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Optic neuritis (ON) is the most common cause of vision loss in young adults. It manifests as acute or subacute vision loss, often accompanied by retrobulbar discomfort or pain during eye movements. Typical ON is associated with Multiple Sclerosis (MS) and is generally mild and steroid-responsive. Atypical forms are characterized by unusual features, such as prominent optic disc edema, poor treatment response, and bilateral involvement, and they are often associated with autoantibodies against aquaporin-4 (AQP4) or Myelin Oligodendrocyte Glycoprotein (MOG). However, in some cases, AQP4 and MOG antibodies will return as negative, plunging the clinician into a diagnostic conundrum. AQP4- and MOG-seronegative ON warrants a broad differential diagnosis, including autoantibody-associated, granulomatous, and systemic disorders. These rare forms need to be identified promptly, as their management and prognosis are greatly different. The aim of this review is to describe the possible rarer etiologies of non-MS-related and AQP4- and MOG-IgG-seronegative inflammatory ON and discuss their diagnoses and treatments. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are nanosized vesicles released by almost all body tissues, representing important mediators of cellular communication, and are thus promising candidate biomarkers for neurodegenerative diseases like Alzheimer's disease (AD). The aim of the present study was to isolate total EVs from plasma and characterize their microRNA (miRNA) contents in AD patients. We isolated total EVs from the plasma of all recruited subjects using ExoQuickULTRA exosome precipitation solution (SBI). Subsequently, circulating total EVs were characterized using Nanosight nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and Western blotting. A panel of 754 miRNAs was determined with RT-qPCR using TaqMan OpenArray technology in a QuantStudio 12K System (Thermo Fisher Scientific). The results demonstrated that plasma EVs showed widespread deregulation of specific miRNAs (miR-106a-5p, miR-16-5p, miR-17-5p, miR-195-5p, miR-19b-3p, miR-20a-5p, miR-223-3p, miR-25-3p, miR-296-5p, miR-30b-5p, miR-532-3p, miR-92a-3p, and miR-451a), some of which were already known to be associated with neurological pathologies. A further validation analysis also confirmed a significant upregulation of miR-16-5p, miR-25-3p, miR-92a-3p, and miR-451a in prodromal AD patients, suggesting these dysregulated miRNAs are involved in the early progression of AD. [ABSTRACT FROM AUTHOR]

We used α-Latrotoxin (α-LTx), the main neurotoxic component of the black widow spider venom, which causes degeneration of the neuromuscular junction (NMJ) followed by a rapid and complete regeneration, as a molecular tool to identify by RNA transcriptomics factors contributing to the structural and functional recovery of the NMJ. We found that Urocortin 2 (UCN2), a neuropeptide involved in the stress response, is rapidly expressed at the NMJ after acute damage and that inhibition of CRHR2, the specific receptor of UCN2, delays neuromuscular transmission rescue. Experiments in neuronal cultures show that CRHR2 localises at the axonal tips of growing spinal motor neurons and that its expression inversely correlates with synaptic maturation. Moreover, exogenous UCN2 enhances the growth of axonal sprouts in cultured neurons in a CRHR2-dependent manner, pointing to a role of the UCN2-CRHR2 axis in the regulation of axonal growth and synaptogenesis. Consistently, exogenous administration of UCN2 strongly accelerates the regrowth of motor axon terminals degenerated by α-LTx, thereby contributing to the functional recovery of neuromuscular transmission after damage. Taken together, our results posit a novel role for UCN2 and CRHR2 as a signalling axis involved in NMJ regeneration. [ABSTRACT FROM AUTHOR]

The relationship between neuroinflammation and depression is a complex area of research that has garnered significant attention in recent years. Neuroinflammation, characterized by the activation of glial cells and the release of pro-inflammatory cytokines, has been implicated in the pathophysiology of depression. The relationship between neuroinflammation and depression is bidirectional; not only can inflammation contribute to the onset of depressive symptoms, but depression itself can also exacerbate inflammatory responses, creating a vicious cycle that complicates treatment and recovery. The present comprehensive review aimed to explore the current findings on the interplay between neuroinflammation and depression, as well as the mechanisms, risk factors, and therapeutic implications. The mechanisms by which neuroinflammation induces depressive-like behaviors are diverse. Neuroinflammation can increase pro-inflammatory cytokines, activate the hypothalamus–pituitary–adrenal (HPA) axis, and impair serotonin synthesis, all of which contribute to depressive symptoms. Furthermore, the activation of microglia has been linked to the release of inflammatory mediators that can disrupt neuronal function and contribute to mood disorders. Stress-induced neuroinflammatory responses can lead to the release of pro-inflammatory cytokines that not only affect brain function but also influence behavior and mood. Understanding these mechanisms is crucial for developing targeted therapies that can mitigate the effects of neuroinflammation on mood disorders. [ABSTRACT FROM AUTHOR]

Immunoglobulin E (IgE)-mediated food allergy has been dramatically increasing in incidence over the last few decades. The combinations of both genetic and environmental factors that affect the microbiome and immune system have demonstrated significant roles in its pathogenesis. The morbidity, and at times mortality, that occurs as the result of this specific, reproducible, but impaired immune response is due to the nature of the shift from a regulatory T (Treg) cellular response to a T helper 2 (Th2) cellular response. This imbalance caused by food allergens results in an interleukin (IL)-4 and IL-13 dominant environment that drives B cell activation and differentiation into IgE-producing plasma cells. The resulting symptoms can range from mild to more severe anaphylaxis, and even death. Current therapeutic strategies involve avoidance and broad symptom management upon accidental exposure; however, no definitive cure exists. This narrative review highlights how the elucidation of the pathogenesis of IgE-mediated food allergy resulted in the development of therapeutics that are more specific to these individual receptors and molecules which have been relatively successful in mitigating this potentially life-threatening allergic response. However, potential adverse effects and re-sensitization following the conclusion of treatment has urged the need for improved therapeutic methods. Therefore, given the understanding of their mechanism of action and the overlap with the mechanism of IgE-mediated food allergies, probiotics and small molecule natural compounds may provide novel therapeutic and preventative strategies. This is compelling, as they have demonstrated success in clinical trials and may provide hope to improve quality of life in allergy patients. [ABSTRACT FROM AUTHOR]

Women diagnosed with advanced-stage ovarian cancer have a much worse survival rate than women diagnosed with early-stage ovarian cancer, but the early detection of this disease remains a clinical challenge. Some recent reports indicate that genetic variations could be useful for the early detection of several malignancies. In this pilot observational retrospective study, we aimed to assess whether mitochondrial DNA (mtDNA) variations could discriminate the most frequent type of ovarian cancer, high-grade serous carcinoma (HGSC), from normal tissue. We identified mtDNA variations from 20 whole-exome sequenced (WES) HGSC samples and 14 controls (normal tubes) using the best practices of genome sequencing. We built prediction models of cancer with these variants, with good performance measured by the area under the curve (AUC) of 0.88 (CI: 0.74–1.00). The variants included in the best model were correlated with gene expression to assess the potentially affected processes. These analyses were validated with the Cancer Genome Atlas (TCGA) dataset, (including over 420 samples), with a fair performance in AUC terms (0.63–0.71). In summary, we identified a set of mtDNA variations that can discriminate HGSC with good performance. Specifically, variations in the MT-CYB gene increased the risk for HGSC by over 30%, and MT-CYB expression was significantly decreased in HGSC patients. Robust models of ovarian cancer detection with mtDNA variations could be applied to liquid biopsy technology, like those which have been applied to other cancers, with a special focus on the early detection of this lethal disease. [ABSTRACT FROM AUTHOR]

