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Biochemical Pharmacology
Pergamon
Biochemical Pharmacology

Pergamon

0006-2952

Biochemical Pharmacology/Journal Biochemical PharmacologySCIISTP
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    Life-long passion for antiviral research and drug development: 80th birthday of Prof. Dr. Erik De Clercq

    Li, GuangdiXu, MingYue, TingtingGu, Weijie...
    16页
    查看更多>>摘要：Since the 1950s, great efforts have been made to develop antiviral agents against many infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV). Among the list of nearly 106 antiviral agents approved in the past five decades, Prof. Erik De Clercq has contributed to the development of 7 antiviral drugs: tenofovir disoproxil fumarate (Viread?) for HIV and HBV treatment, tenofovir alafenamide (Vemlidy?) for HIV and HBV treatment, brivudine (Zostex?) for HSV-1 and VZV treatment, valacyclovir (Valtrex?) for HSV and VZV treatment, adefovir dipivoxil (Hepsera?) for HBV treatment, stavudine (Zerit?) for HIV treatment, and cidofovir (Vistide?) for treating HCMV retinitis in AIDS patients. In addition to the above antiviral drugs, his contributions include two anti-cancer drugs: rabacfosadine (Tanovea?-CA1) for canine lymphoma and plerixafor (Mozobil?) for multiple myeloma and non-Hodgkin?s lymphoma. These achievements are driven by his life-long passions for antiviral research and successful collaborations worldwide. To honor the 80th birthday of Prof. Erik De Clercq, this study highlights his scientific achievements and the importance of life-long passions and collaborations in the success of antiviral research and drug development.
      原文链接:
    • NSTL
    • Elsevier

    Berberine induces anti-atopic dermatitis effects through the downregulation of cutaneous EIF3F and MALT1 in NC/Nga mice with atopy-like dermatitis

    Andoh, TsugunobuYoshihisa, YokoRehman, Mati UrTabuchi, Yoshiaki...
    11页
    查看更多>>摘要：Atopic dermatitis (AD) is a chronic inflammatory skin disease with severe pruritus. Berberine, a naturally occurring isoquinoline alkaloid, has anti-inflammatory effects. This study investigated the effects and molecular mechanisms of berberine on AD-like symptoms in mice. In this study, NC/Nga mice with atopy-like dermatitis (dermatitis mice), fibroblast and mast cells were used. In dermatitis mice, intermittent oral administrations of berberine 3 times a week for 12 days inhibited skin symptom, itching, cutaneous infiltration of eosinophils and mast cells, and the expression of cutaneous eotaxin, macrophage migration inhibitory factor (MIF) and IL-4. Berberine also attenuated IL-4/MIF-induced eotaxin in fibroblasts and allergen-induced MIF and IL-4 in mast cells. In mast cells, the GeneChip? microarray showed that antigen increased the expression of EIF3F and MALT1, inhibited by berberine. The siRNAs for them inhibited the expression of MIF and IL-4 in antigenstimulated mast cells. These results suggest that berberine improves AD-like symptoms through the inhibition of the eotaxin and pro-inflammatory cytokine expression and the related inflammatory cell recruitment. It is also suggested that the downregulation of EIF3F and MALT1 by berberine is involved in suppressing the cytokine expression. Taken together, berberine or berberine-containing crude drugs are expected to contribute to the improvement of AD symptoms.
      原文链接:
    • NSTL
    • Elsevier

    Improvement of the skeletal phenotype in a mouse model of diastrophic dysplasia after postnatal treatment with N-acetylcysteine

    Paganini, ChiaraTota, Chiara GramegnaMonti, LucaMonti, Ilaria...
    11页
    查看更多>>摘要：Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by mutations in the SLC26A2 gene encoding for a sulfate/chloride transporter. When SLC26A2 is impaired intracellular level of sulfate is reduced leading to the synthesis of undersulfated proteoglycans. In normal chondrocytes, the main source of intracellular sulfate is the extracellular uptake through SLC26A2, but a small amount comes from the catabolism of sulfur-containing amino acids and other thiols. Here N-acetylcysteine (NAC), an extensively used drug, is proposed as alternative source of intracellular sulfate in an animal model of DTD (dtd mouse). Mutant and wild type mice were treated twice a day with hypodermic injections of 250 mg NAC/kg body weight for one week after birth. At the end of the treatment, an improvement trend in cartilage proteoglycan sulfation and in the skeletal phenotype of treated dtd mice were observed. Thus, a longer treatment lasted three weeks starting from birth was performed. Treated mutant mice showed a significant increase of cartilage proteoglycan sulfation and a relevant improvement of the skeletal phenotype based on measurements of several bony elements and bone quality by DEXA and micro CT. Moreover, the amelioration of the overall growth plate morphology in treated dtd mice suggested a partial rescue of the endochondral ossification process. Overall, the results prove that NAC is an effective source of intracellular sulfate for dtd mice in the postnatal period. This finding paves the way for a potential pharmacological treatment of DTD patients taking advantage from a drug repositioning strategy.
      原文链接:
    • NSTL
    • Elsevier

