BACKGROUND AND PURPOSE:Anthracycline-induced cardiotoxicity, particularly from doxorubicin, remains a major limitation in cancer therapy, contributing to heart failure and long-term morbidity. Prokineticin receptor-1 (PKR1), involved in cardiomyocyte survival and anti-fibrotic signalling, represents a promising therapeutic target. This study evaluated the cardioprotective potential of IS39, a novel non-peptide PKR1 agonist, in models of doxorubicin-induced cardiac injury. EXPERIMENTAL APPROACH:In silico ADME-toxicity profiling, scaffold optimisation and molecular docking were used to refine non-peptide PKR1 agonists, replacing the dehydroamide moiety of first-generation compounds with a D-aminoacyl group to enhance metabolic stability. The lead compound IS39 was evaluated in vitro in primary cardiomyocytes and in vivo in a murine model of doxorubicin-induced cardiotoxicity. Parallel studies assessed potential interference with doxorubicin antitumour activity in breast cancer cell lines and 3D tumour spheroids. Endpoints included cardiomyocyte viability, oxidative stress, fibrotic markers, cardiac function, histopathology and systemic tolerability. KEY RESULTS:IS39 selectively activated PKR1, reduced reactive oxygen species, suppressed profibrotic gene expression and protected cardiomyocytes from doxorubicin-induced cytotoxicity in vitro. These effects were abolished by PKR1 knockdown or antagonism, confirming on-target activity, and IS39 did not impair doxorubicin antitumour efficacy. In vivo, IS39 preserved left ventricular ejection fraction, attenuated myocardial fibrosis and apoptosis, and improved cardiac morphology. However, systemic IS39 administration exacerbated doxorubicin-associated weight loss and did not improve overall survival. CONCLUSIONS AND IMPLICATIONS:IS39 confers cardioprotection via PKR1-mediated antioxidant and antifibrotic mechanisms. Despite systemic tolerability limitations, these findings support PKR1 as a therapeutic target and justify development of tissue-selective PKR1 agonists for cardio-oncology applications.

Breast cancer continues to be the most common malignancy in women and a major contributor of cancer-related mortality, emphasizing the need for novel therapeutic agents. A novel series of thienopyrimidine analogues were designed as dual Aurora B and VEGFR-2 inhibitors. Among them, compound M1 showed the highest potency, displaying strong cytotoxicity against breast MCF-7 (IC50 = 3.61 µM) and MDA-MB-231 (IC50 = 5.37 µM) cells, comparable to Doxorubicin and superior to Sorafenib. The in vitro enzyme inhibition assays revealed that M1 inhibited Aurora B and VEGFR-2 with IC50 values of 0.037 and 0.220 µM, respectively. In MDA-MB-231 cells, M1 induced G1-phase arrest and enhanced apoptosis, reducing viable cells to 54.6% and increasing total apoptotic cells to 21.3%. In vivo, M1 reduced tumor volume by 58.6% in a DMBA-induced breast cancer model, comparable to Doxorubicin (64.8%) but with lower systemic toxicity. Histopathology and caspase-3 staining confirmed reduced malignancy and restored apoptotic activity. Molecular docking and dynamics suggested stable binding of M1 within Aurora B and VEGFR-2 active sites.

Dual inhibition by a single small molecule has emerged as a promising paradigm in anticancer therapy. Carbonic anhydrase isoforms IX/XII (CA IX/XII) and vascular endothelial growth factor (VEGF) are hypoxia-responsive enzymes that drive tumorigenesis and progression in hypoxic tumors through distinct mechanisms. In this study, we rationally designed and synthesized two series of 2-thioquinazolin-4-one-tethered benzenesulfonamides 7a-e, 10a-e as novel CA IX/XII and VEGFR-2 inhibitors. Lead compounds 10c and 10e exhibited potent multitarget inhibition, with IC50 values of 0.145 and 0.069 μM (VEGFR-2), 0.168 and 0.077 μM (CA IX), 0.154 and 0.205 μM (CA XII), which were comparable to those of sorafenib and acetazolamide standards. These agents demonstrated broad-spectrum cytotoxicity against HeLa, HepG2, HCT-116, and MCF-7 cell lines (IC50 = 11.57–21.43 μM for 10c; 7.81–19.50 μM for 10e). Mechanistic studies confirmed the induction of G2/M arrest by 10e, triggering 47.25

