Growth of breast cancer cells by leptin is mediated via activation of the inflammasome: Critical roles of estrogen receptor signaling and reactive oxygen species production.
In this study, we investigated the role of inflammasomes in leptin-induced growth of breast cancer cells. Herein, we showed that leptin activated NLRP3 inflammasomes in MCF-7 breast cancer cells, as determined by activation of caspase-1, maturation of interleukin-1β, and increased expression of the inflammasome components, including NLRP3 and ASC. Interestingly, inhibition of the inflammasome by treatment with a pharmacological inhibitor of caspase-1 or gene silencing of NLRP3 prevented leptin-induced increase in cell viability. Moreover, suppression of apoptosis and cell cycle promotion by leptin were also significan...
Source: Biochemical Pharmacology - January 8, 2019 Category: Drugs & Pharmacology Authors: Raut PK, Kim SH, Choi DY, Jeong GS, Park PH Tags: Biochem Pharmacol Source Type: research

SARM: from immune regulator to cell executioner.
Abstract SARM is the fifth and most conserved member of the Toll/Il-1 Receptor (TIR) adaptor family. However, unlike the other TIR adaptors, MyD88, Mal, TRIF and TRAM, SARM does not participate in transducing signals downstream of TLRs. By contrast SARM inhibits TLR signalling by interacting with the adaptors TRIF and MyD88. In addition, SARM also has positive roles in innate immunity by activating specific transcriptional programs following immune challenge. SARM has a pivotal role in activating different forms of cell death following cellular stress and viral infection. Many of these functions of mammalian SARM ...
Source: Biochemical Pharmacology - January 8, 2019 Category: Drugs & Pharmacology Authors: Carty M, Bowie AG Tags: Biochem Pharmacol Source Type: research

Potentialization of anticancer agents by identification of new chemosensitizers active under hypoxia.
Calve Benjamin LE Abstract Hypoxia is one of the most important biological phenomena that influences cancer agressiveness and chemotherapy resistance. Cancer cells display dysregulated pathways notably resulting from oncogene expression. Tumors also show modifications in extracellular pH, extracellular matrix remodeling, neo-angiogenesis, hypoxia compared to normal tissues. Classically, the conventional anticancer therapies are efficient in cancer cells in normoxic conditions but under hypoxia, chemoresistance may occur. The addition of compounds that potentiate their activity in low oxygen environment could be a ...
Source: Biochemical Pharmacology - January 7, 2019 Category: Drugs & Pharmacology Authors: Sébastien M, Gysel Mégane V, Aurélie B, Maso Thomas D, Carine M, Johan W, Calve Benjamin LE Tags: Biochem Pharmacol Source Type: research

Involvement Of Cell Oxidant Status And Redox State In The Increased Non-Enzymatic Ethanol Oxidation By The Regenerating Rat Liver.
In conclusion, data clearly show that an important fraction of ethanol is metabolized through a non-enzymatic-mediated oxidative event, which could largely contribute to the deleterious effect of ethanol on the proliferating liver. PMID: 30625299 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - January 6, 2019 Category: Drugs & Pharmacology Authors: Hernández-Muñoz R, Lucinda Contreras-Zentella M Tags: Biochem Pharmacol Source Type: research

Calcineurin/p38mapk/hsp27-dependent pathways are involved in the attenuation of postischemic mitochondrial injury afforded by sodium bicarbonate co-transporter (nbce1) inhibition.
In this study, we aimed to elucidate the effects of a-L3 on post-ischemic mitochondrial state and dynamics analysing the involved mechanisms. Isolated rat hearts were assigned to the following groups: 1) Non-ischemic control (NIC): 110 min of perfusion; 2) Ischemic control (IC): 30 min of global ischemia and 60 min of reperfusion (R); 3) a-L3: a-L3 was administered during the initial 10 min of R; 4) SB + a-L3: SB202190 (p38MAPK inhibitor) plus a-L3. Infarct size (IS) was measured by TTC staining. Developed pressure (LVDP), maximal velocities of rise and decay of LVP (+dP/dt max, -dP/dt max) and end-diastolic pressure (LVED...
Source: Biochemical Pharmacology - January 4, 2019 Category: Drugs & Pharmacology Authors: Pardo AC, Arbeláez LFG, Fantinelli JC, Aiello EA, Mosca SM Tags: Biochem Pharmacol Source Type: research

Natural modulators of the hallmarks of immunogenic cell death.
Abstract Natural compounds act as immunoadjuvants as their therapeutic effects trigger cancer stress response and release of damage-associated molecular patterns (DAMPs). These reactions occur through an increase in the immunogenicity of cancer cells that undergo stress followed by immunogenic cell death (ICD). These processes result in a chemotherapeutic response with a potent immune-mediating reaction. Natural compounds that induce ICD may function as an interesting approach in converting cancer into its own vaccine. However, multiple parameters determine whether a compound can act as an ICD inducer, including t...
Source: Biochemical Pharmacology - January 4, 2019 Category: Drugs & Pharmacology Authors: Radogna F, Dicato M, Diederich M Tags: Biochem Pharmacol Source Type: research

Systemic administration of serotonin exacerbates abdominal pain and colitis via interaction with the endocannabinoid system.
CONCLUSIONS: Our study shows a link between 5-HT and endocannabinoid signaling pathways in IBD. Thus, pharmacological blockade of 5-HT signaling or supplementation with endocannabinoids in the gut might be of benefit in severe cases of abdominal pain in IBD. PMID: 30611738 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - January 3, 2019 Category: Drugs & Pharmacology Authors: Salaga M, Binienda A, Piscitelli F, Mokrowiecka A, I Cygankiewicz A, Verde R, Malecka-Panas E, Kordek R, Krajewska WM, Di Marzo V, Fichna J Tags: Biochem Pharmacol Source Type: research

