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Biochemical Pharmacology

Ruta Dekeryte, Claire Hull, Kaja Plucińska, Shakil Khan, Sarah Kamli-Salino, Nimesh Mody, Nicola Morrice, Chris McLaughlin, Victor Gault, Bettina Platt, Mirela Delibegovic
We recently reported that brain-specific human β-secretase 1 (BACE1) knock-in (PLB4), a mouse model of 'sporadic' Alzheimer's disease (AD), also develops a severe diabetic phenotype characterised by impaired glucose homeostasis, decreased insulin sensitivity and a fatty liver phenotype. Hence, we here aimed to assess if targeted anti-diabetic therapies (Liraglutide and Fenretinide) would attenuate the diabetic and behavioural phenotype of these mice. PLB4 and wild-type (WT) controls were administered Liraglutide or Fenretinide for ten consecutive weeks alongside vehicle-treated mice...
May 16, 2019: Biochemical Pharmacology
Giovanna Grimaldi, Giuliana Catara, Luca Palazzo, Annunziata Corteggio, Carmen Valente, Daniela Corda
Among the post-translational modifications, ADP-ribosylation has been for long time the least integrated in the scheme of the structural protein modifications affecting physiological functions. In spite of the original findings on bacterial-dependent ADP-ribosylation catalysed by toxins such as cholera and pertussis toxin, only with the discovery of the poly-ADP-ribosyl polymerase (PARP) family the field has finally expanded and the role of ADP-ribosylation has been recognised in both physiological and pathological processes, including cancer, infectious and neurodegenerative diseases...
May 15, 2019: Biochemical Pharmacology
Yasuhiro Uno, Norie Murayama, Hiroshi Yamazaki
Cytosolic sulfotransferases (SULTs), drug-metabolizing enzymes essential for the metabolism of endogenous biochemicals and foreign compounds, have been characterized in humans, but remain to be investigated in cynomolgus macaques, important species in drug metabolism studies. In this study, based on the genome data, cynomolgus SULT1A1, SULT1A3, SULT1B1, SULT1C2v1, SULT1C2v2, SULT1C4, SULT1E1, and SULT2A1 cDNAs were isolated and characterized. Among these, cynomolgus SULT1C2v2 was highly homologous to human SULT1C2P1 (pseudogene)...
May 14, 2019: Biochemical Pharmacology
Tu-Shuai Li, Li Chen, Shan-Chun Wang, Yan-Zi Yang, Hong-Jiang Xu, Hong-Mei Gu, Xiao-Juan Zhao, Ping Dong, Ying Pan, Zhan-Qiang Shang, Xi-Quan Zhang, Ling-Dong Kong
High fructose intake is a risk of glomerular podocyte dysfunction. Podocyte apoptosis has emerged as a major cause of podocyte loss, exacerbating proteinuria. Magnesium isoglycyrrhizinate (MgIG) is usually used as a hepatoprotective agent in clinic. Liver and kidney injury often occurs in human diseases. Recent report shows that MgIG improves kidney function. In this study, we found that MgIG significantly alleviated kidney dysfunction, proteinuria and podocyte injury in fructose-fed rats. It also restored fructose-induced podocyte apoptosis in rat glomeruli and cultured differentiated podocytes...
May 11, 2019: Biochemical Pharmacology
Simon Lind, Martina Sundqvist, Rikard Holmdahl, Claes Dahlgren, Huamei Forsman, Peter Olofsson
Despite the steadily increased numbers of formyl peptide receptor (FPR) ligands identified over the years, few have been characterized in studies using animal disease models and even less have entered clinical trials in human subjects. A small-molecule compound, Act-389949, was however recently tested in a phase I clinical trial and found to be safe and well tolerated in healthy human subjects. The desired anti-inflammatory property of Act-389949 was proposed to be mediated through FPR2, one of the FPRs expressed in neutrophils, but no basic characterization was included in the study...
