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Background Streptozotocin (STZ) is a glucose analogue commonly used for inducing diabetes in experimental animals. This study is intended to investigate the ability of captopril (Cap) pretreatment to augment STZ-induced diabetogenic effect in an experimental rat model. If this hypothesis were proven, Cap administration to rats could reduce the dosage of STZ by augmenting its effect and resulting in a subsequent reduction in STZ cost. Forty-two adult male Wistar rats were randomly divided into seven groups: a control group that fed a normal diet, whereas the other six experimental groups were fed a high-fat diet (HFD). The six groups were then divided into STZ-30, STZ-30-Cap, STZ-40, STZ-40-Cap, STZ-50, and STZ-50-Cap. All Cap-received groups were supplemented with 50 mg/kg Cap orally one hour just before intraperitoneal (I.P.) injection of STZ. 30-STZ, 40-STZ, and 50-STZ-treated groups were injected once with STZ I.P. at doses of 30, 40, and 50 mg/kg, respectively. An intraperitoneal glucose tolerance test (IPGTT) was done. Pancreatic tissue was obtained to measure Tumor necrosis factor alpha (TNF-α), interleukin one beta (IL-1β), and nitric oxide (NO) by enzyme-linked immunosorbent assay (ELISA) and glucose transporter 2 (GLUT2) gene expression by reverse transcription polymerase chain reaction (RT-PCR). Pancreatic sections were examined by hematoxylin and eosin (H&E) stain, and immunohistochemical staining by anti-insulin and anti-TNF-α antibodies. Results Results indicated that administration of Cap before STZ in different doses significantly augmented the hyperglycemic state that was evident by intraperitoneal glucose tolerance test, and markedly increased pancreatic pro-inflammatory markers. Histological analysis of islets of Langerhans indicated degeneration with extensive vacuolations associated with a significant decrease in mean area % of insulin immunoreactivity and an increase in optical density of TNF-α immunoreactivity. Conclusion These findings pointed to the ability of captopril pretreatment to augment the hyperglycemic state and the diabetogenic response that was induced secondary to STZ injection in an experimental rat model.

Background Disturbed intestinal integrity and increased permeability are linked to dysbiosis. This disruption involves GIT-related and unrelated diseases, such as neurological diseases. Intake of a high-fat diet (HFD) leads to an imbalance of gut microbiota and regression of bacteria producing “short-chain fatty acids (SCFAs)”. These SCFAs can modulate brain functions. Therefore, we investigated the therapeutic effect of Clostridium Butyricum (CB) bacteria extracted from human faeces on intestinal and neurological impairments induced by HFD and explored their modulation of tight junction protein expression. Materials and methods Twenty-four adult male rats were classified into the control group, which received regular rat chow; the HFD group, which received HFD for 16 weeks; and the HFD-Microbiota group, which received HFD as in group II for 16 weeks, but from week 9 received CB (dose of 2 ml (2.3 × 10 11  cfu/ml) daily till scarification. Results The microbiota improved working memory, episodic-like memory, and emotional memory. Also, there was a substantial decline in the animals’ body weights, serum lipopolysaccharides, interleukin-1β, tumour necrosis factor-α, insulin, glucose, and HOMA index compared to the HFD group. A remarkable increase in brain and colonic claudin-5 and occluding expression of its gene in the microbiota-treated group in comparison with the HFD group was reported. SCFAs, intestinal, brain claudin-5, and occludin genes were positively correlated. Also, a positive correlation was found between the F/B ratio and both brain beta-amyloid and Tau proteins. Conclusion Repeated intake of CB hindered systemic /neuroinflammation, enhanced the tight junction proteins’ expression in the gut/brain barrier, and improved cognitive functions.

Background Malignant tumors of the breast are the most diagnosed cancers in females globally. Recent evidence suggests that carbohydrate restriction (CR), especially ketogenic diets, has become a potential treatment approach for many malignancies, including breast cancer. Tamoxifen (TAX) is a selective estrogen receptor modulator (ERM) that can reduce the risk of cancer recurrence. The current work was designed to assess the impact of CR on the proliferation of breast adenocarcinoma cells and to compare this impact with that of TAX. Study groups included: group 1: vehicle-treated mice; group 2: the Ehrlich group: injected Ehrlich ascites carcinoma (EAC) cells (2.5 × 10 6 ) in 0.25 ml isotonic saline; group 3: CR group: mice were supplied with a diet regimen of severe CR throughout the study and injected EAC at week 7; group 4: hormonal therapy (HT) group: mice in this group injected with EAC at week 7 and then received TAX at a dose of 20 mg/kg 3 times/week orally for 3 weeks; and lastly group 5: the group of combined intervention. The mice in the CR, HT, and the combined groups received Ehrlich cancer cells at the same dose and route as the Ehrlich group. Results CR and HT groups demonstrated a significant decrease in levels of insulin-like growth factor (IGF-1), carbohydrate antigen (CA 15–3), hexokinase 2 (HK2), hypoxia-inducible factor-1 (HIF-1) α, and malondialdehyde (MDA) compared to the Ehrlich group. Additionally, the mean area % of caspase-3 was significantly increased, and the mean area % of Ki67 and estrogen receptor (ER)α was significantly decreased. Conclusions The combined treatment demonstrated the most advantageous outcome, as evidenced by reduced CA 15–3 levels, tumor size, and the mean area % of Ki67. This suggests that the addition of severe CR to the conventional therapy of breast cancer has a beneficial effect.

