Search Results (596)

Resveratrol (RSV), a polyphenol found in a variety of berries and wines, is known for its anti-inflammatory, anticancer, and antioxidant properties. It has been suggested that RSV may play a role in the regulation of metabolic disorders, including diabetes and insulin resistance. However, in recent years, it has been reported to completely inhibit Akt kinase function in liver cells. Akt is a central protein involved in the metabolic function of insulin and is regulated by the phosphatidylinositol-3-kinase (PI3K) pathway. In this study, we examined the effect of RSV on insulin-induced insulin receptor (IR) phosphorylation and proteins involved in the PI3K/Akt pathway in a hepatic cell model, clone 9 (C9), and in hepatoma cells, Hepa 1-6 (H1-6). In both cell lines, RSV inhibited tyrosine phosphorylation of IR and insulin-induced activation of Akt. We also evaluated the effect of RSV on the activation of protein tyrosine phosphatase 1B (PTP1B), which is associated with IR dephosphorylation, and found that RSV increased PTP1B-Tyr¹⁵² phosphorylation in a time- and concentration-dependent manner. Furthermore, we found that the protein kinase C (PKC) inhibitors BIM and Gö6976 prevented the inhibition of Akt phosphorylation by RSV and increased the phosphorylation of Ser/Thr residues in IR, suggesting that PKC is involved in the inhibition of the insulin pathway by RSV. Thus, classical PKC isoforms impair the PI3K/Akt pathway at the IR and GSK3 and GS downstream levels; however, IRS-Tyr⁶³² phosphorylation remains unaffected. These results suggest that RSV can lead to insulin resistance by activating PTP1B and PKC, consequently affecting glucose homeostasis in hepatic cells. Full article

Platelets have long been known to be critically involved in hemostasis and thrombosis. However, platelets are also recognized as metabolically active cells that require well-regulated mitochondrial function to support their multiple functions in hemostasis, thrombosis, and inflammation. Mitochondrial activity has also recently been shown to play a crucial role in determining platelet activation, survival, and pro-inflammatory potential. A key nexus in these processes is the mitochondrial permeability transition pore (mPTP), a high-conductance channel in the inner mitochondrial membrane. Sustained mPTP opening triggers mitochondrial depolarization, the cessation of ATP synthesis, osmotic swelling, and, finally, platelet dysfunction or clearance. However, its transient opening might play physiological signaling roles. This review summarizes the current understanding of the molecular components and regulatory factors governing the platelet mPTP, explores its physiological and pathological relevance, and evaluates its potential as a therapeutic target in cardiovascular disease, inflammation, cancer, and potentially neurodegenerative diseases. We also highlight the ongoing challenges and crucial future directions in deciphering the complexities of platelet mitochondrial dynamics and mPTP functions. Full article

The present investigation highlights the importance of evaluating the painting process on a composite material, namely the Kevlar validation process. Kevlar, a synthetic fabric, is well known for its remarkable strength and durability. Kevlar is used in the construction of spaceships and airplanes because it is lightweight and five times stronger than steel. This paper will present the methods for measuring paint layer thickness in accordance with EN ISO 2808:2019, confirming that organic coatings have fully cured, and coating thickness will be measured using magnetic currents. This study will also address the topic of determining liquid resistance. The protocols for manufacturing the Kevlar specimen are in accordance with ISO 2812-2:2018 using the water immersion method and structural testing. The investigation also demonstrates the progress of the framing test following immersion in Airbus PTP metal test tubes. Full article

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson’s disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation. Full article