May 11, 2019: Biochemical Pharmacology
Jianhua Yu, Lawrence Shi, Xinggui Shen, Yunfeng Zhao
Uncoupling protein 2 (UCP2) is upregulated in several human cancers which contributes to tumorigenesis. However, whether UCP2 expression is amplified in cholangiocarcinoma and whether UCP2 promotes cholangiocarcinoma progression are not known. Our results found that in human cholangiocarcinoma tissues, UCP2 was highly expressed in tumors and its levels were negatively associated with prognosis. Importantly, lymph node invasion of cholangiocarcinoma was associated with higher UCP2 expression. In cholangiocarcinoma cells, cell proliferation and migration were suppressed when UCP2 expression was inhibited via gene knockdown...
May 11, 2019: Biochemical Pharmacology
Jiecheng Ye, Jiwei Ma, Chan Liu, Jianxian Huang, Lihui Wang, Xueyun Zhong
Esophageal squamous cell carcinoma (ESCC) is one of the most common and aggressive cancers worldwide, especially in China, with poor prognosis due to the lack of effective therapeutic strategies. Here, the anticancer effect and pharmacological mechanism of a newly synthesized Fe(II) phenanthroline complex was studied in ESCC. Our data showed that transferrin receptor 1 (TFR1) was specifically overexpressed in ESCC tissues compared to its expression in normal esophageal tissues, a finding further supported by public datasets...
May 9, 2019: Biochemical Pharmacology
Nele Van Der Steen, Alessandro Leonetti, Kaylee Keller, Henk Dekker, Niccola Funel, Filip Lardon, Rob Ruijtenbeek, Marcello Tiseo, Christian Rolfo, Patrick Pauwels, Godefridus J Peters, Elisa Giovannetti
INTRODUCTION: Lung squamous cell carcinomas (SCC) typically harbor a strong activation of epidermal growth factor receptor (EGFR) pathway. Since one of the most common resistance mechanisms against EGFR inhibition relies on the activation of cMET parallel signaling, we investigated the efficacy of a dual blockade with erlotinib and crizotinib in EGFR and cMET wild-type lung SCC cell lines. METHODS: Drug sensitivity assays were performed on LUDLU, SKMES-1, H1703, Calu1 and H520 cells...
May 9, 2019: Biochemical Pharmacology
Zhuo-Xun Wu, Qiu-Xu Teng, Chao-Yun Cai, Jing-Quan Wang, Zi-Ning Lei, Yuqi Yang, Ying-Fang Fan, Jian-Ye Zhang, Jun Li, Zhe-Sheng Chen
Overexpression of ABCB1 transporters plays a crucial role in mediating multidrug resistance (MDR). Therefore, it is important to inhibit ABCB1 activity in order to maintain an effective intracellular level of chemotherapeutic drugs. Tepotinib is a MET tyrosine kinase inhibitor with potential anticancer effect and it is currently in clinical trials. In this study, we investigated whether tepotinib could antagonize ABC transporters-mediated MDR. Our results suggest that tepotinib significantly reversed ABCB1-mediated MDR but not ABCG2- or ABCC1-mediated MDR...
May 9, 2019: Biochemical Pharmacology
Kang-Yo Lee, Wonseok Lee, Seung-Hwan Jung, Jungmin Park, Hyungtai Sim, You-Jin Choi, Young-Jun Park, Yeonseok Chung, Byung-Hoon Lee
Acetaminophen (APAP)-induced liver injury (AILI) is initiated by the generation of a reactive metabolite and ultimately leads to hepatocyte necrosis. Necrotic cells secrete damage-associated molecular patterns that activate hepatic nonparenchymal cells and induce an inflammatory response. Fetuin-A is a hepatokine with reported involvement in low-grade inflammation in many diseases, due to acting as an endogenous ligand for TLR4. However, little is known about the role of fetuin-A in AILI. In this study, we showed that fetuin-A is involved in the aggravation of hepatotoxicity during the initial phase of AILI progression...