Developments in bile salt based therapies: a critical overview.
Abstract Bile acids, amphipathic molecules known for their facilitating role in fat absorption, are also recognized as signalling molecules acting via nuclear and membrane receptors. Of the bile acid-activated receptors, the Farnesoid X Receptor (FXR) and the G protein-coupled bile acid receptor-1 (Gpbar1 or TGR5) have been studied most extensively. Bile acid signaling is critical in the regulation of bile acid metabolism itself, but it also plays a significant role in glucose, lipid and energy metabolism. Activation of FXR and TGR5 leads to reduced hepatic bile salt load, improved insulin sensitivity and glucose ...
Source: Biochemical Pharmacology - December 21, 2018 Category: Drugs & Pharmacology Authors: Donkers JM, Roscam Abbing RLP, van de Graaf SFJ Tags: Biochem Pharmacol Source Type: research

Schedule-dependent synergistic effects of 5-fluorouracil and selumetinib in KRAS or BRAF mutant colon cancer models.
Abstract Combination of MEK inhibitor and 5-FU had showed limited efficacy in clinical trials. We previously reported that acquired resistance to 5-FU was related with continued activation of salvage pathway. Here we investigated whether combination of 5-FU and a MEK inhibitor had treatment sequence-dependent synergistic effects in KRAS or BRAF mutant colon cancer models. Treatment with 5-FU followed by selumetinib (FS) induced highest cell death and synergy compared with reverse (SF) and concomitant (cFS) treatment in six cell lines. SF or cFS combination induced synergy in 1 or 2 cell lines, respectively, in whi...
Source: Biochemical Pharmacology - December 20, 2018 Category: Drugs & Pharmacology Authors: Jang HY, Kim DH, Lee HJ, Kim WD, Kim SY, Hwang JJ, Lee SJ, Moon DH Tags: Biochem Pharmacol Source Type: research

Contrasting effects of microtubule destabilizers versus stabilizers on induction of death in G1 phase of the cell cycle.
Abstract Microtubule targeting agents (MTAs) have been reported to manifest their cytotoxic effects not only in mitosis but also in interphase. However, the relationship between phase-specific susceptibility and MTA concentration, especially with respect to microtubule integrity, remains poorly defined. In addition, whether microtubule stabilizers and destabilizers act similarly or differ in the ability to induce interphase death is unclear. In order to resolve these uncertainties, we report here the results of a systematic comparison of primary acute lymphoblastic leukemia (ALL) and HeLa cells treated with three ...
Source: Biochemical Pharmacology - December 19, 2018 Category: Drugs & Pharmacology Authors: Delgado M, Urbaniak A, Chambers TC Tags: Biochem Pharmacol Source Type: research

An N6-methyladenosine at the transited codon 273 of p53 pre-mRNA promotes the expression of R273H mutant protein and drug resistance of cancer cells.
This study uncovers a novel function of pre-mRNA m6A as a determinant of mutant protein expression in cancer cells heterozygously carrying the TP53 R273H mutation. Suppressing both RNA methylation and ceramide glycosylation might constitute an efficacious and specific approach for targeting TP53 missense mutations coding for a G>A transition, thereby improving cancer treatments. PMID: 30578766 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - December 19, 2018 Category: Drugs & Pharmacology Authors: Uddin MB, Roy KR, Hosain SB, Khiste SK, Hill RA, Jois SD, Zhao Y, Tackett AJ, Liu YY Tags: Biochem Pharmacol Source Type: research

Tumor cell escape from therapy-induced senescence.
Abstract H460 non-small cell lung, HCT116 colon and 4T1 breast tumor cell lines induced into senescence by exposure to either etoposide or doxorubicin were able to recover proliferative capacity both in mass culture and when enriched for the senescence-like phenotype by flow cytometry (based on β-galactosidase staining and cell size, and a senescence-associated reporter, BTG1-RFP). Recovery was further established using both real-time microscopy and High-Speed Live-Cell Interferometry (HSLCI) and was shown to be accompanied by the attenuation of the senescence-associated secretory phenotype (SASP). Cells enri...
Source: Biochemical Pharmacology - December 18, 2018 Category: Drugs & Pharmacology Authors: Saleh T, Tyutyunyk-Massey L, Murray GF, Alotaibi MR, Kawale AS, Elsayed Z, Henderson SC, Yakovlev V, Elmore LW, Toor A, Harada H, Reed J, Landry JW, Gewirtz DA Tags: Biochem Pharmacol Source Type: research

RNA interference screen identifies NAA10 as a regulator of PXR transcription.
Abstract The pregnane X receptor (PXR) is a principal xenobiotic receptor crucial in the detection, detoxification, and clearance of toxic substances from the body. PXR plays a vital role in the metabolism and disposition of drugs, and elevated PXR levels contribute to cancer drug resistance. Therefore, to modulate PXR activity and mitigate drug resistance, it is imperative to fully understand its regulation. To this end, we screened a transcription factor siRNA library in pancreatic cancer cells that express high levels of PXR. Through a comprehensive deconvolution process, we identified N-alpha-acetyltransferase...
Source: Biochemical Pharmacology - December 16, 2018 Category: Drugs & Pharmacology Authors: Oladimeji PO, Wright WC, Wu J, Chen T Tags: Biochem Pharmacol Source Type: research

