Osteosarcoma cell death induced by innovative scaffolds doped with chemotherapeutics.

Osteosarcoma (OS) cancer treatments include systemic chemotherapy and surgical resection. In the last years, novel treatment approaches have been proposed, which employ a drug-delivery system to prevent offside effects and improves treatment efficacy. Locally delivering anticancer compounds improves on high local concentrations with more efficient tumour-killing effect, reduced drugs resistance and confined systemic effects. Here, the synthesis of injectable strontium-doped calcium phosphate (SrCPC) scaffold was proposed as drug delivery system to combine bone tissue regeneration and anticancer treatment by controlled release of methotrexate (MTX) and doxorubicin (DOX), coded as SrCPC-MTX and SrCPC-DOX, respectively. The drug-loaded cements were tested in an in vitro model of human OS cell line SAOS-2, engineered OS cell line (SAOS-2-eGFP) and U2-OS. The ability of doped scaffolds to induce OS cell death and apoptosis was assessed analysing cell proliferation and Caspase-3/7 activities, respectively. To determine if OS cells grown on doped-scaffolds change their migratory ability and invasiveness, a wound-healing assay was performed. In addition, the osteogenic potential of SrCPC material was evaluated using human adipose derived-mesenchymal stem cells. Osteogenic markers such as (i) the mineral matrix deposition was analysed by alizarin red staining; (ii) the osteocalcin (OCN) protein expression was investigated by enzyme-linked immunosorbent assay test, and (iii) the osteogenic process was studied by real-time polymerase chain reaction array. The delivery system induced cell-killing cytotoxic effects and apoptosis in OS cell lines up to Day 7. SrCPC demonstrates a good cytocompatibility and it induced upregulation of osteogenic genes involved in the skeletal development pathway, together with OCN protein expression and mineral matrix deposition. The proposed approach, based on the local, sustained release of anticancer drugs from nanostructured biomimetic drug-loaded cements is promising for future therapies aiming to combine bone regeneration and anticancer local therapy.

Tofacitinib restores psoriatic arthritis fibroblast-like synoviocytes function via autophagy and mitochondrial quality control modulation.

OBJECTIVES: To evaluate the in vitro effect of tofacitinib on autophagy activity of psoriatic arthritis (PsA) fibroblast-like synoviocytes (FLS), and to confirm its activity on inflammatory and invasive properties of FLS and synovial cells, deepening the impact on mitochondrial function. METHODS: FLS, peripheral blood mononuclear cells (PBMCs), and synovial cells from active PsA patients were cultured with tofacitinib 1 µM or vehicle control for 24 h. Autophagy was measured by Western blot and by fluorescence microscopy. Chemokines/cytokines released into culture supernatants were quantified by ELISA, while invasive properties of FLS by migration assays. Specific mitochondrial probes were adopted to measure intracellular reactive oxygen species (ROS), mitochondrial potential, morphology, turnover and mitophagy. Oxygen consumption rate (OCR), reflecting oxidative phosphorylation, was quantified using the Seahorse technology. Differences were determined by adopting the non-parametric Wilcoxon signed rank test. RESULTS: 18 patients with moderately-to-severely active PsA were enrolled. Tofacitinib significantly increased the levels of the autophagy markers LC3-II and ATG7 in PsA FLS compared to vehicle control, suggesting an increase in spontaneous autophagy activity; no effect was highlighted in PBMCs and synovial cells cultures. Tofacitinib reduced migration properties of PsA FLS, and reduced MCP-1 and IL-6 release into FLS and synovial cells cultures supernatants. Furthermore, tofacitinib decreased intracellular ROS production, increased basal OCR, ATP production and maximal respiratory capacity, and enhanced mitophagy and mitochondrial turnover. CONCLUSIONS: The JAK inhibitor tofacitinib reduces the pro-invasive and pro-inflammatory properties of PsA FLS. Autophagy induction and mitochondrial quality control modulation by tofacitinib might contribute to FLS function restoration.

