Shi, Xiuping Chen
Ulcerative colitis (UC) is a chronic and relapsing inflammatory disorder of the colon and rectum with increasing morbidity in recent years. 15,16-dihydrotanshinone Ӏ (DHT) is a natural product with multiple bioactivities. In this study, we aimed to investigate the protective effect and potential mechanisms of DHT on UC. Dextran sulfate sodium salt (DSS) was administrated in drinking water for 7 days to induce UC in mice. DHT (10 and 25 mg/kg) significantly alleviated DSS-induced body weight loss, disease activity index (DAI) scores, and improved histological alterations of colon tissues...
February 26, 2018: Toxicology and Applied Pharmacology
Zai-Ming Liu, Qian-Xue Chen, Zhi-Biao Chen, Dao-Feng Tian, Ming-Chang Li, Jun-Min Wang, Long Wang, Bao-Hui Liu, Shen-Qi Zhang, Fei Li, Hui Ye, Long Zhou
Traumatic brain injury (TBI) is a leading cause of disability and mortality in young adults worldwide. The pathophysiology is not fully understood. Programmed necrosis (necroptosis) is a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Receptor-interacting protein 3 (RIP3) plays an important role in programmed necrosis. However, the effect of RIP3-related pathway in TBI is little to be known. We attempted to explore the significance of RIP3 in regulating TBI in vivo...
February 19, 2018: Biochemical and Biophysical Research Communications
Simone Fulda
Necroptosis represents a form of programmed cell death that can be engaged by various upstream signals, for example by ligation of death receptors, by viral sensors or by pattern recognition receptors. It depends on several key signaling proteins, including the kinases Receptor-Interacting Protein (RIP)1 and RIP3 and the pseudokinase mixed-lineage kinase domain-like protein (MLKL). Necroptosis has been implicated in a number of physiological and pathophysiological conditions and is disturbed in many human diseases...
February 21, 2018: Cell Cycle
Rui Chen, Jiehua Xu, Yanling She, Ting Jiang, Shanyao Zhou, Huacai Shi, Cheng Li
Necrostatin-1 (Nec-1) is a selective and potent allosteric inhibitor of necroptosis by specifically inhibiting the activity of receptor‑interacting protein (RIP) 1 kinase. The aim of the present study was to determine the effect of Nec‑1 on an anoxia model comprising mouse skeletal C2C12 myotubes. In the present study, a hypoxic mimetic reagent, cobalt chloride (CoCl2), was used to induce hypoxia in C2C12 myotubes. The cytotoxic effects of CoCl2‑induced hypoxia were determined by a Cell Counting kit‑8 assay and flow cytometry...
February 6, 2018: International Journal of Molecular Medicine
Anthony C Tang, Seyed M Rahavi, Shan-Yu Fung, Henry Y Lu, Hong Yang, Chinten J Lim, Gregor S Reid, Stuart E Turvey
Proteasome inhibitors have emerged as an effective therapy for the treatment of haematological malignancies; however, their efficacy can be limited by the development of tumour resistance mechanisms. Novel combination strategies including the addition of TLR adjuvants to increase cell death and augment immune responses may help enhance their effectiveness. Although generally thought to inhibit inflammatory responses and NF-κB activation, we found that under specific conditions proteasome inhibitors can promote inflammatory responses by mediating IL-1β maturation and secretion after TLR stimulation...
February 7, 2018: Cell Death & Disease
Meng-Shian Chen, Sheng-Fan Wang, Chih-Yi Hsu, Pen-Hui Yin, Tien-Shun Yeh, Hsin-Chen Lee, Ling-Ming Tseng
Cancer cells exhibit an abnormal amino acid metabolism and a dependence on specific amino acids, which might provide potential targets for treating cancer patients. In this study, we demonstrated that human triple negative breast cancer (TNBC) cells were highly susceptible to cystine starvation. We found that necrostatin-1 (Nec-1, a RIP1 inhibitor), necrosulfonamide (an MLKL inhibitor), deferoxamine (an ion chelator), ferrostatin-1 (a ferroptosis inhibitor) and RIP1 knockdown can prevent cystine-starvation-induced cell death, suggesting that cystine starvation induces necroptosis and ferroptosis in TNBC cells...
