| 1. |
- Abohalaka, Reshed, et al.
(author)
-
Endocannabinoid metabolism inhibition ameliorates ovalbumin-induced allergic airway inflammation and hyperreactivity in Guinea pigs.
- 2022
-
In: Life sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 306
-
Journal article (peer-reviewed)abstract
- Endocannabinoids are biologically active cannabinoid-related substances endogenously synthesized in many mammalian tissues. Mainly two enzymes carry out their degradation; Fatty Acid Amide Hydrolase (FAAH) and Monoacylglycerol Lipase (MAGL). Endocannabinoids are shown to affect the modulation of inflammatory processes and airway responsiveness. In the present study, we investigated the effects of FAAH and MAGL inhibitor treatments in experimental allergic airway inflammation in guinea pigs.Guinea pigs were sensitized and challenged by ovalbumin to induce an allergic asthma model. Then, the effects of FAAH inhibitor URB597, MAGL inhibitor JZL184, and dual (FAAH/MAGL) inhibitor JZL195 on airway inflammation and hyperreactivity were evaluated.Ovalbumin challenge increased airway reactivity, IgE in serum, IL-4, and IL-13, and the percentage of eosinophils in bronchoalveolar lavage (BAL). In addition, inhibition of FAAH or MAGL enzymes leads to an increase in endocannabinoid levels. The selective inhibition of the FAAH enzyme prevented inflammation indicators such as cytokine production and inflammatory cell infiltration but had a negligible effect on airway hyperreactivity. However, the inhibition of the MAGL enzyme or dual inhibition of both FAAH and MAGL enzymes tent to moderate both pulmonary inflammation and airway hyperreactivity.We have previously demonstrated that modulation of endocannabinoid levels in the airways by FAAH or MAGL inhibition can be useful in preventing acute lung inflammation. The results of the present study further suggest that FAAH and MAGL inhibitor treatment can also be a promising strategy for bronchial hyperreactivity and airway inflammation in allergic asthma.
|
|
| 2. |
|
|
| 3. |
- Akbari, Ali, et al.
(author)
-
Free and hydrogel encapsulated exosome-based therapies in regenerative medicine.
- 2020
-
In: Life sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 249
-
Journal article (peer-reviewed)abstract
- Over the last few decades, mesenchymal stem cells-derived exosomes (MSCs-Ex) have attracted a lot of attention as a therapeutic tool in regenerative medicine. Exosomes are extracellular vehicles (EVs) that play important roles in cell-cell communication through various processes such as stress response, senescence, angiogenesis, and cell differentiation. Success in the field of regenerative medicine sparked exploration of the potential use of exosomes as key therapeutic effectors of MSCs to promote tissue regeneration. Various approaches including direct injection, intravenous injection, intraperitoneal injection, oral administration, and hydrogel-based encapsulation have been exploited to deliver exosomes to target tissues in different disease models. Despite significant advances in exosome therapy, it is unclear which approach is more effective for administering exosomes. Herein, we critically review the emerging progress in the applications of exosomes in the form of free or association with hydrogels as therapeutic agents for applications in regenerative medicine.
|
|
| 4. |
- Alhamad, Dima W., et al.
(author)
-
The inhibition of autophagy by spautin boosts the anticancer activity of fingolimod in multidrug-resistant hepatocellular carcinoma
- 2022
-
In: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 304
-
Journal article (peer-reviewed)abstract
- The contribution of autophagy to drug resistance has been studied in several cancers. However, there is no clear evidence about the role of autophagy in the resistance to chemotherapy in cancers, such as hepatocellular carcinoma (HCC). HCC is characterized by a poor prognosis and limited therapeutic options. Moreover, the emergence of multidrug-resistance (MDR) hinders successful treatment. Therefore, understanding how autophagy is regulated in resistant HCC is essential for sensitizing this malignancy to chemotherapy. This work demonstrated that basal and induced autophagy differ between parental and resistant Hep3B cells. In optimum growth conditions, the basal level of autophagy was low in resistant Hep3B (Hep3B-R) cells compared to the wild-type Hep3B (Hep3B-P) cells. However, in metabolic or therapeutic stress conditions, the rate of autophagy flux was much faster in the resistant cells. The work also confirmed the pro-survival function of autophagy in HCC. Besides, it demonstrated that the autophagy inhibitor, spautin, acted synergistically with fingolimod (FTY720) to promote cell death. The combination treatment resulted in superior reactive oxygen species (ROS) production and significant induction of apoptosis. In addition, spautin potentiated the effect of FTY720 against cell survival pathways like the Akt and ERK. Interestingly, the results indicated that Hep3B-R cells were more sensitive to autophagy inhibition than their parental counterparts. Collectively, this work revealed that combining spautin with chemotherapeutic agents that induce cytoprotective autophagy such as FTY720 is a promising approach to overcome MDR in HCC.