SARS-CoV-2 infection as a model to study the effect of cinnamaldehyde as adjuvant therapy for viral pneumonia.

BACKGROUND: The recent pandemic outbursts, due to SARS-CoV-2, have highlighted once more the central role of the inflammatory process in the propagation of viral infection. The main consequence of COVID-19 is the induction of a diffuse pro-inflammatory state, also defined as a cytokine storm, which affects different organs, but mostly the lungs. We aimed to prove the efficacy of cinnamaldehyde, the active compound of cinnamon, as an anti-inflammatory compound, able to reduce SARS-CoV-2 induced cytokine storm. RESULTS: We enrolled 53 COVID-19 patients hospitalized for respiratory failure. The cohort was composed by 39 males and 13 females, aged 65.0 ± 9.8 years. We reported that COVID-19 patients have significantly higher IL-1ß and IL-6 plasma levels compared to non-COVID-19 pneumonia patients. In addition, human mononuclear cells (PBMCs) isolated from SARS-CoV-2 infected patients are significantly more prone to release pro-inflammatory cytokines upon stimuli. We demonstrated, using in vitro cell models, that macrophages are responsible for mediating the pro-inflammatory cytokine storm while lung cells support SARS-CoV-2 replication upon viral infection. In this context, cinnamaldehyde administration significantly reduces SARS-CoV-2-related inflammation by inhibiting NLRP3 mediated IL-1ß release in both PBMCs and THP-1 macrophages, as well as viral replication in CaLu-3 epithelial cells. Lastly, aerosol-administered cinnamaldehyde was able to significantly reduce IL-1ß release in an in vivo lung-inflammatory model. CONCLUSION: The obtained results suggest the possible use of cinnamaldehyde as a co-adjuvant preventive treatment for COVID-19 disease together with vaccination, but also as a promising dietary supplement to reduce, more broadly, viral induced inflammation.

The NLRP3 Inflammasome in Neurodegenerative Disorders: Insights from Epileptic Models.

Neuroinflammation represents a dynamic process of defense and protection against the harmful action of infectious agents or other detrimental stimuli in the central nervous system (CNS). However, the uncontrolled regulation of this physiological process is strongly associated with serious dysfunctional neuronal issues linked to the progression of CNS disorders. Moreover, it has been widely demonstrated that neuroinflammation is linked to epilepsy, one of the most prevalent and serious brain disorders worldwide. Indeed, NLRP3, one of the most well-studied inflammasomes, is involved in the generation of epileptic seizures, events that characterize this pathological condition. In this context, several pieces of evidence have shown that the NLRP3 inflammasome plays a central role in the pathophysiology of mesial temporal lobe epilepsy (mTLE). Based on an extensive review of the literature on the role of NLRP3-dependent inflammation in epilepsy, in this review we discuss our current understanding of the connection between NLRP3 inflammasome activation and progressive neurodegeneration in epilepsy. The goal of the review is to cover as many of the various known epilepsy models as possible, providing a broad overview of the current literature. Lastly, we also propose some of the present therapeutic strategies targeting NLRP3, aiming to provide potential insights for future studies.

The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches.

Calcific aortic valve stenosis (CAVS) is among the most common causes of cardiovascular mortality in an aging population worldwide. The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1α), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1α in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein, we identify the molecular mechanisms involved, showing that TRAP1 (1) binds both mitochondrial and cytosolic ribosomes, as well as translation elongation factors; (2) slows down translation elongation rate; and (3) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.

The Tricky Connection between Extracellular Vesicles and Mitochondria in Inflammatory-Related Diseases.

