Normal Male Rats Research Articles

Distinct Roles of Astrocytes and GABAergic Neurons in the Paraventricular Thalamic Nucleus in Modulating Diabetic Neuropathic Pain

Diabetic neuropathic pain (DNP) is a common chronic complication of diabetes mellitus and a clinically common form of neuropathic pain (NP). The thalamus is an important center for the conduction and modulation of nociceptive signals. The paraventricular thalamic nucleus (PVT) is an important midline nucleus of the thalamus involved in sensory processing, but the specific role of PVT astrocytes and GABAergic neurons in DNP remains unclear. Here, we examined the activity of PVT astrocytes and neurons at various time points during the development of DNP by fluorescence immunohistochemistry and found that the activity of PVT astrocytes was significantly increased while that of PVT neurons was significantly decreased 14 days after streptozotocin (STZ) injection in male rats. The inhibition of PVT astrocytes by chemogenetic manipulation relieved mechanical allodynia in male DNP model rats, whereas the activation of PVT astrocytes induced mechanical allodynia in normal male rats. Interestingly, chemogenetic activation of GABAergic neurons in the PVT alleviated mechanical allodynia in male DNP model rats, whereas chemogenetic inhibition of GABAergic neurons in the PVT induced mechanical allodynia in normal male rats. These data demonstrate the distinct roles of PVT astrocytes and GABAergic neurons in modulating DNP, revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.Significance StatementSome studies have focused on the role of paraventricular thalamic nucleus (PVT) glutamatergic neurons in neuropathic pain (NP) and anxiety. However, the role of PVT astrocytes and GABAergic neurons in diabetic neuropathic pain (DNP) has not been studied. We used chemogenetic techniques to bidirectionally regulate the activity of PVT astrocytes or GABAergic neurons and found that PVT astrocyte activation promotes NP, while PVT GABAergic neuron activation may mediate antinociceptive effects. These findings clarify the critical roles of PVT astrocytes and GABAergic neurons in modulating DNP, providing insight for the development of new strategies for the prevention and treatment of DNP and revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.

Baseline-dependent enhancement of working memory by memantine in male rats: Involvement of NMDA receptor subunits and CaMKII signaling

N-methyl-d-aspartate (NMDA) receptors, activated by glutamate, play a crucial role in learning and memory. Memantine (MEM), a non-competitive NMDA receptor antagonist, is currently prescribed for the treatment of Alzheimer's disease or dementia, which meanwhile simultaneously promotes a need to clarify its potential pro-cognitive effects that exist in normal healthy individuals. However, the neurobehavioral mechanisms underlying the cognitive improvement by MEM in normal individuals remain to be elucidated. This study aimed to assess the effects of MEM on working memory, measured by a discrete paired-trial delay alternation task in a T-maze in normal male rats. The impacts of MEM were hypothesized to vary depending on different baseline levels of working memory performance. Neurochemical examination of the levels of calcium/calmodulin-dependent kinase 2 (CaMKII) and NMDA receptor subunits within five targeted brain regions was conducted after behavioral tests. The results showed that acute administration of MEM enhanced working memory performance, with 2.5, 5.0, and 10 mg/kg doses increasing task accuracy compared to the vehicle, particularly in low performers. Neurochemically, the protein expression of CaMKII in the amygdala and that of the glutamate (Glu) N2A subunit in the dorsal striatum were greater in the low-performance group than in the high-performance group. Additionally, the protein expression of the GluN2A subunit in the dorsal striatum was negatively associated with task performance at baseline. The expression of GluN1 and GluN2B in the nucleus accumbens was negatively associated with task performance in the retest three weeks after drug treatment. These findings underscore the baseline-dependent improvement of working memory resulting from MEM administration, with observed drug effects associated with alterations in the levels of NMDA receptor subunits in striatal subareas and CaMKII in the amygdala.

Spirulina Unleashed: A Pancreatic Symphony to Restore Glycemic Balance and Improve Hyperlipidemia and Antioxidant Properties by Transcriptional Modulation of Genes in a Rat Model.

