Amyloid‐beta induces different expression pattern of tissue transglutaminase and its isoforms on olfactory ensheathing cells: Modulatory effect of indicaxanthin

Herein, we assessed the effect of full native peptide of amyloid‐beta (Aβ) (1‐42) and its fragments (25‐35 and 35‐25) on tissue transglutaminase (TG2) and its isoforms (TG2‐Long and TG2‐ Short) expression levels on olfactory ensheathing cells (OECs). Vimentin and glial fibrillary acid protein (GFAP) were also studied. The effect of the pre‐treatment with indicaxanthin from Opuntia ficus‐indica fruit on TG2 expression levels and its isoforms, cell viability, total reactive oxygen species (ROS), superoxide anion (O2−), and apoptotic pathway activation was assessed. The levels of Nestin and cyclin D1 were also evaluated. Our findings highlight that OECs exposure to Aβ(1‐ 42) and its fragments induced an increase in TG2 expression levels and a different expression pattern of its isoforms. Indicaxanthin pre‐treatment reduced TG2 overexpression, modulating the expression of TG2 isoforms. It reduced total ROS and O2− production, GFAP and Vimentin levels, inhibiting apoptotic pathway activation. It also induced an increase in the Nestin and cyclin D1 expression levels. Our data demonstrated that indicaxanthin pre‐treatment stimulated OECs self-renewal through the reparative activity played by TG2. They also suggest that Aβ might modify TG2 conformation in OECs and that indicaxanthin pre‐treatment might modulate TG2 conformation, stimulating neural regeneration in Alzheimer’s disease

Synthesis and biological evaluation of phosphonated dihydroisoxazole nucleosides

Phosphonated isoxazolinyl nucleosides have been prepared via 1,3-dipolar cycloaddition reaction of nitrile oxides with corresponding vinyl or allyl nucleobases for antiviral studies. The cytotoxicity, the anti-HSV activity and the RT-inhibitory activity of the obtained compounds were evaluated and compared with those of AZT and diethyl{(10SR,40RS)-10-[[(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)]-30-methyl-20-oxa-30-azacyclopent-40-yl]}methylphosphonate, a saturated phosphonated dihydroisoxazole nucleoside analogue

Synthesis of phosphonated carbocyclic 2 '-oxa-3 '-aza-nucleosides: Novel inhibitors of reverse transcriptase

Phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides have been synthesized in good yields by 1,3-dipolar cycloaddition methodology. The cytotoxicity and the reverse transcriptase inhibitory activity of the obtained compounds have been investigated. Phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides, while showing low levels of cytotoxicity, exert a specific inhibitor activity on two different reverse transcriptases, which is comparable with that of AZT, opening new perspectives on their possible use as therapeutic agents, in anti-retroviral and anti-HBV chemotherapy

Phosphonated Carbocyclic 2'-Oxa-3'-azanucleosides as New Antiretroviral Agents

Phosphonated carbocyclic 2¢-oxa-3¢-azanucleosides have been synthesized and tested for their antiretroviral activity. The obtained results have shown that some of the compounds were as powerful as azydothymidine in inhibiting the reverse transcriptase activity of the human retrovirus T-cell leukemia/lymphotropic virus type 1 and in protecting human peripheral blood mononuclear cells against human retrovirus T-cell leukemia/ lymphotropic virus type 1 transmission in vitro. These data indicate that phosphonated carbocyclic 2¢-oxa- 3¢-azanucleosides possess the necessary requirements to efficiently counteract infections caused by human retroviruses

Onychomycosis: Recommendations for Diagnosis, Assessment of Treatment Efficacy, and Specialist Referral. The CONSONANCE Consensus Project

