The preferential effect of Clemastine on F3/Contactin-1/Notch-1 compared to Jagged-1/Notch-1 justifies its remyelinating effect in an experimental model of multiple sclerosis in rats.

Clemastine (CLM) is repurposed to enhance remyelination in multiple sclerosis (MS) patients. CLM blocks histamine and muscarinic receptors as negative regulators to oligodendrocyte differentiation. These receptors are linked to the canonical and non-canonical Notch-1 signaling via specific ligands; Jagged-1 and F3/Contactin-1, respectively. Yet, there are no previous studies showing the influence of CLM on Notch entities. Herein, the study aimed to investigate to which extent CLM aligns to one of the two Notch-1 arms in experimental autoimmune encephalomyelitis (EAE) rat model. Three groups were utilized where first group received vehicles. The second group was injected by spinal cord homogenate mixed with complete Freund's adjuvant on days 0 and 7. In the third group, CLM (5 mg/kg/day; p.o) was administered for 15 days starting from the day of the first immunization. CLM ameliorated EAE-associated motor and gripping impairment in rotarod, open-field, and grip strength arena beside sensory anomalies in hot plate, cold allodynia, and mechanical Randall-Selitto tests. Additionally, CLM alleviated depressive mood observed in tail suspension test. These findings harmonized with histopathological examinations of Luxol-fast blue stain together with enhanced immunostaining of myelin basic protein and oligodendrocyte lineage gene 2 in corpus callosum and spinal cord. Additionally, CLM enhanced oligodendrocyte myelination and maturation by increasing 2',3'-cyclic nucleotide 3'-phosphodiesterase, proteolipid protein, aspartoacylase as well. CLM restored the level of F3/Contactin-1 in the diseased rats over Jagged-1 level; the ligand of the canonical pathway. This was accompanied by elevated gene expression of Deltex-1 and reduced hairy and enhancer-of-split homologs 1 and 5. Additionally, CLM suppressed microglial and astrocyte activation via reducing the expression of ionized calcium-binding adaptor molecule-1 as well as glial fibrillary acidic protein, respectively. These results outlined the remyelinating beneficence of CLM which could be due to augmenting the non-canonical Notch-1 signaling over the canonical one.

Antiarthritic activity of Physalis peruviana fruit extract via inhibition of inflammatory mediators: Integrated in vitro, in vivo and in silico study.

ETHNOPHARMACOLOGICAL RELEVANCE: P. peruviana fruit, native to Andean region, is cultivated worldwide for its adaptability to various soil natures and climatic conditions. It is increasingly consumed for its high nutritional profile and history of ethnomedical uses including treatment of arthritis. Little pharmacological evidences support this folk use except for previous in vitro study that reported significant inhibition of protein denaturation. AIM OF THE STUDY: The study aims at providing new in vivo evidence on antiarthritic activity of P. peruviana fruits in vivo that justifies its traditional use through mechanism-based experiment. MATERIAL AND METHODS: Inhibition of inflammatory mediators is considered one of the key treatments to alleviate painful symptoms of rheumatoid arthritis (RA). Anti-inflammatory activity was assessed against COX-1 and COX-2 activity in vitro. Serum TNFα, IL-1ß and IL-6 were traced using in vivo model of adjuvant-induced arthritis. Gross/inflammatory changes in rat paw, relative mass indices of spleen and liver were further investigated together with joint tissue histoarchitecture. Seven metabolites from different phytochemical classes, that were previously reported in P. peruviana fruit, were evaluated in silico against TNF-α target protein (PDB ID: 2AZ5) to assess their inhibitory effect. This was followed by assessment of their drug-likeness based on Lipinski's rule according to their physicochemical and pharmacokinetic properties. RESULTS: High dose of extract (E-1000 mg) improved adjuvant-induced cachexia and attenuated immune-inflammatory responses in paw and serum parameters, with equipotent effect to MTX, in addition to minimal side effect profile on spleen and liver. Histopathological study of knee joint tissues confirmed dose-dependent improvement in arthritic groups treated with P. peruviana fruit extracts. The insilico study recommended steroidal lactones withaperuvin E/C and hydroxywithanolide E as promising lead compounds for inhibiting TNF enzyme as evidenced by docking scores of 6.301, 5.488 and 5.763 kcal/mol, respectively, fitting as well the Lipinski's rule of drug likeness. CONCLUSION: The study provided novel approach that rationalize folk use of P. peruviana fruit in treatment of arthritis.

