Search Results (385)

Mitochondrial homeostasis is controlled by biogenesis, dynamics, and mitophagy. Mitochondrial dysfunction plays a central role in cardiovascular and renal disease and omega-3 fatty acids (FAs) are beneficial for cardiovascular disease. We investigated whether omega-3 fatty acids (FAs) regulate mitochondrial biogenesis, dynamics, and mitophagy in the kidney and heart of adenine-induced uremic rats. Eighteen male Sprague Dawley rats were divided into normal control, adenine control, and adenine with omega-3 FA groups. Using Western blot analysis, the kidney and heart expression of mitochondrial homeostasis-related molecules, including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), dynamin-related protein 1 (Drp1), and phosphatase and tensin homolog-induced putative kinase 1 (PINK1) were investigated. Compared to normal, serum creatinine and heart weight/body weight in adenine control were increased and slightly improved in the omega-3 FA group. Compared to the normal controls, the expression of PGC-1α and PINK1 in the kidney and heart of the adenine group was downregulated, which was reversed after omega-3 FA supplementation. Drp1 was upregulated in the kidney but downregulated in the heart in the adenine group. Drp1 expression in the heart recovered in the omega-3 FA group. Mitochondrial DNA (mtDNA) was decreased in the kidney and heart of the adenine control group but the mtDNA of the heart was recovered in the omega-3 FA group. Drp1, which is related to mitochondrial fission, may function oppositely in the uremic kidney and heart. Omega-3 FAs may be beneficial for mitochondrial homeostasis by activating mitochondrial biogenesis and PINK1-dependent mitophagy in the kidney and heart of uremic rats. Full article

The relationship of Amyotrophic Lateral Sclerosis, Parkinson’s disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene Drp1 in Drosophila melanogaster and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and Drp1 mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the Dopa decarboxylase-Gal4 (Ddc-Gal4) transgene was exploited to direct the expression of Drp1 and Drp1-RNAi transgenes in select neurons. Here, the knockdown of Drp1 seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of Buffy suppresses the poor climbing induced by the knockdown of the Drp1 function. The consequences of Drp1 overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival Bcl-2 gene Buffy or by the co-knockdown of the pro-cell death Bcl-2 homologue Debcl. Alteration of the expression of Drp1 acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of Buffy can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of Drp1 or the RNA interference of Drp1 has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease. Full article

The vehicle routing problem with time windows (VRPTW) is a widely studied combinatorial optimization problem in supply chains and logistics within the last decade. Recent research has explored the potential of deep reinforcement learning (DRL) as a promising solution for the VRPTW. However, the challenge of addressing the VRPTW with many conflicting objectives (MOVRPTW) still remains for DRL. The MOVRPTW considers five conflicting objectives simultaneously: minimizing the number of vehicles required, the total travel distance, the travel time of the longest route, the total waiting time for early arrivals, and the total delay time for late arrivals. To tackle the MOVRPTW, this study introduces the MTMO/DRP-AT, a multi-task multi-objective evolutionary search algorithm, by making full use of both DRL and the multitasking mechanism. In the MTMO/DRL-AT, a two-objective MOVRPTW is constructed as an assisted task, with the objectives being to minimize the total travel distance and the travel time of the longest route. Both the main task and the assisted task are simultaneously solved in a multitasking scenario. Each task is decomposed into scalar optimization subproblems, which are then solved by an attention model trained using DRL. The outputs of these trained models serve as the initial solutions for the MTMO/DRL-AT. Subsequently, the proposed algorithm incorporates knowledge transfer and multiple local search operators to further enhance the quality of these promising solutions. The simulation results on real-world benchmarks highlight the superior performance of the MTMO/DRL-AT compared to several other algorithms in solving the MOVRPTW. Full article

