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John S Ikonomidis, Elizabeth K Nadeau, Adam W Akerman, Robert E Stroud, Rupak Mukherjee, Jeffrey A Jones
OBJECTIVE: Membrane type-1 matrix metalloproteinase (MT1-MMP) is elevated during thoracic aortic aneurysm (TAA) development in mouse models, and plays an important role in the activation of matrix metalloproteinase (MMP)-2 and the release of matrix- bound transforming growth factor-β. In this study, we tested the hypothesis that MT1-MMP is subject to protein kinase C (PKC)-mediated regulation, which alters intracellular trafficking and activity with TAAs. METHODS: Levels of MMP-2, native and phosphorylated MT1-MMP, and PKC-δ were measured in aortic tissue from patients with small TAAs (<5 cm; n = 8) and large TAAs (>6...
November 14, 2016: Journal of Thoracic and Cardiovascular Surgery
Morena Mischitelli, Mohamed Jemaà, Mustafa Almasry, Caterina Faggio, Florian Lang
BACKGROUND/AIMS: The phytochemical polyphenol rottlerin is a potent activator of diverse Ca2+ -sensitive K+ channels. Those channels play a decisive role in the execution of eryptosis, the suicidal death of erythrocytes, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling involved in the stimulation of eryptosis includes increase of cytosolic Ca2+ activity ([Ca2+]i) and ceramide. The present study explored, whether rottlerin induces eryptosis and, if so, to test for the involvement of Ca2+ entry and ceramide...
November 25, 2016: Cellular Physiology and Biochemistry
Jingna Su, Lixia Wang, Xuyuan Yin, Zhe Zhao, Yingying Hou, Xiantao Ye, Xiuxia Zhou, Zhiwei Wang
Rottlerin, a natural product isolated from Mallotus philippinensis, has been characterized as an effective chemoprevention agent in inhibiting tumor cell growth. Although multiple studies have revealed the role of rottlerin in tumorigenesis, the molecular mechanism of rottlerin-mediated anti-tumor activity has not been fully elucidated. It has been reported that Skp2 (S-phase kinase associated protein 2) plays an oncogenic role in human malignancies, indicating that inactivation of Skp2 could be a promising approach for the treatment of cancers...
2016: American Journal of Cancer Research
Dongshan Zhang, Jian Pan, Xudong Xiang, Yu Liu, Guie Dong, Man J Livingston, Jian-Kang Chen, Xiao-Ming Yin, Zheng Dong
Nephrotoxicity is a major adverse effect in cisplatin chemotherapy, and renoprotective approaches are unavailable. Recent work unveiled a critical role of protein kinase Cδ (PKCδ) in cisplatin nephrotoxicity and further demonstrated that inhibition of PKCδ not only protects kidneys but enhances the chemotherapeutic effect of cisplatin in tumors; however, the underlying mechanisms remain elusive. Here, we show that cisplatin induced rapid activation of autophagy in cultured kidney tubular cells and in the kidneys of injected mice...
October 31, 2016: Journal of the American Society of Nephrology: JASN
Binh Thanh Nguyen, Min Park, Jae-Chul Pyun, Young Sook Yoo, Min-Jung Kang
An assay for protein kinase C delta (PKCδ) activity based on the quantification of a synthetic substrate using capillary electrophoresis with laser-induced fluorescence detection was developed. The peptides labeled with fluorescein isothiocyanate F-ERK (where ERK is extracellular signal-regulated kinase) and the phosphorylated form, P-F-ERK, were utilized for the method development and validation. The migration time of F-ERK and P-F-ERK were 6.3 ± 0.1 and 8.7 ± 0.2 min, respectively. LOD and LOQ values of F-ERK were 2 and 6 ng/mL and those of P-F-ERK were 4 and 12 ng/mL...
October 26, 2016: Electrophoresis
Michael Saul, Petra Majdak, Samuel Perez, Matthew Reilly, Theodore Garland, Justin S Rhodes
Though exercise is critical for health, many lack the motivation to exercise, and it is unclear how motivation might be increased. To uncover the molecular underpinnings of increased motivation for exercise, we analyzed the transcriptome of the striatum in four mouse lines selectively bred for high voluntary wheel running and four non-selected control lines. The striatum was dissected and RNA was extracted and sequenced from four individuals of each line. We found multiple genes and gene systems with strong relationships to both selection and running history over the previous 6 days...
October 17, 2016: Genes, Brain, and Behavior
Han Liu, Chunlei Yu, Tianjiao Xu, Xiaojie Zhang, Miaoxian Dong
There are several factors, like oxidative stress and neurons loss, involving neurodegenerative diseases such as Parkinson's disease (PD). The combination of antioxidant and anti-apoptotic agent is becoming a promising approach to fight against PD. This study evaluates the hypothesis that paeoniflorin (PF) and β-ecdysterone (β-Ecd) synergize to protect PC12 cells against toxicity induced by PD-related neurotoxin rotenone. The combination of PF and β-Ecd, hereafter referred to as the PF/β-Ecd, at suboptimal concentrations increased the viability of rotenone-exposed PC12 cells in a synergistic manner...
