The Hypothalamic-Pituitary-Gonadal Axis in Men with Schizophrenia.

Schizophrenia is a severe mental disorder with a chronic, progressive course. The etiology of this condition is linked to the interactions of multiple genes and environmental factors. The earlier age of onset of schizophrenia, the higher frequency of negative symptoms in the clinical presentation, and the poorer response to antipsychotic treatment in men compared to women suggests the involvement of sex hormones in these processes. This article aims to draw attention to the possible relationship between testosterone and some clinical features in male schizophrenic patients and discuss the complex nature of these phenomena based on data from the literature. PubMed, Web of Science, and Google Scholar databases were searched to select the papers without limiting the time of the publications. Hormone levels in the body are regulated by many organs and systems, and take place through the neuroendocrine, hormonal, neural, and metabolic pathways. Sex hormones play an important role in the development and function of the organism. Besides their impact on secondary sex characteristics, they influence brain development and function, mood, and cognition. In men with schizophrenia, altered testosterone levels were noted. In many cases, evidence from available single studies gave contradictory results. However, it seems that the testosterone level in men affected by schizophrenia may differ depending on the phase of the disease, types of clinical symptoms, and administered therapy. The etiology of testosterone level disturbances may be very complex. Besides the impact of the illness (schizophrenia), stress, and antipsychotic drug-induced hyperprolactinemia, testosterone levels may be influenced by, i.a., obesity, substances of abuse (e.g., ethanol), or liver damage.

Cornus mas L. Extract Targets the Specific Molecules of the Th17/Treg Developmental Pathway in TNBS-Induced Experimental Colitis in Rats.

Given that one of the crucial events in the pathogenesis of inflammatory bowel disease is the loss of homeostasis between Th17 and Treg cells, targeting the specific molecules of the Th17/Treg axis developmental pathway is a promising strategy for inflammatory bowel disease prevention and treatment. The current study aimed to assess the impact of cornelian cherry (Cornus mas L.) extract, rich in iridoids and polyphenols known for their potential anti-inflammatory activity, at two doses (20 or 100 mg/kg) on the crucial factors for Th17/Treg cell differentiation in the course of experimental colitis and compare this action with that of sulfasalazine. This study was conducted on the biobank colon tissue samples collected during the previous original experiment, in which colitis in rats was induced by trinitrobenzenesulfonic acid (TNBS). The levels of IL-6, RORγt, total STAT3, p-STAT3, and Foxp3 were determined by ELISA. The expression of PIAS3 mRNA was quantified by qPCR. Cornelian cherry extract at a dose of 100 mg/kg counteracted the TNBS-induced elevation of IL-6, RORγt, and p-STAT3 levels and a decrease in Foxp3 level and PIAS3 mRNA expression, while given concomitantly with sulfasalazine was more effective than sulfasalazine alone in reversing the TNBS-induced changes in IL-6, RORγt, total STAT3, p-STAT3, Foxp3 levels, and PIAS3 mRNA expression. The beneficial effect of cornelian cherry extract on experimental colitis may be due to its immunomodulatory activity reflected by the influence on factors regulating the Th17/Treg axis.

Do Medical Universities Students Use Cognitive Enhancers while Learning?-Conclusions from the Study in Poland.

BACKGROUND: Stress and everyday problems may impact memory and cognition. Therefore, many people use cognitive enhancers (CEs), sold for prescription, as over-the-counter drugs, or dietary supplements, believing they may help with everyday functioning. Our study was designed to answer whether taking CEs is common among Medical University students and to identify which substances are mainly used. METHODS AND RESULTS: An anonymous online questionnaire was answered by 479 students of Medical (88%) and Dentistry (12%) Faculties in Poland. Women constituted the majority of respondents (63%). CEs were used by 53% of respondents, with the most frequent being caffeine, ginseng, nicotine, theanine, ginkgo, and lecithin. Some persons used CEs that are available only with a prescription. The most important reasons for the use of CEs were to increase arousal and improve concentration (mentioned by 81% and 73%, respectively). Over 65% of students experienced some undesired/adverse effects after taking CEs, with tachycardia being the most common, followed by sleep disturbances (reported by 51% and 40%, respectively). CONCLUSIONS: More than half of the respondents from the Medical and Dentistry Faculties reported using CEs, despite their unproven efficacy and not-well-established safety. This raises significant concern about the knowledge of young persons regarding CEs and should encourage universities to undertake educational actions.

