Publications by authors named "Debanjan Dhar"

41 Publications

Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet.

Cell Mol Gastroenterol Hepatol 2021 May 29. Epub 2021 May 29.

Department of Medicine, University of California San Diego, La Jolla, California. Electronic address:

Background & Aims: How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH-HCC progression, as well as regression.

Methods: Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development.

Results: Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment.

Conclusions: The Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure.
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http://dx.doi.org/10.1016/j.jcmgh.2021.05.010DOI Listing
May 2021

The impact of genetic risk on liver fibrosis in non-alcoholic fatty liver disease as assessed by magnetic resonance elastography.

Aliment Pharmacol Ther 2021 Jul 11;54(1):68-77. Epub 2021 May 11.

Division of Gastroenterology, NAFLD Research Center, University of California at San Diego, La Jolla, CA, USA.

Background: Variants in multiple genetic loci modify the risk of non-alcoholic fatty liver disease (NAFLD) and cirrhosis but there are limited data on the quantitative impact of variant copies on liver fibrosis.

Aim: To investigate the effect of PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 genotype on liver fibrosis assessed by magnetic resonance elastography (MRE), a reproducible, accurate, continuous biomarker of liver fibrosis.

Methods: This is a cross-sectional analysis derived from a well-characterised cohort at risk for NAFLD who underwent genotyping and MRE assessment. Liver stiffness (LS) was estimated using MRE and advanced fibrosis was defined as liver stiffness ≥3.63 kilopascals (kPa). Univariable and multivariable linear and logistic regression analysis, were used to assess the association between genotype and MRE.

Results: Two hundred sixty-four patients (63% women) with a mean age 53 (±17) years, and 31% Hispanic ethnicity with genotyping and MRE were included. The odds of advanced fibrosis were 3.1 (95% CI: 1.1-8.9, P = 0.04) for CG and 6.5 (95% CI: 2.2-18.9, P < 0.01) for GG compared to CC PNPLA3 genotype. Each PNPLA3 risk variant copy was associated with 0.40 kPa (95% CI: 0.19-0.61, P < 0.01) increase in LS on MRE in analysis adjusted for age, sex and BMI and there was significant genotype-age interaction (P < 0.01). Conversely, the protective TA allele in HSD17B13 was associated with a -0.41 kPa (95% CI: -0.76 to -0.05, P = 0.03) decrease in liver stiffness on MRE multivariable analysis.

Conclusion: Knowledge of PNPLA3 and HSD17B13 genotype may assist in the non-invasive risk stratification of NAFLD with closer monitoring recommended for those with high genetic risk.
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http://dx.doi.org/10.1111/apt.16392DOI Listing
July 2021

Redox-Induced Structural Reorganization Dictates Kinetics of Cobalt(III) Hydride Formation via Proton-Coupled Electron Transfer.

J Am Chem Soc 2021 Mar 23;143(9):3393-3406. Epub 2021 Feb 23.

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States.

Two-electron, one-proton reactions of a family of [CoCp(dxpe)(NCCH)] complexes (Cp = cyclopentadienyl, dxpe = 1,2-bis(di(aryl/alkyl)phosphino)ethane) form the corresponding hydride species [HCoCp(dxpe)] (dxpe = dppe (1,2-bis(diphenylphosphino)ethane), depe (1,2-bis(diethylphosphino)ethane), and dcpe (1,2-bis(dicyclohexylphosphino)ethane)) through a stepwise proton-coupled electron transfer process. For three [CoCp(dxpe)(NCCH)] complexes, peak shift analysis was employed to quantify apparent proton transfer rate constants from cyclic voltammograms recorded with acids ranging 22 p units. The apparent proton transfer rate constants correlate with the strength of the proton source for weak acids, but these apparent proton transfer rate constants curiously plateau () as the reaction becomes increasingly exergonic. The absolute apparent proton transfer rate constants across both these regions correlate with the steric bulk of the chelating diphosphine ligand, with bulkier ligands leading to slower kinetics ( = 3.5 × 10 M s, = 1.7 × 10 M s, = 7.1 × 10 M s). Mechanistic studies were conducted to identify the cause of the aberrant -Δp trends. When deuterated acids are employed, deuterium incorporation in the Cp ring is observed, indicating protonation of the CoCp(dxpe) species to form the corresponding hydride proceeds via initial ligand protonation. Digital simulations of cyclic voltammograms show ligand loss accompanying initial reduction gates subsequent PCET activity at higher driving forces. Together, these experiments reveal the details of the reaction mechanism: reduction of the Co(III) species is followed by dissociation of the bound acetonitrile ligand, subsequent reduction of the unligated Co(II) species to form a Co(I) species is followed by protonation, which occurs at the Cp ring, followed by tautomerization to generate the stable Co(III)-hydride product [HCoCp(dxpe)]. Analysis as a function of chelating disphosphine ligand, solvent, and acid strength reveals that the ligand dissociation equilibrium is directly influenced by the steric bulk of the phosphine ligands and gates protonation, giving rise to the plateau of the apparent proton transfer rate constant with strong acids. The complexity of the reaction mechanism underpinning hydride formation, encompassing dynamic behavior of the entire ligand set, highlights the critical need to understand elementary reaction steps in proton-coupled electron transfer reactions.
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http://dx.doi.org/10.1021/jacs.0c11992DOI Listing
March 2021

Heterogeneity of hepatic stellate cells in a mouse model of non-alcoholic steatohepatitis (NASH).

