Effect of dexpanthenol on cyclophosphamide-induced ovarian toxicity: a histological and molecular study in rats.

RESEARCH QUESTION: Does dexpanthenol work as an effective therapeutic agent against cyclophosphamide (CYC)-induced premature ovarian failure (POF) in rats? DESIGN: A total of 28 female Wistar Albino rats were randomly divided into four groups (n = 7 per group). The POF and POF plus dexpanthenol groups were intraperitoneally administered CYC at an initial dose of 50 mg/kg, followed by 8 mg/kg for 14 days. The dexpanthenol and POF plus dexpanthenol groups were both intraperitoneally administered dexpanthenol at a dose of 500 mg/kg/day for 15 days. RESULTS: In the group administered CYC, the following was observed: a decrease in the ovarian index; a decrease in the numbers of primordial, primary, secondary and antral follicles; an increase in the number of corpus luteum and atretic follicles; a decrease in proliferation cell nuclear antigen immunoreactivity; a significant reduction in anti-Müllerian hormone and oestradiol levels; and an increase in serum FSH levels compared with controls. Dexpanthenol, on the other hand, reversed these effects. Quantitative reverse transcription polymerase chain reaction analyses showed that dexpanthenol increased Bcl-2, Akt1, mTOR, Nrf2 and HO-1 in CYC-induced ovarian tissues, but decreased Bax, Cas3, Hsp27, Hsp70, and Hsp90. Dexpanthenol treatment has a potential for inhibiting the intrinsic apoptotic pathway and oxidative stress levels in ovarian tissues via the downregulation of the mRNA expression of heat shock proteins and the activation of Nrf2/HO-1 pathways. CONCLUSIONS: Our findings demonstrated that dexpanthenol is an effective agent against POF caused by CYC; however, further experimental and clinical data are needed to use it effectively.

Lipid-lowering, anti-inflammatory, and hepatoprotective effects of isorhamnetin on acetaminophen-induced hepatotoxicity in mice.

Isorhamnetin is a hepatoprotective flavonoid molecule derived from the leaves and fruits of Hippophae rhamnoides L. However, the protective effect of isorhamnetin on acetaminophen (APAP) induced hepatotoxicity is still unknown. Thus, we aimed to investigate the lipid-lowering, anti-inflammatory, and hepatoprotective effects of isorhamnetin on APAP-induced hepatotoxicity in mice. Hepatotoxicity was induced by a single injection of APAP (300 mg/kg, intraperitoneally). Isorhamnetin (50 or 100 mg/kg, orally) and N-acetylcysteine (NAC) (200 mg/kg, orally), or vehicle control, were administered 1 h before the administration of APAP. Total antioxidant status (TAS) and total oxidative status (TOS) of liver tissue and levels of inflammatory factors (TNF-α, IL-1ß, and IL-6) were analyzed by ELISA. Lipid profiles and liver function parameters were measured using an autoanalyzer. In addition, liver tissue was examined histopathologically. Isorhamnetin treatment significantly reduced the APAP-induced increase in the liver weight and liver index; it also reduced the APAP-induced increase in serum liver parameters (ALT, AST, ALP, and LDH) (p < 0.05). Isorhamnetin significantly reduced APAP-induced oxidative stress and inflammation by increasing TAS levels and decreasing TOS, TNF-α, IL-1ß, and IL-6 levels (p < 0.05). Moreover, isorhamnetin treatment significantly regulated lipid profiles (TG, T-C, LDL-C, and HDL-C levels) that changed in response to APAP administration (p < 0.05). In histopathological examination, liver degeneration observed in the APAP group was significantly reduced in the NAC and isorhamnetin-treated groups (p < 0.05). This study suggests that isorhamnetin has a significant protective effect on APAP-induced hepatotoxicity in mice through its lipid-lowering, antioxidant, and anti-inflammatory effects.

Phase-1 bioactivation mechanisms of aflatoxin through AhR, CAR and PXR nuclear receptors and the interactions with Nigella sativa seeds and thymoquinone in broilers.