    Inactivation of Wnt/beta-catenin/renin angiotensin axis by tumor necrosis factor-alpha inhibitor, infliximab, ameliorates CKD induced in rats

    Abdelghafour, Asmaa M.Hammad, Sally K.Younis, Nahla N.Mohamed, Hoda E....
    9页
    查看更多>>摘要：Infliximab (IFX), a chimeric monoclonal antibody against tumor necrosis factor-? (TNF-?), is widely used to treat autoimmune diseases and chronic diseases associated with inflammation. TNF-? was reported to inhibit klotho, reactivate ?-catenin and cause tubular cell injury in vitro. Whether the inhibition of TNF-? can regulate Wnt/ ?-catenin pathway via klotho in CKD in vivo is not studied yet. We aimed to investigate the impact of IFX on Wnt/ ?-catenin pathway in doxorubicin (DOX)-induced nephropathy. Doxorubicin (3.5 mg/kg; i.p., twice weekly for 3 weeks) increased serum cystatin-C, urine albumin/creatinine ratio (UACR), but depleted renal podocin. It markedly increased renal contents of TNF-?, interleukin-6 (IL-6), interleukin-1? (IL1?). DOX decreased the renal expression of klotho which in turn increased Wnt1, active ?-catenin/total ?-catenin ratio in renal tissue. Significant increase in renal gene expression of RENIN, ACE, and AT1 was observed. Moreover, renal fibronectin and collagen deposition increased in renal tissue. Treatment with either IFX (5 mg/kg, once; i.p.), losartan (LOS, 10 mg/kg/day, orally) or their combination significantly improved renal function, inhibited inflammatory cytokines and fibrosis. Renal TNF-? was negatively correlated with renal klotho. On the hand, it was positively correlated with renal Wnt1 and active ?-catenin/total ?-catenin ratio. The combined IFX and LOS treatment was the most effective in improving all studied parameters. In conclusion, this study proved, for the first time, the inhibitory effect of IFX on renal Wnt/?-catenin signaling in DOX-induced nephropathy in vivo by up-regulating renal klotho. Therefore, these results suggest a new role for IFX in chronic kidney disease via targeting renal Wnt/?-catenin/ renin angiotensin axis.
      原文链接:
    • NSTL
    • Elsevier

    Discovery of small molecule positive allosteric modulators of the secretin receptor

    Dengler, Daniela G.Harikumar, Kaleeckal G.Pollari, SirkkuSun, Qing...
    22页
    查看更多>>摘要：The secretin receptor (SCTR) is a prototypic Class B1 G protein-coupled receptor (GPCR) that represents a key target for the development of therapeutics for the treatment of cardiovascular, gastrointestinal, and metabolic disorders. However, no non-peptidic molecules targeting this receptor have yet been disclosed. Using a highthroughput screening campaign directed at SCTR to identify small molecule modulators, we have identified three structurally related scaffolds positively modulating SCTRs. Here we outline a comprehensive study comprising a structure?activity series based on commercially available analogs of the three hit scaffold sets A (2sulfonyl pyrimidines), B (2-mercapto pyrimidines) and C (2-amino pyrimidines), which revealed determinants of activity, cooperativity and specificity. Structural optimization of original hits resulted in analog B2, which substantially enhances signaling of truncated secretin peptides and prolongs residence time of labeled secretin up to 13-fold in a dose-dependent manner. Furthermore, we found that investigated compounds display structural similarity to positive allosteric modulators (PAMs) active at the glucagon-like peptide-1 receptor (GLP-1R), and we were able to confirm cross-recognition of that receptor by a subset of analogs. Studies using SCTR and GLP-1R mutants revealed that scaffold A, but not B and C, likely acts via two distinct mechanisms, one of which constitutes covalent modification of Cys-347GLP-1R known from GLP-1R-selective modulators. The scaffolds identified in this study might not only serve as novel pharmacologic tools to decipher SCTR- or GLP-1R-specific signaling pathways, but also as structural leads to elucidate allosteric binding sites facilitating the future development of orally available therapeutic approaches targeting these receptors.
      原文链接:
    • NSTL
    • Elsevier