Targeting Lineage-Specific Transcription Factors and Cytokines of the Th17/Treg Axis by Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Attenuates TNBS-Induced Experimental Colitis.

The pharmacotherapy of inflammatory bowel disease (IBD) is still not fully effective and safe. Attempts to search for new IBD drugs remain an incessant research aim. One of the novel approaches is targeting the developmental pathway molecules and effector cytokines of Th17/Treg axis. This study aimed to elucidate the impact of new pyrrolo[3,4-d]pyridazinone derivatives, compounds 7b, 10b, or 13b, on the course of experimental colitis in rats and to assess whether these new compounds may influence Th17/Treg axis. Rats were pretreated with studied compounds intragastrically before intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid used for colitis induction. Body weight loss, disease activity index, colon index, and colon tissue damage were analyzed to evaluate the severity of colitis. The colonic levels of RORγt, STAT3, CCR6, Foxp3, IL-6, IL-10, IL-17, TNF-α, IL-23, and PGE2 were assessed. Pretreatment with compounds 7b and 13b alleviated the severity of colitis and concomitantly counteracted the increased levels of RORγt, STAT3, CCR6, IL-6, IL-17, IL-23, TNF-α, and PGE2. The beneficial effect of compounds 7b and 13b may be due to the decrease in the levels of Th17-specific transcription factors and cytokines. The studied compounds might therefore constitute a promising therapeutic strategy in Th17/Treg imbalance-driven inflammatory conditions such as IBD.

Factors That Influence the Use of Dietary Supplements among the Students of Wroclaw Medical University in Poland during the COVID-19 Pandemic.

BACKGROUND AND AIM: The use of dietary supplements (DS) and over-the-counter (OTC) drugs is increasing every year. The COVID-19 pandemic might additionally influence the use of such preparations. The study aimed to investigate factors influencing the use of dietary supplements (DS), including stress-relieving supplements, by the students. METHODS: In the cross-sectional study, 624 students of the Wroclaw Medical University in Poland, from the second to the last year of studies, completed the anonymous questionnaire, consisting of 22 items, about the use of DS/OTC drugs during the academic year 2020/2021. Obtained data were analyzed using Pearson's chi-square test, the U-Mann Whitney test, the Kruskal-Wallis test with the post-hoc analysis, and with logistic regression. RESULTS: About 70% of students declared the use of any DS, 33% used DS for stress, anxiety, depression, or sleeping problems, and 59% used other DS. The most important factors influencing the decision to take any kind of DS were Division (p = 0.0001, odds ratio [OR]: 0.35, and confidence interval [CI]: 0.21-0.59), a self-estimated level of stress (p = 0.014, OR: 1.13, CI: 1.03-1.25), and self-estimated level of knowledge about DS (p = 0.0000, OR: 1.31, CI: 1.19-1.36). In the case of students taking DS for stress, anxiety, depression, or sleeping problems, the level of stress and the declared knowledge had the greatest impact on the decision for such a use of DS (p = 0.0001, OD: 1.24, CI: 1.11-1.39 and p = 0.0000, OD: 1.35, CI: 1.22-1.5, respectively). The COVID-19 pandemic did not change the pattern of DS/OTC drug usage in about 33% of students. Those who started taking DS during the pandemic accounted for 19% of all students. CONCLUSIONS: The use of DS is common among Wroclaw Medical University students with some differences between subgroups of respondents. Additionally, despite declared good knowledge about DS, most students declare the need to learn more about them.

Effect of a Low Dose of Carvedilol on Cyclophosphamide-Induced Urinary Toxicity in Rats-A Comparison with Mesna.