When the protective mechanisms of the gastroesophageal mucosa are overwhelmed by injurious factors, the structural and functional mucosal integrity is compromised, resulting in a wide spectrum of disorders. Poliprotect has recently been shown to be non-inferior to standard-dose omeprazole for the treatment of endoscopy-negative patients with heartburn and/or epigastric pain or burning. Here, we provide preclinical data describing the mechanism of action of the Poliprotect formulation, a 100% natural, biodegradable, and environmental friendly medical device according to EU 2017/745 and containing UVCB (unknown or variable composition, complex-reaction products, or biological materials) substances of botanical and mineral origin, according to the REACH and European Chemical Agency definitions. Different in vitro assays demonstrated the capability of Poliprotect to adhere to mucus-secreting gastric cells and concomitantly deliver a local barrier with buffering and antioxidant activity. In studies conducted in accordance with systems biology principles, we evaluated the effects of this barrier on human gastric cells exposed to acidic stress. Biological functions identified via Ingenuity Pathway Analysis highlighted the product's ability to create a microenvironment that supports the mucosal structural and functional integrity, promotes healing, and restores a balanced mucosal inflammatory status. Additionally, transepithelial electrical resistance and an Ussing chamber showed the product's capability of preserving the integrity of the gastric and esophageal epithelial barriers when exposed to an acid solution. Two in vivo models of erosive gastropathy further highlighted its topical protection against ethanol- and drug-induced mucosal injury. Overall, our findings sustain the feasibility of a paradigm shift in therapeutics R&D by depicting a very innovative and desirable mode of interaction with the human body based on the emerging biophysical, rather than the pharmacological properties of these therapeutic agents. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction and chronic inflammation are determining factors in the development and progression of chronic degenerative diseases, such as hypertension and atherosclerosis. Among the shared pathophysiological characteristics of these two diseases is a metabolic disorder of lipids and lipoproteins. Therefore, the contents and quality of the lipids and proteins of lipoproteins become the targets of therapeutic objective. One of the stages of lipoprotein formation occurs through the incorporation of dietary lipids by enterocytes into the chylomicrons. Consequently, the composition, structure, and especially the properties of lipoproteins could be modified through the intake of bioactive compounds. The objective of this review is to describe the roles of the different lipid and protein components of lipoproteins and their receptors in endothelial dysfunction and the development of hypertension. In addition, we review the use of some non-pharmacological treatments that could improve endothelial function and/or prevent endothelial damage. The reviewed information contributes to the understanding of lipoproteins as vehicles of regulatory factors involved in the modulation of inflammatory and hemostatic processes, the attenuation of oxidative stress, and the neutralization of toxins, rather than only cholesterol and phospholipid transporters. For this review, a bibliographic search was carried out in different online metabases. [ABSTRACT FROM AUTHOR]

Hypoxia is a well-known characteristic of the tumor microenvironment which significantly influences cancer development and is closely linked to unfavorable outcomes. Long noncoding RNAs (lncRNAs), which are part of the noncoding genome, have garnered increasing attention because of their varied functions in tumor metastasis. Long noncoding RNAs (lncRNAs) are defined as noncoding RNAs which are longer than 200 nucleotides, and they regulate diverse cellular processes by modulating gene expression at the transcriptional, post-transcriptional and epigenetic levels. Hypoxia is a well-established environmental factor which enhances the metastasis of solid tumors. Epithelial-mesenchymal transition (EMT) represents one of the key mechanisms triggered by hypoxia which contributes to metastasis. Numerous lncRNAs have been identified as being upregulated by hypoxia. These lncRNAs significantly contribute toward cancer cell migration, invasion and metastasis. Recent studies have identified a crucial role for these hypoxia-induced lncRNAs in chemotherapy resistance. These hypoxia-related lncRNAs can be plausible therapeutic targets for devising effective cancer therapies. [ABSTRACT FROM AUTHOR]

The integrity of esophageal epithelial cells in patients with gastroesophageal reflux disease (GERD) or GERD-like symptoms is the first mechanism of protection to decrease the sensitivity to gastric reflux and heartburn symptoms. We investigated the protective effects of Poliprotect® (PPRO), a CE-marked medical device, on esophageal epithelial integrity using in vitro and ex vivo models. In vitro, the protective effects of PPRO were tested on Caco-2 cells. PPRO demonstrated safety and protection against oxidative damage induced by hydrogen peroxide. It also preserved epithelial integrity by maintaining transepithelial electrical resistance (TEER) against damage from calcium removal or bile acid exposure (taurodeoxycholic acid, TDCA). Ex vivo, esophageal biopsies from patients subjected to endoscopy were mounted in Ussing chambers and exposed to damaging agents (HCl or HCl + TDCA). Untreated biopsies (control) showed significant loss of epithelial resistance (up to −33%). In contrast, low concentrations of PPRO (50–100 µg/mL) provided strong protection against these damages (p < 0.001), even after 60 min of washing. Histological analysis confirmed the barrier-enhancing effect of PPRO. Overall, PPRO effectively protected the esophageal epithelium from damage in both models, suggesting its potential role in alleviating GERD or GERD-like symptoms by strengthening mucosal barriers and reducing epithelial sensitivity to reflux. [ABSTRACT FROM AUTHOR]

CXCL12 and CXCR4 proteins and mRNAs were monitored in the dorsal root ganglia (DRGs) of lumbar (L4–L5) and cervical (C7–C8) spinal segments of naïve rats, rats subjected to sham operation, and those undergoing unilateral complete sciatic nerve transection (CSNT) on post-operation day 7 (POD7). Immunohistochemical, Western blot, and RT-PCR analyses revealed bilaterally increased levels of CXCR4 protein and mRNA in both lumbar and cervical DRG neurons after CSNT. Similarly, CXCL12 protein levels increased, and CXCL12 mRNA was upregulated primarily in lumbar DRGs ipsilateral to the nerve lesion. Intrathecal application of the CXCR4 inhibitor AMD3100 following CSNT reduced CXCL12 and CXCR4 protein levels in cervical DRG neurons, as well as the length of afferent axons regenerated distal to the ulnar nerve crush. Furthermore, treatment with the CXCR4 inhibitor decreased levels of activated Signal Transducer and Activator of Transcription 3 (STAT3), a critical transforming factor in the neuronal regeneration program. Administration of IL-6 increased CXCR4 levels, whereas the JAK2-dependent STAT3 phosphorylation inhibitor (AG490) conversely decreased CXCR4 levels. This indicates a link between the CXCL12/CXCR4 signaling axis and IL-6-induced activation of STAT3 in the sciatic nerve injury-induced pro-regenerative state of cervical DRG neurons. The role of CXCR4 signaling in the axon-promoting state of DRG neurons was confirmed through in vitro cultivation of primary sensory neurons in a medium supplemented with CXCL12, with or without AMD3100. The potential involvement of conditioned cervical DRG neurons in the induction of neuropathic pain is discussed. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) contribute to endothelial dysfunction, platelet activation, and coagulation abnormalities, promoting thrombus formation. Given the growing interest in non-pharmacological approaches to modulate oxidative stress, we examine the potential of various dietary interventions and antioxidant supplementation in reducing oxidative damage and preventing thrombotic events. Key dietary patterns, such as the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and ketogenic diets, as well as antioxidant-rich supplements like curcumin, selenium, and polyphenols, demonstrate promising effects in improving oxidative stress markers, lipid profiles, and inflammatory responses. This review highlights recent advances in the field, drawing from in vitro, ex vivo, and clinical studies, and underscores the importance of integrating dietary strategies into preventive and therapeutic approaches for managing thrombosis and cardiovascular health. Further research is needed to better understand long-term effects and personalize these interventions for optimizing patient outcomes. [ABSTRACT FROM AUTHOR]

