Fenofibrate ameliorates nitroglycerin-induced migraine in rats: Role of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways.

Migraine, a debilitating neurological condition, significantly affects patients' quality of life. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist approved for managing dyslipidemia, has shown promise in treating neurological disorders. Therefore, this study aims to investigate the protective effects of fenofibrate against nitroglycerin (NTG)-induced chronic migraine in rats. Migraine was induced in rats by administering five intermittent doses of NTG (10 mg/kg, i. p.) on days 1, 3, 5, 7, and 9. Rats were treated with either topiramate (80 mg/kg/day, p. o.), a standard drug, or fenofibrate (100 mg/kg/day, p. o.) from day 1-10. Fenofibrate significantly improved mechanical and thermal hypersensitivity, photophobia, and head grooming compared to topiramate. These effects were associated with reduced serum levels of nitric oxide (NO), calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating polypeptide (PACAP). Furthermore, fenofibrate down-regulated c-Fos expression in the medulla and medullary pro-inflammatory cytokine contents. Additionally, fenofibrate attenuated NTG-induced histopathological changes in the trigeminal ganglia and trigeminal nucleus caudalis. These effects were associated with the inhibition of CGRP/p-CREB/purinergic 2X receptor 3 (P2X3) and nerve growth factor (NGF)/protein kinase C (PKC)/acid-sensing ion channel 3 (ASIC3) signaling pathways. This study demonstrates that fenofibrate attenuated NTG-induced migraine-like signs in rats. These effects were partially mediated through the inhibition of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways. The present study supports the idea that fenofibrate could be an effective candidate for treating migraine headache without significant adverse effects. Future studies should explore its clinical applicability.

Berberine loaded thermosensitive lipid nanoparticles: in vitro characterization, in silico study, and in vivo anti-arthritic effect.

Thermoresponsive drug delivery systems have been used to treat diseases that cause hyperthermia or elevated body tissue temperatures, viz., rheumatoid arthritis and different cancers. The aim of the study was to enhance berberine (BER) release using thermosensitive nanostructured lipid carriers (TNLCs) through intra-articular administration for the management of arthritis. TNLCs were prepared using binary mixtures of stearic acid and decanoic acid as solid and liquid lipids, respectively. Lipid mixtures with an optimum melting point were assessed using differential scanning calorimetry studies. In vitro characterization of the BER TNLCs included particle size, zeta potential, entrapment efficiency, and drug release at 37 °C and 41 °C. Joint diameter measurement, real-time polymerase chain reaction (RT-PC) analysis, enzyme-linked immunosorbent assay (ELISA) for inflammatory markers, and histological evaluation of the dissected joints were all performed in vivo on rats with adjuvant-induced arthritis. In vitro characterization revealed negatively charged BER-loaded TNLCs with a spherical shape, particle size less than 500 nm, BER entrapment efficiency up to 79%, and a high drug release rate at an elevated temperature of 41 °C. In silico studies revealed the affinity of BER to different formula components and to the measured biomarkers. In vivo assessment of the optimum TNLCs showed that BER TNLCs were superior to the BER solution suspension regarding their effect on inflammatory biomarkers, joint diameter, and histological studies.

Quercus coccinea Münchh leaves polyphenols: Appraisal acute lung injury induced by lipopolysaccharide in mice.

Genus Quercus is a well-known source for its polyphenolic content and important biological activity. Plants belonging to the Quercus genus were traditionally used in asthma, inflammatory diseases, wound healing, acute diarrhea, and hemorrhoid. Our work intended to study the polyphenolic profile of the Q. coccinea (QC) leaves and to assess the protective activity of its 80% aqueous methanol extract (AME) against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Together, the potential molecular mechanism was investigated. Nineteen polyphenolic compounds (1-18), including tannins, flavone, and flavonol glycosides. Phenolic acids and aglycones were purified and identified from the AME of QC leaves. Treatment with AME of QC showed an anti-inflammatory effect evidenced by a remarkable decline in the count of white blood cells and neutrophils which was in harmony with decreasing the levels of high mobility group box-1, nuclear factor kappa B, tumor necrosis factor-α, and interleukin 1 beta. In addition, the antioxidant activity of QC was documented through the significant reduction in malondialdehyde level and elevation of reduced glutathione level and superoxide dismutase activity. Furthermore, the mechanism involved in the pulmonary protective effect of QC involved the downregulation of the TLR4/MyD88 pathway. The AME of QC showed a protective effect against LPS-induced ALI through the powerful anti-inflammatory and antioxidant activities which are linked to its abundancy with polyphenols.

