ABSTRACT
AIMS: Type 2 diabetes mellitus (T2DM) can lead to brain dysfunction and a series of neurological complications. Previous research demonstrated that a novel palmitic acid (5-PAHSA) exerts effect on glucose tolerance and chronic inflammation. Autophagy was important in diabetic-related neurodegeneration. The aim of the present study was to investigate whether 5-PAHSA has specific therapeutic effects on neurological dysfunction in diabetics, particularly with regard to autophagy. METHODS: 5-PAHSA was successfully synthesized according to a previously described protocol. We then carried out a series of in vitro and in vivo experiments using PC12 cells under diabetic conditions, and DB/DB mice, respectively. PC12 cells were treated with 5-PAHSA for 24 h, while mice were administered with 5-PAHSA for 30 days. At the end of each experiment, we analyzed glucolipid metabolism, autophagy, apoptosis, oxidative stress, cognition, and a range of inflammatory factors. RESULTS: Although there was no significant improvement in glucose metabolism in mice administered with 5-PAHSA, ox-LDL decreased significantly following the administration of 5-PAHSA in serum of DB/DB mice (p < 0.0001). We also found that the phosphorylation of m-TOR and ULK-1 was suppressed in both PC12 cells and DB/DB mice following the administration of 5-PAHSA (p < 0.05 and p < 0.01), although increased levels of autophagy were only observed in vitro (p < 0.05). Following the administration of 5-PAHSA, the concentration of ROS decreased in PC12 cells and the levels of CRP increased in high-dose group of 5-PAHSA (p < 0.01). There were no significant changes in terms of apoptosis, other inflammatory factors, or cognition in DB/DB mice following the administration of 5-PAHSA. CONCLUSION: We found that 5-PAHSA can enhance autophagy in PC12 cells under diabetic conditions. Our data demonstrated that 5-PAHSA inhibits phosphorylation of the m-TOR-ULK1 pathway and suppressed oxidative stress in PC12 cells, and exerted influence on lipid metabolism in DB/DB mice.
Subject(s)
Autophagy-Related Protein-1 Homolog/antagonists & inhibitors , Autophagy/drug effects , Neuroprotective Agents/pharmacology , Palmitic Acid/pharmacology , Stearic Acids/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Animals , Autophagy/physiology , Autophagy-Related Protein-1 Homolog/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Male , Mice , Mice, Inbred C57BL , Neuroprotective Agents/therapeutic use , PC12 Cells , Palmitic Acid/therapeutic use , Phosphorylation/drug effects , Phosphorylation/physiology , Rats , Signal Transduction/drug effects , Signal Transduction/physiology , Stearic Acids/therapeutic use , TOR Serine-Threonine Kinases/metabolismABSTRACT
BACKGROUND: MEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors. PATIENTS AND METHODS: Eligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005-0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response. RESULTS: From November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks. CONCLUSION: IT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations. TRIAL REGISTRATION NUMBER: NCT02556463.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Neoplasms/drug therapy , Neoplasms/radiotherapy , Stearic Acids/therapeutic use , Animals , Antibodies, Monoclonal/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Female , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Male , Mice , Palliative Care , Stearic Acids/pharmacologyABSTRACT
Diabetes mellitus (DM) is currently a major global health problem, which is associated with the development of cognitive dysfunction. However, although numerous clinical drugs for hyperglycemia have been used at present, safer and more effective therapeutic intervention strategies for diabetic cognitive impairments are still a huge challenge. Recently, several studies have indicated that a novel class of branched palmitic acid esters of hydroxyl stearic acids (PAHSAs) may have anti-diabetes and anti-inflammatory effects in insulin-resistant mice. Herein, whether the 9-PAHSA that one of the PAHSAs can attenuates DM-associated cognitive impairment in a mouse model of type 2 diabetes has been investigated. Our results showed that 9-PAHSA mildly prevented deficits of spatial working memory in Y-maze test while reversed the preference bias toward novel mice in Social choice test. Furthermore, the effect of REST on cognitive impairment of diabetes was explored for the first time. It was found that the expression of REST in diabetic mice increased, and the expression of target protein BDNF (Brain-derived neurotrophic factor) was decreased. After administration of 9-PAHSA, the situation was reversed. In summary, we conclude that exogenous supplement of 9-PAHSA can improve DM-related cognitive impairment to some extent, and the protective effect may be associated with decreased REST/NRSF (repressor element-1 silencing transcription factor/neuron-restrictive silence factor) and upregulated BDNF expression in frontal cortex.