|
|
| 5. |
|
|
| 6. |
- Barbosa, Pedro, et al.
(author)
-
CD8+Treg cells play a role in the obesity-associated insulin resistance
- 2024
-
In: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 336
-
Journal article (peer-reviewed)abstract
- Obesity-related chronic low-grade inflammation may trigger insulin resistance and type 2 diabetes (T2D) development. Cells with regulatory phenotype have been shown to be reduced during obesity, especially CD4+ Treg cells. However, little is known about the CD8+ Treg cells. Therefore, we aim to characterize the CD8+ Treg cells in human peripheral blood and adipose tissue, specifically, to address the effect of obesity and insulin resistance in this regulatory immune cell population. A group of 42 participants with obesity (OB group) were recruited. Fourteen of them were evaluated pre-and post-bariatric surgery. A group of age-and sex-matched healthy volunteers (n = 12) was also recruited (nOB group). CD8+ Treg cell quantification and phenotype were evaluated by flow cytometry, in peripheral blood (PB), subcutaneous (SAT), and visceral adipose tissues (VAT). The OB group displayed a higher percentage of CD8+ Treg cells in PB, compared to the nOB. In addition, they were preferentially polarized into Tc1-and Tc1/17-like CD8+ Treg cells, compared to nOB. Moreover, SAT displayed the highest content of CD8+ Tregs infiltrated, compared to PB or VAT, while CD8+ Tregs infiltrating VAT displayed a higher percentage of cells with Tc1-like phenotype. Participants with pre-diabetes displayed a reduced percentage of TIM-3+CD8+ Tregs in circulation, and PD-1+CD8+ Tregs infiltrated in the VAT. An in-crease in the percentage of circulating Tc1-like CD8+ Treg cells expressing PD-1 was observed post-surgery. In conclusion, obesity induces significant alterations in CD8+ Treg cells, affecting their percentage and phenotype, as well as the expression of important immune regulatory molecules.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Belfrage, Per, et al.
(author)
-
Dispersion of viable pig liver cells with collagenase
- 1975
-
In: Life Sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 17:8, s. 1219-1225
-
Journal article (peer-reviewed)abstract
- Viable suspended hepatocytes were prepared from surgical biopsy specimens of pig and human liver by digestion with collagenase. Initial perfusion of the tissue through cannulated blood vessels with 0.5 mM EGTA followed by 0.2% collagenase gave the best results. 20−870 × 106 cells of which 60–95 % excluded trypan blue were obtained from 5–30 g pig liver pieces, while results with human liver specimens were usually less satisfactory. In some experiments, however, viable cells, as judged by vital stain exclusion and ability to synthesize lipids were obtained in sufficient yield. In the pig hepatocytes glycerolipid synthesis from [3H] glycerol and oxidation and esterification of [14C] oleic acid had the same characteristics as those observed earlier in rat hepatocytes.
|
|
| 10. |
- Bitar, Milad S., et al.