Aflatoxins (AFs) are metabolised in two main phases in the liver. Cytochrome p450 enzyme (CYP) 1A1 and CYP2A6 are expressed through AhR, CAR and PXR nuclear receptors in phase-1 biotransformation of AFs. This study is the first to examine phase-1 biotransformation mechanisms of AF and the activity of Nigella sativa seed (NS) and its active ingredient thymoquinone (TQ) on these enzymes and receptors at the molecular level in broilers. Six groups of one day old broiler chicken (20 animals per group) were fed either control feed or a diet containing Aspergillus parasiticus NRRL 2999 culture material (total AFs 2 mg/kg), TQ (300 mg/kg), and NS (5%), either alone or as AF + TQ and AF + NS. Randomly selected from each group, 10 chicks were necropsied, and the livers were removed. Histopathological examination and serum biochemistry results revealed that AF caused hydropic and fatty degenerations, periportal inflammatory infiltrations, acinar arrangement, and biliary duct proliferation in livers and a significant increase at AST, ALT, ALP and GGT levels while significant decreases at serum cholesterol and total protein levels. These aflatoxicosis lesions and deteriorations in biochemistry levels were significantly ameliorated by NS or TQ (p < 0.05). AF was immunohistochemically found to increase strongly the nuclear receptors of AhR, PXR, CAR, and the enzyme activity of CYP1A1 and CYP2A6 responsible for its metabolism, leading to the emergence of toxic effects. Addition of TQ or NS to AF-containing diets improved the negative effects of AF on these receptors and enzymes significantly (p < 0.05). It was concluded that TQ and NS successfully alleviated liver injury by inhibiting or reducing the bioactivation of AF through phase-1 nuclear receptors and CYP-450 enzymes modulation.

Protective effects of nobiletin on cisplatin induced neurotoxicity in rats.

OBJECTIVES: This study was designed to investigate the possible antioxidant, antiapoptotic and neuroprotective effects of nobiletin on cisplatin-induced neurotoxicity rat model by evaluating neurotrophins, antioxidants and histopathology. METHODS: Forty male Wistar Albino rats were divided into four groups: control, cisplatin (CIS), cisplatin + nobiletin (CIS + NOB) and nobiletin + cisplatin (NOB + CIS). CIS + NOB was applied nobiletin (10 mg/kg, i.p.) during the last four days whereas NOB + CIS was applied nobiletin during the first four days of the study. Cisplatin (4 mg/kg, i.p. twice a day) was administered to the experimental groups on the 5th day of the study. All rats were sacrificed on the 10th day of the study. BDNF, NGF, G6PD, GPx, tGSH and MDA levels were determined in brain. In addition, routin histolopathological analysis and caspase-3 immunoreactivity assay were conducted. RESULTS: BDNF concentrations increased in nobiletin-administered groups, compared to Control and CIS and that the increase was statistically significant in NOB + CIS (p < 0.05). It was also found that G6PD activity increased (p < 0.05) in the nobiletin-administered groups, compared to control and CIS. Histopathologically, neuronal degeneration, oedema and gliosis increased in CIS compared to Control, and nobiletin administration decreased neuronal degeneration and oedema compared to CIS (p < 0.05). Cisplatin increased (p < 0.05) caspase-3 immunoreactivity in cerebrovascular endothelium and neurons compared to Control, while nobiletin administration decreased caspase-3 immunoreactivity in cerebrovascular endothelium. Caspase-3 immunoreactivity in neurons decreased only in NOB + CIS (p < 0.05). CONCLUSION: Nobiletin increased BDNF concentration and G6PD activity in brain and when evaluated together with histopathological and immunohistochemical findings, it may have antioxidant, antiapoptotic and neuroprotective effects against cisplatin.

Potential effects of Resatorvid and alpha lipoic acid on gentamicin-induced nephrotoxicity in rats.

