Anti-arthritic and immunomodulatory efficacy of Micromeria biflora Benth extract and its fractions in rats by restoring oxidative stress, metalloproteinases, pro-inflammatory and anti-inflammatory cytokines network.

Micromeria biflora (M.B) Benth has proven anti-inflammatory efficacy, thereby, the goal of the current investigation was to assess the anti-arthritic potential of M.B ethanolic extract and fractions as well as to investigate the likely mechanism of action. The effectiveness of M.B against acute arthritic manifestations was assessed using an arthritic model prompted by formaldehyde, whereas a chronic model was developed using an adjuvant called Complete Freund's in Sprague-Dawley rats. Weekly evaluations were conducted for parameters involving paw volume, body weight, and arthritic score; at the completion of the CFA model, hematological, biochemical and oxidative stress parameters as well as the level of various mediators (PGE2, IL-1ß, TNFα, IL6, MMP2, 3, 9, VEGF, NF-ĸB, IL-10, and IL-4) were evaluated. The results demonstrated the plant's ability to treat arthritis by showing a significant decrease in paw volume, arthritic score, and histological characteristics. The levels of NF-ĸB, MMP2, 3, 9, IL6, IL1ß, TNFα, and VEGF were all significantly reduced after treatment with plant extract and fractions. Plant extract and its fractions substantially preserved body weight loss, oxidative stress markers and levels of IL-4 and 1L-10. PGE2 levels were also shown to be reduced in the treatment groups, supporting the M.B immunomodulatory ability. