This study evaluated the effect of green tea extract and metformin and its interaction on markers of oxidative stress and inflammation in overweight women with insulin resistance. After screening, 120 women were randomly allocated in 4 groups: Placebo (PC): 1g of microcrystalline cellulose/day; Green tea (GT): 1 g (558 mg polyphenols) of standardized dry extract of green tea/day and 1 g of placebo/day; Metformin (MF): 1 g of metformin/day and 1 g of placebo/day; Green Tea and Metformin (GTMF): 1 g (558 mg polyphenols) and 1 g of metformin/day. All groups were followed-up for 12 weeks with assessment of oxidative damage to lipids and proteins, specific activity of antioxidant enzymes and inflammatory cytokine serum levels. The association of green tea with metformin significantly reduced IL-6 (GTMF: –29.7((–62.6)–20.2))(p = 0.004). Green tea and metformin isolated reduced TNF-α (GT: –12.1((–18.0)–(–3.5)); MF: –24.5((–38.60)–(–4.4)) compared to placebo (PB: 13.8 (1.2–29.2))(P < 0.001). Also, isolated metformin reduced TGF-β (MF: –25.1((–64.4)–0.04)) in comparison to placebo (PB: 6.3((–1.0)–16.3))(p = 0.038). However, when combined, their effects were nullified either for TNF-α (GTMF: 6.0((–5.7)–23.9) and for TGF-β (GTMF: –1.8((–32.1)–8.5). This study showed that there is a drug-nutrient interaction between green tea and metformin that is dependent on the cytokine analyzed.

Aging is the most prominent risk factor for many diseases, which is considered to be a complicated biological process. The rate of aging depends on the effectiveness of important mechanisms such as the protection of DNA from free radicals, which protects the structural and functional integrity of cells and tissues. In any organism, not all organs may age at the same rate. Slowing down primary aging and reaching maximum lifespan is the most basic necessity. In this process, it may be possible to slow down or stabilise some diseases by using the compounds for both dietary and pharmacological purposes. Natural compounds with antioxidant and anti-inflammatory effects, mostly plant-based nutraceuticals, are preferred in the treatment of age-related chronic diseases and can also be used for other diseases. An increasing number of long-term studies on synthetic and natural compounds aim to elucidate preclinically and clinically the mechanisms underlying being healthy and prolongation of life. To delay age-related diseases and prolong the lifespan, it is necessary to take these compounds with diet or pharmaceuticals, along with detailed toxicological results. In this review, the most promising and utilised compounds will be highlighted and it will be discussed whether they have toxic effects in short/long-term use, although they are thought to be used safely.

Polycystic ovary syndrome (PCOS) is a complex disorder in which the aetiology is still not explained very well. The PI3K/PTEN (phosphatidylinositol 3-kinase/phosphatase and tensin homolog deleted on chromosome 10) pathway is an important pathway that is involved in many mechanisms, including proliferation, growth and motility. PTEN plays a role in granulosa cell proliferation and regulates the differentiation process. The aim of this study was to investigate the expression levels of Pten and Pik3ca in PCOS mouse models with and without any treatment procedures. Three groups of mouse models, PCOS, a PCOS group with clomiphene citrate treatment, and a PCOS group with the combination of clomiphene citrate, metformin and pioglitazone treatment, were established. Ovarian tissues, which were obtained from these groups and a control group with no PCOS, were embedded in paraffin and RNA was extracted. cDNA was synthesized and real-time PCR was conducted to evaluate the expression levels of Pten and Pik3ca. The results of this study showed that both Pten and Pik3ca genes were expressed in the ovarian tissues from the mouse models. Although one-way analysis of variance results showed that Pten was expressed significantly differently in the samples, individual Student’s t-tests did not show any significantly different expression levels in each group. This study is important as it shows the expression patterns of two genes in PCOS mouse models with different treatment strategies, including clomiphene citrate, metformin and pioglitazone. The results of this study formed the basis of research studies and investigations into different genes within the PTEN pathway, as well as other pathways that are under investigation.

