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Research Project
White tea WTEA as a promising agent against sufertility/infetility promoted by diabetes mellitus: synesgistic or single component effect
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Effect of white tea on the reproductive function of diabetic or prediabetic individuals
Publication . Dias, Tânia Isabel Rodrigues Amaral; Oliveira, Pedro Fontes; Silva, Branca Maria Cardoso Monteiro da; Casal, Susana
The prevalence of diabetes mellitus (DM) has been increasing in young men worldwide. Patients
with DM have a dysfunction on insulin secretion and/or insulin action, resulting in
hyperglycemia. Insulin dysregulation affects glucose homeostasis in the body, having a
deleterious impact on male fertility. Sertoli cells (SCs) are essential for the maintenance of
male reproductive potential as they provide the physical and nutritional support that allows
the differentiation of germ cells into fully competent spermatozoa. SCs function highly relies
on glucose metabolism, which is their preferred substrate. Many diabetic patients are subfertile
or infertile due to altered SCs function, impaired spermatogenesis and poor sperm quality. The
primary strategy to counteract DM and its complications includes nutritional changes and
physical activity. However, these interventions are usually unsuccessful alone and need to be
complemented with medication. Still, the efficacy of conventional drugs is limited, they are
expensive and have several secondary effects. In recent years, natural products, including tea
and its components, demonstrated promising antioxidant and antidiabetic properties. Besides,
the treatment of prediabetes can be an effective approach as it can occur up to 10 years before
the progression of the disease to a more severe state. In this research project, we aimed to
unravel the effects of white tea (WTEA) on male reproductive function and its protective role
against reproductive dysfunctions induced by prediabetes. Further, we aimed to investigate if
the effects of WTEA are due to a combined effect of all WTEA components or to a predominant
effect of one of its most bioactive components. WTEA is the rarest and less studied type of tea,
but it presents a potent antioxidant potential due to its high catechin content. Through proton
nuclear magnetic resonance (1H-NMR), we verified that this type of tea is particularly rich in
caffeine, epigallocatechin gallate (EGCG) and L-theanine. Using an in vitro model of rat SCs or
human SCs (hSCs) we evaluated the effects of WTEA extract (0.5 mg/mL) and its main bioactive
compounds (caffeine, EGCG and L-theanine) on cells metabolism, mitochondrial functionality
and oxidative profile. WTEA extract modulated rat SCs metabolism and stimulated the
production of lactate, which is essential for germ cells survival. Supplementation of hSCs
culture media with 50 μM of caffeine, EGCG, or L-theanine for 24 hours induced alterations in
hSCs metabolism that are important for the improvement of male reproductive potential. It
resulted in an increase or maintenance of lactate production, showing a protective role against
oxidative damages. However, at 50 μM, these compounds also induced some alterations in hSCs
proliferation and mitochondrial functionality that may compromise hSCs function. The WTEA
extract (0.5 mg/mL) showed a better improvement on SCs, highlighting the importance of the
combined effect of all the tea components for its beneficial effect. We also conducted ex vivo
studies using rat epididymal spermatozoa to evaluate the potential of WTEA extract (0.5 mg/mL
or 1 mg/mL) and the three selected components as an additive for a sperm storage medium at
room temperature for short periods. In these studies, the concentrations of caffeine (71 μg/mL)
EGCG (82 μg/mL) and L-theanine (19 μg/mL), were selected based on their concentration in the WTEA extract. Sperm viability decreases over time in refrigerated samples, thus in certain
cases the short-term storage at room temperature can be advantageous, such as for samples
transport or assisted reproductive technology. These studies allowed us to conclude that the
WTEA extract (especially at 1 mg/mL) was a better additive to the sperm storage medium at
room temperature than each of the components alone, as it kept spermatozoa viability for 3
days equivalently to values obtained at the collection time. Although the combination of the
three selected components together showed a higher improvement in spermatozoa viability, it
also stimulated protein oxidation, supporting the beneficial combined effect of all the
components constituting the WTEA extract. This led us to study the in vivo effect of a regular
consumption of WTEA on the reproductive function of a rat model of prediabetes. The
prediabetic rats showed alterations in the testicular and epididymal metabolism, resulting in
poor sperm quality. WTEA ingestion by prediabetic rats for two months prevented many of the
metabolic dysfunctions induced by the disease in the testis and epididymis, resulting in the
improvement of sperm motility and viability. Our results indicate that WTEA regular
consumption can be a cost-effective strategy to improve prediabetes-induced reproductive
dysfunctions, paving the way for WTEA to be used for the development of new antioxidant
therapies for the improvement of male fertility.
8-(3-phenylpropyl)-1,3,7-triethylxanthine is a synthetic caffeine substitute with stronger metabolic modulator activity
Publication . Carrageta, David F; Dias, Tânia R.; Jarak, Ivana; Alves, Marco G; Oliveira, P.F.; Walt, Mietha Van Der; Terre'Blanche, Gisella; Monteiro, Mariana P.; Silva, Branca M.
Caffeine is one of the most worldwide consumed methylxanthines. It is well-known for its thermogenic and cell metabolism modulating effects. Based on methylxanthines' chemical structure, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (PTX) is a novel adenosine antagonist with higher receptor affinity than caffeine. Therefore, we hypothesized that PTX metabolic effects could be stronger than those of caffeine. For that purpose, murine 3T3-L1 cells were cultured in the presence of increasing doses of PTX or caffeine (0.1, 1, 10 and 100 μM) for 24 h. Cytotoxicity was evaluated by reduction of tetrazolium salt (MTT) and lactate dehydrogenase (LDH) release. Cell metabolites released to the culture medium were identified and quantified by proton nuclear magnetic resonance (1H NMR). Cellular oxidative profile was also evaluated. Our results showed that PTX displayed no signs of cytotoxicity at all studied concentrations. When compared with caffeine, PTX increased glucose, pyruvate, and glutamine consumption, as well as lactate, alanine, and acetate production. Additionally, PTX decreased protein oxidation, thus protecting against oxidative stress-induced damage. These results illustrate that PTX is a stronger and less cytotoxic caffeine substitute with potential applications as metabolic modulator and a good candidate for novel drug design.
Implications of epigallocatechin-3-gallate in cultured human Sertoli cells glycolytic and oxidative profile
Publication . Dias, Tânia R.; Alves, Marco G; Silva, Joaquina; Barros, Alberto; Sousa, Mário; Casal, Susana; Silva, Branca M.; Oliveira, Pedro F.
Sertoli cells are crucial for the success of spermatogenesis, which is the biological process that ensures male fertility. These cells present high metabolic rates, being often subjected to high oxidative stress levels that, if uncontrolled, may compromise male fertility. Since the most abundant tea catechin, epigallocatechin-3-gallate (EGCG), has demonstrated a potent preventive activity against oxidative stress, we have evaluated its effect at concentrations of 5 and 50μM, on the metabolism, mitochondrial functionality and oxidative profile of human Sertoli cells (hSCs). While, the highest concentration of EGCG (50μM) increased glucose and pyruvate consumption, it decreased the conversion of pyruvate to alanine to sustain a regular lactate production. However, despite maintaining Krebs cycle functionality, EGCG (50μM) decreased mitochondrial membrane potential of hSCs, which could compromise the normal rates of ATP production. Interestingly, oxidative damages to proteins and lipids decreased in this experimental group, which may be valuable for the nutritional support of spermatogenesis.
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Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
POR_NORTE
Funding Award Number
SFRH/BD/109284/2015