LH-21, a CB1 antagonist, reduces hepatotoxic damage produced by paracetamol overdose in a mice model.

Drug-induced liver injury (DILI) is one of the main causes of hepatic acute failure. Paracetamol can cause it when is ingested in excessive doses, leading to the depletion of the antioxidant mechanisms of the hepatocytes and a series of processes that conclude with cell death. One of the altered metabolic pathways is the endocannabinoid system (ECS), which has become a very interesting target to alleviate these events due to its involvement in inflammatory processes. For this reason, the triazole-derived compound LH-21, a cannabinoid receptor Cb1 antagonist, was used for the treatment of DILI in 8-week-old male C57BL/6 mice. In the present study, fasting mice were subjected to an oral overdose of paracetamol (300 mg/kg) and treated 2 hours later with 3 mg/kg of LH-21. After 24 hours, the animals were sacrificed and the livers were collected to determine the hepatic levels of metabolites related to antioxidant mechanisms, the expression of proteins involved in the generation of cellular damage and the transcription grade of the different components of the ECS. The observed results showed that LH-21 treatment raises GSH levels and total antioxidant capacity, in addition to reducing malondialdehyde values. Furthermore, the phosphorylation degree of Jnk and Stat3, as well as the activation status of Casp3, diminished. Regarding the ECS, the expression of Ppara, Cnr1, Cnr2 and Gpr55 did return to normal levels. This suggests that LH-21 effectively blocks the Cb1 activity, allowing the correct function of Ppar-α that promotes a cellular anti-inflammatory state and the relief of the symptoms produced by DILI. These results exhibit a promising perspective for the prevention or treatment of some toxic effects of paracetamol overdose with LH-21. Nevertheless, these findings are a first step to continue studying the involvement of the ECS in this type of liver disease and investigating the effectiveness of this Cb1 antagonist against the pathophysiology of DILI.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Environmental Enrichment, Age, and PPARα Interact to Regulate Proliferation in Neurogenic Niches

Peroxisome proliferator-activated receptor alpha (PPARα) ligands have been shown to modulate recovery after brain insults such as ischemia and irradiation by enhancing neurogenesis. In the present study, we investigated the effect of the genetic deletion of PPARα receptors on the proliferative rate of neural precursor cells (NPC) in the adult brain. The study was performed in aged Pparα −/− mice exposed to nutritional (treats) and environmental (games) enrichments for 20 days. We performed immunohistochemical analyses of cells containing the replicating cell DNA marker 5-bromo-2′ -deoxyuridine (BrdU+) and the immature neuronal marker doublecortin (Dcx+) in the main neurogenic zones of the adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ), and/or hypothalamus. Results indicated a reduction in the number of BrdU+ cells in the neurogenic zones analyzed as well as Dcx+ cells in the SGZ during aging (2, 6, and 18 months). Pparα deficiency alleviated the age-related reduction of NPC proliferation (BrdU+ cells) in the SVZ of the 18-months-old mice. While no genotype effect on NPC proliferation was detected in the SGZ during aging, an accentuated reduction in the number of Dcx+ cells was observed in the SGZ of the 6-months-old Pparα −/− mice. Exposing the 18-months-old mice to nutritional and environmental enrichments reversed the Pparα −/−-induced impairment of NPC proliferation in the neurogenic zones analyzed. The enriched environment did not modify the number of SGZ Dcx+ cells in the 18 months old Pparα −/− mice. These results identify PPARα receptors as a potential target to counteract the naturally observed decline in adult NPC proliferation associated with aging and impoverished environments.Grant sponsor: 7th Framework Programme of European Union. Grant number: HEALTH-F2-2008-223713, REPROBESITY to FR. Grant sponsor: Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad (MINECO), UEERDF. Grant numbers: PI13/02261 to FR. and CP12/03109 to JS. Grant sponsor: Red de Trastornos Adictivos, ISCIII, MINECO. Grant number: RD12/0028/0001 to FR. Grant sponsor: Plan Nacional Sobre Drogas, Ministerio de Sanidad y Consumo. Grant number: PNSD2010/143 and PNSD2015/047 to JS. Grant sponsor: Fundació La Marató de TV3. Grant number: 386/C/2011. Grant sponsor: Consejería de Economía, Innovación y Ciencia, Junta de Andalucía, UE/ERDF. Grant numbers: PI45403 and CTS-8221 to FR. Grant sponsor: Consejería de Salud, Junta de Andalucía, UE/ERDF. Grant number: SAS111224 to FR. JS, FP and AS hold “Miguel Servet” research contracts from the National System of Health, ISCIII (grant numbers: CP12/03109, CP14/00212 and CP14/00173, respectively