Mitochondria are organelles present in almost all eukaryotic cells, where they represent the main site of energy production. Mitochondria are involved in several important cell processes, such as calcium homeostasis, OXPHOS, autophagy, and apoptosis. Moreover, they play a pivotal role also in inflammation through the inter-organelle and inter-cellular communications, mediated by the release of mitochondrial damage-associated molecular patterns (mtDAMPs). It is currently well-documented that in addition to traditional endocrine and paracrine communication, the cells converse via extracellular vesicles (EVs). These small membrane-bound particles are released from cells in the extracellular milieu under physio-pathological conditions. Importantly, EVs have gained much attention for their crucial role in inter-cellular communication, translating inflammatory signals into recipient cells. EVs cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Studies have shown that EVs may transport mitochondrial portions, proteins, and/or mtDAMPs to modulate the metabolic and inflammatory responses of recipient cells. Overall, the relationship between EVs and mitochondria in inflammation is an active area of research, although further studies are needed to fully understand the mechanisms involved and how they may be targeted for therapeutic purposes. Here, we have reported and discussed the latest studies focused on this fascinating and recent area of research, discussing of tricky connection between mitochondria and EVs in inflammatory-related diseases.

1,3,8-Triazaspiro[4.5]decane Derivatives Inhibit Permeability Transition Pores through a FO-ATP Synthase c Subunit Glu119-Independent Mechanism That Prevents Oligomycin A-Related Side Effects.

Permeability transition pore (PTP) molecular composition and activity modulation have been a matter of research for several years, especially due to their importance in ischemia reperfusion injury (IRI). Notably, c subunit of ATP synthase (Csub) has been identified as one of the PTP-forming proteins and as a target for cardioprotection. Oligomycin A is a well-known Csub interactor that has been chemically modified in-depth for proposed new pharmacological approaches against cardiac reperfusion injury. Indeed, by taking advantage of its scaffold and through focused chemical improvements, innovative Csub-dependent PTP inhibitors (1,3,8-Triazaspiro[4.5]decane) have been synthetized in the past. Interestingly, four critical amino acids have been found to be involved in Oligomycin A-Csub binding in yeast. However, their position on the human sequence is unknown, as is their function in PTP inhibition. The aims of this study are to (i) identify for the first time the topologically equivalent residues in the human Csub sequence; (ii) provide their in vitro validation in Oligomycin A-mediated PTP inhibition and (iii) understand their relevance in the binding of 1,3,8-Triazaspiro[4.5]decane small molecules, as Oligomycin A derivatives, in order to provide insights into Csub interactions. Notably, in this study we demonstrated that 1,3,8-Triazaspiro[4.5]decane derivatives inhibit permeability transition pores through a FO-ATP synthase c subunit Glu119-independent mechanism that prevents Oligomycin A-related side effects.

Novel Aryl Sulfonamide Derivatives as NLRP3 Inflammasome Inhibitors for the Potential Treatment of Cancer.

The NLRP3 inflammasome is a critical component of innate immunity that senses diverse pathogen- and host-derived molecules. However, its aberrant activation has been associated with the pathogenesis of multiple diseases, including cancer. In this study, we designed and synthesized a series of aryl sulfonamide derivatives (ASDs) to inhibit the NLRP3 inflammasome. Among these, compounds 6c, 7n, and 10 specifically inhibited NLRP3 activation at nanomolar concentrations without affecting the activation of the NLRC4 and AIM2 inflammasomes. Furthermore, we demonstrated that these compounds reduce interleukin-1ß (IL-1ß) production in vivo and attenuate melanoma tumor growth. Moreover, metabolic stability in liver microsomes of 6c, 7n, and 10 was studied along with plasma exposure in mice of the most interesting compound 6c. Therefore, we generated potent NLRP3 inflammasome inhibitors, which can be considered in future medicinal chemistry and pharmacological studies aimed at developing a new therapeutic approach for NLRP3 inflammasome-driven cancer.

Evaluation of the Synovial Effects of Biological and Targeted Synthetic DMARDs in Patients with Psoriatic Arthritis: A Systematic Literature Review and Meta-Analysis.