Hyperlipidemia is the root cause of numerous chronic conditions, leading to high mortality rates around the globe. Spirulina (Arthrospira platensis) microalgae serve as a promising reservoir of bioactive compounds with diverse pharmacological properties. The current study examined the nutritional profile of spirulina powder in relation to strict glycemic control, specifically focusing on its potential to lower lipid levels. In an in vivo investigation, normal healthy male Wistar albino rats (n = 60) were divided into two groups: a negative control group (NC) of ten rats and a high-fat diet group (n = 50) that were fed a cholesterol-rich diet until their cholesterol levels reached or exceeded 250 mg/dL. Subsequently, the hypercholesterolemic rats were then randomly allocated to several treatment groups: a positive control (PC); a standard treatment diet (STD) involving fenofibrate at a dose of 20 mg/kg body weight; and three experimental groups (T1, T2, and T3) that received spirulina powder supplementation at doses of 300, 600, and 900 mg per kg body weight, respectively, for the period of 12 weeks. Blood samples were analyzed for oxidative stress biomarkers, insulin levels, lipid profiles, liver function, and expression of gene levels in the diabetogenic pathway. The study utilized spectrophotometric colorimetric methods to identify oxidative stress biomarkers, serum kit methods to measure lipid profiles and liver enzymes, and the assessment of qPCR for mRNA quantity. According to the research findings, spirulina powder has certain noteworthy features. It had the greatest quantity of chlorogenic acid (4052.90 µg/g) among seven phenolics and two flavonoid compounds obtained by HPLC-UV analysis. Furthermore, the proximate analysis demonstrated that spirulina is high in protein (16.45 ± 0.8%) and has a significant energy yield of 269.51 K-calories per 100 g. A maximal spirulina dose of 900 mg/kg/wt significantly lowered oxidative stress, cholesterol, triglyceride, low-density lipoproteins (LDL), and insulin levels (p ≤ 0.05). In contrast, high-density lipoprotein (HDL) and total antioxidant capacity (TAC) levels increased significantly (p ≤ 0.05) compared to all other groups, except the NC group. The study provides remarkable proof about the pharmacological impact of spirulina powders. Significant reductions (p ≤ 0.05) in liver enzymes {alanine aminotransferase (ALT) and aspartate aminotransferase (AST)} were observed across all treatment groups, with the exception of the NC, compared to the positive control. The treatment groups had significantly greater gene expression levels of INS-1, PDX-1, IGF-1, and GLUT-2 than the positive control group (p ≤ 0.05). These findings highlight spirulina's potential as a long-term regulator of hyperglycemia in rat models with induced hyperlipidemia, owing to its phenolic bioactive components that serve as antioxidants.

Effects of nitric oxide inhalation on pulmonary arterial impedance: differences between normal and pulmonary hypertension male rats.

Nitric oxide (NO) inhalation improves pulmonary hemodynamics in participants with pulmonary arterial hypertension (PAH). Although it can reduce pulmonary vascular resistance (PVR) in PAH, its impact on the dynamic mechanics of pulmonary arteries and its potential difference between control and participants with PAH remain unclear. PA impedance provides a comprehensive description of PA mechanics. With an arterial model, PA impedance can be parameterized into peripheral pulmonary resistance (Rp), arterial compliance (Cp), characteristic impedance of the proximal arteries (Zc), and transmission time from the main PA to the reflection site. This study investigated the effects of inhaled NO on PA impedance and its associated parameters in control and monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) male rats (6/group). Measurements were obtained at baseline and during NO inhalation at 40 and 80 ppm. In both groups, NO inhalation decreased PVR and increased the left atrial pressure. Notably, its impact on PA impedance was frequency dependent, as revealed by reduced PA impedance modulus in the low-frequency range below 10 Hz, with little effect on the high-frequency range. Furthermore, NO inhalation attenuated Rp, increased Cp, and prolonged transmission time without affecting Zc. It reduced Rp more pronouncedly in MCT-PAH rats, whereas it increased Cp and delayed transmission time more effectively in control rats. In conclusion, the therapeutic effects of inhaled NO on PA impedance were frequency dependent and may differ between the control and MCT-PAH groups, suggesting that the effect on the mechanics differs depending on the pathological state.NEW & NOTEWORTHY Nitric oxide inhalation decreased pulmonary arterial impedance in the low-frequency range (<10 Hz) with little impact on the high-frequency range. It reduced peripheral pulmonary resistance more pronouncedly in pulmonary hypertension rats, whereas it increased arterial compliance and transmission time in control rats. Its effect on the mechanics of the pulmonary arteries may differ depending on the pathological status.