Hepatology 2021 Feb 7. Epub 2021 Feb 7.

Department of Medicine, University of California San Diego, La Jolla, CA, USA, La Jolla.

In clinical and experimental non-alcoholic steatohepatitis (NASH), the origin of the scar-forming myofibroblast is the hepatic stellate cell (HSC). We used foz/foz mice on a Western diet to characterize in detail the phenotypic changes of HSCs in a NASH model. We examined the single cell expression profiles (scRNA-Seq) of HSCs purified from the normal livers of foz/foz mice on a chow diet, in NASH with fibrosis of foz/foz mice on a Western diet, and in livers during regression of NASH after switching back to a chow diet. Selected genes were analyzed using immunohistochemistry, qRT-PCR, and shRNA-knockdown in primary mouse HSCs. Our analysis of the normal liver identified two distinct clusters of quiescent HSCs that correspond to their acinar position of either pericentral vein or periportal vein. The NASH livers had four distinct HSC clusters, including one representing the classic fibrogenic myofibroblast. The three other HSC clusters consisted of a proliferating cluster, an intermediate activated cluster, and an immune and inflammatory cluster. The livers with NASH regression had one cluster of inactivated HSCs, which was similar to, but distinct from, the quiescent HSCs. Conclusion: Analysis of scRNA-Seq in combination with an interrogation of previous studies has revealed an unanticipated heterogeneity of HSC phenotypes under normal and injured states.
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http://dx.doi.org/10.1002/hep.31743DOI Listing
February 2021

Emerging Metabolic and Transcriptomic Signature of PNPLA3-Associated NASH.

Hepatology 2021 Apr;73(4):1248-1250

Division of Gastroenterology, University of California San Diego, La Jolla, CA.

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http://dx.doi.org/10.1002/hep.31735DOI Listing
April 2021

Metabolic interaction between amino acid deprivation and cisplatin synergistically reduces phosphoribosyl-pyrophosphate and augments cisplatin cytotoxicity.

Sci Rep 2020 11 16;10(1):19907. Epub 2020 Nov 16.

Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0652, USA.

Cisplatin is a mainstay of cancer chemotherapy. It forms DNA adducts, thereby activating poly(ADP-ribose) polymerases (PARPs) to initiate DNA repair. The PARP substrate NAD is synthesized from 5-phosphoribose-1-pyrophosphate (PRPP), and we found that treating cells for 6 h with cisplatin reduced intracellular PRPP availability. The decrease in PRPP was likely from (1) increased PRPP consumption, because cisplatin increased protein PARylation and PARP1 shRNA knock-down returned PRPP towards normal, and (2) decreased intracellular phosphate, which down-regulated PRPP synthetase activity. Depriving cells of a single essential amino acid decreased PRPP synthetase activity with a half-life of ~ 8 h, and combining cisplatin and amino acid deprivation synergistically reduced intracellular PRPP. PRPP is a rate-limiting substrate for purine nucleotide synthesis, and cisplatin inhibited de novo purine synthesis and DNA synthesis, with amino acid deprivation augmenting cisplatin's effects. Amino acid deprivation enhanced cisplatin's cytotoxicity, increasing cellular apoptosis and DNA strand breaks in vitro, and intermittent deprivation of lysine combined with a sub-therapeutic dose of cisplatin inhibited growth of ectopic hepatomas in mice. Augmentation of cisplatin's biochemical and cytotoxic effects by amino acid deprivation suggest that intermittent deprivation of an essential amino acid could allow dose reduction of cisplatin; this could reduce the drug's side effects, and allow its use in cisplatin-resistant tumors.
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http://dx.doi.org/10.1038/s41598-020-76958-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670436PMC
November 2020

Quantitative Effects of Disorder on Chemically Modified Amorphous Carbon Electrodes.

ACS Appl Energy Mater 2020 Aug 27;3(8):8038-8047. Epub 2020 Jul 27.

Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States.

Real materials are disordered. This disorder influences the properties of these materials and the chemical processes that occur at their interfaces. Gaining a molecular-level understanding of the underlying physical manifestations caused by disordered materials is crucial to unraveling and ultimately controlling the efficiency and performance of these materials in a range of energy-related devices. This understanding necessitates measurement techniques through which disorder can be detected, quantified, and monitored. However, such quantitative measurements are notoriously difficult, as effects often average out in ensemble measurements. In this work, we describe how a combination of electrochemical and spatially resolved surface spectroscopy measurements illuminate a molecular-level picture of disorder in materials. Using amorphous carbon as an intrinsically disordered material, we covalently attached a monolayer of ferrocene. Interfacial electron transfer across the amorphous carbon-ferrocene interface is highly sensitive to disruptions of order. By systematically varying linker properties and surface loadings, the influence of lateral interactions between nonuniformly distributed ferrocene headgroups on ensemble electrochemical measurements is demonstrated. Electrochemical and imaging data collectively indicate that conformational flexibility of the ferrocene moieties provides a mechanism to elude repulsive and unbalanced lateral interactions, while rigid linkages provide direct information about the underlying disorder of the material. This study is the first of its kind to quantify and visualize molecular disorder and heterogeneity with an experimental model accessed through ensemble measurements.
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http://dx.doi.org/10.1021/acsaem.0c01434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505236PMC
August 2020

Western Diet Promotes Renal Injury, Inflammation, and Fibrosis in a Murine Model of Alström Syndrome.