Gentamicin is an aminoglycoside antibiotic with a rapid bactericidal effect on the treatment of many infections. However, its use at high concentrations for more than 7 days causes nephrotoxic side effects. This study investigated the potential of Resatorvid and alpha lipoic acid (ALA) in mitigating gentamicin-induced nephrotoxicity in rats, considering biochemical, histopathological, and molecular parameters. This study randomly distributed 34 Wistar albino rats into four groups: healthy control (n = 6), Gentamicin (80 mg/kg, n = 7), Gentamicin + Sham (%10 hydroalcoholic solution, n = 7), Gentamicin + Resatorvid (5 mg/kg, n = 7), and Gentamicin + ALA (100 mg/kg, n = 7). Resatorvid treatment led to a statistically significant decrease in urinary IL-18, KIM-1, and NGAL levels, whereas ALA treatment significantly reduced KIM-1 levels compared to the gentamicin-only group. Both Resatorvid and ALA showed partial reductions in urine creatinine levels. Moreover, treatments with Resatorvid and ALA resulted in statistically significant decreases in NRF-2, CAS-3, and NR4A2 expressions. However, only Resatorvid demonstrated a statistically significant decrease in NF-B expression. These findings highlight the potential of Resatorvid in ameliorating gentamicin-induced nephrotoxicity, thereby expanding the therapeutic utility of gentamicin and enhancing its efficacy against infections.

Congenital feline tuberculosis: the first case report.

This study presents the first report of congenital tuberculosis in an 8-month-old male British Shorthair cat. The case was examined using histopathological and immunohistochemical methods. The cat was referred to a private veterinary clinic with general respiratory system problems and subsequent deterioration, leading to death. The cat owner granted permission for the cat necropsy and pathological examinations at Department of Pathology, Faculty of Veterinary Medicine, Selçuk University, Konya, Türkiye. During systemic necropsy, white round foci with diameters ranging from 3.00 to 5.00 mm were observed in the lung and spleen. Tissue samples were collected from the lung, spleen, liver, heart, kidney, mediastinal lymph nodes and brain for histopathological examinations. The tissues were subjected to routine histological tissue processing and sections were stained with Hematoxylin and Eosin and Ziehl-Neelsen. Additionally, Mycobacterium spp. antibodies were used for immunohistochemical staining. Microscopic examination revealed exudative tuberculosis lesions, areas of necrosis without a fibrous capsule and karyorrhectic cells only in the lung and spleen. Acid-resistant bacteria observed by ZN staining in the lesioned areas of the lung and spleen were identified as Mycobacterium spp. using immunohistochemical staining. No positive staining was observed in other organs using ZN and immunohistochemical methods. As a result, congenital tuberculosis was diagnosed in a cat for the first time, especially in relation to lesions in the spleen.

Exploring the combined therapeutic efficacy of bexarotene and icariin in type 2 diabetic rats.

OBJECTIVES: The aim of this study was to determine the single and combined antidiabetic activity and side effects of the retinoid X receptor agonist bexarotene and the thioredoxin-interacting protein inhibitor and peroxisome proliferator-activated receptor γ and AMP-activated protein kinase activator icariin. METHODS: The rats were grouped as healthy (control), diabetes, diabetes + bexarotene (20 mg/kg), diabetes + icariin (60 mg/kg), diabetes + bexarotene (10 mg/kg) + icariin (30 mg/kg) low-dose combination and diabetes + bexarotene (20 mg/kg) + icariin (60 mg/kg) high-dose combination groups. KEY FINDINGS: Icariin treatment led to a significant reduction in glucose levels compared with the diabetes control group, a remarkable outcome observed 45 days after the initial application. HbA1c levels of the icariin and low-dose combination treatment groups were significantly lower than in the diabetes group. Notably, icariin treatment also significantly elevated HOMA-ß levels, which is indicative of improved ß-cell function. Icariin significantly decreased glucose levels at 30 and 120 min in the oral glucose tolerance test. Moreover, it ameliorated hepatocyte degeneration, hepatic cord dissociation, congestion, mononuclear cell infiltration in the liver, and degeneration in the pancreas. CONCLUSIONS: Icariin treatment exhibited robust antidiabetic effects with fewer side effects than other treatment options in this study. In future studies, long-term and varying doses of icariin will contribute to the development of novel antidiabetic drugs.

Protective and therapeutic effects of nobiletin against cisplatin-induced nephrotoxicity in rats.

