Targeting inflammation and oxidative stress for protection against ischemic brain injury in rats using cupressuflavone.

Inflammatory responses and oxidative stress contribute to the pathogenesis of brain ischemia/reperfusion (IR) injury. Naturally occurring bioflavonoids possess antioxidant and anti-inflammatory properties. The phytochemicals of Juniperus sabina L., known as "Abhal" in Saudi Arabia, have been studied and cupressuflavone (CUP) has been isolated as the major bioflavonoid. This study aimed to investigate the neuroprotective potential of CUP in reducing brain IR damage in rats and to understand probable mechanisms. After 60 min of inducing cerebral ischemia by closing the left common carotid artery (CCA), blood flow was restored to allow reperfusion. The same surgical procedure was performed on sham-operated control rats, excluding cerebral IR. CUP or vehicle was given orally to rats for 3 days prior to ischemia induction and for a further 3 days following reperfusion. Based on the findings of this study, compared to the IR control group, CUP-administered group demonstrated reduced neurological deficits, improved motor coordination, balance, and locomotor activity. Additionally, brain homogenates of IR rats showed a decrease in malondialdehyde (MDA) level, an increase in reduced glutathione (GSH) content, and an increase in catalase (CAT) enzyme activity following CUP treatment. CUP suppressed neuro-inflammation via reducing serum inflammatory cytokine levels, particularly those of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß) and enhancing the inflammatory cytokine levels, such as Nuclear factor kappa- B (NF-κB), TANK-binding kinase-1 (TBK1), and interferon beta (IFN-ß) in brain tissues. Furthermore, CUP ameliorated the histological alterations in the brain tissues of IR rats. CUP significantly suppressed caspase-3 expression and downregulated the Toll-like receptor 4 (TLR4)/NF-κB signaling pathway as a result of suppressing High mobility group box 1 (HMGB1). To our knowledge, this is the first study to document the neuroprotective properties of CUP. Thus, the study findings revealed that CUP ameliorates IR-induced cerebral injury possibly by enhancing brain antioxidant contents, reducing serum inflammatory cytokine levels, potentiating the brain contents of TBK1 and IFN-ß and suppressing the HMGB1/TLR-4 signaling pathway. Hence, CUP may serve as a potential preventive and therapeutic alternative for cerebral stroke.

Immunological interactions in helminths-SARS CoV-2 coinfection: Could old enemy be a friend today?

Helminths are metazoan parasites affecting about one third of the worldwide population. Chronic helminth infections (CHIs) confer immunological tolerance to harmless and self-antigens mediated by regulatory T cells (Treg) that are up-regulated. In coronavirus disease 2019 (COVID-19), abnormal adaptive immune response and unrestrained innate immune response could result in local and systemic immune-mediated tissue damage. COVID-19 and CHIs establish complicated immune interactions due to SARS-CoV-2-induced immunological stimulation and CHIs-induced immunological tolerance. However, COVID-19 severity in patients with CHIs is mild, as immuno-suppressive anti-inflammatory cytokines counterbalance the risk of cytokine storm. Here, an overview of the interplay between helminths and COVID-19 severity is given. CHIs through helminth-derived molecules may suppress SARS-CoV-2 entry and associated hyperinflammation through attenuation of the TLR4/NF-kB signalling pathway. In addition, CHIs may reduce the COVID-19 severity by reducing the SARS-CoV-2 entry points at ACE2/DPP4/CD147 axis in the initial phase and immunomodulation in the late phase of the disease by suppressing TLR4/NF-kB signalling pathway.

Identification of Potential Inhibitors for the Treatment of Alkaptonuria Using an Integrated In Silico Computational Strategy.

Alkaptonuria (AKU) is a rare genetic autosomal recessive disorder characterized by elevated serum levels of homogentisic acid (HGA). In this disease, tyrosine metabolism is interrupted because of the alterations in homogentisate dioxygenase (HGD) gene. The patient suffers from ochronosis, fractures, and tendon ruptures. To date, no medicine has been approved for the treatment of AKU. However, physiotherapy and strong painkillers are administered to help mitigate the condition. Recently, nitisinone, an FDA-approved drug for type 1 tyrosinemia, has been given to AKU patients in some countries and has shown encouraging results in reducing the disease progression. However, this drug is not the targeted treatment for AKU, and causes keratopathy. Therefore, the foremost aim of this study is the identification of potent and druggable inhibitors of AKU with no or minimal side effects by targeting 4-hydroxyphenylpyruvate dioxygenase. To achieve our goal, we have performed computational modelling using BioSolveIT suit. The library of ligands for molecular docking was acquired by fragment replacement of reference molecules by ReCore. Subsequently, the hits were screened on the basis of estimated affinities, and their pharmacokinetic properties were evaluated using SwissADME. Afterward, the interactions between target and ligands were investigated using Discovery Studio. Ultimately, compounds c and f were identified as potent inhibitors of 4-hydroxyphenylpyruvate dioxygenase.

