Search Results (28,354)

Cyclodextrins (CDs) have gained increasing attention as versatile platforms for enhancing drug delivery to the central nervous system, particularly in overcoming the restrictive properties of the blood–brain barrier (BBB). Owing to their unique cyclic oligosaccharide structure, CDs are capable of forming inclusion complexes with a wide range of therapeutic agents, thereby improving their solubility, stability, and bioavailability. In addition to their role as excipients, growing evidence indicates that CDs can actively modulate biological processes, including membrane fluidity and cholesterol homeostasis, which are critical factors in neurological disorders. This review explores the application of CDs in facilitating drug transport across the BBB through multiple mechanisms, including carrier-mediated transport, receptor-mediated transcytosis, and nanoparticle-based delivery systems. Special emphasis is placed on their use in the treatment of neurodegenerative and neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Niemann–Pick type C disease, and other central nervous system disorders. In these contexts, CD-based formulations have demonstrated the ability to enhance brain targeting, reduce pathological protein aggregation, and improve therapeutic outcomes in preclinical models. This review uniquely integrates cyclodextrin’s physicochemical properties with specific blood–brain barrier transport mechanisms, proposing a structure–transport–therapy framework that enables a more predictive understanding of brain-targeted drug delivery. Full article

Background/Objectives: Since 2015, pulmonary arterial hypertension (PAH)-specific medications have been fully reimbursed in Lithuania. To describe the current situation of PAH treatment in the country and to determine survival during different PAH treatment regimens. Methods: The data from the Institute of Hygiene and the State Data Agency of Lithuania cases with administrative codes I27.0 and I27.8 have been evaluated. Results: In 2025, 225 confirmed cases of PAH were treated with PAH-specific medications in two PH centers. At least one PAH-specific medication was prescribed to 163 (72.4%) female and 62 (27.6%) male patients. Among these, 96 (42.7%) received sildenafil monotherapy, 82 (36.4%) received a combination of sildenafil and an ERA, 36 (16.0%) were on triple PAH-specific therapy (including selexipag or treprostinil), and 11 (4.9%) received other regimens due to specific medical considerations. The age of adults treated with sildenafil monotherapy vs. other therapies was 63.9 ± 14.8 (n = 117) and 51.5 ± 17.3 (n = 116) years, respectively (p < 0.05). A total of 191 PAH patients who received targeted therapy died during the observational period 2017–2025. Of these, 105 received monotherapy, 57 sildenafil and endothelin receptor antagonist and 29 triple therapies (treprostinil [n = 19], selexipag [n = 6], or inhaled iloprost [n = 4] were prescribed as the third drug). Patients who died and received triple therapy were younger than those on mono- and dual therapy (age at diagnosis 45.0 ± 21.6, 67.2 ± 14.7 and 61.6 ± 16.3 years, respectively, p < 0.01). Survival was longer in patients on dual therapy compared with monotherapy (43.1 ± 28.1 vs. 31.7 ± 25.0 months, p = 0.04), and the longest was in those receiving triple therapy (59.9 ± 29.4 months; p < 0.05). Conclusions: The availability of reimbursed medications dramatically increased the number of treated PAH cases in Lithuania. In 2025, most of the PAH patients received sildenafil monotherapy. Patients treated with sildenafil only were significantly older than the rest of cohort. In the survival analysis, combination PAH therapies were more often prescribed to younger patients and were associated with longer duration of life than monotherapy. Full article

G protein-coupled receptor kinase 5 (GRK5) is an important therapeutic target involving cardiovascular diseases, cancer, and inflammatory disorders. However, the features of its activation as an essential function regulation process have been poorly understood, limiting related drug development. The work utilizes a molecular dynamics simulation coupled with an interpretable machine learning model to identify key structure and dynamics determinants distinguishing the active and inactive states of GRK5. Benefiting from the unbiased and data-driven framework, the work reveals that the active site tether (AST) is a dominant activation-associated feature, acting as a conformational switch that regulates kinase domain movements. Beyond this canonical element, we also uncover two previously underappreciated structure modules contributing to GRK5 activation, such as the coupling interaction between the α10/α11 helix interface with the N-terminal lipid-binding domain (NLBD) in the active state, and the α5 helix region that facilitates large-scale RH domain reorientation. Conformation dynamics analyses further indicate that GRK5 activation involves disruption of the interdomain interactions and interaction coupling between AST, αN-helix, kinase domain N-lobe, NLBD, and α10/α11 hinge. These observations provide valuable insights into understanding the GPK5 activation mechanism and also highlight the power of machine learning in capturing functionally conformational changes, and in turn offering a methodological guideline for the studying of the protein function mechanism. Full article