Preclinical Evidence for the Role of the Yin/Yang Angiotensin System Components in Autism Spectrum Disorder: A Therapeutic Target of Astaxanthin.

Autism spectrum disorder (ASD) prevalence is emerging with an unclear etiology, hindering effective therapeutic interventions. Recent studies suggest potential renin-angiotensin system (RAS) alterations in different neurological pathologies. However, its implications in ASD are unexplored. This research fulfills the critical gap by investigating dual arms of RAS and their interplay with Notch signaling in ASD, using a valproic acid (VPA) model and assessing astaxanthin's (AST) modulatory impacts. Experimentally, male pups from pregnant rats receiving either saline or VPA on gestation day 12.5 were divided into control and VPA groups, with subsequent AST treatment in a subset (postnatal days 34-58). Behavioral analyses, histopathological investigations, and electron microscopy provided insights into the neurobehavioral and structural changes induced by AST. Molecular investigations of male pups' cortices revealed that AST outweighs the protective RAS elements with the inhibition of the detrimental arm. This established the neuroprotective and anti-inflammatory axes of RAS (ACE2/Ang1-7/MasR) in the ASD context. The results showed that AST's normalization of RAS components and Notch signaling underscore a novel therapeutic avenue in ASD, impacting neuronal integrity and behavioral outcomes. These findings affirm the integral role of RAS in ASD and highlight AST's potential as a promising treatment intervention, inviting further neurological research implications.

Comprehensive phytochemical characterization of Persea americana Mill. fruit via UPLC/HR-ESI-MS/MS and anti-arthritic evaluation using adjuvant-induced arthritis model.

Persea americana Mill. (avocado fruit) has many health benefits when added to our diet due to various pharmacological activities, such as preventing bone loss and inflammation, modulating immune response and acting as an antioxidant. In the current study, the total ethanol extract (TEE) of the fruit was investigated for in vitro antioxidant and anti-inflammatory activity via DPPH and cyclooxygenase enzyme inhibition. Biological evaluation of the antiarthritic effect of the fruit extract was further investigated in vivo using Complete Freund's Adjuvant (CFA) arthritis model, where the average percentages of body weight change, inhibition of paw edema, basal paw diameter/weight and spleen index were estimated for all animal groups. Inflammatory mediators such as serum IL-6 and TNF-α were also determined, in addition to histopathological examination of the dissected limbs isolated from all experimental animals. Eighty-one metabolites belonging to different chemical classes were detected in the TEE of P. americana fruit via UPLC/HR-ESI-MS/MS. Two classes of lyso-glycerophospholipids; lyso-glycerophosphoethanolamines and lysoglycerophosphocholines were detected for the first time in avocado fruit in the positive mode. The TEE of fruit exhibited significant antioxidant and anti-inflammatory activity in vitro. In vivo anti-arthritic activity of the fruit TEE improved paw parameters, inflammatory mediators and spleen index. Histopathological findings showed marked improvements in the arthritic condition of the excised limbs. Therefore, avocado fruit could be proposed to be a powerful antioxidant and antiarthritic natural product.

Evaluation of the skin protective effects of niosomal-entrapped annona squamosa against UVA irradiation.

Annona squamosa is a medicinal plant that has been used in folk medicine since antiquity. The goal of this study is to see how effective Annona squamosa leaf extract (A.S.L.E) or its niosomal-entrapped preparation is at protecting skin from UVA irradiation. The prepared niosomal-entrapped A.S.L.E has been characterized via spectrophotometry and transmission electron microscopy imaging. Furthermore, the entrapment efficiency and in vitro release of A.S.L.E were determined. In this study, ex vivo and freshly prepared samples from the dorsal region of the rats' skin were used as biological samples, which were divided into five groups: control UVA-unexposed, unprotected UVA-exposed, A.S.L.E-protected UVA-exposed, and niosomal-entrapped A.S.L.E UVA-exposed. UVA irradiation was performed by exposing the skin samples to a UVA-producing lamp for 4 h. Samples from various groups were then examined using FTIR spectroscopy, histopathology, and protein electrophoresis methods. The results showed that A.S.L.E has a skin protective effect against UVA irradiation. The niosomal-entrapped A.S.L.E was more effective than the native plant leaf extract in protecting skin from the damaging effects of UVA. Therefore, the nanotechnologically formulated preparation, niosomal-entrapped A.S.L.E, can be used as an effective photoprotector (sunscreen) against the adverse effects of UVA radiation.