May 8, 2019: Biochemical Pharmacology
Christina A Vivelo, Vinay Ayyappan, Anthony K L Leung
ADP-ribosylation-the addition of one or multiple ADP-ribose units onto proteins-is a therapeutically important post-translational modification implicated in cancer, neurodegeneration, and infectious diseases. The protein modification regulates a broad range of biological processes, including DNA repair, transcription, RNA metabolism, and the structural integrity of nonmembranous structures. The polymeric form of ADP-ribose, poly(ADP-ribose), was recently identified as a signal for triggering protein degradation through the ubiquitin-proteasome system...
May 8, 2019: Biochemical Pharmacology
Alvin Z Lu, Ryan Abo, Yue Ren, Bin Gui, Jan-Rung Mo, Danielle Blackwell, Tim Wigle, Heike Keilhack, Mario Niepel
Poly-ADP-ribose polymerases (PARPs) are a family of enzymes responsible for transferring individual or chains of ADP-ribose subunits to substrate targets as a type of post-translational modification. PARPs regulate a wide variety of important cellular processes, ranging from DNA damage repair to antiviral response. However, most research to date has focused primarily on the polyPARPs, which catalyze the formation of ADP-ribose polymer chains, while the monoPARPs, which transfer individual ADP-ribose monomers, have not been studied as thoroughly...
May 7, 2019: Biochemical Pharmacology
Shulin Tang, Shuang Chen, Boyan Huang, Jun Jiang, Jikai Wen, Yiqun Deng
The type B trichothecene mycotoxin deoxynivalenol (DON), colloquially known as "vomitoxin", is the most commonly detected trichothecene in cereal-based foods, exerting acute and chronic toxic effects on animals and causing serious safety-related concerns. At the cellular and molecular levels, DON can inhibit macromolecule synthesis by binding to ribosomes and may disrupt cell proliferation, differentiation and apoptosis. However, the molecular mechanisms underlying the cytotoxicity of DON remain to be determined...
May 7, 2019: Biochemical Pharmacology
Anudeep Kaur, Lovedeep Singh, Nirmal Singh, Manpreet S Bhatti, Rajbir Bhatti
Fibromyalgia (FM) is a chronic pain syndrome involving complex interplay of biogenic amines and NMDA receptor mediated hypersensitization of nociceptive pathways. Clinical management of FM is poorly addressed with only a few available therapeutic options. Coumarins are active phenolic molecules of natural origin found to have broad pharmacological activities. Current investigation explores the role of naturally occurring coumarin, imperatorin in mouse model of fibromyalgia. Administration of reserpine (0.5 mg/kg, s...
May 7, 2019: Biochemical Pharmacology
Bin Zhang, Mei Meng, Shufen Xiang, Zhifei Cao, Xingdong Xu, Zhe Zhao, Tong Zhang, Bowen Chen, Ping Yang, Ye Li, Quansheng Zhou
The mitogen-activated protein kinase (MAPK, 1K) family members ERK, JNK, and p38 play a divergent role in either promoting tumorigenesis or tumor-suppression. Activation of ERK and JNK promotes tumorigenesis; whereas, escalation of p38 inhibits carcinogenesis. As these three MAPK members are controlled by the common up-stream MAPK signaling proteins which consist of MAPK kinases (2K) and MAPK kinase kinases (3K), how to selectively actuate tumor-suppressive p38, not concurrently stimulate tumorigenic ERK and JNK, in cancer cells is a challenge for cancer researchers, and a new opportunity for novel anti-cancer drug discovery...