Anti-hyperglycemic and antioxidant effect of fucoidan extract from Lessonia trabeculata in alloxan-induced diabetes rats

The objective of this research was to evaluate a nutritional strategy based on the consumption of a fucoidan extract from brown algae Lessonia trabeculata to control oxidative stress in experimental alloxan-induced insulin-dependent diabetes mellitus rats. Over 30 days, 75, 100, and 125 mg kg−1 of body weight of fucoidan doses were administered and both positive and negative control (n = 5 per group). Serum, liver, pancreas, and kidney biochemical indicators of oxidative stress improvement were evaluated. Measures included lipid peroxidation, superoxide dismutase and catalase activity, and antioxidant activity by assessment of free radical scavenging power and histopathological changes. The results showed an increase in the activity of antioxidant enzymes while reducing oxidative damage (lipid peroxidation index) in serum (p ≤ 0.05) and tissues (p ≤ 0.05). Further, no liver necrosis was observed in treated groups, unlike the Type 1 diabetes positive control group that presented mild necrosis and moderate congestion. In the pancreas, treated rats presented mild oedema, while the positive control group showed moderate oedema. A significant protective effect against oxidative stress caused by alloxan-induced diabetes was found in this model, therefore it can be concluded that fucoidan extracted from the Lessonia trabeculata algae could be considered a good functional compound for the control of oxidative stress in diabetic patients. Because diabetes is such a widespread public health issue, developing fucoidan-based products could be a natural way to improve patients' quality of life.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Funding for open access charge: Universidad de Málaga / CBUA This work was supported by grants from the following institutions: L.T.L-G., E.V.A.S., L.A.A-M. and J.A.C-P. are supported by Project “Desarrollo e Implementación de Procesos Tecnológicos de Validación Analítica y Bioactiva para fucoidano de algas pardas como suplementos nutricionales para humanos”, Convenio N°143-PNICP-PIAP-2015, INNOVATE-PERU. J.D. hold a “Miguel Servet” (CP21/00021) research contract from the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (ISCIII) co-funded by European Social Fund (ESF), “Investing in your future”, Gobierno de España

Endocrine and Metabolic impact of oral ingestion of a carob-pod derived natural syrup containing D-Pinitol: potential use as a novel sweetener in diabetes

The use of added sugars or non-nutritive sweeteners in processed foods and soft drinks are being blamed for multiple complications associated with obesity and diabetes. High fructose content contributes to obesity and liver steatosis, and excessive consumption of non-nutritive sweeteners can generate gut dysbiosis complicating the metabolic control exerted by the liver. Beyond its evolutionary significance in the selection of foods with a high glucose content as an energy source, the fact is that the consumption of sweets produces a hedonic pleasure in our brain. Then, the challenge stands at: how do we control the use of added sugars while providing a safe, palatable, sweet flavour to foods?. The present work explores an alternative approach, in humans and rodents, for sweetening through the use of a simple carob-pod-derived syrup which contains the inositol D-Pinitol. This inositol is known as an insulin sensitizer in muscle capable of keeping glycaemia while avoiding both unnecessary insulin secretion and the conversion of carbohydrates into fat depots .Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Analysis of the expression of metabolic sensors and inflammation mediators in the brain of animals with genetic obesity exposed to adiponectin activator NP1

