The Effects of Bioactive Compounds on Human Brain Structures and Diseases.

The human brain is the most intricate organ in the body [...].

Bioactive Compounds and Their Influence on Postnatal Neurogenesis.

Since postnatal neurogenesis was revealed to have significant implications for cognition and neurological health, researchers have been increasingly exploring the impact of natural compounds on this process, aiming to uncover strategies for enhancing brain plasticity. This review provides an overview of postnatal neurogenesis, neurogenic zones, and disorders characterized by suppressed neurogenesis and neurogenesis-stimulating bioactive compounds. Examining recent studies, this review underscores the multifaceted effects of natural compounds on postnatal neurogenesis. In essence, understanding the interplay between postnatal neurogenesis and natural compounds could bring novel insights into brain health interventions. Exploiting the therapeutic abilities of these compounds may unlock innovative approaches to enhance cognitive function, mitigate neurodegenerative diseases, and promote overall brain well-being.

Stage-Dependent Levels of Brain-Derived Neurotrophic Factor and Matrix Metalloproteinase 9 in the Prognosis of Colorectal Cancer.

PURPOSE: The development of sensitive and non-invasive biomarkers for the early detection of CRC and determination of their role in the individual stages of CRC. METHODS: MMP-9 expression in serum and tissue, and BDNF expression in plasma were detected using the ELISA method. MMP-9 and BDNF in the tissue were also determined by immunohistochemical staining. RESULTS: To assess the balance between changes in survival and tumor progression, we compared BDNF/MMP-9 ratios in tissues of living and deceased individuals. The tissue BDNF/MMP-9 ratio (evaluated immunohistochemically) decreased significantly with the progression of the disease in living patients. The BDNF/MMP-9 ratio was statistically significantly reduced in stages II and III compared to the benign group. However, in deceased individuals, the ratio showed an opposite tendency. CONCLUSION: The determination of the tissue BDNF/MMP9 ratio can be used as a prognostic biomarker of CRC.

Exploring the Potential of Cannabinoid Nanodelivery Systems for CNS Disorders.

Cannabinoids have a major therapeutic value in a variety of disorders. The concepts of cannabinoids are difficult to develop, but they can be used and are advantageous for a number of diseases that are not sufficiently managed by existing treatments. Nanoconjugation and encapsulation techniques have been shown to be effective in improving the delivery and the therapeutic effectiveness of drugs that are poorly soluble in water. Because the bioavailability of cannabinoids is low, the challenge is to explore different administration methods to improve their effectiveness. Because cannabinoids cross the blood-brain-barrier (BBB), they modify the negative effects of inflammatory processes on the BBB and may be a key factor in the improvement of BBB function after ischemic disease or other conditions. This review discusses various types of cannabinoid administration, as well as nanotechnologies used to improve the bioavailability of these compounds in CNS diseases.

Atranorin, a Secondary Metabolite of Lichens, Exhibited Anxiolytic/Antidepressant Activity in Wistar Rats.

Atranorin (ATR) is one of lichens' many known secondary metabolites. Most current studies have investigated the various effects of ATR in vitro and only sporadically in vivo. The latest data indicate that ATR may have anxiolytic/antidepressive effects. This study aimed to analyze the potential of ATR in a depression-like state in male Wistar rats. Pregnant females were stressed by restricting their mobility in the final week of pregnancy three times a day for 45 min each, for three following days. After birth, progeny aged 60 days was stressed repeatedly. The male progeny was divided into three groups as follows: CTR group as a healthy control (n = 10), DEP group as a progeny of restricted mothers (n = 10), and ATR group as a progeny of restricted mothers, treated daily for one month with ATR (n = 10; 10 mg/kg of body weight, p.o.). Our results show that ATR acts as an antioxidant and markedly changes animal behavior. Concomitantly, hippocampal neurogenesis increases in the hilus and subgranular zone, together with the number of NeuN mature neurons in the hilus and CA1 regions. Our results indicate a potential antidepressant/anxiolytic effect of ATR. However, further studies in this area are needed.

Relationship between FGF 23, SDMA, Urea, Creatinine and Phosphate in Relation to Feline Chronic Kidney Disease.

