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Background and objectives: Aroma therapy is a complementary therapy using essential oils diluted with carrier oils. Jojoba oils have been widely used as carrier oils. However, limited information is available regarding their effects on blood biochemical parameters. This study aimed to investigate the effect of transdermal administration of jojoba oil on blood biochemical parameters in mice. Materials and Methods: Eight-week-old male hairless mice were randomly divided into naïve control and treatment groups. In the treatment group, mice were topically administered 4 μL of jojoba oil, per gram of body weight, on the dorsa 30 min before euthanasia. Thereafter, serum biochemical parameters were assayed, and gene expression was analyzed in various tissues via a real-time polymerase chain reaction. Results: Serum non-esterified fatty acid (NEFA) levels increased significantly 30 min after topical application of jojoba oil (p < 0.05). Atgl was significantly upregulated in the liver (p < 0.05), and Atgl upregulation in the liver was positively correlated with serum NEFA levels (r = 0.592, p < 0.05). Furthermore, a trend of decreasing fatty acid trafficking-related gene (FABPpm, FATP-1, FATP-3, and FATP-4) expression in the skin after topical application of jojoba oil (p = 0.067, 0.074, 0.076, and 0.082, respectively) was observed. Conclusions: Serum NEFA levels were elevated 30 min after transdermal administration of jojoba oil. The mechanisms of elevated serum NEFA levels might be related to both enhanced lipolysis in the liver and reduced fatty acid trafficking in the skin.

The aim of this study was to investigate the changes in hepatic oxidative phosphorylation (OXPHOS) complexes (COs) in patients and cows with non‐alcoholic steatohepatitis (NASH) and to investigate the mechanism that links mitochondrial dysfunction and hepatic insulin resistance induced by non‐esterified fatty acids (NEFAs). Patients and cows with NASH displayed high blood NEFAs, TNF‐α and IL‐6 concentrations, mitochondrial dysfunction and insulin resistance. The protein levels of peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), mitofusin‐2 (Mfn‐2) and OXPHOS complexes (human: COI and COIII; cow: COI‐IV) were significantly decreased in patients and cows with NASH. NEFA treatment significantly impaired mitochondrial function and, increased reactive oxygen species (ROS) production, and excessive ROS overactivated the JNK and p38MAPK pathways and induced insulin resistance in cow hepatocytes. PGC‐1α and Mfn‐2 overexpression significantly decreased the NEFA‐induced ROS production and TNF‐α and IL‐6 mRNA expressions, reversed the inhibitory effect of NEFAs on mitochondrial function and attenuated the overactivation of the ROS‐JNK/p38MAPK pathway, alleviated insulin resistance induced by NEFAs in cow hepatocytes and HepG2 cells. These findings indicate that NEFAs induce mitochondrial dysfunction and insulin resistance mediated by the ROS‐JNK/p38MAPK pathway. PGC‐1α or Mfn‐2 overexpression reversed the lipotoxicity of NEFAs on mitochondrial dysfunction and insulin resistance. Our study clarified the mechanism that links hepatic mitochondrial dysfunction and insulin resistance in NASH.

