Mechanisms underlying biological effects of cruciferous glucosinolate-derived isothiocyanates/indoles: a focus on metabolic syndrome

An inverse correlation between vegetable consumption and the incidence of cancerhas long been described. This protective effect is strongerwhen cruciferous vegetablesare specifically consumed. The beneficial properties of vegetables are attributed totheir bioactive components like fiber, antioxidants vitamins, antioxidants, minerals, andphenolic compounds. Cruciferous vegetables contain all these molecules; however, whatmakes them different are their sulfurous components, called glucosinolates, responsiblefor their special smell and taste. Glucosinolates are inactive biologically in the organismbut are hydrolyzed by the enzyme myrosinase released as a result of chewing, leading tothe formation of active derivatives such as isothiocyanates and indoles. A considerablenumber ofin vitroandin vivostudies have reported that isothiocyanates and indoleselicit chemopreventive potency through multiple mechanisms that include modulationof phases I and II detoxification pathway enzymes, regulation of cell cycle arrest,and control of cell growth, induction of apoptosis, antioxidant activity, anti-angiogeniceffects, and epigenetic regulation. Nuclear erythroid 2-related factor 2 (Nrf2) and Nuclearfactor-κB (NF-κB) are key and central regulators in all these processes witha main rolein oxidative stress and inflammation control. It has been described that isothiocyanatesand indoles regulate their activity directly and indirectly. Today, the metabolic syndrome(central obesity, insulin resistance, hyperlipidemia, and hypertension) is responsible for amajority of deaths worldwide. All components of metabolic syndrome are characterizedby chronic inflammation with deregulation of the PI3K/AKT/mTOR, MAPK/EKR/JNK,Nrf2, and NF-κB signaling pathways. The effects of GLSs derivatives controlling thesepathways have been widely described in relation to cancer. Changes in food consumptionpatterns observed in the last decades to higher consumptionof ultra-processed foods,with elevation in simple sugar and saturated fat contents and lower consumptionof vegetables and fruits have been directly correlated withmetabolic syndromeprevalence. In this review, it is summarized the knowledge regarding the mechanismsby which cruciferous glucosinolate derivatives (isothiocyanates and indoles) directly and indirectly regulate these pathways. However, the review places a special focus onthe knowledge of the effects of glucosinolates derivativesin metabolic syndrome, sincethis has not been reviewed before

Corticosteroid-Binding Globulin is expressed in the adrenal gland and its absence impairs corticosterone synthesis and secretion in a sex-dependent manner

Corticosteroid-binding globulin (CBG) is synthesized by the liver and secreted into the bloodstream where binds to glucocorticoids. Thus CBG has the role of glucocorticoid transport and free hormone control. In addition, CBG has been detected in some extrahepatic tissues without a known role. CBG-deficient mice show decreased total corticosterone levels with missing of classical sexual dimorphism, increased free corticosterone, higher adrenal gland size and altered HPA axis response to stress. Our aim was to ascertain whether CBG deficiency could affect the endocrine synthetic activity of adrenal gland and if the adrenal gland produces CBG. We determined the expression in adrenal gland of proteins involved in the cholesterol uptake and its transport to mitochondria and the main enzymes involved in the corticosterone, aldosterone and catecholamine synthesis. The results showed that CBG is synthesized in the adrenal gland. CBG-deficiency reduced the expression of ACTH receptor, SRB1 and the main genes involved in the adrenal hormones synthesis, stronger in females resulting in the loss of sexual dimorphism in corticosteroid adrenal synthesis, despite corticosterone content in adrenal glands from CBG-deficient females was similar to wildtype ones. In conclusion, these results point to an unexplored and relevant role of CBG in the adrenal gland functionality related to corticosterone production and release

New roles for corticosteroid binding globulin and opposite expression profiles in lung and liver.