The aims of this systematic literature review (SLR) were to identify the effects of approved biological and targeted synthetic disease modifying antirheumatic drugs (b/tsDMARDs) on synovial membrane of psoriatic arthritis (PsA) patients, and to determine the existence of histological/molecular biomarkers of response to therapy. A search was conducted on MEDLINE, Embase, Scopus, and Cochrane Library (PROSPERO:CRD42022304986) to retrieve data on longitudinal change of biomarkers in paired synovial biopsies and in vitro studies. A meta-analysis was conducted by adopting the standardized mean difference (SMD) as a measure of the effect. Twenty-two studies were included (19 longitudinal, 3 in vitro). In longitudinal studies, TNF inhibitors were the most used drugs, while, for in vitro studies, JAK inhibitors or adalimumab/secukinumab were assessed. The main technique used was immunohistochemistry (longitudinal studies). The meta-analysis showed a significant reduction in both CD3+ lymphocytes (SMD -0.85 [95% CI -1.23; -0.47]) and CD68+ macrophages (sublining, sl) (SMD -0.74 [-1.16; -0.32]) in synovial biopsies from patients treated for 4-12 weeks with bDMARDs. Reduction in CD3+ mostly correlated with clinical response. Despite heterogeneity among the biomarkers evaluated, the reduction in CD3+/CD68+sl cells during the first 3 months of treatment with TNF inhibitors represents the most consistent variation reported in the literature.

Comprehensive Analysis of Mitochondrial Dynamics Alterations in Heart Diseases.

The most common alterations affecting mitochondria, and associated with cardiac pathological conditions, implicate a long list of defects. They include impairments of the mitochondrial electron transport chain activity, which is a crucial element for energy formation, and that determines the depletion of ATP generation and supply to metabolic switches, enhanced ROS generation, inflammation, as well as the dysregulation of the intracellular calcium homeostasis. All these signatures significantly concur in the impairment of cardiac electrical characteristics, loss of myocyte contractility and cardiomyocyte damage found in cardiac diseases. Mitochondrial dynamics, one of the quality control mechanisms at the basis of mitochondrial fitness, also result in being dysregulated, but the use of this knowledge for translational and therapeutic purposes is still in its infancy. In this review we tried to understand why this is, by summarizing methods, current opinions and molecular details underlying mitochondrial dynamics in cardiac diseases.

Palmitoylation and PDE6δ regulate membrane-compartment-specific substrate ubiquitylation and degradation.

Substrate degradation by the ubiquitin proteasome system (UPS) in specific membrane compartments remains elusive. Here, we show that the interplay of two lipid modifications and PDE6δ regulates compartmental substrate targeting via the SCFFBXL2. FBXL2 is palmitoylated in a prenylation-dependent manner on cysteines 417 and 419 juxtaposed to the CaaX motif. Palmitoylation/depalmitoylation regulates its subcellular trafficking for substrate engagement and degradation. To control its subcellular distribution, lipid-modified FBXL2 interacts with PDE6δ. Perturbing the equilibrium between FBXL2 and PDE6δ disrupts the delivery of FBXL2 to all membrane compartments, whereas depalmitoylated FBXL2 is enriched on the endoplasmic reticulum (ER). Depalmitoylated FBXL2(C417S/C419S) promotes the degradation of IP3R3 at the ER, inhibits IP3R3-dependent mitochondrial calcium overload, and counteracts calcium-dependent cell death upon oxidative stress. In contrast, disrupting the PDE6δ-FBXL2 equilibrium has the opposite effect. These findings describe a mechanism underlying spatially-restricted substrate degradation and suggest that inhibition of FBXL2 palmitoylation and/or binding to PDE6δ may offer therapeutic benefits.

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein we identify the molecular mechanisms involved, demonstrating that TRAP1: i) binds both mitochondrial and cytosolic ribosomes as well as translation elongation factors, ii) slows down translation elongation rate, and iii) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.

Calcium Homeostasis in the Control of Mitophagy.