Drug treatment strategies that interfere with adipokines secreted by adipose tissue, such as adiponectin and leptin, have been recently developed for treating obesity. Adiponectin is able of reducing both, food intake and body weight through both,  its action on the hypothalamus, and concerted actions on glucose and insulin sensitivity, and oxidation of fatty acids in peripheral tissues. Furthermore, in vitro studies have shown that adiponectin attenuates inflammation in endothelial, muscle and macrophage cells. Leptin acts synergistically with adiponectin in the regulation of energy balance, inhibiting food intake, and being its levels regulated in the hypothalamus through the endocannabinoid system and the peptides NPY/AgRP, POMC and orexins. Therefore, the restoration of normal adiponectin levels can be considered a good clinical option for the treatment of obesity. Recently, a new thiazole-derived drug called NP-1 has been described as an adiponectin promoter activator able to promote adiponectin release. We investigated the effects of NP-1 in the hypothalamus of lean (fa/-) and obese (fa/fa) leptin signaling deficient Zucker rats, after a 15-day exposure to vehicle or NP-1 (5 mg/Kg). Brains were removed and frozen and the hypothalamus was dissected out from a coronal section, following the rodent atlas of Paxinos. Protein extraction was performed from the obtained tissue to analyze it by Western Blot, and RNA was isolated to determine gene expression by RT-qPCR. Treatment with NP-1 increased circulating TNFα, which led to weight loss through decreased intake. NP-1 reduced the expression of adiponectin and TNF α receptors in the hypothalamus. It also reduced mRNA expression of intake promoters such as NPY, AGRP and hypocretin-1, and a specific obesity-dependent modulation of POMC. Leptin deficiency-induced obesity was associated with specific insulin resistance preventing NP-1-induced sensitization of insulin signaling (Phosphorylation of IRS1 and PI3K) in lean animals. Finally, NP-1 was able to decrease ERK1/ERk2 and NFkB activation, suggesting reduced inflammation of the hypothalamus. In conclusión, NP-1 modulates feeding through increased TNFα and regulation of hypothalamic neuropeptides without increasing inflammation

Pharmacological Blockade of Cannabinoid CB1 Receptors in Diet-Induced Obesity Regulates Mitochondrial Dihydrolipoamide Dehydrogenase in Muscle

Funding: This work was supported by CIBERobn (CB06/03/1008), Ministerio de Economía y Competitividad (MINECO) (PG: BFU2012-33334), Instituto de Salud Carlos III (ISCIII), MINECO, co-funded by UE-ERDF program (JS: CP12/03109), Red de Trastornos Adictivos (FRF: RD12/0028/0001, PG: RD12/0028/0004, JM: RD12/0028/0013), The Basque Country Government (PG: BCG IT764-13), Consejería de Economía, Innovación y Ciencia, Junta de Andalucía, UE-ERDF (FRF: CTS-8221, JM: CVI-6656), Consejería de Salud, Junta de Andalucía, UE-ERDF (FRF: SAS111224), and University of the Basque Country UPV/EHU (PG: UFI11/41). JS, FJP and AS hold “Miguel Servet” research contracts from the National System of Health, ISCIII, UE-ERDF (CP12/03109, CP14/00212, and CP14/00173 respectively)Peer reviewedPublisher PD

Analisis Optimasi Produksi Sumur Gas Lift Lapangan Awiligar dengan Perbandingan Desain Ulang dan Konversi Esp

Sumur minyak yang berproduksi akan mengalami penurunan produksi dikarenakan turunnya tekanan formasi sehingga dibutuhkan pengangkatan buatan.Sumur – sumur pada Lapangan Awiligar sebagian besar berproduksi dengan pengangkatan buatan gas lift. Lapangan Awiligar bertujuan meningkatkan produksi harian, sehingga perlu dilakukan optimasi diantaranya optimasi sumur – sumur gas lift. Sumur gas lift yang dikaji adalah Sumur M-150, Sumur – M-155, Sumur M-160, dan Sumur M-165 karena water cut yang tidak terlalu tinggi diantara sumur gas lift lainnya dan produksi yang lebih tinggi dari sumur gas lift lainnya.Optimasi dilakukan dengan perbandingan antara menambah jumlah laju injeksi gas, mendesain ulang posisi katup, dan menkonversi menjadi Electric Submersible Pump (ESP) dimana skenario terbaik dilihat dari lifting cost terkecil. Hasil skenario terbaik untuk optimasi sumur kajian adalah dengan konversi menjadi ESP dikarenakan produksi yang lebih besar dan lifting cost yang lebih rendah dari gas lift

d-Pinitol promotes tau dephosphorylation through a cyclin-dependent kinase 5 regulation mechanism: A new potential approach for tauopathies?