(author)
-
Inflammation and apoptosis in aortic tissues of aged type II diabetes : Amelioration with alpha-lipoic acid through phosphatidylinositol 3-kinase/Akt- dependent mechanism
- 2010
-
In: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 86:23-24, s. 844-853
-
Journal article (peer-reviewed)abstract
- Aims: Endothelial dysfunction is a key triggering event in the development of cardiovascular diseases and the current study explored this phenomenon in the context of inflammation, apoptosis, reactive oxygen species (ROS) and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway during chronic diabetes. Main methods: alpha-Lipoic acid (ALA) and wortmannin (WM) were chronically administered to aged Goto Kakizaki (GK) rats, a genetic model of non-obese type II diabetes. Key indices of inflammation, apoptosis and oxidative stress were assessed using western blotting, real-time PCR and immunofluoresence-based techniques. Key findings: A chronic inflammation (e.g., increased mRNA/protein levels of INF-alpha, ICAM, fractalkine, CD-68, myeloperoxidase) in connection with increased caspase-based apoptotic cell death and heightened state of oxidative stress (HSOS)- appear to exist in diabetic cardiovascular tissues. An assessment of NF-kappa B dynamics in aged diabetic vessels revealed not only a marked increase in cytosolic phosphorylated levels of I kappa B-alpha, NIK, IRK but also an enhancement in nuclear localization of p65 concomitantly with augmented NF-kappa B-DNA binding activity. Most of the aforementioned cardiovascular-based diabetic abnormalities including reduced activities of PI3K and Akt kinase were ameliorated following chronic ALA therapy. WM, given to GK rats negated the anti-inflammatory and anti-apoptotic actions of ALA. Significance: Our data highlight a unifying mechanism whereby HSOS through an induction of NF-kappa B activity together with an impairment in PI3K/Akt pathway favors pro-inflammatory/pro-apoptotic diabetic vascular milieu that culminate in the onset of endothelial dysfunction, a phenomenon which appears to be amenable to treatment with antioxidants and/or PI3/Akt mimetics (e.g., ALA).
|
|
| 11. |
- Björkman, Sven, et al.
(author)
-
Cerebral uptake of morphine in the pig calculated from arterio-venous plasma concentration gradients: an alternative to tissue microdialysis
- 1995
-
In: Life Sciences. - 1879-0631 .- 0024-3205. ; 57:25, s. 2335-2345
-
Journal article (peer-reviewed)abstract
- The aim of this study was to characterize the reversible cerebral uptake of morphine in the pig by measuring the changing arterio-venous plasma concentration gradient over the brain. Seven pigs were anaesthetized by continuous infusions of ketamine and pancuronium and ventilated with oxygen in nitrous oxide. During and after 5-min intravenous infusions of morphine hydrochloride, blood samples were drawn from a central artery and from the internal jugular vein. Concomitantly, cerebral blood flow (CBF) was repeatedly measured as clearance of 133Xe from the brain after intracarotid injection. Plasma concentrations of morphine and, in samples from two animals, morphine glucuronides were assayed by high-performance liquid chromatography. Drug flux (Jnet) from arterial blood to brain was calculated from the arterio-venous plasma concentration gradients, the blood:plasma concentration ratio and CBF. Uptake of morphine from arterial blood to brain was very rapid, with a maximal Jnet typically at 3 min after the beginning of the infusion. The initial cerebral extraction of morphine was close to 50%. When the arterial and jugular venous concentration curves crossed, 1-5 min after the end of the infusion, the initially rapid uptake of morphine changed into a slow and steady release. The cerebral extraction of morphine glucuronides was comparable to that of morphine, however, Jnet was lower due to lower plasma concentrations at time of maximal extraction. The findings demonstrate how the cerebral uptake and release of morphine and its metabolites can be studied with a method that is entirely non-invasive to the brain and permits very flexible sampling. Uptake and release of drug is observed directly and need not be inferred from cerebral concentration curves.
|
|
| 12. |
- Bouchatta, Otmane, et al.
(author)
-
Acute and chronic glue sniffing effects and consequences of withdrawal on aggressive behavior
- 2016
-
In: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 152, s. 14-20
-
Journal article (peer-reviewed)abstract
- Drug abuse act on brain mechanisms that cause a high-risk individual to engage in aggressive and violent behavior. While a drug-violence relationship exists, the nature of this relationship is often complex, with intoxication, neurotoxic, and withdrawal effects often being confused and/or confounded. Glue sniffing is often a springboard to the abuse of more addictive drugs. Despite its high prevalence and serious consequences, we know relatively little about the aggressive behavioral effects of volatile inhalants abuse, especially glue. The aim of the present study was to investigate the link between the duration of glue exposure, a common substance abuse problem in Morocco, and the level of aggressive behavior during withdrawal. For this we used the isolation-induced aggression model "residents" in three groups of mice. The first group served as control resident animals (n=10, without exposure); the second group as experimental resident mice (n=10) tested before and after acute (first day) and chronic exposure to the glue, and at 1 and 2weeks of withdrawal; and the third group of 10 intruder animals. The results showed that the number of attacks decreased (halved) and the latency of the first attack increased (doubled) following acute glue sniffing. However, the effects of chronic exposure and of 1week of withdrawal led to an increase in the intensity of agonistic encounters. After 2weeks of withdrawal, the intensity of aggressive behavior decreased again. These results indicated that chronic glue exposure and the first week of withdrawal are associated with increased aggression in mice.