Cytotoxic anthraquinones are natural products that modulate apoptosis and oncogenic signaling pathways. In this study, three fungal anthraquinones citreorosein (1), skyrin (2), and rugulosin A (3) were investigated for cytotoxic, antiproliferative, and pro-apoptotic effects using in vitro assays. Rugulosin A (3) exhibited cytotoxic activity against six tumorigenic cell lines (IC50 = 0.138-1.475 μM). Although less potent than the nanomolar-range reference drug Epothilone B (IC50 < 0.1 μM), rugulosin A showed submicromolar-to-low micromolar efficacy with notable selectivity toward cancer cells, which is considered significant for an unoptimized natural product scaffold. Its antiproliferative activity against K562 cells (GI50 = 3.69 μM), benchmarked against Imatinib (GI50 = 0.373 μM), also falls within the active range of natural product leads. Caspase-Glo 3/7 and CellEvent assays demonstrated concentration-dependent apoptosis induction by 3 (p < 0.05), supported by Western blot detection of cleaved PARP-1 and caspase-3. Network pharmacology analysis identified ten potential gene targets enriched in oncogenic pathways, with AKT1, PIK3CA, and MAPK14 p38α emerging as putative key regulators. Molecular docking revealed strong binding energies (-10.1, -9.8, and -11.0 kcal/mol), along with a stable molecular dynamics simulations data. These findings highlight rugulosin A (3) as a promising anticancer lead that modulates major apoptosis signaling pathways.

The development of dual-directed anticancer agents has emerged as an effective strategy to simultaneously modulate tumor proliferation and angiogenesis while overcoming resistance associated with single-target therapies. In the present study, a novel series of benzofuran-based aryl urea derivatives incorporating a 1,3,4-thiadiazole linker were designed as dual VEGFR-2/BRAFWT inhibitors using sorafenib as a pharmacophoric template. The in vitro cytotoxic activity of the synthesized compounds against cervix HeLa, prostate PC-3, colon HCT-116, and breast MCF-7 cancer cell lines was evaluated. Most derivatives showed variable activity, with 5-bromobenzofuran analogues displaying superior potency. Compound 7j emerged as the most active analogue, with IC50 values of 7.83-13.27 μM and reduced toxicity toward normal lung fibroblast WI-38 cells. Enzymatic assays revealed potent dual inhibition of VEGFR-2 and BRAFWT by 7j (IC50 = 0.044 and 0.071 μM, respectively), outperforming sorafenib and vemurafenib. Mechanistic studies showed that 7j induced G2/M cell cycle arrest and promoted apoptosis in HeLa cells. This effect was associated with upregulation of BAX, p53, and caspase-9, downregulation of Bcl-2, and activation of the intrinsic apoptotic pathway. Additionally, in silico studies including molecular docking and molecular dynamics simulations demonstrated stable ligand-target interactions and favorable binding modes of 7j across both VEGFR-2 and BRAF, supporting the proposed hybrid design strategy. Overall, compound 7j represents a promising dual VEGFR-2/BRAFWT inhibitor and highlights benzofuran-based scaffolds as valuable platforms for anticancer drug development.