Topiramate potential neurotoxicity and mitigating role of ginger oil in mice brain.

Topiramate has multiple pharmacological mechanisms that are efficient in treating epilepsy and migraine. Ginger has been established to have gingerols and shogaols that cause migraine relief. Moreover, Topiramate has many off-label uses. Thus, it was necessary to explore the possible neurotoxicity of Topiramate and the role of ginger oil in attenuating the Topiramate neurotoxicity. Male albino mice were orally gavaged with Topiramate, ginger oil (400 mg/kg), and Topiramate plus ginger oil with the same pattern for 28 days. Oxidative stress markers, acetylcholinesterase (AchE), gamma-aminobutyric acid (GABA), and tumor necrosis factor-alpha (TNF-α) were examined. Histopathological examination, immunohistochemical glial fibrillary acidic protein (GFAP), and Bax expression analysis were detected. The GABAAR subunits, Gabra1, Gabra3, and Gabra5 expression, were assessed by RT-qPCR. The investigation showed that Topiramate raised oxidative stress markers levels, neurotransmitters, TNF-α, and diminished glutathione (GSH). In addition, Topiramate exhibited various neuropathological alterations, strong Bax, and GFAP immune-reactivity in the cerebral cortex. At the same time, the results indicated that ginger oil had no neurotoxicity. The effect of Topiramate plus ginger oil alleviated the changes induced by Topiramate in the tested parameters. Both Topiramate and ginger oil upregulated the mRNA expression of gabra1 and gabra3, while their interaction markedly downregulated them. Therefore, it could be concluded that the Topiramate overdose could cause neurotoxicity, but the interaction with ginger oil may reduce Topiramate-induced neurotoxicity and should be taken in parallel.

Selenium nanoparticles enhance the efficacy of homologous vaccine against the highly pathogenic avian influenza H5N1 virus in chickens.

A proper vaccination against avian influenza viruses in chicken can significantly reduce the risk of human infection. Egypt has the highest number of recorded humans highly pathogenic avian influenza (HPAI)-H5N1 infections worldwide despite the widespread use of homologous vaccines in poultry. Enhancing H5N1 vaccine efficacy is ultimately required to better control HPAI-H5N1. The aim of this study is to boost chicken immunity by combined with inactivated HPAI-H5N1 with selenium nanoparticles (SeNPs). The chickens groups 1-3 were fed diets supplemented with SeNPs concentrations (0.25, 0.5, and 1 mg/kg) for 3 weeks and then vaccinated (inactivated HPAI-H5N1). while groups 4,5 and 6 were fed with SeNPs free diets and administered with 0.5 ml of the vaccine combined with 0.02, 0.06, and 0.1 mg/dose of SeNPs and then all groups were challenged with homologous virus 3 weeks post-vaccination (WPV). Group 7, 8 were used as control positive and negative respectively. At 4, 5, and 6 WPV, antibody titer was considerably higher in the group fed a meal supplemented with 1 mg SeNPs/kg. In contrast, both methods of SeNPs supplementation significantly increased the Interleukin 2 (IL2), Interleukin 6 (IL6), and Interferon γ (IFNγ) expressions in the blood cells in a dose-dependent manner, with a higher expression observed in the group that was vaccinated with 0.1 mg/dose. After the challenge, all groups that received SeNPs via diet or vaccines dose showed significant reduction in viral shedding and milder inflammation in lung, trachea, spleen, and liver in addition to higher expression of IL2, IL6, and IFNγ, with the highest expression observed in the group that was vaccinated with 0.1 mg/dose compared the plain vaccinated group. The groups of 1 mg SeNPs/kg and combined vaccinated with 0.1 mg/dose showed the best vaccine efficacy. However, the group vaccinated with 0.1 mg/dose showed the earliest reduction in viral shedding. Overall, SeNPs supplementation in the diet and the administration of the vaccine formula with SeNPs could enhance vaccine efficacy and provide better protection against HPAI-H5N1 in chickens by enhancing cellular immunity and reducing inflammation. We recommend using SeNPs as a vaccine combination or feeding with diet to increase the immunity and vaccine efficacy against H5N1.

The anti-Alzheimer potential of Tamarindus indica: an in vivo investigation supported by in vitro and in silico approaches.