    The anti-melanogenic effects of ellagic acid through induction of autophagy in melanocytes and suppression of UVA-activated ?-MSH pathways via Nrf2 activation in keratinocytes

    Yang, Hsin-LingLin, Chia-PeiGowrisankar, Yugandhar VudhyaHuang, Pei-Jane...
    15页
    查看更多>>摘要：Ellagic acid (EA) is a natural phenol antioxidant in different fruits, vegetables, and nuts. As a copper iron chelator from the tyrosinase enzyme?s active site, EA was reported to inhibit melanogenesis in melanocytes. Here, we demonstrated the anti-melanogenic mechanisms of EA through autophagy induction in melanoma B16F10 cells and the role of Nrf2 and UVA (3 J/cm2)-activated ?-melanocyte stimulating hormone (?-MSH) pathways in keratinocyte HaCaT cells. In vitro data showed that EA suppressed the tyrosinase activity and melanogenesis by suppressing cAMP-mediated CREB and MITF signaling mechanisms in ?-MSH-stimulated B16F10 cells. ERK, JNK, and AKT pathways were involved in this EA-regulated MITF downregulation. Notably, EA induced autophagy in B16F10 cells was evidenced from increased LC3-II accumulation, p62/SQSTM1 activation, ATG4B downregulation, acidic vesicular organelle (AVO) formation, PI3K/AKT/mTOR inhibition, and Beclin-1/Bcl-2 dysregulation. Interestingly, 3-MA (an autophagy inhibitor) pretreatment or LC3 silencing (siRNA transfection) of B16F10 cells significantly reduced EA-induced anti-melanogenic activity. Besides this, in UVAirradiated keratinocyte HaCaT cells, EA suppressed ROS production and ?-MSH generation. Moreover, EA mediated the activation and nuclear translocation of Nrf2, leading to antioxidant ?-GCLC, HO-1, and NQO-1 protein expression in HaCaT cells. However, Nrf2 knockdown has significantly impaired this effect, and there was an uncontrolled ROS generation following UVA irradiation. JNK, PKC, and ROS pathways were involved in the activation of Nrf2 in HaCaT cells. In vivo experiments using the zebrafish model confirmed that EA inhibited tyrosinase activity and endogenous pigmentation. In conclusion, ellagic acid is an effective skin-whitening agent and might be used as a topical applicant.
      原文链接:
    • NSTL
    • Elsevier

    Pharmacokinetics of metformin in collagen-induced arthritis rats

    Liu, ShuwenYe, LingChen, MinghaoYou, Guoquan...
    9页
    查看更多>>摘要：Due to the elevated presence of cytokines, the expressions of metabolic enzymes and drug transporters are altered in rheumatoid arthritis (RA). Given the high incidence of diabetes in patients with RA, the aim of the present study was to investigate the metformin pharmacokinetics of a single oral dose in rats with collageninduced arthritis (CIA). Blood and urine samples were collected at different timepoints, and analyzed by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Tissue samples were also collected to investigate the expression of metabolic enzymes and drug transporters by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blot. The results indicated that the bioavailability of metformin was markedly decreased in the CIA rats. Moreover, metformin was not metabolized by enzymes of rat liver microsomes, suggesting that the decreased bioavailability of metformin was independent of the liver metabolism. In addition, the mRNA, protein expression level and activity of the renal organic cation transporter 2 (OCT2) was markedly increased, suggesting that the enhanced renal clearance of metformin in CIA rats may be due to the up-regulated activity of OCT2. In conclusion, our study suggested that the reduced bioavailability of metformin in CIA rats is possibly related to the up-regulated function of the renal protein OCT2.
      原文链接:
    • NSTL
    • Elsevier

    PDE4 inhibition as a therapeutic strategy for improvement of pulmonary dysfunctions in Covid-19 and cigarette smoking

    Lugnier, ClaireAl-Kuraishy, Hayder M.Rousseau, Eric
    9页
    查看更多>>摘要：Angiotensin-converting enzyme 2 (ACE2) is the binding-site and entry-point for SARS-CoV-2 in human and highly expressed in the lung. Cigarette smoking (CS) is the leading cause of pulmonary and cardiovascular diseases. Chronic CS leads to upregulation of bronchial ACE2 inducing a high vulnerability in COVID-19 smoker patients. Interestingly, CS-induced dysregulation of pulmonary renin-angiotensin system (RAS) in part contributing into the potential pathogenesis COVID-19 pneumonia and acute respiratory distress syndrome (ARDS). Since, CS-mediated ACE2 activations is not the main pathway for increasing the risk of COVID-19, it appeared that AngII/AT1R might induce an inflammatory-burst in COVID-19 response by up-regulating cyclic nucleotide phosphodiesterase type 4 (PDE4), which hydrolyses specifically the second intracellular messenger 3?, 5?-cyclic AMP (cAMP). It must be pointed out that CS might induce PDE4 up-regulation similarly to the COVID-19 inflammation, and therefore could potentiate COVID-19 inflammation opening the potential therapeutic effects of PDE4 inhibitor in both COVID-19-inflammation and CS.
      原文链接:
    • NSTL
    • Elsevier

