Reduced Adenosine Triphosphate Research Articles

How halogenated aromatic compounds affect the electron supply and consumption in glucose supported denitrification?

Halogenated aromatic compounds possess bidirectional effects on denitrifying bio-electron behavior, providing electrons and potentially interfering with electron consumption. This study selected the typical 4-chlorophenol (4-CP, 0–100 mg/L) to explore its impact mechanism on glucose-supported denitrification. When COD(glucose)/COD(4-CP)=28.70–3.59, glucose metabolism remained the dominant electron supply process, although its removal efficiency decreased to 73.84–49.66 %. When COD(glucose)/COD(4-CP)=2.39–1.43, 4-CP changed microbial carbon metabolism priority by inhibiting the abundance of glucose metabolizing enzymes, gradually replacing glucose as the dominant electron donor. Moreover, 5–100 mg/L 4-CP reduced adenosine triphosphate (ATP) by 15.52–24.67 % and increased reactive oxygen species (ROS) by 31.13–63.47 %, causing severe lipid peroxidation, thus inhibiting the utilization efficiency of glucose. Activated by glucose, 4-CP dechlorination had stronger electron consumption ability than NO2−-N reduction (NO3−-N > 4-CP > NO2−-N), combined with the decreased nirS and nirK genes abundance, resulting in NO2−-N accumulation. Compared with the blank group (0 mg/L 4-CP), 5–40 mg/L and 60–100 mg/L 4-CP reduced the secretion of cytochrome c and flavin adenine dinucleotides (FAD), respectively, further decreasing the electron transfer activity of denitrification system. Micropruina, a genus that participated in denitrification based on glucose, was gradually replaced by Candidatus_Microthrix, a genus that possessed 4-CP degradation and denitrification functions after introducing 60–100 mg/L 4-CP.

A Versatile Chitosan-Based Hydrogel Accelerates Infected Wound Healing via Bacterial Elimination, Antioxidation, Immunoregulation, and Angiogenesis.

Drug-resistant bacterial infection of cutaneous wounds causes great harm to the human body. These infections are characterized by a microenvironment with recalcitrant bacterial infections, persistent oxidative stress, imbalance of immune regulation, and suboptimal angiogenesis. Treatment strategies available to date are incapable of handling the healing dynamics of infected wounds. A Schiff base and borate ester cross-linked hydrogel, based on phenylboronic acid-grafted chitosan (CS-PBA), dibenzaldehyde-grafted poly(ethylene glycol), and tannic acid (TA), is fabricated in the present study. Customized phenylboronic acid-modified zinc oxide nanoparticles (ZnO) are embedded in the hydrogel prior to gelation. The CPP@ZnO-P-TA hydrogel effectively eliminates methicillin-resistant Staphylococcus aureus (MRSA) due to the pH-responsive release of Zn2+ and TA. Killing is achieved via membrane damage, adenosine triphosphate reduction, leakage of intracellular components, and hydrolysis of bacterial o-nitrophenyl-β-d-galactopyranoside. The CPP@ZnO-P-TA hydrogel is capable of scavenging reactive oxygen and nitrogen species, alleviating oxidative stress, and stimulating M2 polarization of macrophages. The released Zn2+ and TA also induce neovascularization via the PI3K/Akt pathway. The CPP@ZnO-P-TA hydrogel improves tissue regeneration in vivo by alleviating inflammatory responses, stimulating angiogenesis, and facilitating collagen deposition. These findings suggest that this versatile hydrogel possesses therapeutic potential for the treatment of MRSA-infected cutaneous wounds.

