4-Acetylantroquinonol B Suppresses Prostate Cancer Growth and Angiogenesis via a VEGF/PI3K/ERK/mTOR-Dependent Signaling Pathway in Subcutaneous Xenograft and In Vivo Angiogenesis Models

Prostate cancer is a major cause of cancer-related mortality in men in developed countries. The compound, 4-acetylantroquinonol B (4AAQB), is isolated from Antrodia cinnamomea (commonly known as Niu-Chang-Chih), which has been shown to inhibit cancer growth. However, the anticancer activity of 4AAQB has not previously been examined in prostate cancer. This study aimed to investigate the effect of 4AAQB on cancer and angiogenesis, as well as to explore its mechanism of action. Human prostate cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC) were used in cell viability, cell migration, and cell cycle functional assays to evaluate the anticancer and antiangiogenic efficacy of 4AAQB in vitro. The effects of 4AAQB in vivo were determined using xenograft and angiogenesis models. The signaling events downstream of 4AAQB were also examined. The 4AAQB compound inhibited PC3 cell growth and migration, and reduced in vivo cancer growth, as shown in a subcutaneous xenograft model. Furthermore, 4AAQB inhibited HUVEC migration, tube formation, and aortic ring sprouting; it also reduced neovascularization in a Matrigel implant angiogenesis assay in vivo. The 4AAQB compound also decreased metastasis in the PC3 prostate cancer model in vivo. Serum or vascular endothelial growth factor (VEGF)-induced VEGF receptor 2 (VEGFR2), phosphoinositide 3-kinase (PI3K)/Ak strain transforming (Akt), and extracellular signal-regulated kinase ½ (ERK ½) phosphorylation were attenuated by 4AAQB in both PC3 and HUVEC. In conclusion, 4AAQB is a potential candidate for prostate cancer therapy.     

The Anxiolytic Drug Buspirone Prevents Rotenone-Induced Toxicity in a Mouse Model of Parkinson’s Disease

A pharmacological and genetic blockade of the dopamine D3 receptor (D3R) has shown to be neuroprotective in models of Parkinson’s disease (PD). The anxiolytic drug buspirone, a serotonin receptor 1A agonist, also functions as a potent D3R antagonist. To test if buspirone elicited neuroprotective activities, C57BL/6 mice were subjected to rotenone treatment (10mg/kg i.p for 21 days) to induce PD-like pathology and were co-treated with increasing dosages of buspirone (1, 3, or 10 mg/kg i.p.) to determine if the drug could prevent rotenone-induced damage to the central nervous system (CNS). We found that high dosages of buspirone prevented the behavioural deficits caused by rotenone in the open field test. Molecular and histological analyses confirmed that 10 mg/kg of buspirone prevented the degeneration of TH-positive neurons. Buspirone attenuated the induction of interleukin-1β and interleukin-6 expression by rotenone, and this was paralleled by the upregulation of arginase-1, brain-derived neurotrophic factor (BDNF), and activity-dependent neuroprotective protein (ADNP) in the midbrain, striatum, prefrontal cortex, amygdala, and hippocampus. Buspirone treatment also improved mitochondrial function and antioxidant activities. Lastly, the drug prevented the disruptions in the expression of two neuroprotective peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). These results pinpoint the neuroprotective efficacy of buspirone against rotenone toxicity, suggesting its potential use as a therapeutic agent in neurodegenerative and neuroinflammatory diseases, such as PD.     

