Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive cartilage and bone erosion. This work aimed to evaluate the metabolomic profile of Medicago sativa L. (MS) (alfalfa) seeds and explore its therapeutic impact against RA in rats. Arthritis was induced by complete Freund's adjuvant (CFA) and its severity was assessed by the arthritis index. Treatment with MS seeds butanol fraction and interlukin-1 receptor antagonist (IL-1RA) were evaluated through measuring interlukin-1 receptor (IL-1R) type 1 gene expression, interlukin-1 beta (IL-1β), oxidative stress markers, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), caspase-3 (Cas-3), intracellular adhesion molecule-1 (ICAM-1), DNA fragmentation, and chromosomal damage. Total phenolics/ flavonoids content in the ethyl acetate, butanol fraction and crude extract of MS seeds were estimated. The major identified compounds were Quercetin, Trans-taxifolin, Gallic acid, 7,4'-Dihydroxyflavone, Cinnamic acid, Kudzusaponin SA4, Isorhamnetin 3-O-beta-D-2'',3'',4''-triacetylglucopyranoside, Apigenin, 5,7,4'-Trihydroxy-3'-methoxyflavone, Desmethylxanthohumol, Pantothenic acid, Soyasapogenol E, Malvidin, Helilandin B, Stigmasterol, and Wairol. Treatment with MS seeds butanol fraction and IL-1RA enhanced all the biochemical parameters and the histopathological features of the ankle joint. In conclusion, Trans-taxifolin was isolated for the first time from the genus Medicago. MS butanol fraction seeds extract and IL-1 RA were considered as anti-rheumatic agents.

Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a-g, 11a-g and 12a-g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e, 9g and 11f are the most effective derivatives against COX-2 with IC50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC50 = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e, 9g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e, 9g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e, 9g and 11f on both isoenzymes.

Although inflammation is a beneficial response to harmful triggers, the associated diseases develop the potential for death-threatening conditions. Citrus species are valuable sources of chemical compounds with diverse structural properties that could alleviate damaging inflammation and reduce serious side effects of synthetic drugs. Kumquats are the smallest trees among the citrus family widely distributed in Asia, Europe, and North America, with little cultivation in Africa. The current study aims to conduct comprehensive chemical, anti-inflammatory and anti-ulcer studies of Citrus japonica, thus focusing attention on extensive cultivation of these species in Africa to enhance their beneficial uses. A comparative chemical profiling of peel and pulp extracts was performed via HPLC-MS/MS analysis, 164 metabolites were annotated aided by the spectral similarity networks. Around 148 of which were visualized as a species-first documentation. Phenolics were the predominant classes including methoxylated flavonoids, O/C-glycosylated flavones, and flavanones with the less common O- or C-O-triglycosyl methoxylated flavones among the genus Citrus. Moreover, the anti-inflammatory study demonstrated the significant activity of the pulp and peel extracts (200 and 400 mg/kg, p.o.) via reducing paw swelling induced by carrageenan at all-time points and decreasing the formation of TNF-α and IL-1β. Moreover, in ethanol-induced gastric ulcer rat model, the high doses of both extracts significantly improved ulcer indexes and suppressed gastric inflammation by inhibiting myeloperoxidase activity and possessed an antioxidant effect via increasing reduced glutathione, decreasing malondialdehyde, and nitric oxide. Additionally, histopathological investigations confirmed the anti-inflammatory and anti-ulcer effects. Considering the two fruit tissues, peels markedly improved inflammatory and gastroprotective properties associated with the high diversity of their flavonoid structures.