GC/MS Analysis, Cytotoxicity, and Antiviral Activities of Annona glabra Hexane Extract Supported by In Silico Study.

Annona glabra Linn is employed in conventional medicine to treat a number of human disorders, including cancer and viruses. In the present investigation, the significant phytochemical components of Annona glabra hexane extract were identified using gas chromatography-mass spectrometry (GC-MS) analysis. Three major compounds were identified in the hexane extract: tritriacontane (30.23%), 13, 17-dimethyl-tritriacontane (22.44%), and limonene (18.97%). MTT assay was used to assess the cytotoxicity of the extract on six human cancer cell lines including liver (HepG-2), pancreas (PANC-1), lung (A-549), breast (MCF-7, HTB-22), prostate (PC-3), and colon (CACO-2, ATB-37). The extract exhibited significant cytotoxic activity against both CACO-2 and A-549 cancer cell lines (IC50 = 47 ± 0.74 µg/mL and 56.82 ± 0.92 µg/mL) in comparison with doxorubicin (IC50 = 31.91 ± 0.81 µg/mL and 23.39 ± 0.43 µg/mL) and of SI of 3.8 and 3.1, respectively. It also induced moderate-to-weak activities against the other cancerous cell lines: PC-3, PANC-1, MCF-7, and HepG-2 (IC50 = 81.86 ± 3.26, 57.34 ± 0.77, 80.31 ± 4.13, and 57.01 ± 0.85 µg/mL) in comparison to doxorubicin (IC50 = 32.9 ± 1.74, 19.07 ± 0.2, 15.48 ± 0.84 and 5.4 ± 0.22 µg/mL, respectively) and SI of 2.2, 3.1, 2.2, and 3.1, respectively. In vitro anti-HSV1 (Herpes simplex 1 virus) and HAV (Hepatitis A virus) activity was evaluated using MTT colorimetric assay with three different protocols to test protective, anti-replicative, and anti-infective antiviral activities, and three separate replications of each experiment were conducted. The plant extract showed promising protective and virucidal activity against HSV1 with no significant difference with acyclovir (79.55 ± 1.67 vs. 68.44 ± 7.62 and 70.91 ± 7.02 vs. 83.76 ± 5.67), while it showed mild protective antiviral activity against HAV (48.08 ±3.46) with no significant difference vs. acyclovir (36.89 ± 6.61). The selected main compounds were examined for their bioactivity through in silico molecular docking, which exhibited that limonene could possess the strongest antiviral properties. These findings support Annona glabra's conventional use, which is an effective source of antiviral and anticancer substances that could be used in pharmaceuticals.

Ultrasound-Assisted Synthesis of Piperidinyl-Quinoline Acylhydrazones as New Anti-Alzheimer's Agents: Assessment of Cholinesterase Inhibitory Profile, Molecular Docking Analysis, and Drug-like Properties.

Alzheimer's disease (AD) is one of the progressive neurological disorders and the main cause of dementia all over the world. The multifactorial nature of Alzheimer's disease is a reason for the lack of effective drugs as well as a basis for the development of new structural leads. In addition, the appalling side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with the marketed treatment modalities and many failed clinical trials significantly limit the use of drugs and alarm for a detailed understanding of disease heterogeneity and the development of preventive and multifaceted remedial approach desperately. With this motivation, we herein report a diverse series of piperidinyl-quinoline acylhydrazone therapeutics as selective as well as potent inhibitors of cholinesterase enzymes. Ultrasound-assisted conjugation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes (4a,b) and (un)substituted aromatic acid hydrazides (7a-m) provided facile access to target compounds (8a-m and 9a-j) in 4-6 min in excellent yields. The structures were fully established using spectroscopic techniques such as FTIR, 1H- and 13C NMR, and purity was estimated using elemental analysis. The synthesized compounds were investigated for their cholinesterase inhibitory potential. In vitro enzymatic studies revealed potent and selective inhibitors of AChE and BuChE. Compound 8c showed remarkable results and emerged as a lead candidate for the inhibition of AChE with an IC50 value of 5.3 ± 0.51 µM. The inhibitory strength of the optimal compound was 3-fold higher compared to neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 8g exhibited the highest potency and inhibited the BuChE selectively with an IC50 value of 1.31 ± 0.05 µM. Several compounds, such as 8a-c, also displayed dual inhibitory strength, and acquired data were superior to the standard drugs. In vitro results were further supported by molecular docking analysis, where potent compounds revealed various important interactions with the key amino acid residues in the active site of both enzymes. Molecular dynamics simulation data, as well as physicochemical properties of the lead compounds, supported the identified class of hybrid compounds as a promising avenue for the discovery and development of new molecules for multifactorial diseases, such as Alzheimer's disease (AD).