Introduction: Onychomycosis is the most common nail disorder in adults, with high recurrence and relapse rates. Its diagnosis may be difficult by non-experts because the clinical signs may overlap with other dermatoses. The treatment may be challenging, as it should be patient-tailored. Methods: An online survey was conducted among European Nail Society (ENS) members to provide recommendations on the diagnosis and assessment of distal lateral subungual onychomycosis (DLSO) in non-specialized clinical environments, as well as recommendations for patient referral. Results: DLSO diagnosis is predominantly based on clinical aspects, and microscopy and fungal culture are commonly employed to establish the diagnosis. Assessment of clinical features is the main method for DLSO follow-up, and the main criterion to define cure is a combination of mycologic cure and clinical cure. The most commonly selected treatments for onychomycosis include oral antifungals, topical antifungals, and nail debridement. According to the nail experts, predisposing factors of DLSO to be evaluated include concurrent tinea pedis diagnosis, immunocompromised status, and diabetes. The minimum clinical aspects to be evaluated for DLSO diagnosis should include subungual hyperkeratosis, white-yellow-orange subungual scales, and absence of salmon-pink coloration. Recommendations for clinical signs that should be evaluated to confirm treatment effectiveness include normal appearance and color of the nail, reduction or absence of scales under the nail, and absence of onycholysis. Recommendations for specialist referral include lack of treatment effectiveness, need of additional therapies, concurrent presence of other diseases or comorbidities, severe DLSO, and presence of a dermatophytoma or involvement of the nail matrix. Conclusions: According to the surveyed nail experts, after evaluating clinical signs and predisposing factors for DLSO, the diagnosis should include subungual hyperkeratosis, nail color (yellow-orange), and onycholysis and thickening. In cases of severe DLSO, when there is treatment failure, concomitant diseases/comorbidities, presence of a dermatophytoma or involvement of the nail matrix, or involvement of several/all nails, referral should be considered

Mycobacterium tuberculosis Immune Response in Patients With Immune-Mediated Inflammatory Disease

Subjects with immune-mediated inflammatory diseases (IMID), such as rheumatoid arthritis (RA), have an intrinsic higher probability to develop active-tuberculosis (TB) compared to the general population. The risk ranges from 2.0 to 8.9 in RA patients not receiving therapies. According to the WHO, the RA prevalence varies between 0.3% and 1% and is more common in women and in developed countries. Therefore, the identification and treatment of TB infection (TBI) in this fragile population is important to propose the TB preventive therapy. We aimed to study the M. tuberculosis (Mtb) specific T-cell response to find immune biomarkers of Mtb burden or Mtb clearance in patients with different TB status and different risk to develop active-TB disease. We enrolled TBI subjects as example of Mtb-containment, the active-TB as example of a replicating Mtb status, and the TBI-IMID as fragile population. To study the Mtb-specific response in a condition of possible Mtb sterilization, we longitudinally enrolled TBI subjects and active-TB patients before and after TB therapy. Peripheral blood mononuclear cells were stimulated overnight with Mtb peptides contained in TB1- and TB2-tubes of the Quantiferon-Plus kit. Then, we characterized by cytometry the Mtb-specific CD4 and CD8 T cells. In TBI-IMID, the TB therapy did not affect the ability of CD4 T cells to produce interferon-γ, tumor necrosis factor-α, and interleukin-2, their functional status, and their phenotype. The TB therapy determined a contraction of the triple functional CD4 T cells of the TBI subjects and active-TB patients. The CD45RA- CD27+ T cells stood out as a main subset of the Mtb-specific response in all groups. Before the TB-preventive therapy, the TBI subjects had higher proportion of Mtb-specific CD45RA-CD27+CD4+ T cells and the active-TB subjects had higher proportion of Mtb-specific CD45RA-CD27-CD4+ T cells compared to other groups. The TBI-IMID patients showed a phenotype similar to TBI, suggesting that the type of IMID and the IMID therapy did not affect the activation status of Mtb-specific CD4 T cells. Future studies on a larger and better-stratified TBI-IMID population will help to understand the change of the Mtb-specific immune response over time and to identify possible immune biomarkers of Mtb-containment or active replication