Potent Disruption Research Articles

Covalent bonding of quaternary ammonium compounds and zwitterionic polymer functional layers on polydimethylsiloxane against Escherichia Coli adhesion.

Quaternary ammonium compounds (QACs) are recognized by the World Health Organization as a useful disinfectant against microbes. The synergistic effect of zwitterionic polymers with QACs as antimicrobial agents rather than QACs alone is yet to be investigated. A potential strategy is the use of covalent bonding to halt the release of minute antibacterials and a hierarchy of functional layers to detain and annihilate microbes. The strategy was tested on a polydimethylsiloxane (PDMS) surface on which quaternized poly(2-dimethylaminoethyl methacrylate) (qDMA+) and sulfobetaine (SBMA) were hierarchically functionalized. Attenuated total reflectance Fourier transform infrared analysis confirmed the quaternization of DMA to qDMA+, grafting of qDMA + on PDMS (PDMS-qDMA+), and grafting of the SBMA overlayer on PDMS-qDMA+ (PDMS-qDMA+-SB). Contact angle measurement showed that PDMS-qDMA + exhibited the lowest contact angle (26.2 ± 2.9°) compared with the hydrophobic PDMS (115.2 ± 1.6°), but that of PDMSqDMA+-SB increased to 56.3 ± 1.3°. The Escherichia coli survival count revealed that PDMS-qDMA+ and PDMS-qDMA+-SB exhibited significantly greater bactericidal ability than PDMS. Confocal laser scanning microscopy revealed fewer dead bacteria on PDMS-qDMA+-SB than on PDMS-qDMA+. Scanning electron microscopy demonstrated that E. coli was disintegrated on the functionalized surface via dual-end cell lysis. To the best of our knowledge, this is the first observation of this type of process. The results confirmed the potent antibacterial and cell disruption activities of the qDMA+ and SBMA modified PDMS surface.

Acute effect of delta-9-tetrahydrocannabinol (THC) on neuromuscular transmission and locomotive behaviours in larval zebrafish.

Given the increasing trend of cannabis use for recreational and therapeutic purposes, a comprehensive examination of cannabis effects is warranted. The principal psychoactive constituent of cannabis, delta-9-tetrahydrocannabinol (THC), is a potent disrupter of neurodevelopment. Nevertheless, the impact of acute exposure to THC on developing motor systems is not well-investigated. In this study, using a neurophysiological whole-cell patch clamp approach we demonstrated that a 30 min exposure to THC can alter spontaneous synaptic activities at neuromuscular junctions of 5-day post-fertilized zebrafish. An increased frequency of synaptic activity and altered decay kinetic properties were documented in the THC-treated larvae. Locomotive behaviours, including swimming activity rate and C-start escape response to sound were also affected by THC. While the THC-treated larvae displayed hyperactivity of their basal swimming levels, their escape response rate to sound stimuli was reduced. These findings suggest that the acute exposure to THC can disrupt neuromuscular transmission and locomotor-driven responses in developing zebrafish.

An insight into bisphenol A, food exposure and its adverse effects on health: A review.

Bisphenol A (BPA) is a synthetic chemical widely employed to synthesize epoxy resins, polymer materials, and polycarbonate plastics. BPA is abundant in the environment, i.e., in food containers, water bottles, thermal papers, toys, medical devices, etc., and is incorporated into soil/water through leaching. Being a potent endocrine disrupter, and has the potential to alter several body mechanisms. Studies confirmed its anti-androgen action and estrogen-like effects, which impart many negative health impacts, especially on the immune system, neuroendocrine process, and reproductive mechanism. Moreover, it can also induce mutagenesis and carcinogenesis, as per recent scientific research. This review focuses on BPA's presence and concentrations in different environments, food sources and the basic mechanisms of BPA-induced toxicity and health disruptions. It is a unique review of its type because it focuses on the association of cancer, hormonal disruption, immunosuppression, and infertility with BPA. These issues are widespread today, and BPA significantly contributes to their incidence because of its wide usage in daily life utensils and other accessories. The review also discusses researched-based measures to cope with the toxic chemical.