Lung cancer stem cells: origin, features, maintenance mechanisms and therapeutic targeting.
Abstract Lung cancer remains the leading cause of cancer-related deaths despite recent breakthroughs in immunotherapy. The widely embraced cancer stem cell (CSC) theory has also been applied for lung cancer, postulating that an often small proportion of tumor cells with stem cell properties are responsible for tumor growth, therapeutic resistance and metastasis. The identification of these CSCs and underlying molecular maintenance mechanisms is considered to be absolutely necessary for developing therapies for their riddance, hence achieving remission. In this review, we will critically address the CSC concept in ...
Source: Biochemical Pharmacology - December 14, 2018 Category: Drugs & Pharmacology Authors: Heng WS, Gosens R, Kruyt FAE Tags: Biochem Pharmacol Source Type: research

Inositol hexakisphosphate increases the size of platelet aggregates.
VL, Windhorst S Abstract The inositol phosphates, InsP5 and InsP6, have recently been identified as binding partners of fibrinogen, which is critically involved in hemostasis by crosslinking activated platelets at sites of vascular injury. Here, we investigated the putative physiological role of this interaction and found that platelets increase their InsP6 concentration upon stimulation with the PLC-activating agonists thrombin, collagen I and ADP and present a fraction of it at the outer plasma membrane. Cone and plate analysis in whole blood revealed that InsP6 specifically increases platelet aggregate size. Th...
Source: Biochemical Pharmacology - December 14, 2018 Category: Drugs & Pharmacology Authors: Brehm MA, Klemm U, Rehbach C, Erdmann N, Kolšek K, Lin H, Aponte-Santamaría C, Gräter F, Rauch BH, Riley AM, Mayr GW, Potter BVL, Windhorst S Tags: Biochem Pharmacol Source Type: research

Development of a novel, sensitive cell-based Corin Assay.
r F Abstract Corin (atrial natriuretic peptide-converting enzyme, EC 3.4.21) is a transmembrane serine protease expressed in cardiomyocytes. Corin exerts its cardioprotective effects via the proteolytic cleavage and activation of pro-atrial natriuretic peptide (pro-ANP) to ANP. We recently described an ANP reporter cell line stably expressing the ANP receptor, a cGMP-dependent cation channel used as a real-time cGMP biosensor, and the Ca2+-sensitive photoprotein aequorin. Here, we describe the generation of a novel reporter cell line expressing the calcium biosensor GCaMP6 instead of aequorin. In contrast to the l...
Source: Biochemical Pharmacology - December 13, 2018 Category: Drugs & Pharmacology Authors: Lambertz P, Theisen L, Längst N, Garvie CW, MacDonald BT, Yu J, Elowe NH, Zubov D, Kaushik VK, Wunder F Tags: Biochem Pharmacol Source Type: research

Darpp-32 and t-Darpp protein products of PPP1R1B: old dogs with new tricks.
We present a case for the development of an anti-t-Darpp therapeutic agent and outline the unique challenges this endeavor will likely encounter. PMID: 30552871 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - December 12, 2018 Category: Drugs & Pharmacology Authors: Avanes BA, Lenz G, Momand J Tags: Biochem Pharmacol Source Type: research

A new human pyridinium metabolite of furosemide, inhibitor of mitochondrial complex I, is a candidate inducer of neurodegeneration.
rin C Abstract Pharmaceuticals and their by-products are increasingly a matter of concern, because of their unknown impacts on human health and ecosystems. The lack of information on these transformation products, which toxicity may exceed that of their parent molecules, makes their detection and toxicological evaluation impossible. Recently we characterized the Pyridinium of furosemide (PoF), a new transformation product of furosemide, the most widely used diuretic and an emerging pollutant. Here, we reveal PoF toxicity in SH-SY5Y cells leading to alpha-synuclein accumulation, reactive oxygen species generation, ...
Source: Biochemical Pharmacology - December 8, 2018 Category: Drugs & Pharmacology Authors: Laurencé C, Zeghbib N, Rivard M, Lehri-Boufala S, Lachaise I, Barau C, Le Corvoisier P, Martens T, Garrigue-Antar L, Morin C Tags: Biochem Pharmacol Source Type: research

Loperamide overcomes the resistance of colon cancer cells to bortezomib by inducing CHOP-mediated paraptosis-like cell death.
We report that combined treatment with Btz and Lop induces paraptosis-like cell death accompanied by severe endoplasmic reticulum (ER)-derived vacuolation. Furthermore, Lop potentiates Btz-mediated ER stress and ER dilation due to misfolded protein accumulation and Ca2+ imbalance, leading to CHOP upregulation and subsequent paraptosis-like cell death. Taken together, our results show for the first time that a combined regimen of PI and Lop may provide an effective and safe therapeutic strategy against solid tumors, including colon cancer, by enhancing the sensitivity to PIs and reducing the side effects of such treatment. ...
Source: Biochemical Pharmacology - December 7, 2018 Category: Drugs & Pharmacology Authors: Young Kim I, June Shim M, Min Lee D, Reum Lee A, Ae Kim M, Jin Yoon M, Ri Kwon M, In Lee H, Ji Seo M, Won Choi Y, Sook Choi K Tags: Biochem Pharmacol Source Type: research