Subject(s)
Cognitive Dysfunction/drug therapy , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/physiopathology , Palmitic Acid/therapeutic use , Stearic Acids/therapeutic use , Aging/blood , Aging/pathology , Animals , Behavior, Animal , Blood Glucose/metabolism , Body Weight , Brain/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Cognitive Dysfunction/blood , Diabetes Mellitus, Experimental/blood , Exploratory Behavior , Male , Memory Disorders/blood , Memory Disorders/complications , Memory Disorders/physiopathology , Mice , Repressor Proteins/metabolism , Social Behavior , Spatial MemoryABSTRACT
Optimizing dietary macronutrients benefits the prevention and management of many human diseases but there is conflicting dietary advice for Parkinson's disease (PD), and no single strategy is universally recommended. Recently, it was shown that dietary stearic acid (C18:0) improves survival and mitochondrial functions in the parkin null Drosophila model of PD. Here, we incorporate stearic acid into high protein and high carbohydrate diets and study survival, climbing ability, mitochondrial membrane potential, respiration, basal reactive oxygen species, and conduct lipidomics assays. We observed that parkin null flies showed improvement in all assays tested when stearic acid was added to the high protein diet but not to the high carbohydrate diet. When lipid proportion was examined, we observed higher levels in flies fed the high protein diet with stearic acid diet and the high carbohydrate diet. Unexpectedly, free levels of fatty acids exhibited opposite trend. Combined, these data suggest that dietary Protein: Carbohydrate ratio and stearic acid influences levels of bound fatty acids. The mechanisms that influence free and bound fatty-acid levels remain to be explored, but one possible explanation is that breakdown products can bind to membranes and improve the mitochondrial functions of parkin null flies.
Subject(s)
Diet , Dietary Supplements , Mitochondria/physiology , Motor Activity/physiology , Parkinson Disease/therapy , Stearic Acids/therapeutic use , Animals , Dietary Carbohydrates , Dietary Proteins , Disease Models, Animal , Drosophila melanogaster , Parkinson Disease/physiopathology , Ubiquitin-Protein LigasesABSTRACT
Skin surface is constantly exposed to environmental and secreted stressors such as UV, air pollution and peroxidized sebum. The current study aims to use reconstructed human skin equivalents to demonstrate topical stressor-induced hyperpigmentation and evaluate bioactives' potential protective effect. Given that polycyclic aromatic hydrocarbons are representative airborne particle-bound organic compounds with known relevance to pigmentation pathways, benzo(a)pyrene was selected as surrogate environmental toxin. On the other hand, squalene monohydroperoxides are well-characterized sebum peroxidation product under UV and pollutant exposure, thus are used as another representative skin stressor. With 3-day continuous exposure, 30 pmol/cm2 of benzo(a)pyrene and 3.4 nmol/cm2 of squalene monohydroperoxides induced significant viability loss, inflammatory response, and approximately 10 shades of pigmentation increase in pigmented living skin equivalents. At the same time, pretreatment and co-treatment with 12-hydroxystearic acid (12-HSA, 20 µmol/L) or niacinamide (5 mmol/L) ameliorated such stressor-induced consequences. Niacinamide was particularly effective against benzo(a)pyrene damage, probably as a substrate for important NAD+ dependent detoxification pathways, while 12-HSA was potent against squalene monohydroperoxides through barrier enhancing, anti-inflammatory, and anti-oxidative mechanisms. In summary, topical stressor-induced hyperpigmentation was achieved in vitro, with known bioactives showing protective benefits.
Subject(s)
Hyperpigmentation/prevention & control , Niacinamide/therapeutic use , Stearic Acids/therapeutic use , Vitamin B Complex/therapeutic use , Benzo(a)pyrene , Biological Assay , Humans , Hyperpigmentation/chemically induced , Melanins/metabolism , Monophenol Monooxygenase/metabolism , Squalene/analogs & derivativesABSTRACT
Nanoemulsions are feasible delivery systems of lipophilic compounds, showing potential as edible coatings with enhanced functional properties. The aim of this work was to study the effect of emulsifier type (stearic acid (SA), Tween 80 (T80) or Tween 80/Span 60 (T80/S60)) and emulsification process (homogenization, ultrasound or microfluidization) on nanoemulsion formation based on oxidized corn starch, beeswax (BW) and natural antimicrobials (lauric arginate and natamycin). The response variables were physicochemical properties, rheological behavior, wettability and antimicrobial activity of BW-starch nanoemulsions (BW-SN). The BW-SN emulsified using T80 and microfluidized showed the lowest droplet size (77.6 ± 6.2 nm), a polydispersion index of 0.4 ± 0.0 and whiteness index (WI) of 31.8 ± 0.8. This BW-SN exhibited a more negative ζ-potential: -36 ± 4 mV, and Newtonian flow behavior, indicating great stability. BW-SN antimicrobial activity was not affected by microfluidization nor the presence of T80, showing inhibition of the deteriorative fungi R. stolonifer, C. gloeosporioides and B. cinerea, and the pathogenic bacterium S. Saintpaul. In addition, regardless of emulsifier type and emulsification process, BW-SN applied on the tomato surface exhibited low contact angles (38.5° to 48.6°), resulting in efficient wettability (-7.0 mN/m to -8.9 mN/m). These nanoemulsions may be useful to produce edible coatings to preserve fresh-produce quality and safety.