Candesartan upregulates angiotensin-converting enzyme 2 in kidneys of male animals by decreased ubiquitination.

Candesartan is a common angiotensin-II receptor-1 blocker used for patients with cardiovascular and renal diseases. Angiotensin-converting enzyme 2 (ACE2) is a negative regulator of blood pressure (BP), and also a major receptor for coronaviruses. To determine whether and how candesartan upregulates ACE2, we examined BP and ACE2 in multi-organs from male and female C57BL/6J mice treated with candesartan (1 mg/kg, i.p.) for 7 days. Relative to the vehicle, candesartan lowered BP more in males than females; ACE2 protein abundances were increased in kidneys, not lungs, hearts, aorta, liver, spleen, brain, or serum, only from males. Ace2-mRNA was similar in kidneys. Candesartan also decreased BP in normal, hypertensive, and nephrotic male rats. The renal ACE2 was increased by the drug in normal and nephrotic male rats but not spontaneously hypertensive ones. In male mouse kidneys, ACE2 was distributed at sodium-hydrogen-exchanger-3 positive proximal-convoluted-tubules; ACE2-ubiquitination was decreased by candesartan, accompanied with increased ubiquitin-specific-protease-48 (USP48). In candesartan-treated mouse renal proximal-convoluted-tubule cells, ACE2 abundances and activities were increased while ACE2-ubiquitination and colocalization with lysosomal and proteosomal markers were decreased. The silence of USP48 by siRNA caused a reduction of ACE2 in the cells. Thus, the sex-differential ACE2 upregulation by candesartan in kidney from males may be due to the decreased ACE2-ubiquitination, associated with USP48, and consequent degradation in lysosomes and proteosomes. This is a novel mechanism and may shed light on candesartan-like-drug choice in men and women prone to coronavirus infections.

Akt Signaling and Nitric Oxide Synthase as Possible Mediators of the Protective Effect of N-acetyl-L-cysteine in Prediabetes Induced by Sucrose.

The aim of this work was to evaluate possible mechanisms involved in the protective effect of N-acetyl-L-cysteine (NAC) on hepatic endocrine-metabolic, oxidative stress, and inflammatory changes in prediabetic rats. For that, normal male Wistar rats (60 days old) were fed for 21 days with 10% sucrose in their drinking water and 5 days of NAC administration (50 mg/kg, i.p.) and thereafter, we determined: serum glucose, insulin, transaminases, uric acid, and triglyceride levels; hepatic fructokinase and glucokinase activities, glycogen content, lipogenic gene expression; enzymatic and non-enzymatic oxidative stress, insulin signaling pathway, and inflammatory markers. Results showed that alterations evinced in sucrose-fed rats (hypertriglyceridemia, hyperinsulinemia, and high liver fructokinase activity together with increased liver lipogenic gene expression and oxidative stress and inflammatory markers) were prevented by NAC administration. P-endothelial nitric oxide synthase (P-eNOS)/eNOS and pAKT/AKT ratios, decreased by sucrose ingestion, were restored after NAC treatment. In conclusion, the results suggest that NAC administration improves glucose homeostasis, oxidative stress, and inflammation in prediabetic rats probably mediated by modulation of the AKT/NOS pathway. Administration of NAC may be an effective complementary strategy to alleviate or prevent oxidative stress and inflammatory responses observed in type 2 diabetes at early stages of its development (prediabetes).