|
|
| 13. |
- Brown, A. Kyle, et al.
(author)
-
Lacto-N-fucopentaose-III ameliorates acute and persisting hippocampal synaptic plasticity and transmission deficits in a Gulf War Illness mouse model
- 2021
-
In: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 279
-
Journal article (peer-reviewed)abstract
- Aims: The present study investigated if treatment with the immunotherapeutic, lacto-N-fucopentaose-III (LNFPIII), resulted in amelioration of acute and persisting deficits in synaptic plasticity and transmission as well as trophic factor expression along the hippocampal dorsoventral axis in a mouse model of Gulf War Illness (GWI).Main methods: Mice received either coadministered or delayed LNFPIII treatment throughout or following, respectively, exposure to a 15-day GWI induction paradigm. Subsets of animals were subsequently sacrificed 48 h, seven months, or 11 months post GWI-related (GWIR) exposure for hippocampal qPCR or in vitro electrophysiology experiments.Key findings: Progressively worsened impairments in hippocampal synaptic plasticity, as well as a biphasic effect on hippocampal synaptic transmission, were detected in GWIR-exposed animals. Dorsoventral-specific impairments in hippocampal synaptic responses became more pronounced over time, particularly in the dorsal hippocampus. Notably, delayed LNFPIII treatment ameliorated GWI-related aberrations in hippocampal synaptic plasticity and transmission seven and 11 months post-exposure, an effect that was consistent with enhanced hippocampal trophic factor expression and absence of increased interleukin 6 (IL-6) in animals treated with LNFPIII.Significance: Approximately a third of Gulf War Veterans have GWI; however, GWI therapeutics are presently limited to targeted and symptomatic treatments. As increasing evidence underscores the substantial role of persisting neuroimmune dysfunction in GWI, efficacious neuroactive immunotherapeutics hold substantial promise in yielding GWI remission. The findings in the present report indicate that LNFPIII may be an efficacious candidate for ameliorating persisting neurological abnormalities presented in GWI.
|
|
| 14. |
- Calles-Escandon, Jorge, et al.
(author)
-
The membrane-associated 40 KD fatty acid binding protein(Berk's protein), a putative fatty acid transporter is present in human skeletal muscle
- 1995
-
In: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 58:1, s. 19-28
-
Journal article (peer-reviewed)abstract
- Muscle tissue (1.1 +/- 0.1 grams) was obtained from seven healthy individuals (3 males, 4 females) using an open incision approach before and after ingestion of either 75 grams of dextrose (N=5) or water (N=2). Purified sarcolemmal membranes from the muscle were prepared using a sucrose step gradient. A polyclonal antibody raised against the purified (99%) rat hepatocyte 40 KD membrane fatty acid binding protein (mFABP-L) was used to probe for this putative transporter in the muscle membranes using Western blot. A single band at the 40 KD MW band was identified which reacted antigenically with the proteinpurified from rat livers. These response of Berk's protein 60-75 minutes after dextrose ingestion (or water) was erratic and no specific trend could be identified. Our data demonstrate that the 40 KD mFABP-L originally isolated from rat liver is also present in human skeletal muscle membrane. This protein may be involved in transport of fatty acids across the membrane of skeletal muscle, however its physiological role in human fatty acidmetabolism remains to be established.
|
|
| 15. |
|
|
| 16. |
- Chemuturi, Nagendra V., et al.