The objectives of this study were to explore the role that eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) plays in heart failure (HF), highlighting the potential connection to oxidative stress pathways. Following PRISMA guidelines, we conducted electronic searches of the literature in MEDLINE and EMBASE focusing on serum EPA and/or DHA and EPA and/or DHA supplementation in adult patients with heart failure or who had heart failure as an outcome of this study. We screened 254 studies, encompassing RCTs, observational studies, and cohort studies that examined HF outcomes in relation to either serum concentrations or dietary supplementation of EPA and/or DHA. The exclusion criteria were pediatric patients, non-HF studies, abstracts, editorials, case reports, and reviews. Eleven studies met our criteria. In meta-analyses, high serum concentrations of DHA were associated with a lower rate of heart failure with a hazard ratio of 0.74 (CI = 0.59–0.94). High serum concentrations of EPA also were associated with an overall reduction in major adverse cardiovascular events with a hazard ratio of 0.60 (CI = 0.46–0.77). EPA and DHA, or n3-PUFA administration, were associated with an increased LVEF with a mean difference of 1.55 (CI = 0.07–3.03)%. A potential explanation for these findings is the ability of EPA and DHA to inhibit pathways by which oxidative stress damages the heart or impairs cardiac systolic or diastolic function producing heart failure. Specifically, EPA may lower oxidative stress within the heart by reducing the concentration of reactive oxygen species (ROS) within cardiac tissue by (i) upregulating nuclear factor erythroid 2-related factor 2 (Nrf2), which increases the expression of antioxidant enzyme activity, including heme oxygenase-1, thioredoxin reductase 1, ferritin light chain, ferritin heavy chain, and manganese superoxide dismutase (SOD), (ii) increasing the expression of copper–zinc superoxide dismutase (MnSOD) and glutathione peroxidase, (iii) targeting Free Fatty Acid Receptor 4 (Ffar4), (iv) upregulating expression of heme-oxygenase-1, (v) lowering arachidonic acid levels, and (vi) inhibiting the RhoA/ROCK signaling pathway. DHA may lower oxidative stress within the heart by (i) reducing levels of mitochondrial-fission-related protein DRP-1(ser-63), (ii) promoting the incorporation of cardiolipin within the mitochondrial membrane, (iii) reducing myocardial fibrosis, which leads to diastolic heart failure, (iv) reducing the expression of genes such as Appa, Myh7, and Agtr1α, and (v) reducing inflammatory cytokines such as IL-6, TNF-α. In conclusion, EPA and/or DHA have the potential to improve heart failure, perhaps mediated by their ability to modulate oxidative stress. Full article

In this study, polysaccharides were extracted at a rate of 87.5% ± 1.5% from native dandelion roots, and the dandelion root polysaccharides (DRPs) were then chemically modified to obtain sulfated polysaccharides (SDRPs) with a degree of substitution of 1.49 ± 0.07. The effects of modification conditions, physicochemical characterizations, structural characteristics, antioxidant properties, hypoglycemic activity, and proliferative effects on probiotics of DRP derivatives were further investigated. Results showed that the optimum conditions for sulfation of DRPs included esterification reagents (concentrated sulfuric acid: n-butanol) ratio of 3:1, a reaction temperature of 0 °C, a reaction time of 1.5 h, and the involvement of 0.154 g of ammonium sulfate. The DRPs and SDRPs were composed of six monosaccharides, including mannose, glucosamine, rhamnose, glucose, galactose, and arabinose. Based on infrared spectra, the peaks of the characteristic absorption bands of S=O and C-O-S appeared at 1263 cm⁻¹ and 836 cm⁻¹. Compared with DRPs, SDRPs had a significantly lower relative molecular mass and a three-stranded helical structure. NMR analysis showed that sulfated modification mainly occurred on the hydroxyl group at C6. SDRPs underwent a chemical shift to higher field strength, with their characteristic signal peaking in the region of 1.00–1.62 ppm. Scanning electron microscopy (SEM) analysis indicated that the surface morphology of SDRPs was significantly changed. The structure of SDRPs was finer and more fragmented than DRPs. Compared with DRPs, SDRPs showed better free radical scavenging ability, higher Fe²⁺chelating ability, and stronger inhibition of α-glucosidase and α-amylase. In addition, SDRPs had an excellent promotional effect on the growth of Lactobacillus plantarum 10665 and Lactobacillus acidophilus. Therefore, this study could provide a theoretical basis for the development and utilization of DRPs. Full article

Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are common retinal diseases responsible for most blindness in working-age and elderly populations. Oxidative stress and mitochondrial dysfunction play roles in these pathogenesis, and new therapies counteracting these contributors could be of great interest. Some molecules, like coenzyme Q₁₀ (CoQ₁₀), are considered beneficial to maintain mitochondrial homeostasis and contribute to the prevention of cellular apoptosis. We investigated the impact of adding CoQ₁₀ (Q) to a nutritional antioxidant complex (Nutrof Total^®; N) on the mitochondrial status and apoptosis in an in vitro hydrogen peroxide (H₂O₂)-induced oxidative stress model in human retinal pigment epithelium (RPE) cells. H₂O₂ significantly increased 8-OHdG levels (p < 0.05), caspase-3 (p < 0.0001) and TUNEL intensity (p < 0.01), and RANTES (p < 0.05), caspase-1 (p < 0.05), superoxide (p < 0.05), and DRP-1 (p < 0.05) levels, and also decreased IL1β, SOD2, and CAT gene expression (p < 0.05) vs. control. Remarkably, Q showed a significant recovery in IL1β gene expression, TUNEL, TNFα, caspase-1, and JC-1 (p < 0.05) vs. H₂O_2, and NQ showed a synergist effect in caspase-3 (p < 0.01), TUNEL (p < 0.0001), mtDNA, and DRP-1 (p < 0.05). Our results showed that CoQ₁₀ supplementation is effective in restoring/preventing apoptosis and mitochondrial stress-related damage, suggesting that it could be a valid strategy in degenerative processes such as AMD or DR. Full article

Apoptosis induction with taxanes or anthracyclines is the primary therapy for TNBC. Cancer cells can develop resistance to anticancer drugs, causing them to recur and metastasize. Therefore, non-apoptotic cell death inducers could be a potential treatment to circumvent apoptotic drug resistance. In this study, we discovered two novel compounds, TPH104c and TPH104m, which induced non-apoptotic cell death in TNBC cells. These lead compounds were 15- to 30-fold more selective in TNBC cell lines and significantly decreased the proliferation of TNBC cells compared to that of normal mammary epithelial cell lines. TPH104c and TPH104m induced a unique type of non-apoptotic cell death, characterized by the absence of cellular shrinkage and the absence of nuclear fragmentation and apoptotic blebs. Although TPH104c and TPH104m induced the loss of the mitochondrial membrane potential, TPH104c- and TPH104m-induced cell death did not increase the levels of cytochrome c and intracellular reactive oxygen species (ROS) and caspase activation, and cell death was not rescued by incubating cells with the pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). Furthermore, TPH104c and TPH104m significantly downregulated the expression of the mitochondrial fission protein, DRP1, and their levels determined their cytotoxic efficacy. Overall, TPH104c and TPH104m induced non-apoptotic cell death, and further determination of their cell death mechanisms will aid in the development of new potent and efficacious anticancer drugs to treat TNBC. Full article

Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic–dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L-related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended. Full article

3-Hydroxy-3-methylglutaric acidemia (HMGA) is a neurometabolic inherited disorder characterized by the predominant accumulation of 3-hydroxy-3-methylglutaric acid (HMG) in the brain and biological fluids of patients. Symptoms often appear in the first year of life and include mainly neurological manifestations. The neuropathophysiology is not fully elucidated, so we investigated the effects of intracerebroventricular administration of HMG on redox and bioenergetic homeostasis in the cerebral cortex and striatum of neonatal rats. Neurodevelopment parameters were also evaluated. HMG decreased the activity of glutathione reductase (GR) and increased catalase (CAT) in the cerebral cortex. In the striatum, HMG reduced the activities of superoxide dismutase, glutathione peroxidase, CAT, GR, glutathione S-transferase, and glucose-6-phosphate dehydrogenase. Regarding bioenergetics, HMG decreased the activities of succinate dehydrogenase and respiratory chain complexes II–III and IV in the cortex. HMG also decreased the activities of citrate synthase and succinate dehydrogenase, as well as complex IV in the striatum. HMG further increased DRP1 levels in the cortex, indicating mitochondrial fission. Finally, we found that the HMG-injected animals showed impaired performance in all sensorimotor tests examined. Our findings provide evidence that HMG causes oxidative stress, bioenergetic dysfunction, and neurodevelopmental changes in neonatal rats, which may explain the neuropathophysiology of HMGA. Full article