Pre-mating administration of theophylline could prevent the transgenerational effects of maternal morphine dependence on offspring anxiety behavior: The role of dopamine receptors

Opioid addiction causes some molecular alterations in the brain reward pathway, such as changes in gene expression that may be transferred to the next generation via epigenetic mechanisms such as histone acetylation. This study aimed to evaluate the effect of theophylline as an HDAC (Histone deacetylases) activator on D1 and D2 dopamine receptor expression in the nucleus accumbens (NAc) and anxiety behavior in the offspring of morphine-dependent female rats. Female rats were exposed to escalating doses of morphine for six days and were then treated with theophylline (20 mg/kg) or saline for 10 days before mating with normal male rats. Male and female offspring were tested for anxiety behavior using an elevated plus maze apparatus. Besides, the expression of D1 and D2 dopamine receptors in the NAc was evaluated by real-time PCR (polymerase chain reaction). Results showed that offspring of morphine-dependent female rats had increased expression of both D1 and D2 receptors in the NAc, as well as decreased anxiety behavior, compared to control offspring. However, the mentioned effects were returned to normal levels in the offspring whose morphine-dependent mothers had received theophylline for 10 days before mating. It is concluded that theophylline may be therapeutically effective in minimizing the adverse consequences of maternal morphine dependence on offspring behavior by restoring normal dopamine receptor expression levels and modulating anxiety. To completely comprehend the underlying mechanisms of this phenomenon, more research is required.

Evaluating the Aphrodisiac Potential of Mirabilis jalapa L. Root Extract: Phytochemical Profiling and In Silico, In Vitro, and In Vivo Assessments in Normal Male Rats.

The traditional use of Mirabilis jalapa L. roots to enhance male sexual performance prompted us to assess the in silico, in vitro, and in vivo aphrodisiac activities of its hydroethanolic extract using normal male rats. Spectroscopic characterization indicated the presence of ß-D-glucopyranoside, methyl-1,9-benzyl-2,6-dichloro-9H-purine, and Bis-(2-ethylhexyl)-phthalate; these compounds have a significant inhibitory effect on the phosphodiesterase-5 (PDE-5) enzyme in silico evaluation and minerals (including zinc, cadmium, and magnesium). Other phytochemical analyses revealed the presence of phenolic compounds and flavonoids. These phytochemicals and minerals may contribute to the aphrodisiac activities of the extract. Additionally, the in vivo study revealed that the administration of M. jalapa root extract (300 mg/kg) significantly enhanced (p < 0.01, p < 0.03) mount, intromission, and ejaculation frequencies while significantly (p < 0.05) decreasing the mount and intromission latencies, as well as the post-ejaculatory interval time, in comparison with the standard drugs sildenafil and ginseng, resulting in enhanced erection and sexual performance in the rats. Furthermore, the extract significantly (p < 0.05) increased penile reflexes and also elevated the levels of testosterone and luteinizing hormones. Extract (300 mg/kg) significantly (p < 0.05) inhibited the PDE-5 enzyme in an in vitro study. Concludingly, the comprehensive findings of this study suggest that a standardized herbal extract derived from M. jalapa roots alleviates erectile dysfunction and premature ejaculation in male rats. M. jalapa root extract proved to be an alternative treatment for erectile dysfunction and premature ejaculation.

Fortification of Fermented Camel Milk with Salvia officinalis L. or Mentha piperita Leaves Powder and Its Biological Effects on Diabetic Rats.

The incorporation of fermented camel milk with natural additives possesses numerous benefits for the treatment of various pathological and metabolic conditions. The present study investigated the impact of fortification of fermented camel milk with sage or mint leaves powder (1 and 1.5%, respectively) on glucose and insulin levels, lipid profile, and liver and kidney functions in alloxan-induced diabetic rats. The gross chemical composition of sage and peppermint leaves powder was studied. The chemical composition of sage and mint extracts was performed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS) of sage and mint extracts. Furthermore, a total of forty-two adult normal male albino rats were included in this study, whereas one group was kept as the healthy control group (n = 6 rats) and diabetes was induced in the remaining animals (n = 36 rats) using alloxan injection (150 mg/kg of body weight). Among diabetic rats groups, a control group (n = 6 rats) was kept as the diabetic control group whereas the other 5 groups (6 rats per group) of diabetic rats were fed fermented camel milk (FCM) or fermented camel milk fortified with 1 and 1.5% of sage or mint leaves powder. Interestingly, the oral administration of fermented camel milk fortified with sage or mint leaves powder, at both concentrations, caused a significant decrease in blood glucose level and lipid profile, and an increase in insulin level compared to the diabetic control and FCM groups. Among others, the best results were observed in the group of animals that received fermented camel milk fortified with 1.5% sage powder. In addition, the results revealed that the fermented camel milk fortified with sage or mint leaves powder improved the liver and kidney functions of diabetic rats. Our study concluded that the use of sage and mint leaves powder (at a ratio of 1.5%) with fermented camel milk produces functional food products with anti-diabetic activity.