Subject(s)
Anti-Infective Agents/therapeutic use , Drug Delivery Systems , Nanocomposites/chemistry , Waxes/chemistry , Anti-Infective Agents/chemistry , Emulsions/chemistry , Emulsions/therapeutic use , Hexoses/chemistry , Hexoses/therapeutic use , Humans , Nanocomposites/therapeutic use , Polysorbates/chemistry , Polysorbates/therapeutic use , Starch/chemistry , Starch/therapeutic use , Stearic Acids/chemistry , Stearic Acids/therapeutic useABSTRACT
Neuroinflammation is an important risk factor for neurodegenerative disorders like Alzheimer's disease. Nicotinic acetylcholine receptors of α7 subtype (α7 nAChRs) regulate inflammatory processes in various tissues, including the brain. N-stearoylethanolamine (NSE) is a biologically active cell membrane component with anti-inflammatory and membrane-protective properties. Previously we found that mice injected with bacterial lipopolysaccharide (LPS) or immunized with recombinant extracellular domain (1-208) of α7 nAChR subunit possessed decreased α7 nAChR levels, accumulated pathogenic amyloid-beta peptide Aß(1-42) in the brain and demonstrated impaired episodic memory compared to non-treated mice. Here we studied the effect of NSE on behavior and brain components of LPS- treated or α7(1-208)-immunized mice. NSE, given per os, non-significantly decreased LPS-stimulated interleukin-6 elevation in the brain, slowed down the α7(1-208)-specific IgG antibody production and prevented the antibody penetration into the brain of mice. NSE prevented the loss of α7 nAChRs and accumulation of α7-bound Aß(1-42) in the brain and brain mitochondria of LPS-treated or α7(1-208)-immunized mice and supported mitochondria resistance to apoptosis by attenuating Ca2+-stimulated cytochrome c release. Finally, NSE significantly improved episodic memory of mice impaired by either LPS treatment or immunization with α7(1-208). The results of our study demonstrate a therapeutic potential of NSE for prevention of cognitive disfunction caused by neuroinflammation or autoimmune reaction that allows suggesting this drug as a candidate for the treatment or prophylaxis of Alzheimer's pathology.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Anti-Inflammatory Agents/therapeutic use , Brain/metabolism , Ethanolamines/therapeutic use , Mitochondria/metabolism , Neurogenic Inflammation/drug therapy , Peptide Fragments/metabolism , Stearic Acids/therapeutic use , Animals , Apoptosis/drug effects , Brain/pathology , Cytochromes c/metabolism , Female , Humans , Immunization , Lipopolysaccharides/immunology , Memory , Mice , Mice, Inbred C57BL , Neuroprotection , Protein Domains/immunology , alpha7 Nicotinic Acetylcholine Receptor/immunology , alpha7 Nicotinic Acetylcholine Receptor/metabolismABSTRACT
BACKGROUND: Pressure ulcers, also known as bed sores, pressure sores or decubitus ulcers develop as a result of a localised injury to the skin or underlying tissue, or both. The ulcers usually arise over a bony prominence, and are recognised as a common medical problem affecting people confined to a bed or wheelchair for long periods of time. Anabolic steroids are used as off-label drugs (drugs which are used without regulatory approval) and have been used as adjuvants to usual treatment with dressings, debridement, nutritional supplements, systemic antibiotics and antiseptics, which are considered to be supportive in healing of pressure ulcers. Anabolic steroids are considered because of their ability to stimulate protein synthesis and build muscle mass. Comprehensive evidence is required to facilitate decision making, regarding the benefits and harms of using anabolic steroids. OBJECTIVES: To assess the effects of anabolic steroids for treating pressure ulcers. SEARCH METHODS: In March 2017 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) comparing the effects of anabolic steroids with alternative treatments or different types of anabolic steroids in the treatment of pressure ulcers. DATA COLLECTION AND ANALYSIS: Two review authors independently carried out study selection, data extraction and risk of bias assessment. MAIN RESULTS: The review contains only one trial with a total of 212 participants, all with spinal cord injury and open pressure ulcers classed as stage III and IV. The participants were mainly male (98.2%, 106/108) with a mean age of 58.4 (standard deviation 10.4) years in the oxandrolone group and were all male (100%, 104/104) with a mean age of 57.3 (standard deviation 11.6) years in the placebo group. This trial compared oxandrolone (20 mg/day, administered orally) with a dose of placebo (an inactive substance consisting of 98% starch and 2% magnesium stearate) and reported data on complete healing of ulcers and adverse events. There was very low-certainty evidence on the relative effect of oxandrolone on complete ulcer healing at the end of a 24-week treatment period (risk ratio RR) 0.81, 95% confidence interval (CI) 0.52 to 1.26) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, we are uncertain whether oxandrolone improves or reduces the complete healing of pressure ulcers, as we assessed the certainty of the evidence as very low.There was low-certainty evidence on the risk of non-serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 3.85, 95% CI 1.12 to 13.26) (downgraded once for imprecision and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, the treatment with oxandrolone may increase the risk of non-serious adverse events reported in participants.There was very low-certainty evidence on the risk of serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 0.54, 95% CI 0.25 to 1.17) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Of the five serious adverse events reported in the oxandrolone-treated group, none were classed by the trial teams as being related to treatment. We are uncertain whether oxandrolone increases or decreases the risk of serious adverse events as we assessed the certainty of the evidence as very low.Secondary outcomes such as pain, length of hospital stay, change in wound size or wound surface area, incidence of different type of infection, cost of treatment and quality of life were not reported in the included trial.Overall the evidence in this study was of very low quality (downgraded for imprecision and indirectness). This trial stopped early when the futility analysis (interim analysis) in the opinion of the study authors showed that oxandrolone had no benefit over placebo for improving ulcer healing. AUTHORS' CONCLUSIONS: There is no high quality evidence to support the use of anabolic steroids in treating pressure ulcers.Further well-designed, multicenter trials, at low risk of bias, are necessary to assess the effect of anabolic steroids on treating pressure ulcers, but careful consideration of the current trial and its early termination are required when planning future research.