Globally, hepatocellular carcinoma (HCC) presents a clinical and financial burden, as it is often diagnosed at a later stage. Cisplatin is one of the most commonly used chemotherapeutics for treating various types of solid tumours; however, it is a double-edged sword due to its cytotoxic effects. Consequently, we hypothesized that combining cisplatin with melatonin could be effective in treating HCC. Additionally, melatonin may mitigate the severe adverse effects of cisplatin on normal cells through its cellular protection, immunomodulation, and antioxidant activities. Forty male adult Wistar rats were randomly divided into five groups: Group 1( n =  8), negative control group. HCC was induced in 32 rats with diethyl nitrosamine and carbon tetrachloride injection. Following induction, rats were divided into group 2 (HCC): diseased control; group 3 (HCC-Cis): HCC rats received cisplatin (2.5 mg/kg I.P. once every week for 3 weeks); group 4 (HCC-Melatonin): HCC rats received melatonin in drinking water (20 mg/L for 3 weeks); and group 5 (HCC-Cis-Melatonin; Combined therapy): the HCC rats received both cisplatin and melatonin . HCC group revealed significant elevation in ALT, AST, and AFP associated with increased TNF-α and MDA levels. Hepatic tissue exhibited a significant increase in VEGF, MDM2, COX-2, and miR-155, and a decrease in caspase-3 associated with hepatic damage, ballooning of hepatocytes, and increased BCL-2 and CD68 immunostaining. Although cisplatin was able to induce HCC apoptosis by COX-2 and MDM2/p53/ miR-155 modulation, it aggravated normal hepatocytic damage that was improved by the antioxidant and anti-inflammatory effects of melatonin. In conclusion, melatonin and cisplatin co-administration may be a viable strategy to preserve liver function by shielding healthy hepatocytes from the cytotoxic effects of cisplatin.

Background and objectives The X-linked bleeding disorder, hemophilia A, is caused by defective production of factor VIII (FVIII). Hemophilic patients require regular FVIII infusions. Recombinant factor replacement poses the safest line of therapy. However, its main drawbacks are high expenses and the higher liability for formation of inhibitors. Recent studies confirmed the ability of bone marrow-derived stem cells to secrete FVIII. This study aims to generate bioscaffold from decellularized liver and subsequently seed it with trans-differentiated human stem cells into hepatic-like cells. This scaffold can then be implanted intraperitoneally or subcutaneously to provide FVIII. Methods After generation of the bioscaffold, seeding of discoid scaffolds with trans-differentiated human hepatocyte-like cells was performed. Then, the generated organoid was implanted into peritoneal cavity or subcutaneous tissue of experimental rats. Results Serum human FVIII was significantly increased in rats subjected to subcutaneous implantation compared intraperitoneal implantation. Immunostaining for detecting Cytokeratin 19 and human anti-globulin confirmed the presence of mature human hepatocytes that were significantly increased in subcutaneous implanted scaffold compared to the intraperitoneal one. Conclusion Implantation of decellularized bioscaffold seeded with trans-differentiated stem cells in rats was successful to establish production of FVIII. Subcutaneous implantation showed higher FVIII levels than intraperitoneal implantation.

Polycystic ovarian syndrome (PCOS) is a complex endocrine-metabolic disorder, and multiple factors contribute to its pathophysiology. The current study assessed a PCOS-like animal model induced by consuming a high-fat sugar (HFHS) diet and compared the treatment outcome of mitochondrial-targeted antioxidants versus heat therapy. Sixty rats were divided into the following study groups: three control groups (negative and positive for the treatments used), HFHS, hot tub therapy (HTT) treatment, and MitoQ10 treatment (500 µmol/L MitoQ10 in clean drinking water daily, from week fourteen till week twenty-two of the study). At week fourteen, PCOS was confirmed by vaginal smear examination; measurements of blood testosterone (T), anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), glucose, and insulin; and determination of the homeostatic model assessment of IR (HOMA-IR). At week 22, blood samples were collected for measurement of the serum LH, FSH, AMH, T, insulin, glucose, lipid profile, kisspeptin, ADAM metallopeptidase with thrombospondin type 1 motif 19 (ADAMTS19), S100 calcium-binding protein B (S100B), fibulin 1 (FBLN1), immunoglobulin free light chains (FLCs), kappa and lambda. Ovaries were examined for morphological changes; for the levels of glutathione (GSH), catalase, SOD, malondialdehyde (MDA), and nitric oxide (NO); and the expression of FK506 binding protein 52 (FKBP52) and the androgen receptor (AR). The consumption of HFHS diet-induced PCOS-like features, which have been ameliorated by both HTT and mitoQ10 as potential therapies, with MitoQ10 showing a superior effect over HTT. Graphical Abstract