Nephron 2020 6;144(8):400-412. Epub 2020 Jul 6.

Division of Nephrology & Hypertension, Department of Medicine, University of California San Diego & VA San Diego Healthcare System, San Diego, California, USA,

Introduction: Alström syndrome is a rare recessive genetic disease caused by mutations in ALMS1, which encodes a protein that is related to cilia function and intracellular endosome trafficking. The syndrome has been linked to impaired glucose metabolism and CKD. Polymorphisms in Alms1 have likewise been linked to CKD, but little is known about the modification of the phenotype by environmental factors.

Methods: To gain further insights, the fat aussie (foz) mouse strain, a genetic murine model of Alström syndrome, was exposed to a normal chow (NC) or to a Western diet (WD, 20% fat, 34% sucrose by weight, and 0.2% cholesterol) and renal outcomes were measured.

Results: Body weight and albuminuria were higher in foz than in wild-type (WT) mice on both diets but WD significantly increased the difference. Measurement of plasma creatinine and cystatin C indicated that glomerular filtration rate was preserved in foz versus WT independent of diet. Renal markers of injury, inflammation, and fibrosis were similar in both genotypes on NC but significantly greater in foz than in WT mice on WD. A glucose tolerance test performed in foz and WT mice on WD revealed similar basal blood glucose levels and subsequent blood glucose profiles.

Conclusions: WD sensitizes a murine model of Alström syndrome to kidney injury, inflammation, and fibrosis, an effect that may not be solely due to effects on glucose metabolism. Polymorphisms in Alms1 may induce CKD in part by modulating the deleterious effects of high dietary fat and sucrose on kidney outcome.
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http://dx.doi.org/10.1159/000508636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011852PMC
July 2020

Mechanisms of liver fibrosis and its role in liver cancer.

Exp Biol Med (Maywood) 2020 01 10;245(2):96-108. Epub 2020 Jan 10.

Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.

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http://dx.doi.org/10.1177/1535370219898141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016420PMC
January 2020

Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice.

J Hepatol 2019 09 7;71(3):573-585. Epub 2019 May 7.

Department of Surgery, University of California San Diego, La Jolla, CA, USA. Electronic address:

Background & Aims: Chronic liver injury often results in the activation of hepatic myofibroblasts and the development of liver fibrosis. Hepatic myofibroblasts may originate from 3 major sources: hepatic stellate cells (HSCs), portal fibroblasts (PFs), and fibrocytes, with varying contributions depending on the etiology of liver injury. Here, we assessed the composition of hepatic myofibroblasts in multidrug resistance gene 2 knockout (Mdr2) mice, a genetic model that resembles primary sclerosing cholangitis in patients.

Methods: Mdr2 mice expressing a collagen-GFP reporter were analyzed at different ages. Hepatic non-parenchymal cells isolated from collagen-GFP Mdr2 mice were sorted based on collagen-GFP and vitamin A. An NADPH oxidase (NOX) 1/4 inhibitor was administrated to Mdr2 mice aged 12-16 weeks old to assess the therapeutic approach of targeting oxidative stress in cholestatic injury.

Results: Thy1 activated PFs accounted for 26%, 51%, and 54% of collagen-GFP myofibroblasts in Mdr2 mice at 4, 8, and 16 weeks of age, respectively. The remaining collagen-GFP myofibroblasts were composed of activated HSCs, suggesting that PFs and HSCs are both activated in Mdr2 mice. Bone-marrow-derived fibrocytes minimally contributed to liver fibrosis in Mdr2 mice. The development of cholestatic liver fibrosis in Mdr2 mice was associated with early recruitment of Gr1 myeloid cells and upregulation of pro-inflammatory cytokines (4 weeks). Administration of a NOX inhibitor to 12-week-old Mdr2 mice suppressed the activation of myofibroblasts and attenuated the development of cholestatic fibrosis.

Conclusions: Activated PFs and activated HSCs contribute to cholestatic fibrosis in Mdr2 mice, and serve as targets for antifibrotic therapy.

Lay Summary: Activated portal fibroblasts and hepatic stellate cells, but not fibrocytes, contributed to the production of the fibrous scar in livers of Mdr2 mice, and these cells can serve as targets for antifibrotic therapy in cholestatic injury. Therapeutic inhibition of the enzyme NADPH oxidase (NOX) in Mdr2 mice reversed cholestatic fibrosis, suggesting that targeting NOXs may be an effective strategy for the treatment of cholestatic fibrosis.
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http://dx.doi.org/10.1016/j.jhep.2019.04.012DOI Listing
September 2019

Mechanistic Dichotomy in Proton-Coupled Electron-Transfer Reactions of Phenols with a Copper Superoxide Complex.