Subject(s)
Oxandrolone/therapeutic use , Pressure Ulcer/drug therapy , Testosterone Congeners/therapeutic use , Female , Humans , Male , Middle Aged , Off-Label Use , Oxandrolone/adverse effects , Starch/therapeutic use , Stearic Acids/therapeutic use , Testosterone Congeners/adverse effects , Wound HealingABSTRACT
Toll-like receptor (TLR) agonists TLR 7/8, MEDI9197, is a imidazoquinoline analogue that can be used for cancer immunotherapy based on its efficacy toward a variety of tumors. Systemic administration of TLR agonists results in stimulation of the immune system throughout the entire body causing undesirable side effects. To minimize these adverse events, local administration of TLR agonists including intratumoral (IT) delivery has been introduced. Here, a poloxamer 407 thermogel formulation for IT delivery of a TLR 7/8 dual agonist, MEDI9197, is described in which the combination of the aqueous thermogel and the ethanolic TLR 7/8 dual agonist, MEDI9197, solution leads to precipitated drug particles within the gel. The in vitro release profile showed an initial burst followed by sustained release. A B16-OVA mouse tumor model was used to assess the in vivo pharmacokinetics, efficacy, and systemic cytokine and chemokine (cytokine) production of the poloxamer 407-based thermogel formulation. The pharmacokinetic evaluation showed that the agonist level within the tumor was reduced by â¼70% over 14 days while serum agonist levels indicated an initial burst at the 6-h time point followed by a drop in serum drug levels over the 14 days of the experiment. The tumor growth inhibition, survival, and serum cytokines for post-IT injection of the poloxamer 407 formulation showed that it slowly released TLR 7/8 agonist, MEDI9197, resulting in more efficacious tumor growth inhibition compared with control groups. In addition, the cytokine levels in circulation indicated that a dose increase led to a decrease in the serum inflammatory and interferon-inducible cytokines levels. This observation could be due to a reduction of drug diffusion and escape from the tumor site due to the precipitation of the drug inside the tumor leading to sustained release. IT delivery of TLR 7/8 dual agonist, MEDI9197, via a thermosensitive gel-based formulation was efficacious and could offer an alternate method of local drug delivery.
Subject(s)
Antineoplastic Agents/administration & dosage , Delayed-Action Preparations/chemistry , Heterocyclic Compounds, 3-Ring/administration & dosage , Melanoma, Experimental/drug therapy , Poloxamer/chemistry , Stearic Acids/administration & dosage , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cytokines/blood , Cytokines/immunology , Drug Delivery Systems , Female , Gels/chemistry , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/therapeutic use , Melanoma, Experimental/blood , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Stearic Acids/pharmacokinetics , Stearic Acids/therapeutic use , Temperature , Toll-Like Receptor 7/immunology , Toll-Like Receptor 8/immunologyABSTRACT
The position of the fatty acids (sn-1, sn-2 and sn-3) (stereospecific numbering (sn)) in triacylglycerol (TAG) molecules produces a characteristic stereospecificity that defines the physical properties of the fats and influences their absorption, metabolism and uptake into tissues. Fat interesterification is a process that implies a positional distribution of fatty acids (FAs) within the TAG molecules, generating new TAG species, without affecting the FA cis-trans natural balance. The interesterified (IE) fats, frequently used in the food industry comprise fats that are rich in long-chain saturated FAs, such as palmitic acid (16:0) and stearic acid (18:0). Within the interesterified fats, a critical role is played by FA occupying the sn-2 position; in fact, the presence of an unsaturated FA in this specific position influences early metabolic processing and postprandial clearance that in turn could induce atherogenesis and thrombogenesis events. Here, we provide an overview on the role of TAG structures and interesterified palmitic and stearic acid-rich fats on fasting and postprandial lipemia, focusing our attention on their physical properties and their effects on human health.
