Chemical characterization of atmospheric particulate matter in Friuli Venezia Giulia (NE Italy) by exploratory data analysis with multisite and multivariate approach

Abstract

The chemical composition of atmospheric particulate (PM10) in the Friuli Venezia Giulia (FVG) region (NE Italy) has been characterized for the first time with the help of exploratory data analysis (EDA) techniques (uni-, bi-, and multivariated, i.e., principal components analysis), molecular and elemental diagnostic ratios, and seasonal trends. Despite that the available analytical data was limited to the parameters routinely analyzed on PM10 by ARPA FVG (11 elements and 16 PAH congeners), the large number of samples and of measured chemical parameters, together with the applied techniques of data analysis, allowed us to extract useful latent information from the dataset, resulting in a greater knowledge of both regional and local features. Specifically, we succeeded in matching data patterns to the known pollution sources of some sampling stations, both industrial (two secondary fusion steelworks and one coke oven) and urban (traffic and domestic heating), and in defining the mainly urban or mainly industrial feature of some questionable sampling stations. This is of paramount importance to check for possible industrial inputs in urban stations, allowing policymakers to implement the most appropriate response.

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Editorial Board

Publication date: June 2018
Source:Cancer Treatment Reviews, Volume 67





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Gyneco-oncological genomics and emerging biomarkers for cancer treatment with immune-checkpoint inhibitors

Publication date: Available online 27 May 2018
Source:Seminars in Cancer Biology
Author(s): Giuseppe Curigliano
In gynecological cancers tumor infiltrating lymphocytes and upregulation of immune-related gene signatures have been associated with a better prognosis. Knowledge of tumor immunogenicity and associated gene signatures suggests that the tumor immune landscape is a key determinant to define patient prognosis and potentially to predict response to immune-checkpoint inhibitors. The aim of this review is to give an overview of immune gene signatures across gynecology histological cancer types, defining their prognostic and potential predictive role. In the current review we will present data on these gene signatures, on immunohistochemical features and their potential importance to select patients potentially eligible to trials with immune-checkpoint inhibitors.



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Congenital hypothyroidism

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Synthesis, characterization and anticancer studies of bis(1-phenylpiperazine dithiocarbamato) Cu(II), Zn(II) and Pt(II) complexes: Crystal structures of 1-phenylpiperazine dithiocarbamato-S,S′ zinc(II) and Pt(II)

Publication date: 15 October 2018
Source:Journal of Molecular Structure, Volume 1170
Author(s): Fartisincha P. Andrew, Peter A. Ajibade
Copper(II), zinc(II) and platinum(II) complexes of phenylpiperazine dithiocarbamate formulated as [CuL2], [PtL2] and [Zn2(μ-L)2(L)2], where L = phenylpiperazine dithiocarbamate were prepared and characterized by elemental analysis IR, UV–Visible, ¹H and ¹³C NMR spectroscopy. Single crystal X-ray structures of the Zn(II) and Pt(II) complexes are also reported. The FTIR spectra of the complexes confirm the bidentate coordination of the ligand to the metal ions by the single band due to ν(CS) observed in the range 1012–1014 cm⁻¹ compared to that of the ligand at 994 cm⁻¹. Electronic spectra of both the Cu(II) and Pt(II) complex are consistent with square planar geometry, this is further confirm in the case of the Pt(II) complex by the single X-ray crystal structure. The molecular structure of the Zn(II) complex indicate a centrosymmetric dimeric compound in which each of the zinc ion is bonded to two molecules of the ligands acting as either bidentate chelating or as bridging coordinating ligand resulting in a distorted octagonal cycle comprising of two zinc ions, two thioureide carbons and four sulphur atoms. The geometry around each zinc ion is a distorted tetrahedral geometry. The Pt(II) complex consist of a monomeric entity where the Pt(II) ion is surrounded by four sulphur donor atoms from the two phenylpiperazine dithiocarbamate ligands forming a slightly distorted square planner geometry around the Pt(II) ion. Anticancer potency of the complexes against three cancer cell lines indicates UACC62 > MCF7 > TK10 at IC50 values of 3.34, 17.52 and 19.83 μM respectively for the Cu(II) complex. MCF7 > TK10 > UACC62 at IC50 of 8.42, 13.40 and 15.14 μM respectively for Zn(II), whereas for the Pt(II) the activity stands at concentration (IC50) >100 μM for all the cell lines.

Graphical abstract

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Investigating the adsorption of nitrobenzene on M/Pd (1 1 1) bimetallic surface as an effective catalyst

Publication date: 1 October 2018
Source:Applied Surface Science, Volume 454
Author(s): Zahra Hajiahmadi, Zahra Tavangar
Understanding the interaction of organic molecule on metal surfaces is essential for a wide range of technological applications. Adsorption of nitrobenzene (NB) on Pd (1 1 1) surface in different positions was investigated with the periodic density functional theory (DFT) calculation. The most favorable adsorption configuration energetically was a parallel configuration that nitrogen located on top of Pd atom with −0.303 eV. In these weakly adsorption, choice of proper exchange-correlation is critical. VdW-C09 functional with −2.46 eV had the most adsorption energy. Some bimetallic surfaces like V/Pd (1 1 1), Fe/Pd (1 1 1), Ni/Pd (1 1 1), Pt/Pd (1 1 1) and Zn/Pd (1 1 1) were investigated in magnetic property and d-band model as well as geometry and energy to find the appropriate surface. The position of d-band center in the vicinity of Fermi energy represented more active bimetallic surfaces. PDOS, work function and charge transfer of the system were studied before and after adsorption of NB on the most appropriate surface (Fe/Pd (1 1 1)). Adsorption of nitrobenzene causes a decrease in work function of the surface and an increment of charge in the interface region.

