Search

Muscular dystrophies (MDs) are genetically heterogeneous diseases characterized by primary skeletal muscle atrophy. The collapse of muscle structure and irreversible degeneration of tissues promote the occurrence of comorbidities, including cardiomyopathy and respiratory failure. Mitochondrial dysfunction leads to inflammation, fibrosis, and adipogenic cellular infiltrates that exacerbate the symptomatology of MD patients. Gastrointestinal disorders and metabolic anomalies are common in MD patients and may be determined by the interaction between the intestine and its microbiota. Therefore, the gut-muscle axis is one of the actors involved in the spread of inflammatory signals to all muscles. In this review, we aim to examine in depth how intestinal dysbiosis can modulate the metabolic state, the immune response, and mitochondrial biogenesis in the course and progression of the most investigated MDs such as Duchenne Muscular Dystrophy (DMD) and Myotonic Dystrophy (MD1), to better identify gut microbiota metabolites working as therapeutic adjuvants to improve symptoms of MD.

Gestational diet has a long-dated effect not only on the disease risk in offspring but also on the occurrence of future neurological diseases. During ontogeny, changes in the epigenetic state that shape morphological and functional differentiation of several brain areas can affect embryonic fetal development. Many epigenetic mechanisms such as DNA methylation and hydroxymethylation, histone modifications, chromatin remodeling, and non-coding RNAs control brain gene expression, both in the course of neurodevelopment and in adult brain cognitive functions. Epigenetic alterations have been linked to neuro-evolutionary disorders with intellectual disability, plasticity, and memory and synaptic learning disorders. Epigenetic processes act specifically, affecting different regions based on the accessibility of chromatin and cell-specific states, facilitating the establishment of lost balance. Recent insights have underscored the interplay between epigenetic enzymes active during embryonic development and the presence of bioactive compounds, such as vitamins and polyphenols. The fruit of Manilkara zapota contains a rich array of these bioactive compounds, which are renowned for their beneficial properties for health. In this review, we delve into the action of each bioactive micronutrient found in Manilkara zapota , elucidating their roles in those epigenetic mechanisms crucial for neuronal development and programming. Through a comprehensive understanding of these interactions, we aim to shed light on potential avenues for harnessing dietary interventions to promote optimal neurodevelopment and mitigate the risk of neurological disorders.

Pathological states marked by oxidative stress and systemic inflammation frequently compromise the functional capacity of muscular cells. This progressive decline in muscle mass and tone can significantly hamper the patient's motor abilities, impeding even the most basic physical tasks. Muscle dysfunction can lead to metabolic disorders and severe muscle wasting, which, in turn, can potentially progress to sarcopenia. The functionality of skeletal muscle is profoundly influenced by factors such as environmental, nutritional, physical, and genetic components. A well-balanced diet, rich in proteins and vitamins, alongside an active lifestyle, plays a crucial role in fortifying tissues and mitigating general weakness and pathological conditions. Vitamin D, exerting antioxidant effects, is essential for skeletal muscle. Epidemiological evidence underscores a global prevalence of vitamin D deficiency, which induces oxidative harm, mitochondrial dysfunction, reduced adenosine triphosphate production, and impaired muscle function. This review explores the intricate molecular mechanisms through which vitamin D modulates oxidative stress and its consequent effects on muscle function. The aim is to evaluate if vitamin D supplementation in conditions involving oxidative stress and inflammation could prevent decline and promote or maintain muscle function effectively.

Sarcopenia refers to the progressive loss and atrophy of skeletal muscle function, often associated with aging or secondary to conditions involving systemic inflammation, oxidative stress, and mitochondrial dysfunction. Recent evidence indicates that skeletal muscle function is not only influenced by physical, environmental, and genetic factors but is also significantly impacted by nutritional deficiencies. Natural compounds with antioxidant properties, such as resveratrol and vitamin D, have shown promise in preventing mitochondrial dysfunction in skeletal muscle cells. These antioxidants can slow down muscle atrophy by regulating mitochondrial functions and neuromuscular junctions. This review provides an overview of the molecular mechanisms leading to skeletal muscle atrophy and summarizes recent advances in using resveratrol and vitamin D supplementation for its prevention and treatment. Understanding these molecular mechanisms and implementing combined interventions can optimize treatment outcomes, ensure muscle function recovery, and improve the quality of life for patients.

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.

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.

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.

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.

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.

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., (Copyright © 2022. Published by Elsevier B.V.)

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.

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.

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., (© 2021. The Author(s).)

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., (© 2021 John Wiley & Sons Ltd.)

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., (© 2021. The Author(s).)

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.

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.

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., Competing Interests: Declaration of Competing Interest The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors declare no conflict of interest.

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.

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/β. 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.