Alcohol-induced ketonemia is associated with lowering of blood glucose, downregulation of gluconeogenic genes, and depletion of hepatic glycogen in type 2 diabetic db/db mice.
Abstract Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g., β-hydroxybutyrate; βOHB) from the liver into the systemic circulation. To date, the impact of ethanol consumption on systemic ketone concentration, glycemic control, and hepatic gluconeogenesis and glycogenesis remains largely unknown, especially in the context of type 2 diabetes. In the present study, ethanol intake (36% ethanol- and 36% fat-derived calori...
Source: Biochemical Pharmacology - December 7, 2018 Category: Drugs & Pharmacology Authors: Srinivasan MP, Shawky NM, Kaphalia BS, Thangaraju M, Segar L Tags: Biochem Pharmacol Source Type: research

The pyrrolopyrimidine colchicine-binding site agent PP-13 reduces the metastatic dissemination of invasive cancer cells in vitro and in vivo.
bin A Abstract Standard chemotherapies that interfere with microtubule dynamics are a chemotherapeutic option used for the patients with advanced malignancies that invariably relapse after targeted therapies. However, major efforts are needed to reduce their toxicity, optimize their efficacy, and reduce cancer chemoresistance to these agents. We previously identified a pyrrolo[2,3d]pyrimidine-based microtubule-depolymerizing agent (PP-13) that binds to the colchicine site of β-tubulin and exhibits anticancer properties in solid human cancer cells, including chemoresistant subtypes. Here, we investigated the t...
Source: Biochemical Pharmacology - December 7, 2018 Category: Drugs & Pharmacology Authors: Gilson P, Couvet M, Vanwonterghem L, Henry M, Vollaire J, Baulin V, Werner M, Orlowska A, Josserand V, Mahuteau-Betzer F, Lafanechère L, Coll JL, Busser B, Hurbin A Tags: Biochem Pharmacol Source Type: research

Effects of inorganic nanoparticles on liver fibrosis: Optimizing a double-edged sword for therapeutics.
Abstract Liver fibrosis is a condition of sustained wound healing in response to chronic liver injury caused by various factors such as viral, cholestatic and inflammatory diseases. Despite significant advances in the understanding of the mechanistic details of fibrosis, therapeutic intervention with the use of anti-fibrotic drugs achieved only marginal efficacy. Among which, pharmacokinetics profile of agents leading to off-targeting and suboptimal distribution are the principal limiting factors. Concurrently, inorganic nanoparticles (NPs) have gained significant recognition in biomedicine, owning to their unique...
Source: Biochemical Pharmacology - December 6, 2018 Category: Drugs & Pharmacology Authors: Tee JK, Peng F, Ho HK Tags: Biochem Pharmacol Source Type: research

Targeting the DNA-PK complex: its rationale use in cancer and HIV-1 infection.
Abstract The DNA-PK complex is the major component of the predominant mechanism of DSB repair in humans. In addition, this complex is involved in many other processes such as DNA recombination, genome maintenance, apoptosis and transcription regulation. Several studies have linked the decrease of the DNA-PK activity with cancer initiation, due to defects in the repair. On another hand, higher DNA-PK expression and activity have been observed in various other tumor cells and have been linked with a decrease of the efficiency of anti-tumor drugs. It has also been shown that DNA-PK is critical for the integration of ...
Source: Biochemical Pharmacology - December 6, 2018 Category: Drugs & Pharmacology Authors: Schwartz C, Rohr O, Wallet C Tags: Biochem Pharmacol Source Type: research

Promising neuroprotective effects of β-caryophyllene against LPS-induced oligodendrocyte toxicity: A mechanistic study.
Promising neuroprotective effects of β-caryophyllene against LPS-induced oligodendrocyte toxicity: A mechanistic study. Biochem Pharmacol. 2018 Dec 05;: Authors: Askari VR, Shafiee-Nick R Abstract Myelin loss subsequent to oligodendrocyte death has been reported in a variety of myelin-associated disorders such as multiple sclerosis (MS). Lipopolysaccharide (LPS) has been shown to elicit cellular responses in the central nervous system (CNS) and trigger immune infiltrates and glial cells to release a variety of inflammatory cytokines and mediators. LPS-induced oligodendrocytes toxicity may be chos...
Source: Biochemical Pharmacology - December 5, 2018 Category: Drugs & Pharmacology Authors: Askari VR, Shafiee-Nick R Tags: Biochem Pharmacol Source Type: research

Mitochondria targeting to oppose the progression of nonalcoholic fatty liver disease.
tincasa P Abstract Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by the excessive accumulation of triglycerides in hepatocytes. NAFLD is the most frequent chronic liver disease in developed countries, and is often associated with metabolic disorders such as obesity and type 2 diabetes. NAFLD definition encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL), to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD, therefore, represents a global public health issue. Mitochondrial dysfunction occurs in NAFLD, an...
Source: Biochemical Pharmacology - November 30, 2018 Category: Drugs & Pharmacology Authors: Grattagliano I, Montezinho LP, Oliveira PJ, Frühbeck G, Gómez-Ambrosi J, Montecucco F, Carbone F, Wieckowski MR, Wang DQ, Portincasa P Tags: Biochem Pharmacol Source Type: research