September 29, 2016: Apoptosis: An International Journal on Programmed Cell Death
Lei Shi, Xiang-Qin Weng, Yan Sheng, Jing Wu, Ming Ding, Xun Cai
Although all-trans retinoic acid (ATRA) is regarded as a prominent example of differentiation therapy, it is not effective for the treatment of other subtypes of acute myeloid leukemia (AML) beyond acute promyelocytic leukemia (APL). Therefore, new strategies need to be explored to extend the efficacy of ATRA-based therapy to non-APL AML patients. In the present study, staurosporine, a protein kinase C (PKC) pan-inhibitor, exhibited synergism with ATRA to promote granulocytic differentiation in poorly ATRA-sensitive U937 cells but not in ATRA unresponsive K562 and Kasumi cells...
September 23, 2016: Oncology Reports
Lixia Wang, Yingying Hou, Xuyuan Yin, Jingna Su, Zhe Zhao, Xiantao Ye, Xiuxia Zhou, Li Zhou, Zhiwei Wang
Rottlerin, isolated from a medicinal plant Mallotus phillippinensis, has been demonstrated to inhibit cellular growth and induce cytoxicity in glioblastoma cell lines through inhibition of calmodulin-dependent protein kinase III. Emerging evidence suggests that rottlerin exerts its antitumor activity as a protein kinase C inhibitor. Although further studies revealed that rottlerin regulated multiple signaling pathways to suppress tumor cell growth, the exact molecular insight on rottlerin-mediated tumor inhibition is not fully elucidated...
September 12, 2016: Oncotarget
Eun-Joo Shin, Duy-Khanh Dang, Hai-Quyen Tran, Yunsung Nam, Ji Hoon Jeong, Young Hun Lee, Kyung Tae Park, Yong Sup Lee, Choon-Gon Jang, Jau-Shyong Hong, Toshitaka Nabeshima, Hyoung-Chun Kim
Para-methoxymethamphetamine (PMMA) is a para-ring-substituted amphetamine derivative sold worldwide as an illegal psychotropic drug. Although PMMA use has been reported to lead to severe intoxication and even death, little is known about the mechanism(s) by which PMMA exerts its neurotoxic effects. Here we found that PMMA treatment resulted in phosphorylation of protein kinase Cδ (PKCδ) and subsequent mitochondrial translocation of cleaved PKCδ. PMMA-induced oxidative stress was more pronounced in mitochondria than in the cytosol...
September 10, 2016: Neurochemistry International
Peng He, Nan Shen, Gongming Gao, Xuefeng Jiang, Huiqing Sun, Dong Zhou, Nanwei Xu, Luming Nong, Kewei Ren
BACKGROUND/AIMS: The present study aimed to analyze the mechanisms by which periodic mechanical stress is translated into biochemical signals, and to verify the important role of signaling molecules including phosphatidylinositol-3-kinase (PI3K)-Akt, protein kinase C (PKC), and epidermal growth factor receptor (EGFR) in chondrocyte proliferation. The effects of periodic mechanical stress on the mitogenesis of chondrocytes have been studied extensively in recent years. However, the mechanisms underlying the ability of chondrocytes to sense and respond to periodic mechanical stress need further investigation...
2016: Cellular Physiology and Biochemistry
Ling Shao, Jiuru Zhao, Haiqiang Zhang
Spring viraemia of carp virus (SVCV) is the causative pathogen of the outbreaks of an acute haemorrhagic and contagious viraemia responsible for the significant mortality in several cyprinid species. However, the endocytic pathway(s) and their regulatory molecules have not been characterized for SVCV. Here, using a combination of specific pharmacological inhibitors, transmission electron microscopy, immunofluorescence microscopy and real-time quantitative PCR, we found that SVCV entered grass carp ovary cells via clathrin-mediated endocytosis and macropinocytosis in a low-pH-dependent manner...
November 2016: Journal of General Virology
Xuyuan Yin, Yu Zhang, Jingna Su, Yingying Hou, Lixia Wang, Xiantao Ye, Zhe Zhao, Xiuxia Zhou, Yali Li, Zhiwei Wang
Studies have investigated the tumor suppressive role of rottlerin in carcinogenesis. However, the molecular mechanisms of rottlerin-induced anti-tumor activity are largely unclear. Skp2 (S-phase kinase associated protein 2) has been validated to play an oncogenic role in a variety of human malignancies. Therefore, inactivation of Skp2 could be helpful for the treatment of human cancers. In the current study, we explore whether rottlerin could inhibit Skp2 expression, leading to inhibition of cell growth, migration and invasion in breast cancer cells...
