The PI3K/Akt/mTOR pathway: A potential pharmacological target in COVID-19.

Coronavirus disease 2019 (COVID-19) has emerged as a serious threat to global health. The disregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) cell signaling pathway observed in patients with COVID-19 has attracted attention for the possible use of specific inhibitors of this pathway for the treatment of the disease. Here, we review emerging data on the involvement of the PI3K/Akt/mTOR pathway in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the clinical studies investigating its tailored inhibition in COVID-19. Current in silico, in vitro, and in vivo data convergently support a role for the PI3K/Akt/mTOR pathway in COVID-19 and suggest the use of specific inhibitors of this pathway that, by a combined mechanism entailing downregulation of excessive inflammatory reactions, cell protection, and antiviral effects, could ameliorate the course of COVID-19.

Cognitive Decline in Rheumatoid Arthritis: Insight into the Molecular Pathogenetic Mechanisms.

Cognitive decline refers to a deterioration of intellectual and learning abilities and related memory problems, and is often associated with behavioral alterations, which prevents sufferers from carrying out the most common daily activities, such as maintaining normal productive interpersonal relationships, communicating, and leading an autonomous life. Numerous studies have highlighted the association between cognitive decline and autoimmune disorders, including rheumatoid arthritis (RA). RA is a chronic, inflammatory, autoimmune disease that involves systems and organs other than the bones and joints, with varying severity among patients. Here, we review the studies investigating the link between cognitive decline and RA, focusing on the main molecular pathogenetic mechanisms involved. The emerging body of data suggests that clinical, psychological, and biological factors may contribute to the pathogenesis of cognitive decline in RA, including cardiovascular complications, chronic pain, depression, inflammatory factors, changes in hormone levels, drug side effects, and genetics. Further studies are warranted in order to fully clarify the basis underlying the association between cognitive decline and RA and to find new possible diagnostic strategies and therapeutic targets for RA patients.

Macrophage Migration Inhibitory Factor (MIF) and Its Homologue d-Dopachrome Tautomerase (DDT) Inversely Correlate with Inflammation in Discoid Lupus Erythematosus.

Discoid Lupus Erythematosus (DLE) is a chronic cutaneous disease of unknown etiology and of immunoinflammatory origin that is characterized by inflammatory plaques and may lead to disfiguring scarring and skin atrophy. Current treatments are limited, with a large proportion of patients either poorly or not responsive, which makes DLE an unmet medical need. Macrophage migration inhibitory factor (MIF) is the prototype of a pleiotropic family of cytokine that also includes the recently discovered homologue D-dopachrome tautomerase (DDT) or MIF2. MIF and DDT/MIF-2 exert several biological properties, primarily, but not exclusively of a proinflammatory nature. MIF and DDT have been suggested to play a key role in the pathogenesis of several autoimmune diseases, such as multiple sclerosis and type 1 diabetes, as well as in the development and progression of certain forms of cancers. In the present study, we have performed an immunohistochemistry analysis for the evaluation of MIF in DLE lesions and normal skin. We found high levels of MIF in the basal layer of the epidermis as well as in the cutaneous appendage (eccrine glands and sebocytes) of normal skin. In DLE lesions, we observed a significant negative correlation between the expression of MIF and the severity of inflammation. In addition, we performed an analysis of MIF and DDT expression levels in the skin of DLE patients in a publicly available microarray dataset. Interestingly, while these in silico data only evidenced a trend toward reduced levels of MIF, they demonstrated a significant pattern of expression and correlation of DDT with inflammatory infiltrates in DLE skins. Overall, our data support a protective role for endogenous MIF and possibly DDT in the regulation of homeostasis and inflammation in the skin and open up novel avenues for the treatment of DLE.

Emerging Neurological and Psychobiological Aspects of COVID-19 Infection.