Chronic kidney disease (CKD) is a common diagnosis in older cats, and its prevalence increases with age. Conventional indirect biomarkers of glomerular filtration rate (GFR) have their limitations, and are not efficient in detecting early decreases in glomerular filtration rate. Recently, symmetric dimethylarginine (SDMA) concentrations have been proposed as a novel biomarker of GFR for the early detection of CKD. This study discusses the relationship between SDMA, FGF 23 and previously used indicators of kidney function, mainly creatinine, urea and phosphate. Ninety-nine cats were included in this study. Based on their SDMA values, 48 cats had CKD and the remaining 51 cats were used as a healthy control group. Serum of these cats was assayed for creatinine, urea and phosphate concentrations as well as FGF 23 values, and correlations between them were evaluated. Cats with CKD had higher FGF 23 concentrations than healthy cats, and no correlation was found between FGF 23 and SDMA, nor between FGF 23 and phosphate. On the other hand, phosphate strongly correlated with SDMA, urea and creatinine, making it a possible independent factor of CKD progression.

Biochemical Properties of Atranorin-Induced Behavioral and Systematic Changes of Laboratory Rats.

Atranorin (ATR) is a secondary metabolite of lichens. While previous studies investigated the effects of this substance predominantly in an in vitro environment, in our study we investigated the basic physicochemical properties, the binding affinity to human serum albumin (HSA), basic pharmacokinetics, and, mainly, on the systematic effects of ATR in vivo. Sporadic studies describe its effects during, predominantly, cancer. This project is original in terms of testing the efficacy of ATR on a healthy organism, where we can possibly attribute negative effects directly to ATR and not to the disease. For the experiment, 24 Sprague Dawley rats (Velaz, Únetice, Czech Republic) were used. The animals were divided into four groups. The first group (n = 6) included healthy males as control intact rats (♂INT) and the second group (n = 6) included healthy females as control intact rats (♀INT). Groups three and four (♂ATR/n = 6 and ♀ATR/n = 6) consisted of animals with daily administered ATR (10mg/kg body weight) in an ethanol-water solution per os for a one-month period. Our results demonstrate that ATR binds to HSA near the binding site TRP214 and acts on a systemic level. ATR caused mild anemia during the treatment. However, based on the levels of hepatic enzymes in the blood (ALT, ALP, or bilirubin levels), thiobarbituric acid reactive substances (TBARS), or liver histology, no impact on liver was recorded. Significantly increased creatinine and lactate dehydrogenase levels together with increased defecation activity during behavioral testing may indicate the anabolic effect of ATR in skeletal muscles. Interestingly, ATR changed some forms of behavior. ATR at a dose of 10 mg/kg body weight is non-toxic and, therefore, could be used in further research.

Clinical Efficacy and Safety of Malarone®, Azithromycin and Artesunate Combination for Treatment of Babesia gibsoni in Naturally Infected Dogs.

Babesia gibsoni is a tick-borne protozoal blood parasite that may cause hemolytic anemia, thrombocytopenia, lethargy, and/or splenomegaly in dogs. Many drugs have been used in management of canine babesiosis such as monotherapy or combined treatment, including diminazene aceturate, imidocarb dipropionate, atovaquone, and antibiotics. This report examines the effectiveness and safety of Malarone®, azithromycin (AZM) and artesunate (ART) combination for the treatment of babesiosis in dogs naturally infected with Babesia gibsoni. Twelve American Pit Bull Terriers were included in the experiment. Examined dogs underwent clinical and laboratory analysis including hematology and biochemistry profile and serum protein electrophoresis. After diagnosis, the dogs received combined therapy with Malarone® (13.5 mg/kg PO q24 h), azithromycin (10 mg/kg PO q24 h) and artesunate (12.5 mg/kg PO q24 h) for 10 days. The combined treatment improved hematology and biochemical parameters to the reference range gradually during the first 14 days already, resulting in the stable values until day 56 after treatment. No clinically apparent adverse effects were reported during treatment and monitoring. No relapses of parasitemia were detected in control days 180, 360, 540 and 720 in all dogs. Results of the study indicate that the combined treatment leads to successful elimination of parasitemia in chronically infected dogs with B. gibsoni.

Addition of palm olein to lard-supplemented diet indicates myocardial dysfunction and augments oxidative stress by authophagy-lysosome pathway in rats.