Tamarindus indica Linn. (Tamarind, F. Fabaceae) is one of the most widely consumed fruits in the world. A crude extract and different fractions of T. indica (using n-hexane, dichloromethane, ethyl acetate, and n-butanol) were evaluated in vitro with respect to their DPPH scavenging and AchE inhibition activities. The results showed that the dichloromethane and ethyl acetate fractions showed the highest antioxidant activities, with 84.78 and 86.96% DPPH scavenging at 0.10 µg mL-1. The n-hexane, dichloromethane, and ethyl acetate fractions inhibited AchE activity in a dose-dependent manner, and the n-hexane fraction showed the highest inhibition at 20 µg mL-1. The results were confirmed by using n-hexane, dichloromethane, and ethyl acetate fractions in vivo to regress the neurodegenerative features of Alzheimer's dementia in an aluminum-intoxicated rat model. Phytochemical investigations of those three fractions afforded two new diphenyl ether derivative compounds 1-2, along with five known ones (3-7). The structures of the isolated compounds were confirmed via 1D and 2D NMR and HRESIMS analyses. The isolated compounds were subjected to extensive in silico-based investigations to putatively highlight the most probable compounds responsible for the anti-Alzheimer activity of T. indica. Inverse docking studies followed by molecular dynamics simulation (MDS) and binding free energy (ΔG) investigations suggested that both compounds 1 and 2 could be promising AchE inhibitors. The results presented in this study may provide potential dietary supplements for the management of Alzheimer's disease.

A Comparative Study of the Antihypertensive and Cardioprotective Potentials of Hot and Cold Aqueous Extracts of Hibiscus sabdariffa L. in Relation to Their Metabolic Profiles.

Ethnopharmacological relevance: Since ancient times, Hibiscus sabdariffa L. calyces have been used as a folk remedy for the treatment of hypertension. However, it is questionable as to whether there is a difference in the antihypertensive activity of the hot or cold aqueous extracts. Aim of the study: We designed this study to specify the best method for water extraction of the antihypertensive metabolites of H. sabdariffa and to confirm their in vivo antihypertensive capabilities. Materials and methods: The powdered dried calyces of H. sabdariffa were independently extracted with cold and hot water. A comparative study was performed between the cold and hot aqueous extracts of H. sabdariffa based on evaluation of the in vitro renin and angiotensin-converting enzyme (ACE) inhibition activities. Additionally, both extracts were subjected to an in vivo study for the evaluation of their antihypertensive activities in L-Nw-Nitro arginine methyl ester (L-NAME)-induced hypertensive rats. Further, a metabolomics study was also performed for both extracts to identify their chemical constituents. Results: The cold and hot extracts significantly reduced the angiotensin II, ACE, and aldosterone levels in the plasma. Furthermore, in the myocardium and aorta, decreased iNOS (inducible nitric oxide synthase) levels and elevated eNOS (endothelial nitric oxide synthase), as well as the rise in plasma NO levels, were reported with both extracts, but better results were displayed with the hot extract, leading to a potential antihypertensive effect. Additionally, the cold and hot Hibiscus extracts induced a cardioprotective effect through reducing necrosis, inflammation, and vacuolization that results from the induction of hypertension, an effect that was more prominent with the hot extract. Moreover, a comprehensive metabolomics approach using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) was able to trace the metabolites in each extraction. Conclusion: The extracts showed different anthocyanin and phenolic compounds, but the hot extract showed higher contents of specific phenolics to which the superior antihypertensive and cardioprotective activities could be related.

Assessment of the Biological Activities of Egyptian Purslane (Portulaca oleracea) Extract after Incorporating Metal Nanoparticles, in Vitro and in Vivo Study.

