Search Results (3,202)

Type 2 diabetes mellitus (T2DM) is a major global health burden characterized by insulin resistance, progressive pancreatic β-cell dysfunction, and chronic metabolic dysregulation. Marine seaweeds have emerged as a valuable source of bioactive natural products, particularly polyphenols and polysaccharides, with promising potential for diabetes management. This review focuses on three major contributions: first, the structural diversity of seaweed-derived polyphenols and polysaccharides; second, their multi-target mechanisms of glucose regulation; and third, the structure–activity relationships governing their bioactivities. Current evidence shows that these compounds may help manage type 2 diabetes in several ways, including inhibition of α-amylase and α-glucosidase, attenuation of oxidative stress and chronic inflammation, enhancement of insulin secretion and insulin sensitivity, regulation of lipid metabolism, and modulation of gut microbiota. Key structural determinants such as degree of polymerization, hydroxyl group density, sulfation level, molecular weight, and chemical modifications are discussed in relation to their functional properties. By linking chemical structure with biological function, these findings highlight marine seaweeds as a rich reservoir of multi-target therapeutic candidates for T2DM management and provide a scientific basis for their development as functional food ingredients or lead compounds for novel diabetes management drugs. Full article

Background and Objectives: Child dental neglect is a clinically significant form of maltreatment that frequently reflects broader challenges related to caregiving within the family environment. Although oral manifestations have been described in prior research, the socio-behavioral profile of responsible caregivers remains insufficiently characterized, particularly in Central and Eastern European contexts. This study aimed to identify caregiver-level socio-behavioral characteristics associated with child dental neglect and to examine their relationships with clinical outcomes. Materials and Methods: A retrospective cross-sectional analytical study was conducted on 333 children (aged 4–17 years) diagnosed with dental neglect, presenting at a municipal hospital and a private dental practice in Oradea, Romania (2020–2024). Caregiver-level variables included age, educational attainment, socioeconomic status, health condition, substance use, and family structure. Associations were analyzed using Fisher’s Exact Test, Pearson Chi-Square, and Mann–Whitney U test, with Bonferroni correction applied where appropriate. Results: Most caregivers were young adults (93.1%), with low educational attainment (40.2% had no formal schooling) and high rates of alcohol use (47.1%). Low family income was present in 89.2% of cases and was significantly associated with non-adherence to the dental treatment plan (p  =  0.039). Caregivers without formal education were associated with neglect in rural areas (43.4% vs. 26.2%; p  <  0.001). Children of drug-using caregivers were significantly older at presentation (median: 12 vs. 8 years; p  =  0.014), and caregiver drug use was more prevalent in urban settings (18.0% vs. 1.8%; p  <  0.001). Over half of the children (52.9%) came from disrupted family environments. Conclusions: Dental neglect was consistently associated with young, poorly educated, and financially disadvantaged caregivers exhibiting high rates of substance use and unstable family structures. These factors may interact in complex ways, highlighting the multifactorial nature of dental neglect. Dental professionals are well positioned for early identification and have a professional and ethical responsibility to integrate child safeguarding into routine clinical practice. Full article

Biogenically synthesized metal-based nanoparticles have emerged as an attractive alternative to traditional physicochemical methods. The conventional way to prepare metal nanoparticles involves using toxic chemicals as reducing agents and stabilizers, which is tedious to handle and highly detrimental to the environment. Hence, biological synthetic routes for the biosynthesis of metal nanoparticles have been widely explored in recent research. It involves using biological molecules present in organisms, such as bacteria, plants, and fungi, as well as vitamins and enzymes, to reduce, stabilize, and regulate nanoparticle growth. These green-synthesized nanoparticles have demonstrated promising biomedical applications, especially as antibacterial, anticancer, anti-inflammatory, and neuroprotective agents, owing to their superior biocompatibility and surface chemistry. In addition, there is potential to develop therapeutic formulations that leverage the interactions between nanoparticles’ properties and biological systems. This review discusses the mechanisms of biogenic synthetic routes, with a detailed discussion of plant, bacterial, enzymatic, fungal, and vitamin-mediated green synthetic metal-based nanoparticles and their applications in biomedical and drug delivery fields. Full article