Blueberries are rich in anthocyanins, which have been studied for many years. Interest in these compounds has grown attributing to their possible therapeutic and beneficial effects. Therefore, this study aimed to investigate the potential antioxidant, anti-inflammatory, hepatoprotective, anti-diabetic

GC-MS and HPLC analyses of the hydromethanolic extracts of the truffles Tirmania nivea (TN) and Tirmania pinoyi (TP) revealed the presence of 18 metabolites and 11 polyphenols, respectively. In vivo, TP extract protected against subcutaneous pentylenetetrazole (scPTZ) and maximal electric shock (MES)-induced convulsions faster than TN. TP (100 and 300 mg/kg) showed 100% protection and longer duration than TN in the scPTZ test. Similarly, at 300 mg/kg, TP demonstrated a quicker start (75%) and longer duration of action (100%) than TN in MES test. In scPTZ test, ED50 of TP demonstrated greater anticonvulsant efficacy than TN. In mice given TP and TN treatments, the brain GABA levels were noticeably increased. TP (100 and 300mg/kg) produced a notable sedative effect in open field test, whereas TN (100 or 300 mg/kg) and TP (300 mg/kg) reduced sleep latency by 79, 52, and 45%, respectively. In writhing test, TN (100 or 300mg/kg) significantly enhanced analgesic efficacy by 50 and 87%, respectively. Comparatively, in formalin test, TP and TN at a dosage of 300 mg/kg decreased the length of the licking by 34 and 59%, respectively. For the first time, this study explains the anticonvulsant, sedative, central, and peripheral analgesic activities of truffle extracts.

Hypoglycemic activity of methanolic extract of Tectona grandis linn. Root in alloxan induced diabetic ratsPooja,Vipin Sharma, K.C.Samanta

This study focused on investigating the phytochemical composition of the total extract and the ethyl acetate fraction of red grape (Vitis vinifera L.) seeds as well as evaluating the total extract as anti-arthritis agents in rats compering with the new treating agent; interleukin-1 receptor antagonist (IL-1RA) and the classical anti-inflammatory drug; indomethacin. HPLC and LC-ESI-MS analysis was applied for identification and quantification the flavonoid and phenolic compounds. Arthritis was induced by using complete Freund's adjuvant (CFA). The percentages of edema as well as the arthritis index were evaluated on the 7th, 14th, 21th and 28th day post CFA-induction. The evaluation was done by measuring serum interleukin-1 beta (IL-1 beta), IL-1 receptor type I gene expression, oxidative stress markers, intracellular adhesion molecule-1 (ICAM-1), caspase-3 (cas-3), c-reactive protein (CRP), prostaglandin E2 (PGE2), total protein content, DNA fragmentation, chromosomal aberration and cytogenic damage. The histopathological features of the ankle joint were analyzed. Stilbenes, phenolic acids, and anthocyanins were the major identified classes in the ethyl acetate fraction, while flavan-3-ol, oligomeric and polymeric procyanidins, flavonoid glucosides and phenolic acids were the main categories in the total extract. Three major proanthocyanidin compounds; gallic-4-O-beta-glucopyranoside, catechin 3,5-di-O-gallate and catechin 3-O-gallate were identified in the ethyl acetate fraction. Treatment with seeds extract and IL-1RA improved the selected parameters by variable degrees. IL-1 RA showed a pronounced treating effect. In conclusion, Vitis vinifera seeds extract and IL-1RA are considered as promising anti-arthritis agents. More studies are required to conduct Vitis vinifera seeds extract and IL-1RA in pharmacological and clinical applications.