J Am Chem Soc 2019 04 25;141(13):5470-5480. Epub 2019 Mar 25.

Department of Chemistry , Washington University in St. Louis , One Brookings Drive, Campus Box 1134 , St. Louis , Missouri 63130-4899 , United States.

The kinetics and mechanism(s) of the reactions of [K(Krypt)][LCuO] (Krypt = 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane, L = a bis(arylcarboxamido)pyridine ligand) with 2,2,6,6-tetramethylpiperdine- N-hydroxide (TEMPOH) and the para-substituted phenols ArOH (X = para substituent NO, CF, Cl, H, Me, Bu, OMe, or NMe) at low temperatures were studied. The reaction with TEMPOH occurs rapidly ( k = 35.4 ± 0.3 M s) by second-order kinetics to yield TEMPO and [LCuOOH] on the basis of electron paramagnetic resonance spectroscopy, the production of HO upon treatment with protic acid, and independent preparation from reaction of [NBu][LCuOH] with HO ( K = 0.022 ± 0.007 for the reverse reaction). The reactions with ArOH also follow second-order kinetics, and analysis of the variation of the k values as a function of phenol properties (Hammett σ parameter, O-H bond dissociation free energy, p K, E) revealed a change in mechanism across the series, from proton transfer/electron transfer for X = NO, CF, Cl to concerted-proton/electron transfer (or hydrogen-atom transfer) for X = OMe, NMe (data for X = H, Me, Bu are intermediate between the extremes). Thermodynamic analysis and comparisons to previous results for LCuOH, a different copper-oxygen intermediate with the same supporting ligand, and literature for other [CuO] complexes reveal significant differences in proton-coupled electron-transfer mechanisms that have implications for understanding oxidation catalysis by copper-containing enzymes and abiological catalysts.
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http://dx.doi.org/10.1021/jacs.9b00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584633PMC
April 2019

NADPH Oxidase 1 in Liver Macrophages Promotes Inflammation and Tumor Development in Mice.

Gastroenterology 2019 03 13;156(4):1156-1172.e6. Epub 2018 Nov 13.

Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California. Electronic address:

Background & Aims: Although there are associations among oxidative stress, reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice after administration of a liver carcinogen.

Methods: Fourteen-day-old Nox1 mice, Nox4 mice, Nox1Nox4 (double-knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months. We also studied the effects of DEN in mice with disruption of Nox1 specifically in hepatocytes (Nox1), hepatic stellate cells (Nox1), or macrophages (Nox1). Some mice were also given injections of the NOX1-specific inhibitor ML171. To study the acute effects of DEN, 8-12-week-old mice were given a single intraperitoneal injection, and liver and serum were collected at 72 hours. Liver tissues were analyzed by histologic examination, quantitative polymerase chain reaction, and immunoblots. Hepatocytes and macrophages were isolated from WT and knockout mice and analyzed by immunoblots.

Results: Nox4 mice and WT mice developed liver tumors within 9 months after administration of DEN, whereas Nox1 mice developed 80% fewer tumors, which were 50% smaller than those of WT mice. Nox1 and Nox1 mice developed liver tumors of the same number and size as WT mice, whereas Nox1 developed fewer and smaller tumors, similar to Nox1 mice. After DEN injection, levels of tumor necrosis factor, interleukin 6 (IL6), and phosphorylated signal transducer and activator of transcription 3 were increased in livers from WT, but not Nox1 or Nox1, mice. Conditioned medium from necrotic hepatocytes induced expression of NOX1 in cultured macrophages, followed by expression of tumor necrosis factor, IL6, and other inflammatory cytokines; this medium did not induce expression of IL6 or cytokines in Nox1 macrophages. WT mice given DEN followed by ML171 developed fewer and smaller liver tumors than mice given DEN followed by vehicle.

Conclusions: In mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow hepatocellular carcinoma progression.
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http://dx.doi.org/10.1053/j.gastro.2018.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409207PMC
March 2019

ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P.

Cell 2018 09 13;175(1):133-145.e15. Epub 2018 Sep 13.

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA. Electronic address:

Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) in response to elevated endoplasmic reticulum (ER) stress. Whereas the onset of simple steatosis requires elevated de novo lipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. We now show that caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. Caspase-2 ablation or pharmacological inhibition prevents diet-induced steatosis and NASH progression in ER-stress-prone mice. Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases, whereas caspase-2-generated S1P proteolytic fragments, which enter the secretory pathway, are potential NASH biomarkers.
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http://dx.doi.org/10.1016/j.cell.2018.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159928PMC
September 2018

Effects of Charged Ligand Substituents on the Properties of the Formally Copper(III)-Hydroxide ([CuOH]) Unit.

Inorg Chem 2018 Aug 2;57(16):9794-9806. Epub 2018 Aug 2.

Department of Chemistry , Washington University in St. Louis , Campus Box 1134, 1 Brookings Drive , St. Louis , Missouri 63130 , United States.