Cultivar-dependent grape berry dehydration in later ripening phases may be associated with energy regulation and ionic homeostasis

Climate warming and drought may alter the progression of sugar accumulation by the grape berry, and contribute to pre-harvest berry shrivel and cell vitality loss which were hypothesised to be associated with solute accumulation cessation and energy status in the berries. To explore the relationship between energy and cultivar-dependent berry cell death, we characterised the variations of pericarp constituents and energy status across five time points, five ripening phases, and three cultivars with various levels of berry shrivel and cell death. Grape berries of Shiraz, Chardonnay and Flame Seedless at the Eichorn-Lorenz stages 33 to 39 were sampled at 5:00, 9:00, 13:00, 17:00 and 21:00 on each sampling day, which were used in the analysis of water percentage, adenosine triphosphate (ATP), ethanol, sugar, L-malic acid, as well as elements with vascular mobility, including potassium (K) and sodium (Na). Shiraz and Chardonnay ceased accumulating sugar and phloem mobile elements during the later ripening phase, while Flame Seedless did not undergo water loss or cease to accumulate solutes in pericarps. Shiraz berry ripening was distinguished by greater pericarp water loss, ATP reduction, increased ion disorder susceptibility as indicated by a lower K/Na ratio, and higher ethanol concentration in the later ripening phase. The Chardonnay pericarp contained the highest ATP concentration and K/Na ratio among the three cultivars. The Flame Seedless pericarp maintained a low but stable K/Na ratio throughout berry ripening. Berry ripening phase impacted the diurnal variations of pericarp water percentage and ATP concentration. The results indicated that energy regulation and ionic homeostasis may be associated with cultivar-dependent grape pericarp hydration, solute accumulation and cell vitality during berry ripening.

Effect of inoculation with arbuscular mycorrhizal fungi on the energy metabolism of selenite-rich amaranth.

A series of pot trials were undertaken to examine the impact of four arbuscular mycorrhizal fungi (AMF), namely Glomus mosseae (G.m), Glomus etunicatum (G.e), Corymbiglomus tortuosum (C.t), and the combined application of Glomus etunicatum and Corymbiglomus tortuosum (G.e + C.t), on the energy metabolism of amaranth plants grown in soil enriched with selenite at a concentration of 0.5 mg kg-1 . The inoculation of four AMFs resulted in an increase in both amaranth biomass and selenium (Se) content in leaves. The activities of phosphoglucose isomerase (PGI) and glucose-6-phosphate dehydrogenase + 6-phosphogluconate dehydrogenase were observed to decrease when AMFs were inoculated, as compared with the absence of AMF inoculation. The inoculation with G.m, C.t, and G.e + C.t resulted in an increase in succinate dehydrogenase activity; however, the inoculation with G.m, G.e, and G.e + C.t led to an increase in ascorbate oxidase activity. Furthermore, the inoculation of all four AMFs resulted in an increase in cytochrome c oxidase activity and the concentrations of oxidized coenzyme I (NAD) and reduced coenzyme I (NADH). The polyphenol oxidase activity of amaranth plants increased when inoculated with G.m and G.e, whereas it decreased when inoculated with C.t and G.e + C.t. Furthermore, the application of all four AMF treatments resulted in a reduction in adenosine triphosphate (ATP) levels and energy charge. It was worth mentioning that there was a clear inverse relationship between the energy charge and the biomass, Se concentration in the leaves. The findings presented in this research indicated that AMF may have an impact on energy metabolism and ultimately the biomass of amaranth by influencing the uptake of Se.

Brain insulin resistance and Alzheimer's disease: a systematic review.

The authors aimed to gather data from the current literature on brain insulin resistance (BIR) and its likely repercussions on neurodegenerative disorders, more specifically AD, through a systematic review. A comprehensive search was conducted in multiple medical databases, including the Cochrane Central Register of Controlled Trials, EMBASE, Medical Literature Analysis and Retrieval System Online (Medline), and PubMed®, employing the descriptors: "insulin resistance", "brain insulin resistance", "Alzheimer's disease", "neurodegeneration", and "cognition". The authors focused their search on English-language studies published between 2000 and 2023 that investigated the influence of BIR on neurodegenerative disorders or offered insights into BIR's underlying mechanisms. Seventeen studies that met the inclusion criteria were selected. The results indicate that BIR is a phenomenon observed in a variety of neurodegenerative disorders, including AD. Studies suggest that impaired glucose utilization and uptake, reduced adenosine triphosphate (ATP) production, and synaptic plasticity changes caused by BIR are linked to cognitive problems. However, conflicting results were observed regarding the association between AD and BIR, with some studies suggesting no association. Based on the evaluated studies, it can be concluded that the association between AD and BIR remains inconclusive, and additional research is needed to elucidate this relationship.

