Immunoglobulin A Mucosal Immunity and Altered Respiratory Epithelium in Cystic Fibrosis

The respiratory epithelium represents the first chemical, immune, and physical barrier against inhaled noxious materials, particularly pathogens in cystic fibrosis. Local mucus thickening, altered mucociliary clearance, and reduced pH due to CFTR protein dysfunction favor bacterial overgrowth and excessive inflammation. We aimed in this review to summarize respiratory mucosal alterations within the epithelium and current knowledge on local immunity linked to immunoglobulin A in patients with cystic fibrosis.

RNA-binding protein dysfunction in neurodegeneration

Protein homeostasis (proteostasis) is a prerequisite for cellular viability and plasticity. In particular, post-mitotic cells such as neurons rely on a tightly regulated safeguard system that allows for regulated protein expression. Previous investigations have identified RNA-binding proteins (RBPs) as crucial regulators of protein expression in nerve cells. However, during neurodegeneration, their ability to control the proteome is progressively disrupted. In this review, we examine the malfunction of key RBPs such as TAR DNA-binding protein 43 (TDP-43), Fused in Sarcoma (FUS), Staufen, Pumilio and fragile-X mental retardation protein (FMRP). Therefore, we focus on two key aspects of RBP dysfunctions in neurodegeneration: protein aggregation and dysregulation of their target RNAs. Moreover, we discuss how the chaperone system responds to changes in the RBP-controlled transcriptome. Based on recent findings, we propose a two-hit model in which both, harmful RBP deposits and target mRNA mistranslation contribute to neurodegeneration observed in RBPathologies.

Engineered Sumoylation-Deficient Prdx6 Mutant Protein-Loaded Nanoparticles Provide Increased Cellular Defense and Prevent Lens Opacity

Aberrant Sumoylation-mediated protein dysfunction is involved in a variety of oxidative and aging pathologies. We previously reported that Sumoylation-deficient Prdx6K(lysine)122/142R(Arginine) linked to the TAT-transduction domain gained stability and protective efficacy. In the present study, we formulated wild-type TAT-HA-Prdx6WT and Sumoylation-deficient Prdx6-loaded poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) to further enhance stability, protective activities, and sustained delivery. We found that in vitro and subconjuctival delivery of Sumoylation-deficient Prdx6-NPs provided a greater protection of lens epithelial cells (LECs) derived from human and Prdx6−/−-deficient mouse lenses against oxidative stress, and it also delayed the lens opacity in Shumiya cataract rats (SCRs) than TAT-HA-Prdx6WT-NPs. The encapsulation efficiencies of TAT-HA-Prdx6-NPs were ≈56%–62%. Dynamic light scattering (DLS) and atomic force microscopy (AFM) analyses showed that the NPs were spherical, with a size of 50–250 nm and a negative zeta potential (≈23 mV). TAT-HA-Prdx6 analog-NPs released bioactive TAT-HA-Prdx6 (6%–7%) within 24 h. Sumoylation-deficient TAT-HA-Prdx6-NPs provided 35% more protection by reducing the oxidative load of LECs exposed to H2O2 compared to TAT-HA-Prdx6WT-NPs. A subconjuctival delivery of TAT-HA-Prdx6 analog-NPs demonstrated that released TAT-HA-Prdx6K122/142R could reduce lens opacity by ≈60% in SCRs. Collectively, our results demonstrate for the first time that the subconjuctival delivery of Sumoylation-deficient Prdx6-NPs is efficiently cytoprotective and provide a proof of concept for potential use to delay cataract and oxidative-related pathobiology in general.

Fertility, Pregnancy and Lactation Considerations for Women with CF in the CFTR Modulator Era

Cystic fibrosis (CF) is an autosomal recessive genetic disorder impacting approximately 80,000 people of all races and ethnicities world-wide. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes a protein of the same name. Protein dysfunction results in abnormal chloride and bicarbonate transport in mucus membranes, including those in the respiratory, gastrointestinal and reproductive tracts. Abnormal anion transport causes viscous secretions at the site of involvement. The majority of people with CF succumb to respiratory failure following recurrent cycles of infection and inflammation in the airways. Historically, providers treated the signs and symptoms of CF, but since 2012, have been able to impact the basic defect for the subset of people with CF who have mutations that respond to the new class of drugs, CFTR protein modulators. With the improved health and longevity afforded by CFTR modulators, more women are interested in parenthood and are becoming pregnant. Furthermore, this class of drugs likely increases fertility in women with CF. However, the safety of CFTR modulators in pregnancy and lactation is only beginning to be established. We summarize available data on the impact of CFTR modulators on fertility, pregnancy and lactation in women with CF.