Phase-inversion in situ implants (PIISIs) represent a versatile polymer platform in which the rational choice of matrix former and solvent system directly governs the macroscopic properties of the resulting depot. This study applied a Quality by Design (QbD) approach to rationalize a bleached shellac–based PIISI, with particular focus on the physicochemical interactions between the polymer and the injection vehicle. Bleached shellac—a natural, low-cost, biodegradable oligomeric resin bearing –COOH, –OH, and ester functional groups—was selected as the matrix former and screened in seven neat solvents and five 1:1 binary combinations at 25% (m/m). Twelve formulations were evaluated against a predefined set of critical quality attributes, including injectability, phase-inversion kinetics, solvent diffusion volume, and implant structure (n = 5 per formulation; mean ± standard deviation (SD); one-way analysis of variance (ANOVA) with Tukey’s post hoc test, p < 0.05). Three lead solvent systems—propylene glycol/N-methylpyrrolidone (PG+NMP), PG/dimethyl sulfoxide (PG+DMSO), and DMSO/benzyl alcohol (DMSO+BA)—were identified as those providing an optimal balance between hydrogen-bond donor/acceptor solvation and controlled solvent extraction. In the second stage, shellac concentration (20–35%) was optimized, with 30% shellac in PG+NMP yielding the fastest phase inversion (~50 s), a structurally uniform matrix, and the lowest swelling (22%). A working mechanistic framework consistent with all observed critical quality attribute (CQA) trends in which solvent hydrogen-bond donor/acceptor balance and water miscibility govern implant architecture is proposed, and it is intended as a hypothesis-generating basis for the rational design of PIISI formulations; direct validation by spectroscopic, thermal-analytical, and biological methods is identified as the next step. The developed formulations are presented as a preliminary physicochemical platform; biological validation (in vitro cytocompatibility and inflammatory response assessment) is required before the system can be considered a validated formulation for dental drug delivery. Full article

Background/Objectives: Medication discrepancies at hospital discharge are common and may contribute to adverse drug events and avoidable healthcare use. Patients with mental health conditions may be at increased risk because of greater clinical complexity, polypharmacy, and fragmented care, but comparative evidence during general hospital admissions is limited. Our primary objective was to determine whether adults with mental health conditions were more likely than those without such conditions to experience unintended medication discrepancies at hospital discharge. Secondary objectives were to examine discrepancy subtypes, assess whether associations differed for serious mental illness versus other mental health conditions, and explore whether associations varied by reconciliation arm. Methods: We conducted a retrospective cohort study using linked data from the RightRx cluster-randomized trial at the McGill University Health Centre (2014–2016) and Quebec administrative databases. Adults with continuous provincial drug coverage for at least 12 months before admission who met study eligibility criteria were included. The primary exposure was any documented mental health condition; secondary analyses distinguished serious mental illness (SMI) from other mental health conditions. The primary outcome was any unintended medication discrepancy at discharge; subtype analyses examined omissions, therapeutic duplications, and unintended dose changes. Results: Among 3567 patients, 877 (24.6%) had a mental health condition. Crude discrepancy prevalence was similar between groups. In the prespecified primary analysis, mental health condition status was associated with lower observed odds of any unintended discrepancy at discharge. This unexpected inverse association should not be interpreted as evidence of a protective effect and may reflect differences in documentation, residual confounding, selection, or other unmeasured processes. Secondary and supplementary analyses, including omission and SMI subgroup comparisons, did not remain statistically significant after Holm correction. Conclusions: These findings suggest that documentation-based discrepancy measures may relate to mental health status in heterogeneous ways, but they require confirmation in independent settings. Full article

