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Estrogens are hormones that play an important role in the digestive tract, including in men. Letrozole is an inhibitor of cytochrome P450 aromatase, an enzyme converting androgens to estrogens. The use of letrozole may cause oxidative stress and endoplasmic reticulum stress in the cells. Factors modulating cellular stress may include vitamin C. The purpose of this study was to examine whether letrozole and/or vitamin C supplementation can affect the morphology of the small intestine, the parameters of endoplasmic reticulum stress, programmed cell death markers, and oxidative damage. Three-month-old male rats were divided into four groups and treated with the following: (I) CTRL—water; (II) CTRL+C—L-ascorbic acid; (III) LET—letrozole; and (IV) LET+C—letrozole + L-ascorbic acid. The morphometrical measurements included epithelial thickness, crypt and lumen area, crypt perimeter, nuclei number in the crypt, and the cell size of crypts. The expression levels of PERK, caspase-3, and catalase were determined. Significant differences in the morphometrical measurements and immunoexpression were observed. This may indicate that chronic treatment with letrozole can affect morphology and induce ER stress, oxidative stress, and programmed cell death in the epithelial cells of the small intestine of adult male rats. Vitamin C supplementation exerts an effect on some parameters of the molecular processes.

(1) Background: The main goal of this study was to analyze the morphology of the rat’s jejunum after long-term treatment with calcineurin inhibitor-based immunosuppressive drugs and to investigate their impact on the location of MMP-2 and its inhibitor TIMP-2, as well as the balance between them. (2) Methods: Twenty-four rats were divided into four groups receiving different immunosuppressive regiments. After six months of treatment, the jejunums were collected and analyzed. (3) Results: immunosuppressive drug panels containing calcineurin inhibitors (CNIs) have a negative impact on the morphology and morphometry of the small intestinal wall. These drugs disrupt the MMP-2/TIMP-2 balance. Both CsA and TAC interfere with the synthesis of intercellular matrix components in the connective tissue of the small intestine. Furthermore, tacrolimus appears to disrupt the MMP-2/TIMP-2 balance in the small intestine the most, as the results show the highest difference between MMP-2 and TIMP-2 expression. The results were also confirmed by digital analysis of tissue segmentation. (4) Conclusions: The research conducted in this study is unique because there is limited information available on the direct effects of immunosuppressive drugs on the expression of MMP-2 and their inhibitors in the jejunum. Additionally, this study involves three drugs instead of one, which accurately reflects the panel of drugs used in organ recipients. Our results suggest that immunosuppressive drugs affect morphology and MMP2/TIMP2 immunoexpression; however, further studies are required. AI-based tools provide a reliable analysis of tissue samples, which represents an exciting approach for future histopathological studies. However, the results of the analyses generated by these tools need to be verified by specialists.

Lagovirus europaeus/GI.2 causes severe and highly fatal Rabbit Hemorrhagic Disease (RHD). Because of its characteristics, this infection is used as an animal model for acute liver failure (ALF). Apoptosis is one of the key processes underlying ALF and has been described as one of the mechanisms of RHD pathogenesis. Apoptotic cell death has been quite well characterized in infection with different variants of GI.1 strains, but so far, the GI.2 genotype has not been widely studied. In this study, we performed an evaluation of apoptotic cell death in hepatocytes of rabbits infected with Lagovirus europaeus/GI.2. We analyzed the expression of genes involved in apoptotic cell death by real-time PCR and performed immunohistochemical (IHC) assays. We showed a significant increase in the expression of caspase-3 and the proapoptotic Bax and anti-apoptotic Bcl-2 in infected animals. In addition, we recorded increased Bax/Bcl-2 ratios. IHC analyses showed the presence of morphological signs of apoptosis in the hepatocytes of infected rabbits. Our results indicate that caspase-3 and proteins from the Bcl-2 families play a key role in apoptosis induced by Lagovirus europaeus/GI.2 infection.