Graphical abstract

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Dataset on experimental investigation of gum arabic coated alumina nanoparticles for enhanced recovery of nigerian medium crude oil

Publication date: August 2018
Source:Data in Brief, Volume 19
Author(s): Oyinkepreye D. Orodu, Kale B. Orodu, Richard O. Afolabi, Eboh A. Dafe
The dataset in this article are related to an experimental Enhanced Oil Recovery (EOR) scheme involving the use of dispersions containing Gum Arabic coated Alumina Nanoparticles (GCNPs) for Nigerian medium crude oil. The result contained in the dataset showed a 7.18% (5 wt% GCNPs), 7.81% (5 wt% GCNPs), and 5.61% (3 wt% GCNPs) improvement in the recovery oil beyond the water flooding stage for core samples A, B, and C respectively. Also, the improvement in recovery of the medium crude oil by the GCNPs dispersions when compared to Gum Arabic polymer flooding was evident in the dataset.



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Data showing the effects of temperature and time variances on nano-additives treatment of mild steel during machining

Publication date: August 2018
Source:Data in Brief, Volume 19
Author(s): Sunday A. Afolalu, Abiodun A. Abioye, Mfon O. Udo, Olayide R. Adetunji, Omolayo M. Ikumapayi, Samuel B. Adejuyigbe
The effects of temperature and time variances on nano-additives treatment of mild steel during machining was presented in this study. Mild steel of 150 kg mass containing 0.56% carbon was charged into the furnace at melting and pouring temperature of 1539 and 1545 °C respectively. Also charged into the furnace with the mild steel were 0.05% max phosphorous and a bit of sulphur. Thereafter, the sample was cooled and annealed at a temperature of 900 °C for 9 h and then cooled to 300 °C of hardening, normalizing and tempering respectively. The treated samples were then soaked with pulverized in palm kernel shell and barium carbonate (20%) energizer at respective temperatures (800, 850, 900 and 950 °C) and time variances (60, 90 and 120 min) in a muffle furnace. The developed tool was tested on a lathe machine to evaluate its performance. The surface and core hardness, wear resistance and toughness were carried out using the hardness tester, Rotopol–V and impact tester respectively. This is essential for predicting the useful life of the tool in service.



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Data on primary hydration characteristics of aqueous electrolytes

Publication date: August 2018
Source:Data in Brief, Volume 19
Author(s): Jyoti Sahu, Vinay A. Juvekar
The data presented in this article support the research article entitled "Development of a rationale for decoupling osmotic coefficient of electrolytes into electrostatic and nonelectrostatic contributions" (Sahu and Juvekar, 2018) [1]. In this article, we have presented the plots of osmotic coefficients against molality for more than hundred aqueous single electrolytes at 25 °C. The linear regions in these plots are marked to show that they are present in all these electrolytes and that these regions extend over a wide range of concentrations. Slopes of the linear regions are used to estimate the primary molar hydration volume as well as the primary hydration number of these electrolytes. These values are also listed and the method of estimation is presented with sample calculation. These data, not only reinforce the observations made in the main article but also provide useful measures for estimation of the nonelectrostatic contribution to the osmotic coefficient.



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Editorial Board

Publication date: April–May 2018
Source:Progress in Neurobiology, Volumes 163–164





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NIR-controlled morphology transformation and pulsatile drug delivery based on multifunctional phototheranostic nanoparticles for photoacoustic imaging-guided photothermal-chemotherapy

Publication date: September 2018
Source:Biomaterials, Volume 176
Author(s): Jun Yang, Shaodong Zhai, Huan Qin, He Yan, Da Xing, Xianglong Hu
Stimuli-responsive nanoparticles are focused to promote the pathological specificity and controlled therapeutic activation in biomedicine, but the multifunctional modulation remains challenging. Herein, size and morphology switchable phototheranostic nanoparticles are developed for photoacoustic (PA) imaging-guided photothermal-chemotherapy. Multifunctional polypyrrole (PPy) nanoparticles with the template of upper critical solution temperature (UCST) polymers are designed to achieve light-controlled pulsatile drug release and concurrent activation of photothermal therapy (PTT). Wherein the UCST-featured inner core is loaded with camptothecin (CPT), the outer corona is tethered with thermo-cleavable doxorubicin (DOX) prodrug and further in-situ coated with PPy, affording the resultant CPT@DOX-UCST/PPy nanoparticles. Upon 808 nm continuous laser illumination, significant heating generated from light-absorbable PPy results in DOX prodrug cleavage and considerable size swelling (∼125-fold), which in turn promotes simultaneous dual drug release, and thus triggering the combined therapeutic activation of PTT and chemotherapy. When laser is switched off, the discontinued photothermal generation makes the nanoparticle shrink back, thereby avoiding the leakage of CPT and DOX. In vivo experiments demonstrate the favorable tumor accumulation and prolonged tumor retention (>24 h) for long-term PA imaging-guided combination therapy. Current multifunctional nanoparticles integrated with light-controlled swelling/shrinking and synergistic therapeutic activation/silence represent a promising platform for precision cancer theranostics.



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eIF4A2 is a host factor required for efficient HIV-1 replication

Publication date: Available online 26 May 2018
Source:Microbes and Infection
Author(s): Jerry Kwame Ndzinu, Hiroaki Takeuchi, Hideki Saito, Takeshi Yoshida, Shoji Yamaoka
Host factors are required for efficient HIV-1 replication. To identify these factors, genome-wide RNA interference screening was performed using a human T cell line. In the present study, we assessed whether eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), a DEAD-box protein identified in our screen, is necessary for efficient HIV-1 replication. Exploiting MT4C5 cells depleted of eIF4A2 by stable expression of eIF4A2-specific short-hairpin RNA (shRNA) using a lentiviral system, we found that depletion of eIF4A2 markedly inhibited the infection of a replication-competent reporter HIV-1. eIF4A2 depletion reduced the efficiency of viral cDNA synthesis with virion entry into target cells being unaffected. Depletion of eIF4A2 also inhibited HIV-1 spreading infection in a knockdown level-dependent manner. These results suggest that HIV-1 requires eIF4A2 for optimal replication in human T cells.