Accumulating evidence shows a strong correlation between type 2 diabetes mellitus, mitochondrial dysfunction, and oxidative stress. We evaluated the effects of dietary peanut shell extract (PSE) supplementation on mitochondrial function and antioxidative stress/inflammation markers in diabetic mice. Fourteen db/db mice were randomly assigned to a diabetic group (DM in AIN-93G diet) and a PSE group (1% wt/wt PSE in AIN-93G diet) for 5 weeks. Six C57BL/6J mice were fed with an AIN-93G diet for 5 weeks (control group). Gene and protein expression in the liver, brain, and white adipose tissue (WAT) were determined using qRT-PCR and Immunoblot, respectively. Compared to the control group, the DM group had (i) increased gene and protein expression levels of DRP1 (fission), PINK1 (mitophagy), and TNFα (inflammation) and (ii) decreased gene and protein expression levels of MFN1, MFN2, OPA1 (fusion), TFAM, PGC-1α (biogenesis), NRF2 (antioxidative stress) and IBA1 (microglial activation) in the liver, brain, and WAT of db/db mice. Supplementation of PSE into the diet restored the DM-induced changes in the gene and protein expression of DRP1, PINK1, TNFα, MFN1, MFN2, OPA1, TFAM, PGC-1α, NRF2, and IBA1 in the liver, brain, and WAT of db/db mice. This study demonstrates that PSE supplementation improved mitochondrial function in the brain, liver, and WAT of db/db mice, in part due to suppression of oxidative stress and inflammation. Full article

Unmanned aerial vehicles (UAVs), or drones, are recognized for their potential to improve efficiency in last-mile delivery. Unlike the vehicle routing problem, drone route design is challenging due to several operational signatures, such as speed optimization, multi-trip operation, and energy consumption estimation. Drone energy consumption is a nonlinear function of both speed and payload. Moreover, the high speed of drones can significantly curtail the drone range, thereby limiting the efficiency of drone delivery systems. This paper addresses the trade-off between speed and flight range in a multi-trip drone routing problem with variable flight speeds (DRP–VFS). We propose a new model to specifically consider energy constraints using a nonlinear energy consumption model and treat drone speeds as decision variables. The DRP–VFS is initially formulated using mixed-integer linear programming (MILP) to minimize energy consumption. To solve large-scale instances, we propose a three-phase adaptive large neighborhood search (ALNS) algorithm and compare its performance with a commercial MIP solver. The experimental results demonstrate that the proposed method is capable of effectively identifying suboptimal solutions in practical scenarios. Furthermore, results indicate that operating drones at variable speeds leads to about 21% energy savings compared to fixed speeds, with advantages in cost savings and range extension. Full article

Background: We aimed to assess medication risks and determine factors influencing the health-related quality of life (HRQOL) in cancer inpatients. Methods: A retrospective analysis was conducted to identify drug-related problems (DRPs) based on medication reviews, including patient-reported outcomes (PROs). Multiple linear regression analyses were performed to identify sociodemographic, disease-related, and drug therapy-related factors influencing changes from hospital admission to discharge in the scales of the EORTC QLQ-C30 questionnaire. Results: A total of 162 inpatients with various hematological and solid cancer diseases was analyzed. Patients received a mean of 11.6 drugs and 92.6% of patients exhibited polymedication resulting in a mean of 4.0 DRPs per patient. Based on PRO data, 21.5% of DRPs were identified. Multiple linear regression models described the variance of the changes in global HRQOL and physical function in a weak-to-moderate way. While drug therapy-related factors had no influence, relapse status and duration of hospital stay were identified as significant covariates for global HRQOL and physical function, respectively. Conclusion: This analysis describes underlying DRPs in a German cancer inpatient population. PROs provided valuable information for performing medication reviews. The multiple linear regression models for global HRQOL and physical function provided explanations for changes during hospital stay. Full article