This study evaluated a prolonged effect of palm oil addition to lard-supplemented diet (PLD) on the oxidative status, lysosomal enzyme activities, markers of hepatotoxicity and basic lipid profile in female rats. Female Sprague-Dawley rats received PLD (10% of total fat: 7.5% from palm oil and 2.5% from lard), and the control group received lard-supplemented diet (2.5% fat) from 28 days of age for 14 weeks. Histopathological evaluation of the liver from animals fed the PLD showed slight steatosis and signs of mild chronic inflammation. Reduction of extramedullary hematopoiesis and an increased ratio of red/white pulp were observed in the spleen. PLD induced oxidative stress (evaluated in the liver, heart, spleen, muscle and kidney) evidenced by an increase in conjugated dienes and malondialdehyde in all tissues except the muscle; protein carbonyl derivatives were increased as well. The changes in the antioxidant enzyme activities in the evaluated tissues were ambiguous except for the prominent increase in the heart. Lysosomal enzyme activities showed a tendency to increase in the heart and kidney and to decrease in the muscle and spleen. The De Ritis ratio, which is a biomarker of hepatotoxicity, was higher in the heart from animals fed the PLD. The palm oil addition to the lard-supplemented diet-induced prominent oxidative stress, particularly in myocardial tissue with involvement of the authophagy-lysosome pathway.

Sexual Dimorphism in Energy Metabolism of Wistar Rats Using Data Analysis.

The prevalence of some chronic diseases, such as cancer or neurodegenerative disorders, differs between sexes. Animal models provide an important tool to adopt potential therapies from preclinical studies to humans. Laboratory rats are the most popular animals in toxicology, neurobehavioral, or cancer research. Our study aimed to reveal the basic differences in blood metabolome (amino acids, biogenic amines, and acylcarnitines) of the adult male (n = 10) and female (n = 10) Wistar rats. Partial least square-discrimination analysis (PLS-DA) and a variance im portance in projection (VIP) score was used to identify the key sex-specific metabolites. All groups of metabolites, as the main markers of energy metabolism, showed a significant sex-dependent pattern. The most important features calculated in PLS-DA according to VIP score were free carnitine (C0), tyrosine (Tyr), and acylcarnitine C5-OH. While aromatic amino acids, such as Tyr and phenylalanine (Phe), were significantly elevated in the blood plasma of males, tryptophan (Trp) was found in higher levels in the blood plasma of females. Besides, significant sex-related changes in urea cycle were found. Our study provides an important insight into sex-specific differences in energy metabolism in rats and indicates that further studies should consider sex as the main aspect in design and data interpretation.

The Plant-Derived Compound Resveratrol in Brain Cancer: A Review.

Despite intensive research, malignant brain tumors are among the most difficult to treat due to high resistance to conventional therapeutic approaches. High-grade malignant gliomas, including glioblastoma and anaplastic astrocytoma, are among the most devastating and rapidly growing cancers. Despite the ability of standard treatment agents to achieve therapeutic concentrations in the brain, malignant gliomas are often resistant to alkylating agents. Resveratrol is a plant polyphenol occurring in nuts, berries, grapes, and red wine. Resveratrol crosses the blood‒brain barrier and may influence the central nervous system. Moreover, it influences the enzyme isocitrate dehydrogenase and, more importantly, the resistance to standard treatment via various mechanisms, such as O6-methylguanine methyltransferase. This review summarizes the anticancer effects of resveratrol in various types of brain cancer. Several in vitro and in vivo studies have presented promising results; however, further clinical research is necessary to prove the therapeutic efficacy of resveratrol in brain cancer treatment.

Melatonin mitigates hippocampal and cognitive impairments caused by prenatal irradiation.