Functional identification of PGM1 in the regulating development and depositing of inosine monophosphate specific for myoblasts.

Inosine monophosphate (IMP) is naturally present in poultry muscle and plays a key role in improving meat flavour. However, IMP deposition is regulated by numerous genes and complex molecular networks. In order to excavate key candidate genes that may regulate IMP synthesis, we performed proteome and metabolome analyses on the leg muscle, compared to the breast muscle control of 180-day-old Jingyuan chickens (hens), which had different IMP content. The key candidate genes identified by a differential analysis were verified to be associated with regulation of IMP-specific deposition. The results showed that the differentially expressed (DE) proteins and metabolites jointly involve 14 metabolic pathways, among which the purine metabolic pathway closely related to IMP synthesis and metabolism is enriched with four DE proteins downregulated (with higher expression in breast muscles than in leg muscles), including adenylate kinase 1 (AK1), adenosine monophosphate deaminase 1 (AMPD1), pyruvate kinase muscle isoenzyme 2 (PKM2) and phosphoglucomutase 1 (PGM1), six DE metabolites, Hypoxanthine, Guanosine, L-Glutamine, AICAR, AMP and Adenylsuccinic acid. Analysis of PGM1 gene showed that the high expression of PGM1 promoted the proliferation and differentiation of myoblasts and inhibited the apoptosis of myoblasts. ELISA tests have shown that PGM1 reduced adenosine triphosphate (ATP) and IMP and uric acid (UA), while enhancing the biosynthesis of hypoxanthine (HX). In addition, up-regulation of PGM1 inhibited the expression of purine metabolism pathway related genes, and promoted the IMP de novo and salvage synthesis pathways. This study preliminarily explored the mechanism of action of PGM1 in regulating the growth and development of myoblasts and specific IMP deposition in Jingyuan chickens, which provided certain theoretical basis for the development and utilization of excellent traits in Jingyuan chickens.

Bioinformatics Analyzes the Mechanisms of Codonopsis Radix in Treating Ovarian Cancer

Background Codonopsis Radix (CR), a renowned traditional Chinese medicine (TCM) formula, has been widely applied for its immunomodulatory, antitumor, antioxidant, neuroprotective, and antiviral effects. However, the multitarget mechanism of CR in ovarian cancer (OC) remains to be elucidated. Objectives We applied bioinformatics and molecular docking techniques to explore possible pharmacological targets, bioactivities, and molecular mechanisms of CR for OC treatment. Materials and Methods We identified 40 common genes associated with CR and OC and obtained core genes through a protein–protein interaction network. Results Enrichment analysis revealed that mitochondrial electron transport was the key biological process involved. Based on the analysis, we selected estrogen receptor 1 (ESR1) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) as the key target genes for molecular docking. In the final verification analysis, we evaluated the effect of the PIK3CA mutation on the survival rate of patients with OC and determined that the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway was the key pathway in the OC treatment. Conclusion These results suggest that CR inhibits the activity of mitochondrial complex II, reduces adenosine triphosphate (ATP) production by mitochondrial electron transport, inhibits PI3K/AKT phosphorylation, and promotes apoptosis in OC cells.

