SH-SY5Y cells undergo changes in peroxisomal metabolism when exposed to decanoic acid.

Medium-chain fatty acids (MCFAs), particularly decanoic acid (C10) and octanoic acid (C8), have garnered attention in recent years for their potential antiepileptic properties. A previous study from our laboratory demonstrated that C10 targets the PPARγ nuclear receptor, increasing the activity of the antioxidant enzyme catalase and thereby possibly modulating peroxisomal content. Here, we examined markers of peroxisomal content and activity in response to C10 and C8 exposure in neuronal-like SH-SY5Y cells. SH-SY5Y were treated with 250 mM C10 or C8 for a period of 6 days. Following this, biochemical markers of peroxisomal content and function were assessed, including acyl-coA oxidase activity, peroxisomal gene expression and peroxisomal VLCFA ß-oxidation. Our findings revealed that C10 treatment augments acyl-CoA oxidase 1 (ACOx1) activity by 129% in comparison to control cells. An exploration into genes related to peroxisomal biosynthesis showed 23% increased expression of PEX11α upon C10 exposure, implying peroxisomal proliferation. Furthermore, it was observed that C10 exposure not only elevated ACOx1 activity but also enhanced peroxisomal ß-oxidation of docosanoic acid (C22). Our findings bolster the premise that C10 functions as a peroxisome proliferator, influencing peroxisomal content and function. Further investigations are required to fully understand the mechanistic details as to how this may be beneficial in epilepsy and the potential implications with regards to peroxisomal disease.

LORE receptor homomerization is required for 3-hydroxydecanoic acid-induced immune signaling and determines the natural variation of immunosensitivity within the Arabidopsis genus.

The S-domain-type receptor-like kinase (SD-RLK) LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION (LORE) from Arabidopsis thaliana is a pattern recognition receptor that senses medium-chain 3-hydroxy fatty acids, such as 3-hydroxydecanoic acid (3-OH-C10:0), to activate pattern-triggered immunity. Here, we show that LORE homomerization is required to activate 3-OH-C10:0-induced immune signaling. Fluorescence lifetime imaging in Nicotiana benthamiana demonstrates that AtLORE homomerizes via the extracellular and transmembrane domains. Co-expression of AtLORE truncations lacking the intracellular domain exerts a dominant negative effect on AtLORE signaling in both N. benthamiana and A. thaliana, highlighting that homomerization is essential for signaling. Screening for 3-OH-C10:0-induced reactive oxygen species production revealed natural variation within the Arabidopsis genus. Arabidopsis lyrata and Arabidopsis halleri do not respond to 3-OH-C10:0, although both possess a putative LORE ortholog. Both LORE orthologs have defective extracellular domains that bind 3-OH-C10:0 to a similar level as AtLORE, but lack the ability to homomerize. Thus, ligand binding is independent of LORE homomerization. Analysis of AtLORE and AlyrLORE chimera suggests that the loss of AlyrLORE homomerization is caused by several amino acid polymorphisms across the extracellular domain. Our findings shed light on the activation mechanism of LORE and the loss of 3-OH-C10:0 perception within the Arabidopsis genus.

The Protective Effect of Uridine in a Rotenone-Induced Model of Parkinson's Disease: The Role of the Mitochondrial ATP-Dependent Potassium Channel.

The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoKATP) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed. The nucleoside uridine, which is a source for the synthesis of the mitoKATP channel opener uridine diphosphate, was able to dose-dependently decrease behavioral disorders and prevent the death of animals, which occurred for about 50% of animals in the model. Uridine prevented disturbances in redox, energy, and ion exchanges in brain mitochondria, and eliminated alterations in their structure and the myelin sheath in the substantia nigra. Cytochemical examination showed that uridine restored the indicators of oxidative phosphorylation and glycolysis in peripheral blood lymphocytes. The specific blocker of the mitoKATP channel, 5-hydroxydecanoate, eliminated the positive effects of uridine, suggesting that this channel is involved in neuroprotection. Taken together, these findings indicate the promise of using the natural metabolite uridine as a new drug to prevent and, possibly, stop the progression of Parkinson's disease.

Caprylic Acid Inhibits High Mobility Group Box-1-Induced Mitochondrial Damage in Myocardial Tubes.