While animal models for schizophrenia, ranging from pharmacological models to lesions and genetic models, are available, they usually mimic only the positive symptoms of this disorder. Identifying a feasible model of chronic schizophrenia would be valuable for studying the possible underlying mechanism and to investigate emerging treatments. Our hypothesis starts from the observation that combining ketamine with isolation could result in long-lasting neuro-psychological deficits and schizophrenia-like features; thus, it could probably be used as the first model of chronic schizophrenia that emphasizes the characteristic of having a multifactorial etiology. By the means of this study, we investigated the effects of ketamine administration combined with isolation in inducing schizophrenia-like symptoms in male albino rats and the brain reactive oxygen species levels. Our results showed that the number of lines crossings in the open field test, the number of open arm entries in the elevated plus maze, and the spontaneous alternations percentage in the Y-maze were significantly lower in the ketamine + isolation group compared to both the control and ketamine + social housing group (p < 0.05). Furthermore, the ketamine + isolation intervention significantly increased the MDA levels and decreased the GPx levels both in the hippocampus and the cortex of the rats. In addition, our premise of creating a model capable of exhibiting both positive and negative symptoms of schizophrenia was also based on adding the aripiprazole treatment to a group of rats. Therefore, we compared the ketamine + social isolation group with the ketamine + social isolation + aripiprazole group in order to attempt to discover if the antipsychotic drug would significantly decrease the potential positive schizophrenia-like symptoms induced by social isolation and ketamine. Given that we obtained significant results, we cautiously presume that this might be an important step in developing our animal model capable of illustrating both positive and negative symptoms of schizophrenia. This study could be a first step towards the creation of a complex animal model capable of exhibiting the multifactorial origin and manifestation of schizophrenia.

Background Preeclampsia is a systemic, multi‐organ endotheliopathy, associated with oxidative injury to the blood–brain barrier (BBB). Preeclampsia initiates a cascade of events that include neuroinflammation. Recently, it was documented that Wnt/β‐catenin signaling pathway exerts neuroprotective effects and maintain BBB integrity. We investigate the protective effect of omega‐3 against neurovascular complication of preeclampsia and its relation to Wnt/β‐catenin signaling pathway. Methodology After confirmation of day 0 pregnancy (G0), 24 adult pregnant female Wistar rats were divided into four groups control pregnant, pregnant supplemented with omega‐3, preeclampsia (PE); female rats received N (ω)‐nitro‐L‐arginine methyl ester (L‐NAME) (50 mg/kg/day SC from day 7 to day 16 of pregnancy for induction of preeclampsia) and PE rats supplemented with omega‐3. The intake of omega‐3 started on day zero (0) of pregnancy until the end of the study (144 mg/kg orally). Results We found that omega‐3 supplementation significantly improved cognitive functions and EEG amplitude, decreased blood pressure, water contents of brain tissues, sFlt‐1, oxidative stress, proteinuria, and enhanced Wnt\\β‐catenin proteins. Histological examination showed improved cerebral microangiopathy, increased expression of claudin‐1 and ‐3, CD31, and VEGF in the cerebral cortical microvasculature and choroid plexus in PE rats treated with omega‐3. A positive correlation between protein expression level of Wnt \\β‐catenin and cognitive functions, and a negative correlation between claudin‐5 relative expression, claudin‐1 and ‐3 area % from one side and water content of the brain tissues from the other side were observed. Conclusion Wnt/β‐catenin signaling pathway suspected to have an important role to improve BBB integrity. Neuroprotective, antioxidant, and anti‐inflammatory effects of omega‐3 were observed and can be suggested as protective supplementation for preeclampsia. Disruption of tight junction structure in BBB leads to brain edema and enhances vascular leakiness. Negative‐regulation of Wnt/β‐catenin signaling decreased its downstream claudin‐1 and ‐3 in preeclamptic rat model. Meanwhile, omega‐3 intake enhanced Wnt/β‐catenin signaling pathway that was associated with increased claudin‐1 and ‐3 expression, reducing Vasogenic edema together with improved cognitive function.