Although expression-based omics has greatly contributed to biological research, the biochemical state of cells or tissues cannot be fully explained by transcript or gene expression data alone. This systematic review investigated when matrix-assisted laser desorption/ionisation (MALDI)-based approaches can support the integration of multiple molecular layers and when they remain limited to single-class molecular mapping. PubMed was searched between 1 February and 8 June 2026. English-language peer-reviewed publications relevant to the principles, methods, molecular classes, or biomedical applications of matrix-assisted laser desorption/ionisation-based multiomics were eligible. Publications outside this scope were excluded. Records were independently screened by two reviewers, and disagreements were resolved through discussion. The findings were narratively synthesised based on the analytical platform, molecular layer, integrated spatial multiomics, spatial application, and biomedical use. The methodological quality and risk of bias were not formally assessed, which limits the certainty and strength of the conclusions drawn from this narrative synthesis. Following the reapplication of the relevance criteria, 111 publications from 1633 identified records were included in the final review. The evidence was reclassified and presented separately as true multilayer MALDI studies, MALDI integrated with orthogonal modalities, and background uniomics or spatial molecular profiling studies. These publications included human, animal, cellular, tissue-based, and methodological studies. These publications cover many molecular classes and biomedical applications. As many publications did not involve human participants, a single pooled participant total was not applicable to this study. Matrix-assisted laser desorption/ionisation-based techniques were used to analyse metabolites, lipids, glycans, peptides, and intact proteins in the reviewed literature. The literature also shows that spatial information can be retained using matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI-IMS). Its ability to map molecular signals back to specific tissue regions or areas associated with disease supports its potential clinical utility. Specific areas of application, such as cancer, neurological, and infectious disease research, are also reviewed. The use of matrix-assisted laser desorption/ionisation-based techniques for biomarker discovery has been evaluated. Small sample sizes, proof-of-concept designs, inconsistent outcome reporting, and limited external validation have limited the evidence. Technical limitations include ion suppression, limited quantification, sample preparation variability, and differing analyte sensitivity. Emerging developments, such as single-cell imaging and AI analysis, have also been explored. Matrix-assisted laser desorption/ionisation enables multiomics when two or more complementary molecular layers are analysed and integrated within the same biological system. When only a single molecular class is analysed, the approach remains spatial molecular mapping rather than multiomic analysis. However, before matrix-assisted laser desorption/ionisation-based approaches can be applied in routine clinical practice, standardised workflows and better quantitative methods are needed. This review received no external funding and was not registered.
Chronic musculoskeletal pain remains a leading cause of disability worldwide, driven by progressive degeneration of cartilage, bone, tendon, intervertebral discs, and peripheral nerves. Conventional interventional approaches primarily address symptoms without restoring structural integrity or tissue homeostasis. Regenerative strategies, including platelet-rich plasma, mesenchymal stem cells, and biomaterials, have demonstrated potential but are limited by variability in outcomes, poor cellular survival, and lack of standardization. Exosomes and extracellular vesicles are key mediators of intercellular communication in tissue repair, reproducing many of the paracrine effects of parent cells while offering improved safety and scalability. These nano-sized vesicles regulate inflammation, angiogenesis, extracellular matrix remodeling, and cell survival across musculoskeletal and neural tissues. Importantly, growing evidence suggests that mechanical cues such as compression, shear stress, and tensile loading not only regulate cellular behavior but also shape exosome biogenesis, cargo composition, and functional effects through mechanotransduction pathways involving integrins, ion channels, and YAP/TAZ signaling. This mechanobiology–exosome interface is particularly relevant in interventional pain medicine, where therapeutics are delivered into mechanically active environments such as joints, discs, tendons, and perineural spaces. Mechanical loading conditions may therefore modulate therapeutic efficacy by shaping both endogenous repair processes and the behavior of administered exosomes. The present investigation reviews the current literature and knowledge on mechanotransduction pathways and exosome biology, with a focus on their intersection in musculoskeletal regeneration. We further examine preclinical and clinical evidence supporting exosome-based therapies in osteoarthritis, degenerative disc disease, tendon and ligament injuries, and neuropathic pain states, alongside key translational challenges including heterogeneity in exosome isolation, dosing, biodistribution, and clinical standardization. Finally, we discuss future directions in mechanobiology-guided exosome engineering and their potential integration into interventional pain practice.