OBJECTIVE: Egyptian Purslane (Portulaca oleracea) is rich in omega-3 fatty acids and a wide range of vitamins and phyto-constituents that were absorbed slowly due to their high molecular weights. Therefore, this study was designed to accelerate the absorption of these phyto-constituents and hence increase their bioavailability by incorporating silver (Ag-NPs) and zinc oxide nanoparticles (ZnO-NPs) due to their impressive properties. METHODS: The major phyto-constituents and different biological activities were quantified in aqueous extract before and after incorporating metal nanoparticles (M-NPs). The efficiency of ZnO-P. nano-extract was studied on cell cycle and apoptosis of human hepatocellular carcinoma (HEPG-2) cells. Then, both Ag- and ZnO-P. nano-extracts were studied against hepatic fibrosis induced by thioacetamide (TAA) in rats through undergoing different hematological and biochemical measurements in addition to the histopathological examination in hepatic tissues compared to the extract itself. RESULTS: The ZnO-P. nano-extract showed significantly (P<0.05) higher antioxidant and scavenging activity due to the existence of higher total polyphenolic content. Also, it exhibited a significantly (P<0.05) higher inhibitory effect on acetyl cholinesterase (AChE) activity and higher cytotoxic activity against HEPG-2 cells. Therefore, ZnO-P. nano-extract was studied against the cell cycle and apoptosis of HEPG-2 cells compared to the extract itself. It was found that ZnO-P. nano-extract was safer than Ag-P. nano-extract. Both Ag- and ZnO- P. nano-extracts were studied against the hepatic fibrosis induced by thioacetamide (TAA) compared to the native extract. It was noticed that ZnO-P. nano-extract exhibited an ameliorative effect against hepatic fibrosis by decreasing levels of inflammatory and fibrotic markers significantly (P<0.05) more than Ag-P. nano-extract. Furthermore, it improved the antioxidant status of the hepatic tissue in addition to restoring the histopathological architecture of liver tissue. CONCLUSION: ZnO-P. nano-extract showed higher in vitro and in vivo biological activities than Ag-P. nano-extract and native P. extract itself.

Repurposing of nifedipine loaded in situ ophthalmic gel as a novel approach for glaucoma treatment.

Glaucoma is a chronic eye disease characterized by elevated intraocular pressure (IOP) which causes severe complications to the eyes and may lead to vision loss. The effective treatment of such diseases motivated the search for novel and unique drugs and delivery systems. It has been reported that, nifedipine (NF) is effective in reducing the elevated IOP due to vasodilatation of eye vascular smooth muscles. NF loaded thermo-sensitive in situ gels were prepared by the cold method using poloxamer 407 (P407) and hydroxypropyl methyl cellulose (HPMC) polymers adopting Box-Behnken experimental design. All the prepared formulae were tested for homogeneity, clarity, pH, isotonicity, gelling capacity, rheological behavior, in vitro drug release and were tested in vivo on rabbits. The prepared in situ gels were homogenous, transparent, having a pH ranged from 5 to 5.5 and undergo sol-gel transition within few seconds physiological temperature. The in situ gels showed sustained in vitro release of NF where about 76% of the loaded drug was released over 12 h. NF loaded in situ gels showed a 45.83 ± 2.91% reduction in the IOP, with no sign of toxicity or irritation to the eye in rabbits. The current investigations clarified the efficiency of this novel and unique NF loaded in situ gel for the control of the IOP compared to the conventional ophthalmic dosage forms.

The protective impact of berberine against doxorubicin-induced nephrotoxicity in rats.

Doxorubicin (DOX) is a well-known anti-neoplastic agent that is widely employed to treat several types of malignancies. The current study was designed to investigate the renoprotective potential of berberine (BEB) on the doxorubicin (DOX)-induced nephrotoxicity and renal fibrosis. Rats were allocated into four groups; Negative Control, DOX nephrotoxic-induced group received a single dose of DOX (20 mg/kg, i.p.), BEB-group received (50 mg/kg, p.o.) for 14 days, and co-treatment group BEB + DOX where rats were pre-treated with BEB for 10 successive days, then received a single dose of DOX on the 11th day, followed by 4 days of receiving BEB. DOX resulted in nephrotoxicity manifested by significant increments in urea, creatinine, and kidney injury molecule (KIM-1), these biochemical findings were supported with the histopathological lesions in renal tissues. Moreover, DOX provoked oxidative stress through enhancing renal malondialdehyde (MDA) and hydrogen peroxide (H2O2) contents, and decreased renal catalase (CAT) activity. DOX triggered renal fibrosis represented by increased transforming growth factor beta-1 (TGF-ß1) and elevated collagen deposition. DOX stimulated apoptosis and inflammation in renal tissues as confirmed by increased immunoexpression of caspase-3 and NF-κB, respectively. These effects were alleviated by BEB co-treatment. Co-treatment with BEB markedly prohibited DOX-induced oxidative damage, inflammation, apoptosis, and fibrosis in renal tissue. Histopathological and immunohistochemical investigations showed the nephroprotective potential of BEB on renal injury, which was consistent with the biochemical findings. Accordingly, it could be concluded that the nephroprotective potential of BEB against DOX-induced kidney injury and fibrosis might be mediated by the anti-oxidant, anti-inflammatory and anti-fibrosis activities.