Alveolar echinococcosis (AE) is a severe disease caused by Echinococcus multilocularis. Its chemotherapeutic treatment is based on benzimidazoles, which are rarely curative and cause several adverse effects. Therefore, it is necessary to develop alternative and safer chemotherapeutic strategies against AE. It has previously been shown that metformin (Met) exhibits considerable in vivo activity on an early-infection model of AE when administered at 50 mg kg−1 day−1 for 8 weeks. Here, the challenge is heightened by a 2-fold increase in parasite inoculum or by starting the treatment 6 weeks post-infection. In both cases, only the combination of Met (100 mg kg−1 day−1) together with a sub-optimal dose of albendazole (ABZ) (5 mg kg−1 day−1) led to a significant reduction in parasite weight compared to the untreated group. Coincidentally, drug combination showed the highest level of damage in E. multilocularis metacestodes. Likewise, Met alone or combined with ABZ led to a decrease in parasite glucose availability, which was evidenced as a lower intracystic glucose concentration. Therefore, the results demonstrate that combination therapy with Met and ABZ offers an alternative to improve the efficacy and reduce the toxicity of the high-dose ABZ monotherapy currently employed.

Metformin is widely used in pregnancy, despite lack of long-term safety for children. We hypothesised that metformin exposure in utero is associated with increased cardiovascular risk. We tested this hypothesis in a follow-up study of children born to obese mothers who had participated in a randomised controlled trial of metformin versus placebo in pregnancy (EMPOWaR). We measured body composition, peripheral blood pressure (BP), arterial pulse wave velocity and central haemodynamics (central BP and augmentation index) using an oscillometric device in 40 children of mean (SD) age 5.78 (0.93) years, exposed to metformin (n = 19) or placebo (n = 21) in utero. There were no differences in any of the anthropometric or vascular measures between metformin and placebo-exposed groups in univariate analyses, or after adjustment for potential confounders including the child’s behaviour, diet and activity levels. Post-hoc sample size calculation indicated we would have detected large clinically significant differences between the groups but would need an unfeasible large number to detect possible subtle differences in key cardiovascular risk parameters in children at this age of follow-up. Our findings suggest no evidence of increased cardiovascular risk in children born to obese mothers who took metformin in pregnancy and increase available knowledge of the long-term safety of metformin on childhood outcomes.

Ficus deltoidea var. deltoidea Jack (FD) is a well-known plant used in Malay folklore medicine to lower blood glucose in diabetic patients. For further research of the antihyperglycemic mechanisms, the protein tyrosine phosphatase 1B (PTP1B)-inhibitory effect of FD was analysed both in vitro and in vivo. To optimise a method for FD extraction, water, 50, 70, 80, 90 and 95 % ethanol extracts were prepared and determined for their total phenolic and triterpene contents, and PTP1B-inhibition capacity. Among the tested extracts, 70 % ethanol FD extract showed a significant PTP1B inhibition (92·0 % inhibition at 200 µg/ml) and high phenolic and triterpene contents. A bioassay-guided fractionation of the 70 % ethanol extract led to the isolation of a new triterpene (3β,11β-dihydroxyolean-12-en-23-oic acid; F3) along with six known compounds. In vivo, 4 weeks’ administration of 70 % ethanol FD extract (125, 250 and 500 mg/kg/d) to streptozotocin–nicotinamide-induced type 2 diabetic rats reversed the abnormal changes of blood glucose, insulin, total Hb, GLUT2, lipid profile, and oxidative stress in liver and pancreas. Moreover, FD reduced the mRNA expression of the key gluconeogenic enzymes (phosphoenolpyruvate carboxykinase and glucose 6-phosphatase) and restored insulin receptor and GLUT2 encoding gene (Slc2a2) expression. In addition, FD significantly down-regulated the hepatic PTP1B gene expression. These results revealed that FD could potentially improve insulin sensitivity, suppress hepatic glucose output and enhance glucose uptake in type 2 diabetes mellitus through down-regulation of PTP1B. Together, our findings give scientific evidence for the traditional use of FD as an antidiabetic agent.

Dietary restriction (DR) has been shown to extend both median and maximum lifespan in a range of animals, although recent findings suggest that these effects are not universally enjoyed across all animals. In particular, the lifespan effect following DR in mice is highly strain-specific and there is little current evidence that DR induces a positive effect on all-cause mortality in non-human primates. However, the positive effects of DR on health appear to be highly conserved across the vast majority of species, including human subjects. Despite these effects on health, it is highly unlikely that DR will become a realistic or popular life choice for most human subjects given the level of restraint required. Consequently significant research is focusing on identifying compounds that will bestow the benefits of DR without the obligation to adhere to stringent reductions in daily food intake. Several such compounds, including rapamycin, metformin and resveratrol, have been identified as potential DR mimetics. Although these compounds show significant promise, there is a need to properly understand the mechanisms through which these drugs act. This review will discuss the importance in understanding the role that genetic background and heterogeneity play in mediating the lifespan and healthspan effects of DR. It will also provide an overview of the most promising current DR mimetics and their effects on healthy lifespan.