Possible protective and therapeutic effects of nobiletin on kidney in a cisplatin-induced nephrotoxicity rat model were investigated. Forty male albino rats were divided into four groups: control, cisplatin (CIS), cisplatin+nobiletin (CIS+NOB), and nobiletin+cisplatin (NOB+CIS). At the end of the study, the rats were subjected to biochemical, histological and immunohistochemical analyzes. Compared to the control group, tGSH (p < 0.05) levels, and G6PD (p < 0.05) and GPx (p < 0.001) activities, were increased in the CIS group; while significant (p < 0.05) decreases occurred in the MDA and TOC levels. Histopathologically, the kidneys of the groups administered nobiletin (CIS+NOB, NOB+CIS) were significantly different from the CIS group, being closer to control group in terms of degeneration and hyaline cylinder formation in the tubules (p < 0.05). While dilatation in the tubules, protein-rich fluid and hyaline cylinder formation in the lumen were most common in the CIS group, a significant decrease (p < 0.05) of these parameters was seen in the nobiletin groups (CIS+NOB, NOB+CIS). This study suggests that nobiletin can be effective in preventing and ameliorating toxic effects of cisplatin on the kidney.

The Usefulness of Serum Brain Damage Biomarkers in Detection and Evaluation of Hypoxic Ischemic Encephalopathy in Calves with Perinatal Asphyxia.

The purpose of the present study was to determine hypoxic brain damage in calves with perinatal asphyxia using brain-specific damage biomarkers. Ten healthy and 25 calves with perinatal asphyxia were enrolled in the study. Clinical examination, neurological status score, and laboratory analysis were performed at admission, 24, 48, and 72 h. Serum concentrations of ubiquitin carboxy-terminal hydrolysis 1 (UCHL1), calcium-binding protein B (S100B), adrenomodullin (ADM), activitin A (ACTA), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP) and creatine kinase-brain (CK-B) were measured. Histopathological and immunohistochemical examinations of the brain tissue were performed in 13 nonsurvivor calves. The neurological status score of the calves with asphyxia was significantly (p < 0.05) lower. Mix metabolic-respiratory acidosis and hypoxemia were detected in calves with asphyxia. Serum UCHL1 and S100B were significantly (p < 0.05) increased, and NSE, ACTA, ADM, and CK-B were decreased (p < 0.05) in calves with asphyxia. Histopathological and immunohistochemical examinations confirmed the development of mild to severe hypoxic-ischemic encephalopathy. In conclusion, asphyxia and hypoxemia caused hypoxic-ischemic encephalopathy in perinatal calves. UCHL1 and S100B concentrations were found to be useful markers for the determination of hypoxic-ischemic encephalopathy in calves with perinatal asphyxia. Neurological status scores and some blood gas parameters were helpful in mortality prediction.

The effects of Nigella sativa seeds and thymoquinone on aflatoxin phase-2 detoxification through glutathione and glutathione-S-transferase alpha-3, and the relationship between aflatoxin B1-DNA adducts in broilers.

The primary pathway of the detoxification of aflatoxin (AF) metabolites occurring at the end of phase-1 biotransformation is glutathione (GSH) conjugation via glutathione-S-transferase (GST) enzyme in phase-2. In this study, the activity of Nigella sativa seeds (NS) and thymoquinone (TQ) on phase-2 detoxification pathways of AF was investigated in light of GSH, GST alpha-3 (GSTA3), and AFB1-DNA adducts detected by the immunohistochemical method in broilers' livers. One-hundred twenty chickens at one-day-old were divided into six groups as the control (CNT), AF, TQ, NS, AF + TQ, and AF + NS groups and fed for 28 days. AF, TQ, and NS were added to the relevant diets at 2 mg/kg, 300 mg/kg, and 5%, respectively. The administration of AF alone strongly stimulated the formation of AFB1-DNA adduct and reduced GSH and GSTA3 levels in hepatocytes (p < 0,01). In contrast, TQ and NS were found to reduce significantly the amount of AFB1-DNA adducts in AF + TQ and AF + NS groups (p < 0,01). We concluded that NS and TQ achieved this by increasing GSH and GSTA3 levels (p < 0,01) thanks to their antioxidant properties, and hence detoxifying the reactive metabolites of AF. Also, we consider that the AFB1-DNA adduct constituted in 28 days can be used as a biomarker for exposure to AF in broilers.