Laurus nobilis L. (Lauraceae), widely recognized as bay laurel, has long held prominence in traditional medicine across diverse cultures and has attracted growing attention within contemporary pharmacological research. This review endeavors to synthesize and critically evaluate evidence from in vitro, in vivo, and clinical studies to elucidate the therapeutic potential of this species, an aromatic evergreen shrub native to the Mediterranean region. Its leaves and essential oil have long been utilized in culinary and traditional medicine, and recent scientific studies have revealed a wide range of pharmacological properties. A comprehensive literature search was conducted using the keyword “Laurus nobilis L.” across Scopus, PubMed, and Google Scholar databases. The search included English-language resources published up to 31 January 2025, focusing on in vitro, in vivo, and human studies. Exclusion criteria encompassed letters, conference proceedings, and articles related to agriculture, genetics, nursing, environmental and veterinary sciences, multidisciplinary studies, and non-medical or pharmaceutical themes. The findings indicate that L. nobilis exhibits diverse pharmacological activities, including wound-healing, dental plaque-reduction, hepatoprotective and gastroprotective effects, antidiabetic activity, antioxidant and anti-inflammatory properties, antimicrobial and antiparasitic effects, neuroprotective potential, antigenotoxic and anti-hypersensitivity actions, and renal protection. This review manuscript seeks to further illuminate the pharmacological potential of Laurus nobilis while articulating the biophysical underpinnings and mechanistic coherence through which its bioactive constituents manifest their therapeutic effects. In conclusion, L. nobilis demonstrates significant promise as a natural, effective, and safe therapeutic candidate for various health conditions. Nonetheless, further clinical research is warranted to substantiate its efficacy and safety, thereby enabling its integration into evidence-based medical practice.
Background: The development of osteoarthritis (OA), a whole-joint disorder that is increasingly recognized, depends on subchondral trabecular bone. Variations in the viscoelastic characteristics of trabecular bone have been proposed to affect load distribution and potentially lead to joint degradation. The viscoelastic response of human trabecular bone in both healthy and osteoarthritic situations was investigated using constitutive modeling and stress-relaxation testing. Fifteen tibial trabecular bone specimens were evaluated using Standard Linear Solid (SLS) models and two-branch generalized Maxwell models following uniaxial stress-relaxation testing. Mechanical, energy, and relaxation-related traits were retrieved and compared between groups. Results: Healthy bone tended to relax stress more slowly and to bear mechanical loads over time to a slightly greater extent than osteoarthritic bone, which tended to relax stress more quickly and had poorer mechanical endurance; these differences were not statistically significant. The Generalized Maxwell model suited the experimental data better than the SLS model (R2 > 0.98), capturing both short- and long-term relaxation mechanisms. Sensitivity analysis revealed higher parameter variability in OA specimens, suggesting possible differences in mechanical heterogeneity and load-dissipation behavior that require further investigation. Conclusions: Although the observed differences were not statistically significant in this exploratory study, the results suggest potential trends toward altered viscoelastic behavior between healthy and osteoarthritic trabecular bone. Future studies with larger cohorts are needed to further investigate osteoarthritis-related biomechanical alterations. Multi-branch viscoelastic modeling may provide sensitive mechanical descriptors for characterizing the relaxation behavior of subchondral bone.
