No abstract

Neuroinflammation is an inflammatory response of the nervous tissue mediated by the production of cytokines, chemokines, and reactive oxygen species. Recent studies have shown that an upregulation of immunoproteasome is highly associated with various diseases and its inhibition attenuates neuroinflammation. In this context, the development of non-covalent immunoproteasome-selective inhibitors could represent a promising strategy for treating inflammatory diseases. Novel amide derivatives, KJ3 and KJ9, inhibit the β5 subunit of immunoproteasome and were used to evaluate their possible anti-inflammatory effects in an in vitro model of TNF-α induced neuroinflammation. Differentiated SH-SY5Y and microglial cells were challenged with 10 ng/mL TNF-α for 24 h and treated with KJ3 (1 µM) and KJ9 (1 µM) for 24 h. The amide derivatives showed a significant reduction of oxidative stress and the inflammatory cascade triggered by TNF-α reducing p-ERK expression in treated cells. Moreover, the key action of these compounds on the immunoproteasome was further confirmed by halting the IkB-α phosphorylation and the consequent inhibition of NF-kB. As downstream targets, IL-1β and IL-6 expression resulted also blunted by either KJ3 and KJ9. These preliminary results suggest that the effects of these two compounds during neuroinflammatory response relies on the reduced expression of pro-inflammatory targets.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). The outbreak of this coronavirus was first identified in Wuhan (Hubei, China) in December 2019, and it was declared as pandemic by the World Health Organization (WHO) in March 2020. Today, several vaccines against SARS-CoV-2 have been approved, and some neutralizing monoclonal antibodies are being tested as therapeutic approaches for COVID-19 but, one of the key questions is whether both vaccines and monoclonal antibodies could be effective against infections by new SARS-CoV-2 variants. Nevertheless, there are currently more than 1000 ongoing clinical trials focusing on the use and effectiveness of antiviral drugs as a possible therapeutic treatment. Among the classes of antiviral drugs are included 3CL protein inhibitors, RNA synthesis inhibitors and other small molecule drugs which target the ability of SARS-COV-2 to interact with host cells. Considering the need to find specific treatment to prevent the emergent outbreak, the aim of this review is to explain how some repurposed antiviral drugs, indicated for the treatment of other viral infections, could be potential candidates for the treatment of COVID-19.

Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-β activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-β binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A2AR and BGN modulation in an in vitro model of TGF-β-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-β at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-β stimulus, cells were treated with two different A2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A2AR antagonists were able to regulate the oxidative stress induced by TGF-β through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1β gene expression was markedly decreased following A2AR antagonist treatment in TGF-β-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A2AR. These results suggest that A2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling.

Drug repositioning is a strategy to identify new uses for approved or investigational drugs that are used off-label outside the scope of the original medical indication. <p> In this review we report the most relevant studies about drug repositioning in hematology, reporting the signalling pathways and molecular targets of these drugs, and describing the biological mechanisms which are responsible for anticancer effects. <p> Although the majority of studies on drug repositioning in hematology concern acute myeloid leukemia and multiple myeloma, numerous studies are present in the literature on the possibility to use these drugs also in other hematological diseases, such as acute lymphoblastic leukemia, chronic myeloid leukemia, and lymphomas. Numerous anti-infectious drugs, chemical entities used for the therapy of neurological or endocrine diseases, oral antidiabetics, statins, medications used to treat high blood pressure and heart failure, bisphosphonate, natural substance such as artemisin and curcumin, have found a place in hematological diseases treatment. Moreover, seve