The SARS-CoV-2 virus, first reported in December 2019 in China, is the causative agent of the current COVID-19 pandemic that, at the time of writing (1 November 2020) has infected almost 43 million people and caused the death of more than 1 million people. The spectrum of clinical manifestations observed during COVID-19 infection varies from asymptomatic to critical life-threatening clinical conditions. Emerging evidence shows that COVID-19 affects far more organs than just the respiratory system, including the heart, kidneys, blood vessels, liver, as well as the central nervous system (CNS) and the peripheral nervous system (PNS). It is also becoming clear that the neurological and psychological disturbances that occur during the acute phase of the infection may persist well beyond the recovery. The aim of this review is to propel further this emerging and relevant field of research related to the pathophysiology of neurological manifestation of COVID-19 infection (Neuro-COVID). We will summarize the PNS and CNS symptoms experienced by people with COVID-19 both during infection and in the recovery phase. Diagnostic and pharmacological findings in this field of study are strongly warranted to address the neurological and psychological symptoms of COVID-19.

Transcriptomic analysis of COVID­19 lungs and bronchoalveolar lavage fluid samples reveals predominant B cell activation responses to infection.

The outbreak of the 2019 coronavirus disease (named, COVID­19), caused by the novel SARS­CoV­2 virus, represents a worldwide severe threat to public health. It is of the utmost importance to characterize the immune responses against the SARS­CoV­2 and the mechanisms of hyperinflammation, in order to design better therapeutic strategies for COVID­19. In the present study, a transcriptomic analysis was performed to profile the immune signatures in lung and the bronchoalveolar lavage fluid samples from COVID­19 patients and controls. Our data concordantly revealed increased humoral responses to infection. The elucidation of the host responses to SARS­CoV­2 infection may further improve our understanding of COVID­19 pathogenesis and suggest better therapeutic strategies.

Upregulation of Tolerogenic Pathways by the Hydrogen Sulfide Donor GYY4137 and Impaired Expression of H2S-Producing Enzymes in Multiple Sclerosis.

The aim of this study was to examine the in vitro effects of the slow-releasing H2S donor GYY4137 on the immune cells involved in the pathogenesis of the central nervous system (CNS) autoimmune disease, multiple sclerosis (MS). GYY4137 specifically potentiated TGF-ß expression and production in dendritic cells and significantly reduced IFN-γ and IL-17 production in the lymph node and spinal cord T cells obtained from mice immunized with CNS antigens. Both the proportion of FoxP3+ regulatory CD4+ T cells in the lymph node cells, and the percentage of IL-17+ CD4+ T cells in the spinal cord cells were reduced upon culturing with GYY4137. Interestingly, the peripheral blood mononuclear cells obtained from the MS patients had a lower expression of the H2S-producing enzyme, 3-mercaptopyruvate-sulfurtransferase (MPST), in comparison to those obtained from healthy donors. A significant inverse correlation between the expression of MPST and several pro-inflammatory factors was also observed. Further studies on the relevance of the observed results for the pathogenesis and therapy of MS are warranted.

Entangling COVID-19 associated thrombosis into a secondary antiphospholipid antibody syndrome: Diagnostic and therapeutic perspectives (Review).

The severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) is a novel ß coronavirus that is the etiological agent of the pandemic coronavirus disease 2019 (COVID­19) that at the time of writing (June 16, 2020) has infected almost 6 million people with some 450,000 deaths. These numbers are still rising daily. Most (some 80%) cases of COVID­19 infection are asymptomatic, a substantial number of cases (15%) require hospitalization and an additional fraction of patients (5%) need recovery in intensive care units. Mortality for COVID­19 infection appears to occur globally between 0.1 and 0.5% of infected patients although the frequency of lethality is significantly augmented in the elderly and in patients with other comorbidities. The development of acute respiratory distress syndrome and episodes of thromboembolism that may lead to disseminated intravascular coagulation (DIC) represent the primary causes of lethality during COVID­19 infection. Increasing evidence suggests that thrombotic diathesis is due to multiple derangements of the coagulation system including marked elevation of D­dimer that correlate negatively with survival. We propose here that the thromboembolic events and eventually the development of DIC provoked by SARS­CoV­2 infection may represent a secondary anti­phospholipid antibody syndrome (APS). We will apply both Baconian inductivism and Cartesian deductivism to prove that secondary APS is likely responsible for coagulopathy during the course of COVID­19 infection. Diagnostic and therapeutic implications of this are also discussed.