Eruca sativa seed extract modulates oxidative stress and apoptosis and up-regulates the expression of Bcl-2 and Bax genes in acrylamide-induced testicular dysfunction in rats.

Acrylamide (ACR) has been previously associated with male sexual dysfunction and infertility. Eruca sativa (L.) (arugula or rocket) have been widely used in traditional remedies in Mediterranean region and western Asia and was known for its strong aphrodisiac effect since Roman times. The current study was designed to investigate LC/MS analysis of total ethanol extract Eruca sativa (L.) and the efficiency and mechanism of action of Eruca sativa seed extract (ESS) in reducing hypogonadism induced by acrylamide in male rats. Male Wistar rats were divided into 6 groups (n = 7): control group, Eruca sativa seed extract (ESS) at doses of 100 and 200 mg\kg, acrylamide (ACR), ACR + ESS 100 mg/kg, and ACR + ESS 200 mg/kg. The animals received ACR at a dose of 10 mg/kg b.wt for 60 days. Sperm indices, testicular oxidative stress, testosterone hormone, and testicular histopathology and immunohistochemistry of PCNA and caspase-3 were investigated. Moreover, the expression level of testicular B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) genes was evaluated. In respect to the LC/MS of total ethanol extract Eruca sativa (L.) seed revealed tentative identification of 39 compounds, which belongs to different classes as sulphur-containing compounds, flavonoids, phenolic acid, and fatty acids. Administration of ESS extract (100, 200 mg/kg) improved semen quality, diminished lipid peroxidation, enhanced testicular antioxidant enzyme, restored serum testosterone level, and reduced testicular degeneration and Leydig cell death in the rats intoxicated with ACR. However, the effects of ESS at the dose of 200 mg/kg were similar to that of control group. Furthermore, ESS treatment significantly induced anti-apoptotic effect indicated by elevation of both Bcl-2 and Bax expressions. Nutriceutics of ESS extract protects testis against ACR-induced testicular toxicity via normalizing testicular steroidogenesis, keeping Leydig cells, and improving oxidative stress status.

Comprehensive metabolomic, lipidomic and pathological profiles of baobab (Adansonia digitata) fruit pulp extracts in diabetic rats.

Baobab fruit pulp Adansonia digitata (AD) has received attention due to its numerous nutritional and medicinal values. In the current study, tentative identification was performed due to limited information available on its phytochemical composition. Phytochemicals from AD fruit pulp were obtained using successive organic solvent fractionation. The LC-MSMS analysis led to identification of 91 metabolites from methanol, butanol and ethyl acetate extracts. Moreover, 20 compounds were identified in the petroleum ether extract based on high resolution ion masses. In vitro antidiabetic and antioxidant properties of selected extracts were investigated using enzyme activity and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, respectively. Biological screening of the antidiabetic effects of target extracts was performed against streptozotocin-induced diabetes in experimental animals, following daily oral treatment for 3 successive weeks. Serum glucose, insulin, adiponectin, superoxide dismutase (SOD), lipid peroxide, cholesterol and HDL levels were measured. Finally, histopathological and immunohistochemical examinations of pancreas were carried out. Results revealed that animal groups treated daily with butanol (BuOH) and petroleum ether extracts of AD (oil) exhibited a significant improvement in carbohydrate and lipid metabolism as well as antioxidant effect. Both extracts revealed superior effects with respect to the total (TT) and ethyl acetate (EtOAc) extracts. Histopathological and immunohistochemical findings supported these results, showing marked protection of the pancreas. Thus, baobab oil and butanolic extract of the fruit pulp protected animals against STZ-induced diabetic changes, in addition to attenuation of lipid peroxidation, hypercholesterolemia and oxidation.

Portulaca oleracea seeds' extract alleviates acrylamide-induced testicular dysfunction by promoting oxidative status and steroidogenic pathway in rats.