Obtaining amorphous forms of drugs is one of the ways to increase bioavailability. This is especially important for active pharmaceutical ingredients belonging to class II and IV according to the biopharmaceutical classification. These compounds include the currently widely used fluoroquinolone antibiotics. They have low solubility in water and are therefore typically used as hydrochlorides. The presence of a strong acid and a charged active pharmaceutical ingredient in the drug increases solubility, but can also lead to additional side effects and decreased permeability. One way to improve the properties of active pharmaceutical ingredients is to convert them to amorphous form. In this study, an amorphous form of the fluoroquinolone antibiotic norfloxacin was obtained, its stability was determined, and its solubility was studied. It was shown that the resulting amorphous form has good temporal stability. The optimal models describing the cold crystallization process are the Nakamura and Sbirrazzuoli models. Despite the slower dissolution kinetics compared to the crystalline sample, the amorphous form shows higher equilibrium solubility values. These results can be used in pharmaceutical engineering to produce amorphous forms of active pharmaceutical ingredients and determine their stability. Full article

This investigation addressed challenges in the delivery of poorly soluble drugs, and the colloidal processing of polymer–ceramic composites by fabrication of advanced supramolecular hydrogels. Polygalacturonic acid (PGA) polymer and 18β-glycyrrhetinic acid (GA) drug, both characterized by poor aqueous solubility, were selected as model building blocks for supramolecular hydrogels. Meglumine (MG) served as a multifunctional component in the gels, acting as a building block as well as an alkalizing and solubilizing agent for PGA and GA. Investigations revealed gel formation mechanisms, which were based on the electrostatic interactions of deprotonated anionic carboxylic groups of PGA and GA with protonated amino groups of MG and the hydrogen bonding of PGA polymer and GA molecules. The feasibility of the fabrication of PGA-MG and GA-MG gels opened an avenue for the fabrication of PGA-GA-MG gels. The composite gels provided a platform for drug delivery, and the kinetics of drug release from the composite gels containing MG excipient were investigated. Composite gels were obtained from colloidal dispersions, containing bioceramics, such as hydroxyapatite, silica, and titania, and bioglass in the PGA solutions in the presence of MG. The results of this investigation pave the way for the fabrication of novel supramolecular and composite gels loaded with various functional materials. Full article

Background: Chronic exposure to addictive substances induces persistent alterations in neural dynamics, reflecting maladaptive brain plasticity. While such changes are well documented using neuroimaging techniques, their electrophysiological signatures—particularly those derived from nonlinear EEG complexity—remain insufficiently explored across diverse substance use profiles. This preliminary study aims to investigate whether nonlinear EEG complexity measures can serve as sensitive biomarkers of maladaptive plasticity in substance use disorder (SUD) across multiple substance categories. Methods: A total of 350 participants were included and categorized into seven groups (n = 50 each): six substance use groups (cannabis, heroin, heroin–cannabis, methamphetamine–cannabis, methamphetamine–heroin, and multi-drug) and one control group without a diagnosis of substance use disorder. Resting state EEG signals were recorded using an eight-channel system. Four nonlinear features, Largest Lyapunov Exponent (LLE), Fractal Dimension (FD), Hurst Exponent (HE), and Kolmogorov Complexity (KC) were extracted. Statistical analysis was performed using two-way ANOVA, and classification was conducted using the K Nearest Neighbour (KNN) algorithm. Results: Significant group differences (p < 0.05) were observed across all nonlinear features. Control participants without a diagnosis of substance use disorder consistently exhibited higher complexity values compared to substance use groups, indicating reduced neural dynamical variability associated with the history of sustained substance uses over multiple years. Region wise analysis revealed that frontal and central cortical areas linked to motor planning and sensorimotor integration were particularly affected. The KNN classifier achieved an accuracy of 98.4%, sensitivity of 100%, and specificity of 96.8%. Conclusions: Nonlinear EEG complexity measures provide a robust electrophysiological marker of substance induced maladaptive brain plasticity. The observed reduction in complexity reflects impaired neural adaptability, particularly within motor control networks. These findings highlight the potential of EEG based complexity metrics for objective assessment, classification, and neurorehabilitation monitoring in substance use disorders. Full article