This survey reviews modern ideas on the structure and functions of mitochondrial and cytosolic aconitase isoenzymes in eukaryotes. Cumulative experimental evidence about mitochondrial aconitases (Aco2) as one of the main targets of reactive oxygen and nitrogen species is generalized. The important role of Aco2 in maintenance of homeostasis of the intracellular iron pool and maintenance of the mitochondrial DNA is discussed. The role of Aco2 in the pathogenesis of some neurodegenerative diseases is highlighted. Inactivation or dysfunction of Aco2 as well as mutations found in the ACO2 gene appear to be significant factors in the development and promotion of various types of neurodegenerative diseases. A restoration of efficient mitochondrial functioning as a source of energy for the cell by targeting Aco2 seems to be one of the promising therapeutic directions to minimize progressive neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

To date, more than 400 types of human papillomavirus (HPV) have been identified. Despite the creation of effective prophylactic vaccines against the most common genital HPVs, the viruses remain among the most prevalent pathogens found in humans. According to WHO data, they are the cause of 5% of all cancers. Even more frequent are persistent and recurrent benign lesions such as genital and common warts. HPVs are resistant to many disinfectants and relatively unsusceptible to external conditions. There is still no drug available to inhibit viral replication, and treatment is based on removing lesions or stimulating the host immune system. This paper presents the systematics of HPV and the differences in HPV structure between different genetic types, lineages, and sublineages, based on the literature and GenBank data. We also present the pathogenesis of diseases caused by HPV, with a special focus on the role played by E6, E7, and other viral proteins in the development of benign and cancerous lesions. We discuss further prospects for the treatment of HPV infections, including, among others, substances that block the entry of HPV into cells, inhibitors of viral early proteins, and some substances of plant origin that inhibit viral replication, as well as new possibilities for therapeutic vaccines. [ABSTRACT FROM AUTHOR]

Mitochondrial quality control is essential in mitochondrial function. To examine the importance of Parkin-dependent mechanisms in mitochondrial quality control, we assessed the impact of modulating Parkin on proteome flux and mitochondrial function in a context of reduced mtDNA fidelity. To accomplish this, we crossed either the Parkin knockout mouse or ParkinW402A knock-in mouse lines to the Polg mitochondrial mutator line to generate homozygous double mutants. In vivo longitudinal isotopic metabolic labeling was followed by isolation of liver mitochondria and synaptic terminals from the brain, which are rich in mitochondria. Mass spectrometry and bioenergetics analysis were assessed. We demonstrate that slower mitochondrial protein turnover is associated with loss of mtDNA fidelity in liver mitochondria but not synaptic terminals, and bioenergetic function in both tissues is impaired. Pathway analysis revealed loss of mtDNA fidelity is associated with disturbances of key metabolic pathways, consistent with its association with metabolic disorders and neurodegeneration. Furthermore, we find that loss of Parkin leads to exacerbation of Polg-driven proteomic consequences, though it may be bioenergetically protective in tissues exhibiting rapid mitochondrial turnover. Finally, we provide evidence that, surprisingly, dis-autoinhibition of Parkin (ParkinW402A) functionally resembles Parkin knockout and fails to rescue deleterious Polg-driven effects. Our study accomplishes three main outcomes: (1) it supports recent studies suggesting that Parkin dependence is low in response to an increased mtDNA mutational load, (2) it provides evidence of a potential protective role of Parkin insufficiency, and (3) it draws into question the therapeutic attractiveness of enhancing Parkin function. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are tissue-resident immune cells distributed in all tissues and strategically located close to blood and lymphatic vessels and nerves. Thanks to the expression of a wide array of receptors, MCs act as tissue sentinels, able to detect the presence of bacteria and parasites and to respond to different environmental stimuli. MCs originate from bone marrow (BM) progenitors that enter the circulation and mature in peripheral organs under the influence of microenvironment factors, thus differentiating into heterogeneous tissue-specific subsets. Even though MC activation has been traditionally linked to IgE-mediated allergic reactions, a role for these cells in other pathological conditions including tumor progression has recently emerged. However, several aspects of MC biology remain to be clarified. The advent of single-cell RNA sequencing platforms has provided the opportunity to understand MCs' origin and differentiation as well as their phenotype and functions within different tissues, including the gut. This review recapitulates how single-cell transcriptomic studies provided insight into MC development as well as into the functional role of intestinal MC subsets in health and disease. [ABSTRACT FROM AUTHOR]

In response to cellular metabolic and signaling cues, the mitochondrial network employs distinct sets of membrane-shaping factors to dynamically modulate organellar structures through a balance of fission and fusion. While these organellar dynamics mediate mitochondrial structure/function homeostasis, they also directly impact critical cell-wide signaling pathways such as apoptosis, autophagy, and the integrated stress response (ISR). Mitochondrial fission is driven by the recruitment of the cytosolic dynamin-related protein-1 (DRP1), while fusion is carried out by mitofusins 1 and 2 (in the outer membrane) and optic atrophy-1 (OPA1) in the inner membrane. This dynamic balance is highly sensitive to cellular stress; when the transmembrane potential across the inner membrane (Δψm) is lost, fusion-active OPA1 is cleaved by the overlapping activity with m-AAA protease-1 (OMA1 metalloprotease, disrupting mitochondrial fusion and leaving dynamin-related protein-1 (DRP1)-mediated fission unopposed, thus causing the collapse of the mitochondrial network to a fragmented state. OMA1 is a unique regulator of stress-sensitive homeostatic mitochondrial balance, acting as a key upstream sensor capable of priming the cell for apoptosis, autophagy, or ISR signaling cascades. Recent evidence indicates that higher-order macromolecular associations within the mitochondrial inner membrane allow these specialized domains to mediate crucial organellar functionalities. [ABSTRACT FROM AUTHOR]

A few cases of multiple sclerosis (MS) onset after COVID-19 vaccination have been reported, although the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed relapsing–remitting MS before and after the outbreak of the COVID-19 pandemic and the impact of COVID-19 vaccination. Potential environmental and genetic predisposing factors were also investigated, as well as clinical patterns. This is a single-centre retrospective cohort study including all patients who presented with relapsing–remitting MS onset between January 2018 and July 2022. Data on COVID-19 vaccination administration, dose, and type were collected. HLA-DRB1 genotyping was performed in three subgroups. A total of 266 patients received a new diagnosis of relapsing–remitting MS in our centre, 143 before the COVID-19 pandemic (until and including March 2020), and 123 during the COVID-19 era (from April 2020). The mean number of new MS onset cases per year was not different before and during the COVID-19 era and neither were baseline patients' characteristics, type of onset, clinical recovery, or radiological patterns. Fourteen (11.4%) patients who subsequently received a new diagnosis of MS had a history of COVID-19 vaccination within one month before symptoms onset. Patients' characteristics, type of onset, clinical recovery, and radiological patterns did not differ from those of patients with non-vaccine-related new diagnoses of MS. The allele frequencies of HLA-DRB1*15 were 17.6% and 22.2% in patients with non-vaccine-related disease onset before and during the COVID-19 era, respectively, while no case of HLA-DRB1*15 was identified among patients with a new diagnosis of MS post-COVID-19 vaccine. In contrast, HLA-DRB1*08+ or HLA-DRB1*10+ MS patients were present only in this subgroup. Although a causal link between COVID-19 vaccination and relapsing–remitting MS cannot be detected, it is interesting to note and speculate about the peculiarities and heterogeneities underlying disease mechanisms of MS, where the interactions of genetics and the environment could be crucial also for the follow-up and the evaluation of therapeutic options. [ABSTRACT FROM AUTHOR]