Significance: Maintenance of mitochondrial quality is essential for cellular homeostasis. Among processes responsible for preserving healthy mitochondria, mitophagy selectively eliminates dysfunctional mitochondria by targeting them to the autophagosome for degradation. Alterations in mitophagy lead to the accumulation of damaged mitochondria, which plays an essential role in several diseases such as carcinogenesis and tumor progression, neurodegenerative disorders, and autoimmune and cardiovascular pathologies. Recent Advances: Calcium (Ca2+) plays a fundamental role in cell life, modulating several pathways, such as gene expression, proliferation, differentiation, metabolism, cell death, and survival. Indeed, because it is involved in all these events, Ca2+ is the most versatile intracellular second messenger. Being a process that limits cellular degeneration, mitophagy participates in cellular fate decisions. Several mitochondrial parameters, such as membrane potential, structure, and reactive oxygen species, can trigger the activation of mitophagic machinery. These parameters regulate not only mitophagy but also the mitochondrial Ca2+ uptake. Critical Issues: Ca2+ handling is fundamental in regulating ATP production by mitochondria and mitochondrial quality control processes. Despite the growing literature about the link between Ca2+ and mitophagy, the mechanism by which Ca2+ homeostasis regulates mitophagy is still debated. Future Directions: Several studies have revealed that excessive mitophagy together with altered mitochondrial Ca2+ uptake leads to different dysfunctions in numerous diseases. Thus, therapeutic modulation of these pathways is considered a promising treatment. Antioxid. Redox Signal. 38, 581-598.

Cancer-Related Increases and Decreases in Calcium Signaling at the Endoplasmic Reticulum-Mitochondria Interface (MAMs).

Endoplasmic reticulum (ER)-mitochondria regions are specialized subdomains called also mitochondria-associated membranes (MAMs). MAMs allow regulation of lipid synthesis and represent hubs for ion and metabolite signaling. As these two organelles can module both the amplitude and the spatiotemporal patterns of calcium (Ca2+) signals, this particular interaction controls several Ca2+-dependent pathways well known for their contribution to tumorigenesis, such as metabolism, survival, sensitivity to cell death, and metastasis. Mitochondria-mediated apoptosis arises from mitochondrial Ca2+ overload, permeabilization of the mitochondrial outer membrane, and the release of mitochondrial apoptotic factors into the cytosol. Decreases in Ca2+ signaling at the ER-mitochondria interface are being studied in depth as failure of apoptotic-dependent cell death is one of the predominant characteristics of cancer cells. However, some recent papers that linked MAMs Ca2+ crosstalk-related upregulation to tumor onset and progression have aroused the interest of the scientific community.In this review, we will describe how different MAMs-localized proteins modulate the effectiveness of Ca2+-dependent apoptotic stimuli by causing both increases and decreases in the ER-mitochondria interplay and, specifically, by modulating Ca2+ signaling.

The inhibition of MDM2 slows cell proliferation and activates apoptosis in ADPKD cell lines.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is characterised by progressive cysts formation and renal enlargement that in most of cases leads to end stage of renal disease (ESRD). This pathology is caused by mutations of either PKD1 or PKD2 genes that encode for polycystin-1 (PC1) and polycystin-2 (PC2), respectively. These proteins function as receptor-channel complex able to regulate calcium homeostasis. PKD1/2 loss of function impairs different signalling pathways including cAMP and mTOR that are considered therapeutic targets for this disease. In fact, Tolvaptan, a vasopressin-2 antagonist that reduces cAMP levels, is the only drug approved for ADPKD treatment. Nevertheless, some ADPKD patients developed side effects in response to Tolvaptan including liver damage. Conversely, mTOR inhibitors that induced disease regression in ADPKD animal models failed the clinical trials. RESULTS: Here, we show that the inhibition of mTOR causes the activation of autophagy in ADPKD cells that could reduce therapy effectiveness by drug degradation through the autophagic vesicles. Consistently, the combined treatment with rapamycin and chloroquine, an autophagy inhibitor, potentiates the decrease of cell proliferation induced by rapamycin. To overcome the dangerous activation of autophagy by mTOR inhibition, we targeted MDM2 (a downstream effector of mTOR signalling) that is involved in TP53 degradation by using RG7112, a small-molecule MDM2 inhibitor used for the treatment of haematologic malignancies. The inhibition of MDM2 by RG7112 prevents TP53 degradation and increases p21 expression leading to the decrease of cell proliferation and the activation of apoptosis. CONCLUSION: The targeting of MDM2 by RG7112 might represent a new therapeutic option for the treatment of ADPKD.