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On the Role of Retinoic Acid in virus induced Inflammatory Response in Cornea

Publication date: Available online 26 May 2018
Source:Microbes and Infection
Author(s): Ujjaldeep Jaggi, Siva Karthik Varanasi, Siddheshvar Bhela, Barry T. Rouse
Ocular infection with herpes simplex virus (HSV) can result in a chronic immune inflammatory lesion that is a significant cause of human blindness. A key to controlling stromal keratitis (SK) lesion severity is to identify cellular and molecular events responsible for tissue damage and to counteract them. One potentially useful approach to achieve such therapy is Retinoic Acid (RA). Here we show that RA therapy reduces the severity of SK by having inhibitory effects on the T effector subtypes responsible for orchestrating SK. RA also served to stabilize the function of regulatory T cell (Treg) which counteract inflammatory cell activity. The Treg stabilizing effect was demonstrated by in vitro studies where RA was shown to retain Foxp3 expression when exposed to proinflammatory conditions such as IL-12 and IL-6+TGF-β. in vivo studies revealed that RA exerted its stabilizing effects by downregulating IL-6R expression on Treg after HSV-1 infection and this helped to control the progression of SK. Since the therapy was effective when used both early and after the initiation of lesions, it may represent a valuable means of therapy when used alone or along with additional therapies.



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Inflammasome components caspase-1 and adaptor protein apoptosis-associated speck-like proteins are important in resistance to Cryptosporidium parvum

Publication date: Available online 26 May 2018
Source:Microbes and Infection
Author(s): Nina N. McNair, Chetna Bedi, Dmitry M. Shayakhmetov, Michael J. Arrowood, Jan R. Mead
Cryptosporidium spp. are opportunistic protozoan parasites that infect epithelial cells in the intestinal tract and cause a flu-like diarrheal illness. Innate immunity is key to limiting the expansion of parasitic stages early in infection. One mechanism in which it does this is through the generation of early cytokines, such as IL-18. The processing and secretion of mature IL-18 (and IL-1β) is mediated by caspase-1 which is activated within an inflammasome following the engagement of inflammasome-initiating sensors. We examined how the absence of caspase-1 and caspase-11, the adapter protein Asc, and other inflammasome components affects susceptibility to cryptosporidial infection by these and other key cytokines in the gut. We found that Casp-11^-/-Casp-1^-/- knockout mice have increased susceptibility to C. parvum infection as demonstrated by the 35-fold higher oocyst production (at peak infection) compared to wild-type mice. Susceptibility correlated with a lack of IL-18 in caspase-1 and caspase1/11 knockout mice, whereas IL-18 is significantly elevated in wildtype mice. IL-1β was not generated in any significant amount following infection nor was any increased susceptibility observed in IL-1β knockout mice. We also show that the adapter protein Asc is important to susceptibility, and that the caspase-1 canonical inflammasome signaling pathway is the dominant pathway in C. parvum resistance.



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Breast and cervical cancer incidence and mortality trends in Russia 1980–2013

Publication date: August 2018
Source:Cancer Epidemiology, Volume 55
Author(s): Anton Barchuk, Alexander Bespalov, Heini Huhtala, Tuvshinjargal Chimed, Irina Laricheva, Alexey Belyaev, Freddie Bray, Ahti Anttila, Anssi Auvinen
BackgroundBreast and cervical cancer are among the leading causes of preventable cancer deaths in women in Russia. The aim of this study is to analyze changes in breast and cervical cancer incidence and mortality trends using data from the Russian State Cancer Registry.MethodsThe age-standardized rates of cervical cancer incidence (1993–2013) and mortality (1980–2013) were analyzed using piecewise linear regression. Age-period-cohort models were used to estimate the temporal effects and provide future predictions.ResultsBreast and cervical cancer incidence rates uniformly increased over two decades from 33.0 to 47.0 per 100,000 and from 10.6 to 14.2 per 100,000, respectively. Breast cancer mortality rates however declined from 17.6 to 15.7 in 2013, while cervical cancer mortality increased steadily from 5.6 to 6.7. Breakpoints in the risk occurred in cohorts born 1937–1953, indicating a recent generational decrease in breast cancer mortality, but a concomitant increase in cervical cancer. Cervical cancer has already surpassed breast cancer in terms of years of life lost (YLL) (23.4 per death vs 18.5 in 2009–2013), while future projections suggest that the annual YLL could reach 1.2 million for cervical cancer and (decline to) 1.8 million for breast cancer by the year 2030.ConclusionThe temporal patterns of breast cancer incidence and mortality in Russia are in line with other countries in Europe, although cervical cancer rates and the risk of occurrence in recent generations is rapidly increasing; these trends underscore the need to place immediate priority in national cervical vaccination and screening programs.



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Problems and solutions in IGRT for cervical cancer

Publication date: Available online 26 May 2018
Source:Reports of Practical Oncology & Radiotherapy
Author(s): Iván Ríos, Ilse Vásquez, Elsa Cuervo, Óscar Garzón, Johnny Burbano
The contribution of Image-guided Radiotherapy (IGRT) to modern radiotherapy is undeniable, being the way to bring into daily practice the dosimetric benefits of Intensity-Modulated Radiotherapy (IMRT). Organ and target motion is constant and unpredictable at the pelvis, thus posing a challenge to the safe execution of IMRT. There are potential benefits of IMRT in the radical treatment of cervical cancer patients, both in terms of dose escalation and decrease of toxicity. But it is essential to find IGRT solutions to control the aspects that can lead to geographic miss targeting or organs at risk (OAR) overdose. This review seeks to describe the problems and possible solutions in the clinical implementation of IMRT/IGRT protocols to treat intact cervical cancer patients.



