Hesperidin Attenuates Titanium Dioxide Nanoparticle-Induced Neurotoxicity in Rats by Regulating Nrf-2/TNF-α Signaling Pathway, the Suppression of Oxidative Stress, and Inflammation.

Background: Titanium dioxide nanoparticles (TiO2NPs) are widely utilized and consumed mainly as food additives. Oxidative stress is considered to be the basic effect of TiO2NPs through biological interactions. Hesperidin (HSP) is a bioflavonoid (flavanone glycoside) with lipid-lowering, inflammation, oxidative stress suppression, antihypertensive, cancer-fighting, and antiedema effects. Objective: This study was to investigate the possible protective influences of HSP of subchronic oral TiO2NP exposure on the brains of rats, including neurotransmitters, oxidative stress/antioxidant parameters, inflammatory markers, and histological changes in the brains of adult male albino rats. Methodology: The experiment was executed on 80 albino rats. The animals were randomly divided into 4 equal groups. The first group served as a control; the second group was treated with oral doses of HSP (100 mg/kg Bw daily); the third group received TiO2NPs (200 mg/kg Bw orally daily); and the fourth group was treated with TiO2NPs and an oral dose of HSP daily for 8 weeks. Blood samples were obtained for biochemical analysis. Neurotransmitters, oxidative stress biomarker levels, and inflammatory markers were measured in brain homogenates. Histological examination of the brain was performed through H&E staining. Results: Coadministration of hesperidin with TiO2NPs orally for 8 weeks decreased the levels of MDA, TNF-α, AChE, and dopamine in brain homogenates, which were increased in the TiO2NP group. It increased the other oxidative biomarkers (SOD, CAT, and GPx) and Nrf-2 expression levels. Brain histological sections of the TiO2NP-treated group show degeneration, necrosis, congestion, and inflammatory cell infiltration that decreased markedly in the coadministration of hesperidin with the TiO2NP group. Conclusion: Hesperidin cotreatment offers significant protection against TiO2NP-induced oxidative stress and biochemical and histological alteration in the brain.

Methanesulfonamide derivatives as gastric safe anti-inflammatory agents: Design, synthesis, selective COX-2 inhibitory activity, histopathological and histochemical studies.

Novel chalcone 3a-c, pyrazoline 4a-i and pyridine 5a-c, 6a&b derivatives bearing methanesulfonamide moiety were synthesized. Their construction was confirmed using spectral data and elemental analysis. The stereo-chemical configuration for compounds 3a-c was predicted by MM2 property and 1H NMR spectra. All the prepared compounds were screened for their in vitro COX-1/COX-2 inhibitory activities and in vivo anti-inflammatory activity. The most active anti-inflammatory derivatives, 4f-4i, after 3, 5 & 7 h were further subjected to histopathological and histochemical studies showing safe effect on gastric mucosa, especially 4h derivative. To explore the mechanism of action of COX-2 inhibitory compounds 4f and 6b with the highest S.I. values, they were docked inside COX-2 active site. Physicochemical properties for 4f-i and 6b derivatives were predicted and compared to the reference drug celecoxib. They showed good oral bio-availability specially pyrazoline derivative 4f and pyridine containing compound 6b.

Targeting Some Key Metalloproteinases by Nano-Naringenin and Amphora coffeaeformis as a Novel Strategy for Treatment of Osteoarthritis in Rats.

Osteoarthritis (OA) represents the highest degenerative disorder. Because cartilage erosion is a common pathological alteration in OA, targeting some key metalloproteinases such as MMP-3, ADAMTS-5 besides their inhibitor TIMP-3 by natural products, could be an effective strategy to protect against osteoarthritis. Forty female Wister rats were categorized into five equal groups. Control, osteoarthritic (OA) (monosodium iodoacetate (MIA) 2 mg/50 µL saline, single intra-articular injection), OA+ indomethacin (2 mg/kg/daily/orally), OA+ nano-naringenin (25 mg/kg/daily/orally), and OA+ Amphora coffeaeformis (772 mg/kg/daily/orally). Treatments were initiated on the 8th day after osteoarthritis induction and continued for 28 days thereafter. Finally, blood and knee joint samples were collected from all rats for biochemical and histopathological evaluations. The current study showed that MIA induced oxidative stress, which resulted in changes in the inflammatory joint markers associated with increased right knee diameter and higher clinical scores for lameness. Amphora coffeaeformis followed by nano-naringenin exhibited a potential anti-arthritic activity by reducing the concentrations of serum MMP-3, ADAMTS-5, and joint MDA and increasing the levels of serum TIMP-3 and joint GSH, similar to indomethacin. The histopathological results confirmed these outcomes. In conclusion, Amphora coffeaeformis and nano-naringenin can be considered as natural therapeutic agents for osteoarthritis owing to their antioxidant and anti-inflammatory activities.