Portal vein thrombosis (PVT), one of the most prevalent hepatic vascular conditions in patients with liver cirrhosis (LC), is associated with high mortality rates. An imbalance between a disintegrin-like metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS-13) enzyme and von Willebrand factor (VWF) is responsible for hypercoagulability, including spontaneous thrombus formation in blood vessels. Herein, we aimed to identify potential prognostic and diagnostic biomarkers in Japanese patients with LC and PVT. In total, 345 patients were divided into two groups: 40 patients who developed PVT (PVT group) and 305 who did not develop PVT (NPVT group). Among the 345 patients with LC, 81% (279/345) were deemed ineligible due to the presence of preventive comorbidities, active or recent malignancies, and organ dysfunction. The remaining 66 patients were divided into two groups: the PVT group (n = 33) and the NPVT group (n = 33). Plasma ADAMTS-13 activity (ADAMTS-13:AC) and the vWF antigen (VWF:Ag) were measured using enzyme-linked immunosorbent assays. Contrast-enhanced, three-dimensional helical computed tomography (CT) was used to detect and characterize PVT. ADAMTS-13:AC was significantly lower in the PVT group than in the NPVT group. No significant differences in plasma vWF:Ag or liver stiffness were observed between the two groups. ADAMTS-13:AC of <18.8 was an independent risk factor for PVT on multivariate analyses (odds ratio: 1.67, 95% confidence interval: 1.21–3.00, p < 0.002). The receiver operating characteristic analysis of ADAMTS-13:AC revealed an area under the curve of 0.913 in PVT detection. Patients with PVT having ADAMTS-13:AC ≥18.8 (n = 17) had higher albumin levels and better prognoses than those with ADAMTS-13:AC <18.8 (n = 16). No significant correlations of ADAMTS-13:AC levels with either fibrin degradation product or D-dimer levels were observed. ADAMTS-13:AC levels could be potential diagnostic and prognostic biomarkers for PVT in Japanese patients with LC. [ABSTRACT FROM AUTHOR]

Nqo15 is a subunit of respiratory complex I of the bacterium Thermus thermophilus, with strong structural similarity to human frataxin (FXN), a protein involved in the mitochondrial disease Friedreich's ataxia (FRDA). Recently, we showed that the expression of recombinant Nqo15 can ameliorate the respiratory phenotype of FRDA patients' cells, and this prompted us to further characterize both the Nqo15 solution's behavior and its potential functional overlap with FXN, using a combination of in silico and in vitro techniques. We studied the analogy of Nqo15 and FXN by performing extensive database searches based on sequence and structure. Nqo15's folding and flexibility were investigated by combining nuclear magnetic resonance (NMR), circular dichroism, and coarse-grained molecular dynamics simulations. Nqo15's iron-binding properties were studied using NMR, fluorescence, and specific assays and its desulfurase activation by biochemical assays. We found that the recombinant Nqo15 isolated from complex I is monomeric, stable, folded in solution, and highly dynamic. Nqo15 does not share the iron-binding properties of FXN or its desulfurase activation function. [ABSTRACT FROM AUTHOR]

To explore the processes of epileptogenesis/ictogenesis, this study determined the age-dependent development of the functional abnormalities in astroglial transmission associated with pannexin1-hemichannel using a genetic rat model of autosomal dominant sleep-related hypermotor epilepsy (ADSHE) named 'S286L-TG'. Pannexin1 expression in the plasma membrane of primary cultured cortical astrocytes and the orbitofrontal cortex (OFC), which is an ADSHE focus region, were determined using capillary immunoblotting. Astroglial D-serine releases induced by artificial high-frequency oscillation (HFO)-evoked stimulation, the removal of extracellular Ca2+, and the P2X7 receptor agonist (BzATP) were determined using ultra-high performance liquid chromatography (UHPLC). The expressions of pannexin1 in the plasma membrane fraction of the OFC in S286L-TG at four weeks old were almost equivalent when compared to the wild type. The pannexin1 expression in the OFC of the wild type non-statistically decreased age-dependently, whereas that in S286L-TG significantly increased age-dependently, resulting in relatively increasing pannexin1 expression from the 7- (at the onset of interictal discharge) and 10-week-old (after the ADSHE seizure onset) S286L-TG compared to the wild type. However, no functional abnormalities of astroglial pannexin1 expression or D-serine release through the pannexin1-hemichannels from the cultured astrocytes of S286L-TG could be detected. Acutely HFO-evoked stimulation, such as physiological ripple burst (200 Hz) and epileptogenic fast ripple burst (500 Hz), frequency-dependently increased both pannexin1 expression in the astroglial plasma membrane and astroglial D-serine release. Neither the selective inhibitors of pannexin1-hemichannel (10PANX) nor connexin43-hemichannel (Gap19) affected astroglial D-serine release during the resting stage, whereas HFO-evoked D-serine release was suppressed by both inhibitors. The inhibitory effect of 10PANX on the ripple burst-evoked D-serine release was more predominant than that of Gap19, whereas fast ripple burst-evoked D-serine release was predominantly suppressed by Gap19 rather than 10PANX. Astroglial D-serine release induced by acute exposure to BzATP was suppressed by 10PANX but not by Gap19. These results suggest that physiological ripple burst during the sleep spindle plays important roles in the organization of some components of cognition in healthy individuals, but conversely, it contributes to the initial development of epileptogenesis/ictogenesis in individuals who have ADSHE vulnerability via activation of the astroglial excitatory transmission associated with pannexin1-hemichannels. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the predominant form of dementia globally. No reliable diagnostic, predictive techniques, or curative interventions are available. MicroRNAs (miRNAs) are vital to controlling gene expression, making them valuable biomarkers for diagnosis and prognosis. This study examines the transcriptome of olfactory ecto-mesenchymal stem cells (MSCs) derived from individuals with the PSEN1(A431E) mutation (Jalisco mutation). The aim is to determine whether this mutation affects the transcriptome and expression profile of miRNAs and their target genes at different stages of asymptomatic, presymptomatic, and symptomatic conditions. Expression microarrays compare the MSCs from mutation carriers with those from healthy donors. The results indicate a distinct variation in the expression of miRNAs and mRNAs among different symptomatologic groups and between individuals with the mutation. Using bioinformatics tools allows us to identify target genes for miRNAs, which in turn affect various biological processes and pathways. These include the cell cycle, senescence, transcription, and pathways involved in regulating the pluripotency of stem cells. These processes are closely linked to inter- and intracellular communication, vital for cellular functioning. These findings can enhance our comprehension and monitoring of the disease's physiological processes, identify new disorder indicators, and develop innovative treatments and diagnostic tools for preventing or treating AD. [ABSTRACT FROM AUTHOR]