Objectives Chitosan is a natural biopolymer that possesses various biological activities. The aim of the current study was to evaluate the potentiality of chitosan and its enzymatically depolymerized products as anticonvulsants.Materials and methods In the current study, chitosan enzymatic depolymerization was carried out using Bacillus cereus chitosanase followed by fractionation of the produced chitooligosaccharides. Phase I anticonvulsant activity of chitosan as well as its enzymatically depolymerized products was evaluated using pentylenetetrazole-induced seizures, maximal electric shock, and neurotoxicity tests. In phase II, median effective dose, median toxic dose, and protective index were determined. In addition, γ-aminobutyric acid brain level and acute toxicity were evaluated.Results and conclusion The results indicated that the fraction with the lower degree of acetylation and longer chains of glucosamine (COSH) possessed rapid onset of action with the highest protection (75%) at 0.5 h and long-acting effect for 4 h. In addition, the median effective dose of COSH was 12.7-fold more potent than the reference ethosuximide, whereas in the maximal electric shock test, COSH showed lower potency than phenytoin. The median toxic dose was 1.4-fold and 7.9-fold higher than ethosuximide and phenytoin, respectively. The protective index was 18.1-fold and 3.98-fold higher than ethosuximide and phenytoin, respectively, with a significant increase in γ-aminobutyric acid neurotransmitter brain level. In an attempt to prolong the anticonvulsant effect of COSH, a nano-formulation was carried out in which the particle size was estimated as 188.7±0.26 nm. After that, an equivalent dose of a combined treatment of COSH and the nanoformula (each 15 mg/kg) was evaluated in which a prolonged effect was achieved up to 24 h.

Background: 4-Aminoquinoline derivatives possess various potential biological properties.The introduction of additional piperazine heterocyclic pharmacophoric moiety tends to haveprofound impact in increasing the activity. The present work was undertaken to investigate thein-vitro and in-vivo anti-inflammatory activity as well as the peripheral and central analgesicactivities of compound 1-(4-(7-chloroquinoline-4-yl)piperazin-1-yl)-2-(4-phenylpiperazin-1-yl)ethanone (5) in experimental models. Methods: The percentage inhibition of the lipopolysaccharide induced NO release of 7-chloro-4-(piperazin-1-yl)quinoline derivatives 1-9 was determined in RAW 264.7 murine macrophagemodel. Western blot analysis was performed to evaluate the effect of compound 5 on proteinexpression of inducible nitric oxide synthase (iNOS). Gene expression of inflammatory markerswas evaluated using real-time polymerase chain reaction. The peripheral and central analgesicactivities of compound 5 were evaluated in mice using writhing and hot-plate tests, respectively.Anti-inflammatory activity was assessed using carrageenan-induced paw edema assay in miceand serum NO and COX-2 levels were measured. Results: Compound 5 demonstrated the highest NO inhibitory activity that was accompaniedby inhibition of iNOS protein expression and decreased gene expression levels of inflammatorymarkers. It revealed a potential peripheral analgesic effect through inhibition of abdominalwrithing in mice treated with doses of 15 and 30 mg/kg and its effect was comparable to diclofenacsodium. Compound 5 possessed an analgesic activity starting from 15 min post administrationand reached its peak at 45 min which was significantly higher than that of tramadol hydrochloridesuggesting its potential as central analgesic agent. It also showed percentage of inhibition ofedema of 34, 50 and 64% at 1, 2, and 3 h respectively, post carrageenan challenge together with asignificant decrease in serum NO and COX-2 levels. Conclusion: The remarkable anti-inflammatory and analgesic activities of compound 5 couldbe attributed to the advantageous introduction of the heterocyclic 7-chloro-4-(piperazin1-yl)quinoline scaffold incorporated with N-phenylpiperzine functional groups linked together withthe ethanone pharmacophoric chain.

In the current work, a series of novel 4-benzyloxy and 4-(2-phenylethoxy) chalcone fibrate hybrids (10a-o) and (11a-e) were synthesized and evaluated as new PPAR alpha agonists in order to find new agents with higher activity and fewer side effects. The 2-propanoic acid derivative 10a and the 2-butanoic acid congener 10i showed the best overall PPARa agonistic activity showing E-max% values of 50.80 and 90.55%, respectively, and EC50 values of 8.9 and 25.0 mu M, respectively, compared to fenofibric acid with E-max = 100% and EC50 = 23.22 mu M, respectively. These two compounds also stimulated carnitine palmitoyltransferase 1A gene transcription in HepG2 cells and PPAR alpha protein expression. Molecular docking simulations were performed for the newly synthesized compounds to study their predicted binding pattern and energies in PPAR alpha active site to rationalize their promising activity. In vivo, compounds 10a and 10i elicited a significant hypolipidemic activity improving the lipid profile in triton WR-1339-induced hyperlipidemic rats, including serum triglycerides, total cholesterol, LDL, HDL and VLDL levels. Compound 10i possessed better anti-hyperlipidemic activity than 10a. At a dose of 200 mg/kg, it demonstrated significantly lower TC, TG, LDL and VLDL levels than that of fenofibrate at the same dose with similar HDL levels. Compounds 10i and 10a possessed atherogenic indices (CRR, AC, AI, CRI-II) like that of fenofibrate. Additionally, a promising antioxidant activity indicated by the increased tissue reduced glutathione and plasma total antioxidant capacity with decreased plasma malondialdehyde levels was demonstrated by compounds 10a and 10i. No histopathological alterations were recorded in the hepatic tissue of compound 10i (200 mg/kg).