With the goal of understanding how distal charge influences the properties and hydrogen atom transfer (HAT) reactivity of the [CuOH] core proposed to be important in oxidation catalysis, the complexes [M][LCuOH] (M = [K(18-crown-6)] or [K(crypt-222)]) and [LCuOH]X (X = BAr or ClO) were prepared, in which SO or NMe substituents occupy the para positions of the flanking aryl rings of the supporting bis(carboxamide)pyridine ligands. Structural and spectroscopic characterization showed that the [CuOH] cores in the corresponding complexes were similar, but cyclic voltammetry revealed the E value for the [CuOH]/[CuOH] couple to be nearly 0.3 V more oxidizing for the [LCuOH] than the [LCuOH] species, with the latter influenced by interactions between the distal -SO substituents and K or Na counterions. Chemical oxidations of the complexes generated the corresponding [CuOH] species as evinced by UV-vis spectroscopy. The rates of HAT reactions of these species with 9,10-dihydroanthracene to yield the corresponding [Cu(OH)] complexes and anthracene were measured, and the thermodynamics of the processes were evaluated via determination of the bond dissociation enthalpies (BDEs) of the product O-H bonds. The HAT rate for [LCuOH] was found to be ∼150 times faster than that for [LCuOH], despite finding approximately the same BDEs for the product O-H bonds. Rationales for these observations and new insights into the roles of supporting ligand attributes on the properties of the [CuOH] unit are presented.
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http://dx.doi.org/10.1021/acs.inorgchem.8b01529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653640PMC
August 2018

Author Correction: Inflammation-induced IgA cells dismantle anti-liver cancer immunity.

Nature 2018 09;561(7721):E1

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, California, 92093, USA.

In this Article, the sentence: "After 7 months of HFD, MUP-uPA mice developed HCC, which contained numerous (usually 50-100 per tumour) non-recurrent coding mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).", should have read: "After 7 months of HFD, MUP-uPA mice developed HCC, which contained numerous (usually 50-100 per tumour) non-recurrent mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).". This has been corrected online. In Extended Data Fig. 6a and b, which show the number of point mutations identified per sample and the mutational signatures, all sequence variants (including non-coding mutations) are shown. Fig. 2d also presents all variants compared to human mutations. In the Supplementary Information to this Amendment, we now provide the comparisons of all variants and coding variants to human mutations.
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http://dx.doi.org/10.1038/s41586-018-0304-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871211PMC
September 2018

Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling.

Cancer Cell 2018 06;33(6):1061-1077.e6

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Pathology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Moores Cancer Center, University of California San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA. Electronic address:

How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors.
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http://dx.doi.org/10.1016/j.ccell.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005359PMC
June 2018

An Overlapping Region between the Two Terminal Folding Units of the Outer Surface Protein A (OspA) Controls Its Folding Behavior.

J Mol Biol 2018 06 27;430(12):1799-1813. Epub 2018 Apr 27.

Okazaki Institute for Integrative Bioscience and Institute for Molecular Science, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan; Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan; Department of Physics, School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; School of Computational Sciences, Korea Institute for Advanced Study (KIAS), Dongdaemun-gu, Seoul 130-722, Korea.

Although many naturally occurring proteins consist of multiple domains, most studies on protein folding to date deal with single-domain proteins or isolated domains of multi-domain proteins. Studies of multi-domain protein folding are required for further advancing our understanding of protein folding mechanisms. Borrelia outer surface protein A (OspA) is a β-rich two-domain protein, in which two globular domains are connected by a rigid and stable single-layer β-sheet. Thus, OspA is particularly suited as a model system for studying the interplays of domains in protein folding. Here, we studied the equilibria and kinetics of the urea-induced folding-unfolding reactions of OspA probed with tryptophan fluorescence and ultraviolet circular dichroism. Global analysis of the experimental data revealed compelling lines of evidence for accumulation of an on-pathway intermediate during kinetic refolding and for the identity between the kinetic intermediate and a previously described equilibrium unfolding intermediate. The results suggest that the intermediate has the fully native structure in the N-terminal domain and the single layer β-sheet, with the C-terminal domain still unfolded. The observation of the productive on-pathway folding intermediate clearly indicates substantial interactions between the two domains mediated by the single-layer β-sheet. We propose that a rigid and stable intervening region between two domains creates an overlap between two folding units and can energetically couple their folding reactions.
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http://dx.doi.org/10.1016/j.jmb.2018.04.025DOI Listing
June 2018

Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas.

Cancer Cell 2017 Dec 16;32(6):824-839.e8. Epub 2017 Nov 16.

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address:

Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed Kras acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals.
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http://dx.doi.org/10.1016/j.ccell.2017.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730340PMC
December 2017

Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity.

Nature 2017 11 8;551(7680):340-345. Epub 2017 Nov 8.

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, California 92093, USA.

The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8 T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8 T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8 T-lymphocyte activation as a tumour-promoting mechanism.
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http://dx.doi.org/10.1038/nature24302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884449PMC
November 2017

Formally Copper(III)-Alkylperoxo Complexes as Models of Possible Intermediates in Monooxygenase Enzymes.

J Am Chem Soc 2017 08 19;139(30):10220-10223. Epub 2017 Jul 19.

Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.

Reaction of [NBu][LCuOH] with excess ROOH (R = cumyl or tBu) yielded [NBu][LCuOOR], the reversible one-electron oxidation of which generated novel species with [CuOOR] cores (formally CuOOR), identified by spectroscopy and theory for the case R = cumyl. This species reacts with weak O-H bonds in TEMPO-H and 4-dimethylaminophenol (PhOH), the latter yielding LCu(OPh), which was also prepared independently. With the identification of [CuOOR] complexes, the first precedent for this core in enzymes is provided, with implications for copper monooxygenase mechanisms.
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http://dx.doi.org/10.1021/jacs.7b05754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132249PMC
August 2017

DNA methylation markers for diagnosis and prognosis of common cancers.

Proc Natl Acad Sci U S A 2017 07 26;114(28):7414-7419. Epub 2017 Jun 26.

Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093;

The ability to identify a specific cancer using minimally invasive biopsy holds great promise for improving the diagnosis, treatment selection, and prediction of prognosis in cancer. Using whole-genome methylation data from The Cancer Genome Atlas (TCGA) and machine learning methods, we evaluated the utility of DNA methylation for differentiating tumor tissue and normal tissue for four common cancers (breast, colon, liver, and lung). We identified cancer markers in a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples. We replicated our findings in a separate TCGA cohort of 791 tumor samples and 93 matched adjacent normal tissue samples, as well as an independent Chinese cohort of 394 tumor samples and 324 matched adjacent normal tissue samples. The DNA methylation analysis could predict cancer versus normal tissue with more than 95% accuracy in these three cohorts, demonstrating accuracy comparable to typical diagnostic methods. This analysis also correctly identified 29 of 30 colorectal cancer metastases to the liver and 32 of 34 colorectal cancer metastases to the lung. We also found that methylation patterns can predict prognosis and survival. We correlated differential methylation of CpG sites predictive of cancer with expression of associated genes known to be important in cancer biology, showing decreased expression with increased methylation, as expected. We verified gene expression profiles in a mouse model of hepatocellular carcinoma. Taken together, these findings demonstrate the utility of methylation biomarkers for the molecular characterization of cancer, with implications for diagnosis and prognosis.
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http://dx.doi.org/10.1073/pnas.1703577114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514741PMC
July 2017

Reactivity of the copper(iii)-hydroxide unit with phenols.

Chem Sci 2017 Feb 27;8(2):1075-1085. Epub 2016 Sep 27.

Department of Chemistry , Center for Metals in Biocatalysis , University of Minnesota , 207 Pleasant St. SE , Minneapolis , MN 55455 , USA . Email:

Kinetic studies of the reactions of two previously characterized copper(iii)-hydroxide complexes (LCuOH and LCuOH, where L = ,'-bis(2,6-diisopropylphenyl)-2,6-pyridine-dicarboxamide and L = ,'-bis(2,6-diisopropyl-4-nitrophenyl)pyridine-2,6-dicarboxamide) with a series of substituted phenols (ArOH where X = NMe, OMe, Me, H, Cl, NO, or CF) were performed using low temperature stopped-flow UV-vis spectroscopy. Second-order rate constants () were determined from pseudo first-order and stoichiometric experiments, and follow the trends CF < NO < Cl < H < Me < OMe < NMe and LCuOH < LCuOH. The data support a concerted proton-electron transfer (CPET) mechanism for all but the most acidic phenols (X = NO and CF), for which a more complicated mechanism is proposed. For the case of the reactions between ArOH and LCuOH in particular, competition between a CPET pathway and one involving initial proton transfer followed by electron transfer (PT/ET) is supported by multiwavelength global analysis of the kinetic data, formation of the phenoxide ArO as a reaction product, observation of an intermediate [LCu(OH)] species derived from proton transfer from ArOH to LCuOH, and thermodynamic arguments indicating that initial PT should be competitive with CPET.
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http://dx.doi.org/10.1039/c6sc03039dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452261PMC
February 2017

Determination of the Cu(III)-OH Bond Distance by Resonance Raman Spectroscopy Using a Normalized Version of Badger's Rule.

J Am Chem Soc 2017 03 20;139(12):4477-4485. Epub 2017 Mar 20.

Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.

The stretching frequency, ν(Cu-O), of the [CuOH] core in the complexes LCuOH (L = N,N'-bis(2,6-diisopropyl-4-R-phenyl)pyridine-2,6-dicarboxamide, R = H or NO, or N,N'-bis(2,6-diisopropylphenyl)-1-methylpiperidine-2,6-dicarboxamide) was determined to be ∼630 cm by resonance Raman spectroscopy and verified by isotopic labeling. In efforts to use Badger's rule to estimate the bond distance corresponding to ν(Cu-O), a modified version of the rule was developed through use of stretching frequencies normalized by dividing by the appropriate reduced masses. The modified version was found to yield excellent fits of normalized frequencies to bond distances for >250 data points from theory and experiment for a variety of M-X and X-X bond distances in the range ∼1.1-2.2 Å (root mean squared errors for the predicted bond distances of 0.03 Å). Using the resulting general equation, the Cu-O bond distance was predicted to be ∼1.80 Å for the reactive [CuOH] core. Limitations of the equation and its use in predictions of distances in a variety of moieties for which structural information is not available were explored.
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http://dx.doi.org/10.1021/jacs.7b00210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975256PMC
March 2017

Copper-Oxygen Complexes Revisited: Structures, Spectroscopy, and Reactivity.