(author)
-
Role of dopamine transporter (DAT) in dopamine transport across the nasal mucosa
- 2006
-
In: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 79:14, s. 1391-1398
-
Journal article (peer-reviewed)abstract
- Dopamine is a catecholamine neurotransmitter necessary for motor functions. Its deficiency has been observed in several neurological disorders, but replacement of endogenous dopamine via oral or parenteral delivery is limited by poor absorption, rapid metabolism and the inability of dopamine to cross the blood-brain barrier. The intranasal administration of dopamine, however, has resulted in improved central nervous system (CNS) bioavailability compared to that obtained following intravenous delivery. Portions of the nasal mucosa are innervated by olfactory neurons expressing dopamine transporter (DAT) which is responsible for the uptake of dopamine within the central nervous system. The objective of these studies was to study the role of DAT in dopamine transport across the bovine olfactory and nasal respiratory mucosa. Western blotting studies demonstrated the expression of DAT and immunobistochemistry revealed its epithelial and submucosal localization within the nasal mucosa. Bidirectional transport studies over a 0.1-1 mM dopamine concentration range were carried out in the mucosal-submucosal and submucosal-mucosal directions to quantify DAT activity, and additional transport studies investigating the ability of GBR 12909, a DAT inhibitor, to decrease dopamine transport were conducted. Dopamine transport in the mucosal-submucosal direction was saturable and was decreased in the presence of GBR 12909. These studies demonstrate the activity of DAT in the nasal mucosa, and provide evidence that DAT-mediated dopamine uptake plays a role in the absorption and distribution of dopamine following intranasal administration.
|
|
| 17. |
- Danielson, Patrik, et al.
(author)
-
Extensive expression of markers for acetylcholine synthesis and of M2 receptors in tenocytes in therapy-resistant chronic painful patellar tendon tendinosis - a pilot study.
- 2007
-
In: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 80:24-25, s. 2235-2238
-
Journal article (peer-reviewed)abstract
- We have recently obtained evidence favoring the occurrence of an up-regulation of a non-neuronal cholinergic system in chronic painful patellar tendon tendinosis. It seems possible that this up-regulation to a certain degree may be involved in the manifestations of the disease. Today, there is a new, very successful, line of treatment of patellar tendinosis in the form of Doppler guided sclerosing injections. However, a few patients seem resistant to this therapy. Therefore, we have in this pilot study investigated biopsies from the patellar tendon of three such therapy-resistant patients, using immunohistochemistry. In situ hybridization was also applied. Comparisons were made with a material of specimens from both normal (n=16) and tendinosis (n=7) tendons, also previously examined. The study showed that there were extensive immunoreactions for choline acetyltransferase (ChAT) and vesicular acetylcholine transporter, as well as for the M(2) muscarinic acetylcholine receptor, in the overwhelming majority of the tenocytes. The immunoreactions were more pronounced than those generally obtained in the tendinosis tissue of the previously studied patients and clearly more pronounced than those of patellar tendon tissue of controls. Also, for the first time, we here present findings of mRNA for ChAT within tenocytes. In conclusion, it appears as if there is an excessive local acetylcholine (ACh) production and an occurrence of marked ACh effects in cases of severe tendinosis. An excessive production of local ACh might be related to pain sensation and the processes that occur in tendinosis development, such as cell proliferation. Thus, the results of this pilot study suggest that non-neuronal ACh is highly involved in the pathology of therapy-resistant patellar tendinosis.
|
|
| 18. |
- Dos Santos, Cristiane, et al.
(author)
-
Glucocorticoids and glucolipotoxicity alter the DNA methylome and function of human EndoC-βH1 cells
- 2022
-
In: Life Sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 307
-
Journal article (peer-reviewed)abstract
- AIMS: Synthetic glucocorticoids, including dexamethasone (DEX), are clinically prescribed due to their immunoregulatory properties. In excess they can perturb glucose homeostasis, with individuals predisposed to glucose intolerance more sensitive to these negative effects. While DEX is known to negatively impact β-cell function, it is unclear how. Hence, our aim was to investigate the effect of DEX on β-cell function, both alone and in combination with a diabetogenic milieu in the form of elevated glucose and palmitate.MAIN METHODS: Human pancreatic EndoC-βH1 cells were cultured in the presence of high glucose and palmitate (glucolipotoxicity) and/or a pharmacological concentration of DEX, before functional and molecular analyses.KEY FINDINGS: Either treatment alone resulted in reduced insulin content and secretion, while the combination of DEX and glucolipotoxicity promoted a strong synergistic effect. These effects were associated with reduced insulin biosynthesis, likely due to downregulation of PDX1, MAFA, and the proinsulin converting enzymes, as well as reduced ATP response upon glucose stimulation. Genome-wide DNA methylation analysis found changes on PDE4D, MBNL1 and TMEM178B, all implicated in β-cell function, after all three treatments. DEX alone caused very strong demethylation of the glucocorticoid-regulated gene ZBTB16, also known to influence the β-cell, while the combined treatment caused altered methylation of many known β-cell regulators and diabetes candidate genes.SIGNIFICANCE: DEX treatment and glucolipotoxic conditions separately alter the β-cell epigenome and function. The combination of both treatments exacerbates these changes, showing that caution is needed when prescribing potent glucocorticoids in patients with dysregulated metabolism.