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Nano liquid chromatography-high-resolution mass spectrometry for the identification of metabolites of the two new psychoactive substances N-(ortho-methoxybenzyl)-3,4-dimethoxyamphetamine and N-(ortho-methoxybenzyl)-4-methylmethamphetamine

Publication date: 1 October 2018
Source:Talanta, Volume 188
Author(s): Achim T. Caspar, Markus R. Meyer, Folker Westphal, Armin A. Weber, Hans H. Maurer
Among the emerging new psychoactive substances (NPS), compounds carrying an N-ortho-methoxybenzyl substituent, the so-called NBOMes, represented a highly potent group of new hallucinogens. Recently, 3,4-dimethoxyamphetamine (3,4-DMA)-NBOMe and 4-methylmethamphetamine (4-MMA)-NBOMe occurred, but no data on their pharmacokinetics were available. According to other NBOMes, they are expected to be extensively metabolized. For detection and identification of their phase I and II metabolites, nano liquid chromatography coupled to high resolution tandem mass spectrometry (nanoLC-HRMS/MS) was used. Rat urine was prepared by simple dilution and incubation mixtures with pooled human liver S9 fraction by precipitation. Furthermore, the results concerning detectability using the new nanoLC approach were compared to those obtained by conventional ultra-high performance LC (UHPLC). In addition, the detectability of the compounds by standard urine screening approaches (SUSAs) routinely used by the authors with UHPLC-HRMS/MS, LC-MSⁿ, and GC-MS was tested. Both NBOMes were extensively metabolized mainly by O-demethylation and conjugation with glucuronic acid (3,4-DMA-NBOMe) or oxidation of the tolyl group to the corresponding carboxylic acid (4-MMA-NBOMe). The developed nanoLC-HRMS/MS approach was successfully applied for identification of 38 3,4-DMA-NBOMe metabolites and 33 4-MMA-NBOMe metabolites confirming its detection power. Furthermore, the solvent saving nanoLC system showed comparable results to the UHPLC-HRMS/MS approach. In addition, an intake of an estimated low common user's dose of the compounds was detectable by all SUSAs only via their metabolites. Suggested targets for urine screening procedures were O-demethyl- and O,O-bis-demethyl-3,4-DMA-NBOMe and their glucuronides and carboxy-4-MMA-NBOMe and its glucuronide and N-demethyl-carboxy-4-MMA-NBOMe.

Graphical abstract

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Definitive Local Therapy is Associated with Improved Overall Survival in Metastatic Cervical Cancer

Publication date: Available online 26 May 2018
Source:Practical Radiation Oncology
Author(s): Sriram Venigalla, David M. Guttmann, Zachary D. Horne, Ruben Carmona, Jacob E. Shabason, Sushil Beriwal
PurposeDefinitive local therapy is often used in metastatic cervical cancer to reduce morbidity associated with local tumor progression. However, the potential benefit of this therapeutic approach has not been rigorously investigated. We hypothesized that definitive local therapy would be associated with improved overall survival (OS) in metastatic cervical cancer.Methods and MaterialsPatients ≥18 years with newly diagnosed metastatic cervical cancer treated with chemotherapy were identified from the National Cancer Database. Patients were dichotomized into the following cohorts¹: definitive local therapy, defined as either concurrent chemoradiotherapy or definitive surgery, or² conservative therapy, defined as systemic therapy with or without palliative radiotherapy. The association between definitive local therapy and OS was assessed using propensity score-weighted Cox proportional hazards models. Potential unmeasured confounding was assessed through sensitivity analyses. Factors associated with receipt of definitive local therapy were identified with multivariable logistic regression.ResultsOf 2,838 total patients, 1,194 (42%) and 1,644 (58%) were treated with definitive local therapy and conservative therapy, respectively. Receipt of definitive local therapy was statistically significantly associated with less comorbidity, lower clinical T stage, and node negative disease. Compared to conservative therapy, definitive local therapy was associated with improved OS (HR=0.57, 95% CI: 0.52-0.62, p ≤ 0.001). Median OS was 19.2 months in the definitive local therapy cohort and 10.1 months in the conservative therapy cohort. These findings were robust to potential unmeasured confounding in sensitivity analyses and on landmark analyses of patients surviving at least 12 months (HR=0.71, 95% CI: 0.62 – 0.82, p ≤ 0.001).ConclusionsDefinitive local therapy is associated with improved OS in patients with metastatic cervical cancer. These findings suggest a novel setting for the use of definitive local therapy in the metastatic setting.



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Drug metabolizing enzymes and their inhibitors' role in cancer resistance

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): Shelly Pathania, Rohit Bhatia, Ashish Baldi, Randhir Singh, Ravindra K. Rawal
Despite continuous research on chemotherapeutic agents, different mechanisms of resistance have become a major pitfall in cancer chemotherapy. Although, exhaustive efforts are being made by several researchers to target resistance against chemotherapeutic agents, there is another class of resistance mechanism which is almost carrying on unattended. This class of resistance includes pharmacokinetics resistance such as efflux by ABC transporters and drug metabolizing enzymes. ABC transporters are the membrane bound proteins which are responsible for the movement of substrates through the cell membrane. Drug metabolizing enzymes are an integral part of phase-II metabolism that helps in the detoxification of exogenous, endogenous and xenobiotics substrates. These include uridine diphospho-glucuronosyltransferases (UGTs), glutathione-S-transferases (GSTs), dihydropyrimidine dehydrogenases (DPDs) and thiopurine methyltransferases (TPMTs). These enzymes may affect the role of drugs in both positive as well negative manner, depending upon the type of tissue and cells present and when present in tumors, can result in drug resistance. However, the underlying mechanism of resistance by drug metabolizing enzymes is still not clear. Here, we have tried to cover various aspects of these enzymes in relation to anticancer drugs.

Graphical abstract

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Taxifolin binds with LXR (α & β) to attenuate DMBA-induced mammary carcinogenesis through mTOR/Maf-1/PTEN pathway