IntroductionChronic hormonal imbalances and associated symptoms characterize ovarian cancer. PARP-1 inhibitors, such as olaparib and ruparib, are used to treat it, but new drugs are needed to overcome toxicity and resistance issues. PARP inhibition in BRCA1/2-mutated cancer cells leads to apoptosis.MethodsWe synthesized silver nanoparticles (AgNPs) from S. bryopteris leaf extract, using it as a stabilizing and reducing agent. The extract was added to the AgNO3 solution and maintained at room temperature for 24 h. The AgNPs were characterized using various techniques, including UV-visible and FTIR spectroscopy, SEM, EDX, Transmission Electron Microscopy, and ICP-MS analysis. The stability of AgNPs was evaluated under different pH and temperature conditions, and their anticancer activity was evaluated against SKOV3 and OVCAR-3 ovarian cancer cells using MTT assay, while IOSE80 cells were used as a non-tumorigenic ovarian epithelial cell model. The binding mechanism of phytochemicals from Selaginella bryopteris to PARP-1 was investigated using computational methods.ResultsSelaginella bryopteris-derived AgNPs showed stronger cytotoxicity than the plant extract against SKOV3 and OVCAR-3 ovarian cancer cells, with IC50 values of 9.56 and 10.45 μg/mL, respectively, and lower toxicity toward IOSE80 cells (IC50 = 19.75 μg/mL). AgNP treatment increased intracellular Reactive Oxygen Species levels, suggesting oxidative-stress-mediated cell death, while in silico analyses highlighted rhamnetin as a promising PARP-1-interacting phytoconstituent.DiscussionThe anticancer properties of AgNPs from S. bryopteris were investigated using analytical, pharmacological, and computational methods. Results showed the stability of AgNPs and their effectiveness against ovarian cancer cells. AgNPs from the S. bryopteris leaf extract showed stronger anticancer activity than the plant extract alone, whereas their possible use as targeted drug delivery or controlled-release platforms remains a future perspective requiring dedicated experimental investigation.

Class I histone deacetylases (HDACs) are frequently overexpressed in colorectal cancer (CRC). Combining computational, synthetic, and biological efforts, we developed novel o-aminobenzamide-based HDAC inhibitors (HDACis) optimized for class I enzyme-specific targeting. Compounds 5d and 5i emerged as lead candidates, showing strong antiproliferative effects in CRC cells with low toxicity in healthy colon epithelium. Both compounds disrupted the G2/M checkpoint through distinct mechanisms. 5i, although less potent (HDAC1 IC50 = 1508 nM), retained selectivity, upregulated p21, and triggered pronounced apoptosis. 5d (Colrestat), one of the most selective class I HDACis to date (HDAC1 IC50 = 41.2 nM, HDAC2 IC50 = 52.5 nM, and HDAC3 IC50 = 74.3 nM), induced H3K9 acetylation, p21 upregulation, and G2/M arrest. The short-term in vitro effects of 5d were modulated by a compensatory upregulation of autophagy. However, in long-term, this protective mechanism becomes insufficient to sustain tumor survival, resulting in strong antitumor efficacy in vivo in the CAM assay for both compounds even outperforming entinostat.

Simultaneous targeting of multiple pathogenic pathways implicated in hyperglycemia and diabetic complications represents a promising therapeutic strategy for managing diabetes mellitus. Herein, we report the design, synthesis, and biological evaluation of a novel series of thiazolidinedione-triazole hybrid derivatives 9a–o as multi-target antidiabetic agents. The target compounds were synthesized through a convergent N-alkylation of 5-arylidene-thiazolidine-2,4-dione potassium salts with α-bromo ketone intermediates bearing a 1,2,3-triazole motif, and their structures were confirmed by ¹H NMR, ¹³C NMR, and elemental analysis. In vitro evaluation revealed potent dual inhibitory activity against α-amylase (α-AMY) and aldose reductase (AR) for several derivatives. Compound 9a emerged as the most promising candidate, with AR inhibition (IC₅₀ = 0.074 µM) surpassing epalrestat (IC₅₀ = 0.107 µM) and α-AMY inhibition (IC₅₀ = 14.57 µM) exceeding acarbose (IC₅₀ = 18.24 µM). Similarly, compound 9j demonstrated exceptional dual potency (AR IC₅₀ = 0.092 µM; α-AMY IC₅₀ = 19.36 µM). DPPH radical scavenging assessment further revealed significant antioxidant activity for the lead compounds, with 9a (IC₅₀ = 42.28 µM) and 9j (IC₅₀ = 56.71 µM) approaching the potency of ascorbic acid (IC₅₀ = 38.49 µM). In vivo evaluation of 9a in a streptozotocin-induced diabetic mouse model demonstrated a significant dose-dependent hypoglycemic effect, reducing blood glucose levels by approximately 44.6