|
|
| 19. |
- Eduardo Roa-Coria, Jose, et al.
(author)
-
N-(4-Methoxy-2-nitrophenyl)hexadecanamide, a palmitoylethanolamide analogue, reduces formalin-induced nociception
- 2012
-
In: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 91:25-26, s. 1288-1294
-
Journal article (peer-reviewed)abstract
- Aims: To investigate the local antinociceptive effect as well as the possible mechanisms of action of a novel analogue of palmitoylethanolamide (PEA) N-(4-methoxy-2-nitrophenyl)hexadecanamide (HD) in the rat formalin test.Main methods: The formalin test was used to assess the antinociceptive activity of HD in vivo. The hydrolysis of anandamide catalyzed by fatty acid amide hydrolase (FAAH) was used to determine the action of HD on FAAH activity in vitro.Key findings: Local peripheral ipisilateral, but not contralateral, administration of HD (10-100 mu g/paw) produced a dose-dependent antinociceptive effect in rats. The CB1 and CB2 receptor antagonists AM281 (0.3-30 mu g/paw) and SR144528 (0.3-30 mu g/paw), respectively, reduced the antinociceptive effect of HD (100 mu g/paw). In addition, methiothepin (0.03-0.3 mu g/paw) and naloxone (5-50 mu g/paw) significantly reduced HD-induced antinociception (100 mu g/paw). In vitro, HD reduced only to a minor extent the hydrolysis of anandamide catalyzed by FAAH.Significance: HD local administration produces antinociception that probably results from an indirect activation of peripheral CB1 and CB2 cannabinoid receptors. Data suggest that 5-HT1 and opioid receptors also participate in the antinociceptive effect of this compound. HD may have potential as analgesic drug.(C) 2012 Elsevier Inc. All rights reserved.
|
|
| 20. |
- Figueiredo, Bryanne Silva, et al.
(author)
-
Coadministration of sitagliptin or metformin has no major impact on the adverse metabolic outcomes induced by dexamethasone treatment in rats
- 2021
-
In: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 286
-
Journal article (peer-reviewed)abstract
- Aims: Glucocorticoids (GC) in excess cause glucose intolerance and dyslipidemia due to their diabetogenic actions. Conceptually, antidiabetic drugs should attenuate these side effects. Thus, we evaluated whether the coadministration of metformin or sitagliptin (or both) with dexamethasone could attenuate GC-induced adverse effects on metabolism. Materials and methods: Adult male rats were treated for 5 consecutive days with dexamethasone (1 mg/kg, body mass (bm), intraperitoneally). Additional groups were coadministered with metformin (300 mg/kg, bm, by oral gavage (og)) or sitagliptin (20 mg/kg, bm, og) or with both compounds in combination. The day after the last treatments, rats were submitted to glucose tolerance tests, pyruvate tolerance test, and euthanized for biometric, biochemical, morphologic, and molecular analyses. Key findings: Dexamethasone treatment resulted in reduced body mass and food intake, increased blood glucose and plasma insulin, dyslipidemia, glucose intolerance, pyruvate intolerance, and increased hepatic content of glycogen and fat. Sitagliptin coadministration improved glucose tolerance compared with the control group, an effect paralleled with higher levels of active GLP-1 during an oral GTT. Overall, sitagliptin or metformin coadministration did not prevent any of the dexamethasone-induced metabolic disturbances. Significance: Coadministration of sitagliptin or metformin result in no major improvement of glucose and lipid metabolism altered by dexamethasone treatment in male adult rats.
|
|
| 21. |
- Fittipaldi, Antonela S., et al.