The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients' survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches.

Meta-Analysis of Transcriptomic Data of Dorsolateral Prefrontal Cortex and of Peripheral Blood Mononuclear Cells Identifies Altered Pathways in Schizophrenia.

Schizophrenia (SCZ) is a psychiatric disorder characterized by both positive and negative symptoms, including cognitive dysfunction, decline in motivation, delusion and hallucinations. Antipsychotic agents are currently the standard of care treatment for SCZ. However, only about one-third of SCZ patients respond to antipsychotic medications. In the current study, we have performed a meta-analysis of publicly available whole-genome expression datasets on Brodmann area 46 of the brain dorsolateral prefrontal cortex in order to prioritize potential pathways underlying SCZ pathology. Moreover, we have evaluated whether the differentially expressed genes in SCZ belong to specific subsets of cell types. Finally, a cross-tissue comparison at both the gene and functional level was performed by analyzing the transcriptomic pattern of peripheral blood mononuclear cells of SCZ patients. Our study identified a robust disease-specific set of dysfunctional biological pathways characterizing SCZ patients that could in the future be exploited as potential therapeutic targets.

Transcriptomic Analysis Reveals Abnormal Expression of Prion Disease Gene Pathway in Brains from Patients with Autism Spectrum Disorders.

The role of infections in the pathogenesis of autism spectrum disorder (ASD) is still controversial. In this study, we aimed to evaluate markers of infections and immune activation in ASD by performing a meta-analysis of publicly available whole-genome transcriptomic datasets of brain samples from autistic patients and otherwise normal people. Among the differentially expressed genes, no significant enrichment was observed for infectious diseases previously associated with ASD, including herpes simplex virus-1 (HSV-1), cytomegalovirus and Epstein-Barr virus in brain samples, nor was it found in peripheral blood from ASD patients. Interestingly, a significant number of genes belonging to the "prion diseases" pathway were found to be modulated in our ASD brain meta-analysis. Overall, our data do not support an association between infection and ASD. However, the data do provide support for the involvement of pathways related to other neurodegenerative diseases and give input to uncover novel pathogenetic mechanisms underlying ASD.

Exploratory Analysis of iPSCS-Derived Neuronal Cells as Predictors of Diagnosis and Treatment of Alzheimer Disease.

Alzheimer's disease (AD) represents the most common neurodegenerative disorder, with 47 million affected people worldwide. Current treatment strategies are aimed at reducing the symptoms and do slow down the progression of the disease, but inevitably fail in the long-term. Induced pluripotent stem cells (iPSCs)-derived neuronal cells from AD patients have proven to be a reliable model for AD pathogenesis. Here, we have conducted an in silico analysis aimed at identifying pathogenic gene-expression profiles and novel drug candidates. The GSE117589 microarray dataset was used for the identification of Differentially Expressed Genes (DEGs) between iPSC-derived neuronal progenitor (NP) cells and neurons from AD patients and healthy donors. The Discriminant Analysis Module (DAM) algorithm was used for the identification of biomarkers of disease. Drugs with anti-signature gene perturbation profiles were identified using the L1000FWD software. DAM analysis was used to identify a list of potential biomarkers among the DEGs, able to discriminate AD patients from healthy people. Finally, anti-signature perturbation analysis identified potential anti-AD drugs. This study set the basis for the investigation of potential novel pharmacological strategies for AD. Furthermore, a subset of genes for the early diagnosis of AD is proposed.

Emerging Role of the Macrophage Migration Inhibitory Factor Family of Cytokines in Neuroblastoma. Pathogenic Effectors and Novel Therapeutic Targets?

