Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson’s disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies

IRE1α Inhibitors as a Promising Therapeutic Strategy in Blood Malignancies

Synthesis, folding, and structural maturation of proteins occur in the endoplasmic reticulum (ER). Accumulation of misfolded or unfolded proteins in the ER lumen contributes to the induction of ER stress and activation of the unfolded protein response (UPR) signaling pathway. Under ER stress, the UPR tries to maintain cellular homeostasis through different pathways, including the inositol-requiring enzyme 1 alpha (IRE1α)-dependent ones. IRE1α is located in an ER membrane, and it is evolutionarily the oldest UPR sensor. Activation of IRE1α via ER stress triggers the formation of the spliced form of XBP1 (XBP1s), which has been linked to a pro-survival effect in cancer cells. The role of IRE1α is critical for blood cancer cells, and it was found that the levels of IRE1α and XBP1s are elevated in various hematological malignancies. This review paper is focused on summarizing the latest knowledge about the role of IRE1α and on the assessment of the potential utility of IRE1α inhibitors in blood cancers

Targeting NLRP3-Mediated Neuroinflammation in Alzheimer’s Disease Treatment

Alzheimer’s disease (AD) is the most common cause of dementia in the general population and, to date, constitutes a major therapeutic challenge. In the pathogenesis of AD, aggregates of amyloid β (Aβ) and neurofibrillary tangles (NFTs) containing Tau-microtubule-associated protein (tau) are known to trigger a neuroinflammatory response with subsequent formation of an inflammasome. In particular, the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is thought to play a crucial role in AD-related pathology. While the mechanisms for NLRP3 activation are not fully understood, it has been demonstrated that, after detection of protein aggregates, NLRP3 induces pro-inflammatory cytokines, such as interleukin 18 (IL-18) or interleukin 1β (IL-1β), that further potentiate AD progression. Specific inhibitors of NLRP3 that exhibit various mechanisms to attenuate the activity of NLRP3 have been tested in in vivo studies and have yielded promising results, as shown by the reduced level of tau and Aβ aggregates and diminished cognitive impairment. Herein, we would like to summarize the current state of knowledge on NLRP3 inflammasome priming, activation, and its actual role in AD pathogenesis, and to characterize the NLRP3 inhibitors that have been studied most and their impact on AD-related pathology

<i>GBA1</i> Gene Mutations in α-Synucleinopathies—Molecular Mechanisms Underlying Pathology and Their Clinical Significance

α-Synucleinopathies comprise a group of neurodegenerative diseases characterized by altered accumulation of a protein called α-synuclein inside neurons and glial cells. This aggregation leads to the formation of intraneuronal inclusions, Lewy bodies, that constitute the hallmark of α-synuclein pathology. The most prevalent α-synucleinopathies are Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). To date, only symptomatic treatment is available for these disorders, hence new approaches to their therapy are needed. It has been observed that GBA1 mutations are one of the most impactful risk factors for developing α-synucleinopathies such as PD and DLB. Mutations in the GBA1 gene, which encodes a lysosomal hydrolase β-glucocerebrosidase (GCase), cause a reduction in GCase activity and impaired α-synuclein metabolism. The most abundant GBA1 gene mutations are N370S or N409S, L444P/L483P and E326K/E365K. The mechanisms by which GCase impacts α-synuclein aggregation are poorly understood and need to be further investigated. Here, we discuss some of the potential interactions between α-synuclein and GCase and show how GBA1 mutations may impact the course of the most prevalent α-synucleinopathies

Attitude and Behaviors towards SARS-CoV-2 Vaccination among Healthcare Workers: A Cross-Sectional Study from Poland

Healthcare workers are particularly exposed to biological risk during their daily occupational activities. Nowadays, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become one of the most widespread infectious agents. In the current study, we performed a survey on the attitude and behavior of Polish healthcare workers (HCW), which comprise physicians (MD) and administrative healthcare assistants (HA) towards the Coronavirus Disease 2019 (COVID-19) vaccination. Our study involved 2300 subjects (42.17% female; 10.96% MD; 5.87% HA). The evaluation was conducted using a Google Forms survey based on original questions and the Depression, Anxiety and Stress Scale—21 Items questionnaire. HCW significantly more often demonstrated their willingness to get vaccinated against the SARS-CoV-2 as compared to the control group (82.95% vs. 54.31%, respectively). The main concern, as regards all groups, was the development of long-term side effects after getting COVID-19 vaccine. The study revealed that depression significantly affects the willingness to get vaccinated. The readiness was significantly strengthened by positive medical history of recommended vaccinations, fear of catching COVID-19, as well as fear of passing on the disease to the relatives. Overall, the percentage of HCW, who want to be vaccinated against COVID-19 remains unsatisfactory. Further works exploring this subject are needed to take a step closer to achieving the herd immunity in the era of the COVID-19 pandemic

Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis

Cancer constitutes a grave problem nowadays in view of the fact that it has become one of the main causes of death worldwide. Poor clinical prognosis is presumably due to cancer cells metabolism as tumor microenvironment is affected by oxidative stress. This event triggers adequate cellular response and thereby creates appropriate conditions for further cancer progression. Endoplasmic reticulum (ER) stress occurs when the balance between an ability of the ER to fold and transfer proteins and the degradation of the misfolded ones become distorted. Since ER is an organelle relatively sensitive to oxidative damage, aforementioned conditions swiftly cause the activation of the unfolded protein response (UPR) signaling pathway. The output of the UPR, depending on numerous factors, may vary and switch between the pro-survival and the pro-apoptotic branch, and hence it displays opposing effects in deciding the fate of the cancer cell. The role of UPR-related proteins in tumorigenesis, such as binding the immunoglobulin protein (BiP) and inositol-requiring enzyme-1&alpha; (IRE1&alpha;), activating transcription factor 6 (ATF6) or the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), has already been specifically described so far. Nevertheless, due to the paradoxical outcomes of the UPR activation as well as gaps in current knowledge, it still needs to be further investigated. Herein we would like to elicit the actual link between neoplastic diseases and the UPR signaling pathway, considering its major branches and discussing its potential use in the development of a novel, anti-cancer, targeted therapy

Cytotoxicity and genotoxicity of bioceramic root canal sealers compared to conventional resin-based sealer

Abstract The aim of this study was to evaluate cytotoxicity and genotoxicity of calcium-silicate based sealers and comparing them with a gold standard—an epoxy-based sealant. Two experimental cell lines were used, gingival fibroblasts (hGF) and monocyte/macrophage peripheral blood cell line (SC). The cytotoxicity (XTT assay) and genotoxicity (comet assay) were evaluated both after 24-h and 48-h incubation. Additionally, after 48-h incubation, the cell apoptosis and cell cycle progression was detected. BioRoot Flow induced a significant decrease in hGF cells viability compared to the negative control groups both after 24-h (p  20% DNA damage). BioRoot Flow and BioRoot RCS, may have potential genotoxic effects and induce apoptosis in hGF cells which may irritate periapical tissues, resulting in a delayed healing. The findings of the study would be useful in selection of an appropriate sealant for root canal filling without causing cytotoxicity and genotoxicity

Molecular Mechanisms Underlying NMDARs Dysfunction and Their Role in ADHD Pathogenesis

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, although the aetiology of ADHD is not yet understood. One proposed theory for developing ADHD is N-methyl-D-aspartate receptors (NMDARs) dysfunction. NMDARs are involved in regulating synaptic plasticity and memory function in the brain. Abnormal expression or polymorphism of some genes associated with ADHD results in NMDAR dysfunction. Correspondingly, NMDAR malfunction in animal models results in ADHD-like symptoms, such as impulsivity and hyperactivity. Currently, there are no drugs for ADHD that specifically target NMDARs. However, NMDAR-stabilizing drugs have shown promise in improving ADHD symptoms with fewer side effects than the currently most widely used psychostimulant in ADHD treatment, methylphenidate. In this review, we outline the molecular and genetic basis of NMDAR malfunction and how it affects the course of ADHD. We also present new therapeutic options related to treating ADHD by targeting NMDAR

Effects of Early versus Standard Central Line Removal on the Growth of Preterm Infants with Very Low Birth Weight: A Non-Inferiority, Randomized Clinical Trial

Very preterm infants are usually supported by parenteral nutrition delivered through central lines (CLs) while progressing with enteral intake, although the optimal time point for their removal is unclear. This study evaluated the impact of the CL discontinuation time on the short-term growth outcomes of preterm infants. A non-inferiority, parallel-group, randomized controlled trial was conducted in four neonatal intensive care units in Poland. Preterm infants with very low birth weight (VLBW) without congenital abnormalities were eligible. Patients were allocated to discontinue central access at an enteral feeding volume of 100 mL/kg/day (intervention group) or 140 mL/kg/day (control group). The study’s primary outcome was weight at 36 weeks’ postmenstrual age, with a non-inferiority margin of −210 g. Overall, 211 patients were allocated to the intervention or control groups between January 2019 and February 2021, of which 101 and 100 were eligible for intention-to-treat analysis, respectively. The mean weight was 2232 g and 2200 g at 36 weeks’ postmenstrual age in the intervention and control groups, respectively. The mean between-group difference was 32 g (95% confidence interval, −68 to 132; p = 0.531), which did not cross the specified margin of non-inferiority. No intervention-related adverse events were observed. Early CL removal was non-inferior to the standard type for short-term growth outcomes in VLBW infants