A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to cardiovascular disease, PCSK9 has attracted intense interest as a therapeutic target. Despite this interest, an orally bioavailable small-molecule inhibitor of PCSK9 with extensive lipid-lowering activity is yet to enter the clinic. We report herein the discovery of NYX-PCSK9i, an orally bioavailable small-molecule inhibitor of PCSK9 with significant cholesterol-lowering activity in hyperlipidemic APOE∗3-Leiden.CETP mice. NYX-PCSK9i emerged from a medicinal chemistry campaign demonstrating potent disruption of the PCSK9-LDLR interaction in vitro and functional protection of the LDLR of human lymphocytes from PCSK9-directed degradation ex vivo. APOE∗3-Leiden.CETP mice orally treated with NYX-PCSK9i demonstrated a dose-dependent decrease in plasma total cholesterol of up to 57%, while its combination with atorvastatin additively suppressed plasma total cholesterol levels. Importantly, the majority of cholesterol lowering by NYX-PCSK9i was in non-HDL fractions. A concomitant increase in total plasma PCSK9 levels and significant increase in hepatic LDLR protein expression strongly indicated on-target function by NYX-PCSK9i. Determinations of hepatic lipid and fecal cholesterol content demonstrated depletion of liver cholesteryl esters and promotion of fecal cholesterol elimination with NYX-PCSK9i treatment. All measured in vivo biomarkers of health indicate that NYX-PCSK9i has a good safety profile. NYX-PCSK9i is a potential new therapy for hypercholesterolemia with the capacity to further enhance the lipid-lowering activities of statins.

Abstract 3696: GS-9716: A potent, selective and orally bioavailable small molecule inhibitor of MCL1 for the treatment of cancer

Abstract MCL1 is an anti-apoptotic member of the BCL2 family of proteins. These anti-apoptotic proteins prevent caspase-mediated cell apoptosis by binding to the pro-apoptotic proteins BIM, BAK and BAX, thereby inhibiting the formation of pores on the outer mitochondrial membrane. In cancer, MCL1 is upregulated to overcome such stress-induced effects, promoting cell survival, therapy resistance, and tumor progression. Here, we describe the in vitro and in vivo activity of GS-9716, a potent and selective MCL1 small molecule inhibitor that binds directly to MCL1 and induces rapid apoptosis in cancer cells by activating the mitochondrial apoptotic pathway. GS-9716 displayed potent and selective disruption of human MCL1-BIM protein dimer in vitro. In hematological and solid tumor cell line models, GS-9716 led to dose dependent reduction of MCL1-BIM and MCL1-BAK protein dimers. MCL1 protein dimer (BAK and BIM) reduction correlated with dose-dependent increases in cleaved caspase (apoptosis marker). GS-9716 potently reduced cellular viability across panels of hematological (Median GI50 = 30 nM) and breast cancer cell lines (Median GI50 = 470 nM). GS-9716 exhibits favorable pharmacokinetics properties with good oral bioavailability across species. GS-9716 dosed daily, once per week, or 7-day cycles of 2 days on/5 days off, resulted in significant tumor growth inhibition against models of multiple myeloma (H929), several TNBC cell line xenografts (HCC1187 and HCC70) and patient-derived xenografts. Also, in these models, GS-9716 demonstrated dose-dependent MCL1 protein dimer (BIM and BAK) reduction and activation of apoptosis in tumors. In addition to single agent activity, GS-9716 showed strong synergy with multiple anti-cancer therapies; robust in vitro synergy was observed with venetoclax in the AML models and as well as with paclitaxel in the TNBC models. The combination treatment of paclitaxel (dosed IV, QW) with GS-9716 (dosed orally, 2 days on/5 days off) in the TNBC HCC1187 xenograft model achieved complete tumor regression. Similar responses were also observed when GS-9716 was dosed with paclitaxel in the TNBC PDX models. GS-9716 is currently in Phase 1 clinical trial evaluating safety, tolerability and pharmacokinetics as monotherapy and in combination with anticancer therapies in adults with advanced solid tumors (NCT05006794). Citation Format: Clinton K. Matson, Thomas Kenney, Bart H. Steiner, Chloe R. Deodato, Anella Yahiaoui, Claudia A. Rubio, Julie T. Chan, Nevena Mollova, Kathleen S. Keegan, Chandrasekar Venkataramani. GS-9716: A potent, selective and orally bioavailable small molecule inhibitor of MCL1 for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3696.