Breast cancer remains a major global health challenge, requiring novel therapeutic strategies that can overcome drug resistance and improve treatment efficacy. This study investigates the synergistic antitumor effects of etoposide, a conventional chemotherapeutic agent, and resveratrol, a natural polyphenol with anticancer properties, in human breast cancer cell lines, with particular focus on their ability to activate the parthanatos cell death pathway. Using MCF-7 (estrogen receptor-positive) and MDA-MB-231 (triple-negative) breast cancer cells, we assessed cell viability via MTT assays and evaluated parthanatos activation through multiple complementary approaches including AIF translocation determined by subcellular fractionation, NAD+ depletion measurement, and gene expression analysis. Synergy was quantified using the Chou–Talalay method across multiple effect levels (ED50, ED75, ED90). To establish causality, Olaparib PARP inhibitor experiments were performed to confirm that PARP-1 hyperactivation is essential for the observed cytotoxic effects. The results demonstrated that the etoposide–resveratrol combination significantly enhanced cell death and inhibited proliferation compared to single-agent treatments, with combination index (CI) values indicating strong synergism (CI = 0.62–0.75 for MCF-7; CI = 0.58–0.71 for MDA-MB-231). This synergy was associated with robust parthanatos activation, evidenced by increased PARP-1 expression, AIF nuclear translocation confirmed by subcellular fractionation, and significant NAD+ depletion. Critically, Olaparib pre-treatment (3 µM) significantly rescued cells from combination-induced death, restored NAD+ levels to near-control values, and prevented AIF translocation, establishing a causal link between PARP-1 hyperactivation and parthanatos-mediated cytotoxicity. The combination also induced significant DNA fragmentation, elevated oxidative stress, and cell death with morphological features consistent with parthanatos, while caspase activity remained low, confirming caspase-independent cell death. These findings suggest that targeting parthanatos with etoposide and resveratrol could offer a promising therapeutic strategy for breast cancer, potentially overcoming resistance and improving efficacy. Further in vivo studies and clinical investigations are needed to validate these results and explore translational applications. Full article

Extensive evidence now confirms Lipoprotein(a) [Lp(a)] as a causal, independent risk factor for atherosclerotic cardiovascular disease. Elevated Lp(a) levels are detected in approximately 20% of the global population, positioning it as a major contributor to residual cardiovascular risk. Circulating Lp(a) levels are determined predominantly by genetic factors, so they are largely unresponsive to lifestyle modifications or conventional lipid-lowering therapies. Therefore, multiple international guidelines now endorse a one-time, lifetime measurement of Lp(a), as lowering Lp(a) concentrations is expected to have a positive impact on the reduction of cardiovascular risk. Currently, the therapeutic landscape of Lp(a) lowering drugs is rapidly evolving. Some RNA-based therapies (antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)) have been demonstrated to reduce plasma Lp(a) concentrations by up to 98% in early-phase clinical trials. The efficacy and safety of these compounds are currently being evaluated in large-scale cardiovascular outcome trials. The results of these studies will be critical in validating the “Lp(a) hypothesis”: specific reduction of Lp(a) levels can lead to a measurable decrease in cardiovascular events. The purpose of this narrative review is to examine and discuss the available evidence on the role of Lp(a) as a risk factor and pharmacological target to provide a practical tool for decision-making in clinical practice. Full article

