Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies.

Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.

Comparison of Vitamin D and Resveratrol Performances in COVID-19.

Over the last few years, we have experienced the infection generated by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) often resulting in an exaggerated immune reaction and systemic inflammation. The preferred treatments against SARS-CoV-2 were those that mitigated immunological/inflammatory dysfunction. A variety of observational epidemiological studies have reported that vitamin D deficiency is often a crucial factor in many inflammatory diseases and autoimmune diseases, as well as the susceptibility to contract infectious diseases, including acute respiratory infections. Similarly, resveratrol regulates immunity, modifying the gene expression and the release of proinflammatory cytokines in the immune cells. Therefore, it plays an immunomodulatory role that can be beneficial in the prevention and development of non-communicable diseases associated with inflammation. Since both vitamin D and resveratrol also act as immunomodulators in inflammatory pathologies, many studies have paid particular attention to an integrated treatment of either vitamin D or resveratrol in the immune reaction against SARS-CoV-2 infections. This article offers a critical evaluation of published clinical trials that have examined the use of vitamin D or resveratrol as adjuncts in COVID-19 management. Furthermore, we aimed to compare the anti-inflammatory and antioxidant properties linked to the modulation of the immune system, along with antiviral properties of both vitamin D and resveratrol.

Chitinase Signature in the Plasticity of Neurodegenerative Diseases.

Several reports have pointed out that Chitinases are expressed and secreted by various cell types of central nervous system (CNS), including activated microglia and astrocytes. These cells play a key role in neuroinflammation and in the pathogenesis of many neurodegenerative disorders. Increased levels of Chitinases, in particular Chitotriosidase (CHIT-1) and chitinase-3-like protein 1 (CHI3L1), have been found increased in several neurodegenerative disorders. Although having important biological roles in inflammation, to date, the molecular mechanisms of Chitinase involvement in the pathogenesis of neurodegenerative disorders is not well-elucidated. Several studies showed that some Chitinases could be assumed as markers for diagnosis, prognosis, activity, and severity of a disease and therefore can be helpful in the choice of treatment. However, some studies showed controversial results. This review will discuss the potential of Chitinases in the pathogenesis of some neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, to understand their role as distinctive biomarkers of neuronal cell activity during neuroinflammatory processes. Knowledge of the role of Chitinases in neuronal cell activation could allow for the development of new methodologies for downregulating neuroinflammation and consequently for diminishing negative neurological disease outcomes.

Anti-inflammatory role of vitamin D in muscle dysfunctions of patients with chronic obstructive pulmonary disease: a comprehensive review.

Vitamin D deficiency is involved in the etiology of a broad range of diseases. Recently, some studies have shown a link between vitamin D and susceptibility to the onset of chronic obstructive pulmonary disease (COPD). COPD is characterized by chronic inflammation and irreversible airway obstruction. Systemic inflammation in COPD patients is associated with a decline in lung function. In addition, inflammation causes various extra-pulmonary symptoms, including muscle deterioration that leads to reduced strength and fatigue endurance, especially in muscles of the lower limb. In COPD the pathophysiological changes related to the inflammatory state affect oxidant-antioxidant balance, which is one of the main mechanisms promoting the progression of this disease and exacerbations. Vitamin D exerts beneficial effects and exhibits anti-inflammatory actions. Vitamin D deficiency in COPD patients affects inflammation, oxidative stress and mitochondrial impairment and can generate the development of skeletal atrophy. This systematic review offers a better understanding of the molecular mechanisms linking vitamin D deficiency to COPD and muscle weakness, and aims to establish whether vitamin D supplementation could be useful to mitigate inflammation in COPD patients.

The Interplay between Ghrelin and Microglia in Neuroinflammation: Implications for Obesity and Neurodegenerative Diseases.

Numerous studies have shown that microglia are capable of producing a wide range of chemokines to promote inflammatory processes within the central nervous system (CNS). These cells share many phenotypical and functional characteristics with macrophages, suggesting that microglia participate in innate immune responses in the brain. Neuroinflammation induces neurometabolic alterations and increases in energy consumption. Microglia may constitute an important therapeutic target in neuroinflammation. Recent research has attempted to clarify the role of Ghre signaling in microglia on the regulation of energy balance, obesity, neuroinflammation and the occurrence of neurodegenerative diseases. These studies strongly suggest that Ghre modulates microglia activity and thus affects the pathophysiology of neurodegenerative diseases. This review aims to summarize what is known from the current literature on the way in which Ghre modulates microglial activity during neuroinflammation and their impact on neurometabolic alterations in neurodegenerative diseases. Understanding the role of Ghre in microglial activation/inhibition regulation could provide promising strategies for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.

Impact of Lung Microbiota on COPD.

There is a fine balance in maintaining healthy microbiota composition, and its alterations due to genetic, lifestyle, and environmental factors can lead to the onset of respiratory dysfunctions such as chronic obstructive pulmonary disease (COPD). The relationship between lung microbiota and COPD is currently under study. Little is known about the role of the microbiota in patients with stable or exacerbated COPD. Inflammation in COPD disorders appears to be characterised by dysbiosis, reduced lung activity, and an imbalance between the innate and adaptive immune systems. Lung microbiota intervention could ameliorate these disorders. The microbiota's anti-inflammatory action could be decisive in the onset of pathologies. In this review, we highlight the feedback loop between microbiota dysfunction, immune response, inflammation, and lung damage in relation to COPD status in order to encourage the development of innovative therapeutic goals for the prevention and management of this disease.

Immunoregulation of Ghrelin in neurocognitive sequelae associated with COVID-19: an in silico investigation.

Some patients suffering from the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) develop an exaggerated inflammatory response triggered by a "cytokine storm" resulting in acute respiratory distress syndrome (ARDS) with the concomitant activation of non-specific inflammatory reactivity in the circulatory system and other organs, leading to multiorgan failure, leaky vasculature, coagulopathies and stroke. Impairment of brain functions may also occur as dysregulations in immune function resulting from neuroendocrine interactions. In this study, we explored, by bioinformatics approaches, the interaction between the multiple inflammatory agents involved in SARS-CoV-2 and Ghrelin (Ghre) together with its receptor GHSR-1A, which are described as anti-inflammatory mediators, in order to investigate what could trigger the hyper-inflammatory response in some SARS-CoV-2 patients. In our analysis, we found several interactions of Ghre and GHSR-1A with SARS-CoV-2 interacting human genes. We observed a correlation between Ghre, angiotensin-converting enzyme 2 ACE2, toll-like receptors 9 (TLR9), and Acidic chitinase (CHIA), whereas its receptor GHSR-1A interacts with chemokine receptor 3 (CXCR3), CCR3, CCR5, CCR7, coagulation factor II (thrombin) receptor-like 1 (F2RL1), vitamin D receptor (VDR), Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and DDP4 in receptor dipeptidyl peptidase-4. To our knowledge, our findings show, for the first time, that Ghre and GHSR-1A may exert an immunomodulatory function in the course of SARS-Cov-2 infection.

Vitamin D Impacts on Skeletal Muscle Dysfunction in Patients with COPD Promoting Mitochondrial Health.