Royal Jelly and Chlorella vulgaris Mitigate Gibberellic Acid-Induced Cytogenotoxicity and Hepatotoxicity in Rats via Modulation of the PPARα/AP-1 Signaling Pathway and Suppression of Oxidative Stress and Inflammation.

Gibberellic acid (GA3) is a well-known plant growth regulator used in several countries, but its widespread use has negative effects on both animal and human health. The current study assesses the protective effect of royal jelly (RJ) and Chlorella vulgaris (CV) on the genotoxicity and hepatic injury induced by GA3 in rats. Daily oral administration of 55 mg/kg GA3 to rats for 6 constitutive weeks induced biochemical and histopathological changes in the liver via oxidative stress and inflammation. Co-administration of 300 mg/kg RJ or 500 mg/kg CV with GA3 considerably ameliorated the serum levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase), γGT (gamma-glutamyl transferase), total bilirubin, and albumin. Lowered malondialdehyde, tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) levels along with elevated SOD (superoxide dismutase), CAT (catalase), and GPx (glutathione peroxidase) enzyme activities indicated the antioxidant and anti-inflammatory properties of both RJ and CV. Also, they improved the histological structure and reduced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions along with up-regulating peroxisome proliferator activated receptor α (PPARα) and down-regulating activator protein 1 (AP-1) gene expression. Additionally, chromosomal abnormalities and mitotic index were nearly normalized after treatment with RJ and CV. In conclusion, RJ and CV can protect against GA3-induced genotoxicity and liver toxicity by diminishing oxidative stress and inflammation, and modulating the PPARα/AP-1 signaling pathway.

Trimethoxyphenyl containing compounds: Synthesis, biological evaluation, nitric oxide release, modeling, histochemical and histopathological studies.

Novel series of trimethoxy phenyl containing chalcone 3, 5, 6, 7, pyrazoline 4a&b, 9a-h and pyrazole 10a&b scaffolds were designed and synthesized. They were characterized by spectral data and elemental analyses. All newly synthesized compounds were screened for their in vitro COX-1/COX-2 inhibitory activities and in vivo anti-inflammatory activity. All the target compounds showed COX-2 inhibitory activity over COX-1. Compound 5c was the most active derivative with higher COX-2 inhibitory activity (IC50 = 0.039 µM) than celecoxib (IC50 = 0.045 µM), and selectivity index value of 321.28 nearly equal to that of celecoxib (S.I. = 326.66). Four additional derivatives 5a, 6, 8b and 9f exhibited excellent COX-2 inhibitory activity (IC50 = 0.041 - 0.049 µM) if compared to the reference drug, celecoxib, with selectivity index values (S.I. = 230.61 - 278.05). Additionally, prolonged in vivo A.I activity was observed in compounds 9e, 9 g, 10a and 10b with % inhibition ranged from 33.21 to 44.52%, after 7 h from carrageenan injection. Compound 9e appeared normal without degeneration similar to celecoxib as resulted from histolopathogical study. Compounds containing NO releasing moieties, 7, 10a and 10b were assesses to overcome the gastrointestinal side effects. Molecular modeling study was operated and achieved a parallel correlation with in vitro COX-2 assay results. Pharmacokinetic study for all the prepared compounds was developed.

Potential Use of Tailored Citicoline Chitosan-Coated Liposomes for Effective Wound Healing in Diabetic Rat Model.

PURPOSE: This study aimed to formulate citicoline-loaded chitosan-coated liposomes (CT-CS-LPs) for topical administration and evaluated for wound healing in a diabetic animal model. METHODS: CT-LPs were formulated via a thin-film hydration approach and coated with chitosan (CS). Box-Behnken statistical design investigated the effects of lipid amount, chitosan concentration, and cholesterol amount on vesicle diameter, surface charge, and entrapment efficiency. The potential of the optimized CT-CS-LPs gel for wound healing was further evaluated in streptozocin-induced diabetic rats. The different healing stages were evaluated by several techniques, including general and special staining techniques, in addition to antibody immunohistochemistry. RESULTS: The optimized CT-CS-LPs obtained had a mean size of 211.6 nm, a 50.7% entrapment efficiency, and a positive surface charge of 32.1 mV. In addition, the optimized CT-CS-LPs exhibited in vitro sustained release behavior. The in vivo experiments revealed that treatment with the optimized CT-CS-LPs boosts the healing process of the skin wound in diabetic rats by reducing inflammation, accelerating re-epithelization, angiogenesis, fibroblast proliferation, and connective tissue remodeling, leading to rapid wound closure. CONCLUSION: Chitosan-coated liposomes containing citicoline have emerged as a potential approach for promoting the healing process in diabetic rats. However, the therapeutic effectiveness of the suggested approach in diabetic patients needs to be investigated.