(1) Background: Hormone-dependent events that occur throughout spermatogenesis during postnatal testis maturation are significant for adult male fertility. Any disturbances in the T/DHT ratio in male progeny born from females fertilized by finasteride-treated male rats (F0:Fin) can result in the impairment of testicular physiology. The goal of this work was to profile the testicular transcriptome in the male filial generation (F1:Fin) from paternal F0:Fin rats. (2) Methods: The subject material for the study were testis from immature and mature male rats born from females fertilized by finasteride-treated rats. Testicular tissues from the offspring were used in microarray analyses. (3) Results: The top 10 genes having the highest and lowest fold change values were mainly those that encoded odoriferous (Olfr: 31, 331, 365, 633, 774, 814, 890, 935, 1109, 1112, 1173, 1251, 1259, 1253, 1383) and vomeronasal (Vmn1r: 50, 103, 210, 211; Vmn2r: 3, 23, 99) receptors and RIKEN cDNA 5430402E10, also known as odorant-binding protein. (4) Conclusions: Finasteride treatment of male adult rats may cause changes in the testicular transcriptome of their male offspring, leading to a defective function of spermatozoa in response to odorant-like signals, which are recently more and more often noticed as significant players in male fertility.

The epididymis is an organ that plays a key role in sperm maturation. The aim of this study was to examine the association between the chronic treatment of mature male rats with letrozole and morphological evaluation and morphometric values of epididymis as well as changes in the number of apoptotic cells in epididymal epithelium. Adult rats were treated with letrozole for 6 months and the epididymis weight, morphology, morphometric values and the number of apoptotic cells in the epithelium were examined. Long-term aromatase inhibition resulted in presence of intraepithelial clear vacuoles, hyperplasia of clear cells and a hyperplastic alteration in the epithelium known as a cribriform change. Moreover, changes in diameters of the epididymal duct and the epididymal lumen and changes in the epididymal epithelium height were observed. The number of apoptotic epithelial cells was increased in letrozole-treated group. It can be indicated that chronic treatment with letrozole can affect morphology, morphometric values and apoptosis in the epididymis of adult male rats. Observed changes are similar to that observed in the aging processes and may also be important for patients treated with aromatase inhibitors.

Finasteride (Fin) causes androgen imbalance by inhibiting the conversion of testosterone (T) to its more active metabolite, dihydrotestosterone (DHT). Androgen receptors (AR) are present (e.g., in hepatocytes), which have well-developed endoplasmic reticulum (ERet). Cellular protein quality control is carried out by ERet in two paths: (i) unfolded protein response (UPR) and/or (ii) endoplasmic reticulum associated degradation (ERAD). ERet under continuous stress can generate changes in the UPR and can direct the cell on the pathway of life or death. It has been demonstrated that genes involved in ERet stress are among the genes controlled by androgens in some tissues. Oxidative stress is also one of the factors affecting the functions of ERet and androgens are one of the regulators of antioxidant enzyme activity. In this paper, we discuss/analyze a possible relationship between androgen imbalance in paternal generation with ERet stress and liver disorders in both paternal and filial generation. In our rat model, hyperglycemia and subsequent higher accumulation of hepatic glycogen were observed in all filial generation obtained from females fertilized by Fin-treated males (F1:Fin). Importantly, genes encoding enzymes involved in glucose and glycogen metabolism have been previously recognized among UPR targets.

Glioblastoma multiforme (GBM) is a brain tumor with a very poor prognosis. For this reason, researchers worldwide study the impact of the tumor microenvironment in GBM, such as the effect of chemokines. In the present study, we focus on the role of the chemokine CCL18 and its receptors in the GBM tumor. We measured the expression of CCL18, CCR8 and PITPNM3 in the GMB tumor from patients (16 men and 12 women) using quantitative real-time polymerase chain reaction. To investigate the effect of CCL18 on the proliferation and migration of GBM cells, experiments were performed using U-87 MG cells. The results showed that CCL18 expression was higher in the GBM tumor than in the peritumoral area. The women had a decreased expression of PITPNM3 receptor in the GBM tumor, while in the men a lower expression of CCR8 was observed. The hypoxia-mimetic agent, cobalt chloride (CoCl2), increased the expression of CCL18 and PITPNM3 and thereby sensitized U-87 MG cells to CCL18, which did not affect the proliferation of U-87 MG cells but increased the migration of the test cells. The results indicate that GBM cells migrate from hypoxic areas, which may be important in understanding the mechanisms of tumorigenesis.