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): Md.Wasimul Haque, Pritha Bose, Mohd. Usman Mohd Siddique, Priyashree Sunita, Antonio Lapenna, Shakti P. Pattanayak
Aim7,12-dimethylbenz(a)anthracene(DMBA), a PAH derivative initializes cascades of signaling events that alters a variety of enzymes responsible for lipid and glucose homeostasis resulting in enhanced availability and consumption of energy producing molecules for the development of carcinogenesis. 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) is a key enzyme regulating the pathway of synthesis of cholesterol whereas liver-X-receptor (LXR) regulates lipid, carbohydrate metabolism in various malignancies including mammary carcinogenesis (MC). In this study Taxifolin (TAX), a potential flavanoid has been subjected to evaluate its anti-cancer potential on (MC).MethodsWe designed to screen the molecular docking analysis of TAX on LXRα, LXRβ, HMG-CoAR, mTOR and PTEN using MAESTRO tool comparing with their reference ligands. MC was developed by the administration of DMBA in the air pouch (under the mammary fat pad) of the female Sprague-Dawley rats (55 days old). After 90 days of cancer induction, the chemotherapeutic potential of TAX was evaluated by administering TAX at different doses (10, 20 and 40 mg/kg b.w./day). Then western blot and RT-qPCR analysis were performed for determination of the protein and mRNA expressions respectively.ResultsThe docking analysis revealed significant interaction with LXR (α&β), HMG-CoAR, mTOR and PTEN. The docking results were validated with the enzyme inhibition assay using HMG-CoAR (EC 1.1.1.34). TAX inhibited the HMG-CoAR activity with an IC50 value of 97.54 ± 2.5 nM whereas the reference molecule pavastatin revealed an IC50 value of 84.35 ± 1.2 nM. Moreover, TAX modulated the energy regulation on DMBA-induced MC in SD-rats by significantly restoring the cancer-induced alterations in body weight, tumor growth and lipid, lipoproteins, lipid metabolizing enzymes and glycolytic enzymes. TAX interacted with LXRs, HMG-CoAR, metabolic enzymes and restored the altered metabolism that accelerates uncontrolled cell proliferation in MC. Moreover, TAX also altered the mRNA and protein expressions of HMG-CoAR, LXR (α,β), Maf1, PTEN, phosphoinositide 3-kinase (PI3K), Akt, mTOR, fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) in a dose dependent manner.ConclusionThese results validate the anti-cancer potential of TAX in DMBA-induced MC through LXR-mTOR/Maf1/PTEN axis.



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Resveratrol inhibits pulmonary fibrosis by regulating miR-21 through MAPK/AP-1 pathways

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): Jing Wang, Fang He, Lingqiang Chen, Qin Li, Song Jin, Hongmei Zheng, Jun Lin, Hong Zhang, Sha Ma, Jian Mei, Juan Yu
ObjectiveTo explore the molecular mechanism of Res in regulation of pulmonary fibrosis (PF).MethodsRats were injected with bleomycin (BLM) to establish a PF model and treated with resveratrol (Res) and/or miR-21 agomir. After 14 days, lung tissues were collected for Hematoxylin-eosin and Masson's staining, and real-time quantitative polymerase chain reaction and Western blot were performed to detect fibrosis-related protein expression and the activation of the TGF-β1/Smad pathway. In vitro, MRC-5 cells were pretreated with TGF-β1, Res, and/or miR-21 agomir. After 48 h, total soluble collagen was detected with a Sircol Soluble Collagen Assay. Subsequently, a miR-21 mimic was transfected into MRC-5 cells, and a luciferase reporter assay was employed to verify whether miR-21 targeted Smad7.ResultsRes reversed the increased levels of miR-21 induced by BLM and alleviated serious PF symptoms, but agomiR-21 treatment effectively impaired the above manifestations. In vivo, miR-21 inhibited the decreases of TGF-β1 and p-Smad2/3 that were induced by Res. In vitro, miR-21 significantly disrupted the positive effect of Res on TGF-β-induced collagen deposition, as well as the levels of Fn, α-SMA, p-Smad2, and Smad7. In addition, Smad7 was found to be a direct target of miR-21-5p. TGF-β stimulation led to an enormous increase in p-c-Jun, c-Jun, and c-Fos, which were significantly reduced by Res. Finally, miR-21 sharply reduced the increased phosphorylation levels of ERK, JNK and p38 that were induced by Res.ConclusionRes inhibits BLM-induced PF by regulating miR-21 through MAPK/AP-1 pathways.

Graphical abstract

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The antidepressant-like effects of Chaihu Shugan San: Dependent on the hippocampal BDNF-TrkB-ERK/Akt signaling activation in perimenopausal depression-like rats

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): Xue-Qin Chen, Cheng-Fu Li, Shu-Jiao Chen, Wen-Na Liang, Miao Wang, Shuang-Shuang Wang, Shu-Qi Dong, Li-Tao Yi, Can-Dong Li
Chaihu Shugan San (CSS), a traditional Chinese medicine formula, has been used to treat depression for hundreds of years. Recently, the antidepressant-like mechanism of CSS has been increasingly evaluated and demonstrated. However, there are few studies focused on the involvement of the neurotrophic system in mediating the antidepressant-like effects of CSS. Considering the high prevalence of perimenopausal depression around the world, the goal of the present study was to determine whether brain-derived neurotrophic factor (BDNF) signaling is required for the antidepressant-like effects of CSS in perimenopausal depressive-like rats. The results indicate that CSS reverses depressive-like behaviors and attenuates the downregulation of BDNF in the hippocampus of perimenopausal rats exposed to chronic unpredictable mild stress (CUMS). We found that the TrkB antagonist K252 not only blocks the effects of CSS on behavioral improvement but also abolishes the activation of CSS in BDNF-TrkB signaling. As a result, the downstream targets of BDNF signaling, such as the ERK and Akt pathways, are significantly inhibited by K252a. Furthermore, CSS increases hippocampal neurogenesis, while K252a fully prevents this action. In conclusion, the present results demonstrate that the activation of the hippocampal BDNF-TrkB-ERK/Akt signaling pathway is required for the antidepressant-like effects of CSS on the depressive-like state during perimenopause. Additionally, this study also demonstrates that neurogenesis is required for the effects of antidepressants in aging perimenopausal animals and provides fundamental evidence for the clinical application of CSS.