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular antioxidant response and a promising therapeutic target for Parkinson’s disease (PD). Resibufogenin (RBG), a bioactive bufadienolide from toad venom, has been identified as a potential Nrf2 agonist; however, its application is limited by cytotoxicity and poor drug-like properties. Herein, we report the rational design, synthesis, and biological evaluation of a series of RBG derivatives modified at the C3, C14–C15, and C17 positions. Systematic structure–activity relationship (SAR) studies identified 2-5c, featuring a C3 2-chloroacryloyl group and a C17 pyrimidine substitution, as a potential Nrf2 activator (EC₅₀ = 4.18 μM), exhibiting approximately 7-fold greater activity than RBG. Importantly, 2-5c demonstrated neuroprotective effects in MPP⁺-induced BV2 microglial cells and effectively ameliorated motor deficits in an MPTP-induced PD mouse model. These findings suggest that 2-5c represents a promising candidate for further investigation in the development of novel Nrf2-based therapies for PD. Full article

Background: Single-target Alzheimer’s disease (AD) therapies have repeatedly failed to modify disease progression, highlighting a critical mismatch between multifactorial pathology and reductionist pharmacology. Methods: We developed a representation learning framework using Knowledge-guided Pre-trained Graph Transformers (KPGT) to enable rational multi-target drug discovery, analyzing 2446 molecules across APP, PSEN1, and VCP. Results: KPGT captured target-specific mechanistic signatures with 99.35% classification accuracy. Geometric midpoint analysis identified 15 bridging candidates with mean pIC₅₀ 8.09. We discovered two orthogonal molecular feature signatures, structural features driving multi-target breadth versus chemical features determining single-target potency, with zero descriptor overlap. Chemical orthogonality (d = 3.86) outperformed functional similarity for predicting synergistic pairs, with 95% overlap between multi-target molecules and synergistic combinations. Conclusions: This framework operationalizes systems-level AD drug discovery through interpretable representation learning. Full article

Background/Objectives: Prostate cancer (PCa) cells are known to heavily depend on lipids to support their growth. We hypothesized that hyperlipidemic factors, for which inhibitors are already available and used to treat cardiovascular disease, would be dysregulated in metastatic PCa (mPCa). The goal of this case-control study, including 35 men per group, was to compare the levels of PCSK9, ANGPTL3, Apo CIII, leptin, and the lipid profile in patients with mPCa versus localized Gleason 8/9 PCa (lPCa) and patients at risk of developing PCa (controls). Methods: Protein levels were assessed using ELISAs, while lipids were measured using the Roche Cobas analytical platform. Results: The following circulating analytes were higher in mPCa: triglycerides (in mmol/L; controls 1.7 ± 1.2, lPCa 1.5 ± 0.7, mPCa 2.3 ± 1.2, p = 0.0004), Apo CIII (in µg/mL; control 110.7 ± 55.7, lPCa 115.0 ± 57.64, mPCa 159.9 ± 96.7, p = 0.0179), ANGPTL3 (in ng/mL; controls 41.7 ± 20.0, lPCa 42.8 ± 24.1, mPCa 57.3 ± 26.9, p = 0.0390), and leptin (in ng/mL, controls 9.6 ± 9.1, lPCa 8.2 ± 7.9, mPCa 17.7 ± 17.8, p < 0.0001). Surprisingly, PCSK9 levels were negatively correlated with LDL in the entire cohort. Conclusions: In this cohort of men, whole-body lipid metabolic rewiring is a feature restricted to the metastatic phase of prostate cancer, suggesting it may play a significant role in the progression toward more aggressive cancer forms. Given the availability of drugs targeting ANGPTL3 and Apo CIII, the therapeutic potential of these drugs should be evaluated in metastatic PCa. Full article