August 25, 2016: Oncotarget
Sapna Pandey, Aditi Chatterjee, Swati Jaiswal, Sanjay Kumar, Ravishankar Ramachandran, Kishore K Srivastava
The molecular bases of disease provide exceptional prospect to translate research findings into new drugs. Nevertheless, to develop new and novel chemical entities takes huge amount of time and efforts, mainly due to the stringent processes. Therefore, drug repurposing is one of such strategies which is being used in recent times to identify new pharmacophores. The essential first step in discovery of the specific inhibitor with low toxicity is the identification and elucidation of pathways exclusive to target pathogen...
September 16, 2016: Biochemical and Biophysical Research Communications
Yu B Lishmanov, A S Gorbunov, L N Maslov
Experiments on isolated perfused rat heart modeled 45-min global ischemia followed by 30-min reperfusion. Ischemic postconditioning was modeled by 3 cycles of reperfusion (30 sec) and ischemia (30 sec). Cardiomyocyte necrosis was assessed by the level of creatine phosphokinase in the perfusate. Postconditioning reduced the release of creatine phosphokinase from the heart by 30%. The cardioprotective effect of ischemic postconditioning was eliminated after inhibition of protein kinase C with cheleritrin or after blockade of δ-isoform of protein kinase C with rottlerin...
July 2016: Bulletin of Experimental Biology and Medicine
Na Rae Lee, Beom Seok Park, Seong Yeol Kim, Ayoung Gu, Da Hye Kim, Ji-Sook Lee, In Sik Kim
Dysregulation of neutrophil apoptosis causes pathogenesis and aggravation of allergy. S100A9 exists as one of the proteins in the neutrophils, triggering inflammatory responses by activating the immune cells. In this study, we investigated whether S100A9 affects constitutive neutrophil apoptosis by activating the monocytes in normal and allergic subjects. Supernatant from human monocytic THP-1 cells after treatment with S100A9 suppressed normal neutrophil apoptosis by inhibiting the activations of caspase 9 and caspase 3...
October 2016: Cytokine
Nirlep Chhiber, Tanzeer Kaur, Surinder Singla
BACKGROUND: Oxalate and/or calcium oxalate, is known to induce free radical production, subsequently leading to renal epithelial injury. Oxidative stress and mitochondrial dysfunction have emerged as new targets for managing oxalate induced renal injury. HYPOTHESIS: Plant products and antioxidants have gained tremendous attention in the prevention of lithiatic disease. Rottlerin, a polyphenolic compound from the fruits of Mallotus phillipensis (Lam.) Müll.Arg., has shown free radical scavenging, antioxidant activity and has been reported to interfere in signaling pathways leading to inflammation and apoptosis...
September 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Lishi Xie, Eddie T Chiang, Xiaomin Wu, Gabriel T Kelly, Prasad Kanteti, Patrick A Singleton, Sara M Camp, Tingting Zhou, Steven M Dudek, Viswanathan Natarajan, Ting Wang, Steven M Black, Joe G N Garcia, Jeffrey R Jacobson
Protein Kinase C (PKC) plays a significant role in thrombin-induced loss of endothelial cell (EC) barrier integrity; however, the existence of more than 10 isozymes of PKC and tissue-specific isoform expression has limited our understanding of this important second messenger in vascular homeostasis. In this study, we show that PKCδ isoform promotes thrombin-induced loss of human pulmonary artery EC barrier integrity, findings substantiated by PKCδ inhibitory studies (rottlerin), dominant negative PKCδ construct and PKCδ silencing (siRNA)...
2016: PloS One
Blessing O M Oyedemi, Vaibhav Shinde, Kamlesh Shinde, Dionysia Kakalou, Paul D Stapleton, Simon Gibbons
Antimicrobial resistance severely limits the therapeutic options for many clinically important bacteria. In Gram-negative bacteria, multidrug resistance is commonly facilitated by plasmids that have the ability to accumulate and transfer refractory genes amongst bacterial populations. The aim of this study was to isolate and identify bioactive compounds from the medicinal plant Mallotus philippensis (Lam.) Mull. Arg. with both direct antibacterial properties and the capacity to inhibit plasmid conjugal transfer...
June 2016: Journal of Global Antimicrobial Resistance
Tatiana Y Prudnikova, Jonathan Chernoff
The p21-activated kinases (PAKs) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt, and Wnt/β-catenin cascades. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including breast, ovary, prostate, and brain cancer. PAK1 genomic amplification at 11q13 is the most common mechanism of Pak1 hyperactivation, though Pak1 mRNA and/or protein may be overexpressed in the absence of gene amplification...
July 18, 2016: Small GTPases
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