Trimethylaminuria and Vascular Complications

Background: Trimethylaminuria (Fish-Odour Syndrome) is a rare metabolic disorder characterized by an unpleasant odour in body secretions similar to rotting fish. The disorder is most commonly caused from mutations affecting the Flavin containing monooxygenase 3 (FMO3) gene, the vital enzyme for the metabolism of trimethylamine. Although uncommon, it is important to be conscious of this condition, which can be devastating psychosocially even with reliable diagnostic tests. We present here an individual with this syndrome who, in addition to the psychosocial difficulties, presented physical complications that we relate to the disease’s physiopathology. Case: R.M.F., 56 years old, lawyer, self-diagnosed at 25 after identifying himself with a disease description in a local newspaper. He describes fish odour symptoms from infancy and his mother used to demand excessive hygiene habits. He has always suffered from social disturbances. At 44, a physician’s investigation detected FMO3 mutation. The patient is not obese, has never smoked and denies any comorbidity, except erectile dysfunction for 10 years. He presented 4 years ago extensive acute venous thrombosis in the right lower limb femoral veins, lateral and medial gastrocnemius, solar and fibular popliteal veins. Laboratory investigation excluded other causes and negative antibodies. Besides, ENMG confirmed last year peripheral motor sensitive polyneuropathy, axonal pattern, distal both lower extremities. The patient failed treatment with modifications in diet and hygiene, but achieved symptomatic improvement after metronidazole. Genetic analysis showed a new homozygotic variant in the FMO3 gene, with substitution of adenine for cytosine and exchange of Threonine for proline at position 307 of the FMO3 protein with protein dysfunction computably predicted. Comments: Considering the deep venous thrombosis and symmetrical peripheral neuropathy developed by the patient, we searched for a possible association with TMAU but we did not find previous reports. However, Weifei Zhu et al. (Circulation, 135(17), 1671–73,2017) have shown TMAO generated by gut microbes contributing to platelet hyper reactivity and causing a prothrombotic phenotype in vivo. Plasma TMAO levels could predict incident thrombosis risk. Also, direct TMAO exposure enhanced platelet activation from multiple agonists stimulus. Although the “chemical sensor” for TMAO within platelets remains unknown, these findings could increase our understanding of the relationship between TMAO and CVD risk. Although the disorder might not appear to be a significant health problem, its social and psychological burden can be devastating, since the few treatments available provide modest benefits. In addition, it may be associated with other complications, including CVD, to which we would like to draw attention with this report

Regulation of Cardiac PKA Signaling by cAMP and Oxidants

Pathologies, such as cancer, inflammatory and cardiac diseases are commonly associated with long-term increased production and release of reactive oxygen species referred to as oxidative stress. Thereby, protein oxidation conveys protein dysfunction and contributes to disease progression. Importantly, trials to scavenge oxidants by systemic antioxidant therapy failed. This observation supports the notion that oxidants are indispensable physiological signaling molecules that induce oxidative post-translational modifications in target proteins. In cardiac myocytes, the main driver of cardiac contractility is the activation of the β-adrenoceptor-signaling cascade leading to increased cellular cAMP production and activation of its main effector, the cAMP-dependent protein kinase (PKA). PKA-mediated phosphorylation of substrate proteins that are involved in excitation-contraction coupling are responsible for the observed positive inotropic and lusitropic effects. PKA-actions are counteracted by cellular protein phosphatases (PP) that dephosphorylate substrate proteins and thus allow the termination of PKA-signaling. Both, kinase and phosphatase are redox-sensitive and susceptible to oxidation on critical cysteine residues. Thereby, oxidation of the regulatory PKA and PP subunits is considered to regulate subcellular kinase and phosphatase localization, while intradisulfide formation of the catalytic subunits negatively impacts on catalytic activity with direct consequences on substrate (de)phosphorylation and cardiac contractile function. This review article attempts to incorporate the current perception of the functionally relevant regulation of cardiac contractility by classical cAMP-dependent signaling with the contribution of oxidant modification.