(author)
-
Ghrelin proteolysis increases in plasma of men, but not women, with obesity
- 2023
-
In: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 313
-
Journal article (peer-reviewed)abstract
- Aims: Since plasma ghrelin can undergo des-acylation and proteolysis, the aim of this study was to investigate the extent to which an enhancement of these reactions is associated to the decrease of ghrelin in plasma after food intake or in individuals with obesity.Main methods: we performed an intervention cross-sectional study, in which levels of ghrelin, desacyl-ghrelin (DAG), glucose, insulin, ghrelin des-acylation and ghrelin proteolysis were assessed in plasma before and after a test meal in 40 people (n = 21 males) with normal weight (NW, n = 20) or overweight/obesity (OW/OB, n = 20).Key findings: Preprandial ghrelin and DAG levels were lower, whereas preprandial ghrelin proteolysis was -4.6-fold higher in plasma of males with OW/OB. In males, ghrelin proteolysis positively correlated with glycemia. Ghrelin and DAG levels were also lower in females with OW/OB, but preprandial ghrelin proteolysis was not different between females with NW or OW/OB. Ghrelin and DAG levels decreased postprandially in males and females, independently of BMI, and ghrelin proteolysis increased postprandially-2 folds only in individuals with NW. Ghrelin des-acylation remained unaffected by BMI or feeding status in both sexes.Significance: Current study shows that ghrelin proteolysis increases in males with obesity as well as after meal in lean individuals. Therefore, ghrelin proteolysis may be an important checkpoint and, consequently, a putative pharmacological target to control circulating ghrelin levels in humans.
|
|
| 22. |
- Forsgren, Sture
(author)
-
Presence of ChAT mRNA and a very marked alpha 7nAChR immunoreaction in the synovial lining layer of the knee joint
- 2012
-
In: Life Sciences. - : Elsevier. - 0024-3205 .- 1879-0631. ; 91:21-22, s. 1043-1047
-
Journal article (peer-reviewed)abstract
- Aims: The aim was to examine if there is evidence of acetylcholine (ACh) production within the synovial lining layer and to examine the pattern of alpha 7nAChR expression in the layer. This layer is of relevance clinically as it becomes thickened in response to both rheumatoid arthritis (RA) and osteoarthritis (OA) and as it has been shown to produce proteases that are involved in the cartilage destruction. Main methods: Synovial tissue specimens from the knee joint of patients with RA and OA undergoing prosthetic surgery were examined. In situ hybridization and immunohistochemistry were used for the evaluation of ChAT reaction patterns. Immunohistochemistry was utilized for demonstration of activity of alpha 7nAChR. Key findings: There were ChAT mRNA reactions in the synovial lining layer of both patient categories. On the other hand, no ChAT immunoreactions were detected in the layer. There was a very marked alpha 7nAChR immunoreaction. Significance: There is a potential for ACh production within the synovial lining layer as there are ChAT mRNA reactions. However, the level of ACh production is apparently very low. It is thus possible that there is a down-regulation of ACh production but an apparent upregulation in expression level of alpha 7nAChR. Based on the knowledge that the non-neuronal cholinergic system can have anti-inflammatory effects, the low level of ACh production in the synovial lining layer can be a drawback for the arthritic joints. (C) 2012 Elsevier Inc. All rights reserved.
|
|
| 23. |
- Gouras, Gunnar, et al.
