ScienceDirect Publication: Biochemical Pharmacology
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TLN-4601 peripheral benzodiazepine receptor (PBR/TSPO) binding properties do ...
23 Jul 2010 at 1:58pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 22 July 2010
T., Bertomeu , V., Zvereff , A., Ibrahim , S.P., Zehntner , A., Aliaga , ...
TLN-4601 is a farnesylated dibenzodiazepinone isolated from Micromonospora sp. with an antiproliferative effect on several human cancer cell lines. Although the mechanism of action of TLN-4601 is unknown, our earlier work indicated that TLN-4601 binds the PBR (peripheral benzodiazepine receptor; more recently known as the translocator protein or TSPO), an 18kDa protein associated with the mitochondrial permeability transition (mPT) pore. While the exact function of the PBR remains a matter of debate, it has been implicated in heme and steroid synthesis, cellular growth and differentiation, oxygen consumption and apoptosis. Using the Jurkat immortalized T-lymphocyte cell line, documented to have negligible...
Y124 at the peripheral anionic site is important for the reactivation of nerv...
23 Jul 2010 at 1:58pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 22 July 2010
Chunyuan, Luo , Carolyn, Chambers , Nagarajan, Pattabiraman , Min, Tong , Prasanthi, Tipparaju , ...
The toxicity of organophosphorus (OP) nerve agents is manifested through irreversible inhibition of acetylcholinesterase (AChE) at the cholinergic synapses, which stops nerve signal transmission, resulting in a cholinergic crisis and eventually death of the poisoned person. Oxime compounds used in nerve agent antidote regimen reactivate nerve agent-inhibited AChE and halt the development of this cholinergic crisis. Due to diversity in structures of OP nerve agents, none of the currently available oximes is able to reactivate AChE inhibited by different nerve agents. To understand the mechanism for the differential activities of oximes toward AChE inhibited by diverse nerve agents in order...
Modulation of HDL Metabolism by the Niacin Receptor GPR109A in Mouse Hepatocytes
23 Jul 2010 at 1:58pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 22 July 2010
Xiaoyu, Li , John S., Millar , Nicholas, Brownell , Daniel J., Rader
The niacin receptor GPR109A is a Gi-protein coupled receptor which mediates the effects of niacin on inhibiting intracellular triglyceride lipolysis in adipocytes. However, the role of GPR109A in mediating the effects of niacin on high density lipoprotein (HDL) metabolism is unclear. We found niacin has no effect on HDL-C in GPR109A knockout mice. Furthermore, niacin lowered intracellular cAMP in primary hepatocytes mediated by GPR109A. We used an adeno-associated viral (AAV) serotype 8 vector encoding GPR109A under the control of the hepatic-specific thyroxine-binding globulin promoter to specifically overexpress GPR109A in mouse liver. Plasma HDL-C, hepatic ABCA1 and the HDL cholesterol production...
Polo-like kinase1 (Plk1) knockdown enhances cisplatin chemosensitivity via up...
23 Jul 2010 at 1:58pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 22 July 2010
Shilpa, Tyagi , Kulpreet, Bhui , Richa, Singh , Madhulika, Singh , Sheikh, Raisuddin , ...
Polo-like kinase 1 (Plk1), a critical regulator of mitotic entry, progression and exit, has been shown to be involved in a variety of cancers and thus is becoming an attractive target for cancer management. In case of DNA damage, Plk1 not only inhibits p53 independent apoptosis by dysfunctioning p73? but also allows cells to recover from growth arrest. Here, we showed the effects of knocking down plk1 gene through small interference RNA (siRNA) on cell cycle progression, proliferation and chemosensitivity of p53 mutant A431 cells to cisplatin (CDDP). The expression of Plk1 was measured by RT-PCR and Western blotting. Anti-proliferative...
On the retinal toxicity of intra ocular glucocorticoids
21 Jul 2010 at 2:06pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 21 July 2010
Alicia, Torriglia , Fatemeh, Valamanesh , Francine, Behar-Cohen
Corticosteroids are hormones involved in many physiological responses such as stress, immune modulation, protein catabolism and water homeostasis. The subfamily of glucocorticoids are used systemically in the treatment of inflammatory diseases or allergic reactions. In the eye, glucocorticoides are used to treat macular oedema, inflammation and neovascularization. The most commonly used glucocorticoid is Triamcinolone acetonide (TA). The pharmaceutical formulation of TA is not adapted for intravitreal administration but has been selected by ophthalmologists because its very low intraocular solubility provides sustained effect. Visual benefits of intraocular TA do not clearly correlate with morpho-anatomical improvements, suggesting potential toxicity. We therefore studied,...