A synergistic analgesic effect of morphine in combination with the CB1 receptor agonist, ACPA, in normal, hypothyroid, and hyperthyroid male rats.

Both cannabinoid and opioid receptors are involved in pain behavior. The administration of morphine and cannabis in rats has been shown to decrease thyroid weight and thyroid‑stimulating hormone (TSH) levels. We hypothesized that the third ventricle, due to its adjacency to the hypothalamus, is involved in the modulation of hypothalamic‑pituitary‑thyroid axis activity and descending pain pathways. The present study examined the effect of intra‑third ventricle administration of morphine and cannabis agents on the modulation of pain behavior in normal, hypothyroid (increased serum TSH), and hyperthyroid (decreased serum TSH) rats using the tail‑flick test. The results indicated that intra‑third ventricle injection of AM251 (CB1 receptor antagonist) caused hyperalgesia, while intra‑third ventricle administration of ACPA (CB1 receptor agonist) and morphine produced analgesia in normal, hypothyroid, and hyperthyroid rats. A non‑effective dose of morphine (0.5 μg/rat) did not attenuate hyperalgesia induced by an effective dose of AM251. Co‑injection of ACPA and morphine into the third ventricle induced anti‑nociceptive effect in normal, hypothyroid, and hyperthyroid rats. An isobolographic analysis demonstrated a synergistic effect between ACPA and morphine in the production of the anti‑nociceptive effect. Consequently, the third ventricle may modulate pain behavior induced by cannabinoid and opioid receptors via descending pain pathways in normal, hypothyroid, and hyperthyroid rats.

Zinc's protective role against hydroxychloroquine-induced cardiac effects in adult male albino rats

BackgroundLong exposure to Hydroxychloroquine (HCQ) has been complicated by some dangerous though infrequent cardiotoxicity. MethodsA total of 40 normal adult male albino rats dispersed into 4 groups were used. Group 1 (Control group), Group II (HCQ treated group), Group III (zinc [Zn]-treated group), and Group IV (HCQ and Zn treated group). Once the experimentation ended, rats were sacrificed and cardiac soft tissue sections were processed twenty-four hours at the end of the experiment for histological study. ResultsCardiac-stained sections revealed that HCQ induced widespread necrosis, dilatation, and vacuolar degeneration. However, the combination of HCQ with Zn ameliorated these damaging effects. Cardiac enzyme parameters were also studied in the 4 groups and revealed CK-MB and troponin were considerably elevated in groups II associated to the control group. ConclusionIt was concluded that Zn revealed a protective role against HCQ cardiomyopathy in adult male albino rats. This might signify an appreciated means for Zn-based treatment in the upcoming subsequent clinical records to adjust doses and guarantee patient safeguard.

The influence of long-term housing in enriched environment on behavior of normal rats and subjected to neonatal pro-inflammatory challenge