Amentoflavone attenuates oxidative stress and neuroinflammation induced by cerebral ischemia/reperfusion in rats by targeting HMGB1-mediated TLR4/NF-κB signaling pathway.

Surveys indicated that stroke classified among the leading cause of death as well as combined death and disability worldwide resulting in a great loss for the global economy. The present study aims to evaluate the neuroprotective potential of the biflavonoid amentoflavone (AMNT) in alleviating cerebral ischemia/reperfusion (IR) injury in rats, and to elucidate the possible underlying mechanism of an experimental condition with similar circumstances to stroke. Cerebral ischemia was achieved through left common carotid artery occlusion for 60 min, followed by blood flow restoration. Sham-operated control rats subjected to the same surgical process except for brain IR. Rats were orally administered AMNT/ or vehicle for three days' prior surgical operation, and for another three days after left brain IR. Rats of all groups were assessed for neurological deficits 24 h following brain IR. Each group was divided into two subgroups one for the rotarod testing and biochemical assessment while the other subgroup to perform the activity cage testing, histopathological study, immunohistochemistry, and gene expression analysis. AMNT enhanced brain levels of GSH and CAT activities, suppressed neuroinflammation via reducing the inflammatory cytokines in the serum, and enhanced brain contents of TBK1 and IFNß. AMNT downregulated TLR4-/NF-κB signaling pathway as a result of the HMGB1 suppression. Moreover, AMNT blocked apoptotic cell death by suppressing the NF-κB signaling pathway and reducing the activation of caspase-3. These findings revealed that AMNT attenuates I/R-induced cerebral injury possibly by regulating the HMGB1-mediated TLR4/NF-kB pathway. Thus, AMNT could provide potential preventive and therapeutic option for cerebral stroke.

Samarcandin protects against testicular ischemia/reperfusion injury in rats via activation of Nrf2/HO-1-mediated antioxidant responses.

The purpose of this study was to evaluate the effectiveness of samarcandin (SMR) in preventing testicular injury caused by ischemia/reperfusion (I/R) in rats. Rats were divided into 4 groups at random: the sham group, the T/D control group (CONT), the T/D group receiving SMR treatment at 10 mg/kg (SMR-10), and the T/D group receiving SMR treatment at 20 mg/kg (SMR-20). When compared to the CONT group, SMR improved the oxidant/antioxidant balance by reducing malondialdehyde (MDA), nitric oxide (NOx), and increasing reduced glutathione (GSH), gluta-thione peroxide (GSH-Px), and superoxide dismutase (SOD). Moreover, SMR increased the levels of the steroid hormones' testosterone (TST), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in the blood as well as controlled the inflammatory mediators; interleukin-6 (IL6), tumor necrosis factor alpha (TNF-α), and nuclear factor κB (NF-κB). Nevertheless, SMR-treated animals showed a considerable downregulation of the apoptotic marker caspase-3. The T/D-induced histopathological changes were reduced and Proliferating Cell Nuclear Antigen (PCNA) protein expression was enhanced by SMR. These effects are associated with upregulation of testicular (Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme oxygenase-1 (HO-1), and downregulation of NF-κB mRNA expression levels. These findings suggest that SMR may be able to prevent T/D-induced testis damage by mainly regulating the expression of Nrf2 and NF-B, which seems to mediate its promising antioxidant, anti-inflammatory and antiapoptotic effects seen in this study.

Phytoconstituents of Sansevieria suffruticosa N.E.Br. Leaves and Its Hepatoprotective Effect via Activation of the NRF2/ARE Signaling Pathway in an Experimentally Induced Liver Fibrosis Rat Model.