Evaluating the efficacy of Nd:YAG fourth harmonic (266 nm) in comparison with ArF excimer (193 nm) in laser corneal reshaping: ex vivo pilot study.

PURPOSE: Laser corneal reshaping is a common eye surgery utilized to overcome many vision disorders. Different UV laser wavelengths can be effective in the treatment. However, the ArF excimer laser (193 nm) is the most commonly used due to its high absorption in the cornea. In the current study, we investigate the efficacy of applying a solid-state laser (Nd:YAG fourth harmonic at 266 nm) for the corneal reshaping procedure. METHODS: The utilized laser is generated using an optical setup based on a BBO nonlinear crystal which converts the Q-switched laser (532 nm) to its fourth harmonic (266 nm). Different pulse energies were applied with the same number of the shoots on ex vivo rabbit corneas, and the histological effect is studied. Moreover, the possible thermal damage on the treated corneal tissues was inspected via electron microscope. Additionally, the DNA damage on the corneal cells due to the application of the proposed laser was examined and compared with the existing technology (ArF Excimer laser at 193 nm) using the comet assay. RESULTS: The histological examination revealed an appropriate ablation result with the minimum thermal effect at 1.5 mJ and 2.0 mJ. The overall results show that applying 50-shoots of the 1.5-mJ pulse energy using the proposed 266-nm solid-state laser produces the optimum ablation effect with the minimum thermal damage, and almost the same DNA damage occurred using the commercial 193-nm ArF excimer laser. CONCLUSION: Solid-state laser at 266 nm could be a good alternative to the common 193-nm excimer laser for corneal reshaping procedures.

Crosstalk between PI3K/AKT/KLF4 signaling and microglia M1/M2 polarization as a novel mechanistic approach towards flibanserin repositioning in parkinson's disease.

Balancing microglia M1/M2 polarization has been shown as a prospective therapeutic strategy for Parkinson's disease (PD). Various vital signaling pathways are likely to govern the microglial phenotype. The implication of 5HT1A receptors in neurodegenerative disorders has raised interest in exploring the repositioning of flibanserin (Flib), a 5HT1A agonist, as an effective neuroprotective agent for PD. Therefore, this study was designed to assess the ability of Flib to modulate microglia phenotype switching from M1 to M2 via PI3K/AKT downstream targets in a rotenone model of PD. Rats received rotenone (1.5 mg/kg) every other day and were concurrently treated with Flib (40 mg/kg/day) with or without wortmannin (15 µg/kg/day), a PI3K inhibitor, for 21 days. Flib improved the motor perturbations induced by rotenone, as confirmed by the reversion of histopathological damage and tyrosine hydroxylase immunohistochemical alterations in both the striata and substantia nigra. The molecular signaling of Flib was elaborated by inducing striatal AKT phosphorylation and the expression of its substantial target, KLF4. Flib induced STAT6 phosphorylation to promote M2 polarization as demonstrated by the increased CD163++ microglial count with striatal arginase activity. In parallel, it markedly inhibited M1 activation as evidenced by the reduction in CD86++ microglia count with striatal proinflammatory mediators, IL-1ß and iNOS. The pre-administration of wortmannin mostly negated Flib's neuroprotective effects. In conclusion, Flib AKT/ KLF4-dependently amended M1/M2 microglial imbalance to exert a promising neuroprotective effect, highlighting its potential as a revolutionary candidate for conquering PD.

Appraisal on the Wound Healing Potential of Deverra tortuosa DC. and Deverra triradiata Hochst Essential Oil Nanoemulsion Topical Preparation.