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic has highlighted the fragility of our therapeutic arsenal against human coronaviruses and the urgent need to develop new antivirals. They should exhibit broad-spectrum activity to address future pandemics and target alternative viral proteins to mitigate resistance. We have previously identified a hit compound based on a 2-phenylquinoline scaffold that is able to hinder SARS-CoV-2 replication through nonstructural protein 13 (nsp13) helicase inhibition. Here we reported a SAR study that led to identify new analogs such as 2-(4-butoxyphenyl)-4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy]-5,7-dimethoxyquinoline (14) and 4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy]-2-(4-isopropoxyphenyl)-5,7-dimethoxyquinoline (15), which exhibited a good antiviral profile (EC50 = 8.06 and 9.11 µM) coupled with a low micromolar inhibition of nsp13 helicase. Time-of-addition assays and binding analyses confirmed helicase as their primary target, while kinetic studies revealed ATP-competitive inhibition. The butoxy derivative 14 also inhibited HCoV-229E and HCoV-OC43 replication, indicating broad-spectrum potential. The safety of the compounds was validated in bronchial epithelium cells BEAS-2B cells and H9c2 cardiac cells, where they did not affect cell viability or reactive oxygen species (ROS) production. Finally, preliminary ADME studies on 15 showed a positive profile in terms of membrane permeability and metabolic stability in plasma and human liver microsomes. This SAR study, along with mechanistic exploration, paves the way for further optimization of 2-phenylquinoline-based compounds.

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen for which new antimicrobial strategies are urgently needed. To facilitate the establishment of the infection, P. aeruginosa produces a remarkable assortment of both cell-associated and extracellular virulence factors. The expression of numerous virulence traits is regulated by the pqs quorum sensing (QS) system, which relies on multiple enzymes for the biosynthesis of 2-alkyl-4-quinolone (AQ) signal molecules and on the transcriptional regulator PqsR, whose activity is triggered by AQ binding. Herein, we report on the design and synthesis of novel quinazolinone-based PqsR modulators, which led to the identification of two novel compounds endowed with anti-PqsR activity in the submicromolar range. Additionally, these derivatives inhibited the production of PqsR-controlled virulence factors in laboratory strains and clinical isolates of P. aeruginosa.

Chronic lymphocytic leukemia (CLL) is a hematological malignancy characterized by the accumulation of mature CD5⁺ B cells largely due to defective apoptosis. Prolonged leukemic cell survival has been linked to downregulation of the pro-apoptotic adaptor p66Shc and its transcription factor STAT4, both of which are typically reduced in CLL patients. To date, a clear mechanistic explanation for STAT4 deficiency in CLL has not yet been provided. Restoring STAT4 expression or activating its residual function may represent an attractive therapeutic strategy. Histone deacetylase 6 (HDAC6) directly deacetylates and suppresses STAT4 in T lymphocytes, suggesting that a similar mechanism may operate in CLL cells. In this study, we hypothesized that HDAC6-mediated STAT4 inhibition also occurs in CLL cells and contributes to leukemic cell survival. Accordingly, we tested the potent HDAC6 inhibitor Taginostat (HDAC6 IC50 = 7.9 nM) and found that it enhanced p66Shc expression and restored apoptosis in CLL cells. These effects were reproduced by HDAC6 silencing. Flow cytometric and western blot analyses showed that Taginostat boosted residual STAT4 activity by enhancing its phosphorylation. Moreover, transient transfection with STAT4-luciferase or STAT4-green fluorescent protein (GFP) constructs demonstrated that Taginostat promoted both the nuclear translocation and transcriptional activity of STAT4. In addition, in vivo experiments conducted in the Eµ-TCL1 mouse model of CLL demonstrated that Taginostat treatment counteracted disease development, significantly reducing the leukemia burden. Collectively, these findings validate HDAC6 inhibition as a valuable therapeutic strategy for promoting STAT4 activation in CLL cells, restoring the apoptotic cascade, and counteracting disease progression.

