Pegylated polymeric micelles of boswellic acid-selenium mitigates repetitive mild traumatic brain injury: Regulation of miR-155 and miR-146a/BDNF/ Klotho/Foxo3a cue.

This study aims to explore the protective machinery of pegylated polymeric micelles of boswellic acid-selenium (PMBS) against secondary neuronal damage triggered by mild repetitive traumatic brain injury (RTBI). After PMBS characterization in terms of particle size, size distribution, zeta potential, and transmission electronic microscopy, the selected formula was used to investigate its potency against experimental RTBI. Five groups of rats were used; group 1 (control) and the other four groups were subjected to RTBI. Groups 2 was RTBI positive control, while 3, 4, and 5 received boswellic acid (BSA), selenium (SEL), and PMBS, respectively. The open-field behavioral test was used for behavioral assessment. Subsequently, brain tissues were utilized for hematoxylin and eosin staining, Nissl staining, Western blotting, and ELISA in addition to evaluating microRNA expression (miR-155 and miR-146a). The behavioral changes, oxidative stress, and neuroinflammation triggered by RTBI were all improved by PMBS. Moreover, PMBS mitigated excessive glutamate-induced excitotoxicity and the dysregulation in miR-155 and miR-146a expression. Besides, connexin43 (Cx43) expression as well as klotho and brain-derived neurotrophic factor (BDNF) were upregulated with diminished neuronal cell death and apoptosis because of reduced Forkhead Box class O3a(Foxo3a) expression in the PMBS-treated group. The current study has provided evidence of the benefits produced by incorporating BSA and SEL in PEGylated polymeric micelles formula. PMBS is a promising therapy for RTBI. Its beneficial effects are attributed to the manipulation of many pathways, including the regulation of miR-155 and miR-146a expression, as well as the BDNF /Klotho/Foxo3a signaling pathway.

Combined laser-activated SVF and PRP remodeled spinal sclerosis via activation of Olig-2, MBP, and neurotrophic factors and inhibition of BAX and GFAP.

A single injection of platelet-rich plasma (PRP) or stromal vascular fraction (SVF) in treating neurological ailments suggests promise; however, there is limited evidence of the efficacy of combination therapy. This trial aimed to determine whether combining SVF and PRP could provide further therapeutic effects in treating multiple sclerosis (MS). Fifteen Persian cats were separated into three groups (n = 5): group I (control negative), and group II (control positive); EB was injected intrathecally into the spinal cord and then treated 14 days later with intrathecal phosphate buffered saline injection, and group III (SVF + PRP), cats were injected intrathecally with EB through the spinal cord, followed by a combination of SVF and PRP 14 days after induction. Therapeutic effects were evaluated using the Basso-Beattie-Bresnahan scale throughout the treatment timeline and at the end. Together with morphological, MRI scan, immunohistochemical, transmission electron microscopy, and gene expression investigations. The results demonstrated that combining SVF and PRP successfully reduced lesion intensity on gross inspection and MRI. In addition to increased immunoreactivity to Olig2 and MBP and decreased immunoreactivity to Bax and GFAP, there was a significant improvement in BBB scores and an increase in neurotrophic factor (BDNF, NGF, and SDF) expression when compared to the positive control group. Finally, intrathecal SVF + PRP is the most promising and safe therapy for multiple sclerosis, resulting in clinical advantages such as functional recovery, MRI enhancement, and axonal remyelination.

Ameliorating diabetes-induced testicular dysfunction by modulating PKC/Nrf2/Bcl-2 signaling: Protective role of sulbutiamine.