Necrostatin-1 mitigates renal ischaemia-reperfusion injury - time dependent - via aborting the interacting protein kinase (RIPK-1)-induced inflammatory immune response.

The recently defined necroptosis process participates in the pathophysiology of several tissue injuries. Targeting the necroptosis mediator receptor-interacting protein kinase (RIPK1) by necrostatin-1 in different phases of ischaemia-reperfusion injury (IRI) may provide new insight into the protection against renal IRI. The rat groups included (n = 8 in each group): 1) Sham; 2) Renal IRI; 3) Necrostatin-1 treatment 20 min before ischaemia induction in a dose of 1.65 mg/kg/intravenous; 4) Necrostatin-1 injection just before reperfusion; 5) Necrostatin-1 injection 20 min after reperfusion establishment; and 6) drug injection at both the pre-ischaemia and at reperfusion time in the same dose. Timing dependent, necrostatin-1 diminished RIPK1 (p < 0.001), and aborted the necroptosis-induced renal cell injury. Necrostatin-1 decreased the renal chemokine (CXCL1), interleukin-6, intercellular adhesion molecule (ICAM-1), myeloperoxidase, and the nuclear factor (NFκB), concomitant with reduced inducible nitric oxide synthase (iNOS), inflammatory cell infiltration, and diminished cell death represented by apoptotic cell count and the BAX/Bcl2 protein ratio. In group 6, the cell injury was minimal and the renal functions (creatinine, BUN and creatinine clearance) were almost normalised. The inflammatory markers were diminished (p < 0.001) compared to the IRI group. The results were confirmed by histopathological examination. In conclusion, RIPK1 inhibition ameliorates the inflammatory immune response induced by renal IRI. The use of two doses was more beneficial as the pathophysiology of cell injury is characterised.

Berberine Encapsulated Lecithin-Chitosan Nanoparticles as Innovative Wound Healing Agent in Type II Diabetes.

The aim of this research is to formulate a lecithin-chitosan based nanoparticulate system loaded with berberine (BER-LC-CTS-NPs) that could be integrated into a topically applied formulation and assessed for healing wounds in a diabetic animal model. In order to formulate BER-LC-CTS-NPs, soybean lecithin, isopropyl myristate, and berberine dispersed in ethanolic solution were added into an aqueous solution of chitosan dropwise with sonication. We assessed the influence of lecithin amount, chitosan amount, and isopropyl myristate concentration on particle diameter, zeta potential, and entrapment and employed a Box-Behnken statistical design. The resulting optimized BER-LC-CTS-NPs had a mean size of 168.4 nm, a surface charge of 33.1 mV, and entrapment of 82.3%. The optimized BER-LC-CTS-NPs showed a sustained in vitro release profile. Furthermore, the potential of the optimized BER-LC-CTS-NPs integrated into a topical gel formulation for wound healing in streptozocin-induced diabetic rats was assessed. Our findings show that combining chitosan and berberine in the nanoparticles produces a synergistic effect when it comes to wound healing. The optimized nanoparticulate system works by reducing inflammation, inducing blood vessels and fibroblast proliferation, and promoting mature collagen fibers deposition. Based on the experimental results, lecithin-chitosan nanoparticles loaded with berberine have evolved as a promising strategy for accelerating wound the healing process in diabetic patients. However, the clinical merits of the developed system need to be investigated in diabetic patients.

Histological, histochemical, and immunohistochemical studies of hippocampus in male New Zealand rabbits.

The present study aims to give detailed histomorphological features of the hippocampus of adult male New Zealand rabbits. Both histological and histochemical specimens were prepared to be examined microscopically by using a light microscope. The hippocampus appeared as C-shaped hippocampal proper, dentate gyrus, and subiculum. The hippocampal proper subdivided along its length according to the density and size of its major constituent pyramidal cells into four distinct regions named Cornu Ammonis (CA1, CA2, CA3, and CA4). With the histochemical preparations, each of these regions consisted of five layers, stratum alveolus, stratum oriens, stratum pyramidale, stratum radiatum, and stratum lacunosum-moleculare. The stratum pyramidale constituted the middle dark zone and contained the principal excitatory neurons and a few interneurons. Histochemically, the pyramidal neurons along all regions of the CA reacted positively to Grimelius silver impregnation, lead hematoxylin, Gomori's aldehyde fuchsin, aldehyde thionine, Gomori's chrome alum hematoxylin, and performic acid alcian blue stains. Immunohistochemically, the pyramidal neurons reacted positively to anti-NSE antibodies. The dentate gyrus was formed of three distinct layers. The subiculum was formed of proper subiculum, presubiculum, and parasubiculum.