Lysine-specific demethylase 4 A (KDM4A) is an Fe2+-dependent epigenetic regulator implicated in various cancers, representing an emerging target for anticancer drug development. However, the high polarity of its catalytic pocket poses a significant challenge in designing potent small-molecule inhibitors. In this study, a structure-based virtual screening workflow was implemented to optimize the known KDM4A inhibitor QC6352 and design novel isonicotinic acid derivatives with improved predicted binding affinity and dynamic stability. Two Python-based workflows employing fragment replacement and molecular breeding strategies were developed to generate virtual libraries while retaining the isonicotinic acid core. A total of 135,000 derivatives were produced and subjected to a hierarchical screening protocol involving molecular docking, ADMET-based filtering, induced fit docking (IFD), molecular dynamics (MD) simulations, and MM-GBSA rescoring. ADMET filtering was based on standard QikProp drug-likeness and pharmacokinetic criteria to prioritize compounds with acceptable predicted physicochemical, absorption, distribution, and safety-related profiles. Among the screened derivatives, QC-L1A and QC-L2B showed the most favorable overall profiles compared with the reference compound QC6352 across multiple computational parameters. QC-L1A exhibited the most favorable binding free energy (ΔGbind = − 30.96 kcal/mol), representing a 3.12 kcal/mol improvement over QC6352 (− 27.84 kcal/mol), along with the lowest mean RMSD (0.807 Å), indicating marked conformational stability. QC-L2B achieved the most favorable IFD score (− 751.02 kcal/mol), surpassing QC6352 by 7.64 kcal/mol, and yielded a ΔGbind of − 29.62 kcal/mol. MD simulations revealed stable coordination between the conserved isonicotinic acid core and the catalytic Fe2+ ion, together with persistent interactions with key active-site residues. Selectivity analysis, performed by IFD-based profiling against KDM4 isoforms and other related JmjC demethylases, indicated a preferential binding profile toward KDM4 family members, particularly KDM4A and KDM4D. Retrosynthetic feasibility was assessed using the Spaya CASP platform, with both lead compounds showing favorable RScore values and practical synthetic routes. Accordingly, these findings highlight the effectiveness of a fragment-guided computational workflow for rational inhibitor optimization and introduce promising scaffolds for KDM4A-targeted drug design.

Microbial fermentation is a primary method by which a variety of foods and beverages are produced. The term refers to the use of microbes such as bacteria, yeasts, and molds to transform carbohydrates into different substances. Fermentation is important for preserving, enhancing flavor, and improving the nutritional quality of various perishable foods. Historical records clearly show that fermented foods and drinks, such as wine, beer, and bread, have been consumed for more than 7000 years. The main microorganisms employed were Saccharomyces cerevisiae, which are predominantly used in alcohol fermentation, and Lactobacillus in dairy and vegetable fermentation. Typical fermented foods and drinks made from yogurt, cheese, beer, wine, cider, and pickles from vegetables are examples. Although there are risks of contamination and spoilage by pathogenic and undesirable microorganisms, advanced technologies and proper control procedures can mitigate these risks. This review addresses microbial fermentation and clarifies its past importance and contribution to food preservation, flavoring, and nutrition. It systematically separates yeasts, molds, and bacteria and explains how they are used in food products such as bread, yogurt, beer, and pickles. Larger producers employ primary production methods such as the artisanal approach, which are explored along with future trends such as solid-state fermentation, the potential of biotechnology in developing new products, and sustainability in new product development. Future research and development strategies can lead to innovations in methods that improve efficiency, product range, and sustainability.