Sansevieria species possess antioxidant and hepatoprotective activities. However, the therapeutic potential of Sansevieria suffruticosa N.E.Br. in liver fibrosis was not evaluated yet. Twenty-seven phytoconstituents were tentatively identified in the phytoconstituents profile of Sansevieria suffruticosa N.E.Br. leaves extract (SSLE) using high-performance liquid chromatography coupled with mass spectrometry (HPLC-ESI/MS-MS). Using column chromatography, hesperetin, 4-hydroxybenzoic acid, ginsenoside Rg2, and quinic acid were isolated from SSLE. The hepatoprotective effect of SSLE via the activation of the NRF2 signaling pathway was evaluated using a rat model of thioacetamide-induced liver fibrosis. Five groups of 6 male adult Wistar rats were used. All animals except the normal control were injected with 200 mg/kg of TAA intraperitoneally twice weekly for 6 weeks. SSLE-treated groups were orally administered 200 and 100 mg/kg/day of the extract, two weeks before the liver fibrosis induction and were continued concomitantly with TAA injection. A reference group received 100 mg/kg b.wt of silymarin orally. SSLE treated groups exhibited a marked reduction in serum alanine transaminase (ALT), aspartate transaminase (AST) and malondialdehyde (MDA) levels compared with the TAA group. The levels of reduced glutathione (GSH) content and hepatic mRNA levels of Nrf2 and HO-1 were significantly increased. Histological findings further confirmed the protective role of SSLE against TAA. In conclusion, the aforementioned results indicated that the hepatoprotective mechanism of SSLE was exerted via activating the Nrf2 pathway to counteract oxidative stress.

Vulgarin, a Sesquiterpene Lactone from Artemisia judaica, Improves the Antidiabetic Effectiveness of Glibenclamide in Streptozotocin-Induced Diabetic Rats via Modulation of PEPCK and G6Pase Genes Expression.

The current investigation assessed the effect of the eudesmanolid, Vulgarin (VGN), obtained from Artemisia judaica (A. judaica), on the antidiabetic potential of glibenclamide (GLB) using streptozotocin (STZ) to induce diabetes. Seven groups of rats were used in the study; the first group received the vehicle and served as normal control. The diabetic rats of the second to the fifth groups were treated with the vehicle (negative control), GLB at 5 mg/kg (positive control), VGN at 10 mg/kg (VGN-10) and VGN at 20 mg/kg (VGN-20), respectively. The diabetic rats of the sixth and seventh groups were administered combinations of GLB plus VGN-10 and GLB plus VGN-20, respectively. The diabetic rats treated with GLB plus VGN-20 combination showed marked improvement in the fasting blood glucose (FBG), insulin and glycated hemoglobin (HbA1c), as well as the lipid profile, compared with those treated with GLB alone. Further, the pancreatic tissues of the diabetic rats that received the GLB+VGN-20 combination showed superior improvements in lipid peroxidation and antioxidant parameters than those of GLB monotherapy. The insulin content of the ß-cells was restored in all treatments, while the levels of glucagon and somatostatin of the α- and δ-endocrine cells were reduced in the pancreatic islets. In addition, the concurrent administration of GLB+VGN-20 was the most effective in restoring PEPCK and G6Pase mRNA expression in the liver. In conclusion, the results demonstrated that the GLB+VGN-20 combination led to greater glycemic improvement in diabetic rats compared with GLB monotherapy through its antioxidant effect and capability to modulate PEPCK and G6Pase gene expression in their livers.

Metabolomic Profiling and Neuroprotective Effects of Purslane Seeds Extract Against Acrylamide Toxicity in Rat's Brain.