Formation of new neurons and glial cells in the brain is taking place in mammals not only during prenatal embryogenesis but also during adult life. As an enhancer of oxidative stress, ionizing radiation represents a potent inhibitor of neurogenesis and gliogenesis in the brain. It is known that the pineal hormone melatonin is a potent free radical scavenger and counteracts inflammation and apoptosis in brain injuries. The aim of our study was to establish the effects of melatonin on cells in the hippocampus and selected forms of behaviour in prenatally irradiated rats. The male progeny of irradiated (1 Gy of gamma rays; n = 38) and sham-irradiated mothers (n = 19), aged 3 weeks or 2 months, were used in the experiment. Melatonin was administered daily in drinking water (4 mg/kg b. w.) to a subset of animals from each age group. Prenatal irradiation markedly suppressed proliferative activity in the dentate gyrus in both age groups. Melatonin significantly increased the number of proliferative BrdU-positive cells in hilus of young irradiated animals, and the number of mature NeuN-positive neurons in hilus and granular cell layer of the dentate gyrus in these rats and in CA1 region of adult irradiated rats. Moreover, melatonin significantly improved the spatial memory impaired by irradiation, assessed in Morris water maze. A significant correlation between the number of proliferative cells and cognitive performances was found, too. Our study indicates that melatonin may decrease the loss of hippocampal neurons in the CA1 region and improve cognitive abilities after irradiation.

Resveratrol Action on Lipid Metabolism in Cancer.

Cancer diseases have the leading position in human mortality nowadays. The age of oncologic patients is still decreasing, and the entire scientific society is eager for new ways to fight against cancer. One of the most discussed issues is prevention by means of natural substances. Resveratrol is a naturally occurring plant polyphenol with proven antioxidant, anti-inflammatory, and anticancer effects. Tumor cells display specific changes in the metabolism of various lipids. Resveratrol alters lipid metabolism in cancer, thereby affecting storage of energy, cell signaling, proliferation, progression, and invasiveness of cancer cells. At the whole organism level, it contributes to the optimal metabolism extent with respect to the demands of the organism. Thus, resveratrol could be used as a preventive and anticancer agent. In this review, we focus on some of the plethora of lipid pathways and signal molecules which are affected by resveratrol during carcinogenesis.

Expression of the neonatal Fc-receptor in placental-fetal endothelium and in cells of the placental immune system.

INTRODUCTION: Starting from the second trimester of pregnancy, passive immunity is provided to the human fetus by transplacental transfer of maternal IgG. IgG transfer depends on the neonatal Fc receptor, FcRn. While FcRn localization in the placental syncytiotrophoblast (STB) has been demonstrated unequivocally, FcRn expression in placental-fetal endothelial cells (pFECs), which are part of the materno-fetal barrier, is still unclear. Therefore, this study aimed to elucidate the spatio-specific expression pattern of FcRn in placental tissue. METHODS: FcRn expression was investigated by western blotting in term placentas and in isolated human placental arterial and venous endothelial cells (HPAEC, HPVEC) using a validated affinity-purified polyclonal anti-peptide antibody against the cytoplasmic tail of FcRn α-chain. In situ localization of FcRn and IgG was studied by immunofluorescence microscopy on tissue sections of healthy term placentas. RESULTS: FcRn expression was demonstrated in placental vasculature particularly, in HPAEC, and HPVEC. FcRn was localized in cytokeratin 7+ STB and in CD31+ pFECs in terminal as well as stem villi in situ. Additionally, CD68+ placental macrophages exhibited FcRn expression in situ. Endogenous IgG partially co-localized with FcRn in STB, pFECs, and in placental macrophages. DISCUSSION: Placental FcRn expression in endothelial cells and macrophages is analogous to the expression pattern in other organs. FcRn expression in pFECs suggests an involvement of FcRn in IgG transcytosis and/or participation in recycling/salvaging of maternal IgG present in the fetal circulation. FcRn expression in placental macrophages may account for recycling of monomeric IgG and/or processing and presentation of immune complexes.

Future Aspects for Cannabinoids in Breast Cancer Therapy.