Corticosteroid-binding globulin (CBG) is the specific plasma transport glycoprotein for glu- cocorticoids. Circulating CBG is mainly synthesized in liver but, its synthesis has been located also in other organs as placenta, kidney and adipose tissue with unknown role. Using an experimental model of acute pancreatitis in cbg -/- mice we investigated whether changes in CBG affect the progression of the disease as well as the metabolism of gluco- corticoids in the lung. Lack of CBG does not modify the progression of inflammation associ- ated to pancreatitis but resulted in the loss of gender differences in corticosterone serum levels. In the lung, CBG expression and protein level were detected, and it is noteworthy that these showed a sexual dimorphism opposite to the liver, i.e. with higher levels in males. Reduced expression of 11 β -HSD2, the enzyme involved in the deactivation of corticoste- rone, was also observed. Our results indicate that, in addition to glucocorticoids transporter, CBG is involved in the gender differences observed in corticosteroids circulating levels and plays a role in the local regulation of corticosteroids availability in organs like lung

Corticosteroid-binding-globulin (CBG)-deficient mice show high pY216-GSK3β and phosphorylated-Tau levels in the hippocampus

Corticosteroid-binding globulin (CBG) is the specific carrier of circulating glucocorticoids, but evidence suggests that it also plays an active role in modulating tissue glucocorticoid activity. CBG polymorphisms affecting its expression or affinity for glucocorticoids are associated with chronic pain, chronic fatigue, headaches, depression, hypotension, and obesity with an altered hypothalamic pituitary adrenal axis. CBG has been localized in hippocampus of humans and rodents, a brain area where glucocorticoids have an important regulatory role. However, the specific CBG function in the hippocampus is yet to be established. The aim of this study was to investigate the effect of the absence of CBG on hippocampal glucocorticoid levels and determine whether pathways regulated by glucocorticoids would be altered. We used cbg-/- mice, which display low total-corticosterone and high free-corticosterone blood levels at the nadir of corticosterone secretion (morning) and at rest to evaluate the hippocampus for total- and free-corticosterone levels; 11β-hydroxysteroid dehydrogenase expression and activity; the expression of key proteins involved in glucocorticoid activity and insulin signaling; microtubule-associated protein tau phosphorylation, and neuronal and synaptic function markers. Our results revealed that at the nadir of corticosterone secretion in the resting state the cbg-/- mouse hippocampus exhibited slightly elevated levels of free-corticosterone, diminished FK506 binding protein 5 expression, increased corticosterone downstream effectors and altered MAPK and PI3K pathway with increased pY216-GSK3β and phosphorylated tau. Taken together, these results indicate that CBG deficiency triggers metabolic imbalance which could lead to damage and long-term neurological pathologies

Effect of cafeteria diet feeding on soleus intramyocellular lipid of Wistar rats

Background: The presence of lipid besides muscle fibres facilitates the energy supply for exercise, but it is also indicative of insulin resistance in the untrained. Muscle lipid is associated with increased dietary energy: hyperlipidic diets induce an increase in intramyocellular lipid deposition in skeletal muscle. Methods: In the present study we analyzed the changes in soleus (a red-fibre muscle) intracellular muscle content under a hyperlipidic (cafeteria) diet in Wistar rats. We also analyzed in parallel the mitochondrial content a relative index of energy output capability. Results: Cafeteria diet-fed rats contained more lipid and mitochondria per unit of muscle section area than controls. Conclusions: The correlation found in the increases of muscle lipid and mitochondria hit at this increase as an adaptation of muscle to oxidize excess energy substrates under conditions of excess energy availability, probably contributing to adaptive thermogenesis

Immune-inflammatory and hypothalamic-pituitary-adrenal axis biomarkers are altered in patients with non-specific low back pain: A systematic review.

This systematic review aimed to investigate immune-inflammatory and hypothalamic-pituitary-adrenal (HPA) axis biomarkers in individuals with non-specific low back pain (NSLBP) compared to healthy control. The search was performed in five databases until 4 November 2021. Two reviewers independently conducted screenings, data extraction, risk of bias, and methodological quality assessment of 14 unique studies. All studies reported the source of the fluid analyzed: nine studies used serum, two used plasma, one used serum and plasma, and two studies used salivary cortisol. We found preliminary and limited evidence (only one study for each biomarker) of increased levels in growth differentiation factor 15 (GDF-15), interleukin-23 (IL-23), transforming growth factor-beta (TGF-β), and soluble tumor necrosis factor receptor 1 (sTNF-R1) in NSLBP. Inconsistent and limited evidence was identified for interleukin-10 (IL-10). Although C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels appear to increase in NSLBP, only one study per each biomarker reported statistically significant differences. Interleukin-1 beta (IL-1β), interleukin-17 (IL-17), interferon gamma (IFN-γ), and high-sensitivity CRP (hsCRP) showed no significant differences. Regarding cortisol, one study showed a significant increase and another a significant decrease. More robust evidence between GDF-15, IL-23, TGF-β, and sTNF-R1 with NSLBP is needed. Moreover, contrary to the findings reported in previous studies, when comparing results exclusively with healthy control, insufficient robust evidence for IL-6, TNF-α, and CRP was found in NSLBP. In addition, cortisol response (HPA-related biomarker) showed a dysregulated functioning in NSLBP, with incongruent evidence regarding its directionality. Therefore, our effort is to find adjusted evidence to conclude which immune-inflammatory and HPA axis biomarkers are altered in NSLBP and how much their levels are affected

Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal

Oleoyl-estrone (OE) is a powerful anti-obesity compound that decreases food intake, decreases insulin resistance and circulating cholesterol. OE stimulates a severe loss of body fat by decreasing adipose tissue lipid synthesis and maintaining lipolysis. Therefore, the body economy loses lipid energy because energy expenditure is maintained. This study analyses the discrepancy between OE effects and the distribution of labelled OE in plasma. Estrone radioimmunoassay of organic solvent plasma extracts of rats treated with OE showed the massive presence of acyl-estrone, but. saponification did not release estrone, but containing similar unknown compound. Analysis of label distribution in plasma after oral gavages of 3H-OE showed the presence of a more hydrophilic compound than OE or any estrogen as well as 3H2O, formed from 3H-OE in the acidic stomach medium. OE was not attached toa specific transporter in plasma. Through serum HPLC analysis we found W, a labelled derivative more hydrophilic than OE or estrone. The results were confirmed using 14C-OE. HPLC-MS/MS studies showed that plasma OE levels were one order of magnitude lower than those of W. When liver cell cytosols from rats laden with 3H-OE were incubated with nuclei from untreated rats, the OE-derived label (i.e., W's) was found attached to nuclear DNA. Neither estradiol nor estrone interfered with its binding. W is a fairly hydrophilic compound of low molecular weight containing the estrone nucleus, but it is not an ester because saponification or esterases do not yield estrone as OE does. It is concluded that OE acts through its conversion to W, its active form; which binds to a nuclear receptor different from that of estrogen. The estimated W serum levels are proportional to the pharmacological OE effects in vivo. We postulate W as a new type of hormone that exerts the full range of in vivo effects thus far attributed to OE. The full identification of W is anticipated to open the way for the development of new OE-like anti-obesity drugs

Modulation of SHBG binding to testosterone and estradiol by sex and morbid obesity.

Objective: Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol.Design: Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 +/- 7 years) premenopausal women (n = 32) and men (n = 30), with normal weight and obesity (BMI > 30 kg/m(2)).Methods: SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritiumlabeled hormones.Results: Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI > 40 kg/m(2)) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels was constant for testosterone, but not for estradiol. The influence of gender was maximal in morbid obesity, with men showing the highest binding/SHBG ratios.Conclusions: The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender and showing different structure, affinities for testosterone and estradiol and also different immunoreactivity