One of the major side effects of cyclophosphamide (CPX)-an alkylating anticancer drug that is still clinically used-is urotoxicity with hemorrhagic cystitis. The present study was designed to evaluate the ability of carvedilol to protect rats from cyclophosphamide-induced urotoxicity. Rats were injected intraperitoneally (i.p.) with CPX (200 mg/kg) and administered carvedilol (2 mg/kg) intragastrically a day before, at the day and a day after a single i.p. injection of CPX, with or without mesna (40, 80, and 80 mg/kg i.p. 20 min before, 4 h and 8 h after CPX administration, respectively). Pretreatment with carvedilol partly prevented the CPX-induced increase in urinary bladder and kidney index, and completely protects from CPX-evoked alterations in serum potassium and creatinine level, but did not prevent histological alterations in the urinary bladder and hematuria. However, carvedilol administration resulted in significant restoration of kidney glutathione (GSH) level and a decrease in kidney interleukin 1ß (IL-1ß) and plasma asymmetric dimethylarginine (ADMA) concentrations. Not only did mesna improve kidney function, but it also completely reversed histological abnormalities in bladders and prevented hematuria. In most cases, no significant interaction of carvedilol with mesna was observed, although the effect of both drugs together was better than mesna given alone regarding plasma ADMA level and kidney IL-1ß concentration. In conclusion, carvedilol did not counteract the injury caused in the urinary bladders but restored kidney function, presumably via its antioxidant and anti-inflammatory properties.

Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]Pyridazinone Exert Anti-Inflammatory Activity without Acute Gastrotoxicity in the Carrageenan-Induced Rat Paw Edema Test.

BACKGROUND AND PURPOSE: Due to the risk of gastrointestinal damage and various tissue toxicity associated with non-steroidal anti-inflammatory drugs (NSAIDs) use, investigating new anti-inflammatory agents with efficacy comparable to that of NSAIDs but reduced toxicity is still a major challenge and a clinical need. Based on our previous study, new 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone, especially 6-butyl-3,5,7-trimethyl-1-[[4-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]methoxy]pyrrolo[3,4-d]pyridazin-4-one and 6-butyl-1-[[4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]methyl]-2-thioxo-1,3,4-oxadiazol-5-yl]methoxy]-3,5,7-trimethyl-pyrrolo[3,4-d]pyridazin-4-one (hereafter referred to as the compounds 10b and 13b, respectively) seem to be promising anti-inflammatory agents. This study aimed to elucidate the effects of these two new derivatives on the course of experimental rat inflammation, liver and kidney function, and gastric mucosa. METHODS: The anti-inflammatory effect of compounds 10b and 13b was evaluated using the carrageenan-induced paw edema test in rats. The increase in paw volume (paw edema), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) levels, histological alterations, and inflammatory cell infiltration in paw tissue were determined. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities, serum urea and creatinine levels, as well as changes in gastric mucosa, were measured as indicators of hepatic, renal, and gastric toxicity. RESULTS: Pretreatment with both novel derivatives at 10 mg/kg and 20 mg/kg doses reduced paw edema, counteracted the increased PGE2 and TNF-α levels, reduced the influx of inflammatory cells, and decreased histopathological alterations in paw tissue. Compound 13b at a dose of 20 mg/kg was more effective than indomethacin in reversing the increased TNF-α levels and reducing the influx of inflammatory cells. Only compound 13b at all studied doses (5, 10, or 20 mg/kg) counteracted the increased MPO level in paw tissue. Both compounds neither caused alterations in ALT, AST, urea, creatinine parameters nor gastric mucosal lesions. CONCLUSION: New compounds exert an anti-inflammatory effect, presumably via inhibiting inflammatory mediators release and inflammatory cell infiltration. Moreover, both possess a more favorable benefit-risk profile than indomethacin, especially compound 13b.

Long-Term Administration of Abacavir and Etravirine Impairs Semen Quality and Alters Redox System and Bone Metabolism in Growing Male Wistar Rats.

