Search Results (362)

Background/Objectives: This study aimed to develop a dry powder inhalation (DPI) formulation of rivaroxaban (RVX) using a combination of bead milling (BM) and jet milling (JM) to enhance lung-targeted delivery for the effective treatment of pulmonary embolism while minimizing systemic exposure. Methods: A carrier-free DPI formulation of RVX was developed using sequential BM and JM, with L-leucine incorporated at various concentrations (1%, 5%, and 10%) as a force control agent. The formulations were characterized for particle morphology, size distribution, crystallinity, and thermal properties. The in-vitro aerodynamic performance was evaluated using a next-generation impactor, while ex-vivo studies assessed anticoagulant activity. Pharmacokinetic and tissue distribution studies were carried out in Sprague Dawley rats following intratracheal administration, and the effects of inhaled RVX were compared with those of oral administration. Results: The optimized BM-JM-5L formulation achieved a Dv50 of 2.58 ± 0.01 µm and a fine particle fraction of 72.10 ± 2.46%, indicating suitability for pulmonary delivery. The two-step milling effectively reduced particle size and enhanced dispersibility without altering RVX’s physicochemical properties. Ex-vivo anticoagulation tests confirmed maintained or improved activity. In-vivo studies showed that pulmonary administration (5 mg/kg) led to a 493-fold increase in lung drug concentration and 2.56-fold higher relative bioavailability vs. oral dosing, with minimal heart tissue accumulation, confirming targeted lung delivery. Conclusions: The two-step milled RVX DPI formulations, particularly BM-JM-5L with 5% leucine, demonstrated significant potential for pulmonary administration by achieving high local drug concentrations, rapid onset, and improved bioavailability at lower doses. These findings highlight the feasibility of RVX as a DPI formulation for pulmonary delivery in treating pulmonary embolism. Full article

Until now, neurodegenerative diseases like Alzheimer’s and Parkinson’s have been studied separately in biochemistry and therapeutic drug development, and no causal link has ever been established between them. This study has developed a Unified Theory, which establishes that the regulation of axon and dendrite-specific 4E-BP2 deamidation rates controls the occurrence and progression of neurodegenerative diseases. This is based on identifying axon-specific 4E-BP2 deamidation as a universal denominator for the biochemical processes of deamidation, translational control, oxidative stress, and neurodegeneration. This was achieved by conducting a thorough and critical review of 224 scientific publications regarding (a) deamidation, (b) translational control in protein synthesis initiation, (c) neurodegeneration and (d) oxidative stress, and by applying my discovery of the fundamental neurobiological mechanism behind neuron-specific 4E-BP2 deamidation to practical applications in medicine. Based on this newly developed Unified Theory and my critical review of the scientific literature, I also designed three biochemical flowsheets of (1) in-vivo deamidation, (2) protein synthesis initiation and translational control, and (3) 4E-BP2 deamidation as a control system of the four biochemical processes. The Unified Theory of Neurodegeneration Pathogenesis based on axon deamidation, developed in this work, paves the way to controlling the occurrence and progression of neurodegenerative diseases such as Alzheimer’s and Parkinson’s through a unique, neuron-specific regulatory system that is 4E-BP2 deamidation, caused by the proteasome-poor environment in neuronal projections, consisting mainly of axons. Full article