Subject(s)
Dietary Fats/therapeutic use , Fatty Acids/chemistry , Hyperlipidemias/diet therapy , Plant Oils/chemistry , Fatty Acids/therapeutic use , Humans , Hyperlipidemias/metabolism , Palmitic Acid/chemistry , Palmitic Acid/therapeutic use , Plant Oils/therapeutic use , Stearic Acids/chemistry , Stearic Acids/therapeutic use , Stereoisomerism , Triglycerides/chemistry , Triglycerides/therapeutic useABSTRACT
Dietary fiber has been reported to prevent preneoplastic colon lesions. The aim of this study was to determine the effect of resistant starches, novel dietary fibers, on the development of colonic preneoplasia and Wnt signaling in azoxymethane (AOM)-treated rats and mice fed resistant starches at 55% of the diet after AOM treatment. Another objective was to determine the effect of resistant starches on the development of preneoplasia in rats treated with antibiotics (Ab), administered between AOM treatment and resistant starch feeding. Diets containing resistant starches, high-amylose (HA7), high-amylose-octenyl succinic anhydride (OS-HA7), or high-amylose-stearic acid (SA-HA7) were compared with control cornstarch (CS). The resistant starch content of the diets did not alter the yield of colonic lesions but animals treated with AOM and fed the diet with the highest resistant starch content, SA-HA7 developed the highest average aberrant crypt foci (ACF) per animal. Mice fed the OS-HA7 diet had decreased expression of some upstream Wnt genes in the colonic crypts. This study suggests that further research is needed to determine if resistant starch impacts colon carcinogenesis in rodents.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Colonic Neoplasms/prevention & control , Prebiotics , Precancerous Conditions/prevention & control , Starch/therapeutic use , Wnt Signaling Pathway , Aberrant Crypt Foci/metabolism , Aberrant Crypt Foci/microbiology , Aberrant Crypt Foci/pathology , Aberrant Crypt Foci/prevention & control , Animals , Anti-Bacterial Agents/adverse effects , Anticarcinogenic Agents/metabolism , Azoxymethane/toxicity , Carcinogens/toxicity , Colon/drug effects , Colon/metabolism , Colon/microbiology , Colonic Neoplasms/metabolism , Colonic Neoplasms/microbiology , Colonic Neoplasms/pathology , Gastrointestinal Microbiome/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Mice, Inbred A , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Precancerous Conditions/metabolism , Precancerous Conditions/microbiology , Precancerous Conditions/pathology , Rats, Inbred F344 , Resistant Starch , Starch/analogs & derivatives , Starch/metabolism , Stearic Acids/metabolism , Stearic Acids/therapeutic use , Succinic Anhydrides/metabolism , Succinic Anhydrides/therapeutic use , Tumor Burden/drug effects , Wnt Signaling Pathway/drug effectsABSTRACT
BACKGROUND: Stearic acid is known as a potent anti-inflammatory lipid. This fatty acid has profound and diverse effects on liver metabolism. The aim of this study was to investigate the effect of stearic acid on markers of hepatocyte transplantation in rats with acetaminophen (APAP)-induced liver damage. METHODS: Wistar rats were randomly assigned to 10-day treatment. Stearic acid was administered to the rats with APAP-induced liver damage. The isolated liver cells were infused intraperitoneally into rats. Blood samples were obtained to evaluate the changes in the serum liver enzymes, including activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) and the level of serum albumin. To assess the engraftment of infused hepatocytes, rats were euthanized, and the liver DNA was used for PCR using sex-determining region Y (SRY) primers. RESULTS: The levels of AST, ALT and ALP in the serum of rats with APAP-induced liver injury were significantly increased and returned to the levels in control group by day six. The APAP-induced decrease in albumin was significantly improved in rats through cell therapy, when compared with that in the APAP-alone treated rats. SRY PCR analysis showed the presence of the transplanted cells in the liver of transplanted rats. CONCLUSION: Stearic acid-rich diet in combination with cell therapy accelerates the recovering of hepatic dysfunction in a rat model of liver injury.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Cell- and Tissue-Based Therapy/methods , Graft Enhancement, Immunologic/methods , Graft Survival/drug effects , Liver/injuries , Stearic Acids/therapeutic use , Acetaminophen/toxicity , Alanine Transaminase/blood , Alanine Transaminase/metabolism , Alkaline Phosphatase/blood , Alkaline Phosphatase/metabolism , Animals , Aspartate Aminotransferases/blood , Aspartate Aminotransferases/metabolism , Female , Hepatocytes/drug effects , Hepatocytes/transplantation , Liver/drug effects , Liver/pathology , Male , Oxidative Stress/drug effects , Rats , Rats, Wistar , Serum Albumin/analysisABSTRACT
Topical pseudoceramides are successfully used in skin barrier repair therapy for atopic dermatitis (AD) and demonstrated to reduce the adverse effects of topical glucocorticoids (GC). However, the molecular mechanisms involved are not fully understood. We investigated whether PC-9S (myristoyl/palmitoyloxostearamide/arachamide MEA, Neopharm, Daejeon, Korea), one of the synthetic pseudoceramides, could stimulate peroxisome proliferator-activated receptor (PPAR)α expression in a hapten [oxazolone (oxa)]-induced AD murine model (oxa-AD mice) and subsequently improved permeability barrier, reduced inflammation, and increased antimicrobial peptides (AMPs) expression. Normal hairless mice and oxa-AD mice were topically treated twice daily with either PC-9S-containing physiologic lipid mixture (PLM), vehicle (PLM), or PPARα agonist for 4 days. Topical PC-9S significantly increased PPARα expression in mouse