Graphical abstract

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Osteoactivin inhibits dexamethasone-induced osteoporosis through up-regulating integrin β1 and activate ERK pathway

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): He Hu, Zhehai Li, Min Lu, Xinyi Yun, Wei Li, Caiyun Liu, Ai Guo
BackgroundsDexamethasone (Dex) is widely used in autoimmune diseases and inflammation treatment. A sever side effect of prolonged exposure to Dex is increased risk of osteoporosis (OP) or even femoral head necrosis, which would cause much suffer to patients. To reveal the mechanism behind this phenomenon, provide therapeutic guidance and potential target, we analyzed the inhibitory mechanism of Dex on osteogenesis of rat-BMSC.MethodsRat BMSC were obtained and characterized with FACS analysis. Osteogenesis and adipogenesis abilities were detected with Oil-O-Red staining, Alizarin Red staining and ALP activity analysis. These BMSC were then treated with Dex in combination with recombinant OA or not and detected for osteogenesis related gene expression with qRT-PCR. Protein interaction and expression were detected by Co-Immunoprecipitation and western blot.ResultsOsteoactivin (OA) could promote integrin β 1 expression and interact with this protein physically, leading to ERK activation and promoting osteogenesis related genes' expression including Runx2, Col1a and OCN in BMSC. Dex, however, could block expression of several upstream genes of OA and decrease OA mRNA and protein level, and eventually suppress integrin β1-ERK activation and lead to decreased osteogenesis, which could finally develop into OP.ConclusionRecombinant OA treated BMSC exerted better osteogenesis potency even with Dex administration. This is because additional OA in medium counter-acts with Dex's influence and rescued osteoblast differentiation via up-regulating integrin β1 and activate ERK/MAPK pathway which promotes osteogenesis. Hence, OA/integrin β1 could serve as potential therapeutic target for OP.



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Melatonin ameliorates bisphenol A-induced perturbations of the prostate gland of adult Wistar rats

Publication date: September 2018
Source:Biomedicine & Pharmacotherapy, Volume 105
Author(s): Samuel Gbadebo Olukole, Samuel Olumide Ajani, Eunice Olufunke Ola-Davies, Damilare Olaniyi Lanipekun, Oluwasanmi Olayinka Aina, Matthew Olugbenga Oyeyemi, Bankole Olusiji Oke
Bisphenol A (BPA) is an endocrine disrupting chemical (EDC) that has been demonstrated to induce alterations in reproductive organs while melatonin (ML), an antioxidant, present in plants and animals, is capable of protecting against EDC-induced alterations. Adult male Wistar rats (average weight, 240 + 10 g) were divided into four groups of ten animals each: Rats in group I (control) received oral 0.2 ml 1% dimethyl sulfoxide (DMSO)/99% canola oil as vehicle; group II received intra-peritoneal 10 mg/kg BW/day ML. Group III received oral BPA dissolved in DMSO and solubilized in canola oil at 10 mg/kg BW/day. Group IV were treated with same dose of BPA as group III with a concomitant intra-peritoneal 10 mg/kg BW/day ML. All treatments lasted for 14 days. BPA significantly increased the prostatic index of the rats while ML ameliorated it. BPA significantly increased serum levels of estrogen as well as prostate-specific antigen but decreased serum testosterone in the rats while concomitant treatment with ML ameliorated these alterations. Also, BPA caused vascular congestion, hyperplasia (functional, reactive and atypical) of prostatic epithelium as well as tubular atrophy the rats while ML attenuated the observed lesions. Decreased localization of αSmooth muscle actin, vimentin and S100 proteins were observed in the BPA-treated rats while these decreases were ameliorated by ML. The present study has shown that sub-acute oral administration of BPA induced alterations in prostatic index, serum hormone levels, down-regulated protein localization and induced morphological lesions of the prostate gland in rats while concomitant treatment with intra-peritoneal ML ameliorated these conditions. Hence, low dose of ML can protect against BPA-induced toxicity of the prostate gland of rats.

Graphical abstract

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Determination of black carbon, PM2.5, particle number and NOx emission factors from roadside measurements and their implications for emission inventory development

Publication date: August 2018
Source:Atmospheric Environment, Volume 186
Author(s): Patricia Krecl, Admir Créso Targino, Thiago Pereira Landi, Matthias Ketzel
The road transportation sector contributes largely to air pollution in urban areas, why the knowledge of accurate vehicle emission factors (EF) is crucial to prepare reliable emission inventories, which, in turn, are strategic tools for air quality management. Curbside and rooftop concentrations of several traffic-related species were measured within a busy street canyon in Londrina (Brazil). EF for NOx, black carbon (BC), fine particles (PM2.5) and particle number (PN) were calculated based on these measurements and on inverse modeling using the Operational Street Pollution Model (OSPM). We highlight the importance of this work in quantifying BC, PM2.5, NOx and PN emissions from vehicles driven in an urban area under real conditions in a continent-sized country where there is a lack of EF studies. In the case of EFPN, we report the first value in the entire South America. Our EF were consistent with results from other on-road studies, but much higher than laboratory measurements conducted in Brazil and Europe, especially for particles (quantified as mass and number). This finding suggests that the EF derived from laboratory tests should be revised for all vehicle categories, since inaccurate values can have major implications on the compilation of official national inventories for the road transportation sector and on the assessment of their health and climate (in the case of BC) impacts. Incorporating certification procedures that more closely resemble real driving conditions is highly recommended. Limitations of the EF determined in this research for application in other studies are also discussed.



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Bottom-up anthropogenic dichloromethane emission estimates from China for the period 2005–2016 and predictions of future emissions

Publication date: August 2018
Source:Atmospheric Environment, Volume 186
Author(s): Yanlin Feng, Pengju Bie, Ziyuan Wang, Lei Wang, Jianbo Zhang
It has been shown that the short-lived halogenated hydrocarbons, such as dichloromethane (DCM), which are not regulated by the Montreal Protocol, have the potential to impact stratospheric ozone. DCM with increasing atmospheric mixing ratios in recent years, is widely used in solvent, foam-blowing and methyl fluoride production sectors in China, which is a large producer as well as consumer of DCM. This study develops a comprehensive emission inventory of anthropogenic DCM in China using a bottom-up method based on the industrial consumption of DCM in China from 2005 to 2016 and makes a projection to 2030. The inventory considered solvent use, polyurethane (PU) foam manufacturing, the chemical industry, and other end uses. Anthropogenic emissions of DCM increased from 101 (80–122) Gg/yr to 318 (254–384) Gg/yr between 2005 and 2016, a increase of 215% over the last 11 years. Solvent use and the manufacture of PU foam agents are the major contributors to total DCM emissions. Under a business as usual (BAU) scenario future Chinese emissions of DCM are predicted to increase to 708 (588–831) Gg/yr by 2030, more than twice the emission IHS, 2016. Chinese emission account for approximately 25%–37% of the 515 Gg/yr estimates by the WMO as average annual global emissions in 2008.