Diabetes is a predictor of nonalcoholic fatty liver disease (NAFLD). There are data suggesting that Tribulus terrestris (TT) saponins act as antidiabetic agents and protect against NAFLD. The effect of saponins may be increased by fermentable fibers such as inulin. The aim of the present study was to investigate the influence of TT saponins and TT saponins plus inulin on the plasma lipid profile and liver fatty acids of rats with induced diabetes mellitus type 2 (T2DM). The study was performed on 36 male Sprague–Dawley rats divided into two main groups: control and diabetic. Animals of the diabetic (DM) group were fed a high-fat diet and injected with streptozotocin (low doses). Animals of the control group (nDM) were on a regular diet and were injected with buffer. After the injections, the animals were split into subgroups: three non-diabetic (nDM): (i) control (c-C); (ii) saponin-treated rats (C-Sap); (iii) rats treated with saponins + inulin (C-Sap + IN), and three diabetic subgroups (DM): (iv) control (c-DM); (v) saponin-treated rats (DM-Sap); (vi) rats treated with saponins + inulin (DM-Sap + IN). Liver fatty acids were extracted and analyzed by gas chromatography, and plasma glucose and lipids were measured. The study showed significant changes in liver morphology, liver fatty acids, plasma lipid profile, and plasma glucose. In summary, supplementation with TT saponins or saponins with inulin for one month decreased the level of steatosis in rats with induced type 2 diabetes. Moreover, there were favorable effects on the plasma lipid profile in the rats. However, additional supplementation with inulin had a negative effect on liver morphology (with a microvesicular type of steatosis) in the non-diabetes group. Moreover, supplementation with inulin had a negative effect on plasma glucose in both diabetic and non-diabetic rats. These data show that a diet enriched with fermentable fibers reveals different effects in different organisms, and not all sources and forms of fiber are beneficial to health.

Background: A growing body of data indicates that the physiology of the liver is sex-hormone dependent, with some types of liver failure occurring more frequently in males, and some in females. In males, in physiological conditions, testosterone acts via androgen receptors (AR) to increase insulin receptor (IR) expression and glycogen synthesis, and to decrease glucose uptake controlled by liver-specific glucose transporter 2 (GLUT-2). Our previous study indicated that this mechanism may be impaired by finasteride, a popular drug used in urology and dermatology, inhibiting 5α-reductase 2, which converts testosterone (T) into dihydrotestosterone (DHT). Our research has also shown that the offspring of rats exposed to finasteride have an altered T–DHT ratio and show changes in their testes and epididymides. Therefore, the goal of this study was to assess whether the administration of finasteride had an trans-generational effect on (i) GLUT-2 dependent accumulation of glycogen in the liver, (ii) IR and AR expression in the hepatocytes of male rat offspring, (iii) a relation between serum T and DHT levels and the expression of GLUT2, IR, and AR mRNAs, (iv) a serum glucose level and it correlation with GLUT-2 mRNA. Methods: The study was conducted on the liver (an androgen-dependent organ) from 7, 14, 21, 28, and 90-day old Wistar male rats (F1:Fin) born by females fertilized by finasteride-treated rats. The control group was the offspring (F1:Control) of untreated Wistar parents. In the histological sections of liver the Periodic Acid Schiff (PAS) staining (to visualize glycogen) and IHC (to detect GLUT-2, IR, and AR) were performed. The liver homogenates were used in qRT-PCR to assess GLUT2, IR, and AR mRNA expression. The percentage of PAS-positive glycogen areas were correlated with the immunoexpression of GLUT-2, serum levels of T and DHT were correlated with GLUT-2, IR, and AR transcript levels, and serum glucose concentration was correlated with the age of animals and with the GLUT-2 mRNA by Spearman’s rank correlation coefficients. Results: In each age group of F1:Fin rats, the accumulation of glycogen was elevated but did not correlate with changes in GLUT-2 expression. The levels of GLUT-2, IR, and AR transcripts and their immunoreactivity statistically significantly decreased in F1:Fin animals. In F1:Fin rats the serum levels of T and DHT negatively correlated with androgen receptor mRNA. The animals from F1:Fin group have statistically elevated level of glucose. Additionally, in adult F1:Fin rats, steatosis was observed in the liver (see Appendix A). Conclusions: It seems that treating male adult rats with finasteride causes changes in the carbohydrate metabolism in the liver of their offspring. This can lead to improper hepatic energy homeostasis or even hyperglycaemia, insulin resistance, as well as some symptoms of metabolic syndrome and liver steatosis.