    Optineurin deletion disrupts metabotropic glutamate receptor 5-mediated regulation of ERK1/2, GSK313/ZBTB16, mTOR/ULK1 signaling in autophagy

    Ibrahim, Karim S.McLaren, Caitlyn J.Abd-Elrahman, Khaled S.Ferguson, Stephen S. G....
    11页
    查看更多>>摘要：Optineurin (OPTN) is a multifunctional protein that mediates a network of cellular processes regulating membrane trafficking, inflammatory responses and autophagy. The OPTN-rich interactome includes Group I metabotropic glutamate receptors (mGluR1 and 5), members of the G?q/11 protein receptor family. Recent evidence has shown that mGluR5, in addition to its canonical G?q/11 protein-coupled signaling, regulates autophagic machinery via mTOR/ULK1 and GSK313/ZBTB16 pathways in both Alzheimer?s and Huntington?s disease mouse models. Despite its potential involvement, the role of OPTN in mediating mGluR5 downstream signaling cascades remains largely unknown. Here, we employed a CRISPR/Cas9 OPTN-deficient STHdhQ7/Q7 striatal cell line and global OPTN knockout mice to investigate whether Optn gene deletion alters both mGluR5 canonical and noncanonical signaling. We find that OPTN is required for mGluR5-activated Ca2+ flux and ERK1/2 signaling following receptor activation in STHdhQ7/Q7 cells and acute hippocampal slices. Deletion of OPTN impairs both GSK313/ZBTB16 and mTOR/ULK1 autophagic signaling in STHdhQ7/Q7 cells. Furthermore, mGluR5-dependent regulation of GSK313/ZBTB16 and mTOR/ULK1 autophagic signaling is impaired in hippocampal slices of OPTN knockout mice. Overall, we show that the crosstalk between OPTN and mGluR5 can have major implication on receptor signaling and therefore potentially contribute to the pathophysiology of neurodegenerative diseases.
      原文链接:
    • NSTL
    • Elsevier

    His452Tyr polymorphism in the human 5-HT2A receptor affects clozapine-induced signaling networks revealed by quantitative phosphoproteomics

    Martin-Guerrero, Sandra M.Alonso, PaulaIglesias, AlbaCimadevila, Marta...
    19页
    查看更多>>摘要：Antipsychotic drugs remain the current standard for schizophrenia treatment. Although they directly recognize the orthosteric binding site of numerous monoaminergic G protein-coupled receptors (GPCRs), these drugs, and particularly second-generation antipsychotics such as clozapine, all have in common a very high affinity for the serotonin 5-HT2A receptor (5-HT2AR). Using classical pharmacology and targeted signaling pathway assays, previous findings suggest that clozapine and other atypical antipsychotics behave principally as 5-HT2AR neutral antagonists and/or inverse agonists. However, more recent findings showed that antipsychotics may also behave as pathway-specific agonists. Reversible phosphorylation is a common element in multiple signaling networks. Combining a quantitative phosphoproteomic method with signaling network analysis, we tested the effect of clozapine treatment on the overall level of protein phosphorylation and signal transduction cascades in vitro in mammalian cell lines induced to express either the human 5-HT2AR or the H452Y variant of the gene encoding the 5-HT2AR receptor. This naturally occurring variation within the 5-HT2AR gene was selected because it has been repeatedly associated with schizophrenia patients who do not respond to clozapine treatment. Our data show that short time exposure (5 or 10 min) to clozapine (10(-5) M) led to phosphorylation of numerous signaling components of pathways involved in processes such as endocytosis, ErbB signaling, insulin signaling or estrogen signaling. Cells induced to express the H452Y variant showed a different basal phosphoproteome, with increases in the phosphorylation of mTOR signaling components as a translationally relevant example. However, the effect of clozapine on the functional landscape of the phosphoproteome was significantly reduced in cells expressing the 5-HT2AR-H452Y construct. Together, these findings suggest that clozapine behaves as an agonist inducing phosphorylation of numerous pathways downstream of the 5-HT2AR, and that the single nucleotide polymorphism encoding 5-HT2AR-H452Y affects these clozapine-induced phosphorylation-dependent signaling networks.
      原文链接:
    • NSTL
    • Elsevier