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Background/Objectives: Glucose Transporter 1 Deficiency Syndrome (GLUT1-DS) is a neurodevelopmental disorder caused by mutations in the gene encoding glucose transporter 1 (GLUT1), which leads to impaired glucose transport into the brain and is characterized by drug-resistant epilepsy. Limited glucose supply disrupts neuronal and astrocytic energy homeostasis, but how hypometabolism translates into network hyperexcitability remains poorly understood. Here, we used induced pluripotent stem cells (iPSCs)-derived brain organoids to examine how reduced metabolic substrate availability shapes epileptiform dynamics in human neuronal circuits from GLUT1-DS. Methods: Brain organoids were generated from a healthy donor or a GLUT1-DS patient and interfaced with multielectrode arrays (MEA) for recording of neuronal activity. A unified Python (v3.10)-based analytical pipeline was developed to quantify spikes, bursts, and power spectral density (PSD) across frequency bands of neuronal activity. Organoids were challenged with reduced glucose, pentylenetetrazol (PTZ), potassium chloride (KCl), and tetrodotoxin (TTX) to assess metabolic and pharmacological modulation of excitability. Results: GLUT1-DS organoids exhibited elevated baseline hyperexcitability compared to healthy control, characterized by increased spike rates, prolonged bursts, increased spikes per burst, and elevated PSD. Reduced glucose availability further amplified these features selectively in GLUT1-DS. Conclusions: Human brain organoids reproduce the pathological coupling between hypometabolism and hyperexcitability in GLUT1-DS. Our platform provides a mechanistic model and quantification tool for evaluating metabolic and anti-epileptic therapeutic strategies.

Photodynamic therapy (PDT) is an established light-based treatment modality that relies on the activation of photosensitizers to generate reactive oxygen species (ROS) and induce localized cytotoxicity. In recent years, microalgae have emerged as a promising and sustainable source of natural photosensitizers due to their ability to biosynthesize structurally diverse pigments with strong light-harvesting capacity. This review provides a comprehensive, application-oriented analysis of microalgae-derived photosensitizers, focusing on chlorophylls and their derivatives, carotenoids, and phycobiliproteins. Particular attention is given to analytical strategies for pigment extraction, purification, and characterization, as well as to photophysical properties, subcellular localization, and ROS-mediated mechanisms underlying photodynamic activity. Recent advances in the chemical modification of algal pigments, including chlorin-based derivatives and 5-aminolevulinic acid-related systems, are critically discussed in relation to structure-activity relationships and translational performance. The accumulated evidence demonstrates that microalgae-derived pigments and their synthetic analogues can achieve efficient singlet oxygen generation, organelle-specific phototoxicity, and favorable therapeutic selectivity. Taken together, these findings highlight microalgae as a renewable and versatile platform for developing next-generation photosensitizers with broad biomedical potential in oncology, dermatology, and antimicrobial photodynamic therapy.

Background/Objectives: Rheumatoid arthritis is an autoimmune disease that induces joint deformity and disability. There are great expectations for biomarkers that would predict the response to treatment. CHI3L1 and CHI3L2 are chitinase-like proteins (CLPs) which lack enzymatic activity. CHI3L1 is expressed by a variety of cells, while reports on CHI3L2 are limited. The aim of the current study is to evaluate gene and protein CHI3L1 and CHI3L2 expressions before and after treatment of patients with RA and to search for correlations with ultrasonography and conventional laboratory parameters. Methods: Twenty-four newly diagnosed RA patients (19 females and five males) were enrolled in the study. Fourteen patients were treated with tofacitinib (TOFA) and 10 patients with methotrexate (MTX) for twenty-four weeks. Conventional biochemical and immunological markers were examined at the start of the treatment and after the follow-up period. The activity of RA was assessed via the Disease Activity Score 28 (DAS28). Gene expression and protein analysis were performed. Results: Ultrasonographic and clinical laboratory parameters showed improvement after therapy in both groups. A decrease in plasma levels of CHI3L1 (p = 0.04 *) and CHI3L2 (p = 0.03 *) were found after treatment with TOFA. No changes in either protein level were detected after MTX therapy, nor were any differences discovered in the gene expression of CLPs after treatment with both therapeutics. Strong correlations between CRP, GUS7 and CLPs were also established. Conclusions: The similar dynamics of CLPs expression in naïve RA patients and their distinct interplay with disease-related parameters after therapy suggest that both proteins may display different functions in RA pathophysiology.