epidermis in vivo and in oxa-AD mice skin comparable with PPARα agonist. Topical PC-9S-containing PLM significantly reduced basal trans-epidermal water loss (TEWL), surface pH, and mast cell infiltrates and prevented the decline of AMPs expression in oxa-AD mice, which were abrogated by PPARα antagonist. Then, oxa-AD mice were treated with super-potent topical GC twice daily for 4 days with or without PC-9S co-applications. Co-treatment with PC-9S-containing PLM suppressed GC-induced increase in basal TEWL, epidermal thinning, reduced loricrin expression, and impaired barrier recovery and these effects were attenuated by PPARα antagonist. Collectively, our findings suggest that pseudoceramide PC-9S-induced stimulation of PPARα expression provides a new mechanism by which pseudoceramides show anti-inflammatory property, improve the permeability and antimicrobial barrier function, and prevent the negative effects of topical GC.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arachidonic Acids/therapeutic use , Ceramides/therapeutic use , Dermatitis, Atopic/drug therapy , PPAR alpha/biosynthesis , Stearic Acids/therapeutic use , Tight Junctions/drug effects , Administration, Topical , Animals , Dermatitis, Atopic/pathology , Female , Glucocorticoids/adverse effects , Inflammation , Membrane Proteins/biosynthesis , Mice , Mice, Hairless , Oxazolone/pharmacology , PPAR alpha/antagonists & inhibitors , Skin/metabolism , Skin/pathologyABSTRACT
BACKGROUND: The Jatropha curcas plant or locally known as "Pokok Jarak" has been widely used in traditional medical applications. This plant is used to treat various conditions such as arthritis, gout, jaundice, wound and inflammation. However, the nature of compounds involved has not been well documented. Hence, this study was conducted to investigate the anti-inflammatory activity of different parts of J. curcas plant and to identify the active compounds involved. METHODS: In this study, methanol (80%) extraction of four different parts (leaves, fruits, stem and root) of J. curcas plant was carried out. Phenolic content of each part was determined by using Folin-Ciocalteau reagent. Gallic acid was used as the phenol standard. Each plant part was screened for anti-inflammatory activity using cultured macrophage RAW 264.7 cells. The active plant part was then partitioned with hexane, chloroform, ethyl acetate and water. Each partition was again screened for anti-inflammatory activity. The active partition was then fractionated using an open column chromatography system. Single spots isolated from column chromatography were assayed for anti-inflammatory and cytotoxicity activities. Spots that showed activity were subjected to gas chromatography mass spectrophotometry (GC-MS) analysis for identification of active metabolites. RESULTS: The hexane partition from root extract showed the highest anti-inflammatory activity. However, it also showed high cytotoxicity towards RAW 264.7 cells at 1 mg/mL. Fractionation process using column chromatography showed five spots. Two spots labeled as H-4 and H-5 possessed anti-inflammatory activity, without cytotoxicity activity. Analysis of both spots by GC-MS showed the presence of hexadecanoic acid methyl ester, octadecanoic acid methyl ester and octadecanoic acid. CONCLUSION: This finding suggests that hexadecanoic acid methyl ester, octadecanoic acid methyl ester and octadecanoic acid could be responsible for the anti-inflammatory activity of the J. curcas root extract.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Inflammation/drug therapy , Jatropha/chemistry , Macrophages/drug effects , Palmitic Acid/pharmacology , Plant Extracts/pharmacology , Stearic Acids/pharmacology , Animals , Anti-Inflammatory Agents/analysis , Anti-Inflammatory Agents/therapeutic use , Mice , Molybdenum , Palmitic Acid/analysis , Palmitic Acid/therapeutic use , Phenols/analysis , Phenols/pharmacology , Phytotherapy , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Plant Roots/chemistry , Stearic Acids/analysis , Stearic Acids/therapeutic use , Tungsten CompoundsABSTRACT
This study investigates the protective effect of N-stearoylethanolamine (NSE), a bioactive N-acylethanolamine , on the lipid profile distribution in the pancreas of obesity-induced insulin resistant (IR) rats fed with prolonged high fat diet (58% of fat for 6 months). The phospholipid composition was determined using 2D thin-layer chromatography. The level of individual phospholipids was estimated by measuring inorganic phosphorus content. The fatty acid (FA) composition and cholesterol level were investigated by gas-liquid chromatography. Compared to controls, plasma levels of triglycerides and insulin were significantly increased in IR rats. The pancreas lipid composition indicated a significant reduction of the free cholesterol level and some phospholipids such as phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer) compared to controls. Moreover, the FA composition of pancreas showed a significant redistribution of the main FA (18:1n-9, 18:2n-6, 18:3n-6 and 20:4n-6) levels between phospholipid, free FA, triglyceride fractions under IR conditions that was accompanied by a change in the estimated activities of Δ9-, Δ6-, Δ5-desaturase. Administration of N-stearoylethanolamine (NSE, 50 mg/kg daily per os for 2 weeks) IR rats triggered an increase in the content of free cholesterol, PtdCho and normalization of PtdEtn, PtdSer level. Furthermore, the NSE modulated the activity of desaturases, thus influenced FA composition and restored the FA ratios in the lipid fractions. These NSE-induced changes were associated with a normalization of plasma triglyceride content, considerable decrease of insulin and index HOMA-IR level in rats under IR conditions.