Human AHR functions in vascular tissue: Pro- and anti-inflammatory responses of AHR agonists in atherosclerosis.
Abstract Despite decades of intense research physiologic aryl hydrocarbon receptor (AHR) functions have not been elucidated. Challenges include marked species differences and dependence on cell type and cellular context. A previous commentary on human AHR functions in skin and intestine has been extended to vascular tissue. Similar functions appear to be operating in vascular tissue including microbial defense, modulation of stem/progenitor cells as well as control of immunity and inflammation. However, AHR functions are Janus faced: Detrimental AHR functions in vascular tissue are well documented, e.g., upon expo...
Source: Biochemical Pharmacology - November 30, 2018 Category: Drugs & Pharmacology Authors: Walter Bock K Tags: Biochem Pharmacol Source Type: research

Mechanisms of vascular dysfunction evoked by ionizing radiation and possible targets for its pharmacological correction.
Abstract Ionizing radiation (IR) leads to a variety of the cardiovascular diseases, including the arterial hypertension. A number of studies have demonstrated that blood vessels represent important target for IR, and the endothelium is one of the most vulnerable components of the vascular wall. IR causes an inhibition of nitric oxide (NO)-mediated endothelium-dependent vasodilatation and generation of reactive oxygen (ROS) and nitrogen (RNS) species trigger this process. Inhibition of NO-mediated vasodilatation could be due to endothelial NO synthase (eNOS) down-regulation, inactivation of endothelium-derived NO, ...
Source: Biochemical Pharmacology - November 30, 2018 Category: Drugs & Pharmacology Authors: Soloviev AI, Kizub IV Tags: Biochem Pharmacol Source Type: research

The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators.
Abstract N-Methyl-D-aspartate receptors (NMDARs) have multiple prominent roles in CNS function but their excessive or insufficient activity contributes to neuropathological/psychiatric disorders. Consequently, a variety of positive and negative allosteric modulators (PAMs and NAMs, respectively) have recently been developed. Although these modulators bind to extracellular domains, in the present report we find that the NMDAR's intracellular C-terminal domains (CTDs) significantly influence PAM/NAM activity. GluN2 CTD deletion robustly affected NAM and PAM activity with both enhancing and inhibiting effects that we...
Source: Biochemical Pharmacology - November 29, 2018 Category: Drugs & Pharmacology Authors: Sapkota K, Dore K, Tang K, Irvine M, Fang G, Burnell ES, Malinow R, Jane DE, Monaghan DT Tags: Biochem Pharmacol Source Type: research

Inorganic polyphosphate protects against lipopolysaccharide-induced lethality and tissue injury through regulation of macrophage recruitment.
In this study, we show that pre- or post-treatment of mice with polyP150 (average chain length of 150 phosphate residues) markedly increases survival from lipopolysaccharide (LPS)-induced shock and inhibits macrophage recruitment to the liver and lungs, resulting in protection against tissue injury. In accord with these in vivo results, pretreatment of cultured peritoneal macrophages with polyP150 inhibited chemotaxis and actin polarization in response to TNFα. PolyP150 also inhibited phosphorylation of stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38, two downstream signaling molecules of the T...
Source: Biochemical Pharmacology - November 22, 2018 Category: Drugs & Pharmacology Authors: Terashima-Hasegawa M, Ashino T, Kawazoe Y, Shiba T, Manabe A, Numazawa S Tags: Biochem Pharmacol Source Type: research

Clomiphene citrate induces nuclear translocation of the TFEB transcription factor and triggers apoptosis by enhancing lysosomal membrane permeabilization.
Abstract The autophagy-lysosome pathway plays a central role in cellular homeostasis by regulating the cellular degradative machinery. The transcription factor EB (TFEB) regulates the biogenesis and function of both lysosomes and autophagosomes, and enhancement of TFEB function has emerged as an attractive therapeutic strategy for lysosome-related disorders. However, little is known about the role of TFEB activation in regulating the cellular fate. Here, we describe that clomiphene citrate (CC), a selective estrogen receptor modulator, promotes nuclear translocation of TFEB and increases lysosomal biogenesis in He...
Source: Biochemical Pharmacology - November 21, 2018 Category: Drugs & Pharmacology Authors: Li W, Lin J, Shi Z, Wen J, Li Y, Liu Z, Diao A Tags: Biochem Pharmacol Source Type: research

Ribosome biogenesis: an emerging druggable pathway for cancer therapeutics.
Abstract Ribosomes are nanomachines essential for protein production in all living cells. Ribosome synthesis increases in cancer cells to cope with a rise in protein synthesis and sustain unrestricted growth. This increase in ribosome biogenesis is reflected by severe morphological alterations of the nucleolus, the cell compartment where the initial steps of ribosome biogenesis take place. Ribosome biogenesis has recently emerged as an effective target in cancer therapy, and several compounds that inhibit ribosome production or function, killing preferentially cancer cells, have entered clinical trials. Recent res...
Source: Biochemical Pharmacology - November 20, 2018 Category: Drugs & Pharmacology Authors: Catez F, Venezia ND, Marcel V, Zorbas C, Lafontaine DLJ, Diaz JJ Tags: Biochem Pharmacol Source Type: research

BubR1 depletion delays apoptosis in the microtubule-depolymerized cells.
Abstract We investigated the role of a spindle assembly checkpoint protein, BubR1, in determining the mechanism of cell killing of an anti-microtubule agent CXI-benzo-84. CXI-benzo-84 dampened microtubule dynamics in live MCF-7 cells. The compound arrested MCF-7 cells in mitosis and induced apoptosis in these cells. Though CXI-benzo-84 efficiently depolymerized microtubules in the BubR1-depleted MCF-7 cells, it did not arrest the BubR1-depleted cells at mitosis. Interestingly, apoptosis occurred in the BubR1-depleted MCF-7 cells in the absence of a mitotic block suggesting that the mitotic block is not a prerequis...
Source: Biochemical Pharmacology - November 20, 2018 Category: Drugs & Pharmacology Authors: Naaz A, Ahad S, Rai A, Surolia A, Panda D Tags: Biochem Pharmacol Source Type: research