Cannabinoids (CBs) from Cannabis sativa provide relief for tumor-associated symptoms (including nausea, anorexia, and neuropathic pain) in the palliative treatment of cancer patients. Additionally, they may decelerate tumor progression in breast cancer patients. Indeed, the psychoactive delta-9-tetrahydrocannabinol (THC), non-psychoactive cannabidiol (CBD) and other CBs inhibited disease progression in breast cancer models. The effects of CBs on signaling pathways in cancer cells are conferred via G-protein coupled CB-receptors (CB-Rs), CB1-R and CB2-R, but also via other receptors, and in a receptor-independent way. THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both. In breast cancer, CB1-R expression is moderate, but CB2-R expression is high, which is related to tumor aggressiveness. CBs block cell cycle progression and cell growth and induce cancer cell apoptosis by inhibiting constitutive active pro-oncogenic signaling pathways, such as the extracellular-signal-regulated kinase pathway. They reduce angiogenesis and tumor metastasis in animal breast cancer models. CBs are not only active against estrogen receptor-positive, but also against estrogen-resistant breast cancer cells. In human epidermal growth factor receptor 2-positive and triple-negative breast cancer cells, blocking protein kinase B- and cyclooxygenase-2 signaling via CB2-R prevents tumor progression and metastasis. Furthermore, selective estrogen receptor modulators (SERMs), including tamoxifen, bind to CB-Rs; this process may contribute to the growth inhibitory effect of SERMs in cancer cells lacking the estrogen receptor. In summary, CBs are already administered to breast cancer patients at advanced stages of the disease, but they might also be effective at earlier stages to decelerate tumor progression.

The effect of 2.45 GHz non-ionizing radiation on the structure and ultrastructure of the testis in juvenile rats.

BACKGROUND: Nowadays, mobile devices that emit non-ionizing electromagnetic radiation (EMR) are predominantly used by juveniles and pubescents. The aim of the present study was to evaluate the effect of whole body pulsed EMR on the juvenile Wistar albino rat testis at a frequency of 2.45 GHz and mean power density of 2.8 mW/cm². METHODS: The investigated animals (n=24) were divided into two control and two EMR groups (5 and 6 week old rats; 6 rats per group). Both EMR groups were irradiated continually for 3 weeks (2h/day) from postnatal days 14 and 21, respectively. RESULTS: EMR caused an irregular shape of seminiferous tubules with desquamated immature germ cells in the lumen, a large number of empty spaces along the seminiferous epithelium and dilated and congested blood vessels in the interstitial tissue of the testis. The cytoplasm of Sertoli cells showed strong vacuolization and damaged organelles, with the cytoplasm full of different heterophagic and lipid vacuoles or the cytoplasm of spermatocytes with swollen mitochondria in both irradiated groups. A significant increase in the total tubular area of seminiferous tubules was observed in both EMR groups compared with controls (P<0.001). A significant increase in the TUNEL-positive apoptotic nuclei (P<0.01) was accompanied by a significant rise in both Cu-Zn-SOD (P<0.01) and Mn-SOD (P<0.001) positive cells in the 6 week old experimental rats compared to control animals. CONCLUSION: Our results confirmed a harmful effect of non-ionizing radiation on the structure and ultrastructure of the juvenile rat testis.

Metformin and melatonin inhibit DMBA-induced mammary tumorigenesis in rats fed a high-fat diet.

The data from in-vitro and in-vivo studies show that both peroral antidiabetic metformin (MF) and pineal hormone melatonin (MT) inhibit the growth of many cancers, including breast cancer. However, most in-vivo studies used standard-type diet with low fat content. Therefore, in this study, we evaluated the chemopreventive effect of MF and MT in an in-vivo model of breast cancer in rats on a high-fat diet (10% of total fat). Mammary carcinogenesis was induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats. Chemoprevention with MF (administered in a diet, 0.2%) and MT (administered in tap water, 20 mg/l) was induced 20 days before the carcinogen administration through the termination of the experiment (14 weeks after carcinogen administration). Tumor growth parameters were analyzed together with histopathological examination and immunohistochemical detection of KI67 (proliferation marker), caspase-3, BAX, BCL-2 (apoptosis markers), and CD24 and CD44 (cancer stem cell markers) in mammary tumor samples. The combination of chemopreventive agents decreased tumor incidence by 29%. Cumulative tumor volume was lower in all groups treated with chemoprevention. Histopathology did not show significant changes in high-grade/low-grade tumor ratio. Immunohistochemistry showed increased expression of BAX in the combination group, and caspase-3 expression increased in both MT and combination groups. MT, and particularly the MF and MT combination, inhibited DMBA-induced mammary tumor growth in rats by apoptosis stimulation in cancer cells. Our results indicate that MT supplements in patients treated with MF may have a considerable effect on the incidence of breast cancer.

Anticancer and Immunomodulatory Effects of Lactobacillus plantarum LS/07, Inulin and Melatonin in NMU-induced Rat Model of Breast Cancer.