Ficus spragueana Mildbr. & Burret (family Moraceae) was reported to have various biological activities. However, its activity in treatment of renal injury has not been investigated yet. The current study aimed to evaluate the effects of F. spragueana leaf extract on nephrotoxicity caused by gentamicin. Gentamicin is an important broad-spectrum antibiotic; nevertheless, it exhibits serious nephrotoxic adverse effects. HPLC-ESI/MS spectrometric analysis of the extract revealed the presence of 37 phenolic compounds. Moreover, five compounds were isolated from the leaf extract, and identified on the basis of spectroscopic analysis. The isolated compounds were syringic acid (1), p-coumaric acid (2), 3',5' O-dicaffeoylquinic acid (3), luteolin-8-C-β-D glucopyranoside (orientin) (4) and 8-methoxy kaempferol-3-O-[α-L-rhamnopyranosyl (1→2) β-D-glucopyranoside] (5). The gentamicin-induced nephrotoxicity model was used to evaluate the protective effect of F. spragueana on renal toxicity biomarkers throughout the development of acute kidney injury. Administration of extract led to improvement in kidney function through inhibition of kidney injury molecule-1, creatinine, blood urea nitrogen and total bilirubin, as well as decreasing the inflammatory markers interlukin1-beta and myeloperoxidase. Furthermore, it reduced the oxidative stress by increasing reduced glutathione and total antioxidant capacity levels while decreasing malondialdehyde and nitric oxide content, and improved renal histopathological injuries.

Background Caffeine is a natural alkaloid present in a variety of highly consumed popular drinks such as coffee, tea and soft drinks as well as chocolate. Its consumption elicits beneficiary psychostimulant that has been linked to a reduced risk of developing Parkinson’s disease (PD). The aim of the present study is to investigate the possible synergistic neuroprotective effects of co-administration of caffeine (CAF) or coffee (COF) with rasagiline (R) or l -dopa against paraquat (PQ)-induced neurochemical and motor behavior impairments in mice. Results In behavioral tests, R + COF increased the locomotor activity in rotarod test compared to l -dopa + COF. l -Dopa combinations decreased the immobility time in FST compared to rasagiline combinations; l -dopa + CAF provided a similar increase in locomotor activity compared to R + CAF. Combination of CAF or COF with l -dopa or rasagiline resulted in a substantial improvement in brain neurotransmitter and antioxidant levels as they significantly increased dopamine and super oxide dismutase but significantly decreased nitric oxide levels as compared to l -dopa or rasagiline, respectively. Furthermore, they also exerted a protective effect against the neurodegenerative histopathological changes induced by PQ. Conclusions Our findings demonstrated co-administration of COF or CAF, adenosine 2A receptor antagonists, along with l -dopa or rasagiline possesses a new therapeutic strategy for the management of PD neurochemical disturbances and motor behavior impairments through preservation of the brain dopamine and serotonin content, antioxidants level and histological features.