Comparison of different chemically modified inhibitors of miR-199b in vivo.
Abstract MicroRNAs (miRNAs) have recently received great attention for their regulatory roles in diverse cellular processes and for their contribution to several human pathologies. Modulation of miRNAs in vivo provides beneficial therapeutic strategies for the treatment of many diseases as evidenced by various preclinical studies. However, specific issues regarding the in vivo use of miRNA inhibitors (antimiRs) such as organ-specific delivery, optimal dosing and formulation of the best chemistry to obtain efficient miRNA inhibition remain to be addressed. Here, we aimed at comparing the in vivo efficacy of differe...
Source: Biochemical Pharmacology - November 16, 2018 Category: Drugs & Pharmacology Authors: Duygu B, Juni R, Ottaviani L, Bitsch N, Wit JBM, de Windt LJ, da Costa Martins PA Tags: Biochem Pharmacol Source Type: research

The roles of ubiquitination in extrinsic cell death pathways and its implications for therapeutics.
Abstract Regulation of cell survival and death, including apoptosis and necroptosis, is important for normal development and tissue homeostasis, and disruption of these processes can cause cancer, inflammatory diseases, and degenerative diseases. Ubiquitination is a cellular process that induces proteasomal degradation by covalently attaching ubiquitin to the substrate protein. In addition to proteolytic ubiquitination, nonproteolytic ubiquitination, such as M1-linked and K63-linked ubiquitination, has been shown to be important in recent studies, which have demonstrated its function in cell signaling pathways tha...
Source: Biochemical Pharmacology - November 16, 2018 Category: Drugs & Pharmacology Authors: Seo J, Wook Kim M, Bae KH, Lee SC, Song J, Lee EW Tags: Biochem Pharmacol Source Type: research

Scutellarin alleviates blood-retina-barrier oxidative stress injury initiated by activated microglia cells during the development of diabetic retinopathy.
In conclusion, SC alleviates BRB breakdown via abrogating retinal inflammatory responses and subsequent oxidative stress injury initiated by microglia cells that is activated by hyperglycemia during DR development. PMID: 30447218 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - November 14, 2018 Category: Drugs & Pharmacology Authors: Mei X, Zhang T, Ouyang H, Lu B, Wang Z, Ji L Tags: Biochem Pharmacol Source Type: research

Isoform-Specific Therapeutic Control of Sulfonation in Humans.
The objective of the current study was to assess whether the NSAID-binding site can be used to regulate sulfuryl transfer in humans in an isoform specific manner. Mefenamic acid (Mef) is a potent (Ki 27nM) NSAID-inhibitor of SULT1A1 - the predominant SULT isoform in small intestine and liver. Acetaminophen (APAP), a SULT1A1 specific substrate, is extensively sulfonated in humans. Dehydroepiandrosterone (DHEA) is specific for SULT2A1, which we show here is insensitive to Mef inhibition. APAP and DHEA sulfonates are readily quantified in urine and thus the effects of Mef on APAP and DHEA sulfonation could be studied non-inva...
Source: Biochemical Pharmacology - November 10, 2018 Category: Drugs & Pharmacology Authors: Cook I, Wang T, Leyh TS Tags: Biochem Pharmacol Source Type: research

Constitutive androstane receptor weakens the induction of panaxytriol on CYP3A4 by repressing the activation of pregnane X receptor.
In conclusion, CAR significantly weakens the ability of PXT to induce CYP3A4 expression by repressing the activation of PXR. There may be a cross-talk mechanism between PXR and CAR on the regulation of CYP3A4 in the presence of PXT. Additionally, a high concentration of PXT (80 μM) induced CYP3A4 via the CAR regulatory pathway. PMID: 30414935 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - November 8, 2018 Category: Drugs & Pharmacology Authors: Hu Q, Yao N, Wu J, Liu M, Liu F, Zhang H, Xiong Y, Xia C Tags: Biochem Pharmacol Source Type: research

From bench to bedside, via desktop. Recent advances in the application of cutting-edge in silico tools in the research of drugs targeting bromodomain modules.
Abstract The discipline of drug discovery has greatly benefited by computational tools and in silico algorithms aiming at rationalization of many related processes, from the stage of early hit identification to the preclinical phases of drug candidate validation. The various methodologies referred to as molecular modeling tools span a broad spectrum of applications, from straightforward approaches such as virtual screening of compound libraries to more advanced techniques involving the precise estimation of free energy upon binding of the candidate drug to its macromolecular target. To this end, we report an overv...
Source: Biochemical Pharmacology - November 8, 2018 Category: Drugs & Pharmacology Authors: Myrianthopoulos V, Mikros E Tags: Biochem Pharmacol Source Type: research