Baicalin inhibited PANX-1/P2Y6 signaling pathway activation in porcine aortic vascular endothelial cells infected by Glaesserella parasuis

Glaesserella parasuis can induce endothelial barrier damage in piglets, although the mechanism by which this pathogen triggers inflammatory damage remains unclear. Baicalin possesses anti-inflammatory and anti-oxidant activities. However, whether baicalin can relieve endothelial barrier damage caused by Glaesserella parasuis infection has not yet been studied. Hence, we evaluated the ability of baicalin to counteract the changes induced by Glaesserella parasuis in porcine aortic vascular endothelial cells. The results showed that Glaesserella parasuis could upregulate the expression of pannexin 1 channel protein and promote the release of adenosine triphosphate, adenosine diphosphate, adenosine 3′-monophosphate, uridine triphosphate, uridine diphosphate, and uridine monophosphate in porcine aortic vascular endothelial cells. The expression level of purinergic receptor P2Y6 was upregulated in porcine aortic vascular endothelial cells triggered by Glaesserella parasuis. In addition, Glaesserella parasuis could activate phospholipase C-protein kinase C and myosin light chain kinase-myosin light chain signaling pathways in porcine aortic vascular endothelial cells. Baicalin could inhibit pannexin 1 channel protein expression, reduce adenosine triphosphate, adenosine diphosphate, adenosine 3′-monophosphate, uridine triphosphate, uridine diphosphate, and uridine monophosphate release, and attenuate the expression level of P2Y6 in porcine aortic vascular endothelial cells induced by Glaesserella parasuis. Baicalin could also reduce the activation of phospholipase C-protein kinase C and myosin light chain kinase-myosin light chain signaling pathways in porcine aortic vascular endothelial cells triggered by Glaesserella parasuis. Our study report that Glaesserella parasuis could promote pannexin 1 channel protein expression, induce nucleosides substance release, and P2Y6 expression in porcine aortic vascular endothelial cells and baicalin could inhibit the expression levels of pannexin 1, nucleosides substance, and P2Y6 in the porcine aortic vascular endothelial cells induced by Glaesserella parasuis, which might be served as some targets for treatment of inflammation disease caused by Glaesserella parasuis.

Diverse Effects of Cryopreservation-Induced Mitochondrial Dysregulation on Cord Blood Cells

Umbilical cord blood transplantation (UCBT) has been performed broadly in clinic by the specific biological and immunological characteristics of umbilical cord blood cells (UCB). UCB-based cell therapy and immune therapy also presents great application potential. UCB was usually cryopreserved for several years before using. Whether and how cryopreservation affects the function of divergent cell populations in UCB still remain to be illuminated. Here, we firstly constructed a single-cell transcriptomic profile of Lineage - CD34 + hematopoietic stem and progenitor cells (HSPCs) and mononuclear cells (MNCs) collected from fresh and cryopreserved UCB with 1, 5, 10 and 19 years. Subpopulations characterized by higher mitochondrial gene expression (Mito high) were identified in all cell populations and found to be increased during cryopreservation. Compared with the fresh group, HSC/MPP cells after cryopreservation showed more active cell cycle and lower expression of HSC/MPP signature genes, especially in the Mito high HSC/MPP cells. Consistently, colony-forming ability as well as long-term hematopoietic reconstitution of HSPCs derived from cryopreserved UCB gradually decreased within 5 years but remained stable thereafter. More importantly, we observed decreased megakaryocyte differentiation ability from cryopreserved HSPCs, which could be partially rescued by antioxidants treatment after cryopreservation. Mechanically, we revealed that the metabolic dysregulation of mitochondria including elevated mitochondrial reactive oxygen species (ROS), reduced adenosine triphosphate (ATP) synthesis and impaired mitochondrial membrane potential of cryopreserved HSPCs led to attenuated hematopoietic reconstitution. Although there was a mild increase of Mito high subpopulations after cryopreservation, the cytokine production levels of T cells and NK cells were comparable to those of fresh samples. Additionally, NK cells exhibited almost same cytotoxic function with the fresh compartments. Taken together, we elucidated the impact of cryopreservation on UCB HSPCs and provided the strategy for rescuing itsfunctional impairment. The unaffected T and NK cells after cryopreservation also paved the way for UCB-based cell therapy and immune therapy. Our study provides important implements for the quality control of applicable UCB both in hematology and immunotherapy.