Skeletal muscle dysfunction is frequently associated with chronic obstructive pulmonary disease (COPD), which is characterized by a permanent airflow limitation, with a worsening respiratory disorder during disease evolution. In COPD, the pathophysiological changes related to the chronic inflammatory state affect oxidant-antioxidant balance, which is one of the main mechanisms accompanying extra-pulmonary comorbidity such as muscle wasting. Muscle impairment is characterized by alterations on muscle fiber architecture, contractile protein integrity, and mitochondrial dysfunction. Exogenous and endogenous sources of reactive oxygen species (ROS) are present in COPD pathology. One of the endogenous sources of ROS is represented by mitochondria. Evidence demonstrated that vitamin D plays a crucial role for the maintenance of skeletal muscle health. Vitamin D deficiency affects oxidative stress and mitochondrial function influencing disease course through an effect on muscle function in COPD patients. This review will focus on vitamin-D-linked mechanisms that could modulate and ameliorate the damage response to free radicals in muscle fibers, evaluating vitamin D supplementation with enough potent effect to contrast mitochondrial impairment, but which avoids potential severe side effects.

Candidate genes of SARS-CoV-2 gender susceptibility.

The severe acute respiratory syndrome coronavirus (SARS-CoV-2) initiated a global viral pandemic since late 2019. Understanding that Coronavirus disease (COVID-19) disproportionately affects men than women results in great challenges. Although there is a growing body of published study on this topic, effective explanations underlying these sex differences and their effects on the infection outcome still remain uncertain. We applied a holistic bioinformatics method to investigate molecular variations of known SARS-CoV-2 interacting human proteins mainly expressed in gonadal tissues (testis and ovary), allowing for the identification of potential genetic targets for this infection. Functional enrichment and interaction network analyses were also performed to better investigate the biological differences between testicular and ovarian responses in the SARS-CoV-2 infection, paying particular attention to genes linked to immune-related pathways, reactions of host cells after intracellular infection, steroid hormone biosynthesis, receptor signaling, and the complement cascade, in order to evaluate their potential association with sexual difference in the likelihood of infection and severity of symptoms. The analysis revealed that within the testis network TMPRSS2, ADAM10, SERPING1, and CCR5 were present, while within the ovary network we found BST2, GATA1, ENPEP, TLR4, TLR7, IRF1, and IRF2. Our findings could provide potential targets for forthcoming experimental investigation related to SARS-CoV-2 treatment.

Impact of chronic obstructive pulmonary disease on passive viscoelastic components of the musculoarticular system.

Chronic obstructive pulmonary disease (COPD) produces skeletal muscle atrophy and weakness, leading to impairments of exercise performance. The mechanical work needed for movement execution is also provided by the passive tension developed by musculoarticular connective tissue. To verify whether COPD affects this component, the passive viscoelastic properties of the knee joint were evaluated in 11 patients with COPD and in 11 healthy individuals. The levels of stiffness and viscosity were assessed by means of the pendulum test, consisting in a series of passive leg oscillations. In addition, to explore the contribution of passive tension in the mechanical output of a simple motor task, voluntary leg flexion-extension movements were performed. Patients with COPD showed a statistically significant reduction in stiffness and viscosity compared to controls. Voluntary execution of flexion-extension movements revealed that the electromyographic activity of the Rectus Femoris and Biceps Femoris was lower in patients than in controls, and the low viscoelastic tension in the patients conditioned the performance of active movements. These results provide novel insights on the mechanism responsible for the movement impairments associated with COPD.

Is the Power Spectrum of Electromyography Signal a Feasible Tool to Estimate Muscle Fiber Composition in Patients with COPD?

A greater proportion of glycolytic muscle fibers is a manifestation of skeletal muscle dysfunction in Chronic Obstructive Pulmonary Disease (COPD). Here, we propose to use the spectral analysis of the electromyographic signal as a non-invasive approach to investigate the fiber muscle composition in COPD. We recorded the electromyographic activity of Rectus Femoris (RF), Vastus Lateralis (VL), Vastus Medialis (VM) and Biceps Femoris (BF) muscles, in ten patients and ten healthy individuals, during non-fatiguing, flexion-extension leg movements. The mean (MNF) and median frequencies (MDF) were calculated, and the most common profiles of electromyographic power spectrum were characterized by using the principal component analysis. Frequency parameters showed higher values in patients with COPD than in the control group for the RF (+25% for MNF; +21% for MNF), VL (+16% for MNF; 16% for MNF) and VM (+22% for MNF; 22% for MNF) muscles during the extension movements and for the BF (+26% for MNF; 34% for MNF) muscle during flexion movements. Spectrum profiles of the COPD patients shifted towards the higher frequencies, and the changes in frequency parameters were correlated with the level of disease severity. This shift of frequencies may indicate an increase in glycolytic muscle fibers in patients with COPD. These results, along with the non-fatigable nature of the motor task and the adoption of a non-invasive method, encourage to use electromyographic spectral analysis for estimating muscle fiber composition in patients with COPD.