Mounting evidence underscores the intricate interplay between the immune system and skeletal muscles in Duchenne muscular dystrophy (DMD), as well as during regular muscle regeneration. While immune cell infiltration into skeletal muscles stands out as a prominent feature in the disease pathophysiology, a myriad of secondary defects involving metabolic and inflammatory pathways persist, with the key players yet to be fully elucidated. Steroids, currently the sole effective therapy for delaying onset and symptom control, come with adverse side effects, limiting their widespread use. Preliminary evidence spotlighting the distinctive features of T cell profiling in DMD prompts the immuno-characterization of circulating cells. A molecular analysis of their transcriptome and secretome holds the promise of identifying a subpopulation of cells suitable as disease biomarkers. Furthermore, it provides a gateway to unraveling new pathological pathways and pinpointing potential therapeutic targets. Simultaneously, the last decade has witnessed the emergence of novel approaches. The development and equilibrium of both innate and adaptive immune systems are intricately linked to the gut microbiota. Modulating microbiota-derived metabolites could potentially exacerbate muscle damage through immune system activation. Concurrently, genome sequencing has conferred clinical utility for rare disease diagnosis since innovative methodologies have been deployed to interpret the functional consequences of genomic variations. Despite numerous genes falling short as clinical targets for MD, the exploration of Tdark genes holds promise for unearthing novel and uncharted therapeutic insights. In the quest to expedite the translation of fundamental knowledge into clinical applications, the identification of novel biomarkers and disease targets is paramount. This initiative not only advances our understanding but also paves the way for the design of innovative therapeutic strategies, contributing to enhanced care for individuals grappling with these incapacitating diseases. [ABSTRACT FROM AUTHOR]

The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver fibrosis. Moreover, TAM receptors exhibit prominent cell-transforming properties, promoting tumor progression, metastasis, and therapy resistance in various cancer entities. Emerging evidence shows that TAM receptors are involved in bone homeostasis by regulating osteoblastic bone formation and osteoclastic bone resorption. Therefore, TAM receptors emerge as new key players of the regulatory cytokine network of osteoblasts and osteoclasts and represent accessible targets for pharmacologic therapy for a broad set of different bone diseases, including primary and metastatic bone tumors, rheumatoid arthritis, or osteoporosis. [ABSTRACT FROM AUTHOR]

The current view of the mitochondrial respiratory chain complexes I, III and IV foresees the occurrence of their assembly in supercomplexes, providing additional functional properties when compared with randomly colliding isolated complexes. According to the plasticity model, the two structural states of the respiratory chain may interconvert, influenced by the intracellular prevailing conditions. In previous studies, we suggested the mitochondrial membrane potential as a factor for controlling their dynamic balance. Here, we investigated if and how the cAMP/PKA-mediated signalling influences the aggregation state of the respiratory complexes. An analysis of the inhibitory titration profiles of the endogenous oxygen consumption rates in intact HepG2 cells with specific inhibitors of the respiratory complexes was performed to quantify, in the framework of the metabolic flux theory, the corresponding control coefficients. The attained results, pharmacologically inhibiting either PKA or sAC, indicated that the reversible phosphorylation of the respiratory chain complexes/supercomplexes influenced their assembly state in response to the membrane potential. This conclusion was supported by the scrutiny of the available structure of the CI/CIII2/CIV respirasome, enabling us to map several PKA-targeted serine residues exposed to the matrix side of the complexes I, III and IV at the contact interfaces of the three complexes. [ABSTRACT FROM AUTHOR]

PsbS is one of the key photoprotective proteins, ensuring the tolerance of the photosynthetic apparatus (PSA) of a plant to abrupt changes in irradiance. Being a component of photosystem II, it provides the formation of quenching centers for excited states of chlorophyll in the photosynthetic antenna with an excess of light energy. The signal for "turning on" the photoprotective function of the protein is an excessive decrease in pH in the thylakoid lumen occurring when all the absorbed light energy (stored in the form of transmembrane proton potential) cannot be used for carbon assimilation. Hence, lumen-exposed protonatable amino acid residues that could serve as pH sensors are the essential components of PsbS-dependent photoprotection, and their pKa values are necessary to describe it. Previously, calculations of the lumen-exposed protonatable residue pKa values in PsbS from spinach were described in the literature. However, it has recently become clear that PsbS, although typical of higher plants and charophytes, can also provide photoprotection in green algae. Namely, the stress-induced expression of PsbS was recently shown for two green microalgae species: Chlamydomonas reinhardtii and Lobosphaera incisa. Therefore, we determined the amino acid sequence and modeled the three-dimensional structure of the PsbS from L. incisa, as well as calculated the pKa values of its lumen-exposed protonatable residues. Despite significant differences in amino acid sequence, proteins from L. incisa and Spinacia oleracea have similar three-dimensional structures. Along with the other differences, one of the two pH-sensing glutamates in PsbS from S. oleracea (namely, Glu-173) has no analogue in L. incisa protein. Moreover, there are only four glutamate residues in the lumenal region of the L. incisa protein, while there are eight glutamates in S. oleracea. However, our calculations show that, despite the relative deficiency in protonatable residues, at least two residues of L. incisa PsbS can be considered probable pH sensors: Glu-87 and Lys-196. [ABSTRACT FROM AUTHOR]

The development of controlled drug delivery systems, in the form of microparticles, is an important area of experimental pharmacology. The success of the design and the quality of the obtained microparticles are determined by the method of manufacture and the properties of the material used as a carrier. The goal is to obtain and characterize microparticles depending on their method of preparation, the chemical composition of the polymer and the load of the drugs. To obtain microparticles, four types of degradable PHAs, differing in their chemical compositions, degrees of crystallinity, molecular weights and temperature characteristics, were used (poly-3-hydroxybutyrate and copolymers 3-hydroxybutyric-co-3-hydroxyvaleric acid, 3-hydroxybutyric-co-4-hydroxybutyric acid, and 3-hydroxybutyric-co-3-hydroxyhexanoic acid). The characteristics of microparticles from PHAs were studied. Good-quality particles with an average particle diameter from 0.8 to 65.0 μm, having satisfactory ζ potential values (from −18 to −50 mV), were obtained. The drug loading content, encapsulation efficiency and in vitro release were characterized. Composite microparticles based on PHAs with additives of polyethylene glycol and polylactide-co-glycolide, and loaded with ceftriaxone and 5-fluorouracil, showed antibacterial and antitumor effects in E. coli and HeLa cultures. The results indicate the high potential of PHAs for the design of modern and efficient drug delivery systems. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent exopeptidase with broad specificity for four to eight amino acid residue substrates. It has a role in the regulation of oxidative stress response NRF2–KEAP1 pathway through the interaction with KEAP1. We have conducted stable isotope labeling by amino acids in a cell culture coupled to mass spectrometry (SILAC-MS) interactome analysis of TRex HEK293T cells using DPP3 as bait and identified SH2 Domain-Containing Protein 3C (SH2D3C) as prey. SH2D3C is one of three members of a family of proteins that contain both the SH2 domain and a domain similar to guanine nucleotide exchange factor domains of Ras family GTPases (Ras GEF-like domain), named novel SH2-containing proteins (NSP). NSPs, including SH2D3C (NSP3), are adaptor proteins involved in the regulation of adhesion, migration, tissue organization, and immune response. We have shown that SH2D3C binds to DPP3 through its C-terminal Ras GEF-like domain, detected the colocalization of the proteins in living cells, and confirmed direct interaction in the cytosol and membrane ruffles. Computational analysis also confirmed the binding of the C-terminal domain of SH2D3C to DPP3, but the exact model could not be discerned. This is the first indication that DPP3 and SH2D3C are interacting partners, and further studies to elucidate the physiological significance of this interaction are on the way. [ABSTRACT FROM AUTHOR]

