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Origanum vulgare L. is an important aromatic plant traditionally used in folk medicine since ancient times. Its growing interest for the scientific community is mainly attributed to its distinctive chemical profile, which includes bioactive compounds, such as polyphenols (phenolic acids and flavonoids) and volatile compounds (essential oil). These components collectively contribute to oregano’s wide spectrum of biological activities. In this study, the volatile components of the essential oil (WEO_OR) and the polyphenolic fraction of the methanolic extract (ME_OR) obtained from leaves and inflorescences of wild Origanum vulgare collected in central Italy were characterized using GC-MS and UHPLC-DAD, respectively. Carvacrol was identified as the major compound in the essential oil, while rosmarinic acid was predominant in the methanolic extract. A comparative analysis was also carried out with a commercially available essential oil (CEO_OR), aiming to evaluate potential differences in chemical composition and antioxidant activity (DPPH, ABTS, and FRAP assays). ME_OR showed the strongest antioxidant activity (DPPH IC50 = 0.052 mg mL−1; ABTS = 3.94 mg TE mL−1; FRAP = 30.58 mg TE g−1), followed by CEO_OR (DPPH IC50 = 0.45 mg mL−1; ABTS = 9.57 mg TE mL−1; FRAP = 7.33 mg TE g−1), while WEO_OR displayed the lowest values (DPPH IC50 = 1.54 mg mL−1; ABTS = 0.10 mg TE mL−1). Furthermore, ME_OR and WEO_OR were tested in vitro using the human hepatoblastoma cell line HepG2 to assess their potential biological activities related to cell survival and oxidative stress. The results indicated that at the tested doses, neither the ME nor the EO showed significant toxicity, as evidenced by the unchanged proliferation rate of HepG2 cells. However, the ME at low doses (50 and 100 μg mL−1) and the EO (0.005%), administered as a pre-treatment, exhibited a protective effect against oxidative stress, as inferred from the reduction in 8-OHdG levels, a marker of oxidative damage to nucleic acids.

In Kenya, the return to the multiparty democracy of the 1990s and the initiation of the Constitutional Review of the early 2000s were two critical junctures that catalysed reform momentum and the development of transnational reform networks. Transnational relations were developed between Kenyan professionals (lawyers and academics among others), their international counterparts, and the local activists representing rural constituencies, so as to influence policymaking during constitutional and land policy reforms. These transnational networks influenced content and shape of land policy narratives by vernacularising the international norms that promote formal recognition of customary land rights. These international norms were not straightforwardly imported into Kenyan policies and statues: intense negotiations amongst actors in policy arenas resulted in their vernacularisation. Kenyan translocal actors appropriated the community land narrative, hybridised and reinterpreted it. This paper documents and analyses how the notion of community land was enshrined in Kenyan policy and constitutional documents through transnational relations. I argue that this notion of community land was shaped to the Kenyan historical and political context, at times defeating the original goal of promoting a property rights model alternative to land privatisation, and at times echoing the colonial category of tribal land, and exclusive territorial control.

: Cathepsins, lysosomal proteases crucial for neuronal proteostasis, mediate the clearance of misfolded and aggregated proteins. Their dysregulation is implicated in neurodegenerative and neuropsychiatric disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. These conditions are characterized by toxic protein accumulation and impaired clearance, which exacerbate cellular stress responses, including the unfolded protein response (UPR), oxidative damage, and mitochondrial dysfunction. This review aims to summarize current knowledge on cathepsin roles in these pathways and assess their therapeutic potential. : A comprehensive literature review was conducted, focusing on recent in vitro and in vivo studies investigating cathepsin function, inhibition, and modulation. Mechanistic insights and pharmacological approaches targeting cathepsins were analyzed, with attention to challenges in translating preclinical findings to clinical settings. : Cathepsins demonstrate a dual role: their proteolytic activity supports neuronal health by degrading toxic aggregates, but altered or insufficient activity may worsen proteotoxic stress. Studies reveal that cathepsins regulate autophagy, apoptosis, and neuroinflammation both intracellularly and extracellularly. Despite promising mechanistic data, clinical translation is hindered by issues such as poor inhibitor selectivity, limited brain penetration, and variability across preclinical models. : Targeting cathepsins presents a promising strategy for treating neurodegenerative and neuropsychiatric disorders, but significant challenges remain. Future research should focus on improving drug specificity and delivery, and on developing standardized models to better predict clinical outcomes.

The immunoproteasome (iCP) is an isoform of the 20S proteasome that is expressed in response to cellular stress or inflammatory stimuli. The primary role of the iCP is to hydrolyze proteins into peptides that can be loaded into the MHC-I complex. Beyond its primary role in the adaptive immune response, it is also involved in the pathogenic mechanism of numerous disease states such as inflammatory conditions and cancer. In the last decade, a huge number of immunoproteasome-specific inhibitors have been described, allowing researchers to elucidate the role of the immunoproteasome as a potential therapeutic target for these diseases. The present manuscript summarizes the latest advances regarding immunoproteasome inhibitors tested against different cancer models. Specifically, it will focus on peptide and non-peptide analogs that have been reported in the last five years, together with their structure–activity relationship (SAR) studies. It aims to provide structural insights into this class of compounds pertaining to their favorable applicability as selective iCP inhibitors in the treatment of cancer.

Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that promote proliferation, invasion, and metastasis. The CXCR4/CXCL12 signaling pathway is gaining attention as a promising target for cancer therapy. CXCR4, a chemokine receptor, is often overexpressed in various types of cancer, including kidney, lung, brain, prostate, breast, pancreas, ovarian, and melanomas. When it binds to its endogenous ligand, CXCL12, it promotes cell survival, proliferation, and migration, crucial mechanisms for the retention of hematopoietic stem cells in the bone marrow and the movement of lymphocytes. The extensive expression of CXCR4 in cancer, coupled with the constant presence of CXCL12 in various organs, drives the activation of this axis, which in turn facilitates angiogenesis, tumor progression, and metastasis. Given the detrimental role of the CXCR4/CXCL12 axis, the search for drugs acting selectively against this protein represents an open challenge. This review aims to summarize the recent advancements in the design and development of CXCR4 antagonists as potential anticancer agents.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic that broke out in 2020 and continues to be the cause of massive global upheaval. Coronaviruses are positive-strand RNA viruses with a genome of ~30 kb. The genome is replicated and transcribed by RNA-dependent RNA polymerase together with accessory factors. One of the latter is the protein helicase (NSP13), which is essential for viral replication. The recently solved helicase structure revealed a tertiary structure composed of five domains. Here, we investigated NSP13 from a structural point of view, comparing its RNA-free form with the RNA-engaged form by using atomistic molecular dynamics (MD) simulations at the microsecond timescale. Structural analyses revealed conformational changes that provide insights into the contribution of the different domains, identifying the residues responsible for domain–domain interactions in both observed forms. The RNA-free system appears to be more flexible than the RNA-engaged form. This result underlies the stabilizing role of the nucleic acid and the functional core role of these domains.

Potassium channels have recently emerged as suitable target for the treatment of epileptic diseases. Among potassium channels, KCNT1 channels are the most widely characterized as responsible for several epileptic and developmental encephalopathies. Nevertheless, the medicinal chemistry of KCNT1 blockers is underdeveloped so far. In the present review, we describe and analyse the papers addressing the issue of KCNT1 blockers’ development and identification, also evidencing the pros and the cons of the scientific approaches therein described. After a short introduction describing the epileptic diseases and the structure–function of potassium channels, we provide an extensive overview of the chemotypes described so far as KCNT1 blockers, and the scientific approaches used for their identification.

Bioactive compounds are abundant in animals originating from marine ecosystems. Ion channels, which include sodium, potassium, calcium, and chloride, together with their numerous variants and subtypes, are the primary molecular targets of the latter. Based on their cellular targets, these venom compounds show a range of potencies and selectivity and may have some therapeutic properties. Due to their potential as medications to treat a range of (human) diseases, including pain, autoimmune disorders, and neurological diseases, marine molecules have been the focus of several studies over the last ten years. The aim of this review is on the various facets of marine (or marine-derived) molecules, ranging from structural characterization and discovery to pharmacology, culminating in the development of some “novel” candidate chemotherapeutic drugs that target potassium channels.

Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 ( NPM1 ) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts. Relapse within acute myeloid leukaemia may be driven by the presence of leukaemia stem cells. Here, the authors use single cell RNA-seq seq to characterise leukemia stem cells, and show miR-126 as a potential marker of resistance.

In patients with severe mitral regurgitation (MR) referred for cardiac surgery, left atrial (LA) remodeling and enlargement are accompanied by mechanical stress, mediated cellular hypertrophy, and interstitial fibrosis that finally lead to LA failure. Speckle tracking echocardiography is a novel non–Doppler-based method that allows an objective quantification of LA myocardial deformation, becoming useful for LA functional analysis. We conducted a study to evaluate the relation between the traditional and novel atrial indexes and the extent of ultrastructural alterations, obtained from patients with severe MR who were undergoing surgical correction of the valvular disease. The study population included 46 patients with severe MR, referred to our echocardiographic laboratory for a diagnostic examination before cardiac surgery. The global peak atrial longitudinal strain (PALS) was measured in all subjects by averaging all atrial segments. LA tissue samples were obtained from all patients. Masson's trichrome staining was performed to assess the extent of the fibrosis. The LA endocardial thickness was measured. A close negative correlation between the global PALS and grade of LA myocardial fibrosis was found (r = −0.82, p <0.0001), with poorer correlations for the LA indexed volume (r = 0.51, p = 0.01), LA ejection fraction (r = 0.61, p = 0.005), and E/E′ ratio (0.14, p = NS). Of these indexes, global PALS showed the best diagnostic accuracy to detect LA fibrosis (area under the curve 0.89), and it appears to be a strong and independent predictor of LA fibrosis. Furthermore, we also demonstrated an inverse correlation between the global PALS and LA endocardial thickness (r = −0.66, p = 0.0001). In conclusion, in patients with severe MR referred for cardiac surgery, impairment of LA longitudinal deformation, as assessed by the global PALS, correlated strongly with the extent of LA fibrosis and remodeling.