Impact of Prenatal and Postnatal Exposure to Endocrine Disrupter DDT on Adrenal Medulla Function

Epinephrine is the most abundant catecholamine hormone, produced by the nervous system and adrenal glands. Endocrine disruption of epinephrine synthesis, secretion and signaling is less studied than steroid and thyroid hormones. Dichlorodiphenyltrichloroethane (DDT) is recognized as one of the most prominent environmental contaminants with a long half-life. It is a potent endocrine disrupter affecting sex steroid, mineralocorticoid, glucocorticoid and thyroid hormone production. Exposure to low doses of DDT is universal and begins in utero. Therefore, we studied adrenal medulla growth and function in male Wistar rats exposed to low doses of DDT during prenatal and postnatal development until puberty and adulthood, as well as rats exposed to DDT since the first day of postnatal development. All the exposed rats demonstrated lowered epinephrine blood levels, gradually reducing with age. DDT was found to inhibit the synthesis of tyrosine hydroxylase and affect the mitochondrial apparatus of epinephrine-producing cells during puberty and even after maturation. Low-dose exposure to DDT from birth resulted in more pronounced changes in adrenomedullary cells and a more profound decrease (up to 50%) in epinephrine secretion in adult rats. Prenatal onset of exposure demonstrated a mild effect on epinephrine-producing function (30% reduction), but was associated with lower rate of adrenal medulla growth during maturation and 25% smaller adrenal medullar size in adult rats. All subjects exposed to low doses of DDT failed to develop adaptive changes and restore proper epinephrine production. These results indicate a dysmorphogenetic effect of prenatal exposure and disruption of secretory function of adrenal chromaffin cells by postnatal exposure to DDT.

Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death.

Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587.

Hexaconazole exposure ravages biosynthesis pathway of steroid hormones: revealed by molecular dynamics and interaction.

Widespread application of hexaconazole for agriculture purpose poses a threat to human health by disrupting normal endocrine homeostasis. To avoid adverse health effects on human, it is crucial to identify the effects of hexaconazole on key enzymes responsible for steroidal hormone synthesis. In view of this, present study was conducted to investigate the interaction mechanisms of hexaconazole with key enzymes in comparison with their food drug administration (FDA) approved inhibitor by molecular docking and molecular dynamics simulations. Results indicate that hexaconazole contacts with the active site of the key enzymes required for steroidal hormonal synthesis. Results pertaining to root-mean-square deviation, root-mean-square calculation, radius of gyration, hydrogen bonding and solvent accessible surface area exhibited that the interaction pattern and stability of interaction of hexaconazole was similar to enzyme specific inhibitor. In addition, ligand and enzyme complex interaction energy of hexaconazole was almost similar to key enzyme and FDA-approved enzyme specific inhibitor complex. This study offers a molecular level of understanding of hexaconazole with different enzymes required for steroidal hormonal synthesis. Findings of the study clearly suggest that hexaconazole has efficacy to stably interact with various enzyme required to progress the pathway of hormonal synthesis. If incessant exposure of hexaconazole occurs during agricultural work it may lead to ravage hormonal synthesis or potent endocrine disruption. The result of binding energy and complex interaction energy is depicted in the graphical abstract.

Correlating seasonal changes of naturally produced brominated compounds to biomarkers in perch from the Baltic Sea.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs), naturally produced by algae and cyanobacteria in the Baltic Sea, are potent disrupters of energy metabolism as well as endocrine disruptors and neurotoxins. In this study, European perch (Perca fluviatilis) from the Baltic Sea were sampled from May until October. OH-PBDEs and ten biomarkers were measured in each individual (n=84 over 18 sampling time points) to study potential correlations between exposure to OH-PBDEs and changes in biomarkers. Several biomarkers showed significant non-linear seasonal variation. In the perch, ethoxyresorufin-O-deethylase (EROD) activity, plasma lactate concentration, and plasma glucose concentration showed a significant positive log-linear correlation with OH-PBDEs, whereas lipid percentage and liver somatic index showed a significant negative log-linear correlation with OH-PBDEs. These results strengthen the concern that OH-PBDEs could cause negative health effects for fish in the Baltic Sea.