Background/Objectives: Diabetes mellitus is a serious global disease characterized by chronic hyperglycemia, resulting from defects in insulin secretion, insulin action, or both. It represents a major health concern affecting millions of people worldwide. This condition can lead to severe complications significantly affecting patients' quality of life. Due to the limitations and side effects of current therapies, the search for safer and more effective antidiabetic agents, particularly from natural sources, has gained considerable attention. This study investigates the antidiabetic potential of seaweed-derived compounds through structure-based virtual screening targeting α-glucosidase. Methods: A library of compounds derived from the Seaweed Metabolite Database was subjected to a hierarchical molecular docking protocol against α-glucosidase. Extra Precision (XP) docking was employed to identify the top-ranked ligands based on their binding affinities. Drug-likeness was assessed according to Lipinski's Rule of Five, followed by pharmacokinetic and toxicity predictions to evaluate ADMET properties. Density Functional Theory (DFT) calculations were performed to analyze the electronic properties and chemical reactivity of the selected compounds. Furthermore, molecular dynamics simulations were carried out to examine the stability and dynamic behavior of the ligand-enzyme complexes. Results: Following XP docking and ADMET prediction, four promising compounds were selected: Colensolide A, Rhodomelol, Callophycin A, and 7-(2,3-dibromo-4,5-dihydroxybenzyl)-3,7-dihydro-1H-purine-2,6-dione. Molecular dynamics simulations further confirmed the structural stability and strong binding interactions of these compounds within the α-glucosidase active site. Conclusions: This investigation demonstrated the important role of seaweed-derived compounds in inhibiting α-glucosidase activity. Further experimental validation is warranted to confirm their biological activity and therapeutic potential.

Tropical almond tree (Terminalia catappa L.), belonging to the Combretaceae family, is an unfurling tree with different edible parts. This review discussed the nutritional content, ethnopharmacological applications, main bioactive components, biological effects and economic potential of T. catappa. T. catappa shows essential applications in medicine, cosmetics and pharmaceutics. The nutritional values of T. catappa are associated with its contents of carbohydrates, minerals, proteins, lipids, vitamins and amino acids. It is used in many ethnopharmacological applications, including a heart stimulator, anti-diarrhoeal, bactericidal, anti-parasitic and anti-stress. T. catappa is used to treat angina pectoris, asthma attacks and bronchitis. The main reported biological activities for T. catappa were antioxidant, antidiabetic, anti-atherosclerosis, antitumor, antimicrobial, anthelmintic, antimalaria, hepatoprotective, insecticidal, anti-inflammatory and antihyperlipidemic activities. The main bioactive components reported in T. catappa encompassed phenolic compounds, alkaloids, diterpenes, fatty acids, galloyl glucose and derivatives, steroids and coumarins. T. catappa shows great economic opportunities which need to be expanded and diversified, taking into account its sustainability.

Background: Cannabidiol (CBD) is a major non-psychoactive phytocannabinoid that exerts multiple biological effects in the body. It has been shown to exert anti-cancer effects in a variety of cancer cells, including acute lymphoblastic leukemia of pre-T cell origin (T-ALL), a highly aggressive hematological malignancy. However, the mechanisms underlying CBD's anti-cancer effects are not fully understood. Furthermore, cancer cells abundantly express surface CD47, which is a negative regulator of phagocytosis and linked with cell survival/death. Little is known about CBD effects on the expression of CD47 in T-ALL cells. The objectives of this study were to address these issues. Methods: Studies were conducted in vitro using Jurkat cells and human peripheral blood mononuclear cells in different culture conditions, CBD concentrations, and in the presence or absence of different reagents. Results: CBD downregulates CD47 expression and induces apoptosis in Jurkat cells. Similar biological effects of CBD were also observed in primary human CD4⁺ T cells, albeit at reduced levels. The CBD's effects on CD47 expression and apoptosis were not rescued by a cannabinoid receptor (CBR)-2 agonist, a CBR-2 antagonist, or an anion channel blocker. However, these effects on CD47 expression and apoptosis were significantly rescued by a Voltage-Dependent Anion Channel (VDAC)-1 oligomerization inhibitor. Conclusions: Overall, we conclude that CBD downregulates CD47 expression and induces apoptosis involving VDAC-1 oligomerization. Furthermore, they also suggest that CBD's pro-apoptotic effects on primary human T cells should also be monitored if it is used as an anti-cancer adjuvant or neo-adjuvant therapeutic in cancer patients.

Background/Objectives: Hypertension represents a leading contributor to cardiovascular disorders and premature mortality. Given the pervasive nature of adverse effects associated with current angiotensin-converting enzyme inhibitors (ACEIs), there is a significant interest in identifying novel bioactive lead compounds from natural sources. This study identifies, for the first time, three novel angiotensin-converting enzyme (ACE) inhibitory peptides released from Bungarus multicinctus (BM) via simulated gastrointestinal digestion (SGD). Methods: Active fractions were enriched by ultrafiltration and subjected to stability assessment. The peptide sequences were then determined using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) and bioinformatics tools, followed by chemical synthesis. Finally, the inhibitory mechanism was investigated using kinetic analysis and molecular docking. Results: The intestinal digest exhibited potent ACE inhibition, with the <5 kDa fraction achieving 79% inhibition at 1 mg/mL and demonstrating favorable stability under varying temperatures, pH, and ionic strengths. Molecular docking revealed strong binding (affinity < -9.9 kcal/mol) of the peptides PPSPPRW, WGFTKF, and PSLFPPRL to key ACE residues-Tyr523, His513, and Arg522-via hydrogen and hydrophobic interactions. Enzyme kinetics characterized PPSPPRW and WGFTKF as competitive inhibitors, and PSLFPPRL as mixed type. The peptides demonstrated acceptable cell viability at lower concentrations, establishing a preliminary safety window for therapeutic application. Conclusions: These findings establish BM as a valuable source of stable, bioactive ACE-inhibitory peptides (ACEIPs) acting as promising lead compounds for antihypertensive therapies.