Tumoral immune escape is an obstacle to successful cancer therapy. Tryptophan (Trp) metabolites along the kynurenine pathway induce immunosuppression involving apoptosis of effector immune cells, which tumors use to escape an immune response. Production of these metabolites is initiated by indoleamine 2,3‐dioxygenase (IDO1). IDO1 inhibitors, however, do not always overcome the immune escape and another enzyme expressed in tumors, Trp 2,3‐dioxygenase (TDO2), has been suggested as the reason. However, without Trp, tumors cannot achieve an immune escape through either enzyme. Trp is therefore key to immune escape. In this perspective paper, Trp availability to tumors will be considered and strategies limiting it proposed. One major determinant of Trp availability is the large increase in plasma free (non‐albumin‐bound) Trp in cancer patients, caused by the low albumin and the high non‐esterified fatty acid (NEFA) concentrations in plasma. Albumin infusions, antilipolytic therapy or both could be used, if indicated, as adjuncts to immunotherapy and other therapies. Inhibition of amino acid uptake by tumors is another strategy and α‐methyl‐DL‐tryptophan or other potential inhibitors could fulfill this role. Glucocorticoid receptor antagonists may have a role in preventing glucocorticoid induction of TDO in host liver and tumors expressing it and in undermining the permissive effect of glucocorticoids on IDO1 induction by cytokines. Nicotinamide may be a promising TDO2 inhibitor lacking disadvantages of current inhibitors. Establishing the Trp disposition status of cancer patients and in various tumor types may provide the information necessary to formulate tailored therapeutic approaches to cancer immunotherapy that can also undermine tumoral immune escape. Targeting availability of the amino acid tryptophan to tumors is the key to overcoming tumoral immune escape. Proposed strategies include lowering plasma free tryptophan levels by albumin infusions and antilipolytic drugs, inhibition of tumoral uptake of tryptophan by inhibitors of amino acid transporter function, and modulation of activities of the tryptophan‐degrading enzymes indoleamine 2,3‐dioxygenase and tryptophan 2,3‐dioxygenase by specific inhibitors, glucocorticoid receptor antagonists and nicotinamide. Establishing the Trp disposition status of cancer patients and in various tumor types may provide the information necessary to formulate tailored therapeutic approaches to cancer immunotherapy that can also undermine tumoral immune escape.

This study examined the effects of goji berries dietary supplementation on the energetic metabolism of doe. Thirty days before artificial insemination, 75 New Zealand White does were assigned to three different diets: commercial standard diet (C) and supplemented with 1% (LG) and 3% (HG) of goji berries, respectively. Body conditions, hormones and metabolites were monitored until weaning. Body weight and BCS were higher in HG than C (p < 0.05). LG showed lower T3/T4 ratio and cortisol concentrations (p < 0.05) and tended to have lower indices of insulin resistances (p < 0.1) than HG. Compared to control, leptin was higher in HG at AI (p < 0.01) and in LG during lactation (p < 0.05). Two principal components were extracted by multivariate analysis describing the relationships between (1) non-esterified fatty acids, insulin and glucose levels, and (2) body conditions and leptin metabolism. The first component highlighted the energy deficit and the insulin resistance of the does during pregnancy and lactation. The second one showed that leptin, body weight and Body Condition Score (BCS) enhance as levels of goji berries in the diet increase. Thus, the effects of goji supplementation are dose-dependent: an improvement on energy metabolism was achieved with a low-dose while the highest dose could determine excessive fattening and insulin resistance in does.

During fasting, cells increase uptake of non-esterified fatty acids (NEFA) and esterify excess into phosphatidic acid (PtdOH), the common precursor of both triacylglycerols and phospholipids, using acylglycerophosphate acyltransferases/lysophosphatidic acid acyltransferases (AGPAT/LPAAT). Knowledge of the regulation of AGPAT enzymes is important for understanding fasting adaptations. Total RNA was isolated from liver, heart, and whole brain tissue of C57BL/6J mice fed ad libitum, or fasted for 16 h. Following fasting, induction of Agpat2 , 3 , 4 , and 5 was observed in the liver, Agpat2 and 3 in heart tissue, and Agpat1 , 2 , and 3 in whole brain tissue. As a result, the relative abundance profile of the individual homologues within specific tissues was found to be significantly altered depending on the nutritive state of the animal. These data demonstrate tissue-specific effects of fasting on the regulation of different Agpat that are implicated in supporting unique downstream glycerolipid synthesis pathways.