Context Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by aggressive and systematic polyarthritis.Objective The present study aimed to isolate and identify the phenolic constituents in Brassica oleracea L. (Brassicaceae) seeds methanolic extract and evaluates its effect against rheumatoid arthritis in rats referring to the new therapy; interleukin-1 receptor antagonist (IL-1RA).Materials and Methods The GC/MS profiling of the plant was determined. Arthritis induction was done using complete Freund’s adjuvant. Arthritis severity was assessed by percentage of edema and arthritis index. IL-1 receptor type I gene expression, interleukin-1β (IL-1β), oxidative stress markers, protein content, inflammatory mediators, prostaglandin-E2 (PGE2), genetic abnormalities and the histopathological features of ankle joint were evaluated.Results For the first time twelve phenolic compounds had been isolated from the seeds extract. Treatment with extract and IL-1RA improved the tested parameters by variable degrees.Conclusions RA is an irreversible disease, where its severity increases with the time of induction. Brassica oleracea L. seeds extract is considered as a promising anti-arthritis agent. IL-1 RA may be considered as an unusual therapeutic agent for RA disease. More studies are needed to consider the seeds extract as a nutraceutical agent and to recommend IL-1RA as a new RA drug.

In this work a set of novel derivatives of parabanic acid 9a-d, 12a-d and 13a-d was synthesized and their anticonvulsant potential was evaluated. All the compounds under investigation exhibited anticonvulsant activity in both scPTZ and MES tests. In phase II anticonvulsant study, the trimethoxy phenyl derivative 9a evoked the highest potency among the tested compounds in scPTZ test. It displayed 1.72- and 17.05-folds activity more than the standard drugs phenobarbital and ethosuximide, respectively. In addition, the margin of safety for compound 9a is better than that of the reference antiepileptic drug ethosuximide. Also, compound 9a was devoid of hepatotoxicity indicated by measurements of serum level of ALT, AST, ALP, albumin and total protein. Furthermore, treatment with compound 9a significantly increased the GABA brain level by 2.56-folds compared to the control value. Additionally, molecular docking was performed on the active site of GABA-AT to clarify the interactions of the most potent compound 9a with the enzyme. In MES test, compound 12a exhibited the most potent activity against electric stimuli-induced seizures with the lowest ED50) = 13.7 mg/kg and protective index > 36.5. Both candidates 9a and 12a could be a good starting point to develop new molecules as novel antiepileptic drugs.

Epilepsy remains one of the most challenging diseases worldwide. According to the WHO, ∼50 million people around the world experience epilepsy with all its implications on the patient’s overall quality of life and social life as well as social stigma. The causes of epilepsy are mostly unknown. Epilepsy treatment is considered as a huge economic burden on the patient and health care systems. This review aimed to shed light on the different types of epilepsy, the different mechanisms of action of the most novel antiepileptic drugs in the market, as well as the current antiepileptic drugs under investigation and undergoing clinical trials.

A series of 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides IXa-l and their acetate esters Xa-l were designed and synthesized as new anticovulsant agents. The evaluation of the anticonvulsant effect was performed in vivo by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) tests in mice. Further, neurotoxicity, hepatotoxicity, and acute toxicity were determined. All the new candidates displayed 100% anticonvulsant activity in the scPTZ screen in the dose range of 0.0057-0.283 mmol/kg. The most potent compounds in the scPTZ screen were Xh (ED50 = 0.0012 mmol/kg), Xd (ED50 = 0.002 mmol/kg), Xf (ED50 = 0.004 mmol/kg), IXj (ED50 = 0.0047 mmol/kg), Xl (ED50 = 0.0076 mmol/kg), and Xi (ED50 = 0.008 mmol/kg). They exhibited higher fold activity in the anticonvulsant potential than the gold standards, phenobarbital and ethosuximide. Compound Xf was active in both scPTZ and MES screens. It showed ED50 of 0.016 mmol/kg in MES screen. In the neurotoxicity screens, none of the test compounds displayed any minimal motor impairment at the maximum administered dose. The 3D pharmacophore model using Biova 1 Discovery Studio 2016 programs exhibited high fit value. The anticonvulsant evaluation results were compatible with the molecular modeling study.