PML at mitochondria-associated membranes governs a trimeric complex with NLRP3 and P2X7R that modulates the tumor immune microenvironment.

Uncontrolled inflammatory response arising from the tumor microenvironment (TME) significantly contributes to cancer progression, prompting an investigation and careful evaluation of counter-regulatory mechanisms. We identified a trimeric complex at the mitochondria-associated membranes (MAMs), in which the purinergic P2X7 receptor - NLRP3 inflammasome liaison is fine-tuned by the tumor suppressor PML. PML downregulation drives an exacerbated immune response due to a loss of P2X7R-NLRP3 restraint that boosts tumor growth. PML mislocalization from MAMs elicits an uncontrolled NLRP3 activation, and consequent cytokines blast fueling cancer and worsening the tumor prognosis in different human cancers. New mechanistic insights are provided for the PML-P2X7R-NLRP3 axis to govern the TME in human carcinogenesis, fostering new targeted therapeutic approaches.

Perspectives on mitochondrial relevance in cardiac ischemia/reperfusion injury.

Cardiovascular disease is the most common cause of death worldwide and in particular, ischemic heart disease holds the most considerable position. Even if it has been deeply studied, myocardial ischemia-reperfusion injury (IRI) is still a side-effect of the clinical treatment for several heart diseases: ischemia process itself leads to temporary damage to heart tissue and obviously the recovery of blood flow is promptly required even if it worsens the ischemic injury. There is no doubt that mitochondria play a key role in pathogenesis of IRI: dysfunctions of these important organelles alter cell homeostasis and survival. It has been demonstrated that during IRI the system of mitochondrial quality control undergoes alterations with the disruption of the complex balance between the processes of mitochondrial fusion, fission, biogenesis and mitophagy. The fundamental role of mitochondria is carried out thanks to the finely regulated connection to other organelles such as plasma membrane, endoplasmic reticulum and nucleus, therefore impairments of these inter-organelle communications exacerbate IRI. This review pointed to enhance the importance of the mitochondrial network in the pathogenesis of IRI with the aim to focus on potential mitochondria-targeting therapies as new approach to control heart tissue damage after ischemia and reperfusion process.

SARS-CoV-2 Infection Prompts IL-1ß-Mediated Inflammation and Reduces IFN-λ Expression in Human Lung Tissue.

Two years after its spreading, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still responsible for more than 2000 deaths per day worldwide, despite vaccines and monoclonal antibody countermeasures. Therefore, there is a need to understand the immune-inflammatory pathways that prompt the manifestation of the disease to identify a novel potential target for pharmacological intervention. In this context, the characterization of the main players in the SARS-CoV-2-induced cytokine storm is mandatory. To date, the most characterized have been IL-6 and the class I and II interferons, while less is known about the proinflammatory cytokine IL-1ß and class III interferons. Here, we report a preliminary study aimed at the characterization of the lung inflammatory context in COVID-19 patients, with a special focus on IFN-λ and IL-1ß. By investigating IFN and inflammatory cytokine patterns by IHC in 10 deceased patients due to COVID-19 infection, compared to 10 control subjects, we reveal that while IFN-ß production was increased in COVID-19 patients, IFN-λ was almost abolished. At the same time, the levels of IL-1ß were dramatically improved, while IL-6 lung levels seem to be unaffected by the infection. Our findings highlight a central role of IL-1ß in prompting lung inflammation after SARS-CoV-2 infection. Together, we show that IFN-λ is negatively affected by viral infection, supporting the idea that IFN-λ administration together with the pharmaceutical blockage of IL-1ß represents a promising approach to revert the COVID-19-induced cytokine storm.