Rhodesain is a cysteine protease that plays a key role in the life cycle of Trypanosoma brucei rhodesiense, an endemic parasite in sub-Saharan Africa and responsible for Human African Trypanosomiasis (HAT), a disease that can be fatal if not treated promptly. Due to the limitations associated with current HAT pharmacological therapy, the search for new targets for the development of antitrypanosomal agents is urgently needed; in this context, rhodesain represents a promising therapeutic target. In this study, new chalcones were synthesized and tested against rhodesain. Given their affinity for the trypanosomal cysteine protease (K_i values in the micromolar range), chalcone 1a was selected to evaluate its effect in combination with the nutraceutical curcumin. The Combination Index (CI) was calculated using Chou and Talalay’s method. The analysis of the CI calculated at different f_a values of enzyme inhibition for the combination curcumin + 1a showed promising results. For all f_a values, the CI is less than one, indicating a synergistic effect when chalcone 1a is combined with curcumin. In particular, at the most significant f_a value (0.90), corresponding to 90% of enzyme inhibition, the CI value is 0.1781, indicating a strong synergism between the synthetic drug and the nutraceutical. The combined use of curcumin and chalcone 1a led to an enhancement of rhodesain inhibitory activity, resulting in a strong synergistic effect and supporting further investigation of this combination. Full article

Background: Perivascular adipose tissue (PVAT) contains adipocytes and a stromal-vascular fraction with immune cells that modulate the adjacent vasculature. The presence of immune cells in PVAT of vascular beds is poorly understood—are they resident or recruited? We propose a novel resident microbiome present in PVAT, given the immune-rich stromal environment. Hypothesis: We hypothesized the existence of distinct bacterial and viral communities in healthy PVAT compared to non-PVAT adipose tissues. Methods: PVAT samples from thoracic and abdominal aorta, mesenteric resistance arteries, non-PVAT tissues (subscapular brown adipose tissue, retroperitoneal white adipose tissue), and fecal samples were collected one year apart from male Dahl SS rats, split into two cohorts (2023 and 2024, n = 3 each). Whole-genome shotgun sequencing (CosmosID) and 16S rRNA gene analysis assessed microbial relative abundance. Results: PVAT harbored bacterial and viral sequences, and species composition varied significantly between cohorts. Bacterial and viral fecal samples showed lower variability. Conclusions: PVAT microbiome differed dramatically from the fecal microbiome, with temporal influences on bacterial and viral diversity, marking the first such report. Despite inherent limitations, these findings establish the potential of PVAT microbiota in vascular biology and immune modulation, paving the development of microbiome-targeted drugs to address vascular dysfunctions. Full article

Proteomics represents a fundamental layer for understanding the molecular complexity of solid tumors by quantifying protein abundance and capturing proteoforms and post-translational modifications undetected in genomics or transcriptomics analyses. As mass spectrometry-based technologies and public proteomics repositories have expanded, opportunities for large-scale data reuse have grown accordingly. Nevertheless, data availability has not been translated into straightforward reuse: differences in experimental design, acquisition strategies, quantification workflows and metadata quality still limit the reproducibility and cross-study comparability. In this review, proteomics data reuse is defined as the systematic reanalysis and integration of publicly available datasets to support precision oncology applications such as biomarker assessment and antibody–drug conjugate target prioritization. We discuss reuse as an end-to-end analytical process, focusing on data analysis workflows, harmonization strategies, and the impact of heterogeneous experimental and analytical choices on interoperability. The increased application of artificial intelligence in proteomics data integration and reuse is also addressed, highlighting its analytical potential while underscoring the risks of overinterpretation when biological context and data structure are not adequately considered. Using colorectal and prostate cancer as representative examples, we illustrate how proteomics data reuse can support biological discovery and translational research, while critically examining the factors that limit robustness and clinical relevance. Full article

Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage; however, drug resistance severely limits its efficacy. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), increased detoxification activities, and overexpression of lysine deacetylases (KDACs), which reduce chromatin accessibility and alter transcriptional regulation. Combining cisplatin with KDAC inhibitors has shown promise, often attributed to increased drug sensitivity through higher chromatin accessibility; however, this hypothesis has not been validated. Here, we synthesized a novel Pt(IV) derivative, ctc-[Pt(NH₃)₂(VPA)(PhB)Cl₂] (cPVP), which combines cisplatin with two KDAC inhibitors, phenylbutyrate and valproic acid. Compared with cisplatin, cPVP induced significantly greater cytotoxicity, and increased DNA damage formation. High-resolution mapping of genomic cisplatin damage and repair indicated that enhanced sensitivity resulted not from altered chromatin accessibility, but from increased drug uptake and the inhibition of NER. Moreover, cPVP prevented the development of resistance to both cisplatin and itself in cancer cells. Together, these results establish the inhibition of nucleotide excision repair, rather than enhanced damage sensitivity due to chromatin accessibility, as the primary mechanism by which KDAC-targeting cisplatin prodrugs overcome resistance to platinum-based therapies. Full article