A Nanoplatform to Amplify Apoptosis-to-Pyroptosis Immunotherapy via Immunomodulation of Myeloid-Derived Suppressor Cells.

Pyroptosis is a programmed cell death to enhance immunogenicity of tumor cells, but pyroptosis-based immunotherapy is limited due to the immune escape involving myeloid-derived suppressor cells (MDSCs). Therefore, designing a nanoplatform to not only trigger apoptosis-pyroptosis transformation but also combat the MDSC-based immune escape is of great significance. As a proof-of-concept study, here, we designed a metal organic framework (MOF)-based nanoplatform to tailor the pyroptosis immunotherapy through disrupting the MDSC-mediated immunosuppression. By pH-responsive zeolitic imidazolate framework-8 (ZIF-8) modified with hyaluronic acid (HA), the chemotherapeutic drug mitoxantrone (MIT) and DNA demethylating agent hydralazine (HYD) were successfully co-encapsulated into ZIF-8 for achieving (M+H)@ZIF/HA nanoparticles. This nanoplatform demonstrated a powerful apoptosis-to-pyroptosis transformation with a potent disruption of MDSC-mediated T cell paralysis via reducing immunosuppressive methylglyoxal by HYD. Overall, our two-pronged nanoplatform (M+H)@ZIF/HA can switch the cold tumor into an arsenal of antigens that stimulate robust immunological responses, while suppressing immune escape, collectively triggering vigorous cytotoxic T cell responses with remarkable tumor elimination and building a long-term immune memory response against metastasis.

Di-n-butyl phthalate disrupts neuron maturation in primary rat embryo neurons and male C57BL/6 mice

ABSTRACT Di-n-butyl phthalate (DBP) is commonly used as a plasticizer and its usage continues to increase in conjunction with plastic consumption. DBP is readily released into air, drinking water, and soil, and unfortunately, is a potent endocrine disrupter that impairs central nervous system functions. Previously DBP was found to (1) arrest the cell cycle of C17.2 neural progenitor cells (NPCs) at the G1 phase, (2) reduce numbers of newly generated neural stem cells in the mouse hippocampus, and (3) adversely affect learning and memory. Other investigators also noted DBP-mediated neurotoxic effects, but as yet, no study has addressed the adverse effects of DBP on neuronal differentiation. Data demonstrated that at 200 μM DBP induced apoptosis in rat embryo primary neurons by increasing reactive oxygen species levels and inducing mitochondrial dysfunction. However, no significant effect was detected on neurons at concentrations of ≤100 μM. In contrast, doublecortin/microtubule associated protein-2 (DCX/MAP2) immunocytochemistry showed that DBP at 100 μM delayed neuronal maturation by increasing protein levels of DCX (an immature neuronal marker), without markedly affecting cell viability. Further in vivo studies confirmed that DCX+ cell numbers were significantly elevated in the hippocampus of DBP-treated mice, indicating that DBP delayed neuronal maturation, which is known to be associated with impaired memory retention. Data demonstrated that DBP might disrupt neuronal maturation, which is correlated with reduced neurocognitive functions.

Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities.

Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a-2d, 3a-3g, and 4a-4t, were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50 = 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.

Impact of Multivalence and Self-Assembly in the Design of Polymeric Antimicrobial Peptide Mimics.

Antimicrobial resistance is an increasingly serious challenge for public health and could result in dramatic negative consequences for the health care sector during the next decades. To solve this problem, antibacterial materials that are unsusceptible toward the development of bacterial resistance are a promising branch of research. In this work, a new type of polymeric antimicrobial peptide mimic featuring a bottlebrush architecture is developed, using a combination of reversible addition-fragmentation chain transfer (RAFT) polymerization and ring-opening metathesis polymerization (ROMP). This approach enables multivalent presentation of antimicrobial subunits resulting in improved bioactivity and an increased hemocompatibility, boosting the selectivity of these materials for bacterial cells. Direct probing of membrane integrity of treated bacteria revealed highly potent membrane disruption caused by bottlebrush copolymers. Multivalent bottlebrush copolymers clearly outperformed their linear equivalents regarding bioactivity and selectivity. The effect of segmentation of cationic and hydrophobic subunits within bottle brushes was probed using heterograft copolymers. These materials were found to self-assemble under physiological conditions, which reduced their antibacterial activity, highlighting the importance of precise structural control for such applications. To the best of our knowledge, this is the first example to demonstrate the positive impact of multivalence, generated by a bottlebrush topology in polymeric antimicrobial peptide mimics, making these polymers a highly promising material platform for the design of new bactericidal systems.