Aims/Introduction Understanding morning–evening variation in metabolic state is critical for managing metabolic disorders. We aimed to characterize this variation from the viewpoints of insulin secretion and insulin sensitivity, including their relevance to the circadian rhythm. Materials and Methods A total of 14 and 10 people without diabetes were enrolled, and underwent a 75‐g oral glucose tolerance test (OGTT) and hyperinsulinemic‐euglycemic clamp study, respectively. Participants completed the OGTT or hyperinsulinemic‐euglycemic clamp at 08.00 hours and 20.00 hours in random order. Before each study, hair follicles were collected. In mice, phosphorylation levels of protein kinase B were examined in the liver and muscle by western blotting. Results Glucose tolerance was better at 08 .00 hours, which was explained by the higher 1‐h insulin secretion on OGTT and increased skeletal muscle insulin sensitivity on hyperinsulinemic‐euglycemic clamp. Hepatic insulin sensitivity, estimated by the hepatic insulin resistance index on OGTT, was better at 20.00 hours. The 1‐h insulin secretion and hepatic insulin resistance index correlated significantly with Per2 messenger ribonucleic acid expression. The change (evening value – morning value) in the glucose infusion rate correlated significantly with the change in non‐esterified fatty acid, but not with clock gene expressions. The change in non‐esterified fatty acid correlated significantly with E4bp4 messenger ribonucleic acid expression and the change in cortisol. In mice, phosphorylation of protein kinase B was decreased in the liver and increased in muscle in the beginning of the active period as, expected from the human study. Conclusions Glucose metabolism in each tissue differed between the morning and evening, partly reflecting lipid metabolism, clock genes and cortisol levels. Deeper knowledge of these associations might be useful for ameliorating metabolic disorders. Glucose tolerance is better at 8 a.m. with the higher insulin secretion. Hepatic insulin sensitivity is poor at 8 a.m., whereas muscle insulin sensitivity is better at 8 a.m. associated with serum NEFA. Insulin secretion and hepatic insulin sensitivity are associated with clock gene.

Objective We have been interested in determining the effects of dietary changes on fuel metabolism and regulation in men with type 2 diabetes mellitus (T2DM). In this study, the changes in 24‐hr circulating lipid profiles were determined when the major fuel source was endogenous versus exogenous fat. Methods Seven males with T2DM were randomized in a crossover design with a 4‐week washout period. A standard mixed (control) diet (30%fat:15%protein:55%carbohydrate) was provided initially. Subsequently, a 72‐hr (3‐day) fast, or a high fat (85%), 15% protein, essentially carbohydrate‐free (CHO‐free) diet was provided for 72 hr. Triacylglycerol (TAG), non‐esterified fatty acids (NEFA), β‐hydroxybutyrate (bHB), and insulin‐like growth factor‐binding protein‐1 (IGFBP‐1) profiles were determined during the last 24 hr of intervention, as well as during the control diet. Results Regardless of the amount of dietary fat (30% vs 85%) and differences in 24‐hr profiles, TAG, NEFA, and bHB all returned to the previous basal concentrations within 24 hr. TAGs and NEFAs changed only modestly with fasting; bHB was elevated and increasing. The IGFBP‐1 profile was essentially unchanged with either diet but increased with fasting. Conclusion A CHO‐free diet resulted in a large increase in TAG and NEFA versus the control diet; however, both were cleared by the following morning. A negative NEFA profile occurred with the control diet. Thus, mechanisms are present to restore lipid concentrations to their original AM concentrations daily. Fasting resulted in stable concentrations, except for a continuing increase in bHB. Glucose and insulin, common fuel regulators, could not explain the results. The 24‐hr response profiles for TAG, NEFA, bHB, and IGFBP‐1 were obtained when ingesting a mixed control diet before, and during the last 48–72 hr when ingesting a CHO‐free diet or fasting in male subjects with untreated type 2 diabetes. Data indicate that subjects are still able to absorb, process, utilize, and if necessary, store large amounts of ingested fats adequately, as well as adjust adequately to short‐term starvation.