BACKGROUND:The rise in the frequency of liver cancer all over the world makes it a prominent area of research in the discovery of new drugs or repurposing of existing drugs. METHODS:This article describes the pharmacophore-based structure-activity relationship (3DQSAR) on the secondary metabolites of Alhagi maurorum to inhibit human liver cancer cell lines Hepatocellular carcinoma (HCC) and hepatoma G2 (HepG2) which represents the molecular level understanding for isolated phytochemicals of Alhagi maurorum. The definite features, such as hydrophobic regions, average shape, and active compounds' electrostatic patterns, were mapped to screen phytochemicals. The 3D-QSAR model generates pharmacophore-based descriptors and alignment of active compounds. Further, docking studies were performed on the active compounds to check out their binding affinity with the active site of the target proteins. It was further validated by applying molecular simulations, and the results were found to be accurate. The geometrical optimization and energy gap of the hit compound were calculated by the density functional theory (DFT). Then, ADMET was performed on this hit compound for drug-like features and toxicity. RESULTS:Out of 59 compounds, eight ligands were found active after the 3D-QSAR study. After that, molecular docking was performed on the active compounds F72, F52, F54, F29, F37, F38, F25, and F29, which were recognized as potential targets, and the docking results showed that compound F52 (also an FDA-approved drug) was the best hit. F52 was found to be the best hit against liver cancer cell lines HCC and HepG2. CONCLUSION:This study would be helpful for early drug discovery optimization and lead identification.

A novel series of quinazoline-1,2,3-triazole hybrid compounds (8-22) were synthesized and evaluated as multi-target directed ligands (MTDLs) against EGFR, VEGFR-2, and COX-2 enzymes for anticancer activity. The synthesized compounds demonstrated significant anticancer activity against four human cancer cell lines (HeLa, HepG2, HCT-116, and MCF-7), with compound 17 emerging as the most potent derivative. Compound 17 exhibited exceptional anticancer activity with IC₅₀ values of 4.93, 2.34, 6.07, and 3.35 μM against HeLa, HepG2, HCT-116, and MCF-7 cell lines, respectively, surpassing doxorubicin (DOX) against HepG2 cells (IC50 = 4.50 μΜ). Importantly, compound 17 demonstrated superior selectivity toward cancer cells over normal human lung fibroblasts (WI-38) with a selectivity index of 11.78, compared to DOX (SI = 1.61). Multi-target enzyme inhibition assays revealed that compound 17 exhibited potent EGFR inhibition (IC₅₀ = 0.0085 μM), comparable to erlotinib (IC₅₀ = 0.0078 μM), strong VEGFR-2 inhibition (IC₅₀ = 0.068 μM), approaching sorafenib's activity (IC₅₀ = 0.056 μM), and significant COX-2 inhibition (IC₅₀ = 0.158 μM), comparable to Celecoxib (IC₅₀ = 0.044 μM). Compound 13 also demonstrated multi-target activity with IC₅₀ values of 0.0323, 0.220, and 0.103 μM against EGFR, VEGFR-2, and COX-2, respectively. Mechanistic studies revealed that compound 17 induces G1-phase cell cycle arrest in MCF-7 cells. The compound triggered a 5.11-fold increase in the Bax/Bcl-2 ratio, 2.90-fold upregulation of caspase-8, and elevated caspase-9 protein levels from 139.48 to 392.53 ng/mL, confirming the intrinsic apoptotic pathway activation. Molecular docking and dynamics simulations provided structural insights into the multi-target binding modes. These findings establish quinazoline-1,2,3-triazole hybrids as promising multi-target anticancer agents, with compound 17 demonstrating exceptional therapeutic potential through the simultaneous inhibition of tumor proliferation, angiogenesis, and inflammation pathways while maintaining favorable selectivity profiles.

After the success of the Special Issue entitled “Novel Antiviral Agents: Synthesis, Molecular Modelling Studies and Biological Investigation” (https://www [...]