The prevalence of testicular dysfunction is increasing as it is a common diabetes mellites (DM) complication. The objective of this study is to explore the potential protective effect of sulbutiamine against testicular hypofunction associated with streptozotocin (STZ)-induced DM in rats. Sulbutiamine was administered orally (60 mg/kg) to male Wistar rats for 8 weeks starting 72 h after a single injection of STZ (45 mg/kg, i.p.). Blood glucose level (BGL), serum testosterone level, sperm number, and motility were determined. Testicular tissue was examined histopathologically, and the Johnson score was evaluated. Levels of malondialdehyde (MDA), protein kinase C (PKC), nuclear factor erythroid-derived 2-like 2 (Nrf2), and proliferating cell nuclear antigen (PCNA) were measured. Apoptosis was evaluated by immunohistochemical determination of B-cell lymphoma protein 2 (Bcl-2), Bcl-2 associated X-protein (Bax), and caspase-3. Sulbutiamine administration managed to reduce BGL and boost testicular function as manifested by increased testicular weight, testosterone level, sperm number, and motility compared to the STZ group. Additionally, histopathological examination revealed an improved histological picture and Johnson score of testicular tissue after sulbutiamine treatment. Sulbutiamine administration reduced testicular PKC, MDA, and PCNA levels and increased Nrf2 compared to the untreated group. Moreover, sulbutiamine treatment suppressed apoptosis triggered by STZ as evidenced by elevated Bcl-2, decreased Bax and reduced caspase-3. The present work revealed for the first time a promising protective role of sulbutiamine against STZ-induced testicular dysfunction which may add to the clinical utility of sulbutiamine. The underlying mechanisms involve reducing BGL and PKC, activating Nrf2 and inhibiting apoptosis.

Sesamol defends neuronal damage following cerebral ischemia/reperfusion: a crosstalk of autophagy and Notch1/NLRP3 inflammasome signaling.

OBJECTIVE: Sesamol (SES) is a phenolic compound found in sesame seed oil. Several studies have revealed its anti-inflammatory and antioxidant properties. However, its complete underlying mechanistic perspective about cerebral ischemia/reperfusion (I/R) lesions has not yet been disclosed. Consequently, we aimed to scrutinize its neuroprotective mechanism against cerebral injury during a global cerebral I/R in a rat model, considering its impact on autophagy and Notch1/NLRP3 inflammasome signaling regulation. METHODS: To affirm our purpose, adult Wistar rats were allotted into five groups: sham and the other four groups in which transient global cerebral ischemia was induced by bilateral common ligation (2VO) for 1 h, then reperfusion for either 24 h or 5 days: I/R (1/24), I/R (1/5), SES + I/R (1/24), and SES + I/R (1/5). In treated groups, SES (100 mg/kg, p.o., for 21 days) was administered before cerebral I/R induction. The assessment of histopathological changes in brain tissues, immunohistochemistry, biochemical assays, ELISA, and qRT-PCR were utilized to investigate our hypothesis. RESULTS: Advantageously, SES halted the structural neuronal damage with lessened demyelination induced by cerebral I/R injury. Restoring oxidant/antioxidant balance was evident by boosting the total antioxidant capacity and waning lipid peroxidation. Furthermore, SES reduced inflammatory and apoptosis markers. Additionally, SES recovered GFAP, Cx43, and autophagy signaling, which in turn switched off the Notch-1/NLRP3 inflammasome trajectory. CONCLUSIONS: Our results revealed the neuroprotective effect of SES against cerebral I/R injury through alleviating injurious events and boosting autophagy, consequently abolishing Notch1/NLRP3 inflammasome signaling.

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.

Development of a New Benzofuran-Pyrazole-Pyridine-Based Molecule for the Management of Osteoarthritis.

Osteoarthritis is a substantial burden for patients with the disease. The known medications for the disease target the mitigation of the disease's symptoms. So, drug development for the management of osteoarthritis represents an important challenge in the medical field. This work is based on the development of a new benzofuran-pyrazole-pyridine-based compound 8 with potential anti-inflammatory and anti-osteoarthritis properties. Microanalytical and spectral data confirmed the chemical structure of compound 8. The biological assays indicated that compound 8 produces multifunctional activity as an anti-osteoarthritic candidate via inhibition of pro-inflammatory mediators, including RANTES, CRP, COMP, CK, and LPO in OA rats. Histopathological and pharmacokinetic studies confirmed the safety profile of the latter molecule. Accordingly, compound 8 is considered a promising anti-osteoarthritis agent and deserves deeper investigation in future trials.

Regulation of PKC/TLR-4/NF-kB signaling by sulbutiamine improves diabetic nephropathy in rats.