This study investigated the effects of terpene compounds from Schinus molle fruit essential oil (EO) against osteoarthritis (OA) using integrated network pharmacology, molecular docking, and molecular dynamics. The EO, obtained by steam distillation (yield: 6.95%), was characterized by GC-MS, detecting 55 peaks (98.61% of the total), of which 49 were identified and dominated mainly by monoterpene hydrocarbons (73.93%), with α-phellandrene (20.35%), camphene (11.36%), and Z-β-ocimene (8.69%) as the major constituents. Additionally, seven compounds with favorable ADME profiles and low predicted toxicity were selected for the target prediction. Overlap analysis between compound targets and osteoarthritis-related genes (Os-teoDIP) revealed 171 common genes that triggered inflammatory pathways, including PI3K-Akt, HIF-1, and NOD-like receptor signaling. Protein–protein interaction network analysis identified 11 hub genes, including TLR4, HSP90AA1, PTGS2, and MAPK1. Molecular docking revealed that γ-cadinene exhibited the best binding affinities, particularly against HSP90AA1 (−6.38 kcal/mol) and TLR4 (−5.87 kcal/mol). A 200 ns molecular dynamics simulation confirmed the stability of the γ-cadinene–TLR4 complex through persistent hydrophobic contacts with residues F379, C391, F409, I310, and F377, with contact occupancy of up to 0.95. The receptor backbone RMSD plateaued between 2.5 and 3.5 Å after equilibration, and the ligand remained in the binding pocket throughout the trajectory. These findings suggest that the terpenes of S. molle EO, particularly γ-cadinene, may modulate the inflammatory pathways related to OA. However, it is necessary to complement experimental validation in vitro and in vivo.
Molecular docking was used to investigate the interactions between tirapazamine (a bioreductive anticancer drug) and bovine serum albumin (BSA), with emphasis on binding site localization and geometry. Docking simulations were performed using SwissDock with the AutoDock Vina 1.2.0 scoring engine. Warfarin (a canonical Sudlow Site I ligand) was docked under the same conditions as a reference to provide a relative comparison of binding orientation within Subdomain IIA. Docking results indicate that tirapazamine occupies a peripheral entrance-region position within Subdomain IIA, with limited polar interactions and substantial solvent exposure. In contrast, warfarin adopts a more enclosed binding orientation consistent with canonical Site I burial. UV–visible measurements across three independent titration experiments yielded apparent association constants of 2.30 ± 1.05 × 104 M−1 (mean ± SD), consistent with a weak interaction regime and supporting the docking results. Geometric analysis further shows that tirapazamine maintains greater minimum ligand–residue distances from core Site I residues than warfarin, consistent with reduced burial. This interpretation is further supported by the physicochemical profile of tirapazamine, which is characterized by low lipophilicity and high polarity, properties that are incompatible with deep binding in hydrophobic pockets (as seen with warfarin). Short-timescale molecular dynamics simulations (2 ns, triplicate) confirmed the stability of the docked poses, with tirapazamine exhibiting markedly lower ligand RMSD variability (0.247 ± 0.002 Å) than warfarin (0.578 ± 0.163 Å), consistent with a stable peripheral binding geometry. Together, these findings support a model in which tirapazamine associates weakly and peripherally with serum albumin, consistent with non-canonical Site I binding.
This study investigated the distribution and dispersion of Sc-47 (47Sc), a β-emitting radionuclide that can be produced in large quantities using accelerators. As the stability of labeled compounds inside the body is essential for nuclear medicine therapy, we examined the biodistribution of free 47Sc to distinguish it from the distribution of compounds labeled with 47Sc. [47Sc]ScCl3 was administered to normal mice. Body distribution, excretion routes, and contamination of laboratory equipment were also measured. 47Sc remained in the blood for long periods and accumulated mainly in the liver and kidneys because of its binding to plasma proteins. Therefore, 47Sc released from the labeled compounds could potentially cause non-specific liver and kidney damage. Most of the 47Sc was eliminated through feces, whereas some was excreted through the urinary system. 47Sc was found in both the liquid and solid components of the blood. Although animal cages were contaminated with excreta, they could be effectively cleaned by wiping with paper. We also used 47Sc produced by us to label PSMA-617 and verified its performance as a nuclear medicine therapeutic agent. Although [47Sc]Sc-PSMA-617 did not exhibit a high accumulation rate in tumors, it demonstrated antitumor activity. This might suggest the usefulness of 47Sc.