Protective role of vitamin D against oxidative stress in diabetic retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus. There is much evidence showing that a high level of mitochondrial overproduction of reactive oxygen species in the diabetic retina contributes in modifying cellular signalling and leads to retinal cell damage and finally to the development of DR pathogenesis. In the last few decades, it has been reported that vitamin D is involved in DR pathogenesis. Vitamin D, traditionally known as an essential nutrient crucial in bone metabolism, has also been proven to be a very effective antioxidant. It has been demonstrated that it modulates the production of advanced glycosylated end products, as well as several pathways including protein kinase C, the polyol pathway leading to the reduction of free radical formation. It prevents the translocation of nuclear factor kappa B, preventing the inflammatory response, acting as an immunomodulator, and modulates autophagy and apoptosis. In this review, we explore the molecular mechanisms by which vitamin D protects the eye from oxidative stress, in order to evaluate whether vitamin D supplementation may be useful to mitigate the deleterious effects of free radicals in DR.

Vitamin D3 as Potential Treatment Adjuncts for COVID-19.

Severe acute respiratory syndrome coronavirus type (SARS-CoV2, also known as COVID-19), which is the latest pandemic infectious disease, constitutes a serious risk to human health. SARS-CoV2 infection causes immune activation and systemic hyperinflammation which can lead to respiratory distress syndrome (ARDS). ARDS victims are characterized by a significant increase in IL-6 and IL-1. Macrophage activation, associated with the "cytokine storm", promotes the dysregulation of the innate immunity. So far, without vaccines or specific therapy, all efforts to design drugs or clinical trials are worthwhile. Vitamin D and its receptor vitamin D receptor (VDR) exert a critical role in infections due to their remarkable impact on both innate and adaptive immune responses and on the suppression of the inflammatory process. The protective properties of vitamin D supplementation have been supported by numerous observational studies and by meta-analysis of clinical trials for prevention of viral acute respiratory infection. In this review, we compare the mechanisms of the host immune response to SARS-CoV2 infection and the immunomodulatory actions that vitamin D exerts in order to consider the preventive effect of vitamin D supplementation on SARS-CoV2 viral infection.

Vitamin D and microbiota: Two sides of the same coin in the immunomodulatory aspects.

The gut microbiota is crucial for host immune response, vitamin synthesis, short chain fatty acids (SCFAs) production, intestinal permeability, nutrient digestion energy metabolism and protection from pathogens. Therefore, gut microbiota guarantees the host's predisposition to gastrointestinal diseases. Intestinal microbiota may be damaged by environmental components with negative health conditions. Dysbiosis consisting in alteration in the gut microbiota has been involved in several disorders including inflammation, allergic reactions, autoimmune diseases, heart diseases, obesity, and metabolic syndrome and even in the state of malignant carcinogenesis existing in humans. Several epidemiological studies have shown that inadequate solar exposure results in vitamin D insufficiency/deficiency which has a strong impact on different immune responses and the occurrence of a wide range of pathological conditions. Additionally, new evidence indicates that the vitamin D pathway plays a key role in gut homeostasis. Due to the strong connection between vitamin D and microbiota, herein we focus on the new findings about intestinal bacteria-immune crosstalk and the impact of vitamin D in gut microbiota regulation, in order to offer new clarifications on their interaction. Understanding the mechanism by which vitamin D can affect the gut microbiota composition and its dynamic activities, as well as the innate and adaptive state of the immune system, is not only a fundamental research but also an opportunity to improve health status.