BACKGROUND: Acrylamide (ACR) is a widespread industrial and food contaminant that garnered considerable attention for its carcinogenic, neurotoxic, and reproductive toxic effects. The antioxidant effects of Portulaca oleracea seeds extract (POS) and its fertility-enhancing effects were inspiring to evaluate the protective potential and pinpoint the mechanisms and molecular targets of the UPLC-MS fingerprinted POS extract on ACR-induced testicular toxicity in rats. METHODS: Male Wistar rats were divided into 6 equal groups of negative control, ACR model (10 mg/kg b.wt.), POS at doses of (200 and 400 mg/kg b.wt.) and POS-treated ACR groups. All treatments were given by oral dosing every day for 60 days. RESULTS: Administration of POS extract reversed the ACR-induced epididymides weight loss with improved semen quality and count, ameliorated the ACR-decreased testicular lesion scoring, testicular oxidative stress, testicular degeneration, Leydig cell apoptosis and the dysregulated PCNA and Caspase-3 expression in a dose-dependent manner. It upregulated the declined level of serum testosterone and the expression of steroidogenic genes such as CYP11A1 and 17ß3-HSD with an obvious histologic improvement of the testes with re-establishment of the normal spermatogenic series, Sertoli and Leydig cells. CONCLUSIONS: The supplementation with POS extract may provide a potential protective effect for ACR-induced testicular dysfunction which is mediated by its antioxidant, antiapoptotic and steroidogenic modulatory effects.

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.

Combination of pomegranate extract and curcumin ameliorates thioacetamide-induced liver fibrosis in rats: impact on TGF-ß/Smad3 and NF-κB signaling pathways.

Protection against liver injury and its consequences is considered an essential issue to minimize the number of annual deaths caused by liver diseases. The present study was designed to evaluate the potential role of pomegranate extract (PE) and/or curcumin in the regression of thioacetamide (TAA)-induced liver fibrosis, focusing on their modulatory effects on Nrf2/HO-1, NF-κB, and TGF-ß/Smad3 signaling pathways. Liver fibrosis was induced in male Wistar rats by intraperitoneal injection of TAA (100 mg/kg) three times a week, for 8 weeks. To assess the protective effects of PE and/or curcumin against TAA-induced liver fibrosis, rats were treated on a daily basis with oral doses of PE (200 mg/kg) and/or curcumin (200 mg/kg) for 8 weeks. The results indicated that PE and/or curcumin attenuated TAA-induced liver fibrogenesis, as evidenced by a significant improvement in the liver function tests (AST, ALT, ALP, and albumin), oxidative stress biomarkers (MDA, SOD, and GSH), and inflammatory biomarkers (NF-ĸB, TNF-α, IL-1ß, iNOS, TGF-ß, and MPO), compared to TAA group. Moreover, treatment with PE and/or curcumin exerted a significant upregulation of Nrf2/HO-1 gene expressions along with significant downregulation of NF-ĸB, TGF-ß, and phospho-Smad3 protein expressions, as well as α-SMA and collagen-1 gene expressions. The histopathological examination has corroborated these findings. In conclusion, hepatoprotective activities of PE and/or curcumin could be linked to their abilities to modulate Nrf2/HO-1, NF-κB, and TGF-ß/Smad3 signaling pathways. It is worth noting that the combination of PE and curcumin exerted superior hepatoprotective effects against TAA-induced liver fibrosis, as compared to monotherapy.

Hibiscus sabdariffa L.: A potent natural neuroprotective agent for the prevention of streptozotocin-induced Alzheimer's disease in mice.

Hibiscus sabdariffa L. (Malvaceae) is one of the well-known traditionally used remedy worldwide. It exhibited numerous pharmacological properties including antioxidant, antidepressant, sedative, anti-inflammatory, antiproliferative, antimicrobial and neuroprotective activities. The aim of this study is to highlight the mechanisms underlying the neuroprotective effects of anthocyanin-enriched extracts of two Hibiscus varieties (white and red calyces) in the management of Alzheimer's disease (AD) in addition to their metabolic profiling. The anthocyanin contents were determined quantitatively using the pH-differential technique and qualitatively by LC/MS/MS. The extracts were tested in vitro for their antioxidant potential as well as acetylcholinesterase inhibition activity and both showed promising activities. The LC/MS/MS analysis allowed the tentative identification of 26 and 24 metabolites in red and white calyces, respectively, represented by anthocyanins, flavonoids, aliphatic and phenolic acids. In vivo, streptozotocin induced AD in mice model was established and Hibiscus extracts were tested at a dose of 200 mg kg-1 compared to celecoxib (30 mg/kg). Histopathology of cerebral cortex and hippocampus, immunohistochemistry for tau- protein and caspase-3 with behavioral tests and measurement of several biochemical parameters were done. Hibiscus prevented memory impairment, and this could be attributed to the amelioration of STZ-induced neuroinflammation and amyloidogenesis. Consequently, Hibiscus represents a promising safe agent that can be repurposed for AD through exerting anti-inflammatory, anti-acetylcholinesterase, antioxidant, and anti-amyloidogenic activities.