One of the serious complications of diabetes mellitus is diabetic nephropathy (DN) which may finally lead to renal failure. The current study aimed to explore the effect of sulbutiamine, a synthetic derivative of vitamin B1, in streptozotocin (STZ)-induced DN and related pathways. Experimental DN was successfully induced 8 weeks after a single low dose of STZ (45 mg/kg, I.P.). Four groups of rats were used in this study and divided randomly into: control group, diabetic group, sulbutiamine control (control + sulbutiamine) group, and sulbutiamine-treated (60 mg/kg) (diabetic + sulbutiamine) group. The fasting blood glucose level (BGL), the levels of kidney injury molecule-1 (Kim-1), urea and creatinine in serum, as well as the renal content of malondialdehyde (MDA), protein kinase C (PKC), toll-like receptor-4 (TLR-4) and nuclear factor kappa B (NF-κB) were determined. Additionally, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and transforming growth factor-ß1 (TGF-ß1) contents were evaluated immunohistochemically. Sulbutiamine treatment decreased fasting BGL and improved the kidney function tests compared to diabetic rats. Moreover, TLR-4, NF-κB, MDA and PKC contents were substantially reduced following sulbutiamine treatment compared to the diabetic group. Sulbutiamine managed to obstruct the production of the pro-inflammatory TNF-α and IL-1ß and suppressed TGF-ß1 level, in addition to attenuating the histopathological changes associated with DN. This study revealed, for the first time, the ability of sulbutiamine to ameliorate STZ-induced diabetic nephropathy in rats. This nephroprotective outcome of sulbutiamine against DN may be attributed to glycemic control in addition to its anti-oxidative, anti-inflammatory and anti-fibrotic effects.

Enhanced Wound Healing Potential of Spirulina platensis Nanophytosomes: Metabolomic Profiling, Molecular Networking, and Modulation of HMGB-1 in an Excisional Wound Rat Model.

Excisional wounds are considered one of the most common physical injuries. This study aims to test the effect of a nanophytosomal formulation loaded with a dried hydroalcoholic extract of S. platensis on promoting excisional wound healing. The Spirulina platensis nanophytosomal formulation (SPNP) containing 100 mg PC and 50 mg CH exhibited optimum physicochemical characteristics regarding particle size (598.40 ± 9.68 nm), zeta potential (-19.8 ± 0.49 mV), entrapment efficiency (62.76 ± 1.75%), and Q6h (74.00 ± 1.90%). It was selected to prepare an HPMC gel (SPNP-gel). Through metabolomic profiling of the algal extract, thirteen compounds were identified. Molecular docking of the identified compounds on the active site of the HMGB-1 protein revealed that 12,13-DiHome had the highest docking score of -7.130 kcal/mol. SPNP-gel showed higher wound closure potential and enhanced histopathological alterations as compared to standard (MEBO® ointment) and S. platensis gel in wounded Sprague-Dawley rats. Collectively, NPS promoted the wound healing process by enhancing the autophagy process (LC3B/Beclin-1) and the NRF-2/HO-1antioxidant pathway and halting the inflammatory (TNF-, NF-κB, TlR-4 and VEGF), apoptotic processes (AIF, Caspase-3), and the downregulation of HGMB-1 protein expression. The present study's findings suggest that the topical application of SPNP-gel possesses a potential therapeutic effect in excisional wound healing, chiefly by downregulating HGMB-1 protein expression.

Chicken Astro virus (CAstV): Isolation and characterization of new strains in broiler flocks with poor performance.

Chicken astroviruses (CAstV) were associated with retarded growth, enteritis, kidney diseases, and white chick syndrome. In the current study, we aimed to evaluate the effect of CAstV infection on growth, performance, and gross and histopathological picture of commercial chicken flocks suffering increased culling rate and decreased performance. Samples were collected for virus isolation, identification, and sequencing on day one, 15 days, and 30 days of age. Body weight, feed conversion rate, and mortality rates were determined. A gross examination was performed, and tissue samples from the liver, intestine, kidneys, heart, and lungs were kept in formalin for histopathological evaluation. Embryos inoculated with CAstV revealed dwarfism, and edema. The cytopathic effect on CAstV inoculated cells included aggregation,, and sloughing. The isolated Egyptian isolates shared the highest nucleotide homology (93%) with the Korean isolate Kr/ADL102655-1/2010 and showed the most distant relation to the Indian isolate Indovax/APF/1319 with 82-83% homology. Body weight exhibited significant reduction with a decrease in feed conversion rate in CAstV infected flocks. Gross examination of CAstV-infected chickens revealed white feathered chicks on day one, and poor body condition in older chickens as well as swollen kidneys. Histopathological examination of CAstV-infected birds showed mild proventriculitis, shortening of intestinal villi, enteritis, focal hepatocellular necrosis, pericarditis, myocarditis, and proliferative response in lung tissue. Kidneys showed interstitial nephritis, urate deposition, and glomerular hypercellularity. CAstV is a chicken pathogen that could be related to decreased performance, and screening of flocks for CAstV might be an essential step for breeders.