Resveratrol is a naturally occurring phenolic compound found in various foods such as red wine, chocolate, peanuts, and blueberries. Both in-vitro and in-vivo studies have shown that it has a broad spectrum of pharmacological effects such as providing cellular protection and promoting longevity. These effects include antioxidant, anti-inflammatory, neuroprotective, and anti-viral properties, as well as improvements in cardio-metabolic health and anti-aging benefits. Additionally, resveratrol has demonstrated the ability to induce cell death and inhibit tumor growth across different types and stages of cancer. However, the dual effects of resveratrol—acting to support cell survival in some contexts, while inducing cell death in others—is still not fully understood. In this study, we identify a novel target for resveratrol: the voltage-dependent anion channel 1 (VDAC1), a multi-functional outer mitochondrial membrane protein that plays a key role in regulating both cell survival and death. Our findings show that resveratrol increased VDAC1 expression levels and promoted its oligomerization, leading to apoptotic cell death. Additionally, resveratrol elevated intracellular Ca²⁺ levels and enhanced the production of reactive oxygen species (ROS). Resveratrol also induced the detachment of hexokinase I from VDAC1, a key enzyme in metabolism, and regulating apoptosis. When VDAC1 expression was silenced using specific siRNA, resveratrol-induced cell death was significantly reduced, indicating that VDAC1 is essential for its pro-apoptotic effects. Additionally, both resveratrol and its analog, trans-2,3,5,4′-tetrahydroxystilbene-2-O-glucoside (TSG), directly interacted with purified VDAC1, as revealed by microscale thermophoresis, with similar binding affinities. However, unlike resveratrol, TSG did not induce VDAC1 overexpression or apoptosis. These results demonstrate that resveratrol-induced apoptosis is linked to increased VDAC1 expression and its oligomerization. This positions resveratrol not only as a protective agent, but also as a pro-apoptotic compound. Consequently, resveratrol offers a promising therapeutic approach for cancer, with potentially fewer side effects compared to conventional treatments, due to its natural origins in plants and food products. Full article

Background/Objectives: Low-frequency alternating current (LFAC) has been shown to induce nerve conduction block (LFACb). However, the effects of LFAC on conduction delay prior to block remain unclear. This study investigates the impact of LFACb on conduction velocity and blocking thresholds in myelinated and unmyelinated fibers using experimental and computational models. Methods: Four models were employed to analyze LFACb effects: (1) in-vivo experiments in earthworms examined conduction delays across nerve bundles with distinct conduction velocities; (2) ex-vivo experiments in canine vagus nerves assessed the upstream and downstream effects of LFAC waveforms ranging from 50 mHz to 500 mHz; (3) in-silico simulations using the Horn, Yoshida, and Schild (HYS) model for unmyelinated fibers explored size-dependent conduction delays and blocking thresholds; and (4) in-silico simulations using the McIntyre, Richardson, and Grill (MRG) model extended to 504 Nodes of Ranvier characterized myelination effects, localized nodal interactions, and diameter-dependent thresholds. Results: LFAC-induced conduction delays were independent of LFAC frequency but strongly influenced by fiber diameter and conduction velocity. Larger fibers exhibited lower block thresholds and shorter delays before block onset. In contrast, smaller fibers demonstrated prolonged subthreshold conduction delays before achieving full block. Conclusions: These findings suggest that LFACb could serve as a neuromodulation tool for selectively blocking larger fibers while preserving smaller fiber function. This has potential applications in functional electrical stimulation (FES) and temporary, non-destructive nerve blocks for clinical and research applications. Full article

Reliable acoustic coupling in a non-handheld mode and reducing the form factor of electronics are specific challenges in making ultrasound wearable. Applications relying on a large field of view (such as tracking of large muscles) induce a need for a large element count to achieve high image quality. In our work, we developed a 256-element linear array for imaging of abdominal muscles with four integrated custom-developed 8:32 multiplexer Integrated Circuits (ICs), allowing the array to be driven by our compact 32 ch electronics. The system is optimized for flexible use in R&D applications and allows adjustable transmit voltages (up to +/−100 V), arbitrary delay patterns, and 12-bit analog-to-digital conversion (ADC) with up to 50 MSPS and wireless (21.6 MBit/s) or USB link. Image metrics (SLL, FWHM) were very similar to a fully populated array driven with a 256 ch system. The contrast allowed imaging of lesions down to 7 cm in the phantom. In a first in-vivo study, we demonstrated reliable acoustic contact even during exercise and were able to visualize deep abdominal muscles such as the TrA. In combination with a muscle tracking algorithm, the change of thickness of the TrA during SSE could be monitored, demonstrating the potential of the approach as biofeedback for physiotherapy training. Full article

