Synthesis and NLRP3-Inflammasome Inhibitory Activity of the Naturally Occurring Velutone F and of Its Non-Natural Regioisomeric Chalconoids

Plant-derived remedies rich in chalcone-based compounds have been known for centuries in the treatment of specific diseases, and nowadays, the fascinating chalcone framework is considered a useful and, above all, abundant natural chemotype. Velutone F, a new chalconoid from Millettia velutina, exhibits a potent effect as an NLRP3-inflammasome inhibitor; the search for new natural/non-natural lead compounds as NLRP3 inhibitors is a current topical subject in medicinal chemistry. The details of our work toward the synthesis of velutone F and the unknown non-natural regioisomers are herein reported. We used different synthetic strategies both for the construction of the distinctive benzofuran nucleus (BF) and for the key phenylpropenone system (PhP). Importantly, we have disclosed a facile entry to the velutone F via synthetic routes that can also be useful for preparing non-natural analogs, a prerequisite for extensive SAR studies on the new flavonoid class of NLRP3-inhibitors

Inflammatory Microenvironment in Early Non-Small Cell Lung Cancer: Exploring the Predictive Value of Radiomics

Patient prognosis is a critical consideration in the treatment decision-making process. Conventionally, patient outcome is related to tumor characteristics, the cancer spread, and the patients’ conditions. However, unexplained differences in survival time are often observed, even among patients with similar clinical and molecular tumor traits. This study investigated how inflammatory radiomic features can correlate with evidence-based biological analyses to provide translated value in assessing clinical outcomes in patients with NSCLC. We analyzed a group of 15 patients with stage I NSCLC who showed extremely different OS outcomes despite apparently harboring the same tumor characteristics. We thus analyzed the inflammatory levels in their tumor microenvironment (TME) either biologically or radiologically, focusing our attention on the NLRP3 cancer-dependent inflammasome pathway. We determined an NLRP3-dependent peritumoral inflammatory status correlated with the outcome of NSCLC patients, with markedly increased OS in those patients with a low rate of NLRP3 activation. We consistently extracted specific radiomic signatures that perfectly discriminated patients’ inflammatory levels and, therefore, their clinical outcomes. We developed and validated a radiomic model unleashing quantitative inflammatory features from CT images with an excellent performance to predict the evolution pattern of NSCLC tumors for a personalized and accelerated patient management in a non-invasive way

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

Increase of Parkin and ATG5 plasmatic levels following perinatal hypoxic‐ischemic encephalopathy

Brain injury at birth is an important cause of neurological and behavioral disorders. Hypoxic‐ischemic encephalopathy (HIE) is a critical cerebral event occurring acutely or chronically at birth with high mortality and morbidity in newborns. Therapeutic strategies for the prevention of brain damage are still unknown, and the only medical intervention for newborns with moderate‐to‐severe HIE is therapeutic hypothermia (TH). Although the neurological outcome depends on the severity of the initial insult, emerging evidence suggests that infants with mild HIE who are not treated with TH have an increased risk for neurodevelopmental impairment; in the current clinical setting, there are no specific or validated biomarkers that can be used to both correlate the severity of the hypoxic insult at birth and monitor the trend in the insult over time. The aim of this work was to examine the presence of autophagic and mitophagic proteins in bodily fluids, to increase knowledge of what, early at birth, can inform therapeutic strategies in the first hours of life. This is a prospective multicentric study carried out from April 2019 to April 2020 in eight third‐level neonatal intensive care units. All participants have been subjected to the plasma levels quantification of both Parkin (a protein involved in mitophagy) and ATG5 (involved in autophagy). These findings show that Parkin and ATG5 levels are related to hypoxic‐ischemic insult and are reliable also at birth. These observations suggest a great potential diagnostic value for Parkin evaluation in the first 6 h of life

Practice patterns and 90-day treatment-related morbidity in early-stage cervical cancer

To evaluate the impact of the Laparoscopic Approach to Cervical Cancer (LACC) Trial on patterns of care and surgery-related morbidity in early-stage cervical cancer

The Role of Mitochondria in Inflammation: From Cancer to Neurodegenerative Disorders

The main features that are commonly attributed to mitochondria consist of the regulation of cell proliferation, ATP generation, cell death and metabolism. However, recent scientific advances reveal that the intrinsic dynamicity of the mitochondrial compartment also plays a central role in proinflammatory signaling, identifying these organelles as a central platform for the control of innate immunity and the inflammatory response. Thus, mitochondrial dysfunctions have been related to severe chronic inflammatory disorders. Strategies aimed at reestablishing normal mitochondrial physiology could represent both preventive and therapeutic interventions for various pathologies related to exacerbated inflammation. Here, we explore the current understanding of the intricate interplay between mitochondria and the innate immune response in specific inflammatory diseases, such as neurological disorders and cancer

Mitochondria-associated membranes (MAMs) and inflammation

The endoplasmic reticulum (ER) and mitochondria are tightly associated with very dynamic platforms termed mitochondria-associated membranes (MAMs). MAMs provide an excellent scaffold for crosstalk between the ER and mitochondria and play a pivotal role in different signaling pathways that allow rapid exchange of biological molecules to maintain cellular health. However, dysfunctions in the ER-mitochondria architecture are associated with pathological conditions and human diseases. Inflammation has emerged as one of the various pathways that MAMs control. Inflammasome components and other inflammatory factors promote the release of pro-inflammatory cytokines that sustain pathological conditions. In this review, we summarize the critical role of MAMs in initiating inflammation in the cellular defense against pathogenic infections and the association of MAMs with inflammation-mediated diseases

Mitochondrial Control of Genomic Instability in Cancer

Mitochondria are well known to participate in multiple aspects of tumor formation and progression. They indeed can alter the susceptibility of cells to engage regulated cell death, regulate pro-survival signal transduction pathways and confer metabolic plasticity that adapts to specific tumor cell demands. Interestingly, a relatively poorly explored aspect of mitochondria in neoplastic disease is their contribution to the characteristic genomic instability that underlies the evolution of the disease. In this review, we summarize the known mechanisms by which mitochondrial alterations in cancer tolerate and support the accumulation of DNA mutations which leads to genomic instability. We describe recent studies elucidating mitochondrial responses to DNA damage as well as the direct contribution of mitochondria to favor the accumulation of DNA alterations

Functions and dys-functions of promyelocytic leukemia protein PML

The promyelocytic leukemia protein PML has been previously recognized as a critical and essential regulator of a broad number of cellular functions. At nuclear level PML forms the PML-nuclear bodies, where it can sequester and influence the post-translational modification of a wide number of proteins, ultimately affecting their regulative role in DNA transcription. In such a way, PML acts as a key player in strategic cellular activities like as the antiviral defense, in the regulation of the cell cycle, in senescence and programmed cell death. In addition, PML can redistribute also at cytoplasmic level, where it associates to the endoplasmic reticulum or is recruited to mitochondrial-associated membranes. Here it can interact with key cellular proteins like as p53 and influence cell metabolism, mitochondrial calcium upload and autophagy. Altogether, all these findings depict PML as a protein able to exert a widespread action mainly focused on pro-apoptotic and cytostatic activities. Anyway, presence of “Janus-like” pro-tumoral behaviors have been reported, prompting for further investigation to better dissect and highlight all the possible roles that PML can assume in the different physiological or pathological environments. In this review, we discuss the role of PML in multiple cellular functions and pathologic scenarios and summarize the players that control PML protein both at nuclear and at cytoplasmic level

Calcium homeostasis in the control of mitophagy

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 like carcinogenesis and tumor progression, neurodegenerative disorders, and autoimmune and cardiovascular pathologies