Subject(s)
Ethanolamines/therapeutic use , Insulin Resistance , Lipid Metabolism/drug effects , Lipids/analysis , Obesity/drug therapy , Pancreas/drug effects , Stearic Acids/therapeutic use , Animals , Diet, High-Fat/adverse effects , Insulin/blood , Insulin/metabolism , Lipids/blood , Male , Obesity/blood , Obesity/complications , Obesity/metabolism , Pancreas/chemistry , Pancreas/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
We previously showed that palmitic acid methyl ester (PAME) and stearic acid methyl ester (SAME) are simultaneously released from the sympathetic ganglion and PAME possesses potent vasodilatory properties which may be important in cerebral ischemia. Since PAME is a potent vasodilator simultaneously released with SAME, our hypothesis was that PAME/SAME confers neuroprotection in rat models of focal/global cerebral ischemia. We also examined the neuroprotective properties of Solutol HS15, a clinically approved excipient because it possesses similar fatty acid compositions as PAME/SAME. Asphyxial cardiac arrest (ACA, 6 min) was performed 30 min after PAME/SAME treatment (0.02 mg/kg, IV). Solutol HS15 (2 ml/kg, IP) was injected chronically for 14 days (once daily). Histopathology of hippocampal CA1 neurons was assessed 7 days after ACA. For focal ischemia experiments, PAME, SAME, or Solutol HS15 was administered following reperfusion after 2 h of middle cerebral artery occlusion (MCAO). 2,3,5-Triphenyltetrazolium staining of the brain was performed 24 h after MCAO and the infarct volume was quantified. Following ACA, the number of surviving hippocampal neurons was enhanced by PAME-treated (68%), SAME-treated (69%), and Solutol-treated HS15 (68%) rats as compared to ACA only-treated groups. Infarct volume was decreased by PAME (83%), SAME (68%), and Solutol HS15 (78%) as compared to saline (vehicle) in MCAO-treated animals. PAME, SAME, and Solutol HS15 provide robust neuroprotection in both paradigms of ischemia. This may prove therapeutically beneficial since Solutol HS15 is already administered as a solublizing agent to patients. With proper timing and dosage, administration of Solutol HS15 and PAME/SAME can be an effective therapy against cerebral ischemia.
Subject(s)
Brain Ischemia/drug therapy , Neuroprotective Agents/therapeutic use , Palmitates/therapeutic use , Polyethylene Glycols/therapeutic use , Stearic Acids/therapeutic use , Vasodilator Agents/therapeutic use , Animals , Disease Models, Animal , Infarction, Middle Cerebral Artery/drug therapy , Male , Rats , Rats, Sprague-DawleyABSTRACT
With the introduction of doxorubicin into mice with Lewis carcinoma in the heart and liver tissues and kidney the organ-antitoxic effects of N-stearoilethanolamine (NSE) were found, which depended on its concentration. Administration of doxorubicin to male mice leads to an increase in the level of urea and creatinine, as well as activation of ALT in blood plasma. Introduction of NSE resulted in normalization of these parameters to the level of intact animals. In the heart tissue doxorubicin has multidirectional effects on the activity of antioxidant enzymes, in particular it decreases the activity of catalase and superoxide dismutase activity increases. Introduction of NSE normalizes these two indicators. It was found that tumor growth leads to an increase in the activity of glutathione peroxidase and superoxide dismutase. Introduction of NSE normalizes activity of these enzymes. Doxorubicin causes an increase in catalase activity in the kidney of mice with tumour, NSE prevented the increase in the activity of the above enzyme. The cancer process leads to increased levels of catalase activity in the liver of tumour-bearing mice, the introduction of NSE decreases the enzyme activity.