Neuroblastoma (NB) is the most frequent extracranial pediatric tumor. Despite the current available multiple therapeutic options, the prognosis for high-risk NB patients remains unsatisfactory and makes the disease a clear unmet medical need. Thus, more tailored therapeutic approaches are warranted to improve both the quality of life and the survival of the patients. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays a key role in several diseases, including cancer. Preclinical and clinical studies in NB patients convergently indicate that MIF exerts pro-tumorigenic properties in NB. MIF is upregulated in NB tumor tissues and cell lines and it contributes to NB aggressiveness and immune-escape. To date, there are only a few data about the role of the second member of the MIF family, the MIF homolog d-dopachrome tautomerase (DDT), in NB. Here, we review the preclinical and clinical studies on the role of the MIF family of cytokines in NB and suggest that MIF and possibly DDT inhibitors may be promising novel prognostic and therapeutic targets in NB management.

Transcriptomic analysis reveals moderate modulation of macrophage migration inhibitory factor superfamily genes in alcohol use disorders.

Alcohol use disorder (AUD) is a primary, chronic and relapsing disease of brain reward, motivation and memory, which is associated with several comorbidities, including major depression and post-traumatic stress disorder. It has been revealed that Ibudilast (IBUD), a dual inhibitor of phosphodiesterase-4 and -10 and of macrophage migration inhibitory factor (MIF), exerts beneficial effects on AUD in rodent models and human patients. Therefore, IBUD has attracted increasing interest, with research focusing on the elucidation of the pathogenic role of MIF and its homologue, D-dopachrome tautomerase (DDT), in the pathogenesis and maintenance of AUD. By using DNA microarray analysis, the current study performed a transcriptomic expression analysis of MIF, DDT and their co-receptors, including CD74, C-X-C chemokine receptor (CXCR)2, CXCR4 and CXCR7 in patients with AUD. The results revealed that the transcriptomic levels of MIF, DDT and their receptors were superimposable in the prefrontal cortex of rodents and patients with AUD and human patients. Furthermore, peripheral blood cells from heavy drinkers exhibited a moderate increase in MIF and DDT levels, both at the baseline and following exposure to alcohol-associated cues, based on individual situations that included alcohol-related stimuli resulting in subsequent alcohol use (buying alcohol and being at a bar, watching others drink alcohol). Considering the overlapping effects of MIF and DDT, the inverse Fisher's χ2 test was performed on unadjusted P-values to evaluate the combined effect of MIF and DDT. The results revealed a significant increase in these cytokines in heavy drinkers compared with controls (moderate drinkers). To the best of our knowledge, the present study demonstrated for the first time that MIF and DDT expression was upregulated in the blood of patients with AUD. These results therefore warrant further study to evaluate the role of MIF and DDT in the development and maintenance of AUD, to evaluate their use as biomarkers to predict the psychotherapeutic and pharmacological response of patients with AUD and for use as therapeutic targets.

The Effect of Omega-3 Fatty Acids on Capsular Tissue around the Breast Implants.

BACKGROUND: One of the most common complications of the use of foreign material, in both reconstructive and cosmetic breast surgery, is capsular contracture. Historically, research on capsular contracture has focused mainly on reducing bacterial contamination through antibiotic solutions. Only secondary studies have focused on pharmacological control of the inflammation process, with particular attention paid to the main inflammation pathway, the arachidonic acid cascade. An important role in the arachidonic acid cascade is played by the omega-3 fatty acids, which are found mainly in oily fish and food supplements. The goal of the present study was to investigate the effects of omega-3 supplements on capsule contraction. METHODS: Female C57BL/6 mice were implanted with custom-made silicone gel implants and divided into two groups. The treated group received omega-3 oil daily while the control group received water daily by gavage. After mice were euthanized, samples of capsules were collected to evaluate thickness and transforming growth factor (TGF)-ß expression. RESULTS: The results showed that capsules in the omega-3 group were thinner and more transparent than those found in the control group. In addition, a significant downregulation of the TGF-ß2 gene transcript was observed in the omega-3 group. CONCLUSIONS: Omega-3 supplementation seems to be effective in reducing the occurrence of capsular formation, mainly through inhibition of the TGF-ß pathway and impairment of collagen deposit. Omega-3 supplementation is a simple and promising method that could be used to prevent or at least reduce capsular contracture after silicone implant surgery.