Chem Rev 2017 02 19;117(3):2059-2107. Epub 2017 Jan 19.

Department of Chemistry, Center for Metals in Biocatalysis, University of Minnesota , 207 Pleasant St. SE, Minneapolis, Minnesota 55455, United States.

A longstanding research goal has been to understand the nature and role of copper-oxygen intermediates within copper-containing enzymes and abiological catalysts. Synthetic chemistry has played a pivotal role in highlighting the viability of proposed intermediates and expanding the library of known copper-oxygen cores. In addition to the number of new complexes that have been synthesized since the previous reviews on this topic in this journal (Mirica, L. M.; Ottenwaelder, X.; Stack, T. D. P. Chem. Rev. 2004, 104, 1013-1046 and Lewis, E. A.; Tolman, W. B. Chem. Rev. 2004, 104, 1047-1076), the field has seen significant expansion in the (1) range of cores synthesized and characterized, (2) amount of mechanistic work performed, particularly in the area of organic substrate oxidation, and (3) use of computational methods for both the corroboration and prediction of proposed intermediates. The scope of this review has been limited to well-characterized examples of copper-oxygen species but seeks to provide a thorough picture of the spectroscopic characteristics and reactivity trends of the copper-oxygen cores discussed.
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http://dx.doi.org/10.1021/acs.chemrev.6b00636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5963733PMC
February 2017

Nickel(II) Complex of a Hexadentate Ligand with Two o-Iminosemiquinonato(1-) π-Radical Units and Its Monocation and Dication.

Inorg Chem 2016 Jun 27;55(12):5759-71. Epub 2016 May 27.

Department of Chemistry, Indian Institute of Technology Kanpur , Kanpur 208 016, India.

Aerobic reaction of a hexadentate redox-active o-aminophenol-based ligand, H4L(3) = N,N'-bis(2-hydroxy-3,5-di-tert-butylphenyl)-2,2'-diamino(diphenyldithio)-ethane, in CH3OH with Ni(II)(O2CCH3)2·4H2O and Et3N afforded isolation of a reddish-brown crystalline solid [Ni(L(3))] 1. Cyclic voltammetry (CV) experiment exhibits two oxidative responses at E1/2 = 0.09 and 0.53 V vs SCE (saturated calomel electrode). Chemical oxidation of 1 in air by [Fe(III)(η(5)-C5H5)2][PF6] and AgBF4 in CH2Cl2 led to the isolation of one-electron oxidized species [1](1+) as purple [1][PF6]·CH2Cl2 and two-electron oxidized species [1](2+) as dark purple [1][BF4]2·CH2Cl2, respectively. X-ray crystallographic analysis at 100(2) K unambiguously established that the ligand is present in [Ni(II){(L(ISQ)O,N)(•-)}{(L(ISQ)O,N)(•-)}{(LS,S)(0)}] 1, [Ni(II){(L(IBQ)O,N)(0)}{(L(ISQ)O,N)(•-)}{(LS,S)(0)}][PF6]·CH2Cl2, and [Ni(II){(L(IBQ)O,N)(0)}{(L(IBQ)O,N)(0)}{(LS,S)(0)}][BF4]2·CH2Cl2, as monoanionic o-iminosemiquinonate(1-) π-radical (Srad = 1/2) (L(ISQ))(•-) and neutral o-iminoquinone (L(IBQ))(0) redox-levels. Complexes 1, [1][PF6]·CH2Cl2, and [1][BF4]2·CH2Cl2 possess an S = 2, 3/2, and 1 ground-state, respectively, established by temperature-dependent (2-300 K) magnetic behavior of 1 and [1][PF6]·CH2Cl2, and a μeff value of [1][BF4]2·CH2Cl2 at 300 K. Both 1 and [1][PF6]·CH2Cl2 exhibit ferromagnetic exchange-coupling between the two electrons of Ni(II) and two/one ligand π-radicals, respectively. The redox processes are shown to be ligand-based. Spectroscopic and redox properties, and density functional theory (DFT) calculations at the CAM-B3LYP-level of theory adequately describe the electronic structure of 1, [1](1+), and [1](2+). The observed UV-vis-NIR absorptions for 1, [1][PF6]·CH2Cl2, and [1][BF4]2·CH2Cl2 have been assigned, based on time-dependent (TD)-DFT calculations.
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http://dx.doi.org/10.1021/acs.inorgchem.5b02688DOI Listing
June 2016

Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2.

Carcinogenesis 2016 06 4;37(6):541-6. Epub 2016 May 4.

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology.

