Geraniol Suppresses Oxidative Stress, Inflammation, and Interstitial Collagenase to Protect against Inflammatory Arthritis.

Geraniol (GER) is a plant-derived acyclic isoprenoid monoterpene that has displayed anti-inflammatory effects in numerous in vivo and in vitro models. This study was therefore designed to evaluate the antiarthritic potential of GER in complete Freund's adjuvant (CFA)-induced inflammatory arthritis (IA) model in rats. IA was induced by intraplantar injection of CFA (0.1 mL), and a week after CFA administration, rats were treated with various doses of methotrexate (MTX; 1 mg/kg) or GER (25, 50, and 100 mg/kg). Treatments were given on every alternate day, and animals were sacrificed on the 35th day. Paw volume, histopathological, hematological, radiographic, and qPCR analyses were performed to analyze the severity of the disease. GER significantly reduced paw edema after 35 days of treatment, and these results were comparable to the MTX-treated group. GER-treated animals displayed a perfect joint structure with minimal inflammation and no signs of cartilage or bone damage. Moreover, GER restored red blood cell and hemoglobin levels, normalized erythrocyte sedimentation rate, platelet, and c-reactive protein values, and also attenuated the levels of rheumatoid factor. RT-qPCR analysis demonstrated that GER decreased mRNA expression of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta. GER also down-regulated the transcript levels of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1, prostaglandin D2 synthase, and interstitial collagenase (MMP-1). Molecular docking of GER with COX-2, TNF-α, and MMP-1 also revealed that the antiarthritic effects of GER could be due to its direct interactions with these mediators. Based on our findings, it is conceivable that the antiarthritic effects of GER could be attributed to downregulation of pro-inflammatory mediators and protease like MMP-1.

In Vitro/In Vivo Evaluation of Clomipramine Orodispersible Tablets for the Treatment of Depression and Obsessive-Compulsive Disorder.

The first and only antidepressant drug on the market with solid proof of clinically significant serotonin and noradrenaline reuptake inhibition is clomipramine (CLP). However, significant first-pass metabolism reduces its absorption to less than 62%. It is heavily protein-bound and broadly dispersed across the body (9-25 L/kg volume of distribution). The purpose of this research was to formulate CLP orodispersible tablets that immediately enable the drug to enter the bloodstream and bypass systemic portal circulation to improve its bioavailability. A factorial design was employed using varied amounts of Plantago ovata mucilage (POM) as a natural superdisintegrant, as well as croscarmellose sodium and crospovidone as synthetic disintegrants. Their physiochemical compatibility was evaluated by FTIR, DSC/TGA, and PXRD analysis. The blend of all formulations was assessed for pre- and post-compaction parameters. The study found that tablets comprising Plantago ovata mucilage as a superdisintegrant showed a rapid in vitro disintegration time, i.e., around 8.39 s, and had an excellent dissolution profile. The anti-depressant efficacy was evaluated by an open-field test (OFT) and the forced swimming test (FST) was applied to create hopelessness and despair behavior as a model of depression in animals (Albino rats). The in vivo study revealed that the efficiency of the optimized formulation (F9) in the treatment of depression is more than the marketed available clomfranil tablet, and may be linked to its rapid disintegration and bypassing of systemic portal circulation.

Imine Derivatives of Benzoxazole Attenuate High-Fat Diet-Induced Hyperlipidemia by Modulation of Lipid-Regulating Genes.

Purpose: Hyperlipidemia being the prominent risk factor of cardiovascular diseases and side effects associated with the current lipid-lowering drugs have attracted the interest of scientists in the quest for new alternatives. In view of the diverse pharmacological potentials of benzoxazole (BZX) compounds, this study was designed to evaluate the antihyperlipidemic activity of imine derivatives of BZX in high-fat diet (HFD)-fed rats. Methods: Hyperlipidemia was induced in Sprague-Dawley rats by using HFD for 28 days. On the 28th day, blood samples were collected, and animals having serum triglycerides (TG) greater than 400 mg/dL and total cholesterol (TC) greater than 280 mg/dL were selected for further study. Hyperlipidemic rats were daily treated with either a vehicle or simvastatin (SIM; 20 mg/kg) or BZX compounds (10, 20, and 30 mg/kg), for 12 consecutive days. After the specified time duration, hyperlipidemic biomarkers were evaluated in the blood samples of sacrificed rats. Liver samples were collected for histopathological and mRNA analyses. Binding affinities of BZX derivatives with different targets were assessed by molecular docking. Results: The present study revealed that the BZX derivatives dose-dependently reduced the serum levels of TC, TG, low-density lipoprotein, and very low-density lipoprotein along with improvement in high-density lipoprotein levels. Similarly, all the compounds reduced HFD-induced alanine transaminase and aspartate aminotransferase levels except BZX-4. Histopathology of liver samples demonstrated mild to moderate fatty changes upon treatment with BZX-1, BZX-2, and BZX-4. The hepatic architecture of the BZX-3-treated samples was close to normal, and only mild inflammation was witnessed in these samples. Moreover, all the compounds significantly increased superoxide dismutase and glutathione levels, indicating their antioxidant potentials. Gene expression data showed that BZX-1 and BZX-3 reduced lipid levels by inhibiting HMGCR, APOB, PCSK9, SRB1, and VCAM1 and via improving PPAR-α and APOE mRNA levels. BZX-2 demonstrated its antihyperlipidemic effects mainly due to inhibition of APOB, while BZX-4-mediated effects appeared to be due to attenuation of APOB, PCSK9, and SRB1. BZX derivatives displayed strong binding affinities with HMGCR, APOB, and VCAM1, which suggested that some of the interactions might be required for inhibition of these target proteins. Conclusions: Based on the current findings, it can be concluded that BZX derivatives exert their antihyperlipidemic effects via modulation of multiple lipid-regulating genes.