Influence of Resveratrol on the Immune Response.

Resveratrol is the most well-known polyphenolic stilbenoid, present in grapes, mulberries, peanuts, rhubarb, and in several other plants. Resveratrol can play a beneficial role in the prevention and in the progression of chronic diseases related to inflammation such as diabetes, obesity, cardiovascular diseases, neurodegeneration, and cancers among other conditions. Moreover, resveratrol regulates immunity by interfering with immune cell regulation, proinflammatory cytokines' synthesis, and gene expression. At the molecular level, it targets sirtuin, adenosine monophosphate kinase, nuclear factor-κB, inflammatory cytokines, anti-oxidant enzymes along with cellular processes such as gluconeogenesis, lipid metabolism, mitochondrial biogenesis, angiogenesis, and apoptosis. Resveratrol can suppress the toll-like receptor (TLR) and pro-inflammatory genes' expression. The antioxidant activity of resveratrol and the ability to inhibit enzymes involved in the production of eicosanoids contribute to its anti-inflammation properties. The effects of this biologically active compound on the immune system are associated with widespread health benefits for different autoimmune and chronic inflammatory diseases. This review offers a systematic understanding of how resveratrol targets multiple inflammatory components and exerts immune-regulatory effects on immune cells.

Fasting and Fast Food Diet Play an Opposite Role in Mice Brain Aging.

Fasting may be exploited as a possible strategy for prevention and treatment of several diseases such as diabetes, obesity, and aging. On the other hand, high-fat diet (HFD) represents a risk factor for several diseases and increased mortality. The aim of the present study was to evaluate the impact of fasting on mouse brain aging transcriptome and how HFD regulates such pathways. We used the NCBI Gene Expression Omnibus (GEO) database, in order to identify suitable microarray datasets comparing mouse brain transcriptome under fasting or HFD vs aged mouse brain transcriptome. Three microarray datasets were selected for this study, GSE24504, GSE6285, and GSE8150, and the principal molecular mechanisms involved in this process were evaluated. This analysis showed that, regardless of fasting duration, mouse brain significantly expressed 21 and 30 upregulated and downregulated genes, respectively. The involved biological processes were related to cell cycle arrest, cell death inhibition, and regulation of cellular metabolism. Comparing mouse brain transcriptome under fasting and aged conditions, we found out that the number of genes in common increased with the duration of fasting (222 genes), peaking at 72 h. In addition, mouse brain transcriptome under HFD resembles for the 30% the one of the aged mice. Furthermore, several molecular processes were found to be shared between HFD and aging. In conclusion, we suggest that fasting and HFD play an opposite role in brain transcriptome of aged mice. Therefore, an intermittent diet could represent a possible clinical strategy to counteract aging, loss of memory, and neuroinflammation. Furthermore, low-fat diet leads to the inactivation of brain degenerative processes triggered by aging.

Nuclear import sequence identification in hOAS3 protein.

OBJECTIVE: The OAS proteins are characterized by their capacity to synthesize 2',5'-linked phosphodiester bonds to polymerize ATP into oligomers of adenosine. OAS3, belonging to OASs gene family, synthesizes dimeric 2-5A that binds to RNase L with low affinity and produces 2-5A oligomers shorter than the tri-tetramer 2-5As produced by other family members. METHODS: For these studies, we used the open source tools cNLS Mapper, PredictProtein and COMPARTMENTS for the nuclear localization signal prediction, UCSF Chimera for molecular graphics and analyses, The Human Protein Atlas to confirm with the IF the OAS3 cell localization and Ensembl Variation Table to identify the presence of putative single nucleotide polymorphisms in the NLS sequence identification. RESULTS: The analysis of OAS3 protein sequence (NP_006178.2) displayed a putative nuclear localization signal (cNLS Mapper score 8 and PP 100 %), identified by 11 and 5 amino acids (LQRQL KRPRP V) located in the outer portion ready to interact with the importin α/ß. Furthermore, we showed that in all cells lines available in the Human Protein Atlas subcell section, the OAS3 was mainly localized in the cytoplasm and nucleus, but not in the nucleoli. We identify six known variant SNPs mapping in the nuclear import sequence, but only three were associated with a missense variation (rs781335794, rs750458641, rs550465943) and were able to strongly reduce the cNLS score. CONCLUSIONS: The catalytically inactive domain of human OAS3 has a potential nuclear import function, susceptible to SNPs, which could determine their roles in the viral infection and IFNs response.