Deverra tortuosa (Desf.) DC. and Deverra. triradiata Hochst. ex Bioss are perennial desert shrubs widely used traditionally for many purposes and they are characteristic for their essential oil. The objective of the present study was to investigate the in vivo wound healing activity of the essential oil (EO) of D. tortuosa and D. triradiata through their encapsulation into nanoemulsion. EO nanoemulsion was prepared using an aqueous phase titration method, and nanoemulsion zones were identified through the construction of phase diagrams. The EO was prepared by hydrodistillation (HD), microwave-assisted hydrodistillation (MAHD), and supercritical fluid extraction (SFE) and analyzed using GC/MS. D. tortuosa oil is rich in the non-oxygenated compound, representing 74.54, 73.02, and 41.19% in HD, MADH, and SFE, respectively, and sabinene represents the major monoterpene hydrocarbons. Moreover, D. triradiata is rich in oxygenated compounds being 69.77, 52.87, and 61.69% in HD, MADH, and SFE, respectively, with elemicin and myristicin as major phenylpropanoids. Topical application of the nanoemulsion of D. tortuosa and D. triradiata (1% or 2%) exhibited nearly 100% wound contraction and complete healing at day 16. Moreover, they exhibit significant antioxidant and anti-inflammatory effects and a significant increase in growth factors and hydroxyproline levels. Histopathological examination exhibited complete re-epithelialization accompanied by activated hair follicles and abundant collagen fibers, especially at a concentration of 2%. Therefore, the incorporation of the two Deverra species into nanoemulsion could professionally endorse different stages of wound healing.

Ethnopharmacological impact of Melaleuca rugulosa (Link) Craven leaves extract on liver inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Melaleuca species have been used by many ethnic communities for the management and treatment of several ailments as hemorrhoids, cough, skin infections, rheumatism, sore throat, pain, inflammation, and digestive system malfunctions. However, the detailed mechanistic pharmacological effect of Melaleuca rugulosa (Link) Craven leaves in the management of liver inflammation has not been yet addressed. AIM OF THE STUDY: The present study aimed to evaluate the anti-inflammatory, antioxidant, and antiapoptotic capacities of the aqueous methanol extract of M. rugulosa leaves in relevance to their flavonoid content using an appropriate in vivo model. MATERIALS AND METHODS: The aqueous methanol extract of M. rugulosa leaves was administered to the rats at three non-toxic doses (250, 500, and 1000 mg/kg) for seven days prior to the initiation of liver-injury induced by paracetamol (3 g/kg). Liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were evaluated in serum samples. The oxidative stress markers including reduced glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) levels as well as the inflammatory markers such as tumour necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB), were assessed in liver homogenate. The results were supported by histopathological and immuno-histochemical studies. The phytochemical investigation of the flavonoid-rich fraction of the aqueous methanol extract was accomplished using different chromatographic and spectroscopic techniques. RESULTS: The aqueous methanol extract of M. rugulosa leaves showed a powerful hepatoprotective activity evidenced by the significant reduction of MDA and NO levels, as well as increasing GSH and catalase activity. Moreover, the extract exhibited anti-inflammatory and antiapoptotic activities witnessed by decreasing TNF-α, NF-κB, iNOS, p-JNK, caspase-3, BAX, and increasing Bcl-2 levels. Moreover, the pretreatment of rats with all doses of M. rugulosa leaves extract showed a significant decrease in liver weight/body weight (LW/BW) ratio, and total bilirubin induced by paracetamol. On the other hand, the chromatographic separation of the flavonoid-rich fraction afforded twenty known flavonoids namely; iso-orientin (1), orientin (2), isovitexin (3), vitexin (4), quercetin-3-O-ß-D-glucuronid methyl ether (5), quercetin-3-O-ß-D-mannuronpyranoside (6), isoquercetin (7), quercitrin (8), kaempferol-3-O-ß-D-mannuronopyranoside (9), kaempferol-7-O-methyl ether-3-O-ß-D-glucopyranoside (10), guaijaverin (11), avicularin (12), kaempferide-3-O-ß-D-glucopyranoside (13), astragalin (14), afzelin (15), luteolin (16), apigenin (17), quercetin (18), kaempferol (19), and catechin (20). CONCLUSION: The aqueous methanol extract of M. rugulosa leaves showed potential hepatoprotective, antioxidant, and anti-inflammatory activities against paracetamol-induced liver inflammation which is correlated at least in part to its considerable phenolic content.