It is well known that neonatal pro-inflammatory challenge (NPC) acquire a predisposition to the development of a number of neuropsychiatric diseases: depression, anxiety disorders, autism, attention deficit hyperactivity disorder. Symptoms of these diseases can manifest themselves in adulthood and adolescent after repeated exposure to negative influences. Preventing the development of the negative consequences of NPC is one of the main tasks for researchers. The exposure to an enriched environment (EE) was shown to have anxiolytic, anti-depressive, and pro-cognitive effects. The present work was aimed to investigate the effects of the long-term EE on anxious-depressive and conditioned fear behavior in normal male and female rats and subjected to NPC. The NPC was induced by subcutaneous administration of lipopolysaccharide (LPS, 50 μg/kg) on 3d and 5th PNDs. The control animals received saline (SAL). The rats were placed in the EE from 25 to 120 PND. Animals housed in the standard conditions (STAND) served as controls. In adult female and male rats of the STAND groups, LPS did not affect the anxiety, depressive-like behavior and conditioned fear. The EE increased motor and search activity in males and females. In the open field, the EE reduced anxiety in males of the SAL and LPS groups and in females of SAL groups compared to the STAND housed animals. In the elevated plus maze, the EE decreased anxiety only in males of the SAL group. In the sucrose preference test, the EE did not change sucrose consumption in males and females of SAL and LPS groups, while, in the forced swimming test, the EE reduced depressive-like behavior in females of both SAL and LPS groups. The enrichment decreased the contextual conditioned fear in male and female of SAL groups, but not of the LPS group, and did not affect the cue conditioned fear. The corticosterone reactivity to the forced swimming stress increased in males of the EE groups. The basal level of IL-1beta in blood serum decreased in males of the SAL-EE group. Thus, the EE reduced anxiety in males, depressive-like behavior in females, and contextual conditioned fear in males and females compared to the STAND housed animals. Although the NPC did not affect these behaviors in the STAND groups, LPS prevented the beneficial EE effects on anxiety and conditioned fear. The opposing effects of LPS were dependent on sex and type of testing.

Histamine signaling in the bed nucleus of the stria terminalis modulates stress-induced anxiety

BackgroundAnxiety disorder is one of the most prevalent psychiatric disorders. Intriguingly, dysfunction of the central histaminergic system, which is recognized as a general regulator for whole-brain activity, may result in anxiety, suggesting an involvement of the central histaminergic signaling in the modulation of anxiety. However, the neural mechanisms involved have not been fully identified. MethodsHere, we examined the effect of histaminergic signaling in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors both in normal and acute restraint stressed male rats by using anterograde tracing, immunofluorescence, qPCR, neuropharmacology, molecular manipulation and behavioral tests. ResultsWe found that histaminergic neurons in the hypothalamus send direct projections to the BNST, which forms a part of the circuitry involved in stress and anxiety. Infusion of histamine into the BNST produced anxiogenic effect. Moreover, histamine H1 and H2 receptors are expressed and distributed in the BNST neurons. Blockade of histamine H1 or H2 receptors in the BNST did not affect anxiety-like behaviors in normal rats, but ameliorated anxiogenic effect induced by acute restraint stress. Furthermore, knockdown of H1 or H2 receptors in the BNST induced anxiolytic effect in acute restraint stressed rats, which confirmed the pharmacological results. LimitationsA single dose of histamine receptor antagonist was used. ConclusionsTogether, these findings demonstrate a novel mechanism for the central histaminergic system in the regulation of anxiety, and suggest that inhibition of histamine receptors may be a useful strategy for treating anxiety disorder.

CEBPB/POU2F2 modulates Endothelin1 expression in prehypertensive SHR vascular smooth muscle cells.

The pathogenesis of hypertension is not fully understood; ET1 is involved in developing essential hypertension. ET1 can promote VSMC proliferation or hypertrophy through autocrine and paracrine effects. Proliferating smooth muscle cells in the aorta are "dedifferentiated" cells that cause increased arterial stiffness and remodeling. Male SHRs had higher aortic stiffness than normal control male WKY rats. Male SHR VSMCs expressed high levels of the ET1 gene, but endothelial cells did not. Therefore, it is necessary to understand the molecular mechanism of enhanced ET1 expression in SHR VSMCs. We identified POU2f2 and CEBPB as the main molecules that enhance ET1 expression in male SHR VSMCs. A promoter activity analysis confirmed that the enhancer region of the ET1 promoter in male SHR VSMCs was from -1309 to -1279 bp. POU2f2 and CEBPB exhibited an additive role in the enhancer region of the ET1 promoter. POU2f2 or CEBPB overexpression sufficiently increased ET1 expression, and co-transfection with the CEBPB and POU2f2 expression plasmids had additive effects on the activity of the ET1 promoter and ET1 secretion level of male WKY VSMCs. In addition, knockdown of POU2f2 also revealed that POU2f2 is necessary to enhance ET1 expression in SHR VSMCs. The enhancer region of the ET1 promoter is highly conserved in rats, mice, and humans. POU2f2 and CEBPB mRNA levels were significantly increased in remodeled human VMSCs. In conclusion, the novel regulation of POU2f2 and CEBPB in VSMCs will help us understand the pathogenesis of hypertension and support the development of future treatments for hypertension.