(author)
-
Critical role of intraneuronal A beta in Alzheimer's disease: Technical challenges in studying intracellular A beta
- 2012
-
In: Life Sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 91:23-24, s. 1153-1158
-
Journal article (peer-reviewed)abstract
- Aims: Multiple lines of evidence have implicated beta-amyloid (A beta) in the pathogenesis of Alzheimer's disease (AD). However, the mechanism(s) whereby A beta is involved in the disease process remains unclear. The dominant hypothesis in AD has been that A beta initiates the disease via toxicity from secreted, extracellular A beta aggregates. More recently, an alternative hypothesis has emerged focusing on a pool of A beta that accumulates early on within AD vulnerable neurons of the brain. Although the topic of intraneuronal A beta has been of major interest in the field, technical difficulties in detecting intraneuronal A beta have also made this topic remarkably controversial. Here we review evidence pointing to the critical role of intraneuronal A beta in AD and provide insights both into challenges faced in detecting intracellular A beta and the prion-like properties of A beta. Main methods: Immunoprecipitation and Western blot are used for A beta detection. Key findings: We highlight that a standard biochemical method can underestimate intraneuronal A beta and that extracellular A beta can up-regulate intracellular A beta. We also show that detergent can remove intraneuronal A beta. Significance: There is a growing awareness that intraneuronal A beta is a key pathogenic pool of A beta involved in causing synapse dysfunction. Difficulties in detecting intraneuronal A beta are an insufficient reason for ignoring this critical pool of A beta. (C) 2012 Elsevier Inc. All rights reserved.
|
|
| 24. |
- Hagforsen, Eva
(author)
-
The cutaneous non-neuronal cholinergic system and smoking related dermatoses : Studies of the psoriasis variant palmoplantar pustulosis
- 2007
-
In: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 80:24-25, s. 2227-2234
-
Journal article (peer-reviewed)abstract
- Palmoplantar pustulosis (PPP) is probably the inflammatory skin disease most strongly associated to smoking. The disease is common in middle-aged, smoking women, and is chronic, sometimes disabling and characterized by pustules, erythema and scaling on the soles and palms. It is often treatment-resistant. PPP patients have a co-morbidity with an increased risk of autoimmune thyroid disease, celiac disease/gluten intolerance, abnormal calcium homeostasis, diabetes type 2, and depression. The sweat gland apparatus is involved in the pathogenesis of PPP since a) the normal structure of the acrosyringium is abolished so the keratin pattern differs to that in normal palmar skin; b) granulocytes migrate outwards in the acrosyringium forming the pustule in the stratum corneum. Acetylcholine (ACh) is the main inducer of sweating. With immunohistochemistry the ACh synthesizing enzyme choline acetyltransferase (ChAT) and the ACh-degrading enzyme acetylcholinesterase (AChE) were found to be strongly expressed in the gland and duct as were the alpha-3 and alpha-7 nicotinic acetylcholine receptors (nAChRs). Smoking influenced the staining intensity of the enzymes and the alpha-3 nAChR in healthy subjects. In involved PPP skin there was a massive infiltration of granulocytes expressing ChAT and alpha-3 nAChR, and mast cells expressing AChE indicating a role for acetylcholine in inflammation. Cessation of smoking resulted in fewer pustules, and less scaling and erythema. The mechanisms for the effect of nicotine/smoking in PPP are still unknown but nicotine may lead to enhanced inflammation in consideration of the properties of the sweat duct and/or nicotine might facilitate autoimmune reactions.
|
|
| 25. |
- Holt, Sandra, et al.
(author)
-
Lipopolysaccharide-induced pulmonary inflammation is not accompanied by a release of anandamide into the lavage fluid or a down-regulation of the activity of fatty acid amide hydrolase.
- 2004
-
In: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 76:4, s. 461-472
-
Journal article (peer-reviewed)abstract
- The effect of lipopolysaccharide inhalation upon lung anandamide levels, anandamide synthetic enzymes and fatty acid amide hydrolase has been investigated. Lipopolysaccharide exposure produced a dramatic extravasation of neutrophils and release of tumour necrosis factor alpha into the bronchoalveolar lavage (BAL) fluid, which was not accompanied by epithelial cell injury. The treatment, however, did not change significantly the levels of anandamide and the related compound palmitoylethanolamide in the cell-free fraction of the BAL fluid. The activities of the anandamide synthetic enzymes N-acyltransferase and N-acylphosphatidylethanolamine phospholipase D and the activity of fatty acid amide hydrolase in lung membrane fractions did not change significantly following the exposure to lipopolysaccharide. The non-selective fatty acid amide hydrolase inhibitor phenylmethylsulfonyl fluoride was a less potent inhibitor of lung fatty acid amide hydrolase than expected from the literature, and a dose of 30 mg/kg i.p. of this compound, which produced a complete inhibition of brain anandamide metabolism, only partially inhibited the lung metabolic activity.
|
|