Background/Objectives: The delayed effects of organophosphate poisoning may manifest years after exposure, often masked by age-related diseases. The aim of this retrospective cohort study was to identify the biochemical “trace” that could remain in patients decades after poisoning. We determined a wide range of biochemical parameters, along with the spectrum of esterified and non-esterified fatty acids (EFAs and NEFAs, respectively), in the blood plasma of a cohort of elderly patients diagnosed with occupational pathology (OP) due to (sub)chronic exposure to organophosphates in the 1980s. Methods: Elderly patients with and without a history of exposure to organophosphates were retrospectively divided into two groups: controls (n = 59, aged 73 ± 4, men 29% and women 71%) and those with OP (n = 84, aged 74 ± 4, men 29% and women 71%). The period of neurological examination and blood sampling for subsequent analysis was from mid-2022 to the end of 2023. Determination of the content of biomarkers of metabolic syndrome, NEFAs, and EFAs in blood plasma was performed by HPLC-MS/MS and GC-MS. Results: The medical histories of the examined elderly individuals with OP and the aged control group included common age-related diseases. However, patients with OP more often had hepatitis, gastrointestinal diseases, polyneuropathy, and an increased BMI. Analysis of metabolic biomarkers revealed, in the OP group, a decrease in the concentrations of 3-hydroxybutyrate (p < 0.05), 2-hydroxybutyrate (p < 0.0001), and acetyl-L-carnitine (p < 0.001) and the activity of butyrylcholinesterase (BChE) (p < 0.05), but an increase in the esterase activity of albumin (p < 0.05). Correlation analysis revealed significant relationships between albumin esterase activity and arachidonic acid concentrations in the OP group (0.64, p < 0.0001). A study of a wide range of fatty acids in patients with OP revealed reciprocal relationships between EFAs and NEFAs. A statistically significant decrease in concentration was shown for esters of margaric, stearic, eicosadienoic, eicosatrienoic, arachidonic, eicosapentaenoic, and docosahexaenoic fatty acids. A statistically significant increase in concentration was shown for non-esterified heptadecenoic, eicosapentaenoic, eicosatrienoic, docosahexaenoic, γ-linolenic, myristic, eicosenoic, arachidonic, eicosadienoic, oleic, linoleic, palmitic, linoelaidic, stearic, palmitoleic, pentadecanoic, and margaric acids. Decreases in the ratios of omega-3 to other unsaturated fatty acids were observed only for the esterified forms. Conclusions: The data obtained allow us to consider an increased level of NEFAs as one of the main cytotoxic factors for the vascular endothelium. Modification of albumin properties and decreased bioavailability of docosahexaenoic acid could be molecular links that cause specific manifestations of organophosphate-induced pathology at late stages after exposure.

Plasma free fatty acid (FFA) concentration is elevated in obesity, insulin resistance (IR), non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and related comorbidities such as cardiovascular disease (CVD). Furthermore, experimentally manipulating plasma FFA in the laboratory setting modulates metabolic markers of these disease processes. In this article, evidence is presented indicating that plasma FFA is a disease risk factor. Elevations of plasma FFA can promote ectopic lipid deposition, IR, as well as vascular and cardiac dysfunction. Typically, elevated plasma FFA results from accelerated adipose tissue lipolysis, caused by a high adipose tissue mass, adrenal hormones, or other physiological stressors. Reducing an individual’s postabsorptive and postprandial plasma FFA concentration is expected to improve health. Lifestyle change could provide a significant opportunity for plasma FFA reduction. Various factors can impact plasma FFA concentration, such as chronic restriction of dietary energy intake and weight loss, as well as exercise, sleep quality and quantity, and cigarette smoking. In this review, consideration is given to multiple factors which lead to plasma FFA elevation and subsequent disruption of metabolic health. From considering a variety of medical conditions and lifestyle factors, it becomes clear that plasma FFA concentration is a modifiable risk factor for metabolic disease.

The plasma kynurenine to tryptophan ([Kyn]/[Trp]) ratio is frequently used to express or reflect the activity of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase (IDO). This ratio is increasingly used instead of measurement of IDO activity, which is often low or undetectable in immune and other cells under basal conditions, but is greatly enhanced after immune activation. The use of this ratio is valid in in vitro studies, eg, in cell cultures or isolated organs, but its ‘blanket’ use in in vivo situations is not, because of modulating factors, such as supply of nutrients; the presence of multiple cell types; complex structural and functional tissue arrangements; the extracellular matrix; and hormonal, cytokine, and paracrine interactions. Determinants other than IDO may therefore be involved in vivo. These are hepatic tryptophan 2,3-dioxygenase (TDO) activity and the flux of plasma-free Trp down the Kyn pathway. In addition, conditions leading to accumulation of Kyn, eg, inhibition of activities of Kyn monooxygenase and kynureninase, could lead to elevation of the aforementioned ratio. In this review, the origin of use of this ratio will be discussed, variations in extent of its elevation will be described, evidence against its indiscriminate use will be presented, and examining determinants other than IDO activity and their correlates will be proposed for future studies.