AIM: Acrylamide (ACR) is an environmental pollutant with well-demonstrated neurotoxic and neurodegenerative effects in both humans and experimental animals. The present study aimed to investigate the neuroprotective effect of Portulaca oleracea seeds extract (PSE) against ACR-induced neurotoxicity in rats and its possible underlying mechanisms. PSE was subjected to phytochemical investigation using ultra-high-performance liquid chromatography (UPLC) coupled with quantitative time of flight mass spectrometry (qTOF-MS). Multivariate, clustering and correlation data analyses were performed to assess the overall effects of PSE on ACR-challenged rats. Rats were divided into six groups including negative control, ACR-intoxicated group (10 mg/kg/day), PSE treated groups (200 and 400 mg/kg/day), and ACR + PSE treated groups (200 and 400 mg/kg/day, respectively). All treatments were given intragastrically for 60 days. PSE markedly ameliorated brain damage as evidenced by the decreased lactate dehydrogenase (LDL), increased acetylcholinesterase (AchE) activities, as well as the increased brain-derived neurotrophic factor (BDNF) that were altered by the toxic dose of ACR. In addition, PSE markedly attenuated ACR-induced histopathological alterations in the cerebrum, cerebellum, hippocampus and sciatic nerve and downregulated the ACR-inclined GFAP expression. PSE restored the oxidative status in the brain as indicated by glutathione (GSH), lipid peroxidation and increased total antioxidant capacity (TAC). PSE upregulated the mRNA expression of protein kinase B (AKT), which resulted in an upsurge in its downstream cAMP response element-binding protein (CREB)/BDNF mRNA expression in the brain tissue of ACR-intoxicated rats. All exerted PSE beneficial effects were dose-dependent, with the ACR-challenged group received PSE 400 mg/kg dose showed a close clustering to the negative control in both unsupervised principal component analysis (PCA) and supervised orthogonal partial least square discriminant analysis (OPLS-Da) alongside with the hierarchical clustering analysis (HCA). The current investigation confirmed the neuroprotective capacity of PSE against ACR-induced brain injury, and our findings indicate that AKT/CREB pathways and BDNF synthesis may play an important role in the PSE-mediated protective effects against ACR-triggered neurotoxicity.

The ameliorative effect of N-acetylcysteine against penconazole induced neurodegenerative and neuroinflammatory disorders in rats.

Penconazole (PEN) is a widely used systemic fungicide to treat various fungal diseases in plants but it leaves residues in crops and food products causing serious environmental and health problems. N-acetylcysteine (NAC) is a precursor of the antioxidant glutathione in the body and exerts prominent antioxidant and anti-inflammatory effects. The present study aimed to explore the mechanistic way of NAC to ameliorate the PEN neurotoxicity in male rats. Twenty-eight male rats were randomly divided into four groups (n = 7) and given the treated material via oral gavage for 10 days as the following: Group I (distilled water), Group II (50 mg/kg body weight [bwt] PEN), Group III (200 mg/kg bwt NAC), and Group IV (NAC + PEN). After 10 days all rats were subjected to behavioral assessment and then euthanized to collect brain tissues to perform oxidative stress, molecular studies, and pathological examination. Our results revealed that PEN exhibits neurobehavioral toxicity manifested by alteration in the forced swim test, elevated plus maze test, and Y-maze test. There were marked elevations in malondialdehyde levels with reduction in total antioxidant capacity levels, upregulation of messenger RNA levels of bax, caspase 3, and caspase 9 genes with downregulation of bcl2 genes. In addition, brain sections showed marked histopathological alteration in the cerebrum and cerebellum with strong bax and inducible nitric oxide synthetase protein expression. On the contrary, cotreatment of rats with NAC had the ability to improve all the abovementioned neurotoxic parameters. The present study can conclude that NAC has a neuroprotective effect against PEN-induced neurotoxicity via its antioxidant, anti-inflammatory, and antiapoptotic effect. We recommend using NAC as a preventive and therapeutic agent for a wide variety of neurodegenerative and neuroinflammatory disorders.

Momordica charantia Extract Protects against Diabetes-Related Spermatogenic Dysfunction in Male Rats: Molecular and Biochemical Study.

More than 90% of diabetic patients suffer from sexual dysfunction, including diminished sperm count, sperm motility, and sperm viability, and low testosterone levels. The effects of Momordica charantia (MC) were studied by estimating the blood levels of insulin, glucose, glycosylated hemoglobin (HbA1c), testosterone (TST), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in diabetic rats treated with 250 and 500 mg/kg b.w. of the total extract. Testicular antioxidants, epididymal sperm characteristics, testicular histopathology, and lesion scoring were also investigated. Testicular mRNA expression of apoptosis-related markers such as antiapoptotic B-cell lymphoma-2 (Bcl-2) and proapoptotic Bcl-2-associated X protein (Bax) were evaluated by real-time PCR. Furthermore, caspase-3 protein expression was evaluated by immunohistochemistry. MC administration resulted in a significant reduction in blood glucose and HbA1c and marked elevation of serum levels of insulin, TST, and gonadotropins in diabetic rats. It induced a significant recovery of testicular antioxidant enzymes, improved histopathological changes of the testes, and decreased spermatogenic and Sertoli cell apoptosis. MC effectively inhibited testicular apoptosis, as evidenced by upregulation of Bcl-2 and downregulation of Bax and caspase-3. Moreover, reduction in apoptotic potential in MC-treated groups was confirmed by reduction in the Bax/Bcl-2 mRNA expression ratio.