Deactivation of the JNK Pathway by GSTP1 Is Essential to Maintain Sperm Functionality

Fifty percent of male subfertility diagnosis is idiopathic and is usually associated with genetic abnormalities or protein dysfunction, which are not detectable through the conventional spermiogram. Glutathione S-transferases (GSTs) are antioxidant enzymes essential for preserving sperm function and maintaining fertilizing ability. However, while the role of GSTP1 in cell signaling regulation via the inhibition of c-Jun N-terminal kinases (JNK) has been enlightened in somatic cells, it has never been investigated in mammalian spermatozoa. In this regard, a comprehensive approach through immunoblotting, immunofluorescence, computer-assisted sperm assessment (CASA), and flow cytometry analysis was used to characterize the molecular role of the GSTP1–JNK heterocomplex in sperm physiology, using the pig as a model. Immunological assessments confirmed the presence and localization of GSTP1 in sperm cells. The pharmacological dissociation of the GSTP1–JNK heterocomplex resulted in the activation of JNK, which led to a significant decrease in sperm viability, motility, mitochondrial activity, and plasma membrane stability, as well as to an increase of intracellular superoxides. No effects in intracellular calcium levels and acrosome membrane integrity were observed. In conclusion, the present work has demonstrated, for the first time, the essential role of GSTP1 in deactivating JNK, which is crucial to maintain sperm function and has also set the grounds to understand the relevance of the GSTP1–JNK heterocomplex for the regulation of mammalian sperm physiology.

Multimetallic Nanoparticles as Alternative Antimicrobial Agents: Challenges and Perspectives

Recently, infectious diseases caused by bacterial pathogens have become a major cause of morbidity and mortality globally due to their resistance to multiple antibiotics. This has triggered initiatives to develop novel, alternative antimicrobial materials, which solve the issue of infection with multidrug-resistant bacteria. Nanotechnology using nanoscale materials, especially multimetallic nanoparticles (NPs), has attracted interest because of the favorable physicochemical properties of these materials, including antibacterial properties and excellent biocompatibility. Multimetallic NPs, particularly those formed by more than two metals, exhibit rich electronic, optical, and magnetic properties. Multimetallic NP properties, including size and shape, zeta potential, and large surface area, facilitate their efficient interaction with bacterial cell membranes, thereby inducing disruption, reactive oxygen species production, protein dysfunction, DNA damage, and killing potentiated by the host’s immune system. In this review, we summarize research progress on the synergistic effect of multimetallic NPs as alternative antimicrobial agents for treating severe bacterial infections. We highlight recent promising innovations of multimetallic NPs that help overcome antimicrobial resistance. These include insights into their properties, mode of action, the development of synthetic methods, and combinatorial therapies using bi- and trimetallic NPs with other existing antimicrobial agents.

Factors of Cell Degeneration or Death caused by Mutant Tau Protein

Tau protein is a microtubule associated protein mainly expressed in neurons. Under pathological conditions, Tau protein is abnormally hyperphosphorylated and separated from microtubules. Abnormal Tau aggregates form nerve fiber tangles, which are insoluble aggregates in the brain. It is due to the microtubule rupture caused by Tau protein dysfunction and it is associated with neurofibrillar degeneration in Alzheimer's disease.This paper studies several reports and research on the structure and function of Tau protein, the role of Tau protein in pathological diseases and its relationship with neurodegenerative diseases. This paper concludes that Tau protein has undergone abnormal modification and aggregation in many neurodegenerative diseases, but the specific type of Tau protein that causes neurotoxicity, as well as the pathogenesis of its phosphorylation and functional injury inducing nerve apoptosis, are still not fully understood. Various abnormal modifications of Tau protein occur under pathological conditions, and fatal cascade events occur at different stages of neuron apoptosis. Therefore, the causes and effects of cytotoxicity mediated by Tau protein are very complicated. Different or even opposite conclusions are sometimes drawn in Tau protein-mediated neurodegeneration studies. This may be due to differences in Tau protein type, gene mutation and protein expression level.