Graphical abstract

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Mechanically robust cryogels with injectability and bioprinting supportability for adipose tissue engineering

Publication date: Available online 26 May 2018
Source:Acta Biomaterialia
Author(s): Dianjun Qi, Shaohua Wu, Mitchell A. Kuss, Wen Shi, Soonkyu Chung, Paul T. Deegan, Alexey Kamenskiy, Yini He, Bin Duan
Bioengineered adipose tissues have gained increased interest as a promising alternative to autologous tissue flaps and synthetic adipose fillers for soft tissue augmentation and defect reconstruction in clinic. Although many scaffolding materials and biofabrication methods have been investigated for adipose tissue engineering in the last decades, there are still challenges to recapitulate the appropriate adipose tissue microenvironment, maintain volume stability, and induce vascularization to achieve long-term function and integration. In the present research, we fabricated cryogels consisting of methacrylated gelatin, methacrylated hyaluronic acid, and 4arm poly(ethylene glycol) acrylate (PEG-4A) by using cryopolymerization. The cryogels were repeatedly injectable and stretchable, and the addition of PEG-4A improved the robustness and mechanical properties. The cryogels supported human adipose progenitor cell (HWA) and adipose derived mesenchymal stromal cell adhesion, proliferation, and adipogenic differentiation and maturation, regardless of the addition of PEG-4A. The HWA laden cryogels facilitated the co-culture of human umbilical vein endothelial cells (HUVEC) and capillary-like network formation, which in return also promoted adipogenesis. We further combined cryogels with 3D bioprinting to generate handleable adipose constructs with clinically relevant size. 3D bioprinting enabled the deposition of multiple bioinks onto the cryogels. The bioprinted flap-like constructs had an integrated structure without delamination and supported vascularization.SignificanceAdipose tissue engineering is promising for reconstruction of soft tissue defects, and also challenging for restoring and maintaining soft tissue volume and shape, and achieving vascularization and integration. In this study, we fabricated cryogels with mechanical robustness, injectability, and stretchability by using cryopolymerization. The cryogels promoted cell adhesion, proliferation, and adipogenic differentiation and maturation of human adipose progenitor cells and adipose derived mesenchymal stromal cells. Moreover, the cryogels also supported 3D bioprinting on top, forming vascularized adipose constructs. This study demonstrates the potential of the implementation of cryogels for generating volume-stable adipose tissue constructs and provides a strategy to fabricate vascularized flap-like constructs for complex soft tissue regeneration.

Graphical abstract

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Androgen blockade based clinical trials landscape in triple negative breast cancer

Publication date: Available online 25 May 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Yaqin Shi, Fang Yang, Doudou Huang, Xiaoxiang Guan
Androgen receptor (AR) targeted treatment has shown promising preliminary results in triple negative breast cancer (TNBC). Identification of AR-associated signaling pathways is of great significance for in-depth understanding of their roles in pathogenesis of TNBC. To meet this objective, preclinical and clinical studies were conducted to clarify the biological interactions of AR signaling and combination strategies based on AR-targeted therapy. Biologically, AR signaling in TNBC which not only interacts with a network of key pathways, involving PI3K/AKT/mTOR, cell cycle, and DNA damage repair pathways, but mediates pivotal processes of tumor initiation and immunogenic modulation, may present an opportunity to overcome the insensitivity of single AR-targeted therapy. Research in investigating androgen-blockade based combination therapy in this aggressive tumor has demonstrated promising benefit in preclinical studies, and comparable clinical trials of combined strategies with CDK4/6 inhibitors, PI3K inhibition, chemotherapy, and immunotherapy, are ongoing. Accordingly, clinical interpretation of AR-related biological interactions, aiming at combined blockade of the signaling pathways may pave a new way for endocrine-based therapy in the treatment of TNBC.



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Mitochondria in Cancer metabolism, an organelle whose time has come?

Publication date: Available online 26 May 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Rebecca G. Anderson, Lais P. Ghiraldeli, Timothy S. Pardee
Mitochondria have long been controversial organelles in cancer. Early discoveries in cancer metabolism placed much emphasis on cytosolic contributions. Initial debate focused on if mitochondria had a role in cancer formation and progression at all. More recently the contributions of mitochondria to cancer development and progression have become firmly established. This has led to the identification of novel targets and inhibitors being studied as new therapeutic approaches. This review will summarize the role of mitochondria in cancer and highlight several agents under development.



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Antibacterial, Antifungal, Anticancer Activities and Structural Bioinformatics Analysis of Six Naturally Occurring Temporins

Publication date: Available online 26 May 2018
Source:Peptides
Author(s): Biswajit Mishra, Xiuqing Wang, Tamara Lushnikova, Yingxia Zhang, Radha M. Golla, Jayaram Lakshmaiah Narayana, Chunfeng Wang, Timothy R. McGuire, Guangshun Wang
Antimicrobial peptides are a special class of natural products with potential applications as novel therapeutics. This study focuses on six temporins (four with no activity data and two as positive controls). Using synthetic peptides, we report antibacterial, antifungal, and anticancer activities of temporins-CPa, CPb, 1Ga, 1Oc, 1Ola, and 1SPa. While temporin-1Ga and temporin-1OLa showed higher antifungal and anticancer activity, most of these peptides were active primarily against Gram-positive bacteria. Temporin-1OLa, with the highest cell selectivity index, could preferentially kill methicillin-resistant Staphylococcus aureus (MRSA), consistent with a reduced hemolysis in the presence of bacteria. Mechanistically, temporin-1OLa rapidly killed MRSA by damaging bacterial membranes. Using micelles as a membrane-mimetic model, we determined the three-dimensional structure of temporin-1OLa by NMR spectroscopy. The peptide adopted a two-domain structure where a hydrophobic patch is followed by a classic amphipathic helix covering residues P3-I12. Such a structure is responsible for anti-biofilm ability in vitro and in vivo protection of wax moths Galleria mellonella from staphylococcal infection. Finally, our bioinformatic analysis leads to a classification of temporins into six types and confers significance to this NMR structure since temporin-1OLa shares a sequence model with 62% of temporins. Collectively, our results indicate the potential of temporin-1OLa as a new anti-MRSA compound, which shows an even better anti-biofilm capability in combination with linezolid.