BACKGROUND/AIM: Chemopreventive activity of a new probiotic strain Lactobacillus plantarum LS/07 (PRO) and prebiotic oligofructose-enriched inulin (PRE) in rat mammary carcinogenesis induced by procarcinogen 7,12-dimethylbenz[a]anthracene has been reported before. This study evaluated the anticancer and immunomodulatory efficacy of PRO, PRE, PRO+PRE (PRO/PRE) and combination with melatonin (PRO+PRE+MEL) in a rat model, when breast cancer was induced by a direct-acting carcinogen N-nitroso-N-methylurea (NMU). MATERIALS AND METHODS: Daily administration of PRO (at a dose of 8.4×10(8) colony-forming units (c.f.u.)/rat), PRE (in the diet, 20 g/kg) and MEL (in tap water, 20 mg/l) started 14 days before the first NMU dose and lasted for 16 weeks. RESULTS: Although tumor growth was not altered, a marked decrease in the ratio of high-/low-grade carcinomas and in tumoral Ki-67 expression was found after PRO+PRE treatment; melatonin augmented these effects. PRO+PRE+MEL combination enhanced CD4(+) and CD8(+) T-cell tumor infiltration induced by PRO/PRE and increased CD25(+)FoxP3(+) regulatory T-cells in tumors. CONCLUSION: In mammary carcinogenesis, Lactobacillus plantarum LS/07 and inulin exert prodifferentiating, antiproliferative and immunomodulatory activities, which are significantly amplified by melatonin co-administration.

The use of native fluorescence analysis of synovial fluid in the diagnosis of medial compartment disease in medium- and large-breed dogs.

We assumed that proteins are most likely responsible for synovial fluid fluorescence and that changes detected in fluorescence intensity are most likely the result of changes in the concentration of fluorescent proteins. Synchronous fluorescent matrices from synovial fluid samples were measured in the excitation wavelength range of 200-350 nm using a luminescence spectrophotometer. The synchronous matrix of synovial fluid consists of 2 dominant fluorescent centers (F1 and F2) in the ultraviolet region. The fluorescence intensities of both centers were significantly higher in pathological samples, with p = 0.001 (a 59% increase of the median value) for the F1 center and p = 0.002 (a 52% increase of the median value) for the F2 center. Receiver operating characteristic analysis confirmed that synovial fluid autofluorescence is a significant predictor of medial compartment disease in dogs, with the area under the curve at 0.776 (F1) and 0.778 (F2). We did not detect any differences in the autofluorescence of synovial fluid between male and female, or any breed-based changes. No position changes of fluorescent centers were recorded in the synovial fluid in diseased dogs compared with healthy dogs. The synovial fluid metabolic fingerprint of canine patients with medial compartment disease differed from that of healthy dogs. Our study demonstrated the feasibility of synovial fluid fingerprinting to identify disease-specific profiles of synovial fluid metabolites.

Neuronal analysis and behaviour in prenatally gamma-irradiated rats.

The intrauterinal development in mammals represents a very sensitive period of life in relation to many environmental factors, including ionizing radiation (IR). The developing nervous system is particularly vulnerable to IR, and the consequences of exposure are of importance because of its potential health risks. The aim of our work was to assess whether prenatal irradiation of rats on the 17th day of embryonic development with a dose of 1 Gy would affect the formation of new cells and the number of mature neurons in the hippocampus and the selected forms of behaviour in the postnatal period. Male progeny of irradiated and control females was tested at ages of 3 weeks, 2 and 3 months. The number of mitotically active cells in the gyrus dentatus (GD) of the hippocampus was significantly reduced in irradiated rats aged 3 weeks. In irradiated rats aged 2 months, a significant reduction of mature neurons in CA1 area and in GD of the hippocampus was observed. The IR negatively influenced the spatial memory in Morris water maze, significantly decreased the exploratory behaviour and increased the anxiety-like behaviour in elevated plus-maze in rats aged 2 months. No significant differences were observed in animals aged 3 months compared with controls of the same age. A significant correlation between the number of mature neurons in the hilus and of the cognitive performances was found. Our results show that a low dose of radiation applied during the sensitive phase of brain development can influence the level of neurogenesis in the subgranular zone of GD and cause an impairment of the postnatal development of mental functions.