Laser-activated autologous adipose tissue-derived stromal vascular fraction restores spinal cord architecture and function in multiple sclerosis cat model.

BACKGROUND: Multiple sclerosis (MS) is the most frequent non-traumatic neurological debilitating disease among young adults with no cure. Over recent decades, efforts to treat neurodegenerative diseases have shifted to regenerative cell therapy. Adipose tissue-derived stromal vascular fraction (SVF) comprises a heterogeneous cell population, considered an easily accessible source of MSCs with therapeutic potential in autoimmune diseases. This study aimed to assess the regenerative capacity of low-level laser-activated SVF in an MS cat model. METHODS: Fifteen adult Persian cats were used in this study: Group I (control negative group, normal cats), Group II (EB-treated group, induced for MS by ethidium bromide (EB) intrathecal injection), and Group III (SVF co-treated group, induced for MS then treated with SVF on day 14 post-induction). The SVF was obtained after digesting the adipose tissue with collagenase type I and injecting it intrathecal through the foramen magnum. RESULTS: The results showed that the pelvic limb's weight-bearing locomotion activity was significantly (P ≤ 0.05) recovered in Group III, and the Basso, Beattie, and Bresnahan (BBB) scores of hindlimb locomotion were significantly higher in Group III (14 ± 0.44) than Group II (4 ± 0.31). The lesion's extent and intensity were reduced in the magnetic resonance imaging (MRI) of Group III. Besides, the same group showed a significant increase in the expression of neurotrophic factors: BDNF, SDF and NGF (0.61 ± 0.01, 0.51 ± 0.01 and 0.67 ± 0.01, respectively) compared with Group II (0.33 ± 0.01, 0.36 ± 0.006 and 0.2 ± 0.01, respectively). Furthermore, SVF co-treated group revealed a significant (P ≤ 0.05) increase in oligodendrocyte transcription factor (Olig2) and myelin basic protein (4 ± 0.35 and 6 ± 0.45, respectively) that was decreased in group II (1.8 ± 0.22 and 2.9 ± 0.20, respectively). Moreover, group III showed a significant (P ≤ 0.05) reduction in Bax and glial fibrillary acidic protein (4 ± 0.53 and 3.8 ± 0.52, respectively) as compared with group II (10.7 ± 0.49 and 8.7 ± 0.78, respectively). The transmission electron microscopy demonstrated regular more compact, and markedly (P ≤ 0.05) thicker myelin sheaths (mm) in Group III (0.3 ± 0.006) as compared with group II (0.1 ± 0.004). Based on our results, the SVF co-treated group revealed remyelination and regeneration capacity with a reduction in apoptosis and axonal degeneration. CONCLUSION: SVF is considered an easy, valuable, and promising therapeutic approach for treating spinal cord injuries, particularly MS.

Evaluation of anti-Alzheimer activity of Echinacea purpurea extracts in aluminum chloride-induced neurotoxicity in rat model.

Alzheimer's disease (AD) is one of the neurodegenerative illnesses that impair individual life & increase the demand for caregivers with no available curative medication right now. Therefore, there is a growing concern about employing herbal medicine to limit AD progression & improve patients' life quality, thus potentiating its add-on therapy. In addition, herbs are cost-effective & accessible with nearly no side effects. In the same vein, our study aimed to investigate the potency of Echinacea purpurea (EP) flower extracts to ameliorate the neurodegenerative effect of Aluminum chloride (AlCl3) in a rat model. Moreover, mechanistic studies, including impact on the cholinesterase activity, redox status, inflammatory mediators, behavior performance, glucose level & histopathology, were carried on. Our results showed that 250 mg/kg of Aqueous (AQ) & Alcoholic (AL) extracts of EP inhibited cholinesterase, restored oxidative balance, down-regulated IL-6 & TNF-α cytokines & improved behavior performance in vivo that was reflected in the brain picture by decreasing neuronal degeneration & amyloid plaques in cerebral cortex & hippocampus. The potency of both extracts was compared to reference drugs & AlCl3 positive control group. The AQ extract showed greater potency against COX-1, COX-2 & α-amylase in vitro, while the AL extract was more potent against cholinesterase in vitro, inflammatory cytokines, behavior & pathological improvement in vivo. Conclusively EP overcame AlCl3-induced neurobehavioral toxicity in the rat model via different pathways, which support its regular administration to postpone progressive neural damage in AD patients.

