Sex-dependent differences in stress-induced depression in Wistar rats are accompanied predominantly by changes in phosphatidylcholines and sphingomyelins.

With a high annual and lifetime prevalence, depression is becoming the leading contributor to the global disease burden. During the COVID-19 crisis, the depression and mood disorders accelerated significantly. Despite the growing evidence, the precise underlying mechanisms of depression disorders (DD) remain unknown. When studying DD in humans, there are many uncontrollable factors such as medication history, age of the patient or living conditions. In this regard, animal models provide an essential step for examining neural circuitry or molecular and cellular pathways in a controlled environment. As far as we know, women have a consistently higher prevalence of DD than men. Thus, the aim of our study was to evaluate sex-related changes in blood metabolites in a model of stress-induced depression in Wistar rats. Pregnant females were stressed using restriction of mobility in the final week of the pregnancy three times a day for 45 minutes each, three following days. After the birth, the progeny aged 60 days was stressed repeatedly. The perturbation in overall energy metabolism as well as in lipid metabolism was found. While in males, phosphatidylcholines (the most phosphatidylcholine with acyl-alkyl residue sum C40:4 - PC ae C40:4), sphingomyelins, and acylcarnitines were changed, in females, lipid metabolism perturbation was seen with the most critical alteration in hydroxysphingomyelin with acyl residue sum C16:1 (SM OH C16:1). Our results confirm that the animal model may be used further in the research of depression. Our results may provide an essential insight into the sex-dependent pathogenesis of depression and contribute to the search for effective treatment and prevention of depression with respect to sex.

"Neural stem cells puzzle" missing piece: telomerase reverse transcriptase expression patterns during nervous system ontogenesis in rats.

For almost three decades, neural stem cells remain still up-to-date and enigmatic topic. The main problem for their studying is the non-existence of an exclusive neural stem cell marker and the heterogeneity of them across the nervous system. As one of the novel markers of neural stem/progenitor cells may serve telomerase reverse transcriptase (TERT), a catalytic subunit of the telomerase enzyme, responsible for retaining the cell immortality. Thus, the aim of our study was to reveal if TERT, as an enzyme for ensuring the immortality of proliferating cells, could be used as a potential marker of neural stem/progenitor cells during the ontogenesis of the rat central nervous system. In this study, we used various markers related to neural stem or progenitor cells character and examined their co-localization with TERT expression. Our experiments were performed on the tissue of the brain and spinal cord during several stages of postnatal development and the neural tube during the 14th embryonal day. Cytoplasmatic TERT expression was found in alar plate progenitors and ventral horn neuroblasts of E14 rats. In the postnatal stages of spinal cord ontogenesis, a cytoplasmatic expression in neurons and nuclear expression in astrocytes was defined. In the brain, nuclear TERT expression was found in neural progenitor cells of neurogenic areas. This study provides the first comparative study of TERT expression across the central nervous system ontogenesis. The nuclear presence of TERT may be used as a potential marker of neural stem/progenitor cells, however, further studies are required to confirm these assumptions.

Defining sex differences in selected lipid metabolites of blood plasma in Wistar rats.

There is an increasing attention to the role that sex/gender plays in health, behavior and outcomes. Even though we know that males and females are not the same, experiments have sometimes been carried out without considering sex in scientific research. It is essential for scientists and clinicians to consider sex differences as one of the underlying physiological determinants of health and disease to provide the building blocks for evidence-based, individualized medicine. Our work aimed to reveal sex-associated differences in lipid metabolite levels of adult female (n = 10) and male (n = 10) Wistar rats, aged 60 days. Partial least square determination analysis (PLS-DA) method and a variance importance in projection (VIP) score was used to identify the key sex-specific metabolites. Our results show that all groups of lipid metabolites: lysophosphatidylcholines (lysoPCs), phosphatidylcholines (PCs), and sphingomyelins (SMs) show a significant sex-dependent pattern. According to our results, more than a half of lysoPCs studied showed sex-specific features. PCs and lysoPCs tend to be significantly elevated in the blood plasma of females. The most distinct increase in more than 90% of SMs has been revealed in female blood plasma, compared with males. According to VIP score, the most important feature was the metabolite PC aa C38:4. Our study points out a sex dimorphism in lipid metabolism. The identification of main lipid features may play a key role in preclinical and clinical practice.