The rGel/BLyS fusion toxin inhibits STAT3 signaling via down-regulation of in...
21 Jul 2010 at 2:06pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 21 July 2010
Mi-Ae, Lyu , Bokyung, Sung , Lawrence H., Cheung , John W., Marks , Bharat B., Aggarwal , ...
Aberrant signal transducer and activator of transcription (STAT) 3 signaling participates in the development and progress of human cancers. We previously generated a highly cytotoxic fusion toxin designated rGel/BLyS for receptor-mediated delivery of the rGel toxin to malignant B cells. In this study, we examined this fusion toxin for its ability to impact STAT3 signaling in diffuse large B cell lymphoma (DLBCL). The activated B cell-like DLBCL lines were found to express higher levels of interleukin-6 receptor (IL-6R) and STAT3 than did the germinal center B cell-like DLBCL lines. Treatment of DLBCL cells with rGel/BLyS resulted in down-regulation of IL-6R...
Serine Phosphorylation of Glutathione S-transferase P1 (GSTP1) by PKC? enhanc...
21 Jul 2010 at 2:06pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 21 July 2010
Simendra, Singh , Tatsunori, Okamura , Francis, Ali-Osman
Recently, we reported that the human GSTP1 is phosphorylated and functionally activated by the PKC class of serine/threonine kinases. In this study, we investigated the contribution of this post-translational modification of GSTP1 to tumor cisplatin resistance. Using two malignant glioma cell lines, MGR1 and MGR3, the ability of PKC?-phosphorylated GSTP1 to catalyze the conjugation of cisplatin to glutathione was assessed and correlated with cisplatin sensitivity and cisplatin-induced DNA interstrand cross-links and apoptosis of the cells. The results showed PKC? activation and associated phosphorylation of GSTP1 to correlate significantly with increased glutathionylplatinum formation, decreased DNA interstrand cross-link formation and increased cisplatin...
Delivery of anti-inflammatory nutraceuticals by nanoparticles for the prevent...
21 Jul 2010 at 2:06pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 21 July 2010
Hareesh B., Nair , Bokyung, Sung , Vivek R., Yadav , Ramaswamy, Kannappan , Madan M., Chaturvedi , ...
Extensive research within the last two decades has revealed that most chronic illnesses, including cancer, diabetes, and cardiovascular and pulmonary diseases, are mediated through chronic inflammation. Thus, suppressing chronic inflammation has the potential to delay, prevent, and even treat various chronic diseases, including cancer. Various nutraceuticals from fruits, vegetables, vitamins, spices, legumes, and traditional Chinese and Ayurvedic medicine have been shown to safely suppress proinflammatory pathways; however, their low bioavailability in vivo limits their use in preventing and treating cancer. We describe here the potential of nanotechnology to fill this gap. Several nutraceuticals, including curcumin, green tea polyphenols, coenzyme Q,...
Quantitative relationship between guanine O6-alkyl lesions produced by Onrigi...
21 Jul 2010 at 2:06pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 21 July 2010
Kimiko, Ishiguro , Yong-Lian, Zhu , Krishnamurthy, Shyam , Philip G., Penketh , Raymond P., Baumann , ...
O6-Alkylguanine-DNA alkyltransferase (AGT) mediates tumor resistance to alkylating agents that generate guanine O6-chloroethyl (OnriginTM and carmustine) and O6-methyl (temozolomide) lesions; however, the relative efficiency of AGT protection against these lesions and the degree of resistance to these agents that a given number of AGT molecules produces are unclear. Measured from differential cytotoxicity in AGT-ablated and AGT-intact HL-60 cells containing 17,000 AGT molecules/cell, AGT produced 12- and 24-fold resistance to chloroethylating (90CE) and methylating (KS90) analogs of OnriginTM, respectively. For 50% growth inhibition, KS90 and 90CE generated 5,600 O6-methylguanines/cell and ?300 O6-chloroethylguanines/cell, respectively. AGT repaired O6-methylguanines until the AGT pool was...
Glutamine As A Mediator Of Ammonia Neurotoxicity: A Critical Appraisal
21 Jul 2010 at 2:06pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 21 July 2010
Jan, Albrecht , Magdalena, Zieli?ska , Michael D., Norenberg
Ammonia is a major neurotoxin implicated in hepatic encephalopathy (HE). Here we discuss evidence that many aspects of ammonia toxicity in HE-affected brain are mediated by glutamine (Gln), synthesized in excess from ammonia and glutamate by glutamine synthetase (GS), an astrocytic enzyme. The degree to which Gln is increased in brains of patients with HE was found to positively correlate with the grade of HE. In animals with HE, a GS inhibitor, methionine sulfoximine (MSO), reversed a spectrum of manifestations of ammonia toxicity, including brain edema and increased intracranial pressure, even though MSO itself increased brain ammonia levels. MSO inhibited,...