Calcium voltage-gated channel subunit alpha 1 C and glial fibrillary acidic protein signaling pathways as a selective biomarker in predicting the efficacy of liposomal loaded co-enzyme Q in the autistic rat model.

Autism spectrum disorder (ASD) is an extreme neuropsychotic disturbance with both environmental and genetic origins. Sodium propionate (PPA) a metabolic bioproduct of gut microbiota is well-thought-out as a successful autism animal model. Nevertheless, Liposomal drug delivery system possess the advantagous of biocompatibility, targeting organs, ability to carry large drug payloads and skipping macrophages for this purpose the current study was carried out to investigate the hypothesis that Calcium Voltage-Gated channel subunit alpha 1 C (CACNA1C) and glial fibrillary acidic protein (GFAP) signaling pathways crosstalk with the efficacy of Co-enzyme Q10 (Co-Q10) and liposomal loaded Co-enzyme Q10 (L Co-Q10) in PPA mediated autistic rat model. Autism was conducted by buffered PPA (500 mg/Kg b.wt) daily for 5 consecutive days subsequently treatment via Co-Q10 in a dose of (10 mg/kg b.wt) and L Co-Q10 (2 mg/kg b.wt) for four weeks then the autistic model was followed for signs of autism at different time intervals of (one, two and four weeks). The control, PPA intoxicated, and treated groups were subjected to behavioral tests (Y-Maze and open field), antioxidant analysis, gene expression analysis, and histological examination at different time intervals of the study. The results revealed that Co-Q10 and L Co-Q10 significantly elevated antioxidative stress biomarkers, comprising superoxide dismutase (SOD), glutathione (GSH), and total antioxidant capacity (TAC). In addition, they significantly ameliorated the oxidative stress biomarker malondialdehyde (MDA). Meanwhile, they significantly downregulated GFAP and CACNA1C mRNA gene expressions, Co-Q10 and LCo-Q10 showed improvement in almost brain regions post PPA histopathological alterations, even better results were manifested via LCo-Q10 groups. These results showed the superiority of LCo-Q10 over Co-Q10 in competing autism. In conclusion: The administration of anti-inflammatory and antioxidant agents such as Co-Q10 and L Co-Q10 may represent a promising strategy to counteract pathological behaviors in ASD model via targeting organs, increasing retention time, and reducing side effects.

Ashwagandha-loaded nanocapsules improved the behavioral alterations, and blocked MAPK and induced Nrf2 signaling pathways in a hepatic encephalopathy rat model.

Ashwagandha (ASH), a vital herb in Ayurvedic medicine, demonstrated potent preclinical hepato- and neuroprotective effects. However, its efficacy is limited due to low oral bioavailability. Accordingly, we encapsulated ASH extract in chitosan-alginate bipolymeric nanocapsules (ASH-BPNCs) to enhance its physical stability and therapeutic effectiveness in the gastrointestinal tract. ASH-BPNC was prepared by emulsification followed by sonication. The NCs showed small particle size (< 220 nm), zeta-potential of 25.2 mV, relatively high entrapment efficiency (79%), physical stability at acidic and neutral pH, and in vitro release profile that extended over 48 h. ASH-BPNC was then investigated in a thioacetamide-induced hepatic encephalopathy (HE) rat model. Compared with free ASH, ASH-BPNC improved survival, neurological score, general motor activity, and cognitive task-performance. ASH-BPNC restored ALT, AST and ammonia serum levels, and maintained hepatic and brain architecture. ASH-BPNC also restored GSH, MDA, and glutathione synthetase levels, and Nrf2 and MAPK signaling pathways in liver and brain tissues. Moreover, ASH-BPNC downregulated hepatic NF-κB immunohistochemical expression. Moreover, the in vivo biodistribution studies demonstrated that most of the administered ASH-BPNC is accumulated in the brain and hepatic tissues. In conclusion, chitosan-alginate BPNCs enhanced the hepatoprotective and neuroprotective effects of ASH, thus providing a promising therapeutic approach for HE.