Myocardial damage significantly impacts the prognosis of patients with cancer; however, the mechanisms of myocardial damage induced by cancer and its treatment remain unknown. We previously reported that medium-chain fatty acids (MCFAs) improve cancer-induced myocardial damage but did not evaluate the differences in effect according to MCFA type. Therefore, this study investigated the role of inflammatory cytokines in cancer-induced myocardial damage and the effects of three types of MCFAs (caprylic acid [C8], capric acid [C10], and lauric acid [C12]). In a mouse model, the C8 diet showed a greater effect on improving myocardial damage compared with C10 and C12 diets. Myocardial tubes differentiated from H9C2 cardiomyoblasts demonstrated increased mitochondrial oxidative stress, decreased membrane potential and mitochondrial volume, and inhibited myocardial tube differentiation following treatment with high-mobility group box-1 (HMGB1) but not interleukin-6 and tumor necrosis factor-α cytokines. However, HMGB1 treatment combined with C8 improved HMGB1-induced mitochondrial damage, enhanced autophagy, and increased mitochondrial biogenesis and maturation. However, these effects were only partial when combined with beta-hydroxybutyrate, a C8 metabolite. Thus, HMGB1 may play an important role in cancer-related myocardial damage. C8 counteracts HMGB1's effects and improves cancer-related myocardial damage. Further clinical studies are required to investigate the effects of C8.

In Vivo Mechanism of Action of Sodium Caprate for Improving the Intestinal Absorption of a GLP1/GIP Coagonist Peptide.

Sodium caprate (C10) has been widely evaluated as an intestinal permeation enhancer for the oral delivery of macromolecules. However, the effect of C10 on the intestinal absorption of peptides with different physicochemical properties and its permeation-enhancing effect in vivo remains to be understood. Here, we evaluated the effects of C10 on intestinal absorption in rats with a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP-GLP1) dual agonist peptide (LY) and semaglutide with different enzymatic stabilities and self-association behaviors as well as the oral exposure of the LY peptide in minipigs. Furthermore, we investigated the mechanism of action (MoA) of C10 for improving the intestinal absorption of the LY peptide in vivo via live imaging of the rat intestinal epithelium and tissue distribution of the LY peptide in minipigs. The LY peptide showed higher proteolytic stability in pancreatin and was a monomer in solution compared to that in semaglutide. C10 increased in vitro permeability in the minipig intestinal organoid monolayer to a greater extent for the LY peptide than for semaglutide. In the rat jejunal closed-loop model, C10 increased the absorption of LY peptide better than that of semaglutide, which might be attributed to higher in vitro proteolytic stability and permeability of the LY peptide. Using confocal live imaging, we observed that C10 enabled the rapid oral absorption of a model macromolecule (FD4) in the rat intestine. In the duodenum tissues of minipigs, C10 was found to qualitatively reduce the tight junction protein level and allow peptide uptake to the intestinal cells. C10 decreased the transition temperature of the artificial lipid membrane, indicating an increase in membrane fluidity, which is consistent with the above in vivo imaging results. These data indicated that the LY's favorable physicochemical properties combined with the effects of C10 on the intestinal mucosa resulted in an ∼2% relative bioavailability in minipigs.

Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling.

Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, potentially leading to a range of positive medical and health-related effects. Here, we determined whether mTORC1 signaling is also a target for decanoic acid, a key component of the medium-chain triglyceride (MCT) ketogenic diet. Using a tractable model system, Dictyostelium, we show that decanoic acid can decrease mTORC1 activity, under conditions of constant glucose and in the absence of insulin, measured by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). We determine that this effect of decanoic acid is dependent on a ubiquitin regulatory X domain-containing protein, mediating inhibition of a conserved Dictyostelium AAA ATPase, p97, a homolog of the human transitional endoplasmic reticulum ATPase (VCP/p97) protein. We then demonstrate that decanoic acid decreases mTORC1 activity in the absence of insulin and under high-glucose conditions in ex vivo rat hippocampus and in tuberous sclerosis complex (TSC) patient-derived astrocytes. Our data therefore indicate that dietary decanoic acid may provide a new therapeutic approach to down-regulate mTORC1 signaling.

(-)-Epigallocatechin-3-Gallate Reduces Perfluorodecanoic Acid-Exacerbated Adiposity and Hepatic Lipid Accumulation in High-Fat Diet-Fed Male C57BL/6J Mice.