Background: Cancer remains a major global health challenge, with treatment efficacy often limited by drug resistance and adverse effects. Drug repurposing offers promising opportunities for developing novel anticancer strategies. This study evaluated the cytotoxic, antiproliferative, and pro-apoptotic effects of metformin and caffeine, administered individually and in combination, in human cancer cell lines, as well as their potential interaction mechanisms. Methods: Human cervical carcinoma (HeLa), lung adenocarcinoma (A549), and colorectal carcinoma (HT29) cell lines were treated with metformin (0.05–50 mM) and caffeine (0.5–5 mM), either alone or in combination, for 24 and 48 h. Cell viability and proliferation were assessed using Trypan Blue and sulforhodamine B (SRB) assays. Apoptosis was analyzed by Annexin V/propidium iodide flow cytometry, and p53 expression in HeLa cells was determined by ELISA. Statistical analysis was performed using a one-way ANOVA followed by Tukey’s post hoc test. Results: Metformin induced dose- and time-dependent cytotoxicity in all tested cell lines, with the lowest IC₅₀ values observed in HeLa and A549 cells after 48 h (2.28 and 3.30 mM, respectively; p < 0.05). Caffeine showed moderate antiproliferative activity, with the strongest effects observed at 2.03 mM in HeLa cells and 2.01 mM in HT29 cells (p < 0.05). The combined treatment produced effects that varied depending on both the cell line and exposure time. At earlier time points, transient synergistic effects were observed in certain cell lines, particularly HeLa cells; however, these effects were not sustained over time. With prolonged exposure, the interaction shifted predominantly toward antagonistic effects, indicating the reduced overall efficacy of the combination compared with the expected additive outcomes. Increased apoptosis and elevated p53 expression further supported the activation of tumor-suppressive pathways. Conclusions: Metformin exhibited significant anticancer activity in vitro, supporting its potential repurposing in oncology. However, the addition of caffeine did not uniformly enhance its efficacy and appeared to exert context-dependent effects. Further in vivo studies are required to confirm the clinical relevance of these findings. Full article

Background/Objectives: Multiple Sclerosis (MS) is a chronic disease with significant clinical and radiological heterogeneity. This fact, together with the increased number of disease-modifying treatments available, poses challenges in the therapeutic decisions and for the overall management of the disease. In this study, an expert panel on MS from Greece aimed to formulate a consensus, in order to provide recommendation on disease-modifying treatment (DMT) initiation and switching, as well as de-escalation strategies in Relapsing MS (RMS). Methods: The study followed two-round voting based on a modified Delphi setting. A questionnaire was constructed by a subgroup of five experts (core group) and was subsequently administered in a printed form to a group of 12 MS experts in total (panel) in a face-to-face meeting. Consensus required at least 80% agreement within the panel in order to signify strong consensus. Results: The panel agreed that the overall therapeutic plan (DMT choice) must take into consideration the degree of disease activity (low/moderate/high). In certain cases with suboptimal response to a moderate-efficacy DMT, a horizontal switch to another moderate-efficacy DMT may be a valid strategy. However, in cases exhibiting disability accumulation, therapy escalation should be preferred. The concept of de-escalation was suggested as an alternative strategy for cases with stable disease receiving a high-efficacy long-term DMT in the long term. Due to the possibility of rebound phenomena with certain medications (such as fingolimod and natalizumab), a bridging strategy could be applied in cases of family planning and drug-related adverse events (such as lymphopenia and hepatotoxicity), especially in PwMS with recent inflammatory activity. Conclusions: Although novel biomarkers may soon help clinicians predict future disability accumulation, currently, regular and detailed patient monitoring seems to be the optimal way to guide clinicians’ decisions on treatment changes. Full article