Rheumatoid arthritis (RA) is frequently accompanied by depression, a comorbidity arising from the interplay of chronic systemic inflammation, neuroimmune activation, oxidative stress, and dysregulation of the gut-brain axis. Increasing evidence suggests that nanomedicine offers unique opportunities for the integrated management of RA-associated depression by enabling precise modulation of both peripheral inflammation and central nervous system (CNS) pathology. This review outlines the biological mechanisms linking RA and depression-including cytokine cascades, mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and microbial metabolite imbalance-and highlights recent progress in nanocarrier platforms capable of dual-site intervention. Liposomes, polymeric nanoparticles (NPs), exosomes, inorganic nanozymes, and emerging carbon-based nanomaterials have demonstrated the ability to target inflamed synovium, reprogram macrophage phenotypes, traverse the blood-brain barrier (BBB), suppress microglial overactivation, enhance neuroplasticity, and restore gut microbial homeostasis. Furthermore, stimulus-responsive nanoplatforms activated by ROS, pH, enzymes, or hypoxia provide spatiotemporally controlled drug release, thereby improving therapeutic precision. Finally, we discuss integrative designs such as dual-targeting nanomedicines, co-delivery systems, and microbiota-modulating nano-interventions, which offer promising strategies for the comprehensive treatment of RA-associated depression. This review aims to provide mechanistic insights and design principles to guide the development of next-generation nanomedicine for coordinated systemic-central modulation in RA comorbidity.

Background: Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication with limited therapeutic options. Jaceosidin (JAC), a natural flavonoid from Folium Artemisiae Argyi, shows potential in cardiovascular diseases, but its role and mechanism in SIMD remain unclear. This study aims to investigate the protective effects of JAC against SIMD and explore the underlying molecular mechanisms. Methods: In vitro, AC16 human cardiomyocytes were stimulated with TNF-α and treated with JAC. Cell viability and apoptosis were assessed using CCK-8 and flow cytometry, respectively. Transcriptomic and metabolomic analyses were performed to identify altered pathways. Molecular docking evaluated JAC's interaction with SIRT2. The SIRT2 inhibitor AGK2 was used to validate its role. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) determined H3K18la enrichment on target gene promoters. In vivo, a murine SIMD model was established via LPS injection, and cardiac function was evaluated by echocardiography. Serum markers (cTnT, CK-MB) and myocardial lactylation levels were measured. Results: JAC significantly attenuated TNF-α-induced injury in AC16 cells by enhancing viability and reducing apoptosis. Multi-omics analyses revealed JAC suppressed glycolysis and lactate production. JAC specifically inhibited histone H3K18 lactylation (H3K18la), and molecular docking indicated strong binding affinity with SIRT2. AGK2 treatment reversed JAC-mediated suppression of H3K18la. ChIP-qPCR confirmed H3K18la directly regulates IL-6, BAX, and BCL-2 expression. In vivo, JAC improved cardiac function (LVEF, LVFS, LVDd, LVDs), reduced serum cTnT and CK-MB levels, and decreased myocardial H3K18la in LPS-treated mice. Conclusions: JAC alleviates SIMD by activating SIRT2, which inhibits H3K18la, thereby modulating inflammatory and apoptotic pathways. This study identifies JAC as a novel metabolic-epigenetic therapeutic agent for SIMD.

Immune dysregulation and chronic inflammation are central contributors to many diseases. Curcuma longa L. and Echinacea purpurea (L.) Moench are widely used medicinal plants with extensive preclinical evidence supporting immunomodulatory effects. Their key metabolites, curcuminoids, turmerones, alkamides, polysaccharides, and caffeic acid derivatives, engage with critical pathways, including NF-κB, MAPK, JAK/STAT, and Nrf2. This interaction modulates cytokine production, oxidative stress responses, and both innate and adaptive immune activities. Although numerous mechanistic and early clinical studies support these actions, human evidence remains inconsistent, partly due to poor and variable oral bioavailability and substantial heterogeneity in extract composition, despite the existence of some standardized preparations. Recent technological strategies, including micelles, phytosomes, phospholipid complexes, nanoemulsions, polymeric nanoparticles, and liposomal systems, have improved solubility, stability, and systemic exposure of key metabolites, particularly curcuminoids. However, clinical results are still limited and often derived from small or heterogeneous trials. This review summarizes the ethnopharmacological background, mechanistic data, clinical findings, and formulation advances for both species and highlights the translational barriers that restrict their therapeutic application. Rigorous clinical studies using standardized and technologically optimized preparations are required to determine the true immunomodulatory potential of C. longa and E. purpurea.