Background/Objectives: Exposure to fine particulate matter (PM_2.5) causes significant respiratory and gastrointestinal health problems. In our prior research, we identified Lactobacillus acidophilus TW01 as a promising strain for mitigating oxidative damage, enhancing wound healing in intestinal epithelial cells, and protecting bronchial cells from cigarette smoke extract. Building upon these findings, this study examines the protective effects of this strain on lung damage induced by particulate matter (PM) through the gut–lung axis in mouse models. Methods: This study evaluated the protective effects of L. acidophilus TW01 against PM_2.5-induced lung injury using two in vivo mouse models (OVA sensitization combined with PM_2.5 exposure and DSS-induced colitis). Results: L. acidophilus TW01 exhibited significant protective effects in two in-vivo models, reducing pro-inflammatory cytokines (TNF-α, IL-6, and IL-5), modulating the immune response (IgG subtypes), and improving gut barrier integrity. Importantly, L. acidophilus TW01 increased the abundance of beneficial gut bacteria (Bifidobacterium and Lactobacillus). Conclusions: These findings highlight the significant protective/therapeutic potential of L. acidophilus TW01 in mitigating the adverse health effects of PM_2.5 exposure, emphasizing the interplay between the gut and lung microbiomes in overall health. The multi-faceted protective effects of this probiotic suggest a novel, multi-pronged therapeutic strategy for addressing the widespread health consequences of air pollution. Full article

This study aimed to develop a novel Transdermal Energy Transmission System (TETS) device that addresses the driveline complications faced by patients with advanced heart failure (HF). Our TETS device utilizes a two-channel configuration with a very-low duty cycle and a pulsed RF power transmission technique, along with elliptically shaped flexible coil inductive coupling elements. We integrated a battery charging controller module into the TETS, enabling it to recharge an implanted Lithium-Ion (Li-Ion) battery that powers low-power-rated Circulatory Assist Devices, or left ventricular assist devices (LVADs). Benchtop measurements demonstrated that the TETS delivered energy from the implanted coils to the battery charging module, at a charging rate of up to 2900 J/h, presented an average temperature increase (ΔT) of 3 °C. We conducted in vivo measurements using four porcine models followed by histopathological analysis of the skin tissue in the implanted coils areas. The thermal profile analysis from the in vivo measurements and the calculated charging rates from the current and voltage waveforms, in porcine models, indicated that the charging rate and temperature varied for each model. The maximum energy charging rate observed was 2200 J/h, with an average ΔT of 3 °C. The exposed skin tissue histopathological analysis results showed no evidence of tissue thermal damage in the in vivo measurements. These results demonstrate the feasibility of our developed TETS device for wireless driving implanted low-power-rated LVADs and Li-Ion charging. Full article

The increasing use of cone beam computed tomography (CBCT) has led to a growing demand for DICOM software that enables the assessment and measurement of craniofacial structures. This study aimed to compare the airway volume and the minimum axial area in patients with cleft lip and palate using five different imaging software programs: Dolphin3D, InVivo Dental, ITK Snap, InVesalius, and NemoFAB. Initially, 100 CBCT scans were selected by an examiner, and their corresponding DICOM files were collected. The oropharyngeal segments were delineated following the manufacturer’s guidelines, using two different segmentation techniques: interactive and fixed threshold. The results were analyzed using the Friedman test and Wilcoxon post hoc test, with a 5% significance level for all statistical tests. The findings for both the minimum axial area and total volume revealed that the median values across the software groups were higher than expected, and significant differences were observed when comparing the groups (p < 0.001). All five software programs showed notable differences in their outputs. Specifically, a statistically significant difference in volume was found across all groups, except between InVivo and ITK-Snap. It is recommended that pre- and post-treatment comparisons be performed using the same software for consistency. Full article