Perfluorodecanoic acid (PFDA), an enduring and harmful organic pollutant, is widely employed in diverse food-related sectors. Our previous studies have provided evidence that PFDA has the potential to facilitate obesity and hepatic fat accumulation induced by high-fat diet (HFD) intake. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, has been suggested to possess potential preventive effects against metabolic abnormalities and fatty liver. The purpose of this research was to investigate the effects of EGCG on PFDA-exacerbated adiposity and hepatic lipid accumulation in HFD-fed mice. The results showed that EGCG reduced body weight gain; tissue and organ weights; blood glucose, serum insulin, HOMA-IR, leptin, and lipid parameters; serum inflammatory cytokines (IL-1ß, IL-18, IL-6, and TNF-α); and hepatic lipid accumulation in PFDA-exposed mice fed an HFD. Further work showed that EGCG improved liver function and glucose homeostasis in mice fed an HFD and co-exposed to PFDA. The elevated hepatic mRNA levels of SREBP-1 and associated lipogenic genes, NLRP3, and caspase-1 in PFDA-exposed mice fed an HFD were significantly decreased by EGCG. Our work provides evidence for the potential anti-obesity effect of EGCG on co-exposure to HFD and PFDA and may call for further research on the bioactivity of EGCG to attenuate the endocrine disruption effects of long-term exposure to pollutants.

In Silico-Based Experiments on Mechanistic Interactions between Several Intestinal Permeation Enhancers with a Lipid Bilayer Model.

Oral administration of drugs is generally considered convenient and patient-friendly. However, oral administration of biological drugs exhibits low oral bioavailability (BA) due to enzymatic degradation and low intestinal absorption. A possible approach to circumvent the low BA of oral peptide drugs is to coformulate the drugs with permeation enhancers (PEs). PEs have been studied since the 1960s and are molecules that enhance the absorption of hydrophilic molecules with low permeability over the gastrointestinal epithelium. In this study, we investigated the impact of six PEs on the structural properties of a model membrane using molecular dynamics (MD) simulations. The PEs included were the sodium salts of the medium chain fatty acids laurate, caprate, and caprylate and the caprylate derivative SNAC─all with a negative charge─and neutral caprate and neutral sucrose monolaurate. Our results indicated that the PEs, once incorporated into the membrane, could induce membrane leakiness in a concentration-dependent manner. Our simulations suggest that a PE concentration of at least 70-100 mM is needed to strongly affect transcellular permeability. The increased aggregation propensity seen for neutral PEs might provide a molecular-level mechanism for the membrane disruptions seen at higher concentrations in vivo. The ability for neutral PEs to flip-flop across the lipid bilayer is also suggestive of possible intracellular modes of action other than increasing membrane fluidity. Taken together, our results indicate that MD simulations are useful for gaining insights relevant to the design of oral dosage forms based around permeability enhancer molecules.

Impact of Intestinal Concentration and Colloidal Structure on the Permeation-Enhancing Efficiency of Sodium Caprate in the Rat.

In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50-300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and Cmax of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60-120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (≥100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.

Perfluorotridecanoic Acid Inhibits Leydig Cell Maturation in Male Rats in Late Puberty via Changing Testicular Lipid Component.

Perfluorotridecanoic acid (PFTrDA) is a long-chain (C13) perfluoroalkyl carboxylic acid. Here, we report the influence of PFTrDA exposure on the maturation of rat Leydig cells in late puberty in vivo. Male Sprague-Dawley rats were administered PFTrDA by gavage of 0, 1, 5, and 10 mg/kg/day from 35 days to 56 days postpartum. PFTrDA had no effect on body weight, testis weight, and epididymis weight. It significantly decreased the serum testosterone level after 5 and 10 mg/kg exposure, while it did not alter the serum estradiol level. The serum luteinizing hormone level was markedly reduced after 10 mg/kg PFTrDA exposure, while the follicle-stimulating hormone level was unchanged. Star, Cyp11a1, Cyp17a1, Hsd3b1, and Insl3 transcript levels in the testis were markedly lowered in the 1-5 mg/kg PFTrDA group and the Lhb transcript level in the pituitary in the 10 mg/kg group. CYP11A1 and HSD11B1-positive Leydig cell numbers were markedly reduced after 10 mg/kg PFTrDA exposure. Testicular triglyceride and free fatty acid (palmitic acid, oleic acid, and linoleic acid) levels were significantly reduced by PFTrDA, while Mgll (up-regulation) and Scarb1 and Elovl5 (down-regulation) expression were altered. AKT1 and AMPK phosphorylation was stimulated after 10 PFTrDA mg/kg exposure. In conclusion, PFTrDA delays the maturation of Leydig cells in late puberty mainly by altering the free fatty acid profile.

Autophagy contributes to angiotensin II induced dysfunction of HUVECs.