Osteoarthritis is the most common human arthritis characterized by degeneration of articular cartilage. Several studies reported that levels of human cartilage glycoprotein chitinase 3-like-1 (CHI3L1) are known as a potential marker for the activation of chondrocytes and the progression of Osteoarthritis (OA), whereas lubricin appears to be chondroprotective. The aim of this study was to investigate the co-expression and co-localization of CHI3L1 and lubricin in normal and osteoarthritic rat articular cartilage to correlate their modified expression to a specific grade of OA. Samples of normal and osteoarthritic rat articular cartilage were analyzed by the Kellgren-Lawrence OA severity scores, the Kraus' modified Mankin score and the Histopathology Osteoarthritis Research Society International (OARSI) system for histomorphometric evaluations, and through CHI3L1 and lubricin gene expression, immunohistochemistry and double immuno-staining analysis. The immunoexpression and the mRNA levels of lubricin increased in normal cartilage and decreased in OA cartilage (normal vs. OA, p < 0.01). By contrast, the immunoexpression and the mRNA levels of CHI3L1 increased in OA cartilage and decreased in normal cartilage (normal vs. OA, p < 0.01). Our findings are consistent with reports suggesting that these two glycoproteins are functionally associated with the development of OA and in particular with grade 2/3 of OA, suggesting that in the future they could be helpful to stage the severity and progression of the disease.

Chitinases belonging to 18 glycosyl hydrolase family is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In humans, despite the absence of endogenous chitin, a number of Chitinases and Chitinase-like Proteins (C/CLPs) have been identified. Chitinases with enzymatic activity have a chitin binding domain containing six cysteine residues responsible for their binding to chitin. In contrast, CLPs do not contain such typical chitin-binding domains, but still can bind to chitin with high affinity. Molecular phylogenetic analyses suggest that active Chitinases result from an early gene duplication event. Further duplication events, followed by mutations leading to loss of chitinase activity, allowed evolution of the chi-lectins. For the majority of the mammalian chitinases the last decades have witnessed the appearance of a substantial number of studies describing their expression differentially regulated during more specific immunologic activities. It is becoming increasingly clear that their function is not exclusive to catalyse the hydrolysis of chitin producing pathogens, but include crucial role in bacterial infections and inflammatory diseases. Here we provide an overview of all family members to shed light on the mechanisms and molecular interactions of Chitinases and CLPs in relation to immune response regulation, in order to delineate their future utilization as diagnostic and prognostic markers for numerous diseases., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Chitinase-3-like-1 protein (CHI3L1) is a glycosyl hydrolase (GH) highly expressed in a variety of inflammatory diseases at infectious and non-infectious etiology. CHI3L1 is produced by a wide variety of cells including monocyte-derived macrophages cell lines such as polarized M1 and M2 type macrophages, osteoclasts and Kupffer cells. In this study we have examined the expression of CHI3L1 during the differentiation and maturation of dendritic cells. Magnetically-isolated peripheral blood monocytes were differentiated toward immature DCs (iDC) and mature DCs (mDCs) through a combination of factors and cytokines. Our result showed, for the first time, that CHI3L1 is expressed during the process of differentiation and maturation of dendritic cells in time dependent manner. Furthermore, the CHI3L1 is evenly distributed in cytoplasm and in the nucleus of both the iDCs and mDCs. These results suggest that CHI3L1 may play crucial role in the DCs immunoresponse., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

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.

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., (© 2016 S. Karger AG, Basel.)

Autophagy is an important homeostatic cellular process encompassing a number of consecutive steps indispensable for degrading and recycling cytoplasmic materials. Basically autophagy is an adaptive response that under stressful conditions guarantees the physiological turnover of senescent and impaired organelles and, thus, controls cell fate by various cross-talk signals. Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and accounts for 5% of all blindness. Although, various metabolic disorders have been linked with the onset of DR, due to the complex character of this multi-factorial disease, a connection between any particular defect and DR becomes speculative. Diabetes increases inflammation, advanced glycation end products (AGEs) and oxidative stress in the retina and its capillary cells. Particularly, a great number of evidences suggest a mutual connection between oxidative stress and other major metabolic abnormalities implicated in the development of DR. In addition, the intricate networks between autophagy and apoptosis establish the degree of cellular apoptosis and the progression of DR. Growing data underline the crucial role of reactive oxygen species (ROS) in the activation of autophagy. Depending on their delicate balance both redox signaling and autophagy, being detrimental or beneficial, retain opposing effects. The molecular mechanisms of autophagy are very complex and involve many signaling pathways cooperating at various steps. This review summarizes recent advances of the possible molecular mechanisms in autophagic process that are involved in pathophysiology of DR. In-depth analysis on the molecular mechanisms leading to autophagy in the retinal pigment epithelial (RPE) will be helpful to plan new therapies aimed at preventing or improving the progression of DR.

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., (© 2016 S. Karger AG, Basel.)