Ascendancy of pyraclostrobin nanocapsule formulation against Rhizoctonia solani: From a perspective of fungus

High-performance pesticide formulations are essential for sustainable agriculture. Among these, nano-pesticides exhibit great advantages in pest control because of their unique size effects. However, the direct effects of nano-formulation fungicides on fungal pathogens remain largely unexplored. In this study, three qualified formulations, suspension concentrate (SC), microcapsules (CS), and nanocapsules (NCS) of pyraclostrobin (PYR) were prepared and utilized to reveal their biocontrol activities against Rhizoctonia solani. Among these three formulations, NCS exhibited notable biocontrol efficacy against R. solani exemplified by an EC50 of 0.319 mg/L for mycelia, distortion of mycelia and abnormalities in cell ultrastructure. Moreover, NCS displayed excellent internalization within R. solani mycelia, contributing to severe damage to cell membrane permeability. Importantly, an equivalent quantity of NCS-PYR showed potent inhibitory effects on the target pathogen, as indicated by reduced adenosine triphosphate (ATP) content and mitochondrial Complex III activity. The NCS consistently exhibited superior in vivo protective and curative activities against R. solani compared to those of CS and SC in rice and faba bean. In summary, we uncovered the strength of rapid efficacy and biocontrol activity of NCS against R. solani and elucidated the advantages of NCS-PYR from the perspective of the target pathogen in agriculture.

Fluoride releasing photothermal responsive TiO2 matrices for antibiosis, biosealing and bone regeneration

Peri-implantitis induced by infection leads to gingival recession, alveolar resorption and eventual dental implant failure. So, antibiosis and biosealing of abutments as well as osseointegration of roots need to be projected seriously during the whole service lifespan of dental implants. In this work, a multipurpose photothermal therapy strategy based on Si/P/F doped TiO2 matrix is proposed to address the above issues. This TiO2 matrix not only has outstanding photothermal response, but also triggers the release of F ions under near-infrared (NIR) light irradiation. Local hyperthermia assisted with the released F ions reduces adenosine triphosphate (ATP) synthesis of staphylococcus aureus (S. aureus), increases bacterial membrane permeability, and induces abundant of reactive oxygen species, resulting in the oxidation of cellular components and eventual death of bacteria. Furthermore, the synergic action of mild photothermal stimulation and Si/P/F ions of TiO2 matrix up-regulates gingival epithelial cells behavior (e.g., hemidesmosome formation) and osteoblasts response in vitro. In an infected model, this TiO2 matrix obviously eliminates bacteria, reduces inflammatory response, improves epithelial sealing and osseointegration, and reduces alveolar resorption by regulating NIR irradiation.

Bioactive Vanadium Disulfide Nanostructure with "Dual" Antitumor Effects of Vanadate and Gas for Immune-Checkpoint Blockade-Enhanced Cancer Immunotherapy.

Bioactive inorganic nanomaterials and the biological effects of metal ions have attracted extensive attention in tumor therapy in recent years. Vanadium (V), as a typical bioactive metal element, regulates a variety of biological functions. However, its role in antitumor therapy remains to be revealed. Herein, biodegradable vanadium disulfide (VS2) nanosheets (NSs) were prepared as a responsive gas donor and bioactive V source for activating cancer immunotherapy in combination with immune-checkpoint blockade therapy. After PEGylation, VS2-PEG exhibited efficient glutathione (GSH) depletion and GSH-activated hydrogen sulfide (H2S) release. Exogenous H2S caused lysosome escape and reduced adenosine triphosphate (ATP) synthesis in tumor cells by interfering with the mitochondrial membrane potential and inducing acidosis. In addition, VS2-PEG degraded into high-valent vanadate, leading to Na+/K+ ATPase inhibition, potassium efflux, and interleukin (IL)-1β production. Together with further induction of ferroptosis and immunogenic cell death, a strong antitumor immune response was stimulated by reversing the immunosuppressive tumor microenvironment. Moreover, the combined treatment of VS2-PEG and α-PD-1 amplified antitumor therapy, significantly suppressed tumor growth, and further elicited robust immunity to effectively defeat tumors. This work highlights the biological effects of vanadium for application in cancer treatment.

NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis

Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 (NOS2) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2-/- mice were protected from age-related OA development. Taken together, the TLR2-NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.

The MAEL expression in mitochondria of human spermatozoa and the association with asthenozoospermia.

The maelstrom spermatogenic transposon silencer (MAEL) function in postmeiotic germ cells remains unclear, and its protein localization in human testis and spermatozoa awaits determination. This study aims to clarify the MAEL expression in human spermatogenesis and to explore its role in sperm function. Twenty-seven asthenozoospermic men, 40 normozoospermic controls, and three obstructive azoospermic men were enrolled. The transcripts of MAEL in the seminiferous epithelium and MAEL downstream targets were identified by bioinformatics analysis. MAEL protein expression in human testis and ejaculated sperms were examined by immunohistochemical and immunogold staining, respectively. The roles of MAEL in mitochondria function were investigated by siRNA knockdown in human H358 cells. The association between MAEL protein levels and clinical sperm features was evaluated. Abundant MAEL was expressed in spermatid and spermatozoa of the human testis. Remarkably, MAEL was located in the mitochondria of ejaculated sperm, and bioinformatics analysis identified GPX4 and UBL4B as MAEL's downstream targets. Knockdown of MAEL sabotaged mitochondria function and reduced adenosine triphosphate (ATP) production in H358 cells. MAEL, GPX4, and UBL4B expression levels were significantly decreased in asthenozoospermic sperms than in controls. The MAEL protein levels were positively correlated with GPX4 and UBL4B in human sperm. Total motile sperm count (TMSC) was positively correlated with protein levels of MAEL, GPX4, and UBL4B in ejaculated sperms. We highlight prominent MAEL expression in the intratesticular spermatid and the mitochondria of ejaculated spermatozoa. MAEL directly binds to GPX4 and UBL4B, and loss of MAEL induces mitochondrial dysfunction. MAEL-mitochondrial function-motility relationship might advance our understanding of the causes of asthenozoospermia.

Mitapivat: A Quinolone Sulfonamide to Manage Hemolytic Anemia in Adults With Pyruvate Kinase Deficiency.

Pyruvate kinase (PK) deficiency is a rare enzyme-linked glycolytic defect resulting in mild-to-severe chronic persistent erythrocyte hemolysis. The disease is an autosomal recessive trait caused by mutations in the PK liver and red blood cell gene characterized by insufficient erythrocyte PK activity. PK deficiency is most diagnosed in persons of northern European descent and managed with packed red blood cell transfusions, chelation, and splenectomy with cholecystectomy. Mitapivat is the first approved therapy indicated for hemolytic anemia in adults with PK deficiency with the potential for delaying splenectomy in mild-moderate disease. Mitapivat is a PK activator that acts by allosterically binding to the PK tetramer and increases PK activity. The red blood cell form of PK is mutated in PK deficiency, which leads to reduced adenosine triphosphate, shortened red blood cell lifespan, and chronic hemolysis. The half-life of elimination is 3-5 hours, with 73% bioavailability, 98% plasma protein binding, and a median duration of response of 7 months. Mitapivat has been investigated through various clinical trials for different therapeutic indications. Pivotal trials that serve the primary focus throughout this article are ACTIVATE, ACTIVATE-T, and RISE. ACTIVATE is a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of mitapivat in adult patients who were not receiving regular blood transfusions. Contrarily, ACTIVATE-T explored the safety and efficacy of mitapivat in adults with PK deficiency who received regular blood transfusions. Both trials demonstrated favorable use of mitapivat in PK deficiency. Focusing on another indication, the ongoing RISE trial investigates the optimal dosage of mitapivat in sickle cell disease. Mitapivat is an appropriate treatment for adults with PK deficiency requiring transfusions and may be considered for patients with symptomatic anemia who do not require transfusions and/or PK deficiency with compensated hemolysis without overt anemia.