The P2X7 receptor (P2X7R) is an ATP-gated nonselective cationic channel that, upon intense stimulation, can progress to the opening of a pore permeable to molecules up to 900 Da. Apart from its broad expression in cells of the innate and adaptive immune systems, it is expressed in multiple cell types in different tissues. The dual gating property of P2X7R is instrumental in determining cellular responses, which depend on the expression level of the receptor, timing of stimulation, and microenvironmental cues, thus often complicating the interpretation of experimental data in comprehensive settings. Here we review the existing literature on P2X7R activity in autoimmunity, pinpointing the different functions in cells involved in the immunopathological processes that can make it difficult to model as a druggable target. [ABSTRACT FROM AUTHOR]

Kidneys are responsible for many crucial biological processes in the human body, including maintaining the water–electrolyte balance, pH, and blood pressure (BP), along with the elimination of toxins. Despite this, chronic kidney disease (CKD), which affects more and more people, is a disease that develops insidiously without causing any symptoms at first. The main purpose of this article is to summarize the existing literature on lercanidipine, with a particular focus on its nephroprotective properties. Lercanidipine is a third-generation dihydropyridine (DHP) blocker of calcium channels, and as such it possesses unique qualities such as high lipophilicity and high vascular selectivity. Furthermore, it acts by reversibly inhibiting L-type and T-type calcium channels responsible for exerting positive renal effects. It has been shown to reduce tissue inflammation and tubulointerstitial fibrosis, contributing to a decrease in proteinuria. Moreover, it exhibited antioxidative effects and increased expression of molecules responsible for repairing damaged tissues. It also decreased cell proliferation, preventing thickening of the vascular lumen. This article summarizes studies simultaneously comparing the effect of lercanidipine with other antihypertensive drugs. There is still a lack of studies on the medications used in patients with CKD, and an even greater lack of studies on those used in patients with concomitant hypertension. Therefore, further studies on lercanidipine and its potential in hypertensive patients with coexisting CKD are required. [ABSTRACT FROM AUTHOR]

Intestinal diseases have always posed a serious threat to human health, with inflammatory bowel disease (IBD) being one of them. IBD is an autoimmune disease characterized by chronic inflammation, including ulcerative colitis (UC) and Crohn's disease (CD). The "alarm" cytokine IL-33, which is intimately associated with Th2 immunity, is a highly potent inflammatory factor that is considered to have dual functions—operating as both a pro-inflammatory cytokine and a transcriptional regulator. IL-33 has been shown to play a crucial role in both the onset and development of IBD. Therefore, this review focuses on the pathogenesis of IBD, the major receptor cell types, and the activities of IL-33 in innate and adaptive immunity, as well as its underlying mechanisms and conflicting conclusions in IBD. We have also summarized different medicines targeted to IL-33-associated diseases. Furthermore, we have emphasized the role of IL-33 in gastrointestinal cancer and parasitic infections, giving novel prospective therapeutic utility in the future application of IL-33. [ABSTRACT FROM AUTHOR]

Acute coronary syndromes due to atherosclerotic coronary artery disease are a leading cause of morbidity and mortality worldwide. Intraplaque hemorrhage (IPH), caused by disruption of Intraplaque leaky microvessels, is one of the major contributors of plaque progression, causing a sudden increase in plaque volume and eventually plaque destabilization. IPH and its healing processes are highly complex biological events that involve interactions between multiple types of cells in the plaque, including erythrocyte, macrophages, vascular endothelial cells and vascular smooth muscle cells. Recent investigations have unveiled detailed molecular mechanisms by which IPH leads the development of high-risk "vulnerable" plaque. Current advances in clinical diagnostic imaging modalities, such as magnetic resonance image and intra-coronary optical coherence tomography, increasingly allow us to identify IPH in vivo. To date, retrospective and prospective clinical trials have revealed the significance of IPH as detected by various imaging modalities as a reliable prognostic indicator of high-risk plaque. In this review article, we discuss recent advances in our understanding for the significance of IPH on the development of high-risk plaque from basic to clinical points of view. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase III (DPP III, EC 3.4.14.4) is a monozinc metalloexopeptidase that hydrolyzes dipeptides from the N-terminus of peptides consisting of three or more amino acids. Recently, DPP III has attracted great interest from scientists, and numerous studies have been conducted showing that it is involved in the regulation of various physiological processes. Since it is the only metalloenzyme among the dipeptidyl peptidases, we considered it important to study the process of binding and exchange of physiologically relevant metal dications in DPP III. Using fluorimetry, we measured the Kd values for the binding of Zn2+, Cu2+, and Co2+ to the catalytic site, and using isothermal titration calorimetry (ITC), we measured the Kd values for the binding of these metals to an additional binding site. The structure of the catalytic metal's binding site is known from previous studies, and in this work, the affinities for this site were calculated for Zn2+, Cu2+, Co2+, and Mn2+ using the QM approach. The structures of the additional binding sites for the Zn2+ and Cu2+ were also identified, and MD simulations showed that two Cu2+ ions bound to the catalytic and inhibitory sites exchanged less frequently than the Zn2+ ions bound to these sites. [ABSTRACT FROM AUTHOR]

Tff1 is a typical gastric peptide secreted together with the mucin, Muc5ac. Tff1-deficient (Tff1KO) mice are well known for their prominent gastric phenotype and represent a recognized model for antral tumorigenesis. Notably, intestinal abnormalities have also been reported in the past in these animals. Here, we have compared the expression of selected genes in Tff1KO mice and their corresponding wild-type littermates (RT-PCR analyses), focusing on different mucosal protection systems along the murine intestine. As hallmarks, genes were identified with maximum expression in the proximal colon and/or the duodenum: Agr2, Muc6/A4gnt/Tff2, Tff1, Fut2, Gkn2, Gkn3, Duox2/Lpo, Nox1. This is indicative of different protection systems such as Tff2/Muc6, Tff1-Fcgbp, gastrokines, fucosylation, and reactive oxygen species (ROS) in the proximal colon and/or duodenum. Few significant transcriptional changes were observed in the intestine of Tff1KO mice when compared with wild-type littermates, Clca1 (Gob5), Gkn1, Gkn2, Nox1, Tff2. We also analyzed the expression of Tff1, Tff2, and Tff3 in the pancreas, liver, and lung of Tff1KO and wild-type animals, indicating a cross-regulation of Tff gene expression. Furthermore, on the protein level, heteromeric Tff1-Fcgbp and various monomeric Tff1 forms were identified in the duodenum and a high-molecular-mass Tff2/Muc6 complex was identified in the proximal colon (FPLC, proteomics). [ABSTRACT FROM AUTHOR]

Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are common in rheumatic diseases, but no studies report the frequency of these in early systemic sclerosis. There are no known biomarkers that can distinguish between patients with ME/CFS, although mitochondrial abnormalities are often demonstrated. We sought to assess the prevalence of ME/CFS in limited cutaneous SSc (lcSSc) patients early in their disease (<5 years from the onset of non-Raynaud's symptoms) and to determine if alterations in mitochondrial electron transport chain (ETC) transcripts and mitochondrial DNA (mtDNA) integrity could be used to distinguish between fatigued and non-fatigued patients. All SSc patients met ACR/EULAR classification criteria. ME/CFS-related symptoms were assessed through validated questionnaires, and the expression of ETC transcripts and mtDNA integrity were quantified via qPCR. SSc patients with ME/CFS could be distinguished from non-fatigued patients through ETC gene analysis; specifically, reduced expression of ND4 and CyB and increased expression of Cox7C. ND4 and CyB expression correlated with indicators of disease severity. Further prospective and functional studies are needed to determine if this altered signature can be further utilized to better identify ME/CFS in SSc patients, and whether ME/CFS in early SSc disease could predict more severe disease outcomes. [ABSTRACT FROM AUTHOR]

The systemic increase in inflammatory mediator levels can induce diverse pathological disorders, including potentially thrombus formation, which may be lethal. Among the clinical conditions in which the formation of thrombi dictates the patient's prognosis, envenomation by Bothrops lanceolatus should be emphasized, as it can evolve to stroke, myocardial infarction and pulmonary embolism. Despite their life-threatening potential, the immunopathological events and toxins involved in these reactions remain poorly explored. Therefore, in the present study, we examined the immunopathological events triggered by a PLA2 purified from B. lanceolatus venom, using an ex vivo human blood model of inflammation. Our results showed that the purified PLA2 from the venom of B. lanceolatus damages human erythrocytes in a dose dependent way. The cell injury was associated with a decrease in the levels of CD55 and CD59 complement regulators on the cell surface. Moreover, the generation of anaphylatoxins (C3a and C5a) and the soluble terminal complement complex (sTCC) indicates that human blood exposure to the toxin activates the complement system. Increased production of TNF-α, CXCL8, CCL2 and CCL5 followed complement activation. The venom PLA2 also triggered the generation of lipid mediators, as evidenced by the detected high levels of LTB4, PGE2 and TXB2. The scenario here observed of red blood cell damage, dysfunctions of the complement regulatory proteins, accompanied by an inflammatory mediator storm, suggests that B. lanceolatus venom PLA2 contributes to the thrombotic disorders present in the envenomed individuals. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are fascinating cells of the innate immune system involved not only in allergic reaction but also in tissue homeostasis, response to infection, wound healing, protection against kidney injury, the effects of pollution and, in some circumstances, cancer. Indeed, exploring their role in respiratory allergic diseases would give us, perhaps, novel therapy targets. Based on this, there is currently a great demand for therapeutic regimens to enfeeble the damaging impact of MCs in these pathological conditions. Several strategies can accomplish this at different levels in response to MC activation, including targeting individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth, or inducing mast cell apoptosis. The current work focuses on and summarizes the mast cells' role in pathogenesis and as a personalized treatment target in allergic rhinitis and asthma; even these supposed treatments are still at the preclinical stage. [ABSTRACT FROM AUTHOR]

Cancer is the leading cause of death worldwide despite the variety of treatments that are currently used. This is due to an innate or acquired resistance to therapy that encourages the discovery of novel therapeutic strategies to overcome the resistance. This review will focus on the role of the purinergic receptor P2RX7 in the control of tumor growth, through its ability to modulate antitumor immunity by releasing IL-18. In particular, we describe how the ATP-induced receptor activities (cationic exchange, large pore opening and NLRP3 inflammasome activation) modulate immune cell functions. Furthermore, we recapitulate our current knowledge of the production of IL-18 downstream of P2RX7 activation and how IL-18 controls the fate of tumor growth. Finally, the potential of targeting the P2RX7/IL-18 pathway in combination with classical immunotherapies to fight cancer is discussed. [ABSTRACT FROM AUTHOR]

When the Coronavirus Disease 2019 (COVID-19) appeared, it was unknown what impact it would have on the condition of patients with autoimmunological disorders. Attention was focused on the course of infection in patients suffering from multiple sclerosis (MS), specially treated with disease-modifying therapies (DMTs) or glucocorticoids. The impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection on the occurrence of MS relapses or pseudo-relapses was important. This review focuses on the risk, symptoms, course, and mortality of COVID-19 as well as immune response to vaccinations against COVID-19 in patients with MS (PwMS). We searched the PubMed database according to specific criteria. PwMS have the risk of infection, hospitalization, symptoms, and mortality due to COVID-19, mostly similar to the general population. The presence of comorbidities, male sex, a higher degree of disability, and older age increase the frequency and severity of the COVID-19 course in PwMS. For example, it was reported that anti-CD20 therapy is probably associated with an increased risk of severe COVID-19 outcomes. After SARS-CoV-2 infection or vaccination, MS patients acquire humoral and cellular immunity, but the degree of immune response depends on applied DMTs. Additional studies are necessary to corroborate these findings. However, indisputably, some PwMS need special attention within the context of COVID-19. [ABSTRACT FROM AUTHOR]

Mast cells may contribute to osteoporosis development, because patients with age-related or post-menopausal osteoporosis exhibit more mast cells in the bone marrow, and mastocytosis patients frequently suffer from osteopenia. We previously showed that mast cells crucially regulated osteoclastogenesis and bone loss in ovariectomized, estrogen-depleted mice in a preclinical model for post-menopausal osteoporosis and found that granular mast cell mediators were responsible for these estrogen-dependent effects. However, the role of the key regulator of osteoclastogenesis, namely, receptor activator of NFκB ligand (RANKL), which is secreted by mast cells, in osteoporosis development has, to date, not been defined. Here, we investigated whether mast-cell-derived RANKL participates in ovariectomy (OVX)-induced bone loss by using female mice with a conditional Rankl deletion. We found that this deletion in mast cells did not influence physiological bone turnover and failed to protect against OVX-induced bone resorption in vivo, although we demonstrated that RANKL secretion was significantly reduced in estrogen-treated mast cell cultures. Furthermore, Rankl deletion in mast cells did not influence the immune phenotype in non-ovariectomized or ovariectomized mice. Therefore, other osteoclastogenic factors released by mast cells might be responsible for the onset of OVX-induced bone loss. [ABSTRACT FROM AUTHOR]