This comprehensive overview presents our continued efforts in high-order finite difference method (FDM) development for adaptive numerical dissipation control in the long-time integration of direct numerical simulation (DNS), large eddy simulation (LES), and implicit LES (ILES) computations of compressible turbulence for gas dynamics and MHD. The focus is on turbulence with shock wave numerical simulations using the adaptive blending of high-order structure-preserving non-dissipative methods (classical central, Padé (compact), and dispersion relation-preserving (DRP)) with high-order shock-capturing methods in such a way that high-order shock-capturing methods are active only in the vicinity of shock/shear waves, and high-gradient and spurious high-frequency oscillation regions guided via flow sensors. Any efficient and high-resolution high-order shock-capturing methods are good candidates for the blending of methods procedure. Typically, the adaptive blending of more than one method falls under two camps: hybrid methods and nonlinear filter methods. They are applicable to unstructured finite volume, finite element, discontinuous Galerkin, and spectral element methods. This work represents the culmination of over 20 years of high-order FDM developments and hands-on experience by the authors and collaborators in adaptive numerical dissipation control using the “high order nonlinear filter approach”. Extensions of these FDM versions to curvilinear nonuniform, freestream-preserving moving grids and time-varying deforming grids were also developed. By examining the construction of these two approaches using the high-order multistage type of temporal discretization, the nonlinear filter approach is made more efficient and less CPU-intensive while obtaining similar accuracy. A representative variety of test cases that compare the various blending of high-order methods with standalone standard methods is illustrated. Due to the fact that our nonlinear filter methods are not well known in compressible turbulence with shock waves, the intent of this comprehensive overview is for general audiences who are not familiar with our nonlinear filter methods. For readers interested in the implementation of our methods into their computer code, it is hoped that the long overview will be helpful. Full article

Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2β did not differ between groups (p > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats. Full article

The Awulale Iron Metallogenic Belt (AIMB) has developed many medium–large iron deposits, of which the Zhibo iron deposit is selected as the research object in this paper. The Zhibo deposit’s ore primarily consists of magnetite as the main mineral, accompanied by extensive epidotization. The mineral assemblage includes diopside, albite, actinolite, epidote, chlorite, K-feldspar, quartz, calcite, chalcopyrite, and pyrite. Magnetite is classified into two groups based on sulfide content and mineral assemblage (MagI for sulfide-free and MagII for sulfide-rich ores). Two-stage mineralization of magnetite has been identified based on mineral assemblages and paragenesis, including the magmatic stage MagI and hydrothermal stage MagII. Mag I shows inhomogeneous backscattered electron (BSE) textures and consists of BSE-light and -dark domains (Mag I-L and MagI-D). Seven subtypes of magnetite have been recognized in this deposit. MagI-L and MagI-D have formed in the magmatic stage and show BSE images in light and dark colors, respectively. MagI-L is anhedral to subhedral and is inclusion-free. MagI-D has mainly replaced MagI-L along fractures and contains inclusions and pores. MagII has formed in the hydrothermal stage and is characterized by coupled dissolution–reprecipitation (DRP) textures. It can be divided into five sub-generations, that is, MagII-1, MagII-2, MagII-3, MagII-L, and MagII-D. MagII-1, MagII-2, and MagII-3 comprise the core–mantle–rim texture, while MagII-L and MagII-D comprise the core–rim texture. MagII-1 is BSE-light and is enriched with inclusions and pores. MagII-2 has partly replaced MagII-1 and exhibits oscillatory zoning under BSE imaging. It also contains inclusions. BSE-light MagII-3 occurs as overgrowth along MagII-2 margins and is inclusion-free. MagI magnetite is enriched with V, Cr, and Ni, whereas MagII is enriched with W, Ta, Nb, Sr, Sb, Sn, Y, Zr, Mg, Al, and Ti, indicating a decreased temperature of magnetite formation. MagI-L crystallizes from the original magma, while MagI-D is formed from the residual magma enriched with incompatible elements. MagII crystallizes from later multiple hydrothermal activities through the dissolution of early magnetite and the re-precipitation of later magnetite or from MagI-D which has later undergone a hydrothermal overprinting process. According to the texture and chemical composition of magnetite from the Zhibo deposit, we suggest that the Zhibo iron deposit was formed from the initial magmatic origin and then underwent a hydrothermal overprinting process. Full article