Highly active antiretroviral therapy (HAART) is used in HIV-infected patients. Alongside the prolongation of patients' life, adverse side effects associated with long-term therapy are becoming an increasing problem. Therefore, optimizing of HAART is extremely important. The study is aimed at evaluating the toxicity of abacavir and etravirine in monotherapy on the reproductive system, liver, kidneys, and bones in young, sexually mature, male rats. Thirty-six 8-week-old male Wistar rats randomized into three 12-animal groups received either normal saline (control), abacavir 60 mg/kg (AB group), or etravirine 40 mg/kg (ET group) once daily for 16 weeks. Semen morphology, oxide-redox state parameters (MDA, SOD, catalase, GPx, glutathione, GSH/GSSG ratio) in tissue homogenates (testes, liver, kidneys), and serum samples were studied. In bones, microcomputed tomography and a four-point bending test were performed. Total sperm count, sperm concentration, motility, and sperm morphology did not differ significantly in AB or ET groups compared to the control. In the flow cytometry of semen, an increased percentage of cells with denatured DNA was noticed for both tested drugs. However, no significant changes of oxide-redox state in testicular homogenates were found, except of increased SOD activity in the AB-receiving group. Additionally, ET significantly altered catalase and GPx in the liver and SOD activity in kidneys. Abacavir decreased catalase in the liver and GSH levels in kidneys. AB caused significant changes to bone microarchitecture (bone volume fraction, trabecular number, connectivity density, total porosity) and increased Young's modulus. Etravirine had a greater impact on macrometric parameters of bones (tibial index, mid-tibial diameter, femur length). After 4 weeks in the ET group, a lower 1,25-dihydroxyvitamin D3 serum concentration was found. The results showed that abacavir and etravirine disturb oxidative stress. An increase in the percentage of sperms with chromatin damage suggests decreased fertility in rats receiving the studied drugs. Both drugs affected bone formation in growing rats. Additionally, etravirine disturbed vitamin D metabolism.

Sitagliptin Modulates Oxidative, Nitrative and Halogenative Stress and Inflammatory Response in Rat Model of Hepatic Ischemia-Reperfusion.

A possibility of repurposing sitagliptin, a well-established antidiabetic drug, for alleviating injury caused by ischemia-reperfusion (IR) is being researched. The aim of this study was to shed some light on the molecular background of the protective activity of sitagliptin during hepatic IR. The expression and/or concentration of inflammation and oxidative stress-involved factors have been determined in rat liver homogenates using quantitative RT-PCR and Luminex® xMAP® technology and markers of nitrative and halogenative stress were quantified using targeted metabolomics (LC-MS/MS). Animals (n = 36) divided into four groups were treated with sitagliptin (5 mg/kg) (S and SIR) or saline solution (C and IR), and the livers from IR and SIR were subjected to ischemia (60 min) and reperfusion (24 h). The midkine expression (by 2.2-fold) and the free 3-nitrotyrosine (by 2.5-fold) and IL-10 (by 2-fold) concentration were significantly higher and the Nox4 expression was lower (by 9.4-fold) in the IR than the C animals. As compared to IR, the SIR animals had a lower expression of interleukin-6 (by 4.2-fold) and midkine (by 2-fold), a lower concentration of 3-nitrotyrosine (by 2.5-fold) and a higher Nox4 (by 2.9-fold) and 3-bromotyrosine (by 1.4-fold). In conclusion, IR disturbs the oxidative, nitrative and halogenative balance and aggravates the inflammatory response in the liver, which can be attenuated by low doses of sitagliptin.

Antiepileptic Stiripentol May Influence Bones.

Bone structure abnormalities are increasingly observed in patients chronically treated with antiepileptic drugs (AEDs). The majority of the available data concern older conventional AEDs, while the amount of information regarding newer AEDs, including stiripentol, is limited. The aim of the study was to assess the effect of stiripentol on bones. For 24 weeks, male Wistar rats, received 0.9% sodium chloride (control group) or stiripentol (200 mg/kg/day) (STP group). In the 16th week of the study, we detected lower serum PINP levels in the STP group compared to the control group. In the 24th week, a statistically significant lower 1,25-dihydroxyvitamin D3 level, higher inorganic phosphate level and higher neutrophil gelatinase-associated lipocalin (NGAL) levels in serum were found in the STP group compared to the control. Micro X-ray computed tomography of the tibias demonstrated lower bone volume fraction, lower trabecular thickness, higher trabecular pattern factor and a higher structure model index in the stiripentol group. Considering the results of this experiment on rats which suggests that long-term administration of stiripentol may impair the cancellous bone microarchitecture, further prospective human studies seem to be justified. However, monitoring plasma vitamin D, calcium, inorganic phosphate and kidney function in patients on long-term stiripentol therapy may be suggested.

Long-term stiripentol administration, an anticonvulsant drug, does not impair sperm parameters in rats.