Dormant, quiescent, tolerant and persister cells: four synonyms for the same target in cancer.
ann D Abstract Although many drugs/treatments are now available for most diseases, too often, resistance to these treatments impedes complete therapeutic success. Acquired resistance is a major problem in many pathologies but it is an acute one in cancers and infections. This is probably because these diseases often require long durations of treatment, which ascribe to the selection of resistant cells. However, the actual mechanisms implicated in the selection process are still under debate. It is becoming increasingly clear that resistance is associated with the heterogeneity of cancer cells or micro-organisms an...
Source: Biochemical Pharmacology - November 8, 2018 Category: Drugs & Pharmacology Authors: Vallette FM, Olivier C, Lézot F, Oliver L, Cochonneau D, Lalier L, Cartron PF, Heymann D Tags: Biochem Pharmacol Source Type: research

Donepezil improves neuropathy through activation of AMPK signalling pathwayin streptozotocin-induced diabetic mice.
In this study, streptozotocin (45 mg/kg for 5 Day, i.p.) was used to induce experimental DN. After confirmation of development of neuropathy, mice were randomly distributed into five groups: Group 1; negative control group received saline (0.9%NaCl), Group 2; diabetic mice received saline, Group (3-5); diabetic mice received daily donepezil (1, 2 or 4 mg/kg, p.o.) respectively for 20 days. Mice were then sacrificed under anesthesia then their sciatic nerve and spinal cord were dissected out and processed for biochemical and histopathological studies. Diabetic mice revealed severe histological abnormalities including degene...
Source: Biochemical Pharmacology - November 8, 2018 Category: Drugs & Pharmacology Authors: Atef MM, El-Sayed NM, Ahmed AAM, Mostafa YM Tags: Biochem Pharmacol Source Type: research

Acyl-CoA Synthetase-4 is implicated in drug resistance in breast cancer cell lines involving the regulation of energy-dependent transporter expression.
Abstract Acyl-CoA synthetase-4 (ACSL4) is an enzyme implicated in estrogen receptor α (ERα) negative regulation and hormone therapy resistance in breast cancer. In addition, ACSL4 has been associated to certain types of hormone resistance in prostate cancer. Chemotherapeutic treatment of disseminated breast cancer is usually faced with therapy resistance associated to ATP-binding cassette (ABC) transporter expression, which detect and eject anti-cancer drugs from cells. In this context, the aim of the present work was to study the role of ACSL4 in anti-cancer drug resistance and the involvement of ABC ...
Source: Biochemical Pharmacology - November 8, 2018 Category: Drugs & Pharmacology Authors: Orlando UD, Castillo AF, Medrano MAR, Solano AR, Maloberti PM, Podesta EJ Tags: Biochem Pharmacol Source Type: research

Serine residues in the α4 nicotinic acetylcholine receptor subunit regulate surface α4β2* receptor expression and clustering.
CONCLUSIONS AND IMPLICATIONS: Effects of α4 nAChR mutants on surface upregulation varied among brain regions, suggesting that the cellular mechanism of α4β2* upregulation is complex and involves cellular identity. We also report for the first time that α4β2* nAChRs form clusters on the neuronal surface and that nicotine treatment alters the characteristics of the clusters in an α4 mutant-dependent manner. This finding adds a previously unknown layer of complexity to the effects of nicotine on α4β2* expression and function. PMID: 30414940 [PubMed - as supplied by publisher] ...
Source: Biochemical Pharmacology - November 8, 2018 Category: Drugs & Pharmacology Authors: Zambrano CA, Escobar D, Ramos-Santiago T, Bollinger I, Stitzel J Tags: Biochem Pharmacol Source Type: research

Poly(ADP-ribosylated) proteins in β-amyloid peptide-stimulated microglial cells.
Poly(ADP-ribosylated) proteins in β-amyloid peptide-stimulated microglial cells. Biochem Pharmacol. 2018 Nov 08;: Authors: Correani V, Martire S, Mignogna G, Caruso LB, Tempera I, Giorgi A, Grieco M, Mosca L, Schininà ME, Maras B, d'Erme M Abstract Amyloid-treated microglia prime and sustain neuroinflammatory processes in the central nervous system activating different signalling pathways inside the cells. Since a key role for PARP-1 has been demonstrated in inflammation and in neurodegeneration, we investigated PARylated proteins in resting and in β-amyloid peptide treated BV2 microg...
Source: Biochemical Pharmacology - November 8, 2018 Category: Drugs & Pharmacology Authors: Correani V, Martire S, Mignogna G, Caruso LB, Tempera I, Giorgi A, Grieco M, Mosca L, Schininà ME, Maras B, d'Erme M Tags: Biochem Pharmacol Source Type: research

Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF- α upregulation.
Non-mitotic effect of albendazole triggers apoptosis of human leukemia cells via SIRT3/ROS/p38 MAPK/TTP axis-mediated TNF-α upregulation. Biochem Pharmacol. 2018 Nov 07;: Authors: Wang LJ, Lee YC, Huang CH, Shi YJ, Chen YJ, Pei SN, Chou YW, Chang LS Abstract Albendazole (ABZ) is a microtubule-targeting anthelmintic that acts against a variety of human cancer cells, but the dependence of its cytotoxicity on non-mitotic effect remains elusive. Thus, we aimed to explore the mechanistic pathway underlying the cytotoxicity of ABZ in human leukemia U937 cells. ABZ-induced apoptosis of U937 cells was c...
Source: Biochemical Pharmacology - November 7, 2018 Category: Drugs & Pharmacology Authors: Wang LJ, Lee YC, Huang CH, Shi YJ, Chen YJ, Pei SN, Chou YW, Chang LS Tags: Biochem Pharmacol Source Type: research

