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.

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.

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.

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.

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.

An Updated Understanding of the Role of YAP in Driving Oncogenic Responses.

Yes-associated protein (YAP) has emerged as a key component in cancer signaling and is considered a potent oncogene. As such, nuclear YAP participates in complex and only partially understood molecular cascades that are responsible for the oncogenic response by regulating multiple processes, including cell transformation, tumor growth, migration, and metastasis, and by acting as an important mediator of immune and cancer cell interactions. YAP is finely regulated at multiple levels, and its localization in cells in terms of cytoplasm-nucleus shuttling (and vice versa) sheds light on interesting novel anticancer treatment opportunities and putative unconventional functions of the protein when retained in the cytosol. This review aims to summarize and present the state of the art knowledge about the role of YAP in cancer signaling, first focusing on how YAP differs from WW domain-containing transcription regulator 1 (WWTR1, also named as TAZ) and which upstream factors regulate it; then, this review focuses on the role of YAP in different cancer stages and in the crosstalk between immune and cancer cells as well as growing translational strategies derived from its inhibitory and synergistic effects with existing chemo-, immuno- and radiotherapies.

Targeting the NLRP3 Inflammasome as a New Therapeutic Option for Overcoming Cancer.

Inflammasomes are multiprotein complexes that regulate the maturation and secretion of the proinflammatory cytokines interleukin-1beta (IL-1ß and interleukin-18 (IL-18) in response to various intracellular stimuli. As a member of the inflammasomes family, NLRP3 is the most studied and best characterized inflammasome and has been shown to be involved in several pathologies. Recent findings have made it increasingly apparent that the NLRP3 inflammasome may also play a central role in tumorigenesis, and it has attracted attention as a potential anticancer therapy target. In this review, we discuss the role of NLRP3 in the development and progression of cancer, offering a detailed summary of NLRP3 inflammasome activation (and inhibition) in the pathogenesis of various forms of cancer. Moreover, we focus on the therapeutic potential of targeting NLRP3 for cancer therapy, emphasizing how understanding NLRP3 inflammasome-dependent cancer mechanisms might guide the development of new drugs that target the inflammatory response of tumor-associated cells.

From Bed to Bench and Back: TNF-α, IL-23/IL-17A, and JAK-Dependent Inflammation in the Pathogenesis of Psoriatic Synovitis.

Psoriatic arthritis (PsA) is a chronic inflammatory immune-mediated disease with a burdensome impact on quality of life and substantial healthcare costs. To date, pharmacological interventions with different mechanisms of action, including conventional synthetic (cs), biological (b), and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs), have been proven efficacious, despite a relevant proportion of failures. The current approach in clinical practice and research is typically "predictive": the expected response is based on stratification according to clinical, imaging, and laboratory data, with a "heuristic" approach based on "trial and error". Several available therapeutic options target the TNF-α pathway, while others are directed against the IL-23/IL-17A axis. Janus kinase inhibitors (JAKis), instead, simultaneously block different pathways, endowing these drugs with a potentially "broad-spectrum" mechanism of action. It is not clear, however, whether targeting a specific pathway (e.g., TNF-α or the IL-23/IL-17 axis) could result in discordant effects over other approaches. In particular, in the case of "refractory to a treatment" patients, other pathways might be hyperactivated, with opposing, synergistic, or redundant biological significance. On the contrary, refractory states could be purely resistant to treatment as a whole. Since chronic synovitis is one of the primary targets of inflammation in PsA, synovial biomarkers could be useful in depicting specific biological characteristics of the inflammatory burden at the single-patient level, and despite not yet being implemented in clinical practice, these biomarkers might help in selecting the proper treatment. In this narrative review, we will provide an up-to-date overview of the knowledge in the field of psoriatic synovitis regarding studies investigating the relationships among different activated proinflammatory processes suitable for targeting by different available drugs. The final objective is to clarify the state of the art in the field of personalized medicine for psoriatic disease, aiming at moving beyond the current treatment schedules toward a patient-centered approach.