Impaired Expression of Tetraspanin 32 (TSPAN32) in Memory T Cells of Patients with Multiple Sclerosis.

Tetraspanins are a conserved family of proteins involved in a number of biological processes. We have previously shown that Tetraspanin-32 (TSPAN32) is significantly downregulated upon activation of T helper cells via anti-CD3/CD28 stimulation. On the other hand, TSPAN32 is marginally modulated in activated Treg cells. A role for TSPAN32 in controlling the development of autoimmune responses is consistent with our observation that encephalitogenic T cells from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mice exhibit significantly lower levels of TSPAN32 as compared to naïve T cells. In the present study, by making use of ex vivo and in silico analysis, we aimed to better characterize the pathophysiological and diagnostic/prognostic role of TSPAN32 in T cell immunity and in multiple sclerosis (MS). We first show that TSPAN32 is significantly downregulated in memory T cells as compared to naïve T cells, and that it is further diminished upon ex vivo restimulation. Accordingly, following antigenic stimulation, myelin-specific memory T cells from MS patients showed significantly lower expression of TSPAN32 as compared to memory T cells from healthy donors (HD). The expression levels of TSPAN32 was significantly downregulated in peripheral blood mononuclear cells (PBMCs) from drug-naïve MS patients as compared to HD, irrespective of the disease state. Finally, when comparing patients undergoing early relapses in comparison to patients with longer stable disease, moderate but significantly lower levels of TSPAN32 expression were observed in PBMCs from the former group. Our data suggest a role for TSPAN32 in the immune responses underlying the pathophysiology of MS and represent a proof-of-concept for additional studies aiming at dissecting the eventual contribution of TSPAN32 in other autoimmune diseases and its possible use of TSPAN32 as a diagnostic factor and therapeutic target.

The Role of Macrophage Migration Inhibitory Factor in Alzheimer's Disease: Conventionally Pathogenetic or Unconventionally Protective?

Recent preclinical and clinical observations have offered relevant insights on the etiopathogenesis of late onset Alzheimer's disease (AD) and upregulated immunoinflammatory events have been described as underlying mechanisms involved in the development of AD. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by several cells of the innate and adaptive immune system, as well as non-immune cells. In the present review, we highlight experimental, genetic, and clinical studies on MIF in rodent models of AD and AD patients, and we discuss emerging therapeutic opportunities for tailored modulation of the activity of MIF, that may potentially be applied to AD patients. Dismantling the exact role of MIF and its receptors in AD may offer novel diagnostic and therapeutic opportunities in AD.

In Silico and In Vivo Analysis of IL37 in Multiple Sclerosis Reveals Its Probable Homeostatic Role on the Clinical Activity, Disability, and Treatment with Fingolimod.

We evaluated the in silico expression and circulating levels of interleukin (IL)37 in patients with different forms of multiple sclerosis (MS) and also upon treatment with different disease-modifying drugs. The combined interpretation of the resulting data strengthens and extends the current emerging concept that endogenous IL37 plays an important role in determining onset and progression of MS. The in silico analysis revealed that production of IL37 from cluster of differentiation (CD)4+ T cells from MS patients was reduced in vitro as compared to healthy controls. The analysis of the datasets also demonstrated that "higher" levels of IL37 production from PBMC entailed significant protection from MS relapses. In addition, the in vivo part of the study showed that IL37 was selectively augmented in the sera of MS patients during a relapse and that treatment with the high potency disease-modifying drug fingolimod significantly increased the frequency of patients with circulating blood levels of IL37 (6/9, 66%) as compared to patients receiving no treatment (n = 48) or platform therapy (n = 59) who had levels of IL37 below the limit of the sensitivity of the assay. This finding therefore anticipates that fingolimod may at least partially exert its beneficial effects in MS by upregulating the production of IL37.

