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modifications of hepatic Cyp8b1 expression and the subsequent alteration of bile acid metabolites

Expression and activity of major drug-metabolizing enzymes (Cyp3a11 and Cyp2c29) were also significantly stimulated

The gut microbiota (GM) exhibits a relatively low level of diversity compared to those of most soil ecosystems and in humans it is comprised of usually no more than nine phyla of microorganisms, of which only two are dominant: the Firmicutes and the Bacteroidetes

colonization of a germfree gut was rapid and remarkably stable, establishing within only a week after first exposure

a study conducted on germfree rats by Nicholls et al. showed that 3 weeks were necessary to obtain a stabilization and “normalization”

the microbiota status affects the systemic metabolism of the host, modulating the metabolic fingerprint of topographically remote organs such as the liver and the kidney

Gut colonization induces a rapid weight gain associated with stimulation of hepatic glycogenesis and triglyceride synthesis

Gut colonization alters bile acid metabolite profiles via modulation of hepatic Cyp8b1 expression

Bile acids are well-known contributors to glucose and lipid metabolism in the liver

GM is known to alter bile metabolism

GM is also known to exert a strong influence on the metabolism of xenobiotics

the amount of BCAAs supplied in the various studies is extremely variable

TK1 LI was found to be a more reliable prognostic marker for 5-year survival than pathological stages, FIGO stages and Ki-67,

nuclear TK1 expression is a reliable prognostic factor in CIN patients, a group of cervical lesion patients that respond positively to treatment

nuclear TK1 expression is correlated with advanced stage of invasive cervical carcinomas

a low TK1 LI can help to identify with a better survival

low TK1 expression in the tumors in these patients might indicate that these tumors have a lower proliferation rate

TK1 is a key kinase in the one-step salvage pathway by which thymidine is introduced into DNA via the salvage pathway

TK1 participates in DNA synthesis and is therefore closely related to the S-phase of the cell cycle, and is correlated with proliferation

TK1 intensity (TK1 synthesis rate) increases from CIN grade I to CIN grade III, but does not further increase in invasive cervical carcinomas.

TK1 intensity seems to be a prognostic factor particularly when pre-malignant cervical lesions progress to malignancy

In general, testosterone concentration is elevated directly following heavy resistance exercise in men

Findings on the testosterone response in women are equivocal with both increases and no changes observed in response to a bout of heavy resistance exercise

Age also significantly affects circulating testosterone concentrations.

Aging beyond 35-40 years is associated with a 1-3% decline per year in circulating testosterone concentration in men

aging results in a reduced acute testosterone response to resistance exercise in men.

In women, circulating testosterone concentration also gradually declines until menopause, after which a drastic reduction is found.

acute increases in testosterone can be induced by resistance exercise

testosterone is an important modulator of muscle mass in both men and women

the overall response of MPS is not maximized. Instead, the limited availability of EAA likely explains the qualitative difference in magnitude of the MPS response to ingestion of BCAAs alone and ingestion of similar amounts of BCAAs as part of intact whey protein

decreased EAA concentrations following leucine ingestion

these data support the notion that EAA availability is the rate-limiting factor for stimulating a maximal MPS response to resistance exercise with BCAA ingestion

We first investigated testosterone production after 24 and 48 h of ibuprofen exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent (β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time

The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early as 14 d of administration

Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group

Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection except in one experiment with DHEA

Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of steroidogenesis.

Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence, expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired

A previous study reported androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk

We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls

the changes in gene expression indicate that the transcriptional machinery behind the endocrine action of Leydig cells was most likely impaired by ibuprofen exposure.

Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription

ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH

The decrease in the free testosterone/LH ratio resulted primarily from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted from ibuprofen’s direct antiandrogenic action

AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis

ibuprofen displayed broad transcription-repression abilities involving steroidogenesis, peptide hormones, and prostaglandin synthesis

a chemical compound, through its effects on the signaling compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in the adult human

The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise response in muscles by repressing transcription

Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates (41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs

ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes in peritubular cells was also affected

short-term exposure

In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated hypogonadism (4), an entity associated with all-cause mortality

compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms

an inverse relationship was recently reported between endurance exercise training and male sexual libido

AMH concentrations are lower in seminal plasma from patients with azoospermia than from men with normal sperm levels

inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men

the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.

after administration of 600 mg of ibuprofen to healthy volunteers

14 d or at the last day of administration at 44 d