Propolis ameliorates cerebral injury in focal cerebral ischemia/reperfusion (I/R) rat model via upregulation of TGF-ß1.

Neuroprotective impact of transforming growth factor ß1 (TGF-ß1) is increasingly recognized in different brain injuries. Propolis exhibits a broad spectrum of biological and pharmacological properties including neuroprotective action. The objective of the investigation was to explore the involvement of TGF-ß1 signaling in the neuroprotective mechanism of propolis in I/R rats. In this study, focal cerebral ischemia model was built by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. The investigation was carried out on 48 rats that were arranged into four groups (n = 12): the sham group, I/R control group, I/R + propolis (50 mg/kg) group and I/R + propolis (100 mg/kg) group. The results revealed that propolis preserved rats against neuronal injury induced by cerebral I/R. It significantly reduced neurological deficit scores and improved motor coordination and locomotor activity in I/R rats. Propolis antagonized the damage induced by cerebral I/R through suppression of malondialdehyde (MDA) and elevation of reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), brain-derived neurotropic factor (BDNF) and dopamine levels in the brain homogenates of I/R rats. Other ameliorations were also observed based on reduction of neurodegeneration and histological alterations in the brain tissues. These results also proposed that the neuroprotective effect of propolis might be related to upregulation of TGF-ß1 and suppressed matrix metallopeptidase-9 (MMP9) mRNA expression.

Effect of olive leaves extract on the antidiabetic effect of glyburide for possible herb-drug interaction.

The concomitant use of olive leaves (OL) and glyburide (GLB) is a possible therapy for diabetic patients. However, there is no report about the effect of OL on the antidiabetic effect of GLB till now. In the current study, the possible interaction of olive leaves extract (OLE) with GLB was assessed to determine if there was any pharmacological benefit over GLB alone. Seven groups of male Sprague Dawley rats were used. Normal rats of the 1st group treated with 2 mL/kg of 3% Tween 80 (vehicle). The 2nd-5th groups were diabetic rats received vehicle, GLB (5 mg/kg), OLE low dose and OLE high dose respectively, while the 6th-7th groups administered combinations of GLB plus OLE low dose and GLB plus OLE high dose, respectively. All treatments were administered orally once daily for 8 weeks. The use of GLB+OLE-500 obviously improved fasting blood glucose (FBG), insulin and glycated hemoglobin (HbA1c) in diabetic rats (95.5 ±â€¯5.55 mg/dL, 6.8 ±â€¯0.16 mg/dL and 6.1 ±â€¯0.29%, respectively) compared to those treated with GLB monotherapy (140.0 ±â€¯6.36 mg/dL, 5.4 ±â€¯0.19 mg/dL and 7.0 ±â€¯0.20%, respectively). The lipid profile [triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)] was significantly improved in diabetic rats exposed to GLB+OLE-500 (35.6 ±â€¯1.51 mg/dL, 48.5 ±â€¯2.74 mg/dL, 25.1 ±â€¯1.21 mg/dL and 17.0 ±â€¯0.82 mg/dL, respectively) in comparison with diabetic group exposed to GLB alone (43.2 ±â€¯2.15 mg/dL, 56.8 ±â€¯2.14 mg/dL, 18.6 ±â€¯0.96 mg/dL, 23.0 ±â€¯1.26 mg/dL, respectively). Additionally, the benefit impacts of GLB+OLE-500GLB+OLE-500 therapy on the antioxidant and lipid peroxidation parameters in the pancreatic tissues of diabetic rats were higher than those of GLB monotherapy. Moreover, GLB plus OLE-500 combination had the greatest effect on restoration of the insulin content of Beta (ß) cells and reduction of the glucagon and somatostatin of Alpha (α) and Delta (δ) endocrine cells in the pancreatic islets among the different treatment. The current study suggests that OL and GLB combination could cause herb-drug interactions through modulation of insulin receptor (INR), glucose transporter 2 (Slc2a2) and peroxisome proliferator-activated receptor α (PPAR-α) genes expression in the liver of diabetic rats.

Olive leaves extract attenuates type II diabetes mellitus-induced testicular damage in rats: Molecular and biochemical study.