Kv11.1 (hERG1) channels, encoded by KCNH2, mediate the rapid delayed rectifier potassium current (I_Kr) crucial for cardiac repolarization. Disruptions, via mutations or antiarrhythmic drugs like dofetilide cause severe arrhythmogenic disorders, including Long QT Syndrome Type 2 (LQT2), Brugada Syndrome (BrS), and Torsades de Pointes (TdP). While Kv11.1’s role in channelopathies and drug-induced arrhythmias is established, understanding its complex regulation and therapeutic targeting remains a challenge. This review synthesizes the structural, functional, and regulatory aspects of Kv11.1 channels and their clinical implications. Recent studies using iPSC-derived cardiomyocytes highlight regulation by PI3K/Akt, PKC, and PKA signaling via phosphorylation (Ser283, Ser890) and interactions with proteins like 14-3-3. Beyond electrophysiology, Kv11.1 influences pathological hypertrophy and non-cardiac functions including insulin secretion. Pharmacological efforts focus on activators to shorten action potential duration and suppress TdP, and blockers with overdose risks. Mutation heterogeneity, exemplified by trafficking impairment (G785D) in LQT2 and gain-of-function (R397C) in BrS, complicates precision therapy. Clinically, systematic risk stratification using electrocardiographic parameters and genotype-specific approaches enables personalized management. Beta-blockers remain first-line therapy for LQTS2, while rigorous avoidance of QT-prolonging medications and electrolyte monitoring form the cornerstones of preventive care. Advancing Kv11.1-targeted therapies with approaches like CRISPR-Cas9 and pharmacological chaperones (e.g., lumacaftor) holds promise for personalized treatments, ultimately reducing arrhythmic events and sudden cardiac death. Full article

Neurological complications, particularly seizures, represent a significant and often under-recognized clinical challenge in pediatric hematologic malignancies. Distinguishing CNS leukemia-associated epilepsy from chemotherapy-induced neurotoxicity is critical for optimizing therapy but remains difficult due to overlapping clinical presentations. This review highlights the distinct molecular mechanisms underlying these two entities. CNS leukemia-associated seizures are primarily driven by blood–brain barrier (BBB) disruption following leukemic infiltration, which triggers a neuroinflammatory cascade involving pro-inflammatory cytokines such as IL-6 and TNF-α, and impairs glutamate homeostasis. In contrast, chemotherapy-induced seizures, particularly those associated with high-dose methotrexate, arise from disrupted folate metabolism, intracellular oxidative stress, and subsequent N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. We provide a comparative analysis of these pathways, integrating current evidence on pharmacogenomic susceptibility—including polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and drug transporter genes—as well as epigenetic factors. By synthesizing these molecular insights, we propose a mechanistic framework for precise clinical differentiation, which may inform biomarker-driven diagnostic approaches and targeted neuroprotective strategies in this vulnerable population. Full article

Lupus nephritis (LN) stands out as one of the most critical complications of systemic lupus erythematosus (SLE), affecting almost 60% of the patient population. Even though more therapies have been made available for LN in the past decade, clinical outcomes remain less than ideal: nearly 10% to 30% of LN cases still advance to end-stage kidney disease (ESKD), still making the management of LN a clinical challenge. Therefore, the primary aim of treatment of LN is simple: to halt the progression toward chronic kidney disease (CKD) and prevent renal failure. In this review, we briefly describe the immunopathological basis of LN, which provides the scientific rationale for new drug development. We will focus on the current in-use medications, especially on proliferative LN, building on the legacy of the 20th century, and we will outline new emerging targeted and innovative therapies. We will also present the standard-of-care as informed by international guidelines and review the management of special groups, including children and pregnant women. Full article