In this study, we investigated the influence of long-term administration of stiripentol on sex hormones and semen quality in young Wistar rats. Investigated animals received for 6 months either stiripentol or saline solution. After one month, stiripentol increased temporarily serum level of testosterone (p < 0.05) and FSH (p < 0.01). However, after 6 months levels of testosterone, FSH, LH, prolactin and SHBG were comparable in both groups. After 6 months, semen analysis did not reveal differences in sperm concentration, total sperm count and sperm motility between groups. However, stiripentol increased the rate of head defect (p < 0.001) and midpiece abnormalities (p < 0.05). Flow cytometry revealed higher percentage of live cells without lipid peroxidation (p < 0.00001) and higher percentage of live spermatozoa with intact acrosomes (p < 0.000001) in rats receiving stiripentol. There was no significant difference between groups in sperm mitochondrial activity and DNA fragmentation index. However, percentage of high DNA stainability cells was increased in stiripentol group (p < 0.001). The data showed that stiripentol does not cause obvious disturbances in young rat's semen. Detected changes in semen morphology and chromatin structure need further explanation, and their influence on rat's fertility should be evaluated.

Morin-5'-Sulfonic Acid Sodium Salt (NaMSA) Attenuates Cyclophosphamide-Induced Histological Changes in Genitourinary Tract in Rats-Short Report.

Cyclophosphamide (CPX) exerts toxicity in the urogenital system. The current study was designed to evaluate the effect of morin-5'-sulfonic acid sodium salt (NaMSA) on CPX-induced urogenital toxicity in rats. NaMSA (100 mg/kg/daily) and CPX (15 mg/kg/daily) alone or in combination and 0.9% NaCl (as a control) were given intragastrically for 10 days. Testes and epididymes from male and urinary bladders from male and female rats were evaluated histologically. In testes and epididymes, morphological changes and relative decrease in sperm count were assessed. In urinary bladders edema, hemorrhage and urothelium erosions were described by 0-2 points scoring system. Reproductive score (RS-in total 6 points) and urinary bladder score (BS-in total 6 points) were thereafter calculated. In CPX-receiving group RS (2.7) and BS (3.3) were significantly higher than in the control (0.5 and 0.25 for RS and BS, respectively). Co-administration of NaMSA reversed most of the morphological changes, which was reflected by lower RS and BS score (0.5 and 1.2 for RS and BS, respectively). The preliminary findings suggest that NaMSA may attenuate CPX-induced histological changes in rat urogenital tract.

Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Exert Antinociceptive Activity in the Tail-Flick and Formalin Test in Rodents and Reveal Reduced Gastrotoxicity.

Despite the availability of the current drug arsenal for pain management, there is still a clinical need to identify new, more effective, and safer analgesics. Based on our earlier study, newly synthesized 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone, especially 10b and 13b, seem to be promising as potential analgesics. The current study was designed to investigate whether novel derivatives attenuate nociceptive response in animals subjected to thermal or chemical noxious stimulus, and to compare this effect to reference drugs. The antinociceptive effect of novel compounds was studied using the tail-flick and formalin test. Pretreatment with novel compounds at all studied doses increased the latency time in the tail-flick test and decreased the licking time during the early phase of the formalin test. New derivatives given at the medium and high doses also reduced the late phase of the formalin test. The achieved results indicate that new derivatives dose-dependently attenuate nociceptive response in both models of pain and exert a lack of gastrotoxicity. Both studied compounds act more efficiently than indomethacin, but not morphine. Compound 13b at the high dose exerts the greatest antinociceptive effect. It may be due to the reduction of nociceptor sensitization via prostaglandin E2 and myeloperoxidase levels decrease.

Cornelian Cherry Iridoid-Polyphenolic Extract Improves Mucosal Epithelial Barrier Integrity in Rat Experimental Colitis and Exerts Antimicrobial and Antiadhesive Activities In Vitro.

