Tamoxifen acts as an oestrogen antagonist in the breast reducing cell proliferation, but in the uterus as an oestrogen agonist resulting in increased cell proliferation. Tamoxifen exerts its tissue-specific effects through the oestrogen receptors (ER or ER ). The levels and functions of the two ERs affect the response of the target tissue to oestrogen and tamoxifen. We examined the control of ER stability in breast and uterine cell lines using western blotting and RT-PCR. In MCF-7 breast-derived cells, ER and ER proteins were rapidly degraded via the proteasome pathway in response to oestradiol; conversely tamoxifen stabilised both receptors. In Ishikawa uterine-derived cells, oestradiol and tamoxifen stabilised ER but led to degradation of ER by the proteasome pathway. Further investigations showed that oestradiol induced activation of the non-genomic ER /Akt signalling pathway in MCF-7 cells. We have demonstrated that the alternative Erk signalling pathway is activated in Ishikawa cells following oestradiol treatment in the absence of an active proteasome pathway and therefore increased levels of ER . In conclusion, our data have demonstrated tamoxifen or oestradiol control of ER subtype stability and that non-genomic activation of transcription pathways is cell specific.

Diarylpropionitrile (DPN) is an estrogen receptor-β-specific agonist that has been linked to neuroprotection, preserving cognitive function with age, the suppression of anxiety-like behaviors, inhibition of cancer growth, and other positive properties. We hypothesized that DPN may have pro-longevity properties. DPN was administered via feed at a dose corresponding to approximately 3 mg/kg/day to ovariectomized female mice beginning at 7 months of age. Mice were followed for the duration of their lifespans while monitoring body mass, aspects of behavior, learning, memory, and frailty. DPN-treated mice gained more body mass over the first 2 years of age (17 months of the study). A test of voluntary running behavior at 24 months of age behavior revealed no deficits in DPN-treated mice, which were as likely as control mice to engage in extended bouts of wheel running, and did so at higher average speeds. DPN administration had anxiolytic-like effects when measured using an elevated plus maze at 9 months of age. A mouse frailty index was used to assess age-related changes. The correlation between age and frailty differed between control and DPN-treated mice. Overall, dietary DPN administration had some beneficial effects on the aging phenotype of ovariectomized female mice with few significant detrimental effects.

Background: Branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) are essential amino acids involved in immune responses, and may have roles in protein malnutrition and sarcopenia. Furthermore, certain liver diseases have been associated with a decreased Fischer’s ratio (BCAAs to aromatic amino acids; phenylalanine, tyrosine, and tryptophan). We aimed to evaluate the safety and efficacy of BCAAs use in patients with cancer undergoing surgery. Methods: MEDLINE, Embase, and CENTRAL were searched (inception to July 24, 2020) for randomized controlled trials (RCTs) and comparative observational studies in English evaluating BCAAs (alone or in combinations) during the oncological peri-operative period. Study selection, data extraction, and quality appraisal were done in duplicate. RCT risk-of-bias was appraised using Cochrane Risk-of-Bias tool, and observational studies’ quality assessment was conducted with Newcastle-Ottawa Scale. Meta-analyses were conducted when appropriate. Results: 20 articles were included comprising 13 RCTs and 6 observational cohort studies in 7 reports and 2019 total participants overall. Among 13 RCTs, 77% involved liver cancer. Methodological study quality scored substantial risk-of-bias across most RCTs. Meta-analysis of RCTs found a 38% decreased risk of post-operative infections in BCAAs group compared to controls (RR = 0.62; 95% CI = 0.44 to 0.87; P = .006; number of RCTs, k = 6; total sample size, N = 389; I2 = 0%). BCAAs were also found to be beneficial for ascites (RR = 0.55; 95% CI = 0.35 to 0.86; P = .008; k = 4; N = 296; I2 = 0%), body weight (MD = 3.24 kg; 95% CI = 0.44 to 6.04; P = .02; k = 3; N = 196; I2 = 24%), and hospitalization length (MD = −2.07 days; 95% CI = −3.97 to −0.17; P = .03; k = 5; N = 362; I2 = 59%). No differences were found between BCAAs and controls for mortality, recurrence, other post-operative complications (liver failure, edema, pleural effusion), blood loss, quality of life, ammonia level, and prothrombin time. No serious adverse events were related to BCAAs; however, serious adverse events were reported due to intravenous catheters. No safety concerns from observational studies were identified. Conclusions: Branched-chain amino acids during the oncological surgical period demonstrated promise in reducing important post-operative morbidity from infections and ascites compared to controls. Blinded, placebo-controlled confirmatory trials of higher methodological quality are warranted, especially using oral, short-term BCAAs-enriched supplements within the context of recent ERAS programs. PROSPERO registration: CRD42018086168.

Background: Objectives were to evaluate probiotics safety and efficacy in oncological surgery. Methods: Systematic review methodology guided by Cochrane, PRISMA, SWiM, and CIOMS. Protocol registered on PROSPERO (CRD42018086168). Results: 36 RCTs (on 3305 participants) and 6 nonrandomized/observational studies were included, mainly on digestive system cancers. There was evidence of a beneficial effect on preventing infections, with 70% of RCTs’ (21/30) direction of effect favoring probiotics. However, five RCTs (17%) favored controls for infections, including one trial with RR 1.57 (95% CI: 0.79, 3.12). One RCT that changed (balanced) its antibiotics protocol after enrolling some participants had mortality risk RR 3.55 (95% CI: 0.77, 16.47; 7/64 vs. 2/65 deaths). The RCT identified with the most promising results overall administered an oral formulation of Lactobacillus acidophilus LA-5 + Lactobacillus plantarum + Bifidobacterium lactis BB-12 + Saccharomyces boulardii. Methodological quality appraisals revealed an overall substantial risk-of-bias, with only five RCTs judged as low risk-of-bias. Conclusions: This large evidence synthesis found encouraging results from most formulations, though this was contrasted by potential harms from a few others, thus validating the literature that “probiotics” are not homogeneous microorganisms. Given microbiome developments and infections morbidity, further high-quality research is warranted using those promising probiotics identified herein.

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