Inhalable Anti-EGFR Antibody-Conjugated Osimertinib Liposomes for Non-Small Cell Lung Cancer.

: Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths globally. The most extensive treatment is Tyrosine Kinase Inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) overexpression. Osimertinib, a third-generation TKI is approved to target EGFR exon 19 deletions or exon 21 L858R mutations.

Interglycosidic C5-C6 rotamer distributions of alkyl O-rutinosides.

The conformational study of carbohydrates is critical to understand the molecular recognition mechanisms underlying their biological functions. Moreover, the systematic study of their conformational patterns can unlock useful tools to design optimized glycomimetics and drug candidates. Using nuclear magnetic resonance, we studied the interglycosidic rotamer equilibria of ester-protected and deprotected alkyl O-rutinosides (α-L-Rha(1,6)β-D-GlcOR).

Conformational Properties of Aryl -Glucosides in Solution.

The conformational study of saccharides and glycomimetics in solution is critical for a comprehensive understanding of their interactions with biological receptors and enabling the design of optimized glycomimetics. Here, we report a nuclear magnetic resonance (NMR) study centered on the conformational properties of the hydroxymethyl group and glycosidic bond of four series of aryl -glucosides. We found that in acetyl-protected and free aryl -β-glucosides, the rotational equilibrium around the C5-C6 bond (hydroxymethyl group) exhibits a linear dependence on the electronic properties of the aglycone, namely, as the aryl's substituent electron-withdrawing character increases, the dominance of the rotamer declines and the contribution rises.

Multivalent Targeting of the Asialoglycoprotein Receptor by Virus-Like Particles.

The asialoglycoprotein receptor (ASGPR) is expressed in high density on hepatocytes. Multivalent variants of galactosyl carbohydrates bind ASGPR with high affinity, enabling hepatic delivery of ligand-bound cargo. Virus-like particle (VLP) conjugates of a relatively high-affinity ligand were efficiently endocytosed by ASGPR-expressing cells in a manner strongly dependent on the nature and density of ligand display, with the best formulation using a nanomolar-, but not a picomolar-level, binder.

Cetuximab-based PROteolysis targeting chimera for effectual downregulation of NSCLC with varied EGFR mutations.

PROteolysis Targeting Chimeras (PROTACs) showed tremendous therapeutic potential in degrading several oncoproteins including undruggable proteins. PROTACs are bifunctional molecules where one-part binds to target protein while the other end recruits protein degradation machinery. With the unveiling advancements in the field of PROTACs, we explored a combinatorial approach by developing antibody-based PROTAC (ABTAC) which may effectively degrade one of the key oncoprotein driving proliferation and progression of cancer - Epidermal growth factor receptor (EGFR).

A Ferrier glycosylation/-dihydroxylation strategy to synthesize spp. lipophosphoglycan-associated βGal(1,4)Man disaccharide.

The Galβ(1→4)Man disaccharide, found in the cell surface lipophosphoglycan (LPG) of species, has been synthesized by a Ferrier glycosylation/-dihydroxylation strategy. This stereoselective method proved efficient for synthesizing the target saccharide in good yield. In addition, we prepared two clickable -glycoside and phospho-glycoside versions of Galβ(1→4)Man to enable conjugation to protein carriers for further immunological and antibody-binding studies.

Bictegravir nanomicelles and anionic pullulan loaded vaginal film: Dual mechanistic pre-exposure prophylaxis (PrEP) for HIV.

Locally delivered pre-exposure prophylaxis (PrEP) has proven to be a promising strategy to combat Human immunodeficiency virus (HIV) transmission but several findings encountered toxicities or proved to be marginally effective in clinical settings. Therefore, innovative, multifunctional, and safer alternatives are being progressively investigated. Herein, we explored negatively charged carbohydrate, anionic pullulan (AP) as a rapidly soluble film-former and novel anti-HIV agent.

Anodic Reactivity of Alkyl -Glucosides.

A voltammetric study of a series of alkyl and aryl -glucosides unveiled the reactivity patterns of alkyl -glucosides toward anodic oxidation and found noteworthy differences with the trends followed by aryl derivatives. The oxidation potential of alkyl -glucosides, estimated herein from square-wave voltammetry peak potentials (), depends on the steric properties of the aglycone. Glucosides substituted with bulky groups exhibit values at voltages more positive than the values of those carrying small aglycones.

Augmented lipid-nanoparticle-mediated in vivo genome editing in the lungs and spleen by disrupting Cas9 activity in the liver.

Systemically delivered lipid nanoparticles are preferentially taken up by hepatocytes. This hinders the development of effective, non-viral means of editing genes in tissues other than the liver. Here we show that lipid-nanoparticle-mediated gene editing in the lung and spleen of adult mice can be enhanced by reducing Cas9-mediated insertions and deletions in hepatocytes via oligonucleotides disrupting the secondary structure of single-guide RNAs (sgRNAs) and also via their combination with short interfering RNA (siRNA) targeting Cas9 messenger RNA (mRNA).

Factors associated with Chikungunya infection in a cohort of women aged 15-39 y in Fortaleza, Brazil.

Background: Outbreaks of Chikungunya virus (CHIKV) occurred in Brazil during 2015-2017. Fortaleza was the city that reported the most cases.

Methods: The first round of a cohort study was conducted among women aged 15-39 y in Fortaleza, Brazil, in 2018 (Zika in Fortaleza).

Caveolin-1-Mediated Tumor Suppression Is Linked to Reduced HIF1α S-Nitrosylation and Transcriptional Activity in Hypoxia.