BACKGROUND AND AIMS: Inflammatory bowel disease pharmacotherapy, despite substantial progress, is still not satisfactory for both patients and clinicians. In view of the chronic and relapsing disease course and not always effective treatment with adverse effects, attempts to search for new, more efficient, and safer substances are essential and reasonable. This study was designed to elucidate the impact of cornelian cherry iridoid-polyphenolic extract (CE) and loganic acid (LA) on adherent-invasive E. coli growth and adhesion in vitro and to assess the effect of pretreatment with CE or LA on the course of intestinal inflammation in rat experimental colitis compared with sulfasalazine. METHODS: Antibacterial and antiadhesive activities of CE and LA were assessed using microdilution, Int407 cell adherence, and yeast agglutination assays. The colitis model was induced by 2,4,6-trinitrobenzenesulfonic acid. Studied substances were administered intragastrically for 16 days prior to colitis induction. Body weight loss; colon index; histological injuries; IL-23, IL-17, TNF-α, and chemerin levels; and STAT3, Muc2, and TFF3 mRNA expression were evaluated. RESULTS: Only CE exerted antimicrobial and antiadhesive activities in vitro and alleviated colonic symptoms. CE coadministrated with sulfasalazine was more effective than single compounds in reversing increased concentrations of TNF-α, IL-17, and chemerin and decreased Muc2 mRNA expression. CONCLUSIONS: CE exerted a protective effect against experimental colitis via impaired mucosal epithelial barrier restoration and intestinal inflammatory response attenuation and given concomitantly with sulfasalazine counteracted colitis in a more effective way than sulfasalazine alone, which indicates their synergistic interaction. The beneficial effect of CE may also be due to its bacteriostatic and antiadhesive activities.

Sitagliptin-Dependent Differences in the Intensity of Oxidative Stress in Rat Livers Subjected to Ischemia and Reperfusion.

PURPOSE: Ischemia/reperfusion (IR) is the main cause of liver damage after transplantation. We evaluated the effect of sitagliptin (STG) on oxidative stress parameters in the rat liver under IR. METHODS: Rats were treated with STG (5 mg/kg) (S and SIR) or saline solution (C and CIR). Livers from CIR and SIR were subjected to ischemia (60 min) and reperfusion (24 h). During reperfusion, aminotransferases (ALT and AST) were determined in blood samples. Thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), paraoxonase-1 (PON1), glutathione peroxidase (GPx), and the mRNA expression of SOD1 were determined in liver homogenates after reperfusion. Different regions of livers were also histologically evaluated. RESULTS: The PON1 activity was higher, and the TBARS level was lower in SIR than in CIR. There was an inverse relationship between TBARS and PON1 levels in the whole cohort. The GPx activity was lower in ischemic than in nonischemic groups regardless of the STG treatment. In SIR, the SOD1 activity was higher compared to that in CIR. In S, the expression of SOD1 mRNA was the highest of all examined groups and positively correlated with the SOD1 activity in the whole animal cohort. During IR aminotransferases, the activity in the drug-treated group was lower in all examined points of time. In drug-treated groups, the percentage of steatosis was higher than that in nontreated groups regardless of IR. CONCLUSIONS: The protective effect of STG on the rat liver, especially its antioxidant properties, was revealed under IR conditions.

Long-term administration of fenspiride has no negative impact on bone mineral density and bone turnover in young growing rats.

BACKGROUND: Fenspiride is an antagonist of H1-histamine receptors that is used to treat acute and chronic respiratory tract infections and otitis media in children and adolescents. OBJECTIVES: The aim of the study was to assess the influence of long-term administration of fenspiride on bone mineral density (BMD) and bone turnover in young growing rats. MATERIAL AND METHODS: The experiment was carried out on 18 young (8-week-old) male Wistar rats receiving either fenspiride 15 mg/kg intragastrically (ig) (group F) or saline solution 4 mL/kg ig (group C) for 3 months. On days 1 and 93, blood samples were collected and serum levels of calcium, phosphorus and markers of bone turnover were measured. On days 2 and 92, BMD was measured with dual-energy x-ray absorptiometry (DXA) using small animal software. RESULTS: We detected no influence of fenspiride on weight gain, total body BMD (0.212 ±0.010 g/cm2 vs 0.204 ±0.024 g/cm2), hind limb BMD (0.264 ±0.016 g/cm2 vs 0.252 ±0.027 g/cm2), or bone macroscopic parameters. There were no significant differences between group F and group C in serum levels of osteocalcin (group F: 0.42 ±0.09 ng/mL vs group C: 0.43 ±0.08 ng/mL), C-terminal telopeptide of type I collagen (F: 0.31 ±0.08 ng/mL vs C: 0.29 ±0.08 ng/mL), osteoprotegerin (F: 5.47 ±0.78 pg/mL vs C: 5.35 ±1.65 pg/mL), receptor activator of nuclear factor kappa B ligand (F: 0.65 ±0.85 pg/mL vs C: 0.56 ±0.86 pg/mL), parathormone (F: 237 ±182 pg/mL vs C: 289 ±200 pg/mL), total calcium (F: 6.38 ±1.50 mg/dL vs C: 6.83 ±1.71 mg/dL), or inorganic phosphorus (F: 5.19 ±1.76 mg/dL vs C: 5.50 ±1.32 mg/dL). CONCLUSIONS: Long-term administration of fenspiride has no negative impact on BMD and bone metabolism in young growing rats.