Studies on bovine oocytes have revealed that the activation of adenosine monophosphate activated protein kinase (AMPK) by millimolar concentrations of metformin controls nuclear maturation. Tuberous sclerosis complex 2 (TSC2) has been identified as a downstream target of AMPK. The objective of this study was to investigate the effects of addition of low concentrations of metformin (1 nM to 10 μM) on the percentage of cultured cumulus–oocyte complexes (COC) giving rise to cleavage-stage embryos and AMPK-mediated TSC2 activation. Metformin was supplemented either throughout in vitro embryo production (IVP) or only during in vitro fertilization (IVF). COC were matured in vitro, inseminated, and presumptive zygotes cultured for a further 72 h post insemination before the percentage of COC that gave rise to zygotes and early embryo development was assessed. The presence of TSC2 in bovine embryos and its possible AMPK-induced activation were assessed by immunocytochemistry. Metformin had a dose-dependent effect on the numbers of cultured COC that gave rise to embryos. Drug treatment either throughout IVP or only during IVF decreased the percentage of ≥8-cell embryos (1 μM, P < 0.05; 10 μM, P < 0.01; and 0.1 μM, 10 μM, P < 0.01, respectively) and increased the percentage of 2-cell embryos (10 μM, P < 0.01 and P < 0.05 respectively). The percentage of cultured COC that gave rise to zygotes was not affected by metformin. TSC2 is expressed in early embryos. Metformin (10 μM) either throughout IVP or during IVF only, increased AMPK-induced PhosphoS1387-TSC2 immunoreactivity (P < 0.01) and this increase corresponded to the total TSC2 protein levels expressed in cells. Our results suggest that there is a dose-dependent negative effect of metformin on the ability of oocytes to cleave following insemination, possibly mediated through an AMPK-induced activation of TSC2.

The adenosine monophosphate-activated protein kinase (AMPK) activators 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) and metformin (MET) inhibit resumption of meiosis in porcine cumulus-enclosed oocytes. The objective of this study was to characterize the inhibitory effect of MET on porcine oocyte meiosis by: (1) determining the effects of an AMPK inhibitor and of inhibitors of signalling pathways involved in MET-induced AMPK activation in other cell types on MET-mediated meiotic arrest in porcine cumulus-enclosed oocytes; (2) determining whether MET and AICAR treatments lead to increased activation of porcine oocyte and/or cumulus cell AMPK as measured by phosphorylation of its substrate acetyl-CoA carboxylase; and (3) determining the effects of inhibition of the AMPK kinase, Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), and Ca2+ chelation on oocyte meiotic maturation and AMPK activation in porcine oocytes and cumulus cells. The AMPK inhibitor compound C (CC; 1 μM) did not reverse the inhibitory effect of AICAR (1 mM) and MET (2 mM) on porcine oocyte meiosis. Additionally, CC had a significant inhibitory effect on its own. eNOS, c-Src and PI-3 kinase pathway inhibitors did not reverse the effect of metformin on porcine oocyte meiosis. The level of acetyl-CoA carboxylase (ACC) phosphorylation in oocytes and cumulus cells did not change in response to culture in the presence of MET, AICAR, CC, the CaMKK inhibitor STO-609 or the Ca2+ chelator BAPTA-AM for 3 h, but STO-609 increased the percentage of porcine cumulus-enclosed oocytes (CEO) that remained at the germinal vesicle (GV) stage after 24 h of culture. These results indicate that the inhibitory effect of MET and AICAR on porcine oocyte meiosis was probably not mediated through activation of AMPK.

Despite decades of research in the field of Alzheimer's disease (AD), a real understanding of its molecular pathophysiology and treatments relevant to the day-to-day lives of patients remain out of reach. Research has, with good reason, focused on certain key pathways and potential mechanisms, but sometimes this has been at the expense of work on other theories, which may be slowing down progress in this field. Interesting theories at present include oxidative stress and caloric restriction. Work on the Aβ cascade should continue but with a shift in focus to its intracellular effects and an awareness that additional pathogenetic factors and processes must be involved – most importantly, brain aging. Hyperphosphorylation of tau, for instance, provides another interesting pathway, with one old drug showing promise in this regard. Moreover, work in epigenetics and on protein homeostasis has produced interesting findings and both lines of investigation may reveal suitable targets for future intervention. Taken together, analysis of the biochemistry of aged neurons and the interplay with pathways of neurodegeneration may lead to a better understanding of AD and how to treat and prevent this condition.