December 29, 2017: Oncotarget
Zhentao Yang, Yan Wang, Yingying Zhang, Xiadi He, Chuan-Qi Zhong, Hengxiao Ni, Xin Chen, Yaoji Liang, Jianfeng Wu, Shimin Zhao, Dawang Zhou, Jiahuai Han
Receptor-interacting protein kinase 3 (RIP3)-regulated production of reactive oxygen species (ROS) positively feeds back on tumour necrosis factor (TNF)-induced necroptosis, a type of programmed necrosis. Glutamine catabolism is known to contribute to RIP3-mediated ROS induction, but the major contributor is unknown. Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135...
February 2018: Nature Cell Biology
Goutham K Ganjam, Nicole Angela Terpolilli, Sebastian Diemert, Ina Eisenbach, Lena Hoffmann, Christina Reuther, Christiane Herden, Joachim Roth, Nikolaus Plesnila, Carsten Culmsee
The tumor-suppressor cylindromatosis (CYLD) is a deubiquitinating enzyme and key regulator of cell proliferation and inflammation. A genome-wide siRNA screen linked CYLD to receptor interacting protein-1 (RIP1) kinase-mediated necroptosis; however, the exact mechanisms of CYLD-mediated cell death remain unknown. Therefore, we investigated the precise role of CYLD in models of neuronal cell death in vitro and evaluated whether CYLD deletion affects brain injury in vivo. In vitro, downregulation of CYLD increased RIP1 ubiquitination, prevented RIP1/RIP3 complex formation, and protected neuronal cells from oxidative death...
January 19, 2018: Cell Death and Differentiation
Zhen Wang, Li-Min Guo, Yong Wang, Hong-Kang Zhou, Shu-Chao Wang, Dan Chen, Ju-Fang Huang, Kun Xiong
Heat shock protein 90α (HSP90α) maintains cell stabilization and regulates cell death, respectively. Recent studies have shown that HSP90α is involved in receptor interacting protein 3 (RIP3)-mediated necroptosis in HT29 cells. It is known that oxygen and glucose deprivation (OGD) can induce necroptosis, which is regulated by RIP3 in neurons. However, it is still unclear whether HSP90α participates in the process of OGD-induced necroptosis in cultured neurons via the regulation of RIP3. Our study found that necroptosis occurs in primary cultured cortical neurons and PC-12 cells following exposure to OGD insult...
November 20, 2017: Journal of Cellular Physiology
Yulin Sun, Linhui Zhai, Shouzhi Ma, Chengpu Zhang, Lina Zhao, Ning Li, Yang Xu, Tao Zhang, Zhimin Guo, Heng Zhang, Ping Xu, Xiaohang Zhao
Receptor interacting protein kinase 3 (RIP3) is a critical regulator of programmed necrotic cell death. Here, we observed that RIP3 was significantly down-regulated in esophageal cancer. And its remaining expression was associated with better response to chemotherapy and prolonged survival. Notably, re-expression of kinase-dead RIP3 also restored cisplatin sensitivity, suggesting that some roles of RIP3 beyond necroptosis may be involved in cisplatin-based chemosensitivity. To investigate the mechanisms, a large-scale quantitative proteomics study was performed after cisplatin treatment in RIP3-knockdown cells...
January 10, 2018: Cancer Letters
Shun-Hang Wen, Luo-Na Lin, Hu-Jun Wu, Lu Yu, Li Lin, Li-Li Zhu, Hai-Yan Li, Hai-Lin Zhang, Chang-Chong Li
AIM: To explore the role of tumor necrosis factor-alpha (TNF-α) on Staphylococcus aureus-induced necroptosis in alveolar epithelial cells. MAIN METHODS: The A549 alveolar epithelial cell line was pretreated with small interfering RNA (siRNA) against receptor interacting protein-3 (RIP3) and then stimulated by S. aureus, where some cells were pretreated with TNF-α or TNF-α with anti-TNF-α antibody simultaneously. A549 cell death was assessed using lactate dehydrogenase (LDH) leakage and flow cytometry analyses...
January 9, 2018: Life Sciences
Fari Ryan, Fariba Khodagholi, Leila Dargahi, Dariush Minai-Tehrani, Abolhassan Ahmadiani
Necroptosis, a novel type of programmed cell death, has been recently implicated as a possible mechanism for cerebral ischemia-reperfusion (I/R) injury. We herein studied time-dependent changes of necroptosis markers along with apoptosis- and autophagy-associated proteins in rat hippocampus at 1, 3, 6, 12, 24, and 48 h after global cerebral I/R injury. Furthermore, to determine the cross talk between autophagy and necroptosis, we examined the effects of pretreatment with bafilomycin-A1 (Baf-A1), as a late-stage autophagy inhibitor, on necroptosis...
January 8, 2018: Neurotoxicity Research
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