Balanç energètic i nitrogenat en l'obesitat genètica i nutricional de la rata

[cat] El treball consisteix en la realització del balanç energètic global i també del balanç nitrogenat, en diferents models d'obesitat. En relació al balanç de nitrogen s'ha utilitzat un enfoc nou, de manera que s'han analitzat tots els components, és a dir, la ingesta, les excretes, per orina i femta, i també el dipositat en l'animal. També s'ha realitzat, utilitzant el mateix plantejament, un balanç detallat de cada un dels diferents aminoàcids. Aquests balanços s'han portat a terme en dos models d'obesitat, per un costat s'estudiat l'obesitat induïda per la dieta, mitjançant la administració d'una dieta hipercalòrica, com és la dieta anomenada "de cafeteria" i que consisteix en oferir a l'animal una varietat d'aliments atraients (dels consumits normalment per l'home), que són en general rics en greixos i glúcids. Per altra banda, s'estudiat l'obesitat de tipus genètic, utilitzant-se la rata de la soca Zucker (fa/fa), caracteritzada per presentar una obesitat que es transmet per herència autosòmica receciva, i a més és una obesitat amb caracteristiques metabòliques similars a l'obesitat humana. També s'ha utilitzat la rata Wistar com a referència atès que ha estat ampliament descrita. Pel que fa a l'estudi del balanç energètic, s'observa que l'administració de una dieta "de cafeteria" comporta un increment en l'acumulació de lípids i també, encara que menys important, de proteïnes. Aquesta alta eficiència en la deposició de greix és predominant en la rata obesa fa/fa i màxima quan està sotmesa a dieta "de cafeteria", mostrant un efecte aditiu. Pel que fa a la eficiència de deposició de proteïnes s'observa que és més alta per aquells grups de rates tractades amb dieta "de cafeteria". Cal destacar, que en cap cas la rata obesa fa/fa mostra una menor eficiència de deposició de proteïnes, contrariament al descrit. En l'estudi del balanç de nitrogen, s'observa que en l'obesitat induïda per la dieta "de cafeteria", en la soca Wistar i també en el fenotip prim de la soca Zucker, la ingesta de nitrogen és més baixa, però en canvi la retenció és similar. Això sembla donar-se gràcies a una absorció de N a nivell intestinal més eficient, perquè es recupera menys N en femta que en els animals amb dieta control (pinso per a rates). També es troba una disminució de l'utilització del N que ha estat absorbit, excretan-se menys nitrogen i menys urea per orina. Aquest comportament no s'observa pel que fa a l'obesitat de la rata fa/fa, ja que aquest animal mostra una menor eficiència en la retenció del N, de manera que presenta una ingesta i unes pèrdues de N, tant en femta com en orina, més elevades que els animals prims, tot i que en valor absoluts el N retingut en el cos es igual al dels animals prims. Quan la rata fa/fa es sotmet a dieta "de cafeteria" mostra un comportament similar a les rates primes, es a dir, redueix la ingesta de nitrogen, però incrementa l'eficiència d'absorció intestinal, excretan-se menys proporció de N en femta, alhora que també redueix el catabolisme nitrogenat, excretant menys N i urea en orina, augmentant doncs la proporció de N ingerit que és retingut en el cos de l'animal. Cal destacar de l'estudi del balanç de N que en tots els casos es troba una proporció de N ingerit que no és recuperat en cap de les fraccions estudiades. Errors metodològics (sobre-estimació de la ingesta, pèrdues de pel, pèrdues de NH+(4) pels pulmons) no poden explicar la quantitat de N no trobat, que representa d'un 10% a un 27% del N ingerit en controls i "cafeteria" respectivament. En diverses ocasions s'ha plantejat la possibilitat de producció de nitrogen gas, en aquest sentit, es descriu que en l'home i el ratolí es produeix un alliberament de N(2) que pot representar fins un 10% del N de la ingesta, i a més, sembla que la producció estigui correlacionada amb la quantitat de proteïna present a la dieta. Quant a l'estudi del balanç d'aminoàcids, es ratifiquen els trets generals observats en el balanç global de N, de manera que les rates sotmeses a dieta "de cafeteria" tenen una més gran eficiència d'absorció, eliminant-se menys aminoàcids per la femta i mostrant una retenció més elevada. Aquest és un fet que s'observa en general per tots els aminoàcids, tant essencials com no essencials, tot i que les taxes d'absorció dels diferents aminoàcids no és uniforme, fet que pot estar relacionat per canvis en els sistemes de transport intestinals induïts per la dieta. Amb l'estudi del balanç detallat de cada aminoàcids s'ha pogut observar que les rates alimentades amb dieta "de cafeteria" seleccionen una dieta que finalment mostra el mateix patró d'aminoàcids que la dieta control, fet que evidencia la capacitat d'aquest animal per controlar d'una manera molt precisa la seva ingesta proteica. Això s'observa en els tres tipus de rates