BACKGROUND: Signal transduction of Angiotensin II (Ang II) induced autophagy and its role in Ang II-induced dysfunction of HUVECs are still unclear. METHODS: HUVECs are stimulated with different doses of Ang II (10-9-10-5 mol/L) for different time (6-48 hours). Autophagy-related protein markers: LC3, Beclin-1 and SQSTM1/p62 are measured by western blot. RESULTS: Incubation with Ang II increases autophagic flux (Beclin-1, autophagosomes formation, and degradation of SQSTM1/p62, LC3-I). Increased autophagic levels are inhibited by pretreatment with Ang II type 1 receptor (AT1) blocker (Candesartan), NADPH Oxidase inhibitor (apocycin), mitochondrial KATP channels inhibitor (5-hydroxydecanoate, 5HD). 3-Methyladenine (inhibitors of autophagy) and rapamycin (activator of autophagy) respectively inhibits or activates Ang II-induced autophagy levels. Ang II decreases phosphorylation of endothelial nitric oxide synthase (eNOS) and NO production in HUVECs. L-NAME (NOS inhibitor) totally mimics the actions of Ang II on eNOS, NO production and autophagy levels. Rapamycin further decreases NO production combined with Ang II. Silence Atg5 completely reverses Ang II-activated autophagy levels. CONCLUSIONS: Our results demonstrate that Ang II stimulation increases autophagy levels via AT1 receptor, NADPH oxidase, mitochondrial KATP channel, eNOS, Atg5 signal pathway in HUVECs, and activation of autophagy contributes to Ang II induced dysfunction of HUVECs.

Junctional Modulation of Round Window Membrane Enhances Dexamethasone Uptake into the Inner Ear and Recovery after NIHL.

Delivery of substances into the inner ear via local routes is increasingly being used in clinical treatment. Studies have focused on methods to increase permeability through the round window membrane (RWM) and enhance drug diffusion into the inner ear. However, the clinical applications of those methods have been unclear and few studies have investigated the efficacy of methods in an inner ear injury model. Here, we employed the medium chain fatty acid caprate, a biologically safe, clinically applicable substance, to modulate tight junctions of the RWM. Intratympanic treatment of sodium caprate (SC) induced transient, but wider, gaps in intercellular spaces of the RWM epithelial layer and enhanced the perilymph and cochlear concentrations/uptake of dexamethasone. Importantly, dexamethasone co-administered with SC led to significantly more rapid recovery from noise-induced hearing loss at 4 and 8 kHz, compared with the dexamethasone-only group. Taken together, our data indicate that junctional modulation of the RWM by SC enhances dexamethasone uptake into the inner ear, thereby hastening the recovery of hearing sensitivity after noise trauma.

10-Hydroxydecanoic Acid Potentially Elicits Antigen-Specific IgA Responses.

The effective antigen (Ag) uptake by microfold cells (M-cells) is important for the induction of an efficient mucosal immune responses. Here, we show that 10-hydroxydecanoic acid (10-HDAA) from royal jelly (RJ) potentially supports M-cell differentiation and induces effective antigen-specific mucosal immune responses in cynomolgus macaques. 10-HDAA increases the expression level of receptor activator of nuclear factor-kappaB (NF-κB) (RANK) in Caco-2 cells, which suggests that 10-HDAA potentially prompts the differentiation of Caco-2 cells into M-cells and increased transcytosis efficiency. This idea is supported by the following observations. Intranasal administration of 10-HDAA increased the number of M-cells in the epithelium overlying nasopharynx-associated lymphoid tissue (NALT) in macaques. Oral administration of 10-HDAA increased the number of M-cells in the follicle-associated epithelium (FAE) covering Peyer's patches (PPs) and significantly increased the antigen-specific immunoglobulin A (IgA) level in macaques. These findings suggest that the exogenous honeybee-derived medium-chain fatty acid 10-HDAA may effectively enhance antigen-specific immune responses.

Simultaneous choice bioassays accompanied by physiological changes identify civetone and decanoic acid as pheromone candidates for giant pandas.