Diabetes mellitus (DM) has emerged as a public healthcare problem. Sustained hyperglycemia has been linked with many complications including impaired male fertility Olive tree (Olea europaea L.) leaves have been extensively used in traditional remedies worldwide to control blood glucose level in DM. In this study, the beneficial role of olive leaves extract (OLE) was investigated to combat diabetes-induced adverse effect on testicular tissues. Thirty male Wistar rats were divided into 5 equal groups: normal control group, streptozotocin (STZ)-diabetic group and diabetic groups which were given glibenclamide (GLB) or OLE at 250 and 500 mg/kg for 9 weeks to investigate the efficiency of olive leaves extract (OLE) in reducing the deleterious effect of diabetes on the reproductive system of male rats. Rats were checked for serum glucose, insulin, testosterone and gonadotropins. Also, testicular antioxidants, epididymal sperm characteristics and testicular histopathology were assessed. Expression of the testicular steroidogenic enzymes, cholesterol side-chain cleavage enzyme (P450 scc) and 17ß-hydroxysteroid dehydrogenase (17ß-HSD) was examined. Moreover, androgen receptor and proliferating cell nuclear antigen (PCNA) protein immunohistochemistry were assessed in testes. STZ-induced diabetes significantly increased serum glucose. However, STZ significantly decreased serum levels of insulin, testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Marked reductions in testicular antioxidants with elevated malondialdehyde (MDA) parallel with deterioration of the testicular histoarchitecture and epididymal sperm characteristics were recorded. Administration of GLB or OLE (250 and 500 mg/kg) resulted in a significant recovery of the above mentioned parameters in STZ-diabetic rats. Interestingly, OLE shows greater glycemic improvement and testicular protection than GLB with the highest percentage protection exhibited by the OLE high dose. Furthermore, OLE significantly induced testicular steroidogenesis in diabetic rat as evidenced by elevated P450 scc and 17ß-HSD mRNA expression. The study proves that OLE possesses a potential protective role against diabetes-induced reproductive disorders, which may be due to its antioxidant activity and its ability to normalize testicular steroidogenesis.

Molecular and biochemical monitoring of the possible herb-drug interaction between Momordica charantia extract and glibenclamide in diabetic rats.

Momordica charantia is used in folk medicine to manage diabetes mellitus. In this study, we investigated the possible herb-drug interaction between M. charantia fruit extract (MCFE) and glibenclamide (GLB) in streptozotocin-diabetic rats. Rats were divided into 7 groups. The 1st group received 3% Tween 80. The 2nd-5th groups were diabetic rats received vehicle, GLB (5 mg/kg), MCFE (250 and 500 mg/kg), respectively. The 6th-7th groups administered GLB plus MCFE (250 and 500 mg/kg), respectively. After 8 weeks, fasting blood glucose (FBG), insulin and glycosylated hemoglobin (HbA1c) levels were assessed. Histopathological and immunohistochemical examinations of the pancreases were done. Quantitative RT-PCR was used to analyze hepatic mRNA expression of insulin receptor (INR), glucose transporter 2 (Slc2a2) and peroxisome proliferator-activated receptor α (PPAR-α) genes. All medicaments greatly reduced FBG in diabetic rats when compared with diabetic control group. GLB plus MCFE combination was better than GLB alone in improving levels of insulin and HbA1c. All medicaments restored insulin content of pancreatic ß-cells and reduced glucagon and somatostatin of alpha and delta endocrine cells. Moreover, GLB plus MCFE-500 was the most efficient in restoring INR, Slc2a2 and PPAR-α mRNA expression to their normal levels. In conclusion, MCFE in combination with GLB gives greater glycemic improvement than GLB monotherapy.

Hepato- and neuro-protective influences of biopropolis on thioacetamide-induced acute hepatic encephalopathy in rats.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that ultimately occurs as a complication of acute or chronic liver failure; accompanied by hyperammonemia. This study aimed to evaluate the potential of biopropolis as a hepato- and neuro-protective agent using thioacetamide (TAA)-induced acute HE in rats as a model. Sixty Wistar rats were divided into 5 groups: Group 1 (normal control) received only saline and paraffin oil. Group 2 (hepatotoxic control) received TAA (300 mg/kg, once). Groups 3, 4, and 5 received TAA followed by vitamin E (100 mg/kg) and biopropolis (100 and 200 mg/kg), respectively, daily for 30 days. Evidences of HE were clearly detected in TAA-hepatotoxic group including significant elevation in the serum level of ammonia, liver functions, increased oxidative stress in liver and brain, apoptotic DNA fragmentation and overexpression of iNOS gene in brain tissue. The findings for groups administered biopropolis, highlighted its efficacy as a hepato- and neuro-protectant through improving the liver functions, oxidative status and DNA fragmentation as well as suppressing the brain expression of iNOS gene. In conclusion, biopropolis, at a dose of 200 mg/kg per day protected against TAA-induced HE through its antioxidant and antiapoptotic influence; therefore, it can be used as a protective natural product.