Objectives: To compare 3D cephalometric analysis performed using AI with that conducted manually by a specialist orthodontist. Methods: The CBCT scans (a field of view of 15 × 15 cm) used in the study were obtained from 30 consecutive patients, aged 18 to 50. The 3D cephalometric analysis was conducted using two methods. The first method involved manual tracing performed with the Invivo 6 software (Anatomage Inc., Santa Clara, CA, USA). The second method involved using AI for cephalometric measurements as part of an orthodontic report generated by the Diagnocat system (Diagnocat Ltd., San Francisco, CA, USA). Results: A statistically significant difference within one standard deviation of the parameter was found in the following measurements: SNA, SNB, and the left interincisal angle. Statistically significant differences within two standard deviations were noted in the following measurements: the right and left gonial angles, the left upper incisor, and the right lower incisor. No statistically significant differences were observed beyond two standard deviations. Conclusions: AI in the form of Diagnocat proved to be effective in assessing the mandibular growth direction, defining the skeletal class, and estimating the overbite, overjet, and Wits parameter. Full article

Deep-sea mineral water (DSW) consists of different compositions and properties. The composition can be varied in different seas all around the world. However, previous studies have investigated that DSW is a potential candidate that can be used to prevent different inflammatory diseases. Even though inflammation is an important protective mechanism in an animal, excessive inflammation causes organ failure and ultimate death. Therefore, the present study was carried out to investigate the anti-inflammatory effect of DSW extracted from the South Korean Sea to unveil its potential as an anti-inflammatory drug. To perform this, first, we have compared the cytotoxic effect of DSW on RAW 264.7 murine macrophage cells with NaCl and normal-sea water (NSW). Results reveal that DSW enhances cell survival while other treatments negatively affect cell survival. Furthermore, we have investigated that DSW reduces the LPS-induced cell apoptosis compared to the NaCl- and NSW-treated cells. Moreover, DSW has the ability to suppress the pro-inflammatory cytokine transcription (TNF-α, IL-1β, and IL-6) and NO production upon LPS treatment. In-vivo survival assay in zebrafish larvae shows a more than 50% survival rate in 10, 20, 30, 40, or 50% concentrations of DSW-treated larvae compared to NaCl- or NSW-treated larvae. Further investigations unveiled that DSW can negatively regulate the neutrophil and macrophage recruitment to the inflammatory site, which was induced by fin-fold amputation in zebrafish larvae and pro-inflammatory cytokine (tnf-α, il-1β, and il-6) secretion. Taken together, the present study concluded that DSW may have the ability to act as an anti-inflammatory drug to suppress excessive inflammation and subsequent consequences. Full article

The Nordic hamstring exercise (NHE) is effective at decreasing hamstring strain injury risk. Limited information is available on the in vivo mechanics of the bicep femoris long head (BF_LH) during the NHE. Therefore, the purpose of this study was to observe kinematic, neuromuscular and in-vivo mechanics of the BF_LH during the NHE. Thirteen participants (24.7 ± 3.7 years, 79.56 ± 7.89 kg, 177.40 ± 12.54 cm) performed three repetitions of the NHE at three horizontal planes (0°, 20° and −20°). Dynamic ultrasound of the dominant limb BF_LH, surface electromyography (sEMG) of the contralateral hamstrings and sagittal plane motion data were simultaneously collected. Repeated measures analysis of variance with Bonferroni post hoc corrections were used on the in vivo mechanics and the kinematic and sEMG changes in performance of the NHE. Likely differences in ultrasound waveforms for the BF_LH were determined. Significant and meaningful differences in kinematics and in vivo mechanics between NHE variations were observed. Non-significant differences were observed in sEMG measures between variations. Changes to the NHE performance angle manipulates the lever arm, increasing or decreasing the amount of force required by the hamstrings at any given muscle length, potentially changing the adaptive response when training at different planes and providing logical progressions ore regressions of the NHE. All NHE variations result in a similar magnitude of fascicle lengthening, which may indicate similar positive adaptations from the utilization of any variation. Full article