Therapeutic Stimulation of Glycolytic ATP Production for Treating ROS-Mediated Cellular Senescence.

Cellular senescence is conditioned through two interrelated processes, i.e., a reduction in adenosine triphosphate (ATP) and the enhancement of reactive oxygen species (ROS) production levels in mitochondria. ATP shortages primarily influence the energy-intensive synthesis of large biomolecules, such as deoxyribonucleic acid (DNA). In addition, as compared to small biomolecules, large biomolecules are more prone to ROS-mediated damaging effects. Based on the available evidence, we suggest that the stimulation of anaerobic glycolytic ROS-independent ATP production could restrain cellular senescence. Consistent with this notion, non-drug related intermittent hypoxia (IH)-based therapy could be effectively applied in sports medicine, as well as for supporting the physical activity of elderly patients and prophylactics of various age-related disorders. Moreover, drug therapy aiming to achieve the partial blockade of respiratory chain and downstream compensatory glycolysis enhancement could prove to be useful for treating cardiovascular, neurological and hormonal diseases. We maintain that non-drug/drug-related therapeutic interventions applied in combination over the entire lifespan could significantly rejuvenate and prolong a high quality of life for individuals.

MiR-199b-5p-AKAP1-DRP1 Pathway Plays a Key Role in ox-LDL-induced Mitochondrial Fission and Endothelial Apoptosis.

Atherosclerosis (AS) remains prevalent despite hyperlipidemia-lowering therapies. Although multiple functions of miR-199b-5p have been implicated in cancers, its role in endothelial apoptosis and AS remains unclear. This study aimed to examine the role of miR-199b-5p in mitochondrial dynamics and endothelial apoptosis. Human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL) were subjected to other treatments, followed by a series analysis. We found that ox-LDL-treated HUVECs were associated with miR-199b-5p downregulation, increased reactive oxygen species level, reduced adenosine triphosphate (ATP) production, mitochondrial fission, and apoptosis, whereas enhanced miR-199b-5p expression or applied mitochondrial division inhibitor 1 (Mdivi-1) markedly reversed these changes. Mechanistically, A-kinase anchoring protein 1 (AKAP1) was confirmed as a downstream target of miR-199b-5p by dual-luciferase activity reporter assay. AKAP1 overexpression reversed the anti-apoptotic effects of miR-199b-5p through the enhanced interaction of AKAP1 and dynamin protein 1 (DRP1) in ox-LDL-treated HUVECs. Moreover, miR-199b-5p downregulation, AKAP1 upregulation, and excessive mitochondrial fission were verified in human coronary AS endothelial tissues. The miR-199b-5p-dependent regulation of AKAP1/DRP1 is required to inhibit hyperlipidemia- induced mitochondrial fission and endothelial injury and may be a promising therapeutic target for AS.

Right Ventricular Maladaptation to Pressure Overload in Fischer Rats Is Associated With Profound Deficiency in Adenylate Kinase 1 and Impaired Ventricular Energetics.