The chitotriosidase (CHIT-1) is a glycosyl hydrolase (GH), which has been found highly expressed in activated macrophages and in different monocyte-derived cell lines such as Kupffer cells and osteoclasts, as well is differently produced in diverse stages of macrophage polarization (M1 and M2). Recent finding suggests that CHIT-1 plays a crucial role in innate and acquired immunity. Dendritic cells (DCs) are a complex group of cells that play a critical role in immune response. The aim of this study was to investigate the presence of CHIT-1 during the differentiation and maturation of DCs. Magnetically-isolated peripheral blood monocytes were differentiated toward immature DCs (iDC) and mature DCs (mDCs). Our results showed, for the first time, that CHIT-1 is expressed during the process of differentiation and maturation of DCs in a time-dependent manner. We found that CHIT1 is evenly distributed in cytoplasm of both the iDCs and mDCs. Additionally, a significantly increased expression of CHIT1 mRNA and protein was observed in mature DCs. These results suggest that CHIT-1 play an important role in the DCs immunoresponse.

Osteolytic bone disease is a common manifestation of multiple myeloma (MM) that leads to progressive skeleton destruction and is the most severe cause of morbidity in MM patients. It results from increased osteolytic activity and decrease osteoblastic function. Activation of mammalian chitinases chitotriosidase (CHIT1) and YKL40 is associated with osteoclast (OCs) differentiation and bone digestion. In the current study, we investigated the effect of two Bortezomib's concentration (2.5 and 5 nM) on osteoclastogenesis by analyzing regulation of chitinase expression. OCs exposition to bortezomib (BO) was able to inhibit the expression of different OCs markers such as RANK, CTSK, TRAP, and MMP9. In addition BO-treatment reduced CHIT1 enzymatic activity and both CHIT1 and YKL40 mRNA expression levels and cytoplasmatic and secreted protein. Moreover, immunofluorescence evaluation of mature OCs showed that BO was able to translocate YKL40 into the nucleus, while CHIT1 remained into the cytoplasm. Since MM cell lines such as U266, SKM-M1 and MM1 showed high levels of CHIT1 activity, we analyzed bone resorption ability of U266 using dentin disk assay resorption pits. Silencing chitinase proteins in U266 cell line with specific small interfering RNA, resulted in pits number reduction on dentine disks. In conclusion, we showed that BO decreases osteoclastogenesis and reduces bone resorption in OCs and U266 cell line by modulating the chitinases CHIT1 and YKL40. These results indicate that chitinases may be a therapeutic target for bone disease in MM patients.

Sardinia is an Italian region with a high incidence of type 1 diabetes mellitus. This study aimed to determine the associations of trace elements with lipid profiles and glycaemic control in patients with T1DM. A total of 192 patients with T1DM who attended the Unit of Diabetology and Metabolic Diseases in Sassari, Italy, were enrolled. Trace elements zinc, copper, selenium, chromium, and iron were measured in whole blood by sector field inductively coupled plasma mass spectrometry. The correlations between metabolic variables and the levels of trace elements were determined. Zinc was positively correlated with total cholesterol (P=0.023), low-density lipoprotein (P=0.0015), and triglycerides (P=0.027). Iron as significantly correlated with TC (P=0.0189), LDL (P=0.0121), and high-density lipoprotein (HDL) (P=0.0466). In males, Cr was positively correlated with HDL (P=0.0079) and Se, in females was correlated with TG (P=0.0113). The mean fasting plasma glucose was166.2mgdL(-1). Chromium was correlated with fasting plasma glucose (P=0.0149), particularly in males (P=0.0038). Overall, 63.5% of the patients had moderate HbA1c (7-9%). Copper was significantly correlated with HbA1c% in males (P=0.0155). In conclusion, the results of this study indicate that trace elements show different associations with lipid levels and glycaemic control in T1DM. Zinc, Fe, and Se were associated with lipid levels whereas Cu and Cr were associated with HbA1c%., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Malignant brain tumors are the most common pediatric solid tumors and are the leading cause of death from childhood cancers. These tumors include several histologic subtypes. Due to the particular properties of brain tumors, such as growth and division, examination of brain tumors and the analysis of results are not simple. Up to date there is a dearth of useful biomarkers that have been validated and clinically implemented for pediatric brain tumors. In order to identify the new genetic alterations we recognized, using microarray dataset, chitinases as new potential biomarkers of CNS tumors. The modulation of chitinases was confirmed also in the different histologic subtypes. Our study revealed that distinct patterns of chitinases expression characterize the diverse histological subtypes. In addition evaluating other lisosomal enzymes such as glycosidases and proteases we found that NEU4, CTBS and GBA2 belonging to glycosidases family and CTSC, CTSK and CTSF belonging to proteases family were differently modulated. Future investigations are needed to be performed before some of these enzymes could finally be used as biomarkers of specific types of CNS neoplasms., (Copyright © 2015 Elsevier GmbH. All rights reserved.)