Chemicals present in urine are thought to play an important role in mate identification in the solitary giant panda (Ailuropoda melanoleuca). During the breeding season, females will deposit chemical signals to advertise sexual receptivity to potential mates. The goal of this study was to determine if specific volatile compounds found in female urine could be considered as pheromones that elicit behavioral and physiological responses in males. Experimental simultaneous choice trials were conducted with captive male giant pandas (n = 3) housed at Memphis Zoo, San Diego Zoo, and Zoo Atlanta. Octanoic acid, 1H-pyrrole-2-carboxaldehyde, decanoic acid, and civetone were selected as stimuli because previous studies reported their elevation in urine during the breeding season. Male interest was determined by a behavioral preference toward these volatile compounds diluted in synthetic urine compared with nontreated synthetic urine. Male urine samples were collected 1 week prior, during, and 1 week after the experimental period to assess changes in urinary semiochemical composition and urinary androgen concentrations. No significant differences in investigation response (p = .395) or flehmen response (p = .600) were found when stimuli were compared; however, decanoic acid and civetone elicited a behavioral preference over the control (response ratio > 0.5). The relative abundance of 16 compounds identified in male urine was significantly elevated (p < .05) above baseline values after the males were exposed to the stimuli. Androgen levels were significantly elevated (p < .05) in one male after exposure to 1H-pyrrole-2-carboxaldehyde, decanoic acid, and civetone. These data suggested that civetone and decanoic acid in female urine may motivate sexual responses in males.

XRCC4, which is inhibited by PFDA, regulates DNA damage repair and cell chemosensitivity.

The mechanism of environmental pollution promoting gastric cancer incidence and difficulty of treatment is not fully understood. In the present article, perfluorodecanoic acid (PFDA), a common persistent environmental pollutant, was used to treat the gastric cell lines and mice to test its genotoxicity. The γ-H2AX immunoblot and plasmid fragment PCR results showed that PFDA had a promotion effect on the DNA double-strand breaks (DSBs) in human and mouse cells. Subsequent results showed that PFDA significantly altered the sensitivity of cells to chemotherapy. Microarray data showed that the expressions of some important DNA repair genes were changed. Further investigation discovered that PFDA inhibition of DNA repair was mediated by X-ray repair cross complementing 4 (XRCC4). The cells deficient in XRCC4 generally exhibited reduced proliferation and premature aging in culture; however, our results indicated that PFDA induced p53 inhibition rescued cells from the apoptosis that was triggered by nonhomologous end-joining (NHEJ) inactivation, and overexpression of p53 expression in PFDA-treated cells enhanced their apoptosis. Finally, T-cell specific factor 4 was suggested by the results as an upstream regulator of XRCC4. This article revealed for the first time that perfluorinated chemicals affect chemotherapeutic sensitivity and the NHEJ pathway, and p53 reduction rescues cells from death.

Disparate Candida albicans Biofilm Formation in Clinical Lipid Emulsions Due to Capric Acid-Mediated Inhibition.

Receipt of parenteral nutrition (PN) remains an independent risk factor for developing catheter-related bloodstream infections (CR-BSI) caused by fungi, including by the polymorphic fungus Candida albicans, which is notoriously adept at forming drug-resistant biofilm structures. Among a variety of macronutrients, PN solutions contain lipid emulsions to supply daily essential fats and are often delivered via central venous catheters (CVCs). Therefore, using an in vitro biofilm model system, we sought to determine whether various clinical lipid emulsions differentially impacted biofilm growth in C. albicans We observed that the lipid emulsions Intralipid and Omegaven both stimulated C. albicans biofilm formation during growth in minimal medium or a macronutrient PN solution. Conversely, Smoflipid inhibited C. albicans biofilm formation by approximately 50%. Follow-up studies revealed that while Smoflipid did not impair C. albicans growth, it did significantly inhibit hypha formation and hyphal elongation. Moreover, growth inhibition could be recapitulated in Intralipid when supplemented with capric acid-a fatty acid present in Smoflipid but absent in Intralipid. Capric acid was also found to dose dependently inhibit C. albicans biofilm formation in PN solutions. This is the first study to directly compare different clinical lipid emulsions for their capacity to affect C. albicans biofilm growth. Results derived from this study necessitate further research regarding different lipid emulsions and rates of fungus-associated CR-BSIs.

New Hydroxydecanoic Acid Derivatives Produced by an Dndophytic Yeast Aureobasidium pullulans AJF1 from Flowers of Aconitum carmichaeli.