Effects of nitrite graded doses on hepatotoxicity and nephrotoxicity, histopathological alterations, and activation of apoptosis in adult rats.

Nitrites are found in several forms; they are widely found in water resources and used as additives and preservatives for food and as a color source. We investigated the hazardous effects of exposing rats to different doses of nitrites. Moreover, we examined such impacts, after acute ingestion, on liver and renal tissues in rats and to what extent this affects the organs' functions. Animals were divided into five groups: one control group 1 (group C) and four sodium nitrite (NaNO2)-treated group (8 rats per group). The four NaNO2-treated groups include group 2 (N20), group 3 (N40), group 4 (N60), and group 5 (N75). NaNO2 was dissolved in distilled water, and single acute dose was orally given by gavage at 20, 40, 60, and 75 mg/kg body weight, respectively. Our results revealed significant increase of liver enzymes activity-aspartate transaminase (AST), alanine aminotransferase (ALT), and creatinine between different groups with increasing doses of nitrite ingestion. The results of hepatic and renal oxidative stress showed significant increase in the malondialdehyde (MDA) levels and significant decrease in the antioxidant parameters, such as reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), as the dose of nitrite increases. Further, the methemoglobin percent showed significant increase with increasing nitrite doses. Abnormal morphological alterations in the liver and kidney tissues were obviously proportional to the administered nitrite doses. The expression of caspase 3 and Bax level showed enhanced induction of immunoexpression, especially in the high doses of nitrites. On the other hand, the maximal immunoexpression level of anti-apoptotic marker Bcl2 was found in lower doses of nitrites, whereas marked decrease of Bcl2 levels was observed in the higher doses. In conclusion, administration of sodium nitrite in a dose-dependent manner is capable of inducing cellular and genetic toxicities and causes disturbance in biochemical analysis, oxidative and anti-oxidative balance, and methemoglobinemia. It also makes histopathological alterations and leads to the activation of apoptosis-related Bax, Bcl2, and caspase 3 genes of liver and kidney tissues in rats.

Pentoxifylline (anti-tumor necrosis factor drug): effective adjuvant therapy in the control of ocular cicatricial pemphigoid.

PURPOSE: The detection of tumor necrosis factor-a (TNF-a) in conjunctiva affected by ocular cicatricial pemphigoid (OCP) may indicate that this cytokine plays an important role in its pathogenesis. The purpose of this randomized, controlled, comparative, blinded study was to evaluate the effectiveness of adding pentoxifylline as an anti-TNF-a drug to the well-documented therapy of steroids and cyclophosphamide in controlling OCP. METHODS: Thirty patients with different grades of OCP were included. They were randomly divided into 2 equal groups. Group A patients received pulse steroid and cyclophosphamide therapy; in addition, group B patients received intravenous pentoxifylline. Patients were evaluated before and after therapy clinically, histopathologically, and serologically (serum level of TNF-a). Twenty controls were included to compare their serum TNF-a level with that measured in patients with OCP. RESULTS: Group B patients showed a more significant improvement in their clinical and histopathologic evaluation. The serum TNF-a was significantly higher in OCP cases prior to therapy compared to the control group (p = 0.0001). Following therapy, serum TNF-a showed a more significant reduction in group B patients (77.4 ± 26.1 to 19.2 ± 15.6) compared to group A patients (50.3 ± 14.3 to 36.2 ± 18.3). CONCLUSIONS: The significantly increased level of serum TNF-a in OCP as compared to controls proves that TNF-a has an important role in the pathogenesis of this disease. The study illustrates that the addition of pentoxifylline to pulse steroid cyclophosphamide therapy is an effective, safe, and economical method in controlling OCP through directly reducing TNF-a levels, with long periods of remission as detected in our 18-month follow-up period.