The liver is a key metabolic organ that is essential for production of blood proteins, lipid and sugar metabolism and detoxification of naturally occurring and foreign harmful chemicals. To maintain its mass and many essential functions, the liver possesses remarkable regenerative capacity, but the latter also renders it highly susceptible to carcinogenesis. In fact, liver cancer often develops in the context of chronic liver injury. Currently, primary liver cancer is the second leading cause of cancer-related deaths, and as the rates of other cancers have been declining, the incidence of liver cancer continues to rise with an alarming rate. Although much remains to be accomplished in regards to liver cancer therapy, we have learned a great deal about the molecular etiology of the most common form of primary liver cancer, hepatocellular carcinoma (HCC). Much of this knowledge has been obtained from studies of mouse models, using either toxic chemicals, a combination of fatty foods and endoplasmic reticulum stress or chronic activation of specific metabolic pathways. Surprisingly, NRF2, a transcription factor that was initially thought to protect the liver from oxidative stress, was found to play a key role in promoting HCC pathogenesis.
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http://dx.doi.org/10.1093/carcin/bgw060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876993PMC
June 2016

Perturbing the Copper(III)-Hydroxide Unit through Ligand Structural Variation.

J Am Chem Soc 2016 Jan 22;138(1):356-68. Epub 2015 Dec 22.

Department of Chemistry, Center for Metals in Biocatalysis, Chemical Theory Center, and Minnesota Supercomputing Institute, University of Minnesota , 207 Pleasant Street Southeast, Minneapolis, Minnesota 55455, United States.

Two new ligand sets, (pipMe)LH2 and (NO2)LH2 ((pipMe)L = N,N'-bis(2,6-diisopropylphenyl)-1-methylpiperidine-2,6-dicarboxamide, (NO2)L = N,N'-bis(2,6-diisopropyl-4-nitrophenyl)pyridine-2,6-dicarboxamide), are reported which are designed to perturb the overall electronics of the copper(III)-hydroxide core and the resulting effects on the thermodynamics and kinetics of its hydrogen-atom abstraction (HAT) reactions. Bond dissociation energies (BDEs) for the O-H bonds of the corresponding Cu(II)-OH2 complexes were measured that reveal that changes in the redox potential for the Cu(III)/Cu(II) couple are only partially offset by opposite changes in the pKa, leading to modest differences in BDE among the three compounds. The effects of these changes were further probed by evaluating the rates of HAT by the corresponding Cu(III)-hydroxide complexes from substrates with C-H bonds of variable strength. These studies revealed an overarching linear trend in the relationship between the log k (where k is the second-order rate constant) and the ΔH of reaction. Additional subtleties in measured rates arise, however, that are associated with variations in hydrogen-atom abstraction barrier heights and tunneling efficiencies over the temperature range from -80 to -20 °C, as inferred from measured kinetic isotope effects and corresponding electronic-structure-based transition-state theory calculations.
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http://dx.doi.org/10.1021/jacs.5b10985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857600PMC
January 2016

Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy.

Nature 2015 May 29;521(7550):94-8. Epub 2015 Apr 29.

1] Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, San Diego, California 92093, USA [2] Department of Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, San Diego, California 92093, USA.

Cancer-associated genetic alterations induce expression of tumour antigens that can activate CD8(+) cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms. Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers. Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms. Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IκB kinase α (IKKα)-BMI1 module in prostate cancer stem cells. Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent that is effective in aggressive prostate cancer. We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGFβ receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours.
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http://dx.doi.org/10.1038/nature14395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501632PMC
May 2015

Hydrogen atom abstraction from hydrocarbons by a copper(III)-hydroxide complex.

J Am Chem Soc 2015 Jan 12;137(3):1322-9. Epub 2015 Jan 12.

Department of Chemistry and Center for Metals in Biocatalysis, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.

With the aim of understanding the basis for the high rate of hydrogen atom abstraction (HAT) from dihydroanthracene (DHA) by the complex LCuOH (1; L = N,N'-bis(2,6-diisopropylphenyl)-2,6-pyridinedicarboxamide), the bond dissociation enthalpy of the reaction product LCu(H2O) (2) was determined through measurement of its pK(a) and E(1/2) in THF solution. In so doing, an equilibrium between 2 and LCu(THF) was characterized by UV-vis and EPR spectroscopy and cyclic voltammetry (CV). A high pK(a) of 18.8 ± 1.8 and a low E(1/2) of -0.074 V vs Fc/Fc(+) in THF combined to yield an O-H BDE for 2 of 90 ± 3 kcal mol(-1) that is large relative to values for most transition metal oxo/hydroxo complexes. By taking advantage of the increased stability of 1 observed in 1,2-difluorobenzene (DFB) solvent, the kinetics of the reactions of 1 with a range of substrates with varying BDE values for their C-H bonds were measured. The oxidizing power of 1 was revealed through the accelerated decay of 1 in the presence of the substrates, including THF (BDE = 92 kcal mol(-1)) and cyclohexane (BDE = 99 kcal mol(-1)). CV experiments in THF solvent showed that 1 reacted with THF via rate-determining attack at the THF C-H(D) bonds with a kinetic isotope effect of 10.2. Analysis of the kinetic and thermodynamic data provides new insights into the basis for the high reactivity of 1 and the possible involvement of species like 1 in oxidation catalysis.
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http://dx.doi.org/10.1021/ja512014zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311965PMC
January 2015