The Streptococcal Protease SpeB Antagonizes the Biofilms of the Human Pathogen Staphylococcus aureus USA300 through Cleavage of the Staphylococcal SdrC Protein.

Streptococcus pyogenes, or group A Streptococcus (GAS), is both a pathogen and an asymptomatic colonizer of human hosts and produces a large number of surface-expressed and secreted factors that contribute to a variety of infection outcomes. The GAS-secreted cysteine protease SpeB has been well studied for its effects on the human host; however, despite its broad proteolytic activity, studies on how this factor is utilized in polymicrobial environments are lacking. Here, we utilized various forms of SpeB protease to evaluate its antimicrobial and antibiofilm properties against the clinically important human colonizer Staphylococcus aureus, which occupies niches similar to those of GAS. For our investigation, we used a skin-tropic GAS strain, AP53CovS+, and its isogenic ΔspeB mutant to compare the production and activity of native SpeB protease. We also generated active and inactive forms of recombinant purified SpeB for functional studies. We demonstrate that SpeB exhibits potent biofilm disruption activity at multiple stages of S. aureus biofilm formation. We hypothesized that the surface-expressed adhesin SdrC in S. aureus was cleaved by SpeB, which contributed to the observed biofilm disruption. Indeed, we found that SpeB cleaved recombinant SdrC in vitro and in the context of the full S. aureus biofilm. Our results suggest an understudied role for the broadly proteolytic SpeB as an important factor for GAS colonization and competition with other microorganisms in its niche.IMPORTANCEStreptococcus pyogenes (GAS) causes a range of diseases in humans, ranging from mild to severe, and produces many virulence factors in order to be a successful pathogen. One factor produced by many GAS strains is the protease SpeB, which has been studied for its ability to cleave and degrade human proteins, an important factor in GAS pathogenesis. An understudied aspect of SpeB is the manner in which its broad proteolytic activity affects other microorganisms that co-occupy niches similar to that of GAS. The significance of the research reported herein is the demonstration that SpeB can degrade the biofilms of the human pathogen Staphylococcus aureus, which has important implications for how SpeB may be utilized by GAS to successfully compete in a polymicrobial environment.

Variability in Assembly of Degradation Operons for Naphthalene and its derivative, Carbaryl, Suggests Mobilization through Horizontal Gene Transfer.

In the biosphere, the largest biological laboratory, increased anthropogenic activities have led microbes to evolve and adapt to the changes occurring in the environment. Compounds, specifically xenobiotics, released due to such activities persist in nature and undergo bio-magnification in the food web. Some of these compounds act as potent endocrine disrupters, mutagens or carcinogens, and therefore their removal from the environment is essential. Due to their persistence, microbial communities have evolved to metabolize them partially or completely. Diverse biochemical pathways have evolved or been assembled by exchange of genetic material (horizontal gene transfer) through various mobile genetic elements like conjugative and non-conjugative plasmids, transposons, phages and prophages, genomic islands and integrative conjugative elements. These elements provide an unlimited opportunity for genetic material to be exchanged across various genera, thus accelerating the evolution of a new xenobiotic degrading phenotype. In this article, we illustrate examples of the assembly of metabolic pathways involved in the degradation of naphthalene and its derivative, Carbaryl, which are speculated to have evolved or adapted through the above-mentioned processes.

Zika virus induces strong inflammatory responses and impairs homeostasis and function of the human retinal pigment epithelium.