A series of (1-(benzyl (aryl) amino) cyclohexyl) methyl esters 7a-n were prepared and screened for their anticonvulsant profile. Screening of these esters 7a-n and their starting alcohols 6a and 6b revealed that compound 7k was the most potent one in the scPTZ screening test with an ED50 value of 0.0056mmol/kg being about 10- and 164-fold more potent than phenobarbital (ED50=0.056mmol/kg) and ethosuximide (ED50=0.92mmol/kg) as reference drugs, respectively. Meanwhile, in the MES test, compounds 7b and 7k at doses 0.0821mmol/kg and 0.0334mmol/kg, exerted 66% and 50% protection of the tested mice, respectively, compared with diphenylhydantoin, which exerted 100% protection at dose 0.16mmol/kg. In the neurotoxicity screen test, almost all esters 7a-n did not show any minimal motor impairment at the maximum administrated dose. The anticonvulsant effectiveness of esters 7a-n was higher than their corresponding alcohols 6a and 6b. Compounds 7b and 7k exhibited pronounced anticonvulsant activity devoid of neurotoxicity in minimal motor impairment test and hepatotoxicity in the serum enzyme activity assay. 3D pharmacophore model using Discovery Studio 2.5 programs showed high fit value. The obtained experimental results of sc-PTZ activity of compounds 7a-n was consistent with the molecular modeling study.

Objective: To explore the in vivo anticancer, anti-angiogenesis and immunomodulatory efficacies of the bioactive polysaccharide isolated from cold aqueous extract of Jania rubens (JCEM) and Pterocladia capillacea (PCEM) as well as hot aqueous extract of Enteromorpha intestinalis (EHEM) against hepatocellular carcinoma rat model (HCC) and to study their chemical composition. Methods: The sugars and amino acids composition of the bioactive polysaccharides of JCEM, PCEM and EHEM were determined using gas liquid chromatography and amino acid analyzer, respectively. These polysaccharide extracts (20 mg/kg b.wt. for 5 weeks) were assessed on hepatocarcinogenesis in rats and alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), glypican-3 (GPC-3), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) and Ig G levels were evaluated. Results: The GLC analysis of JCEM, PCEM and EHEM polysaccharide revealed the presence of 10, 9 and 10 sugars, in addition the amino acid analyser enable identification of 16, 15 and 15 amino acids, respectively. These polysaccharide extracts of JCEM, PCEM and EHEM produced significant decrease in serum AFP, CEA, GPC-3, HGF and VEGF compared with untreated HCC group. JCEM, PCEM and EHEM had an immunostimulatory responses by increasing the IgG levels as compared by naive value (1.23, 1.53 and 1.17 folds), respectively. The bioactive polysaccharides in HCC induced rats improved the humoral immune response. The photomicrographs of liver tissue sections of the groups of HCC treated with polysaccharide extracts of Jania rubens and Enteromorpha intestinalis showed intact histological structure. Moreover, fractions HE1, HE4, HE7 obtained from polysaccharide of EHEM showed moderate cytotoxic activity against Hep G2 in vitro with IC50 73.1, 42.6, 76.2 mu g/mL. However, fractions of PCEM and JCEM show no or weak cytotoxicity against Hep G2 in vitro where the cytotoxic activity of their crude polysaccharide extract proved synergetic effect. Conclusions: The pronounced antitumor activity of sulphated polysaccharide-protein complexes of JCEM and EHEM is due to direct cytotoxic activity, anti-hepatocarcinogensis, and anti-angiogenesis. In addition, JCEM, PCEM and EHEM had an immunostimulatory response and improved the humoral immune response in HCC induced rats.

Trastuzumab (TRZ) is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. There is some evidence that overweight could influence anticancer drug-induced cardiotoxicity, though no study has evaluated the impact of moderate overweight, induced by postnatal nutritional programming, on the cardiotoxic effects of DOX alone or in combination with TRZ.