Inorganic polyphosphate (polyP) is an evolutionarily conserved polymer that has recently gained relevance in neuronal physiology and pathophysiology. Although its roles, such as mitochondrial bioenergetics, calcium homeostasis, and the oxidative stress response, for example, are increasingly recognized, its specific implications in neurological disorders remain underexplored. This review focuses on synthesizing the current knowledge of polyP in the context of central nervous system (CNS) diseases, highlighting how its involvement in key mitochondrial processes may influence neuronal survival and function. In particular, we examine recent evidence linking polyP to mechanisms relevant to neurodegeneration, such as the modulation of the mitochondrial permeability transition pore (mPTP), regulation of amyloid fibril formation, and oxidative stress responses. In addition, we analyze the emerging roles of polyP in inflammation and related cell signaling in CNS disorders. By organizing the existing data around the potential pathological and protective roles of polyP in the CNS, this review identifies it as a candidate of interest in the context of neurodegenerative disease mechanisms. We aim to clarify its relevance and stimulate future research on its molecular mechanisms and translational potential. Full article

Nitric oxide (NO) has a dual effect on mitochondria. Incubating liver mitochondria with NO improves oxidative phosphorylation (OXPHOS) efficiency by decreasing state 4 respiration more than ATP synthesis and preventing mitochondrial permeability transition pore (mPTP) opening. We evaluated the effect of L-arginine (L-arg), an NO donor, on isolated liver mitochondrial respiration and mPTP in sepsis. Male mice were subjected to cecal ligation and perforation (CLP) with saline resuscitation or sham. After 8, 24, and 48 h, with and without L-arg, we measured isolated liver mitochondrial respiration and cytochrome c oxidase (COX) activity using polarographic methods and calcium retention capacity (CRC) to assess the mPTP and NO metabolites via the Griess reaction. Mitochondrial NO synthase (mtNOS) was identified by Western blot. CLP decreased state 3 respiration at 24 and 48 h, decreased COX activity at 8, 24, and 48 h, and increased state 4 respiration and decreased the respiratory control ratio (RCR) and CRC at 48 h. L-arg increased NO levels at 8 h, decreased state 4 respiration more than state 3 respiration (−39% versus −12%) at 48 h, decreased the CRC in the CLP groups at 24 and 48 h, but did not improve RCR. Our data suggests that L-arg does not restore liver mitochondrial OXPHOS efficiency or prevent mPTP opening in the late or recovery phases of sepsis. Full article

The genus Grypoctonus Speiser, 1928 (Diptera: Asilidae) is a fuzzy-looking assassin fly, and adults have only been observed in autumn and winter. Currently containing four described species, this genus is readily distinguished from other Chinese asilids by the presence of two r-m crossveins. Through integrative taxonomic analysis of over 200 specimens from multiple Chinese provinces, we combined morphological assessment with DNA barcoding and four species delimitation methods (ABGD, ASAP, mPTP, and GMYC). Four species are newly described: G. aureus sp. nov., G. sagittatus sp. nov., G. solarius sp. nov., and G. yongshani sp. nov. (the latter described solely from morphological examination of historical specimens). Genetic analyses revealed distinct barcoding gaps, with an interspecific distance of 1.38–7.07% versus an intraspecific distance of no more than 0.92%. We revised the generic diagnosis, provided a distribution map, and a revised key to all known species of Grypoctonus. Full article

Multi-vendor interoperability is essential for the stable operation, scalability, and successful market adoption of Time-Sensitive Networking (TSN). Conformance tests address protocol conformance. Informal interoperability testing and plugfests help to improve the quality and interoperability of specific implementations, and of the underlying international standard documents. This paper presents three findings related to time synchronization in a multi-vendor TSN system. Differing interpretations of released standards and inconsistent setting of relevant system parameters resulted in undesirable behavior impacting the performance of the complete TSN system. The findings relevant to the standards themselves have been submitted to IEEE as maintenance items or are already being considered in work in progress at IEEE. In addition to interoperability testing, the importance of consistent system engineering and industry-specific TSN profiles are identified as important ingredients for successful implementation of TSN-based systems. Full article

Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article

Background/Objectives: Venous thromboembolism (VTE) is a preventable cause of morbidity in the neurocritical ill patient population. There is ongoing debate regarding the optimal timing and choice of pharmacologic thromboprophylaxis (PTP) and how these decisions relate to balancing the risk of bleeding complications with the development of VTE. Our review assesses the available data to provide un updated perspective to clinicians. Methods: A literature search was performed in December 2024 in PubMed and EMBASE. We focused on the timing of PTP initiation and the comparison of enoxaparin (ENX) with unfractionated heparin (UFH) in patients with traumatic brain injury (TBI), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), spinal or spinal cord injury (SCI), or requirement for neurosurgical intervention. Results: We included 90 articles spanning a total of 669,725 patients with injuries of interest within neurocritical care. The existing data largely signaled a benefit of early administration (<24–72 h) of PTP in VTE prevention, though some studies suggested increased risks of complications. Data to inform a preference for PTP agent was less robust, though a signal of benefit for enoxaparin is suggested for subsets of patients with acute brain injury such as TBI. The data quality is limited by the large body of retrospective studies, the heterogeneity of study populations, outcome definitions, study methodologies, and the lack of detailed reporting of relevant factors. Conclusions: Our review provides an updated assessment of the available data on PTP timing and choice in neurocritically ill patients with hemorrhages or surgical need, with a practice-focused overview for clinicians balancing VTE risk with bleeding risk. The data suggest that in most circumstances, early PTP appears safe and indicated, and that low-molecular weight heparin (LMWH) can be considered over UFH in certain subsets of patients. Still, data gaps and conflicting results highlight the need for patient-specific decision making and indicate that more robust research is warranted to inform optimal clinical practice. Full article

Background: Tariquidar (Tq) is an inhibitor of the multidrug resistance (MDR) proteins relevant to ATP-binding cassette transporters (ABC transporters), which suppresses the ATP-dependent efflux of a variety of hydrophilic and amphipathic compounds, including anticancer drugs. Tq is a representative of a new generation of MDR inhibitors with high affinity to ABC proteins. However, there are still no data on the possible effect of Tq on mitochondria as an important target in the regulation of cell death or survival. Methods: We investigated the influence of Tq on the Ca²⁺-dependent mitochondrial permeability transition pore (mPTP). The effect of Tq was assessed using several parameters, including the calcium load, membrane potential, and mitochondrial swelling. To evaluate the specific targets of Tq, selective inhibitors of components of the mitochondrial pore were used, including adenine nucleotides, carboxyatractylozide (Catr) and bongkrekic acid (BA), oligomycin, and cyclosporine A. Results: Tq decreased the calcium retention capacity, activated mitochondrial swelling, and lowered the influence of ADP and ATP, the inhibitors of the Ca²⁺-induced pore opening, at their low concentrations. These effects of Tq were observed in both calcium-load and swelling assays, thus mimicking the effect of Catr, a selective inhibitor of adenine nucleotide translocase (ANT). Tq also decreased the protective effect of BA, an inhibitor of ANT and mPTP, on the calcium retention capacity of mitochondria. Further, Tq dose-dependently decreased the inhibitory effect of a low ATP concentration but not of high concentrations, at which the effect of Tq was activated by oligomycin, an inhibitor of F-ATP synthase. Conclusions: The influence of Tq extends to mitochondria, specifically to the regulation of membrane permeability, promoting the activation of pore opening, probably through an interaction with ANT, a component of the pore-forming complex. The effect of Tq on the opening of mPTP is strongly dependent on the concentrations of adenine nucleotides and, consequently, on the functional state of mitochondria. The direct influence of Tq on mitochondria can be considered as a new activity that promotes the sensitization of cells to various treatments and stimuli. Full article