Nocturnal resveratrol administration inhibits chemically induced breast cancer formation in rats.

Resveratrol (RES) is well known natural polyphenol with proven antioxidant, antiinflammatory and anticarcinogenic properties. Since mode of application may be important for cancer-preventive effects of RES, the aim of this study was to evaluate a possible delay in the initiation and progression of chemically induced mammary carcinogenesis in female Sprague-Dawley rats after the nocturnal administration of RES. Application of a high dose of RES (100 mg/kg body weight), starting 2 weeks before the first N-methyl-N-nitrosourea dose (NMU) (50 mg/kg body weight), reduced tumor incidence and markedly prolonged latency period (P < 0.01) in the NMU + RES group in comparison to NMU tumor bearing animals. In addition, the tumor volume decreased significantly (P < 0.05) together with tumor frequency (P < 0.05). We also observed that food but not water intake was significantly reduced by 17% between weeks 4 and 12 in the NMU + RES group leading to a pronounced reduction in the body mass of about 25% as compared to untreated controls. In addition to direct effects of RES in tumor tissues, this polyphenol did also improve metabolic functions in RES-treated animals since it normalizes hypoproteinemia and urea levels and increases the number of lymphocytes when compared with NMU. Higher level of reactive oxygen species (ROS) in leukocytes and the elevation of proinflammatory plasma cytokines IL-1 and IL-2 may contribute to the observed reduction in tumor development. These results indicate for the first time that nocturnal administration of a high dose of RES significantly affects tumor development in vivo. Therefore, we conclude that RES is a promising candidate for cancer chemoprevention. However, it should be noted that the mode of application might significantly affect RES ability to fight cancer.

Rosiglitazone shows partial oncostatic effect in rat mammary carcinogenesis.

Peroral antidiabetics from thiazolidinedione (glitazone) group showed oncostatic effects in preclinical models. This study evaluated chemopreventive effects of rosiglitazone in N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats. N-methyl-N-nitrosourea was administered in two intraperitoneal doses each per 50 mg/kg b.w. between 40th and 51st postnatal days. Rosiglitazone was administered in a diet at a concentration of 10 ppm and 100 ppm, respectively, 9 days before the first carcinogen dose until the termination of the experiment. During the experiment the animals were weekly weighed and palpated for the presence of mammary tumors and estimation of latency period, tumor frequency per group and animal, and tumor volume were recorded. The experiment was terminated 16 weeks after the first carcinogen dose, basic tumor growth parameters and selected metabolic and hormonal variables were evaluated. Chemoprevention with higher rosiglitazone dose decreased tumor frequency per group by 44%, other tumor parameters (incidence, tumor frequency per animal) were decreased insignificantly (at both doses), latency period was not changed. Rosiglitazone administration decreased cumulative tumor volume, more efficiently at lower dose. Glycaemia and insulinaemia decreased after lower rosigitazone dose administration but glycaemia did not exceed normal values. Higher rosiglitazone dose alleviated some metabolic alterations resulting from cancer progression more effectively but induced a prominent cardiac hypertrophy.

Melatonin enhanced bexarotene efficacy in experimental mammary carcinogenesis.

The aim of this paper was to test lower, safe bexarotene dose administered alone and in combination with melatonin to improve its efficacy. Mammary carcinogenesis was induced by N-methyl-N-nitrosourea in female Sprague-Dawley rats, administered in two doses intraperitoneally between 42.-54. postnatal days and chemoprevention was initiated 7 days prior to first N-methyl-N-nitrosourea injection and lasted 15 weeks. Bexarotene, particularly in combination with melatonin decreased mammary tumor incidence and frequency with a shift from poorly to well differentiated carcinomas. Bexarotene alleviated glycaemia and liver/heart muscle glycogen concentration decreased as well as liver/thymus malondialdehyde increased in comparison with control group. The combination of bexarotene and melatonin is therefore beneficial in preventive-curative model of experimental mammary carcinogenesis and may be applied in oncological practice as such.