Acute Respiratory Distress Syndrome (ARDS) involves intense pulmonary inflammation, endothelial damage, and fibrin accumulation, often requiring oxygen therapy. Plasminogen (PLG), a fibrinolytic zymogen, has therapeutic potential for resolving fibrin deposits in the lungs but is vulnerable to oxidative degradation during aerosolization. This study presents a clinically feasible inhalable formulation of PLG complexed with hydroxypropyl-β-cyclodextrin (HP-β-CD), intended to preserve enzymatic function during nebulization under oxygen-rich conditions. Using a ready-to-use eye-drop solution (PLG-OMP), the formulation is repurposed for off-label inhalable administration and prepared with minimal handling suitable for hospital pharmacy protocols. Spectroscopic analyses confirmed complexation, and FT-IR demonstrated HP-β-CD's protective effect against methionine oxidation. Consistently, computer-based investigation at oxidation-relevant sites revealed binding of HP-β-CD close to methionine residues, supporting the spectroscopic evidence of a shielding effect. Aerodynamic evaluation via mesh nebulization showed favorable lung deposition profiles (MMAD ∼ 2.1 μm, FPF ∼ 84 %). Enzymatic activity post-nebulization in oxygen flow remained > 95 % when complexed with HP-β-CD, compared to ∼ 57 % for unprotected PLG. In vitro lysis of human clots was confirmed in both urokinase-triggered and cell-activated degradation models. The latter employed a cell-based model wherein LPS-stimulated macrophages-triggered lysis of human clots through inflammation-induced activation of nebulised PLG. D-dimer quantification verified consistent fibrinolytic performance across both models. These results establish a robust foundation for targeted fibrinolytic therapy in ARDS, combining formulation simplicity with biological relevance to support clinical translation.

Among genetic retinal disorders, retinitis pigmentosa (RP) is characterized by degeneration of rod photoreceptors caused by a large number of diverse mutations, most of which act through different pathways to which epigenetic targets also contribute. The eraser enzymes lysine demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) play major roles in the development of rod photoreceptors, and their inhibitors were shown to block inherited rod degeneration, preserving vision and contributing to a general anti-inflammatory profile at the retinal level. In this work, we proposed the development of polypharmacological agents targeting class I HDAC/LSD1 enzymes with the aim of treating the rd10 mice model of RP. The new small library of compounds is typified by hybrid (±)-3d, which showed IC50 values of 1702, 842, and 358 nM against HDAC1, HDAC2, and HDAC3, respectively, while inhibiting LSD1 with an IC50 value of 1074 nM. When tested on hydrogen peroxide-stressed ARPE-19 and 661W retinal cells at a concentration of 10 μM, (±)-3d showed a promising antioxidant profile, increasing the cellular levels of acetylated and methylated histone H3, and was selected for further studies also in light of its calculated IH-L. In the rd10 mice RP model, a single intravitreal injection of (±)-3d, at the same concentration used in cells, enhanced photoreceptor survival, downregulated retinal expression of the inflammatory genes GFAP, Ccl2, and Ccl12, and effectively preserved the retinal pigment epithelium barrier. Furthermore, (±)-3d promoted the acetylation and methylation of histone H3, thus confirming the engagement of both class I HDAC and LSD1.

The SARS-CoV-2 nonstructural protein 15 (Nsp15) is an endoribonuclease that plays a critical role in viral replication and immune evasion through its NendoU domain. The unique enzymatic mechanism of Nsp15 has attracted considerable attention as a potential therapeutic target, and the identification of its inhibitors could facilitate the development of novel antiviral agents against coronaviruses. Although biochemical and structural studies have provided important insights into Nsp15 function, no comprehensive review has yet focused on computational approaches applied to the discovery of Nsp15 inhibitors. Consequently, this study aims to address this gap by summarizing recent in silico research focused on the structure, function, and inhibition of Nsp15. Special attention is given to inhibitors derived from both natural and synthetic sources, as well as their binding interactions and predicted pharmacological potential. By integrating current computational findings, this review highlights novel prospects for the rational design of Nsp15-targeted therapeutics to combat SARS-CoV-2 and other related pathogenic coronaviruses.