The impact of sitagliptin, inhibitor of dipeptidyl peptidase-4 (DPP-4), on the ADMA-DDAH-NO pathway in ischemic and reperfused rat livers.

BACKGROUND: A correlation between the level of asymmetric dimethylarginine (ADMA) - the inhibitor of the nitric oxide (NO) synthesis - and the liver function and survival after a liver transplantation has been reported. OBJECTIVES: The aim of this study was to evaluate the effect of sitagliptin -the inhibitor of dipeptidyl peptidase-4 (DPP-4) - on the NO-ADMA-dimethylarginine dimethylaminohydrolase (DDAH) pathway in rat livers subjected to ischemia/reperfusion (IR). MATERIAL AND METHODS: The rats received sitagliptin (5 mg/kg, per os - p.o.) (groups: S - livers not subjected to IR procedure, and SIR - livers subjected to IR procedure) or a saline solution (groups: C - livers not subjected to IR procedure, and CIR - livers subjected to IR procedure) for 14 days; following this, livers in the SIR and CIR groups were subjected to ischemia (60 min) and reperfusion (24 h). Aminotransferases were measured before the surgery; additionally, the arginine (ARG), ADMA and symmetric dimethylarginine (SDMA) levels were estimated just before ischemia and during reperfusion (at 0.5, 4 and 24 h). After IR, citrulline, the DDAH activity, mRNA for type 1 DDAH (DDAH1), and arginine methyltransferase type 1 (PRMT1) were determined. RESULTS: The increase in the initial level of ARG/ADMA0 (A/A) ratio in group S compared to group C verged on statistical significance. At 0.5 and 4 h of reperfusion, the highest concentration of ADMA was found in group CIR. At those time points, the ARG level and the A/A ratio were decreased in groups CIR and SIR as compared to groups C and S, respectively. The alanine transaminase (ALT) activity was lower in the sitagliptin-treated group than in the non-treated one. The DDAH and citrulline levels were reduced in group CIR as compared to group C, but were greater in group SIR as compared to group S. The PRMT1 mRNA expression was higher in groups CIR and SIR, compared to groups C and S, respectively. CONCLUSIONS: The increased A/A ratio suggests a protective effect of sitagliptin on livers not subjected to IR. Changes in the DDAH activity and the PRMT1 mRNA expression also imply the protective activity of sitagliptin during IR.

Age-related differences in function and structure of rat livers subjected to ischemia/reperfusion.

INTRODUCTION: Liver function is affected during ischemia/reperfusion (IR). The current state of knowledge about liver aging processes during IR is incomplete. We evaluated the effects of aging on liver structure and function under IR conditions. MATERIAL AND METHODS: Animals were divided into control (C-2) and ischemia/reperfusion (IR-2) groups of young rats (2-4 months old) and C-12 and IR-12 groups of old rats (12-14 months old). The livers from IR-2 and IR-12 groups were subjected to partial ischemia (60 min), followed by global reperfusion (4 h). Blood samples were obtained during reperfusion (0, 30 and 240 min) to estimate the activity of aminotransferases (ALT, AST). After IR, tumor necrosis factor-α (TNF-α), interleukin-1b (IL-1b), malondialdehyde (MDA), and superoxide dismutase (SOD) were determined in liver homogenates. RESULTS: At all points of reperfusion, an increase in aminotransferase activity levels in the ischemic groups was observed; mainly between IR-12 and C-12 rats. The concentration of TNF-α was significantly higher in young animals (in non-ischemic groups: p = 0.09, in ischemic groups: p = 0.05). Under IR conditions, the concentration of IL-1b dropped (p = 0.05). The concentration of MDA was significantly higher in mature animals (in non-ischemic groups: p = 0.09, in ischemic groups: p = 0.05). In ischemic groups an increase in necrosis rate was observed regardless of age. Rats in the IR-12 group showed the most pronounced changes in hepatic architecture, including increased micro- and macrosteatosis and parenchymal cell destruction. CONCLUSIONS: The function and structure of mature livers slightly deteriorate with age and these differences are more noticeable under IR conditions.