Multiple component pharmacokinetics after oral administration of Gnaphalium affine extract in rats.

Gnaphalium affine is traditionally used to treat hyperuricemia and gout in China. Recently, the hypouricemic and renal protective effects of G. affine extract (GAD) have been deeply evaluated. However, little is known about the pharmacokinetics (PKs) of bioactive constituents in GAD. This study was aimed to investigate the individual and holistic pharmacokinetics of ten bioactive components (including caffeic acid, caffeoylquinic acids, and flavonoids) in rats after single and multiple administration of GAD. GAD was orally dosed to normal male rats at doses of 225, 450 or 900 mg/kg/day for 10 consecutive days and also orally administrated to uric acid nephropathy (UAN) rats at a dose of 900 mg/kg/day for 28 consecutive days. Integrated PKs of multiple components were calculated by area under the curve (AUC)-based weighting approach. All the components showed a double-peak phenomenon in terms of their plasma concentration-time curves suggesting that the components undergo enterohepatic circulation. The integrated AUC increased in a good dose-proportional manner with GAD dose. Compared with that in normal rats, the plasma exposure of caffeic acid and caffeoylquinic acids increased by 2.3- to 4.3-fold after 10-day chronic treatment of 900 mg/kg GAD in UAN rats. Modest drug accumulation was observed after 28-day chronic treatment.

Study the effect of a drug depakene (Valproic acid) in the serum levels of immune proteins in albino male rats.

This study aimed to investigate the effect of administration of depakene (valproic acid)(VPA) (15 mg/Kg of body weight, orally) on serum protein levels, including immune proteins, because its functions and the importance of these proteins in the body and they are overlapping, and that was by measured protein levels before and after treatment as concentrations of total protein (Tp), albumin and globulin in normal male rats and in rats that treated with VPA drug along the period of experiment (30) days. The results showed a significant decrease (P&lt;0.05) in concentrations of total protein and albumin in comparison with normal control group, whereas did not observe significant differences (P&lt;0.05) in globulin concentration compared with normal control group, despite of, there was a little decrease in globulin concentration in rats group that administrated the drug under study but non-significant. It could be concluded of the present study that the VPA drug have an greater side effects on concentration and function of proteins in serum, and subsequently, may extending these effects to comprise its effect on the immunity, osmotic pressure, blood volume, nutrients exchange between the blood and tissues, glomerular infiltration rate, transport many of materials and hormones, and several of physiological and biochemical functions which correlated with the serum proteins

Identifying and Study of some of Phytochemical compounds and Anti-Jaundice Activity for powder of leaves and seeds of Moringa oleifera in male albino rats.

The present study aimed to revealing and identifying some of phytochemical compounds, bioactive fatty acids and antioxidants for powder of leaves and seeds of Moringa oleifera that cultivated in Iraq which have been many identified by using modern techniques such as gas chromatography mass spectrometry (GC-MS) technique. And then study and test the preventive and Therapy effects for powder of leaves and seeds in present study against hepatotoxicity that induced by carbon tetrachloride (CCl4) and against jaundice. These effects were tested by measuring total bilirubin concentrations of total bilirubin and γ-glutamyl transferase (GGT) in serum of normal male rats, exposed to CCl4 and that treated with powder of leaves and seeds of Moringa oleifera along the period of experiment (30) days, used (20) albino male rats divide to (4) groups, that is meaning (5) rats for each group. The rats group that exposed to CCl4 caused a significant increase (P&lt;0.05) in concentrations of total bilirubin and GGT enzyme in comparison with normal control group. Whereas the animals which exposed to CCl4 then treated with powder of leaves and seeds of Moringa oleifera lead to significant decrease (P&lt;0.05) in total bilirubin and GGT enzyme concentration in comparison with the group that exposed to CCl4 only. It could be concluded of this study that using powder of leaves and seeds of Moringa oleifera may be have Preventive and therapeutic effects against damage and hepatotoxicity, subsequently, anti-jaundice activity through its nutritional and antioxidant influences for remove of free radicals and repairing cellular and tissues from toxic damage