The fruit of Momordica cochinchinensis Spreng., commonly known as Gac fruit, contains arils rich in carotenoids and unsaturated fatty acids, making it suitable for use as a natural colorant, flavor enhancer, and dietary supplement. This study examined Gac oil extracted from locally cultivated Gac fruit in Taiwan and evaluated the impact of different encapsulation methods and press through packaging (PTP) packaging on its oxidative stability during storage. The Gac oil was found to contain exceptionally high levels of β-carotene (up to 6047.52 ± 16.15 ppm) and lycopene (3192.84 ± 20.21 ppm). Among the tested formulations, soft capsules demonstrated lower peroxide value (PV) and better retention of carotenoids, including lycopene β-carotene compared to hard capsules. Furthermore, capsules stored in PTP packaging exhibited enhanced protection against oxidation. Overall, soft capsules combined with PTP packaging provided the most effective approach for maintaining the nutritional quality and oxidative stability of Gac oil during storage. Full article

Currently, knowledge of the effects of different frequencies of administration of bedside physiotherapy programs (PTPs) on hospitalized COVID-19 patients is limited. Therefore, this study aimed to compare the effects of administering PTPs once or twice during hospitalization versus daily PTPs until discharge. Fifty-two COVID-19 patients were equally assigned to two groups, matched by gender and age (1:1 ratio). Experimental Group 1 (Ex-G1) received PTPs one to two times during hospitalization, while Experimental Group 2 (Ex-G2) received daily PTPs until discharge. The outcomes assessed included the survival rate, length of hospitalization (LoH), intensive care unit (ICU) referrals, and in-hospital complications. Most participants were classified as having mild to moderate COVID-19, with a mean age of 45 years. No significant differences were observed between the groups in all primary outcomes, including the survival rate (p = 1.000), LoH (p = 0.117), ICU referrals (p = 0.313), and complications (p = 0.555). The overall survival rate was 98%. One Ex-G2 participant was referred to the ICU, while complications occurred in two Ex-G1 and four Ex-G2 participants. In summary, for patients with mild to moderate COVID-19, one to two bedside physiotherapy sessions produced comparable results to daily physiotherapy in terms of the survival rate, LoH, ICU referrals, and in-hospital complications. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss and limited therapeutic options. Metal-based drugs have emerged as promising alternatives in the search for effective treatments, and vanadium coordination complexes have shown significant potential due to their neuroprotective and anti-aggregant properties. This review explores the advances in the development of vanadium-based metallodrugs for AD, focusing on their ability to modulate amyloid-beta (Aβ) aggregation, oxidative stress, and neuroinflammation. Recent in vitro and in vivo studies highlight the efficacy of oxovanadium (IV) and peroxovanadium (V) complexes in inhibiting Aβ fibril formation and reducing neuronal toxicity. Additionally, the interaction of vanadium complexes with key biological targets, such as peroxisome proliferator-activated receptor gamma (PPARγ) and protein-tyrosine phosphatase 1B (PTP1B), suggests a multifaceted therapeutic approach. While these findings underscore the potential of vanadium compounds as innovative treatments for AD, further research is needed to optimize their bioavailability, selectivity, and safety for clinical applications. Full article

An efficient protocol was developed for the microwave-mediated metallation of 5-(4-methoxycarbonylphenyl)-10,15,20-tris(pentafluorophenyl)porphyrin (P1) with bis(benzonitrile)platinum dichloride salt and subsequent 1,3-dipolar cycloaddition of the resulting PtP1 with an azomethine ylide to give two isomeric metallochlorins: PtC1 (main isomer) and PtC3. The methyl ester group of metalloporphyrin PtP1 and metallochlorin PtC1 was successfully hydrolysed in an alkaline medium to yield the corresponding derivatives PtP2 and PtC2 in moderate-to-good yields. As a proof of concept of the reactivity of the carboxy group in PtP2 and PtC2, these compounds were conjugated with a hydroxylated derivative of indomethacin, a known potent non-steroidal anti-inflammatory, obtaining the conjugates PtP2-Ind and PtC2-Ind. The obtained platinum(II) porphyrins and chlorins were characterized by UV-Vis, NMR spectroscopy and mass spectrometry. The structure of PtP1 was also confirmed by X-ray crystallography. Singlet oxygen generation studies were carried out, as well as theoretical calculations, which demonstrated that the prepared Pt(II) complexes can be considered potential photosensitizers for PDT. Full article