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dietary supplementation of aged mice with the probiotic bacterium Lactobacillus reuteri makes them appear to be younger than their matched untreated sibling mice

These results indicate that gut microbiota induce modulation of local gastrointestinal immunity resulting in systemic effects on the immune system which activate metabolic pathways that restore tissue homeostasis and overall health

all these studies we consistently observed that young and aged mice consuming purified L. reuteri organisms had particularly large testes and a dominant male behavior.

The testes of probiotic-fed aged mice were rescued from both seminiferous tubule atrophy and interstitial Leydig cell area reduction typical of the normal aging process. Preservation of testicular architecture despite advanced age or high-fat diet coincided with remarkably high levels of circulating testosterone. The beneficial effects of probiotic consumption were recapitulated by the depletion of the pro-inflammatory cytokine Il-17.

feeding of L. reuteri consistently increased the gonadal weights, consumption of a non-pathogenic strain of Escherichia coli (E. coli) K12 organisms did not affect testicular weight

mice with dietary L. reuteri supplements were rescued from diet-induced obesity and had normal body weight and lean physique

Despite the comparable numbers of ST profiles, we determined that testes from L. reuteri-treated mice had increased ST cross-sectioned profiles

the probiotic organism induced prominent Leydig cell accumulations in the interstitial tissue between the ST's

The probiotic-associated increase of interstitial Leydig cell areas was sustained with advancing age at 7 (CD vs CD+LR, P = 0.0025; CD+E.coli vs CD+LR, P = 0.0251) and 12 months

mice eating L. reuteri had profoundly increased levels of circulating testosterone regardless of the type of diet they consumed

blocking pro-inflammatory Il-17 signaling entirely recapitulates the beneficial effects of probiotics

previous studies we found that dietary probiotics counteract obesity [19] and age-related integumentary pathology [18] at least in part by down-regulating systemic pro-inflammatory IL-17A-dependent signaling

Testes histomorphometry and serum androgen concentration data were both suggestive of a probiotic-associated up-regulation of spermatogenesis in mice

Lactobacillus reuteri we discovered that aging male animals had larger testes compared to their age-matched controls

xamined testes of probiotic microbe-fed mice and found that they had less testicular atrophy coinciding with higher levels of circulating testosterone compared to their age-matched controls

Similar testicular health benefits were produced using systemic depletion of the pro-inflammatory cytokine Il-17 alone, implicating a chronic inflammatory pathway in hypogonadism

One specific aspect of this paradigm is reciprocal activities of pro-inflammatory Th-17 and anti-inflammatory Treg cells

Feeding of L. reuteri organisms was previously shown to up-regulate IL-10 levels and reduce levels of IL-17 [19] serving to lower systemic inflammation

insufficient levels of IL-10 may increase the risk for autoimmunity, obesity, and other inflammatory disease syndromes

Westernized diets are also low in vitamin D, a nutrient that when present normally works together with IL-10 to protect against inflammatory disorders

Physiological feedback loops apparently exist between microbes, host hormones, and immunity

The hormone testosterone has been shown to act directly through androgen receptors on CD4+ cells to increase IL-10 expression

studies in both humans and rodents suggest that hypogonadism is due to age-related lesions in testes rather than irregular LH metabolism

We postulate that probiotic gut microbes function symbiotically with their mammalian hosts to impart immune homeostasis to maintain systemic and testicular health [34]–[35] despite suboptimal dietary conditions.

Dietary factors and diet-induced obesity were previously shown to increase risk for age-associated male hypogonadism, reduced spermatogenesis, and low testosterone production in both humans and mice [2]–[4], [8]–[11], [14]–[17], phenotypic features that in this study were inhibited by oral probiotic therapy absent milk sugars, extra protein, or vitamin D supplied in yogurt.

Similar beneficial effects of probiotic microbes on testosterone levels and sperm indices were reported in male mice that had been simultaneously supplemented with selenium

L. reuteri-associated prevention of age- and diet-related testicular atrophy correlates with increased numbers and size of Leydig cells

the initial changes of testicular atrophy begin to occur in mice from the age of 6 moths onwards [7] and indicates that the trophic effect of L. reuteri on Leydig cells is a key event which precedes and prevents age-related changes in the testes of mice. This effect is reminiscent of earlier studies describing Leydig cell hyperplasia and/or hypertrophy in the mouse and the rat testis that were achievable by the administration of gonadotropins, including human chorionic gonadotropin, FSH and LH

chemosensitizing

pharmacological concentrations of AA can sensitize cancer cells to chemotherapy, enhancing its antineoplastic effect

synergistic effect with conventional chemotherapeutic drugs is a fact already reported, in various types of cancer, by numerous authors, namely in pancreatic (Espey et al., 2011), prostate (Gilloteaux et al., 2014), lung (Lee et al., 2017), breast (Kurbacher et al., 1996; Wu et al., 2017) and ovarian (Ma et al., 2014) cancers.

chemosensitizing effect of vitamin C has already been proven by several authors in various types of cancer

intravenous pharmacological concentrations, may not only potentiate the effects of conventional chemotherapy, but also improve the quality of life of cancer patients

AA reinforced the anti-proliferative activity of 5-FU

Combined treatment induced a reduction of 11.5% and 43% in cell viability compared with AA or Iri therapies, respectively, emphasizing the synergistic effect

cytotoxic effect occurred with treatment with Iri alone, but also this effect was further potentiated by the presence of AA.

association of AA with Oxa showed very promising results, considering that a synergistic effect was demonstrated, in almost all conditions

AA and Oxa seem to act synergistically by the activation of the intrinsic pathway of apoptosis, translated on the statistically significant increase of the ratio between BAX and BCL-2 proteins, which in turn is associated with a decrease of Δψm

Previous results obtained by our group showed that AA mediates reactive oxygen species (ROS) formation capable of irreparably damaging DNA

oxidative role of AA may be a key factor on the synergistic anti-cancer mechanism