Hepatocyte Growth Factor Mediates the Antifibrogenic Action of Ocimum bacilicum Essential Oil against CCl4-Induced Liver Fibrosis in Rats.

The current investigation aimed to evaluate the antifibrogenic potential of Ocimum basilicum essential oil (OBE) and further to explore some of its underlying mechanisms. Three groups of rats were used: group I (control), group II (CCl4 model) and group III (OBE-treated) received CCl4 and OBE 2 weeks after the start of CCl4 administration. Oxidative damage was assessed by the measurement of MDA, NO, SOD, CAT, GSH and total antioxidant capacity (TAC). Liver fibrosis was assessed histopathologically by Masson's trichrome staining and α-smooth muscle actin (α-SMA) immunostaining. Expression of hepatocyte growth factor (HGF) and cytochrome P450 (CYP2EI isoform) was estimated using real-time PCR and immunohistochemistry. OBE successfully attenuated liver injury, as shown by histopathology, decreased serum transaminases and improved oxidative status of the liver. Reduced collagen deposition and α-SMA immuopositive cells indicated an abrogation of hepatic stellate cell activation by OBE. Furthermore, OBE was highly effective in stimulating HGF mRNA and protein expression and inhibiting CCl4-induced CYP2E1 down-regulation. The mechanism of antifibrogenic action of OBE is hypothesized to proceed via scavenging free radicals and activating liver regeneration by induction of HGF. These data suggest the use of OBE as a complementary treatment in liver fibrosis.

Vitamin E attenuates neurotoxicity induced by deltamethrin in rats.

BACKGROUND: The safety of Deltamethrin (DM) has been raised as a point of concern. The current investigation was envisaged to explore the responsiveness of oxidative stress parameters, DNA fragmentation and expression levels of TP53, cycloxygenase 2 (COX2) and cytochrome p4502E1 (CYP2E1) as toxicological endpoint in rats treated with DM. as well as attention was provided to the neuroprotective effect of vitamin E (VE). METHODS: Four different groups of rats were used in this study, group I served as control, group II received DM (0.6 mg/kg BW), group III received both DM plus VE and finally group IV received VE only (200 mg/kg BW). The treatment regimen was extending for one month for all groups and the brain tissues were collected for further analysis. RESULTS: The obtained results showed a highly statistically significant increase in lipid peroxidation (LPO) content, nitric oxide concentration, and DNA fragmentation percentage and expression level of CYP2E1, TP53 and COX2 genes, in addition statistical significant reduction in total antioxidant capacity in DM treated group as compared to control were detected. Oral administration of VE attenuated the neurotoxic effects of DM through improvement of oxidative status, DNA fragmentation percentage and suppressing the expression level of CYP2E1, TP53 and COX2 genes. CONCLUSION: From this study we concluded that VE supplementation has beneficial impacts on DM neurotoxicity in rats through its antioxidant and antiapoptotic properties.

Biochemical and computational inhibition of α-glucosidase by novel metronidazole-linked 1H-1,2,3-triazole and carboxylate moieties: kinetics and dynamic investigations.

In the current study, metronidazole derivatives containing 1H-1,2,3-triazole and carboxylate moieties were evaluated in vitro and by computational methods for their anti-diabetic potential to insight into their medicinal use for the management of type II diabetes mellitus. Interestingly all 14 compounds displayed high to significant inhibitory capability against the key carbohydrate's digestive enzyme α-glucosidase with IC50 values in range of 9.73-56.39 µM, as compared to marketed drug acarbose (IC50 = 873.34 ± 1.67 µM). Compounds 5i and 7c exhibited the highest inhibition, therefore, these two compounds were further evaluated for their mechanistic studies to explore its type of inhibition. Compounds 5i and 7c both displayed a concentration-dependent (competitive type of inhibition) with Ki values 7.14 ± 0.01, 6.15 ± 0.02 µM, respectively, which conclude their favourable interactions with the active site residues of the α-glucosidase. Interestingly all compounds are non-cytotoxic against BJ cell line. To further validate our findings, in-silico approaches like molecular docking, and molecular dynamic simulations were applied to investigate the mode of bindings of compounds with the enzyme and identifies their inhibition mechanism, which strongly complements our experimental findings.Communicated by Ramaswamy H. Sarma.