The Deubiquitinase OTUB1 Is a Key Regulator of Energy Metabolism

Dysregulated energy metabolism is a major contributor to a multitude of pathologies, including obesity and diabetes. Understanding the regulation of metabolic homeostasis is of utmost importance for the identification of therapeutic targets for the treatment of metabolically driven diseases. We previously identified the deubiquitinase OTUB1 as substrate for the cellular oxygen sensor factor-inhibiting HIF (FIH) with regulatory effects on cellular energy metabolism, but the physiological relevance of OTUB1 is unclear. Here, we report that the induced global deletion of OTUB1 in adult mice (Otub1 iKO) elevated energy expenditure, reduced age-dependent body weight gain, facilitated blood glucose clearance and lowered basal plasma insulin levels. The respiratory exchange ratio was maintained, indicating an unaltered nutrient oxidation. In addition, Otub1 deletion in cells enhanced AKT activity, leading to a larger cell size, higher ATP levels and reduced AMPK phosphorylation. AKT is an integral part of insulin-mediated signaling and Otub1 iKO mice presented with increased AKT phosphorylation following acute insulin administration combined with insulin hypersensitivity. We conclude that OTUB1 is an important regulator of metabolic homeostasis.     

Blood–Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke

Globally, stroke is a leading cause of death and long-term disability. Over the past decades, several efforts have attempted to discover new drugs or repurpose existing therapeutics to promote post-stroke neurological recovery. Preclinical stroke studies have reported successes in identifying novel neuroprotective agents; however, none of these compounds have advanced beyond a phase III clinical trial. One reason for these failures is the lack of consideration of blood–brain barrier (BBB) transport mechanisms that can enable these drugs to achieve efficacious concentrations in ischemic brain tissue. Despite the knowledge that drugs with neuroprotective properties (i.e., statins, memantine, metformin) are substrates for endogenous BBB transporters, preclinical stroke research has not extensively studied the role of transporters in central nervous system (CNS) drug delivery. Here, we review current knowledge on specific BBB uptake transporters (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents); organic cation transporters (OCTs in humans; Octs in rodents) that can be targeted for improved neuroprotective drug delivery. Additionally, we provide state-of-the-art perspectives on how transporter pharmacology can be integrated into preclinical stroke research. Specifically, we discuss the utility of in vivo stroke models to transporter studies and considerations (i.e., species selection, co-morbid conditions) that will optimize the translational success of stroke pharmacotherapeutic experiments.     

High Iron and Iron Household Protein Contents in Perineuronal Net-Ensheathed Neurons Ensure Energy Metabolism with Safe Iron Handling

A subpopulation of neurons is less vulnerable against iron-induced oxidative stress and neurodegeneration. A key feature of these neurons is a special extracellular matrix composition that forms a perineuronal net (PN). The PN has a high affinity to iron, which suggests an adapted iron sequestration and metabolism of the ensheathed neurons. Highly active, fast-firing neurons—which are often ensheathed by a PN—have a particular high metabolic demand, and therefore may have a higher need in iron. We hypothesize that PN-ensheathed neurons have a higher intracellular iron concentration and increased levels of iron proteins. Thus, analyses of cellular and regional iron and the iron proteins transferrin (Tf), Tf receptor 1 (TfR), ferritin H/L (FtH/FtL), metal transport protein 1 (MTP1 aka ferroportin), and divalent metal transporter 1 (DMT1) were performed on Wistar rats in the parietal cortex (PC), subiculum (SUB), red nucleus (RN), and substantia nigra (SNpr/SNpc). Neurons with a PN (PN⁺) have higher iron concentrations than neurons without a PN: PC 0.69 mM vs. 0.51 mM, SUB 0.84 mM vs. 0.69 mM, SN 0.71 mM vs. 0.63 mM (SNpr)/0.45 mM (SNpc). Intracellular Tf, TfR and MTP1 contents of PN⁺ neurons were consistently increased. The iron concentration of the PN itself is not increased. We also determined the percentage of PN⁺ neurons: PC 4%, SUB 5%, SNpr 45%, RN 86%. We conclude that PN⁺ neurons constitute a subpopulation of resilient pacemaker neurons characterized by a bustling iron metabolism and outstanding iron handling capabilities. These properties could contribute to the low vulnerability of PN⁺ neurons against iron-induced oxidative stress and degeneration.     