There is a growing interest in methods that illuminate the contributions of individual positions to a protein’s function by site-saturating mutagenesis. However, a commonly used approach for assessing variant libraries with deep mutational scanning relies on readouts of biological fitness, which is influenced by many protein properties (ligand binding, catalysis, allosteric effector binding, allosteric coupling between effector and substrate, etc.). Biochemical assays are required to distinguish among these factors. To facilitate the generation and biochemical evaluation of the functions of large numbers of substituted positions, we co-express updated plasmids coding a series of amber suppressor tRNA in a high-throughput workflow; these plasmids are available at Addgene. As an example, our goal is to evaluate whether allosteric mechanisms are conserved among homologs. Because homologs often have <50% identity, and up to 30% of a protein’s positions can contribute to allosteric function, we reason that the set of “allosteric” positions likely differs among homologs. Our high-throughput workflow includes the following steps: Step (1) an amber suppressor tRNA-based mutagenesis protocol; Step (2) a robotic system for protein expression/purification and functional assays; and Step (3) a method for aggregating results from multiple substitutions at each position into a composite score.
We herein report the anticancer activity and molecular docking studies of a series of amide derivatives of two nonsteroidal anti-inflammatory drugs (mefenamic acid and ibuprofen). The hypothesis of drug repurposing has been successfully employed to explore the promising anticancer activity of analogs of known anti-inflammatory agents. The compounds have been tested for their inhibitory potential against cervical cancer cell lines by MTT assay using 5-fluorouracil as the reference standard. Among the compounds screened, 3aa [2-(2,3-dimethylamino)phenyl)(1H-indol-1-yl)methanone] and 3ad [2-(2,3-dimethylphenylamino)phenyl)(9H-carbazol-9-yl)methanone] displayed good potency of less than 25 µg/mL half-maximal inhibitory concentration (IC50). The docking analysis has confirmed that molecule 3aa effectively binds to the active site of the target protein CDK2, with a docking score of −9.21 Kcal/mol and a binding energy of −46.44 Kcal/mol, involving a hydrogen bond with Ile 10. The molecule 3ad also exhibited a good glide score of −6.78 Kcal/mol with the binding energy of −45.90 Kcal/mol. As many of the tested compounds displayed promising potency against cervical cancer cell lines, our investigation revealed the importance of drug repurposing in the development of lead molecules in medicinal chemistry.
Chagas disease remains a major neglected parasitic illness in Latin America and other endemic regions, and benznidazole (BZN) is still the primary trypanosomacidal drug despite its incompletely understood mechanism of action. This work provides a detailed biophysical characterization of the conformational behavior and vibrational properties of benznidazole (BZN), a first-line trypanocidal drug still widely used for the treatment of Chagas disease. Using density functional theory combined with relaxed potential energy surface scans in vacuum and implicit water, two low-energy conformers (BZN1 and BZN2) were identified, separated by moderate rotational barriers and a small energy difference, indicating that both are intrinsically accessible at room temperature. For each conformer, infrared and Raman spectra were calculated and assigned via vibrational mode analysis, then compared with FT-IR and FT-Raman spectra recorded for pharmaceutical-grade polycrystalline BZN. The theoretical and experimental spectra show excellent agreement, with a Raman band in the 1350-1400 cm-1 region emerging as a sensitive conformational marker: the experimental maximum at 1359cm-1 matches the most intense BZN1 mode, whereas the corresponding BZN2 band appears about 13cm-1 higher in frequency. This clear spectroscopic fingerprint demonstrates that the solid drug is overwhelmingly composed of the BZN1 conformer, despite the theoretical accessibility of BZN2. Overall, the study links the conformational landscape of benznidazole to its vibrational signatures and highlights Raman spectroscopy, supported by quantum chemical calculations, as a powerful tool for conformational and potential polymorphic control of this clinically important nitroimidazole.