The impact of mangiferin from Belamcanda chinensis on experimental colitis in rats.

BACKGROUND: Inflammatory bowel disease (IBD) [including Crohn's disease (CD) and ulcerative colitis (UC)] constitutes an important clinical problem. The pathogenesis of IBD remains unclear. It is believed that immune dysfunction, inflammatory mediators and oxidative damage play crucial roles in development of IBD. The condition is clinically associated with symptoms ranging from mild to severe during relapses, depending on the affected segment of the gastrointestinal tract. Bloody diarrhea with mucus, abdominal pain, weight loss and anemia are initial symptoms of both CD and UC. Differences between diseases become more evident in time, along with the development of intestinal and extraintestinal complications. Mangiferin (1,3,6,7-tetrahydroxyxanthone-C-2-ß-D-glucoside), a natural polyphenol in plants, exerts antioxidant and anti-inflammatory effects making it an interesting option for the treatment of inflammatory pathologies associated with oxidative stress in humans, such as IBD. PURPOSE: The aim of the current study was to elucidate the impact of mangiferin on colon tissues in 2,4,6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. METHODS: Mangiferin was obtained from Belamcanda chinensis rhizomes by a multistage process. Groups of rats were pre-treated with 10, 30 or 100 mg/kg of mangiferin, or with distilled water administered intragastrically for 16 days. An ethanol solution of TNBS or saline was given rectally on the day 15 of the experiment. The experiment was terminated on the day 17. The colon was removed, cleaned, weighed and examined macro- and microscopically. Determination of tumor necrosis factor α (TNF-α), interleukin 17 (IL-17), malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were performed spectrophotometrically in homogenates of colon tissues. RESULTS: Rats in the TNBS group developed symptoms of colitis, including: body weight loss, colon mass index increase and damage of intestinal tissues with concomitant increase in TNF-α, IL-17, MDA levels and decreased SOD activity. In non-TNBS-treated rats mangiferin did not cause any changes of studied parameters. Pre-treatment with mangiferin exerted a protective effect, reducing the intensity of damage caused by TNBS. Mangiferin at the doses of 30 and 100 mg/kg reduced the macro- and microscopic damage score and the MDA level in colon tissues. Only at the dose of 100 mg/kg, mangiferin decreased TNF-α and IL-17 concentrations, and SOD activity in colon tissues. CONCLUSION: Mangiferin attenuates inflammatory changes of colon tissues in experimental, TNBS-induced colitis in rats. Protective effect exerted by mangiferin depends primarily on its anti-inflammatory activity and secondarily on its antioxidant properties.

Oral administration of kaempferol inhibits bone loss in rat model of ovariectomy-induced osteopenia.

BACKGROUND: Postmenopausal osteoporosis and osteoporotic fractures constitute an increasing problem in developing countries. Kaempferol, isolated from seeds of Cuscuta chinensis, is an active flavonoid inhibiting in vitro osteoclast activity. The aim of the presented research was an assessment of kaempferol effect on estrogen-deficiency-induced bone structure disturbances in rats. METHODS: The study was performed on 24 Wistar female rats divided into 3 groups: SHAM - rats undergoing a "sham" surgery, OVX-C - control group of animals that underwent ovariectomy, OVX-K - rats undergoing ovariectomy and receiving kaempferol for 8 weeks (from day 56 to day 112). RESULTS: In the OVX-K group, contrary to the OVX-C one, there was no significant decrease in femoral bone mineral density (BMD). A significant increase in Young's modulus was observed in the OVX-K group compared to the OVX-C (15.33±2.51GPa vs. 11.14±1.93GPa, p<0.05). A decreased bone turnover was detected in the OVX-K group. Tissue volume ratio (BV/TV) and trabecular bone perimeter were increased in the OVX-K group compared to the OVX-C one (0.241±0.037 vs. 0.170±0.022, p<0.05 and 15.52±2.78mm vs. 9.67±3.07mm, p<0.05, respectively). CONCLUSION: Kaempferol has a beneficial influence on estrogen-deficiency-induced disturbances of bone structure in rats.