A natural biological adhesive from snail mucus for wound repair

The discovery of natural adhesion phenomena and mechanisms has advanced the development of a new generation of tissue adhesives in recent decades. In this study, we develop a natural biological adhesive from snail mucus gel, which consists a network of positively charged protein and polyanionic glycosaminoglycan. The malleable bulk adhesive matrix can adhere to wet tissue through multiple interactions. The biomaterial exhibits excellent haemostatic activity, biocompatibility and biodegradability, and it is effective in accelerating the healing of full-thickness skin wounds in both normal and diabetic male rats. Further mechanistic study shows it effectively promotes the polarization of macrophages towards the anti-inflammatory phenotype, alleviates inflammation in chronic wounds, and significantly improves epithelial regeneration and angiogenesis. Its abundant heparin-like glycosaminoglycan component is the main active ingredient. These findings provide theoretical and material insights into bio-inspired tissue adhesives and bioengineered scaffold designs.

Acute and sub-acute oral toxicity studies of crude aqueous and ethanolic extracts of Tapinanthus preussii leaf in normal adult male wistar albino rats

Tapinanthus preussii (African mistletoe), is widely used in ethno medicine for the prevention and management of numerous diseases. Hence this study was aimed at evaluating the acute and sub-acute toxicological effects of its crude aqueous and ethanolic leaf extracts in Wistar albino rats. Acute toxicity tests were conducted in two phases by a single oral administration of both extracts at increasing dosages: 10, 100, 1000, 1600 2,900 and 5000 mg/kg body weight of the rats. This resulted in no clinical signs or symptoms of toxicity within 24h, 72h and 14 days revealing that both extracts were safe up to 5000 mg/kg. In the sub-acute toxicity study, the rats received increasing dosages of both aqueous and ethanolic extracts (200, 350 and 500 mg/kg body weight) p. o. daily for 28 days. The absolute bodyweight, liver function markers (serum aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), bilirubin, albumin and total proteins) and kidney function indices (urea, creatinine and electrolytes) were not significantly (p>0.05) different in all the extracts treated groups compared to the control. This indicates that both extracts were safe since they were neither hepatotoxic nor nephrotoxic. Histopathological studies revealed no lesions in the liver and kidney of extract treated groups further confirming the safety of both extracts. Therefore these results validate the safety of this medicinal plant use indigenously to alleviate various diseases, optimize health and useful in pharmacological studies.

Changes of the genome-wide DNA methylation level in various regions of the rat brain with incomplete cerebral ischemia

To quantify genome-wide DNA methylation in the olfactory bulbs, fronto-parietal and occipital regions, and cerebellum in normal male Wistar rats and in modeling incomplete cerebral ischemia caused by permanent bilateral occlusion of the common carotid arteries. The study was performed on 23 male Wistar rats divided into groups: «Sham operation» and «Cerebral ischemia». The level of genome-wide methylation of CCGG sites was determined by methyl-sensitive restriction using MspI/HpaII endonucleases followed by densitometric analysis of electrophoregrams by ImageJ software. Incomplete cerebral ischemia on the 7th day leads to 56.3% (95% CI: 33.2-76.90) mortality. In the surviving rats of the «Cerebral ischemia» group, compared with the animals of the «Sham operation» group, a pronounced neurological deficit was observed, which was accompanied by changes in the level of whole-genome DNA methylation in the nervous tissue of brain structures (p<0.05). Incomplete cerebral ischemia in male Wistar rats was characterized by interhemispheric asymmetry in the severity and direction of the epigenomic reaction of the nervous tissue in both ischemic and non-ischemic areas of the brain. It is likely that it is precisely this dynamics of changes in the status of genome-wide DNA methylation in the nervous tissue that imparts plasticity to neuronal function during ischemic damage.