May 7, 2019: Biochemical Pharmacology
Maofeng Wang, Chia-Chia Chao, Po-Chun Chen, Po-I Liu, Yi-Chen Yang, Chen-Ming Su, Wei-Chien Huang, Chih-Hsin Tang
Lung cancers have a predilection for metastasizing to bone. The matricellular glycoprotein thrombospondin (TSP)-2 regulates multiple biological functions and has a critical role in tumor development and metastasis, although its effects are uncertain in lung cancer bone metastasis. This study demonstrates that TSP-2 expression is highly correlated with lung cancer tumor stage and that the TSP-2 neutralizing antibody reduces osteoclast formation in conditioned medium obtained from lung cancer cells. We also found that TSP-2 promotes osteoclastogenesis through the RANKL-dependent pathway and that TSP-2-mediated osteoclastogenesis involves the transactivation of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) via the inhibition of miR-486-3p expression...
May 7, 2019: Biochemical Pharmacology
Boyan Huang, Peiqiang Mu, Xiaoxuan Chen, Shulin Tang, Wenchu Ye, Wenya Zhu, Yiqun Deng
Aflatoxin B1 (AFB1 ), a member of the aflatoxin family, is a common contaminant in foods and feeds, and AFB1 exposure is associated with various clinical conditions. Thus far, research on the toxicity of AFB1 has mainly focused on its induction of liver cancer, but little research has been reported on renal toxicity, especially with regards to the underlying molecular mechanisms. In this study, we found that AFB1 treatment significantly induced kidney damage and reduced kidney weight. The human kidney cell line HEK293T was used to further study the molecular mechanism of the toxicity of AFB1 to kidney cells...
May 7, 2019: Biochemical Pharmacology
Yan Chen, Zong-Yue Chen, Lin Chen, Jing-Yu Zhang, Ling-Yun Fu, Ling Tao, Yue Zhang, Xiao-Xia Hu, Xiang-Chun Shen
Triple-negative breast cancer (TNBC) is characterized by elevated metastasis, low survival, and poor response to therapy. Although many specific and effective agents for treating TNBC have been investigated, promising therapeutic options remain elusive. Here, we screened the inhibitory activities of three main components of Lithospermum erythrorhizon Sieb. et Zucc (shikonin, acetylshikonin, and β,β-dimethylacrylshikonin) on TNBC cells. The results revealed that shikonin potently decreased the viabilities of TNBC MDA-MB-231 and 4T1 cells but showed less cytotoxicity to normal mammary epithelial MCF-12A cells...
May 6, 2019: Biochemical Pharmacology
Feng Li, Xiaowei Song, Guifeng Su, Yiliang Wang, Zhaoyang Wang, Shurong Qing, Jiaoyan Jia, Yuan Wang, Lianzhou Huang, Kai Zheng, Yifei Wang
Inflammatory events are tightly associated with the death caused by Herpes simplex virus 1 (HSV-1) infection of the brain. Heat shock protein 90 (Hsp90) is a molecular chaperone that is stimulated in response to many stressful conditions (e.g., inflammation and hypoxia) and Hsp90 inhibitors are suggested to be potent inhibitors of the inflammatory response. The aim of this study was to investigate the effect of Hsp90 inhibitor AT-533 on HSV-1-induced inflammation. AT-533 at a non-antiviral concentration was found to show prominent inhibitory effect on the production of cytokines induced by HSV-1 infection, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and interleukin 1β (IL-1β)...
May 6, 2019: Biochemical Pharmacology
M Ontiveros, D Rinaldi, M Marder, M V Espelt, I Mangialavori, M Vigil, J P Rossi, M Ferreira-Gomes
Research on flavonoids from plant sources has recently sparked increasing interest because of their beneficial health properties. Different studies have shown that flavonoids change the intracellular Ca2+ homeostasis linked to alterations in the function of mitochondria, Ca2+ channels and Ca2+ pumps. These findings hint at plasma membrane Ca2+ -ATPase (PMCA) involvement, as it transports Ca2+ actively to the extracellular medium coupled to ATP hydrolysis, thus maintaining ion cellular homeostasis. The present study aims to investigate the effect of several natural flavonoids on PMCA both in isolated protein systems and in living cells, and to establish the relationship between flavonoid structure and inhibitory activity on PMCA...
May 6, 2019: Biochemical Pharmacology
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