Modeling the influence of changes in aliphatic structure on char surface area during coal pyrolysis

The influence of changes in aliphatic structure on char surface area during coal pyrolysis was modeled, and the effect was introduced to a previous char surface area model for lignite pyrolysis established based on the chemical percolation devolatilization (CPD) model. The modified model can predict not only the N₂ and CO₂ char surface area during rapid pyrolysis of three lignites but also the CO₂ char surface area of two high-volatile bituminous coals; the agreement of the modified model with experiments is improved at high temperatures. The decrease in aliphatic chain length can reduce adsorption positions around aromatic core, and decrease char surface area. When mass release is more than 55% at about 1,100 K, the predicted N₂ char surface area starts to decrease with further generation of volatiles, and the increase of predicted CO₂ char surface area with increasing generation of volatiles also become slow at the end of mass release.     

Effect of phase maldistribution on performance of two-phase catalytic monolith reactor and its comparison with trickle bed reactor

Monolith reactors are widely considered as an alternative to the conventional trickle bed reactor. For the commercial deployment of monolith reactors, comparative performance studies are required. Reliable comparative and performance studies require a detailed understanding of the effect of phase distribution/maldistribution on the performance studies. In this work, performance and comparative studies were carried out in a relatively large column that was 4.8 cm in diameter. Experiments were performed in the same conditions that were used in studies for which phase distribution data were available. Since the properties of the catalyst used were different in both the reactors, the apparent kinetics were studied to facilitate the comparison. The hydrogenation of alpha-methyl styrene (AMS) was used as a test reaction. From the performance studies, it was found that the effect of maldistribution on the performance was stronger than the catalyst availability. From the comparative studies, it was found that the monolith reactor with maldistributed flow conditions provides higher productivity than the trickle bed reactor.     

Statistical Data Analysis in the Era of Big Data

Big data is on everyone's lips and often raises emotions. On the one hand, the notion is a basis for much technological optimism, mostly directed towards new business models, or simplifications and optimizations in professional and private life. On the other hand, it is a basis for dystopic perspectives, which are targeted, e.g., at profiling of the individual and their privacy space, overarching optimization in daily life and intransparency of decision making. In this article, after a short historical prolog, it is discussed what distinguishes big data from traditional data analysis. The underlying mathematical methods are introduced and scientific successes are reported. Additionally, the risks and limits – especially regarding the derivation of causal relationships – of data analysis are discussed.     

Viscoelastic and thermal properties of natural rubber low-density polyethylene composites with boric acid and borax

The influence of boric acid (BA) and borax (BO) neutron-absorbing fillers on thermal stability and viscoelastic behavior of natural rubber (NR) low-density polyethylene composites has been studied. The thermal degradation and dynamic mechanical properties of the composites have been analyzed as a function of temperature. The results revealed the enhancement of thermal stability of the composites by the addition of BA and BO fillers. The flame resistance of the material was improved by the addition of both the fillers. The storage modulus was found to be dependent upon the temperature and nature of the filler. The amount of NR chains immobilized by filler particles has been quantified from dynamic mechanical analysis and secondary filler/filler interactions have been verified by the Payne effect analysis. Finally, the experimental results have been compared with theoretical predictions.     

Polyphenol conjugated poly(beta-amino ester) polymers with hydrogen peroxide triggered degradation and active antioxidant release

Oxidative stress has been implicated as a primary or secondary player to numerous diseases. A potential approach to control oxidative stress induced diseases is to deliver small antioxidant compounds to compromised sites at equivalent rates of reactive oxygen species (ROS) generation. This becomes a complicated task as antioxidant molecules typically have poor bioavailability and stability. Antioxidants synthesized into poly(beta-amino ester) (PBAE) crosslinked polymers have shown improved delivery by enhancing stability while allowing controlled release through hydrolysis. The tunable crosslinked networks show significant response to specific oxidizing environments, where free radicals can be present. Curcumin conjugated PBAE bulk films have proportional rates of accelerated degradation, thus faster release of curcumin, in a range of low concentrations of hydrogen peroxide (H₂O₂)_, where 2′2-azobis(2-amidinopropane) dihydrochloride has no substantial impact. This effect suggests the possibility to create a system that releases its therapeutic agent in direct relationship to the need through ROS signaling. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48647.