Herein, we report a simple procedure regarding the photodynamic therapy (PDT) treatment as a minimally invasive modality for treating superficial bladder cancer that utilizes a photosensitizer, light, and oxygen to generate cytotoxic reactive oxygen species (ROS). This study evaluates the histopathological and morphological changes induced by PDT in an ex vivo model of low-grade (LG) pTa non-muscle-invasive bladder cancer (NMIBC). We investigated the efficacy of exogenous protoporphyrin IX (PpIX) and Rose Bengal (RB) by incubating tissue samples (n = 30) with an oxygen-saturated solution of PpIX (1-3 mM) or RB (0.3-0.5 mM) for one hour. Since the criticism of using frozen tissue in research already exists, this framing explains how to mitigate those limitations. Thus, we use oxygen-saturated solutions PpIX and oxygen-saturated solutions of RB. We discussed a few aspects related to the use of frozen tissue in PDT. Frozen tissue preserves lipids critical for assessing membrane damage and maintains higher levels of metabolic markers like antioxidant molecules like glutathione and more likely lack factors such as metabolic activity, intact cell membranes, and oxygenation. It is critical to differentiate between "artifactual" changes and the "pathological" death of cells. Thus, we used histopathological microscopy observation typically used in daily clinical investigations to characterize cells before and after PDT. Following irradiation with the light dose of 72 J/cm2 (410 nm or 532 nm at 300 mW for 15 min), hematoxylin-eosin staining revealed concentration-dependent apoptotic changes, including chromatin condensation, pyknosis, and nuclear fragmentation. While both agents induced cell death, RB demonstrated faster and more intense cytotoxicity than PpIX. These findings provide microscopic evidence of PDT-induced tumor destruction and suggest that RB is a potent candidate for further preclinical evaluation. At 410 nm (deep blue/violet), light penetration in biological tissue is very shallow, typically only around 0.3 to 1 mm; therefore, in a 2 mm thick tissue sample, most of the light would be absorbed within the first millimeter, with minimal light reaching the full depth of tissues. In this protocol, the generated ROS is used to destroy tumor tissue by attacking the cellular microenvironment directly. This led to immediate membrane disruption and lipid peroxidation. The proof-of-concept is an early-stage study designed to verify that a PDT treatment is feasible, safe, and biologically active in an ex vivo model of LG pTa NMIBC.
Lactose is widely used as a pharmaceutical excipient, yet little is known about how its physicochemical behavior may be influenced by pretreatment history and weak environmental magnetic conditions. In this pilot study, we investigated oxidation-reduction potential (ORP) and UV absorbance of 0.2% aqueous lactose solutions prepared from lactose powders with different pretreatment histories: Active water, Native water, and untreated control. Samples were exposed for 30 min to three static magnetic field conditions: weak geomagnetic field (similar to 4 mu T), ambient geomagnetic field (similar to 30 mu T), and elevated static field (similar to 750 mu T). UV/VIS spectroscopy was performed in the 200-400 nm range, with particular focus on the deep-UV absorption maximum near 200 nm. The strongest differentiation between pretreated samples and control occurred under weak geomagnetic conditions. In this weak-field regime, pretreated lactose solutions showed higher ORP values and a same-direction trend toward increased UV absorbance near 200 nm relative to untreated lactose. Across all samples, both ORP and UV absorbance decreased with increasing magnetic field strength, indicating a consistent field-dependent shift in the overall physicochemical state of the lactose solutions, particularly in redox balance and deep-UV optical response. The same-direction changes in ORP and increased 200 nm absorbance at the group level suggests that weak-field conditions may influence oxidation-related processes, potentially including the formation or stabilization of lactose oxidation products such as lactobionic acid. These findings indicate that lactose-containing aqueous systems may be sensitive to both pretreatment history and low-intensity magnetic environments, with potential implications for pharmaceutical formulation stability, quality control, and biotechnological reproducibility.