Endothelial cell transient receptor potential channel C5 (TRPC5) is essential for endothelium-dependent contraction in mouse carotid arteries.
In this study, the molecular identity of Ca2+-permeable channels in endothelial cells and its function were investigated. Vascular tension was measured by wire myograph. EDCs were elicited by acetylcholine (ACH) in the presence of NG-nitro-L-arginine methyl ester (L-NAME). [Ca2+]i was measured using a Ca2+-sensitive fluorescence dye. Enzyme Immunoassay (EIA) was used for prostaglandin measurement. Immunohistochemical staining found the expression of transient receptor potential channel C5 (TRPC5) in endothelial and smooth muscle cells of mouse carotid arteries. ACH-induced EDC in male mouse carotid arteries was found to be...
Source: Biochemical Pharmacology - November 7, 2018 Category: Drugs & Pharmacology Authors: Liang C, Zhang Y, Zhuo D, Lo CY, Yu L, Lau CW, Kwan YW, Tse G, Huang Y, Yao X Tags: Biochem Pharmacol Source Type: research

Hepatic cytochrome P450 metabolism suppressed by mast cells in type 1 allergic mice.
Abstract Mast cells and Kupffer cells secrete interleukin (IL)-1β, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, which stimulate excess nitric oxide (NO) producing-inducible NO synthase (iNOS). Unlike Kupffer cells, immunoglobulin E-sensitized mast cells elicit sustained NO production. We investigated the participation of mast cell-released NO and cytokine-derived iNOS activation in type 1 allergy-suppressed hepatic cytochrome P450 (CYP) metabolism. Aminoguanidine, a selective iNOS inhibitor, completely suppressed serum nitrate plus nitrite (NOx) concentrations after primary and secondary...
Source: Biochemical Pharmacology - November 2, 2018 Category: Drugs & Pharmacology Authors: Tanino T, Bando T, Nojiri Y, Okada Y, Nagai N, Ueda Y, Sakurai E Tags: Biochem Pharmacol Source Type: research

3-dehydroandrographolide protects against lipopolysaccharide-induced inflammation through the cholinergic anti-inflammatory pathway.
In this study, murine macrophage RAW 264.7 cells and BALB/c mice were treated with LPS (lipopolysaccharide, 100 ng/ml in vitro; 3 mg/kg, intratracheal) to establish inflammation models. 3-DA attenuated the release of pro-inflammatory cytokines IL-6 and TNF-α, inhibited the degradation and phosphorylation of IκBα, and suppressed the nuclear translocation of NF-κB p65 as well as the phosphorylation of Akt at Ser473 in LPS-stimulated RAW 264.7 macrophage cells. Furthermore, 3-DA increased α7nAchR expression level and bound with α7nAchR. More importantly, the anti-inflammatory effects of 3-D...
Source: Biochemical Pharmacology - November 1, 2018 Category: Drugs & Pharmacology Authors: Lu Z, Xie P, Zhang D, Sun P, Yang H, Ye J, Cao H, Huo C, Zhou H, Chen Y, Ye W, Yu L, Liu J Tags: Biochem Pharmacol Source Type: research

A power law function describes the time- and dose-dependency of V γ9Vδ2 T cell activation by phosphoantigens.
A power law function describes the time- and dose-dependency of Vγ9Vδ2 T cell activation by phosphoantigens. Biochem Pharmacol. 2018 Nov 01;: Authors: Hsiao CC, Wiemer AJ Abstract Phosphoantigens stimulate Vγ9Vδ2 T cells after binding to BTN3A1 in target cells and cell-cell contact. We evaluated phosphoantigens including diphosphates, bisphosphonates, and prodrugs for ability to induce leukemia cells to stimulate Vγ9Vδ2 Tcell interferon-γ secretion. Most compounds displayed time-dependent activity at exposure times between 15-240 minutes. Potency (EC50 values)...
Source: Biochemical Pharmacology - November 1, 2018 Category: Drugs & Pharmacology Authors: Hsiao CC, Wiemer AJ Tags: Biochem Pharmacol Source Type: research

Corrigendum to 'Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro' [Biochem. Pharmacol. 148 (2018) 288-297].
PMID: 30390497 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - October 31, 2018 Category: Drugs & Pharmacology Authors: Misra A, Prakash P, Aggarwal H, Dhankani P, Kumar S, Prakash Pandey C, Pugh N, Bihan D, Kumar Barthwal M, Farndale RW, Kumar Dikshit D, Dikshit M Tags: Biochem Pharmacol Source Type: research

Identification of a 2-propanol analogue modulating the non-enzymatic function of indoleamine 2,3-dioxygenase 1.
Abstract Indoleamine 2,3 dioxygenase 1 (IDO1) is a metabolic enzyme that catalyzes the conversion of the essential amino acid tryptophan (Trp) into a series of immunoactive catabolites, collectively known as kynurenines. Through the depletion of Trp and the generation of kynurenines, IDO1 represents a key regulator of the immune responses involved in physiologic homeostasis as well as in neoplastic and autoimmune pathologies. The IDO1 enzyme has been described as an important immune checkpoint to be targeted by catalytic inhibitors in the treatment of cancer. In contrast, a defective expression/activity of the enz...
Source: Biochemical Pharmacology - October 31, 2018 Category: Drugs & Pharmacology Authors: Albini E, Coletti A, Greco F, Pallotta MT, Mondanelli G, Gargaro M, Belladonna ML, Volpi C, Bianchi R, Grohmann U, Macchiarulo A, Orabona C Tags: Biochem Pharmacol Source Type: research