Insights into the role of P2X7R/DUSP6/ERK1/2 and SIRT2/MDM2 signaling in the nephroprotective effect of berberine against cisplatin-induced renal fibrosis in rats.

AIMS: Several signaling events have been identified for mediating cisplatin-induced chronic inflammation and progressive renal fibrosis, but the majority of them have not yet been established as therapeutic targets. This study investigated the modulatory effects of berberine on purinergic 2X7 receptors (P2X7R) and some potential intracellular profibrogenic signaling as molecular mechanisms that could hinder renal fibrosis associated with cisplatin administration in rats. MAIN METHODS: For induction of kidney injury, rats were injected with cisplatin (1 mg/kg, i.p.) daily for two weeks. Concurrently, the rats were treated with berberine (100 or 200 mg/kg, p.o). The gene expressions of P2X7R, dual-specificity phosphatase 6 (DUSP6), and murine double-minute 2 (MDM2) were determined. The expressions of alpha smooth-muscle actin and tumor necrosis factor alpha (TNF-α) were assessed by immunohistochemical staining. Phosphorylated extracellular signal-regulated kinase 1/2, (p-ERK1/2) was evaluated by western blotting. Sirtuin 2 (SIRT2), kidney injury molecule-1, and galectin-3 were measured by enzyme-linked immunosorbent assay. The degree of renal fibrosis was assessed by microscopic examination and picrosirius red staining. KEY FINDINGS: Berberine effectively inhibited cisplatin-induced renal histopathological changes, enhanced renal function, and markedly mitigated inflammatory and fibrotic alterations as well as TNF-α protein expression. Additionally, P2X7R, p-ERK1/2, MDM2, and SIRT2 were suppressed and DUSP6 was upregulated by berberine. SIGNIFICANCE: The nephroprotective effects of berberine were mediated in part by downregulating P2X7R and modulating DUSP6-mediated inactivation of ERK1/2 as well as by suppressing SIRT2/MDM2-triggered renal fibrosis.

Morphomolecular characterization of Strongylus vulgaris isolated from donkeys with special references to histopathological study on the affected organs.

Equine gastrointestinal tract is infected with Strongylus vulgaris (S. vulgaris) which is highly pathogenic parasite for its harmful effect on cranial mesenteric artery during its migration. So, this study was applied for identification of S. vulgaris in donkeys ultramorphologically and molecularly. In addition to, detection of the pathological effect of larval stage of S. vulgaris on the mesenteric arterial system using histopathology and immunohistochemistry. During the period from September to December; 2019, 60 male and 20 female donkeys at the Giza Zoo was postmortem examined. S. vulgaris adults and larvae were collected from the large intestine and cranial mesenteric arteries (CMAs), respectively. Ultramorphological examination of the collected adults was done using scanning electron microscope (SEM). DNA was extracted from 5 larvae and 6 adults for further conventional PCR studies and sequencing of the internal transcriped spacer 2 (ITS2) gene. The ITS2 gene were amplified and showed bands at 148 base pair (bp). The ITS2 gene nucleotide sequences of all isolates were aligned using Basic Local Alignment Search Tool (BLAST). Histological sections of S. vulgaris affected mesenteric arteries exhibited the presence of the parasite larvae either in the lumen with thrombus formation or attached to the intima. Most of the detected inflammatory cell populations were CD68-positive cells. From these results, it can be concluded that the ribosomal spacers genes could be used as markers for Strongylus species identification in eggs collected from equine feces as a beneficial method of diagnosis. Also, it could be important in disease surveillance, improving preventive measures and developing an effective control strategy.

Differential effects of cancer modifying agents during radiation therapy on Ehrlich solid tumor-bearing mice: A comparative investigation of metformin and ascorbic acid.