Novel mannich-based derivative of 2-mercaptobenzimidazole (AK7): a new candidate for the treatment of inflammatory arthritis owing to its NF-κB1 inhibitory potential.

This study investigated the anti-arthritic potential of novel mannich-based derivatives of 2-mercaptobenzimidazole (AK7 and AK9) in rats. The compounds were characterized by NMR and FTIR spectroscopies and their acute anti-inflammatory effects were measured by carrageenan (CRG)-induced paw edema model. The most potent doses of AK7 and AK9 were subsequently evaluated in the complete Freund's adjuvant (CFA)-induced inflammatory arthritis model. AK7 and AK9 inhibited CRG-induced inflammation in a dose-dependent fashion and a similar reduction in CFA-induced paw inflammation was observed. Moreover, X-ray and histopathological analyses of AK7-treated animals displayed normal joint structure whereas AK9, despite of its anti-inflammatory effects, failed to protect against cartilage destruction. Interestingly, biochemical analysis revealed a better safety profile for AK7 than for AK9 and methotrexate. Both compounds suppressed mRNA levels of pro-inflammatory mediators (IRAK1, NF-κB1, TNF-α, IL1B) while only AK7 reduced the transcript levels of interstitial collagenase (MMP1). Molecular docking analysis of AK7 and AK9 with TNF-α and MMP1 also supported the experimental data. These findings clearly highlight the beneficial effects of AK7 in the prevention and/or treatment of inflammatory arthritis.

Amino Acid Conjugates of 2-Mercaptobenzimidazole Ameliorates High-Fat Diet-Induced Hyperlipidemia in Rats via Attenuation of HMGCR, APOB, and PCSK9.

PURPOSE: This study was designed to explore the antihyperlipidemic effects of amino acid derivatives of 2-mercaptobenzimidazole (4J and 4K) in high-fat diet (HFD)-fed rats. METHODS: Male Sprague-Dawley rats were divided into nine groups which received either standard diet or HFD for 28 days. Blood samples were taken on 27th day from HFD-fed rats to ensure hyperlipidemia. HFD-induced hyperlipidemic rats later received daily dosing of either vehicle or simvastatin (SIM; 20 mg/kg) or 4J/4K compounds (10, 20, and 30 mg/kg) for 12 consecutive days. On 40th day, animals were sacrificed, and blood samples were collected for the determination of serum lipid profile and liver function parameters. Liver samples were harvested for histopathological, antioxidant, and qPCR analyses. Molecular docking of tested compounds with HMGCR was also performed to assess the binding affinities. RESULTS: 4J and 4K dose dependently decreased serum total cholesterol, triglycerides, low-density lipoprotein, very low-density lipoproteins, alanine transaminase (ALT), and aspartate aminotransferase (AST) levels while significantly alleviated high-density lipoproteins. However, SIM failed to reduce AST and ALT levels. Moreover, tested compounds displayed antioxidant effects by inducing superoxide dismutase and glutathione levels. Histopathology data also displayed protective effects of 4J and 4K against HFD-induced fatty changes and hepatic damage. In addition, 4J and 4K downregulated transcript levels of HMGCR, APOB, PCSK9, and VCAM1, and molecular docking analysis also supported the experimental data. CONCLUSION: It is conceivable from this study that 4J and 4K exert their antihyperlipidemic effects by modulating multiple targets regulating lipid levels.

Synthesis of pH-Sensitive Cross-Linked Basil Seed Gum/Acrylic Acid Hydrogels by Free Radical Copolymerization Technique for Sustained Delivery of Captopril.

The pH-sensitive polymeric matrix of basil seed gum (BSG), with two different monomers, such as acrylic acid (AA) and N, N-Methylene-bis-acrylamide (MBA), was selected to use in hydrogels preparation through a free radical copolymerization technique using potassium per sulfate (KPS) as a cross linker. BSG, AA and MBA were used in multiple ratios to investigate the polymer, monomer and initiator effects on swelling properties and release pattern of captopril. Characterization of formulated hydrogels was done by FTIR, DSC/TGA, XRD and SEM techniques to confirm the stability. The hydrogels were subjected to a variety of tests, including dynamic swelling investigations, drug loading, in vitro drug release, sol-gel analyses and rheological studies. FTIR analysis confirmed that after the polymeric reaction of BSG with the AA monomer, AA chains grafted onto the backbone of BSG. The SEM micrographs illustrated an irregular, rough, and porous form of surface. Gel content was increased by increasing the contents of polymeric gum (BSG) with monomers (AA and MBA). Acidic and basic pH effects highlighted the difference between the swelling properties with BSG and AA on increasing concentration. Kinetic modelling suggested that Korsmeyer Peppas model release pattern was followed by the drug with the non-Fickian diffusion mechanism.