Beta Secretase (BACE1) is a well-validated target for Alzheimer's therapies, but there has been attrition in drug development. Herein, we leveraged machine learning (ML), virtual screening and molecular dynamics (MD) to identify novel compounds with potential activity against BACE1. We developed ML algorithms to distinguish active and inactive compounds from public databases. Molecular docking and dynamics were used to explore the inhibition mechanism, thermodynamic stability, and the flap dynamics of the BACE1-ligand complexes. Random Forest Classifier (RF) showed excellent metrics (accuracy: 0.9807; F1 score: 0.9804; specificity 0.9977), compared to other models. Molecular docking with predicted actives revealed compounds BA1, BA2, and BA3 with strong affinity for BACE1. Compound BA2, a cysteinyl sulfoxide derivative, showed good stability (RMSD) during simulations (1.307 +/- 0.109 & Aring;) compared to Verubecestat (1.602 +/- 0.159 & Aring;). MMGBSA-based binding free energy (Delta Gbind; kcal/mol) showed that BA2 (-33.820 +/- 4.254) had comparatively lower energy than Verubecestat (-21.090 +/- 6.183). BA2 maintained electrostatic interactions with the catalytic dyad (Asp36 and Asp232) and Thr76 of the flap. BA2 also maintained the flaps in a semi-open conformation (d0: 11.807 +/- 0.401 & Aring;) throughout the simulation. Our study clearly demonstrates the utility of ML in prioritization of compounds before molecular docking and MD in early phases of drug discovery.
Cynodon dactylon (Bermuda grass) is a perennial medicinal grass widely distributed across tropical and subtropical regions and known for its antioxidant and anti-inflammatory properties. The present study aimed to identify bioactive metabolites from the leaves of C. dactylon and evaluate their potential interaction with PTEN-induced kinase 1 (PINK1), a crucial regulator of mitochondrial quality control implicated in neurodegenerative disorders, particularly Parkinson's disease. GC-MS analysis identified a total of 95 phytochemicals, of which the top 20 metabolites were selected based on retention time and area percentage. These metabolites were subjected to virtual screening using PyRx, with ATP employed as the reference ligand. Among the screened metabolites, 5,8,11-eicosatrienoic acid was the high-affinity compound which predicted a binding affinity of -5.9 kcal/mol and forming two hydrogen bond interactions within the PINK1 active site. The docked complexes were further evaluated through a 100 ns molecular dynamics simulation in replicates that showed stable binding of the protein-ligand complex, as reflected by RMSD values, reduced residue fluctuations and stable radius of gyration and solvent-accessible surface area. These findings suggest that 5,8,11-eicosatrienoic acid from C. dactylon may act as a potential PINK1 modulator for Parkinson's disease.