The Varicella-Zoster virus IE4 protein: a conserved member of the herpesviral...
20 Jul 2010 at 2:02pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 20 July 2010
Isabelle, Ote , Jacques, Piette , Catherine, Sadzot-Delvaux
During a viral infection, in addition to cellular mRNAs, amounts of viral mRNAs have to be efficiently transported to the cytoplasm for translation. It is now established that herpesviruses encode a conserved gene family whose proteins act as viral mRNA export factors that mediate nucleocytoplasmic transport of viral transcripts and eventually modulate through this mechanism the antiviral response. This conserved family of proteins contains the IE4 protein of Varicella-Zoster virus (VZV). Here, we compared the functional characteristics of IE4 with those of its herpesviral homologues and proposed a model by which IE4 would be able to recruit the essential TAP/NXF1...
Oncostatin M up-regulates the ER chaperone Grp78/BiP in liver cells
20 Jul 2010 at 2:02pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 20 July 2010
Stefan, Vollmer , Claude, Haan , Iris, Behrmann
OSM, a cytokine of the IL-6 type cytokine family, regulates inflammatory processes (acute phase, tissue remodeling, angiogenesis), cell differentiation and proliferation. Inflammation is discussed to favor carcinogenesis and the inflammatory cytokine OSM was lately described to upregulate HIF-1?, whose upregulation is also observed in many cancers. In this study we demonstrate that OSM, and to a lesser degree by IL-6, induces the expression of Grp78/BiP, an ER chaperone associated with tumor development and poor prognosis in cancer. In contrast, IFN-? or TNF-?.had no effect on Grp78 expression. The up-regulation seems to be specific to liver cells, as it occurs in...
Inflammation Dysregulates Notch Signaling In Endothelial Cells: Implication O...
19 Jul 2010 at 2:08pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 17 July 2010
Thibaut, Quillard , Julie, Devallière , Stéphanie, Coupel , Béatrice, Charreau
Although the involvement of the Notch pathway in several areas of vascular biology is now clearly established, its role in vascular inflammation at the endothelial level remains to be elucidated. In this study, we demonstrated that proinflammatory cytokines drive a specific regulation of the Notch pathway in vascular endothelial cells (ECs). In arterial ECs, TNF? strongly modulates the pattern of Notch expression by decreasing Notch4 expression while increasing Notch2 expression. Changes in Notch expression were associated with a reduction in hes1 and hey2 expression and in CBF1 reporter gene activity, suggesting that TNF? regulates both Notch expression and activity. Notch2...
Human papillomavirus type 16 E5 oncoprotein as a new target for cervical canc...
19 Jul 2010 at 2:08pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 17 July 2010
Mi-Kyung, Kim , Hee Seung, Kim , Su-Hyeong, Kim , Jung-Min, Oh , Jae Yong, Han , ...
Human papillomavirus (HPV) infection is considered to be the necessary cause of cervical cancer. E6 and E7 oncoproteins of HPV have been known to play major roles in malignant transformation of cervical cells, inhibiting the tumor suppressors p53 and Rb. However, the role of E5 oncoprotein has been relatively less defined.HPV 16 E5 is a hydrophobic membrane-bound protein which associates with the Golgi apparatus, endoplasmic reticulum and perinuclear membrane. Accumulating evidences have suggested that E5 oncoprotein may also contribute to cervical carcinogenesis through modulating cellular signaling pathways in addition to augmenting the immortalization potential of E6 and E7. Multiple mechanisms,...
Signaling to Heme Oxygenase-1 and its Anti-Inflammatory Therapeutic Potential
19 Jul 2010 at 2:08pm
Publication year: 2010
Source: Biochemical Pharmacology, In Press, Accepted Manuscript, Available online 17 July 2010
Ananta, Paine , Britta, Eiz-Vesper , Rainer, Blasczyk , Stephan, Immenschuh
Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. Induction of HO-1 protects against the cytotoxicity of oxidative stress and apoptotic cell death. More recently, HO-1 has been recognized to have major immunomodulatory and anti-inflammatory properties, which have been demonstrated in HO-1 knockout mice and a human case of genetic HO-1 deficiency. Beneficial protective effects of HO-1 in inflammation are not only mediated via enzymatic degradation of proinflammatory free heme, but also via production of the anti-inflammatory compounds bilirubin and carbon monoxide. The immunomodulatory role of HO-1 is associated with its cell type-specific...

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