Transcriptomic Analysis Reveals Involvement of the Macrophage Migration Inhibitory Factor Gene Network in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive hereditary muscular disease with X-linked recessive inheritance, that leads patients to premature death. The loss of dystrophin determines membrane instability, causing cell damage and inflammatory response. Macrophage migration inhibitory factor (MIF) is a cytokine that exerts pleiotropic properties and is implicated in the pathogenesis of a variety of diseases. Recently, converging data from independent studies have pointed to a possible role of MIF in dystrophic muscle disorders, including DMD. In the present study, we have investigated the modulation of MIF and MIF-related genes in degenerative muscle disorders, by making use of publicly available whole-genome expression datasets. We show here a significant enrichment of MIF and related genes in muscle samples from DMD patients, as well as from patients suffering from Becker's disease and limb-girdle muscular dystrophy type 2B. On the other hand, transcriptomic analysis of in vitro differentiated myotubes from healthy controls and DMD patients revealed no significant alteration in the expression levels of MIF-related genes. Finally, by analyzing DMD samples as a time series, we show that the modulation of the genes belonging to the MIF network is an early event in the DMD muscle and does not change with the increasing age of the patients, Overall, our analysis suggests that MIF may play a role in vivo during muscle degeneration, likely promoting inflammation and local microenvironment reaction.

Could the Combination of Two Non-Psychotropic Cannabinoids Counteract Neuroinflammation? Effectiveness of Cannabidiol Associated with Cannabigerol.

Background and Objectives: Neuroinflammation is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this study, we investigate the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of two non-psychoactive phytocannabinoids, cannabigerol (CBG) and cannabidiol (CBD). Materials and Methods: The motoneuron-like cell line NSC-34 differentiated by serum deprivation and with the additional treatment of all-trans retinoic acid (RA) is a valid model to investigate molecular events linked to neurodegeneration in ALS. Results: Pre-treatment with CBG (at 2.5 and 5 µM doses) alone and in combination with CBD (at 2.5 and 5 µM doses) was able to reduce neuroinflammation induced by a culture medium of LPS-stimulated macrophages. In particular, the pre-treatment with CBD at a 5 µM dose decreased TNF-α levels and increased IL10 and IL-37 expression. CBG-CBD association at a 5 µM dose also reduced NF-kB nuclear factor activation with low degradation of the inhibitor of kappaB alpha (IkBα). CBG and CBD co-administered at a 5 µM dose decreased iNOS expression and increased Nrf2 levels. Furthermore, the pre-treatment with the association of two non-psychoactive cannabinoids downregulated Bax protein expression and upregulated Bcl-2 expression. Our data show the anti-inflammatory, anti-oxidant, and anti-apoptotic effects PPARγ-mediated. Conclusions: Our results provide preliminary support on the potential therapeutic application of a CBG-CBD combination for further preclinical studies.

Autism Spectrum Disorder and miRNA: An Overview of Experimental Models.

Autism spectrum disorder (ASD) is a complex neuropsychiatric disorder characterized by deficits in social interactions, communication, language, and in a limited repertoire of activities and interests. The etiology of ASD is very complex. Genetic, epigenetic, and environmental factors contribute to the onset of ASD. Researchers have shown that microRNAs (miRNAs) could be one of the possible causes associated with ASD. miRNAs are small noncoding mRNAs that regulate gene expression, and they are often linked to biological processes and implicated in neurodevelopment. This review aims to provide an overview of the animal models and the role of the different miRNAs involved in ASD. Therefore, the use of animal models that reproduce the ASD and the identification of miRNAs could be a useful predictive tool to study this disorder.