The Senegal tree (Sengalia senegal) is the primary plant source of Gum Arabic (GA), a natural secretion rich in soluble fiber and bioactive polysaccharides. It has longstanding uses in traditional medicine, nutrition, and pharmaceuticals. The present study aimed to evaluate the phytochemical profile, antimicrobial, anti-inflammatory, and anticancer activities of GA methanolic extract (GAME), supported by molecular docking analysis of its key compounds. The gas chromatography-mass spectrometry (GCMS) analysis of the GAME identified many compounds, such as 9-octadecenoic acid (38.29%), methyl ester (15.52), 1,2-benzenedicarboxylic acid, 3-nitro (9.8%), hexadecadienoic acid, methyl ester (8.5), and & aacute;-d-mannofuranoside, methyl (7.38). The molecular docking analysis showed that 9-octadecenoic acid had strong binding affinity with target proteins, which included xanthine oxidase (XO), lipoxygenase (LOX), and cyclooxygenase-2 (COX-2), with the highest affinity to XO (-137.03 kcal/mol) and lipoxygenase (-135.09 kcal/mol). GAME possessed broad-spectrum antibacterial activity against Salmonella typhimurium (S. typhimurium), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), and Staphylococcus aureus (S. aureus), with a zone of inhibition from 16.28 to 16.93 mm. B. subtilis was resistant to the tested extract. The extract also showed good membrane stability and potent inhibition of albumin, XO, LOX, and COX-2, with IC50 values of 31.62, 13.02, 27.6, and 28.99 mu g/mL, respectively. The cytotoxic assessment demonstrated moderate, dose-dependent effects on the Caco-2 (colorectal adenocarcinoma) and HeLa (cervical carcinoma) cell lines. These findings highlight the therapeutic potential of GA as a natural plant source of antibacterial, anti-inflammatory and anticancer agents. The combination of molecular docking with in vitro assays provides strong evidence supporting its application in the development of plant-based pharmaceuticals. This research suggests that GA could be a useful ingredient in the creation of anti-inflammatory and antibacterial drugs derived from plants.
A Fixed-dose combination (FDC) therapy of ezetimibe (EZT) and atorvastatin (ATV) is increasingly prescribed for high-risk hyperlipidemic patients with cardiovascular disease. However, the pharmaceutical production of FDC EZT/ATV tablets often results in poor ATV dissolution under acidic conditions, failing to meet regulatory requirements. This study aimed to improve ATV dissolution in acidic media through nanosuspension (NS) technology and microenvironmental pH modification. The experimental stages included preparation and characterization of ATV-NS, optimization of FDC EZT/ATV-nanocrystal tablets with pH modifiers, and evaluation of dissolution similarity (f(2)) against the innovator product Atozet (R). ATV-NS was prepared via sonication and high-pressure homogenization using different stabilizers. Poloxamer 188-stabilized ATV-NS demonstrated optimal stability (particle size: 466.6 +/- 8.9 nm; polydispersity index: 0.12 +/- 0.10; zeta potential: -44.20 +/- 0.06 mV) and significantly enhanced solubility (p < 0.05) compared with pure ATV. FDC EZT/ATV-nanocrystal tablets incorporating pH modifiers achieved f(2) values for ATV of 52.36, 51.31, and 51.09 in NaCl/HCl pH 1.2, acetate buffer pH 4.5, and phosphate buffer pH 6.8, respectively. In contrast, EZT exhibited f(2) values of 18.18, 16.72, and 14.66 (acceptable range: 50-100). Although complete profile similarity was not obtained for EZT, ATV dissolution in acidic media improved significantly (p < 0.05), supporting the feasibility of developing a bioequivalent generic FDC EZT/ATV tablet.
Alzheimer's disease (AD) is the most common form of dementia, characterized by the progressive accumulation of amyloid beta (A beta) plaques and neurofibrillary tangles of tau protein in and around neurons. However, these markers appear relatively late in the disease, and their direct causality is incompatible with clinical observations. Extensive data suggest that dysregulation of Ca2+ signaling is an early event in the pathogenesis of AD. In familial AD (FAD), mutations in presenilin are shown to alter Ca2+ homeostasis by affecting the gating properties and/or the expression levels of inositol 1,4,5-trisphosphate (IP3) receptors (IP(3)Rs) and ryanodine receptor (RyRs)-the main channels responsible for Ca2+ release from the endoplasmic reticulum (ER). Thus, understanding the mechanism through which these channels disrupt Ca2+ homeostasis at different spatiotemporal scales is crucial to determining their role in AD. Here, we use computational modeling to investigate how the gating kinetics of single IP3R in FAD-affected cells differ from those in wildtype (WT) cells and how these differences translate to impaired Ca2+ signaling at subcellular and whole-cell levels. Our detailed analysis reveals a significantly lower threshold for Ca2+ oscillations at the whole-cell level in terms of agonist concentration, with higher frequency and amplitudes in FAD-affected cells. These results shed new light on the observed Ca2+ hyperactivity in the pre-clinical stage of AD, reporting high-frequency Ca2+ oscillations in neurons.