Background/Objectives: Type 2 diabetes is a group of metabolic disorders whose pathophysiological outcome is sustained hyperglycemia. Several medications are available for the treatment. SGLT2 simultaneously inhibits glucose and sodium reabsorption in the renal proximal tubule, resulting in urinary glucose excretion. This study assessed the pharmacokinetic profiles of two empagliflozin 25 mg drug products under fasting conditions in healthy Mexican subjects to establish bioequivalence. Methods: This was a randomized, open-label, two-way crossover, single-dose, prospective study with a 7-day washout period. Eligible subjects were healthy adult Mexican volunteers. The drugs were dosed orally, according to the randomization, after 10 h of fasting and 4 h before breakfast, with 250 mL of 10% glucose solution at room temperature. Serial blood samples were collected before and after dosing. Empagliflozin concentrations were analyzed using high-performance liquid chromatography–tandem mass spectrometry. Results: A total of 32 subjects were enrolled, and 30 completed the study. Pharmacokinetic parameters C_max, t_max, AUC_0–t, AUC _0–∞, and t_½ of empagliflozin for test and reference formulation, expressed as mean ± SD, were 578.28 ± 125.60 ng/mL, 2.72 ± 0.85 h, 4370.88 ± 769.50 ngh/mL, 4423.93 ± 776.02 ngh/mL, 7.62 ± 0.83 h, and 593.99 ± 156.78 ng/mL, 2.86 ± 1.00 h, 4313.24 ± 885.02 ngh/mL, 4368.04 ± 887.75 ngh/mL, and 7.61 ± 0.68 h, respectively. The 90% CI for C_max, AUC_0–t, and AUC _0–∞ were 98.30 [92.72–104.22], 101.72 [98.77–104.77], and 101.64 [98.73–104.63], respectively. Serious adverse events were not observed. Conclusions: Our study demonstrated bioequivalence between the empagliflozin formulations tested in healthy subjects under fasting conditions. Full article

Eicosanoids and their receptors act as key regulators of inflammation, calcium homeostasis, mitochondrial function, and cardiomyocyte survival, thereby contributing to the onset and progression of cardiac dysfunction. This review aims to summarize the evidence to underscore the pivotal role of eicosanoids and their receptors in the pathophysiology of cardiomyopathy, analysing the potential protective activity of traditional and natural compounds to counteract cardiovascular disease onset and progression. Among eicosanoid receptors, prostaglandin E2 receptor 3 (EP3), prostaglandin E2 receptor 4 (EP4), chemoattractant receptor expressed on type 2 helper T cells (CRTH2), and thromboxane prostanoid (TP) emerge as critical modulators with distinct and often opposing effects on cardiac physiology. While EP3 and CRTH2 are predominantly associated with detrimental outcomes such as impaired contractility and enhanced apoptosis, EP4 signalling consistently demonstrates cardioprotective properties, including improved calcium handling and preservation of mitochondrial integrity. These findings highlight the therapeutic potential of selectively targeting eicosanoid receptor pathways to mitigate cardiac remodelling and dysfunction. In parallel, increasing attention has been directed toward natural bioactive compounds as complementary strategies for cardioprotection. Polyphenols, flavonoids, carotenoids, and other nutraceuticals exert beneficial effects through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, often intersecting with eicosanoid signalling pathways. Their ability to modulate oxidative stress and inflammatory responses suggests a promising role in preventing or attenuating cardiomyopathy, particularly in metabolic and drug-induced contexts. Future research should focus on well-designed clinical trials, a deeper characterization of receptor-specific signalling networks, and the development of targeted therapies that combine pharmacological and nutraceutical approaches. Overall, a better understanding of eicosanoid-mediated mechanisms may open new ways for cardiomyopathy prevention and treatment, ultimately improving patient outcomes and reducing the burden of cardiovascular disease. Full article

Natural products are the fundamentals of drug discovery due to their exceptional structural diversity and biological activity’s evolutionary optimization. The review provides a critical and integrative analysis of natural products in pharmaceutical chemistry, highlighting their significance for current biomedicine and pharmacotherapy. The review is organized around a system that connects structure, function, and translation, focusing on structural analysis, scaffold design, and mechanistic understanding in major disease-relevant therapeutic areas. Investigations on representative compounds like paclitaxel, artemisinin, and curcumin are presented to explain the way molecular architecture regulates pharmacological activity, drug selectivity, and clinical performance. The review evaluates significant medicinal chemistry strategies, including semisynthetic modification, prodrug design, and scaffold optimization, and their crucial roles in enhancing potency, pharmacokinetics, and safety. We critically examine the latest advancements in drug delivery technologies, particularly those based on nanotechnology and carrier-free methods, regarding their translational potential and regulatory concern. Current challenges pertaining to pharmacokinetics and ADMET properties, as well as the standardization of analysis, are also examined, emphasizing their impact on reproducibility in research. Researchers investigate the role and limitations of emerging fields such as genome mining, synthetic biology, and network pharmacology in enhancing discovery pipelines. Thus, this review integrates chemical, pharmacological, and translational approaches and suggests an effective strategy to overcome challenges in the development of natural products as the next generation of precision medicine therapeutic agents. Full article