18 Pág. Departamento de Reproducción animal.Recent evidence links brain insulin resistance with neurodegenerative diseases, where hyperphosphorylated tau protein contributes to neuronal cell death. In the present study, we aimed to evaluate if d-pinitol inositol, which acts as an insulin sensitizer, affects the phosphorylation status of tau protein.This research was funded by the European Regional Development Funds-European Union (ERDF-EU), FATZHEIMER project (EU-LAC HEALTH 2020, 16/T010131), “Una manera de hacer Europa”; Ministerio de Economía, Industria y Competitividad, Gobierno de España, Programa Estatal de Investigación, Desarrollo e Innovación Orientada a los Retos de la Sociedad (RTC-2016-4983-1); ERDF-EU-Instituto de Salud Carlos III (ISCIII), Proyectos de investigación en salud (PI19/01577); Consejería de Salud y Familias, Junta de Andalucía, Proyecto de Investigación en Salud (PI-0139-2018); Consejería de Economía, Conocimiento y Universidad, Junta de Andalucía, Plan Andaluz de Investigación, Desarrollo e Innovación (P18-TP-5194); Delegación del Gobierno para el Plan Nacional sobre Drogas, Ministerio de Salud, Gobierno de España (PND2020/048). D.M-V. (FI20/00227) holds a “PFIS” predoctoral contract from the National System of Health, ERDF-EU-Instituto de Salud Carlos III. A.J.L.-G. (IFI18/00042) holds an “iPFIS” predoctoral contract from the National System of Health, ERDF-EU-ISCIII. P.R. (CP19/00068), F.J.P. (CPII19/00022) and J.D. (CP21/00021) hold a “Miguel Servet” research contract from the National System of Health, ISCIII co-funded by European Social Fund, “Investing in your future,” Gobierno de España.Peer reviewe

Benzyl-1,2,4-triazoles as CB1 cannabinoid receptor ligands: preparation and In vitro pharmacological evaluation

In a previous study, we have identified 3-alkyl-1,5-diaryl-1H-1,2,4-triazoles to be a novel class of cannabinoid type 1 receptor (CB1R) antagonists. In order to expand the number of cannabinoid ligands with a central 1,2,4-triazole scaffold, we have synthesized a novel series of 1-benzyl-1H-1,2,4-triazoles, and some of them were evaluated by CB1R radioligand binding assays. Compound 12a showed the most interesting pharmacological properties, possessing a CB1R affinity in the nanomolar range.The authors gratefully acknowledge research support from Spanish Grant SAF--C- as well as a grant from the “Programa de Biomedicina de la Comunidad de Madrid” (S/BMD-)

Obesity as a Condition Determined by Food Addiction: Should Brain Endocannabinoid System Alterations Be the Cause and Its Modulation the Solution?

Obesity is a complex disorder, and the number of people affected is growing every day. In recent years, research has confirmed the hypothesis that food addiction is a determining factor in obesity. Food addiction is a behavioral disorder characterized by disruptions in the reward system in response to hedonic eating. The endocannabinoid system (ECS) plays an important role in the central and peripheral control of food intake and reward-related behaviors. Moreover, both obesity and food addiction have been linked to impairments in the ECS function in various brain regions integrating peripheral metabolic signals and modulating appetite. For these reasons, targeting the ECS could be a valid pharmacological therapy for these pathologies. However, targeting the cannabinoid receptors with inverse agonists failed when used in clinical contexts as a consequence of the induction of affective disorders. In this context, new classes of drugs acting either on CB1 and/or CB2 receptors or on synthetic and degradation enzymes of endogenous cannabinoids are being studied. However, further investigation is necessary to find safe and effective treatments that can exert anti-obesity effects, normalizing reward-related behaviors without causing important adverse mood effects.This work was supported by grants from the following institutions: RETICS Networks Subpro-gram (Addictive Disorders Network, RD16/0017/0001) funded by Instituto de Salud Carlos III (ISCIII); Proyectos de Desarrollo tecnológico (Grant DTS19/00125) funded by Ministerio de Ciencia, Innovación y Universidades and the European Regional Development Fund/European Social Fund (FEDER/ESF); Health Research Project (grant PI19/01577) funded by, Ministerio de Ciencia, Innovación y Universidades, ISCIII and FEDER/ESF; Plan Nacional Sobre Drogas (Grant PND2018/044) funded by the Government Delegation for the National Plan on Drugs, Ministerio de Salud, Servicios Sociales e Igualdad and FEDER/FSE; Health Research Project (Grant PI-0139-2018) Consejería de Salud y Familias de la Junta De Andalucía.Ye