BackgroundZika virus (ZIKV) has recently re-emerged as a pathogenic agent with epidemic capacities as was well illustrated in South America. Because of the extent of this health crisis, a number of more serious symptoms have become associated with ZIKV infection than what was initially described. In particular, neuronal and ocular disorders have been characterized, both in infants and in adults. Notably, the macula and the retina can be strongly affected by ZIKV, possibly by a direct effect of the virus. This is supported by the detection of replicative and infectious virus in lachrimal fluid in human patients and mouse models.MethodsHere, we used an innovative, state-of-the-art iPSC-derived human retinal pigment epithelium (RPE) model to study ZIKV retinal impairment.FindingsWe showed that the human RPE is highly susceptible to ZIKV infection and that a ZIKV African strain was more virulent and led to a more potent epithelium disruption and stronger anti-viral response than an Asian strain, suggesting lineage differences. Moreover, ZIKV infection led to impaired membrane dynamics involved in endocytosis, organelle biogenesis and potentially secretion, key mechanisms of RPE homeostasis and function.InterpretationTaken together, our results suggest that ZIKV has a highly efficient ocular tropism, which creates a strong inflammatory environment that could have acute or chronic adverse effects.FundThis work was funded by Retina France, REACTing and La Région Languedoc-Roussillon.

Fluorinated Oligoethylenimine Nanoassemblies for Efficient siRNA-Mediated Gene Silencing in Serum-Containing Media by Effective Endosomal Escape

Efficient small interfering RNA (siRNA) delivery in the presence of serum is of crucial importance for effective gene therapy. Fluorinated vectors are considered to be attractive candidates for siRNA-mediated gene therapy because of their delivery efficacy in serum-containing media. However, the mechanisms driving the superior gene transfection behavior of fluorinated vectors are still not well-understood, and comprehensive investigations are warranted. Herein, we fabricated a library of perfluorooctanoyl fluoride-fluorinated (PFF-fluorinated) oligoethylenimines (f xOEIs, x is the PFF:OEI feeding ratio), which can readily form nanoassemblies (f xOEI NAs) capable of efficient siRNA delivery in cells cultured in medium both devoid of and supplemented with fetal bovine serum (FBS). The gene silencing test in serum-containing medium revealed that the f0.7OEI/siRNA NAs achieved a luciferase silencing of ∼88.4% in Luc-HeLa cells cultured in FBS-containing medium, which was almost 2-fold greater than the silencing efficacy of siRNA delivered by the commercially available vector Lipo 2000 (∼48.8%). High levels of apolipoprotein B silencing were also achieved by f0.7OEI/siRNA NAs in vivo. For an assessment of the underlying mechanisms of the efficacy of gene silencing of fluorinated vectors, two alkylated OEIs, aOEI-C8 and aOEI-C12, were fabricated as controls with similar molecular structure and hydrophobicity to that of f0.7OEI, respectively. In vitro investigations showed that the superior gene delivery exhibited by f0.7OEI NAs derived from the potent endosomal disruption capability of fluorinated vectors in the presence of serum, which was essentially attributed to the serum protein adsorption resistance of the f0.7OEI NAs. Therefore, this work provides an innovative approach to siRNA delivery as well as insights into fluorine-associated serum resistance.

Abstract 867: Blocking breast cancer metastasis by targeting HuR-FOXQ1 signaling axis