STW 5 is effective against nonsteroidal anti-inflammatory drugs induced gastro-duodenal lesions in rats.

BACKGROUND: Proton pump inhibitors are often used to prevent gastro-intestinal lesions induced by nonsteroidal anti-inflammatory drugs. However, they are not always effective against both gastric and duodenal lesions and their use is not devoid of side effects. AIM: To explore the mechanisms mediating the clinical efficacy of STW 5 in gastro-duodenal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs), exemplified here by diclofenac, in a comparison to omeprazole. METHODS: Gastro-duodenal lesions were induced in rats by oral administration of diclofenac (5 mg/kg) for 6 successive days. One group was given concurrently STW 5 (5 mL/kg) while another was given omeprazole (20 mg/kg). A day later, animals were sacrificed, stomach and duodenum excised and divided into 2 segments: One for histological examination and one for measuring inflammatory mediators (tumor necrosis factor α, interleukins-1ß and 10), oxidative stress enzyme (heme oxygenase-1) and apoptosis regulator (B-cell lymphoma 2). RESULTS: Diclofenac caused overt histological damage in both tissues, associated with parallel changes in all parameters measured. STW 5 and omeprazole effectively prevented these changes, but STW 5 superseded omeprazole in protecting against histological damage, particularly in the duodenum. CONCLUSION: The findings support the therapeutic usefulness of STW 5 and its superiority over omeprazole as adjuvant therapy to NSAIDs to protect against their possible gastro-duodenal side effects.

Effect of antiepileptic drug (Topiramate) and cold pressed ginger oil on testicular genes expression, sexual hormones and histopathological alterations in mice.

Sexual dysfunction in the epileptic patient is difficult to confirm whether it is ailment or therapy related. Antiepileptic drugs often use in reproductive age, through reproductive progress and maturation. On the other side, cold-pressed oils are rich in bioactive phytochemicals with health-promoting traits. The target of this work was to appraise the sexual dysfunction of antiepileptic Topiramate (TPM) and cold pressed ginger oil (CPGO) as antiepileptic alternative medicine in male mice. Fifty-four adult male albino mice were divided into nine groups (n = 6 mice). One group given saline and used as negative control; another one was given corn oil as vehicle. Six groups administered orally with TPM or CPGO at 100, 200 and 400 mg/kg. Moreover, group of animals co-administrated orally CPGO with TPM (400 mg/kg) to study their interaction. Fatty acid profile and tocols composition of CPGO were determined. in vitro assays were undertaken to evaluate radical scavenging traits of CPGO utilizing sable 1,1-diphenyl-2-picrylhydrazyl (DPPH·) and galvinoxyl radicals. The study investigated antioxidant and oxidative stress markers, sexual hormones levels, mRNA levels of vascular endothelial growth factor (Vegfa), synaptonemal complex protein (Sycp3), Wilms tumor gene (Wt1) as well as histopathological and immunohistochemical examination. Strong radical scavenging potential of CPGO against stable DPPH· and galvinoxyl radicals was recorded. The results revealed that TPM caused a dose-dependent reduction in the antioxidant activities and testosterone content, while, malonaldehyde (MDA) and nitric oxide (NO) as oxidative stress markers were elevated. Vegfa and Sycp3 mRNA expression down-regulated at all Topiramate tested doses, but Wt1 up-regulated at 400 mg/kg. TPM (400 mg/kg) revealed histological alterations associated with strong positive Bax immune reactive spermatogoneal and Leydig cells. Ginger oil elevated the CAT and SOD (antioxidant enzymes), serum testosterone and diminished the oxidative stress, up regulated the expression of Vegfa and Sycp3 and down-regulated the Wt1 expression. Meanwhile, CPGO revealed no histopathological alterations and no Bax immune-reactive cells. CPGO co-administration with TPM (400 mg/kg) attenuated the TPM toxicity. High doses of TPM may exhibit sexual dysfunction but CPGO is safe and has androgenic property. CPGO co-administration could protect the antiepileptic patient from the TPM sexual dysfunction.