Many therapies require the transport of therapeutic compounds or substances encapsulated in carriers that reduce or, if possible, eliminate their direct contact with healthy tissue and components of the immune system, which may react to them as something foreign and dangerous to the patient’s body. To date, inorganic nanoparticles, solid lipids, micelles and micellar aggregates, liposomes, polymeric micelles, and other polymer assemblies were tested as drug carriers. Specifically, using polymers creates a variety of options to prepare nanocarriers tailored to the chosen needs. Among polymers, aliphatic polyesters are a particularly important group. The review discusses controlled synthesis of poly(β-butyrolactone)s, polylactides, polyglycolide, poly(ε-caprolactone), and copolymers containing polymacrolactone units with double bonds suitable for preparation of functionalized nanoparticles. Discussed are syntheses of aliphatic polymers with controlled molar masses ranging from a few thousand to 10⁶ and, in the case of polyesters with chiral centers in the chains, with controlled microstructure. The review presents also a collection of methods useful for the preparation of the drug-loaded nanocarriers: classical, developed and mastered more recently (e.g., nanoprecipitation), and forgotten but still with great potential (by the direct synthesis of the drug-loaded nanoparticles in the process comprising monomer and drug). The article describes also in-vitro and model in-vivo studies for the brain-targeted drugs based on polyester-containing nanocarriers and presents a brief update on the clinical studies and the polyester nanocarrier formulation approved for application in the clinics in South Korea for the treatment of breast, lung, and ovarian cancers. Full article

Cathepsin S (CatS) is a proteolytic enzyme and a member of the cysteine protease family of proteolytic enzymes. Cathepsins S, K, and L are particularly similar in terms of their amino acid sequences and interactions with substrates, and this has made it difficult to develop inhibitors with specificity for either CatS, CatK, or CatL. The involvement of CatS in various disease pathophysiologies (autoimmune disorders, cardiovascular diseases, cancer, etc.) has made it a very important target in drug development. Efforts have been made since the early 1990s to develop a specific CatS inhibitor without any major success. Following many failed efforts to develop an inhibitor for CatS, it was discovered that interactions with the amino acid residues at the S2 and S3 pockets of CatS are critical for the identification of CatS-specific inhibitors. Amino acid residues at these pockets have been the target of recent research focused on developing a non-covalent, reversible, and specific CatS inhibitor. Methods applied in the identification of CatS inhibitors include molecular modeling, in-vitro screening, and in-vivo studies. The molecular modeling process has proven to be very successful in the identification of CatS-specific inhibitors, with R05459072 (Hoffmann-La Roche) and LY3000328 (Eli Lilly Company) which has completed phase 1 clinical trials. CatS inhibitors identified from 2011 to 2023 with promising prospects are discussed in this article. Full article

This study aimed to assess the anti-inflammatory properties of a bioactive glutamic-alanine rich glycoprotein (GP) derived from Undaria pinnatifida on both LPS-stimulated RAW264.7 cells, peritoneal macrophages, and mouse models of carrageenan- and xylene-induced inflammation, investigating the underlying molecular mechanisms. In both in-vitro and in-vivo settings, GP was found to reduce the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) while also inhibiting the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂) in response to lipopolysaccharide (LPS) stimulation. GP treatment significantly impeded the nuclear translocation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by blocking the phosphorylation of IKKα and IκBα, leading to a reduction in proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Additionally, GP effectively inhibited the activation of mitogen-activated protein kinases (MAPKs), with specific inhibitors of p38 and extra-cellular signal regulated kinase (ERK) enhancing GP’s anti-inflammatory efficacy. Notably, GP administration at 10 mg/kg/day (p.o.) markedly reduced carrageenan-induced paw inflammation and xylene-induced ear edema by preventing the infiltration of inflammatory cells into targeted tissues. GP treatment also downregulated key inflammatory markers, including iNOS, COX-2, IκBα, and NF-κB, by suppressing the phosphorylation of p38 and ERK, thereby improving the inflammatory index in both carrageenan- and xylene-induced mouse models. These findings suggest that marine resources, particularly seaweeds like U. pinnatifida, could serve as valuable sources of natural anti-inflammatory proteins for the effective treatment of inflammation and related conditions. Full article