Neurodegeneration and Neuroinflammation in Diabetic Retinopathy: Potential Approaches to Delay Neuronal Loss.

In spite of the extensive research the complex pathogenesis of diabetic retinopathy (DR) has not been fully elucidated. For many years it has been thought that diabetic retinopathy manifests only with microangiopathic lesions, which are totally responsible for the loss of vision in diabetic patients. In view of the current knowledge on the microangiopathic changes in the fundus of the eye, diabetic retinopathy is perceived as a neurodegenerative disease. Several clinical tools are available to detect neuronal dysfunction at early stages of diabetes. Many functional changes in the retina can be identified before vascular pathology develops, suggesting that they result from a direct effect of diabetes on the neural retina. In the course of diabetes there is a chronic loss of retinal neurons due to increased frequency of apoptosis. The neuronal apoptosis begins very early in the course of diabetes. This observation has led to suggestions that precautions against DR should be implemented immediately after diabetes is diagnosed. Neurodegeneration cannot be reversed; therefore treatments preventing neuronal cell loss in the retina need to be developed to protect diabetic patients. This review is an attempt to summarize what is currently known about the mechanisms of neuronal apoptosis in the context of diabetic retinopathy and vascular degeneration as well as about potential treatments of DR.

Chitinase 3 Like-1: An Emerging Molecule Involved in Diabetes and Diabetic Complications.

Chitinase 3 like-1 (CHI3L1) is a chitinase-like protein member of family 18 chitinases, expressed in innate immune cells and involved in endothelial dysfunction and tissue remodelling. Since CHI3L1 is highly expressed in a variety of inflammatory diseases of infectious and non-infectious aetiology, it is recognised as a non-invasive prognostic biomarker for inflammation. A variety of studies revealing the increase in CHI3L1 levels in obesity, insulin resistance and in pathological conditions, such as atherosclerosis, coronary artery disease, acute ischaemic stroke, nephropathy, diabetic retinopathy and osteolytic processes, have suggested that CHI3L1 may also play a critical role in the evolution and complication of diabetes mellitus (DM). In this review we highlight the impact of CHI3L1 expression in DM and its contribution to the complication of this disease.

Chitotriosidase: A New Inflammatory Marker in Diabetic Complications.

Chitotriosidase (CHIT1) belongs to chitinase family. So far this enzyme has been the best investigated human chitinase regarding its biological activity and association with various disorders. In a healthy population, CHIT1 activity is very low and originates in the circulating polymorphonuclear cells. Conversely, during the development of acute/chronic inflammatory disorders, the enzymatic activity of CHIT1 increases significantly. Recently, CHIT1 has also been involved in the pathogenesis of diabetes mellitus (DM). Mounting evidence from experimental studies revealing the increase of CHIT1 levels in pathological conditions, such as atherosclerosis, coronary artery disease, acute ischemic stroke, cerebrovascular dementia, nonalcoholic fatty liver disease, and osteolytic processes suggest its critical role in the evolutions and complications of DM. This review is addressed to provide mechanistic insights by highlighting the relationship between CHIT1 and diabetes, and their contribution in the exacerbation of this disease.