Endophytes have been recognized as a source for structurally novel and biologically active secondary metabolites. Among the host plants for endophytes, some medicinal plants that produce pharmaceuticals have been reported to carry endophytes, which could also produce bioactive secondary metabolites. In this study, the medicinal plant Aconitum carmichaeli was selected as a potential source for endophytes. An endophytic microorganism, Aureobasidium pullulans AJF1, harbored in the flower of Aconitum carmichaeli, was cultured on a large scale and extracted with an organic solvent. Extensive chemical investigation of the extracts resulted in isolation of three lipid type compounds (1-3), which were identified to be (3R,5R)-3,5-dihydroxydecanoic acid (1), (3R,5R)-3-(((3R,5R)-3,5-dihydroxydecanoyl)oxy)-5-hydroxydecanoic acid (2), and (3R,5R)-3-(((3R,5R)-5-(((3R,5R)-3,5-dihydroxydecanoyl)oxy)-3-hydroxydecanoyl)oxy)-5-hydroxydecanoic acid (3) by chemical methods in combination with spectral analysis. Compounds 2 and 3 had new structures. Absolute configurations of the isolated compounds (1-3) were established using modified Mosher's method together with analysis of NMR data for their acetonide derivatives. All the isolates (1-3) were evaluated for antibiotic activities against Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and their cytotoxicities against MCF-7 cancer cells. Unfortunately, they showed low antibiotic activities and cytotoxic activities.

Dynamic Restructuring of the Myocardial Mitochondria in Response to Uridine Modulation of the Activity of Mitochondrial ATP-Dependent Potassium Channel under Conditions of Acute Hypoxic Hypoxia.

We studied the effects of in vivo modulation of activity of mitochondrial ATP-dependent potassium channel (mitoKATP) by uridine on the morphofunctional state of mitochondria in rat cardiomyocytes under conditions of acute hypoxia. Preinjection of uridine to animals reduced the number of structurally modified mitochondria, but had practically no effect on their morphogenesis after hypoxia. Uridine in vivo stimulated the formation of micromitochondria and their release into the cytoplasm. The number of "maternal" mitochondria containing three and more new micromitochondria, increased as well. The use of mitoKATP blocker 5-hydroxydecanoate in parallel with uridine abolished its protective effect, as it significantly inhibited the formation of micromitochondria in rat cardiomyocytes after acute hypoxic exposure.

PI3K-AKT Pathway Protects Cardiomyocytes Against Hypoxia-Induced Apoptosis by MitoKATP-Mediated Mitochondrial Translocation of pAKT.

BACKGROUND/AIMS: The phosphatidylinositol-3-kinase -AKT (PI3K-AKT) is an important intracellular signal pathway in regulating cell proliferation, differentiation and apoptosis. In previous studies, we've demonstrated that PI3K-AKT pathway protects cardiomyocytes from ischemic and hypoxic apoptosis through mitochondrial function. However, the molecular mechanisms underlying hypoxia-induced cardiomyocyte apoptosis via PI3K-AKT pathway remain ill-defined. Here, we addressed this question. METHODS: Cardiomyocytes were exposed to hypoxia, with/without different inhibitors and then protein levels were assessed by Western blotting. RESULTS: We found that the PI3K-AKT pathway was activated in cardiomyocytes that were exposed to hypoxia. Moreover, the phospho-AKT (pAKT) translocated from cytosol to mitochondria via mitochondrial adenosine triphosphate-dependent potassium (mitoKATP), leading to an increase in cytochrome c oxidase (CcO) activity to suppress apoptosis. On the other hand, the mitoKATP specific blocker, 5-hydroxydecanote (5-HD), or suppression of CcO using siRNA, inhibited the pAKT mitochondrial translocation to maintain the CcO activity, resulting in mitochondrial dysfunction and cellular apoptosis induced by hypoxia. CONCLUSION: These findings suggest that the anti-apoptotic effect of the PI3K-AKT pathway through pAKT translocation to mitochondrial via mitoKATP may be conducted through modification of CcO activity.

Perampanel and decanoic acid show synergistic action against AMPA receptors and seizures.

Perampanel is an adjunctive treatment for epilepsy that works through the direct inhibition of AMPA receptors. The same molecular mechanism has recently been shown for a fatty acid, decanoic acid, prescribed in the medium chain triglyceride ketogenic diet for the treatment of patients with drug-resistant epilepsy. Because each compound has been proposed to act through a distinct AMPA receptor binding site, we predicted that perampanel and decanoic acid would act synergistically against AMPA receptors and, consequently, seizures. Here, we show a synergistic interaction between perampanel and decanoic acid in direct AMPA receptor inhibition, in an ex vivo model of seizure activity, and against seizure-induced activity in human brain slices. These data support a potential role for combination treatment using perampanel and dietary decanoic acid to provide enhanced seizure control.