Subject(s)
Antioxidants/therapeutic use , Carcinoma, Lewis Lung/drug therapy , Doxorubicin/toxicity , Ethanolamines/therapeutic use , Kidney/drug effects , Liver/drug effects , Myocardium/enzymology , Stearic Acids/therapeutic use , Alanine Transaminase/blood , Alanine Transaminase/metabolism , Animals , Antioxidants/administration & dosage , Antioxidants/metabolism , Aspartate Aminotransferases/blood , Aspartate Aminotransferases/metabolism , Blood Urea Nitrogen , Carcinoma, Lewis Lung/blood , Carcinoma, Lewis Lung/enzymology , Creatinine/blood , Dose-Response Relationship, Drug , Doxorubicin/therapeutic use , Ethanolamines/administration & dosage , Kidney/enzymology , Kidney/metabolism , Liver/enzymology , Male , Mice , Myocardium/metabolism , Organ Specificity , Stearic Acids/administration & dosageABSTRACT
OBJECTIVE: to investigate the radiomodifying properties of N-stearoilethanolamine (NSE) in experiment under different conditions of a combined impact of ionizing radiation and stress. METHODS: biochemical, statistical. RESULTS: The radiomodifying properties of N-stearoilethanolamine were revealed under different conditions of a combined impact of ionizing radiation and stress according to the indices of plasma concentrations of TBA-active products, nitrite-anions and catalase activity. CONCLUSIONS: The radioprotective properties of NSE at a dose of 10.0 mg/kg before and after a single total 6.0 Gy irradiation of animals. The radioprotective properties of NSE are identified at a dose of 10.0 mg/kg of animal bodyweight before and after stress. The radiosensitizing properties of NSE occur upon the drug administration in a dose of 10.0 mg/kg before the combined impact of 6.0 Gy ionizing radiation and stress.
Subject(s)
Ethanolamines/therapeutic use , Gamma Rays/adverse effects , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents/therapeutic use , Stearic Acids/therapeutic use , Stress, Psychological/complications , Animals , Antioxidants/metabolism , Dose-Response Relationship, Drug , Drug Administration Schedule , Ethanolamines/administration & dosage , Lipid Peroxidation/drug effects , Lipid Peroxidation/radiation effects , Male , Radiation Dosage , Radiation Injuries, Experimental/metabolism , Radiation Injuries, Experimental/psychology , Radiation-Protective Agents/administration & dosage , Rats , Stearic Acids/administration & dosage , Stress, Psychological/metabolism , Stress, Psychological/psychologyABSTRACT
UNLABELLED: The study objective was to explore the peculiarities of peripheral blood values in rats under the combined influence of 10.0 mg/kg N-stearoylethanolamine (NSE) and 6.0 Gy dose of ionizing radiation to identify the radiomodifying properties of the drug. METHODS: hematological, statistical. RESULTS: it was found that NSE injection to irradiated rats leads to exacerbation of hematopoietic system disorders indicating to radiosensitizing effect of the substance. CONCLUSIONS: The radiosensitizing effect of the drug was established according to qualitative and quantitative abnormalities in peripheral blood values of the rats. Effect of the NSE drug on the rate of recovery processes (i.e. retardation) in the peripheral blood of rats after irradiation was established under these experimental conditions.
Subject(s)
Ethanolamines/adverse effects , Gamma Rays/adverse effects , Hematopoiesis , Radiation Injuries, Experimental/blood , Radiation-Protective Agents/adverse effects , Stearic Acids/adverse effects , Animals , Blood Cell Count , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Drug Administration Schedule , Ethanolamines/administration & dosage , Ethanolamines/therapeutic use , Hematopoiesis/drug effects , Hematopoiesis/radiation effects , Male , Radiation Dosage , Radiation Injuries, Experimental/prevention & control , Radiation-Protective Agents/administration & dosage , Radiation-Protective Agents/therapeutic use , Rats , Stearic Acids/administration & dosage , Stearic Acids/therapeutic use , Whole-Body IrradiationABSTRACT
Non-viral vesicle composing of low-molecular weight polyethylenimine-conjugated stearic acid-g-chitosan oligosaccharide (CSOSA-g-PEI) was synthesized for gene delivery and therapy. The synthesized CSOSA-g-PEI had good ion-buffer capabilities and DNA-binding capacity, which could form positively charged nano-sized particles (100-150 nm) with plasmid DNA; in vitro gene transfection tests demonstrated that CSOSA-g-PEI presented much lower cytotoxicity and corresponding transfection efficiency in comparison with Lipofectamine 2000 in both human cancer cells (Hela and MCF-7). The gene transfection of CSOSA-g-PEI/pDNA could be further enhanced in the presence of serum or by adding arginine during incubation of CSOSA-g-PEI micelles with plasmid DNA. The biodistribution experiments demonstrated CSOSA-g-PEI conjugate highly localized in the tumor tissue and indicated a persistently increased accumulation. In vivo antitumor activity results showed that CSOSA-g-PEI/plasmid pigment epithelium-derived factor formulation could effectively suppress the tumor growth (above 60% tumor inhibition) without systematic toxicity against animal body after intravenous injection.