Caveolin-1 (CAV1) is a well-established nitric oxide synthase inhibitor, whose function as a tumor suppressor is favored by, but not entirely dependent on, the presence of E-cadherin. Tumors are frequently hypoxic and the activation of the hypoxia-inducible factor-1α (HIF1α) promotes tumor growth. HIF1α is regulated by several post-translational modifications, including S-nitrosylation.

Glycan-Modified Virus-like Particles Evoke T Helper Type 1-like Immune Responses.

Dendritic cells (DCs) are highly effective antigen-presenting cells that shape immune responses. Vaccines that deliver antigen to the DCs can harness their power. DC surface lectins recognize glycans not typically present on host tissue to facilitate antigen uptake and presentation.

Author Correction: Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER-mitochondria communication during the early phase of ER stress.

Following publication of the article, the authors wrote to point out the following mistake.

Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER-mitochondria communication during the early phase of ER stress.

Close contacts between endoplasmic reticulum and mitochondria enable reciprocal Ca exchange, a key mechanism in the regulation of mitochondrial bioenergetics. During the early phase of endoplasmic reticulum stress, this inter-organellar communication increases as an adaptive mechanism to ensure cell survival. The signalling pathways governing this response, however, have not been characterized.

Cross Talk between Adipose Tissue and Placenta in Obese and Gestational Diabetes Mellitus Pregnancies Exosomes.

Obesity is an important public health issue worldwide, where it is commonly associated with the development of metabolic disorders, especially insulin resistance (IR). Maternal obesity is associated with an increased risk of pregnancy complications, especially gestational diabetes mellitus (GDM). Metabolism is a vital process for energy production and the maintenance of essential cellular functions.

Virus-like Particle Display of the α-Gal Carbohydrate for Vaccination against Infection.

Secreted and surface-displayed carbohydrates are essential for virulence and viability of many parasites, including for immune system evasion. We have identified the α-Gal trisaccharide epitope on the surface of the protozoan parasites and , the etiological agents of visceral and cutaneous leishmaniasis, respectively, with the latter bearing larger amounts of α-Gal than the former. A polyvalent α-Gal conjugate on the immunogenic Qβ virus-like particle was tested as a vaccine against infection in a C57BL/6 α-galactosyltransferase knockout mouse model, which mimics human hosts in producing high titers of anti-α-Gal antibodies.

Intracellular acidification increases adenosine transport in human umbilical vein endothelial cells.

Introduction: Adenosine is taken up via human equilibrative nucleoside transporters 1 (hENT1) and 2 (hENT2) at a physiological extracellular pH (pHo ∼7.4) in human umbilical vein endothelial cells (HUVECs). Acidic pHo increases the uptake of adenosine and 5-hydroxytryptamine (5HT) via hENT4 in this cell type.

Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor.

A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR.

Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer.

Cancer cells generate protons (H) that are extruded to the extracellular medium mainly via the Na/H exchanger 1 (NHE1), which regulates intracellular pH (pHi) and cell proliferation. In primary cultures of human ascites-derived ovarian cancer cells (haOC) we assayed whether NHE1 was required for pHi modulation and cell proliferation. Human ovary expresses NHE1, which is higher in haOC and A2780 (ovarian cancer cells) compared with HOSE cells (normal ovarian cells).

Virus-like Particle Display of the α-Gal Epitope for the Diagnostic Assessment of Chagas Disease.

The α-Gal antigen [Galα(1,3)Galβ(1,4)GlcNAcα] is an immunodominant epitope displayed by infective trypomastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. A virus-like particle displaying a high density of α-Gal was found to be a superior reagent for the ELISA-based serological diagnosis of Chagas disease and the assessment of treatment effectiveness. A panel of sera from patients chronically infected with T.

Nitric oxide and pH modulation in gynaecological cancer.

Nitric oxide plays several roles in cellular physiology, including control of the vascular tone and defence against pathogen infection. Neuronal, inducible and endothelial nitric oxide synthase (NOS) isoforms synthesize nitric oxide. Cells generate acid and base equivalents, whose physiological intracellular concentrations are kept due to membrane transport systems, including Na /H exchangers and Na /HCO transporters, thus maintaining a physiological pH at the intracellular (~7.

Intracellular and extracellular pH dynamics in the human placenta from diabetes mellitus.

The placenta is a vital organ whose function in diseases of pregnancy is altered, resulting in an abnormal supply of nutrients to the foetus. The lack of placental vasculature homeostasis regulation causes endothelial dysfunction and altered vascular reactivity. The proper distribution of acid- (protons (H(+))) and base-equivalents through the placenta is essential to achieve physiological homeostasis.

Nitric Oxide is a Central Common Metabolite in Vascular Dysfunction Associated with Diseases of Human Pregnancy.

Preeclampsia (PE), gestational diabetes mellitus (GDM), and maternal supraphysiological hypercholesterolaemia (MSPH) are pregnancy-related conditions that cause metabolic disruptions leading to alterations of the mother, fetus and neonate health. These syndromes result in fetoplacental vascular dysfunction, where nitric oxide (NO) plays a crucial role. PE characterizes by abnormal increase in the placental blood pressure and a negative correlation between NO level and fetal weight, suggesting that increased NO level and oxidative stress could be involved.

Amblyomma sculptum tick saliva: α-Gal identification, antibody response and possible association with red meat allergy in Brazil.

The anaphylaxis response is frequently associated with food allergies, representing a significant public health hazard. Recently, exposure to tick bites and production of specific IgE against α-galactosyl (α-Gal)-containing epitopes has been correlated to red meat allergy. However, this association and the source of terminal, non-reducing α-Gal-containing epitopes have not previously been established in Brazil.