Telmisartan (TEL) is a non-peptide, orally administered antihypertensive agent primarily known as angiotensin II type 1 (AT1) blocker. In this review, we provide a detailed overview of how TEL modulates voltage-gated Na+ current (INa) and affects action potential (AP) firing behavior. TEL exerts differential stimulatory effects on the peak and late components of INa when subjected to brief depolarizing pulses across a range of cell types, such as mHippoE-14 hippocampal neuron, cultured dorsal root ganglion neurons, and HL-1 atrial cardiomyocytes. TEL can augment the inactivating (persistent) INa elicited by ascending long ramp pulse in mHippoE-14 cells. By using a parvalbumin-expressing interneuron-based modeled cell combined with bifurcation analysis, it is possible to predict how applied current influences subthreshold oscillations and the generation of somatic spiking in the presence of TEL. According to the Hodgkin-Huxley model, mimicking the action of TEL—characterized by an increased peak amplitude of INa and a slowed inactivation time course—leads to the emergence of periodic oscillations in membrane potential. Using a Markovian process, a separate model can also be mathematically constructed, showing that changes in certain rate constants can simulate the effect of TEL on INa in cardiac cells. The molecular docking prediction between TEL and the NaV1.7 channel was made by expected formation of hydrophobic interactions as well as hydrogen bonding. Beyond its antagonistic action on AT1 receptor and agonistic activation of peroxisome proliferator-activator-γ, the direct stimulation of INa may also contribute to its modulation of AP firing in various excitable cells. Current evidence supports TEL’s modulatory impact on NaV channel activity and cellular excitability, while also acknowledging that the mechanism—whether direct or indirect—remains under investigation.
Coaggregation by bridging bacteria such as Fusobacterium nucleatum is considered a key element in dental biofilm development and maturation. Previous studies showed that sublethal exposure to blue light caused damage to cell membrane integrity. The aim of the present study was to test the effect of blue light phototoxicity on this bacterium's ability to coaggregate with the early colonizer Streptococcus sanguinis. Fusobacterium nucleatum bacterial cells were suspended in coaggregation buffer (CAB) and exposed to blue light (400-500 nm) for 0, 70, 140 and 280 s (i.e., fluences of 0, 96, 192 and 384 J/cm2, respectively). Following blue light exposure, samples were mixed with Streptococcus sanguinis suspensions and coaggregation was measured using a visual scale, spectrophotometric analysis and light microscopy. Results showed that blue light exposure significantly reduced the ability of Fusobacterium nucleatum to coaggregate with Streptococcus sanguinis. These results suggest that blue light antibacterial phototoxicity may be considered as a viable option in preventing dental biofilm-related conditions.
Pulse wave propagation through blood vessels is affected by many biophysical parameters that change with aging. The aim of this study was to investigate both theoretically and experimentally how the pulse wave velocity changes in the vertical position and to introduce a new parameter in biophysics: pulse wave acceleration (PWA). Using a biophysical model of the cardiovascular system, placed in horizontal and vertical positions, pressure waveforms were measured along the arterial tree at several sites at different diastolic pressures and pump frequencies. Blood flow waveforms on the carotid and femoral arteries in the supine and standing positions were measured on the subjects. The results showed that the pulse pressure wave accelerates in the direction of gravity and decelerates in the opposite direction both in the model and in humans. A new biophysical parameter, PWA, was defined, and the experimental results are in agreement with the mathematical model. Due to the acceleration of the pulse wave, the reflected wave in the standing position arrives earlier in systole and contributes to the increase in pressure. This emerging biophysical parameter may contribute to a better understanding of the phenomenon of wave propagation of blood through blood vessels.
