The association of lysosomal dysfunction and neurodegeneration has been documented in several neurodegenerative diseases, including Alzheimer’s Disease (AD). Herein, we investigate the association of lysosomal enzymes with AD at different stages of progression of the disease (mild and severe) or with mild cognitive impairment (MCI). We conducted a screening of two classes of lysosomal enzymes: glycohydrolases (β-Hexosaminidase, β-Galctosidase, β-Galactosylcerebrosidase, β-Glucuronidase) and proteases (Cathepsins S, D, B, L) in peripheral blood samples (blood plasma and PBMCs) from mild AD, severe AD, MCI and healthy control subjects. We confirmed the lysosomal dysfunction in severe AD patients and added new findings enhancing the association of abnormal levels of specific lysosomal enzymes with the mild AD or severe AD, and highlighting the difference of AD from MCI. Herein, we showed for the first time the specific alteration of β-Galctosidase (Gal), β-Galactosylcerebrosidase (GALC) in MCI patients. It is notable that in above peripheral biological samples the lysosomes are more sensitive to AD cellular metabolic alteration when compared to levels of Aβ-peptide or Tau proteins, similar in both AD groups analyzed. Collectively, our findings support the role of lysosomal enzymes as potential peripheral molecules that vary with the progression of AD, and make them useful for monitoring regenerative medicine approaches for AD.

Unfolded protein response (UPR) and endoplasmic reticulum (ER) stress are aspects of SARS‐CoV‐2‐host cell interaction with proposed role in the cytopathic and inflammatory pathogenesis of this viral infection. The role of the NF‐kB pathway in these cellular processes remains poorly characterized. When investigated in VERO‐E6 cells, SARS‐CoV‐2 infection was found to markedly stimulate NF‐kB protein expression and activity. NF‐kB activation occurs early in the infection process (6 hpi) and it is associated with increased MAPK signaling and expression of the UPR inducer IRE‐1α. These signal transduction processes characterize the cellular stress response to the virus promoting a pro‐inflammatory environment and caspase activation in the host cell. Inhibition of viral replication by the viral protease inhibitor Nelfinavir reverts all these molecular changes also stimulating c‐Jun expression, a key component of the JNK/AP‐1 pathway with important role in the IRE‐1α‐mediated transcriptional regulation of stress response genes with anti‐inflammatory and cytoprotection function. The present study demonstrates that UPR signaling and its interaction with cellular MAPKs and the NF‐kB activity are important aspects of SARS‐CoV‐2‐host cell interaction that deserve further investigation to identify more efficient therapies for this viral infection.

Human herpes virus-8 (HHV-8)-associated primary effusion lymphoma (PEL) is an unusual lymphoma confined to the body cavities, which primarily affects human immunodeficiency virus (HIV)-positive men at high risk for Kaposi's sarcoma (KS). We describe two HIV-negative elderly Italian men, who developed pleural HHV-8-positive PEL in association with other diseases (systemic hypertension, colonic carcinoma, chronic obstructive airways disease, dilated cardiomyopathy), but without KS. Thoracic computed tomography revealed unilateral pleural effusion and pleural thickening. Thoracentesis disclosed large lymphoma cells, with no T- or B-cell associated antigens, clonal rearrangement of the immunoglobulin heavy chain gene and the presence of HHV-8 but not Epstein-Barr virus deoxyribonucleic acid sequences. Our cases differ from most pleural effusion lymphomas, in that they are non-acquired immunodeficiency syndrome-related. This highlights the possible human herpes virus-8-associated primary effusion lymphoma risk among elderly human immunodeficiency virus-negative patients, particularly Italians, in whom human herpes virus-8 seroprevalence rates and incidence of classic Kaposi's sarcoma are high.