Autophagy is a self-degradative homeostatic mechanism that plays an important role in tumor viability, metabolic reprogramming, and drug resistance. Circulating tumor DNA (ctDNA) is fragmented DNA that comes from dying tumor cells and leaks out into the blood stream. ctDNA can now be measured through blood tests and is a non-invasive way to identify cancer. ctDNA has shown promise for early detection of cancer, prognosis, and monitoring treatment response in real time. There is emerging mechanistic evidence suggesting a potential relationship between autophagy and ctDNA dynamics which has been discussed as a new autophagy–ctDNA axis. Autophagy can affect ctDNA levels by promoting or suppressing apoptosis and necrosis of tumor cells. When autophagy is cytoprotective, less DNA would be shed into the bloodstream. When autophagy is inhibited or defective, more DNA would be released because of increased genomic instability. Stressors found within the tumor microenvironment (TME) like hypoxia, oxidative stress, and nutrient depletion can also induce autophagy and indirectly affect ctDNA. Targeting autophagy therapeutically with drugs that induce or inhibit autophagy such as chloroquine (CQ) or mechanistic target of rapamycin (mTOR) inhibitors can affect ctDNA concentrations. Although emerging mechanistic evidence suggests a potential relationship between autophagy and ctDNA dynamics, direct clinical studies validating this interaction remain lacking. Therefore, this review presents the autophagy–ctDNA relationship as a hypothetical and exploratory model that warrants further mechanistic and translational investigation in cancer development, therapeutic resistance, and clinical applications. Full article

Background and Objectives: Potential anti-neoplastic effects of resveratrol, which has antioxidant features combined with clomipramine, which has antineoplastic features, or with gemcitabine, used as a nucleoside analog widely used in chemotherapy, were evaluated together and individually on the HL-60 leukemia cells in this in vitro screening study. Materials and Methods: HL-60 cells were treated with gemcitabine, clomipramine, resveratrol, or their combinations at concentrations ranging from 1 to 200 µM. Cell viability was assessed at 24, 48, and 72 h using the trypan blue exclusion method, and results are expressed as a percentage of time-matched untreated controls. Cell proliferation was further evaluated by bromodeoxyuridine (BrdU) immunohistochemical labeling. All experiments were performed in triplicate, and statistical analyses were conducted using one-way analysis of variance (ANOVA) with post hoc comparisons. Results: Gemcitabine markedly reduced HL-60 cell viability at all concentrations and time points (p < 0.001), indicating strong time-dependent cytotoxicity, with a significant drop in BrdU proliferation index at 48 h (p < 0.001). Clomipramine exhibited a biphasic response: high concentrations decreased viability (p < 0.05), while low concentrations allowed partial recovery by 72 h. Resveratrol showed concentration-dependent cytotoxicity, with reduced viability at high concentration and near-control levels at low concentration by 72 h; BrdU indices remained significantly lower than control (p < 0.001). Combination treatments with gemcitabine showed no additive cytotoxic or antiproliferative effects (p > 0.05). A transient enhanced effect was observed in the clomipramine + resveratrol group at 24 h (p < 0.01 vs. clomipramine; p < 0.05 vs. gemcitabine). Conclusions: Gemcitabine, clomipramine, and resveratrol all exhibited inhibitory effects on cell proliferation in HL-60 cell cultures. However, the combination treatments did not show additional cytotoxicity or additive effects. These findings suggest that while each of these compounds individually has the potential to inhibit cell growth, their combined application does not enhance the cytotoxic effects beyond those observed with single treatments. These findings highlight the necessity of a rational approach when considering novel drug combinations. Full article