A dual-target strategy was designed for the application of lignin nanoparticles in the lipase mediated biosynthesis of novel 3-O-ethyl-L-ascorbyl-6-ferulate and 3-O-ethyl-L-ascorbyl-6-palmitate and in their successive solvent-shift encapsulation in order to improve stability and antioxidant activity against temperature and pH-dependent degradation. The loaded lignin nanoparticles were fully characterized in terms of kinetic release, radical scavenging activity and stability under pH 3 and thermal stress (60 °C), showing improved antioxidant activity and high efficacy in the protection of ascorbic acid esters from degradation. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful lesions on intertriginous body areas such as the axillary, inguinal, and perianal sites. Given the limited treatment options for HS, expanding our knowledge of its pathogenetic mechanisms is a prerequisite for novel therapeutic developments. T cells are assumed to play a crucial role in HS pathogenesis. However, it is currently unknown whether blood T cells show specific molecular alterations in HS. To address this, we studied the molecular profile of CD4+ memory T (Thmem) cells purified from the blood of patients with HS and matched healthy participants. About 2.0% and 1.9% of protein-coding transcripts were found to be up- and down-regulated in blood HS Thmem cells, respectively. These differentially expressed transcripts (DETs) are known to be involved in nucleoside triphosphate/nucleotide metabolic processes, mitochondrion organization, and oxidative phosphorylation. The detected down-regulation of transcripts involved in oxidative phosphorylation suggest a metabolic shift of HS Thmem cells towards glycolysis. The inclusion of transcriptome data from skin from HS patients and healthy participants in the analyses revealed that in HS skin lesions, the expression pattern of transcripts identified as DETs in blood HS Thmem cells was very similar to the expression pattern of the totality of protein-coding transcripts. Furthermore, there was no significant association between the extent of the expressional changes in the DETs of blood HS Thmem cells and the extent of the expressional changes in these transcripts in HS skin lesions compared to healthy donor skin. Additionally, a gene ontology enrichment analysis did not demonstrate any association of the DETs of blood HS Thmem cells with skin disorders. Instead, there were associations with different neurological diseases, non-alcoholic fatty liver disease, and thermogenesis. The levels of most DETs linked to neurological diseases showed a positive correlation to each other, suggesting common regulatory mechanisms. In summary, the transcriptomic changes in blood Thmem cells observed in patients with manifest cutaneous HS lesions do not appear to be characteristic of the molecular changes in the skin. Instead, they could be useful for studying comorbidities and identifying corresponding blood biomarkers in these patients. [ABSTRACT FROM AUTHOR]

The P2X7 receptor is a trimeric ligand-gated cation channel activated by extracellular adenosine 5′-triphosphate. The study of animals has greatly advanced the investigation of P2X7 and helped to establish the numerous physiological and pathophysiological roles of this receptor in human health and disease. Following a short overview of the P2X7 distribution, roles and functional properties, this article discusses how animal models have contributed to the generation of P2X7-specific antibodies and nanobodies (including biologics), recombinant receptors and radioligands to study P2X7 as well as to the pharmacokinetic testing of P2X7 antagonists. This article then outlines how mouse and rat models have been used to study P2X7. These sections include discussions on preclinical disease models, polymorphic P2X7 variants, P2X7 knockout mice (including bone marrow chimeras and conditional knockouts), P2X7 reporter mice, humanized P2X7 mice and P2X7 knockout rats. Finally, this article reviews the limited number of studies involving guinea pigs, rabbits, monkeys (rhesus macaques), dogs, cats, zebrafish, and other fish species (seabream, ayu sweetfish, rainbow trout and Japanese flounder) to study P2X7. [ABSTRACT FROM AUTHOR]

Apelin is an endogenous ligand for the G protein-coupled receptor APJ and has multiple biological activities in human tissues and organs, including the heart, blood vessels, adipose tissue, central nervous system, lungs, kidneys, and liver. This article reviews the crucial role of apelin in regulating oxidative stress-related processes by promoting prooxidant or antioxidant mechanisms. Following the binding of APJ to different active apelin isoforms and the interaction with several G proteins according to cell types, the apelin/APJ system is able to modulate different intracellular signaling pathways and biological functions, such as vascular tone, platelet aggregation and leukocytes adhesion, myocardial activity, ischemia/reperfusion injury, insulin resistance, inflammation, and cell proliferation and invasion. As a consequence of these multifaceted properties, the role of the apelinergic axis in the pathogenesis of degenerative and proliferative conditions (e.g., Alzheimer's and Parkinson's diseases, osteoporosis, and cancer) is currently investigated. In this view, the dual effect of the apelin/APJ system in the regulation of oxidative stress needs to be more extensively clarified, in order to identify new potential strategies and tools able to selectively modulate this axis according to the tissue-specific profile. [ABSTRACT FROM AUTHOR]

Shigellosis causes more than 200,000 deaths worldwide and most of this burden falls on Low- and Middle-Income Countries (LMICs), with a particular incidence in children under 5 years of age. In the last decades, Shigella has become even more worrisome because of the onset of antimicrobial-resistant strains (AMR). Indeed, the WHO has listed Shigella as one of the priority pathogens for the development of new interventions. To date, there are no broadly available vaccines against shigellosis, but several candidates are being evaluated in preclinical and clinical studies, bringing to light very important data and information. With the aim to facilitate the understanding of the state-of-the-art of Shigella vaccine development, here we report what is known about Shigella epidemiology and pathogenesis with a focus on virulence factors and potential antigens for vaccine development. We discuss immunity after natural infection and immunization. In addition, we highlight the main characteristics of the different technologies that have been applied for the development of a vaccine with broad protection against Shigella. [ABSTRACT FROM AUTHOR]

For a long time, Substance Use Disorders (SUDs) were not considered a component in the etiology of dementia. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders introduced substance-induced neurocognitive disorders, incorporating this notion to clinical practice. However, detection and monitoring of neurodegenerative processes in SUD patients remain a major clinical challenge, especially when early diagnosis is required. In the present study, we aimed to investigate new potential biomarkers of neurodegeneration that could predict cognitive impairment in SUD patients: the circulating concentrations of Neurofilament Light chain protein (NfL) and Brain-Derived Neurotrophic Factor (BDNF). Sixty SUD patients were compared with twenty-seven dementia patients and forty healthy controls. SUD patients were recruited and assessed using the Psychiatric Research Interview for Substance and Mental (PRISM) and a battery of neuropsychological tests, including the Montreal Cognitive Assessment test for evaluation of cognitive impairment. When compared to healthy control subjects, SUD patients showed increases in plasma NfL concentrations and NfL/BDNF ratio, as well as reduced plasma BDNF levels. These changes were remarkable in SUD patients with moderate–severe cognitive impairment, being comparable to those observed in dementia patients. NfL concentrations correlated with executive function and memory cognition in SUD patients. The parameters "age", "NfL/BDNF ratio", "first time alcohol use", "age of onset of alcohol use disorder", and "length of alcohol use disorder diagnosis" were able to stratify our SUD sample into patients with cognitive impairment from those without cognitive dysfunction with great specificity and sensibility. In conclusion, we propose the combined use of NfL and BDNF (NfL/BDNF ratio) to monitor substance-induced neurocognitive disorder. [ABSTRACT FROM AUTHOR]

Muscle wasting is a major pathological feature observed in Duchenne muscular dystrophy (DMD) and is the result of the concerted effects of inflammation, oxidative stress and cell senescence. The inducible form of proteasome, or immunoproteasome (IP), is involved in all the above mentioned processes, regulating antigen presentation, cytokine production and immune cell response. IP inhibition has been previously shown to dampen the altered molecular, histological and functional features of 3-month-old mdx mice, the animal model for DMD. In this study, we described the role of ONX-0914, a selective inhibitor of the PSMB8 subunit of immunoproteasome, in ameliorating the pathological traits that could promote muscle wasting progression in older, 9-month-old mdx mice. ONX-0914 reduces the number of macrophages and effector memory T cells in muscle and spleen, while increasing the number of regulatory T cells. It modulates inflammatory markers both in skeletal and cardiac muscle, possibly counteracting heart remodeling and hypertrophy. Moreover, it buffers oxidative stress by improving mitochondrial efficiency. These changes ultimately lead to a marked decrease of fibrosis and, potentially, to more controlled myofiber degeneration/regeneration cycles. Therefore, ONX-0914 is a promising molecule that may slow down muscle mass loss, with relatively low side effects, in dystrophic patients with moderate to advanced disease. [ABSTRACT FROM AUTHOR]