Graphical abstract

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Bone turnover: Biology and assessment tools

Publication date: Available online 26 May 2018
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Pawel Szulc
Bone turnover includes two processes: resorption (removal of old bone) and formation (laying down of new bone). N-terminal propeptide of type I procollagen (PINP) and C-telopeptide of type I collagen (CTX-I) are markers of bone formation and resorption, respectively, that the International Osteoporosis Foundation and the International Federation of Clinical Chemistry recommend for clinical use. Bone turnover markers (BTM) are subject to sources of variability, including feeding (lower resorption) and recent fracture (increased levels of all markers). Controllable patient-related factors should be adapted as much as possible (eg blood collection after an overnight fast) to minimize pre-analytical variability. Uncontrollable factors should be considered in the interpretation of the BTM measurements. BTM do not improve prediction of bone loss or fracture within an individual. In osteoporotic patients, BTM may help to assess the response to anabolic and antiresorptive therapies, to assess compliance to the treatment, or to indicate possible secondary causes of osteoporosis. BTM reflect changes in bone metabolism induced by anti-osteoporotic treatment. Anti-resorptive drugs induce a rapid dose-dependent decrease in bone resorption, whereas bone formation stimulating medications increase the levels of bone formations markers. BTM may be used for monitoring anti-osteoporosis therapy. The expected effect during the anti-resorptive therapy is to decrease the PINP by at least 10 ng/mL and to attain the target level of less than 35 ng/mL. The expected effect during the bone formation-stimulating therapy is to increase the PINP by at least 10 ng/mL and to attain the target level of more than 69 ng/mL.



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Central Precocious Puberty: From Genetics to Treatment

Publication date: Available online 26 May 2018
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Rebecca Schneider Aguirre, Erica A. Eugster
Central precocious puberty (CPP) results from early activation of the hypothalamic - pituitary -gonadal (HPG) axis and follows the same sequence as normal puberty. While many factors involved in pubertal initiation remain poorly understood, the kisspeptin system is known to play a key role. Currently, mutations in the kisspeptin system, MKRN3, and DLK1 have been identified in sporadic and familial cases of CPP. The diagnosis is based on physical exam findings indicating advancing puberty and on laboratory tests confirming central HPG axis activation. GnRH analogs are the mainstay of treatment and are used with the goal of height preservation. Newer extended release formulations continue to be developed. Currently there is no evidence of long-term complications associated with treatment. However, many areas remain to be explored such as targeted therapies and aspects of clinical management. Further investigation into psychological effects and additional data regarding long-term outcomes, particularly in males, is needed.



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Update on Osteoporosis in Men

Publication date: Available online 26 May 2018
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Robert A. Adler
Osteoporosis in men remains under-diagnosed and under-appreciated. After a low trauma fracture, a man is less likely to have evaluation and treatment. The lifetime risk for osteoporotic fracture in older men may range from 13 to 25%, and as men live longer, there will be more fractures. Newer strategies for determining which men should have bone density testing are emerging. Information from observational studies are providing insights that allow targeted testing and treatment of those men at the highest risk for fracture. Treatment with most of the same medications used in women is efficacious and generally safe. Nonetheless, the fear of side effects of treatments for an asymptomatic disorder (before a fracture) and other barriers have made management challenging in men at risk for fracture. This review provides updates on epidemiology, pathophysiology, evaluation and treatment of male osteoporosis.



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Familial Hypocalciuric Hypercalcemia and Related Disorders

Publication date: Available online 26 May 2018
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Janet Y. Lee, Dolores M. Shoback
Familial hypocalciuric hypercalcemia (FHH) causes hypercalcemia by three genetic mechanisms: inactivating mutations in the calcium-sensing receptor, the G-protein subunit α11, or adaptor-related protein complex 2, sigma 1 subunit. While hypercalcemia in other conditions causes significant morbidity and mortality, FHH generally follows a benign course. Failure to diagnose FHH can result in unwarranted treatment or surgery for the mistaken diagnosis of primary hyperparathyroidism (PHPT), given the significant overlap of biochemical features. Determinations of urinary calcium excretion greatly aid in distinguishing PHPT from FHH, but overlap still exists in certain cases. It is important that 24-hour urine calcium and creatinine be included in the initial workup of hypercalcemia. FHH should be considered if low or even low normal urinary calcium levels are found in what is typically an asymptomatic hypercalcemic patient. The calcimimetic cinacalcet has been used to treat hypercalcemia in certain symptomatic causes of FHH.



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Paget’s Disease of Bone

Publication date: Available online 26 May 2018
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Natasha M. Appelman-Dijkstra, Socrates E. Papapoulos
Paget's disease of bone is a focal disorder of bone remodelling that progresses slowly and leads to changes in the shape and size of affected bones and to skeletal, articular and vascular complications. In some parts of the world it is the second most common bone disorder after osteoporosis though in recent years its prevalence and severity appear to decrease. The disease is easily diagnosed and effectively treated but its pathogenesis remains incompletely understood.



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The Krebs Uric Acid Cycle: A Forgotten Krebs Cycle

Publication date: Available online 26 May 2018
Source:Trends in Biochemical Sciences
Author(s): Jack G. Salway
Hans Kornberg wrote a paper entitled 'Krebs and his trinity of cycles' commenting that every school biology student knows of the Krebs cycle, but few know that Krebs discovered two other cycles. These are (i) the ornithine cycle (urea cycle), (ii) the citric acid cycle (tricarboxylic acid or TCA cycle), and (iii) the glyoxylate cycle that was described by Krebs and Kornberg. Ironically, Kornberg, codiscoverer of the 'glyoxylate cycle', overlooked a fourth Krebs cycle – (iv) the uric acid cycle.



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