estudiades, incloent-hi la rata Zucker obesa (fa/fa), malgrat presentar un control energètic global alterat. També es pot afirmar que la dieta "de cafeteria" aporta una proporció d'aminoàcids adequada, i no és deficient en aquest sentit, tal i com s'ha suggerit en algunes ocasions. Per la composición de la dieta consumida pels animals, comparant control i "cafeteria", suggerim que el millor aprofitament de la proteïna que es dóna en la dieta "de cafeteria" pot ser causat per la més gran proporció de greix que aquesta conté. Fent referència a la deposició dels diferents aminoàcids en el cos de l'animal, s'observa que la dieta de cafeteria no afecta a una acreció diferencial d'aminoàcids, però sí que afecta a la velocitat de creixement, promovent un increment d'aquest en tots els tipus de rates. Per altra banda, s'observen diferencies de soca, de manera que la rata Zucker prima para de créixer abans que la rata Wistar. Pel que fa a la rata obesa, segueix creixent durant més temps que les rates controls primes, mantenint durant tot el periode estudiat una taxa d'acreció proteica elevada, fet que pot indicar una alteració en el senyal d'atur del creixement. També s'ha estudiat els nivells dels aminoàcids plasmàtics, aixr com d'altres paràmetres plasmàtics com urea, glucosa, proteïnes i N(o)-amínic, per tal de copsar quina és la disponibilitat dels aminoàcids pels diferents teixits, així com la seva metabolització. En aquest sentit es troba que la dieta "de cafeteria" incrementa en general el nivell dels aminoàcids plasmàtics en la rata prima, però contrariament disminueixen en la rata obesa sotmesa a aquesta dieta, fet que es podria relacionar amb unes pèrdues per orina d'aminoàcids més elevades, indicant una possible alteración de la filtració a nivell renal. En els grups de rates tractades amb dieta control no s'obseven en general diferencies entre els nivells plasmàtics dels diferents aminoàcids entre rates primes i obeses, a excepció dels aminoàcids de cadena ramificada que mostren uns nivells significativamente més elevats en les rates obeses, tret possiblement relacionat amb la resistència a la insulina present en aquests animals. En tots els casos l'urea plasmàtica disminueix amb la dieta "de cafeteria", mentre que els nivells de glucosa incrementen. S'observa també un comportament diferent pel que fa a l'excreció d'aminoàcids per orina, de manera que en les rates de la soca Zucker els nivells d'aminoàcids en orina són més elevats per la dieta "de cafeteria", contrariament al que passa amb la soca Wistar. El patró d'aminoàcids en orina no és diferent en els casos de la rata prima i obesa, excepte per la Hyp que no es troba en l'orina de la rata obesa amb dieta control.[eng] The carcass accretion of lipid, protein and carbohydrate was measured in Wistar, Zucker lean and Zucker obese rats fed a controlled standard or "cafeteria" diets from days 30 to 60 after birth. In all, groups the cafeteria· diet induced a higher carcass energy deposition than the reference diet. Obese Zucker rats deposited larger amounts of lipids than other animals studied, the effect of cafeteria-diet in these animals were partly' additive. In all groups, cafeteria-feeding induced a relative increase in fat deposition as well as increases in gross weight and protein. The nitrogen balance of Wistar and Zucker rats (Iean and obese) fed reference and cafeteria diets also has been determined by measuring the intake, fecal and urinary excretion and nitrogen deposition in the body. Obese Zucker rats showed a lower proportion of dietary nitrogen absorption and body nitrogen retention than lean rats. Cafeteria-diet increased the retention of dietary nitrogen and lowered urinary nitrogen losses in both obese and lean rats. The accurate measurement of nitrogen intake, excretion and deposition showed a consistent proportion of nitrogen unaccounted for (10-26% of net intake) in the studied fractions, which proportion was higher in the cafeteria diet-fed rats. The individual amino acid balance also has been determined with the same experimental set up. All rats cafeteria-feeding had a higher dietary protein digestion/absorption efficiency for all amino acids in general and had a grew faster than reference diet-feeding rats. The obese rats wasted a high proportion of dietary amino acids when given reference-diet, but not on the cafeteria-diet. Cafeteria feeding results in an essentially equal amino acid intake to that from the reference diet. In general the urinary losses of amino acids were small. Cafeteria-diet induced an increase of plasma amino acids levels in lean rats, but not effect was found in obese rats

Carta de Montserrat Esteve Ràfols al Rector de la UB interposant reclamació contra actuació en la convocatòria de plaça de Professor Titular de Fisiologia Animal

Relacionat amb 22-022, 22-023, 22-025, 22-026, 22-027 i 22-028