We explored the mechanism of maladaptive right ventricular (RV) remodeling in Fischer compared with Sprague-Dawley (SD) rats exposed to pressure overload. Pulmonary hypertension was induced by injection of the VEGFR antagonist, SU5416, followed by a 3-week exposure to hypoxia (Sugen chronic hypoxia). In vivo oxidative metabolism was assessed by RV/left ventricle ratio of [11C]acetate positron emission tomography clearance (kmono). Unbiased, global transcriptional and proteomic profiling was performed in Fischer and SD rats at baseline and after Sugen chronic hypoxia. All Fischer rats succumbed to RV failure by 5 weeks, whereas SD rats showed preserved RV function and 88% survival beyond 9 weeks (P<0.0001). Fischer rats exhibited increased oxidative metabolism at 4 weeks (P<0.05) and impaired RV efficiency compared with SD (work metabolic index: 52±10 versus 91±27 mmHg·mL/cm2, respectively; P<0.05), but no differences in mitochondrial complex activity. AK1 (adenylate kinase 1) was among the top 10 differentially expressed genes between Fischer and SD rats, with markedly lower RV expression in Fischer rats (FC: 3.36, P<0.05), confirmed by proteomic analysis and validated by Western blotting (>10-fold reduction, P<0.001). While whole-genome sequencing failed to reveal any coding region mutations in Fischer rats, there was a unique variant in a highly conserved upstream flanking region likely involved in the regulation of AK1 expression. Therefore, Fischer rats exhibit profound AK1 deficiency and inefficient cardiac energetics likely related to reduced adenosine triphosphate shuttling from the mitochondria to the contractile fibers. This represents a novel mechanism for RV failure in response to chronic increases in afterload.

Cardiac energy metabolism disorder mediated by energy substrate imbalance and mitochondrial damage upon tebuconazole exposure

Tebuconazole exposure has been described as an increasing hazard to human health. An increasing number of recent studies have shown a positive association between tebuconazole exposure and cardiovascular disease risk, which is characterized by the reduction of adenosine triphosphate (ATP) synthesis. However, researches on the damage of tebuconazole exposure to energy metabolism and the related molecular mechanisms are limited. In the present study, male C57BL/6 mice were treated with tebuconazole at different low concentrations for 4 weeks. The results indicated that tebuconazole could accumulate in the heart and further induce the decrease of ATP content in the mouse heart. Importantly, tebuconazole induced an obvious shift in substrate utilization of fatty acid and glucose by disrupting their corresponding transporters (GLUT1, GLUT4, CD36, FABP3 and FATP1) expression, and significantly repressed the expression of mitochondrial biogenesis (Gabpa and Tfam) and oxidative phosphorylation (CS, Ndufa4, Sdhb, Cox5a and Atp5b) related genes in a dose-dependent manner. Further investigation revealed that these alterations were related to the IRS1/AKT and PPARγ/RXRα pathways. These findings contribute to a better understanding of triazole fungicide-induced cardiovascular disease by revealing the key indicators associated with this phenomenon.

Monitoring the effectiveness of surgical handwashing in healthcare workers of a fourth level operating room using bioluminescence assays

Aims: To assesses the effectiveness of surgical handwashing (S-HW) in healthcare workers (HCWs) in terms of organic material and bacteria elimination by means of bioluminescence assays.&#x0D; Methods: 62-HCWs were subjected to bioluminescence analyses to determine adenosine triphosphate (ATP) and colony forming units (CFU) of Enterobacteriaceae (EB) and E. coli before and after S-HW. A checklist to evaluate adherence to hand hygiene (HH) protocol was implemented.&#x0D; Results: ATP before HH (510.9/RLU) was reduced after S-HW (54.6/RLU), evidencing a significant decrease (p=0.001). Regarding the bacteria, 26.6/CFU and 4/CFU for EB and E. coli were reported before S-HW, respectively. After S-HW, CFU decreased for EB (21.8/CFU) and E. coli (3.5/CFU) without showing a significant reduction (p=0.679). Low ATP did not evidence a direct relation with EB (p=0.082) and E. coli (p=0.680) reduction. Surgical instrument professionals (p=0.001), general surgeons (p=0.001), residents (p=0.017), orthopedists (p=0.029) and otolaryngologists (p=0.029) evidenced a reduction in ATP after S-HW. Factors such as S-HW direction, surgical soap, moments and time of S-HW implemented showed a statistically significant difference in reduction of ATP, but not in CFU.&#x0D; Conclusion: Although there was a reduction in elimination of ATP, there was no evidence of a decrease in bacteria. This finding not only allowed to identify potential errors in S-HW processes, but also permitted to generate strategies to improve HH to prevent healthcare-associated infections.