BACKGROUND: This work was carried out to compare the modifying roles of ascorbic and metformin during Ehrlich (ESC) tumor-bearing mice irradiation. METHODS: Fifty Swiss albino male mice were segmented into seven groups, including one control group and six Ehrlich induced tumors treated with ascorbic, ascorbic plus radiation, metformin, metformin plus radiation, and radiation only. Many tests, including behavioral, biochemical, immunohistochemistry, gene expression, DNA fragmentation, oxidative stress markers, and EPR, were performed to interrogate the modifying effects on tumor and liver tissues. RESULTS: Remarkable apoptosis was found in metformin irradiated animals compared to irradiated ascorbic counterparts. The irradiated metformin mice showed the greatest reduction in PCNA. There was a significant reduction of DNA fragmentation in the liver tissues of the irradiated metformin group. Irradiated metformin and irradiated ascorbic acid animals showed a reduced signal of ERK as well as c-Fos genes. There was a tendency of metformin and metformin irradiated animals to reduce MDA levels in liver tissues. ESC-bearing mice treated with ascorbic or metformin showed an improvement in the spontaneous alternation percentage (SAP%) and improved short-term memory. There was also an improvement in long memory tests. CONCLUSIONS: The study added more preclinical evidence on the utility of metformin in cancer treatment during radiotherapy. Metformin was shown to reduce lipid peroxidation in irradiated healthy tissues, increase tumor cytotoxicity, downregulate critical pathways involved in tumor progression and proliferation, and enhance tumor apoptosis. Controlled clinical trials using metformin are highly warranted.

Selenium nanoparticles impart robust neuroprotection against deltamethrin-induced neurotoxicity in male rats by reversing behavioral alterations, oxidative damage, apoptosis, and neuronal loss.

This study investigated the neuroprotective role of selenium nanoparticles (SeNPs) on deltamethrin-induced neurotoxicity in rats. A total of 32 adult male Wister rats were allocated into the following four groups: 1) control, 2) deltamethrin (0.6 mg/kg), 3) SeNPs (0.5 mg/kg), and 4) deltamethrin + SeNPs. All agents were administered orally three times per week for 2 months. Locomotor behavior, anxiety-like behavior, biochemical parameters, including brain oxidative damage biomarkers (Malondialdehyde (MDA) and reduced glutathione (GSH)), brain acetylcholinesterase (AChE), and brain genotoxicity were evaluated. The gene expression levels of IGF-1 and Bcl2 were also determined. Moreover, a brain histopathological examination associated with the immunohistochemical determination of Bax in brain tissue was performed. Deltamethrin-intoxicated rats showed a reduction in the locomotor activity associated with a highly anxious state. They also displayed a disturbance in the brain redox state with a decrease in the brain AChE levels and a high DNA fragmentation percentage. Furthermore, they showed a decrement in the immunohistochemical GFAP levels as well as IGF-1 and Bcl2 gene expression levels with an increase in the immunohistochemical Bax levels. All these changes were confirmed by brain histopathology. Interestingly, SeNPs ameliorated all these changes and restored the normal brain architecture. In conclusion. SeNPs possess a potent medicinal activity due to their antioxidant and anti-inflammatory activity. Therefore, SeNPs can be a potential agent in ameliorating deltamethrin-induced neurotoxicity.

Possible Implication of Nrf2, PPAR-γ and MAPKs Signaling in the Protective Role of Mangiferin against Renal Ischemia/Reperfusion in Rats.

Mangiferin (Mang) is a known glucosylxanthone that has proven its shielding effect against ischemia/reperfusion (Is/R). However, its full underlying mechanistic perspective against renal Is/R induced lesions is not fully revealed. Consequently, the purpose of this study is to track further non-investigated modulatory signals of Mang against the renal Is/R model involving nuclear factor erythroid 2-related factor (Nrf)2/heme oxygenase (HO)-1, peroxisome proliferator-activated receptor (PPAR)-γ/nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) signaling. To ratify our aim, Mang was administrated (20 mg/kg, i.p for seven days) before the induction of bilateral Is/R. Mechanistic maneuver revealed that Mang balanced oxidative state via increasing the expression of the antioxidant Nrf2/HO-1 cue with subsequent enhancement of GSH besides MDA lessening. Additionally, Mang enhanced PPAR-γ mRNA expression and declined p-p38 MAPK and p-JNK expression with concomitant NF-κB downsizing leading to iNOS/NOx and TNF-α rebating. Furthermore, the Mang anti-apoptotic trait was affirmed by enriching Bcl-2 expression as well as decreasing Bax and caspase-3 expression. All these potentials were in the line with the molecular docking results and the improved histopathological findings and renal function biomarkers. Consequently, Mang provided plausible protective mechanisms against renal Is/R-related events, possibly by amending oxidative status, inflammatory mediators, and apoptotic cell death through the involvement of Nrf2, PPAR-γ, MAPK, JNK, and NF-κB signaling.