Abstract As most of treatment options do not work very well for metastatic cancer. Patients with metastatic cancer have a greatly lower survival rate compared with patients with local cancer. Metastasis remains a life-threat to cancer patients and an unmet medical need. The RBP Hu antigen R (HuR) is overexpressed in virtually all malignancies tested, including breast cancer. Cytoplasmic HuR accumulation correlates with high-grade malignancy, poor distant disease-free survival and serves as a prognostic factor for poor clinical outcome in breast cancer. HuR promotes tumorigenesis by promoting mRNA stability and translation of proteins implicated in proliferation, survival, angiogenesis, invasion, and metastasis. We found that silencing of HuR inhibited cell invasion in vitro in breast cancer. Using RIP-seq (ribonucleoprotein immunoprecipitation-sequencing), a transcription factor FOXQ1, which is recently revealed to implicate in breast cancer invasion and metastasis processes, is found to be a direct HuR target. Furthermore, exogenous introduction of FOXQ1 can rescue cell invasive ability inhibited by HuR knockout. Taken together, HuR-FOXQ1 signaling axis is a potential target for blocking breast cancer metastasis. RNA-binding proteins had previously been considered “undruggable” due to lack of a well-defined binding pocket for target RNAs. Using high throughput screening followed by structure-based rational design and lead optimization, we have identified small molecules that inhibit HuR-mRNA interaction at nM to sub-µM potency. Our lead compound, KH-3, potently inhibits breast cancer cell growth and decreases cell invasion in vitro similar to HuR knockout, as well as increasing the expression of epithelial marker E-cadherin. FOXQ1 overexpression abolishes the effect of KH-3 on blocking metastasis in breast cancer cells, demonstrating that the HuR inhibitor KH-3 inhibits cell metastasis by blocking FOXQ1 function. Moreover, KH-3 treatment disrupts HuR-FOXQ1 interaction in RNP-IP and FOXQ1 3′-UTR luciferase reporter assays. In vivo efficacy studies show that KH-3 not only exhibits potent antitumor efficacy in orthotopic xenograft models of breast cancer, but also efficiently blocks lung metastasis in experimental metastatic cancer model. In conclusion, we identified a potent and specific small molecule disrupter of HuR-FOXQ1 interaction for potential novel anti-metastatic therapy of breast cancer with HuR overexpression. Citation Format: Xiaoqing Wu, Gulhumay Gardashova, Lan Lan, Yu Zhan, Jiajun Liu, Dan A. Dixon, Jeffrey Aubé, Danny R. Welch, Liang Xu. Blocking breast cancer metastasis by targeting HuR-FOXQ1 signaling axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 867.

“둔한 삶”의 꿈 : 레베카 하딩 데이비스의 「제철공장의 삶」 에 나타난 탈출로서의 예술

The representation of industrial laborers as passive and unrevolutionary in “Life in the Iron Mills” has often been under scholarly rebuke. The novella is even judged to be a failed realism, for it gives an odd account of the atypical laborer who prefers art to work, not the stout laborer proud of his or her work while fighting against exploitative capitalists. But no laborers are the same. Art may function as alternative exit for laborers who suffer. Previously intertwined, labor and art took separate paths since the Industrial Revolution, when laborers were no longer permitted to exert his artistic talent. In this tragic disengagement of art and labor, this paper claims, the atypical hunger of an obscure laborer for art in “Life in the Iron Mills” showcases the potent disruption of capitalist stratification rather than the traitorous refusal of labor solidarity.

Co-Administration of Vitamin E and Testosterone Attenuates The Atrazine-Induced Toxic Effects on Sperm Quality and Testes in Rats.

Objective Atrazine (ATZ) as a widely used herbicide is considered as a potent endocrine disrupter which adversely affects reproductive systems in both genders. This study aimed to assess the effects of testosterone (T)- and vitamin E (VitE)- alone and their coadministration on testicular function and sperm parameters after exposure to ATZ in rats. Materials and Methods In this experimental study, the rats (n=30) are assigned into the following 5 groups: control-sham group (n=6) receiving corn oil, ATZ group (n=6) receiving 200 mg/kg ATZ alone, ATZ+VitE group (n=6) receiving 150 mg/kg ATZ+VitE, ATZ+T group (n=6) receiving 400 µg/kg ATZ+T, and ATZ+VitE+T group (n=6) receiving ATZ+VitE+T for 48 consecutive days. Total antioxidant capacity (TAC), total thiol molecules (TTM), and malondialdehyde (MDA) were analyzed. Serum levels of T, luteinizing hormone (LH), and inhibin-B (IN-B) were also determined. Histological examination and sperm analysis were performed. The data were analyzed using Graph-Pad Prism software version 2.01. Results Co-administration of VitE and T significantly (P<0.05) increased ATZ-decreased TAC and TTM levels and reduced ATZ-increased MDA content. T and VitE significantly (P<0.05) increased serum levels of ATZ-reduced T (1.94 ± 0.96), IN-B (122.10 ± 24.33) and LH (0.40 ± 0.10). The T+VitE animals showed a reduction in apoptotic cells and an increase in Leydig cells steroidogenesis. Co-administration of T and VitE significantly (P<0.05) reduced the ATZ-induced DNA disintegrity and chromatin de-condensation. VitE and T protected germinal cells RNA and protein contents against ATZ-induced damages. ConclusionT and VitE in simultaneous form of administration were able to normalize the ATZ-induced derangements through promoting antioxidant capacity and endocrine function.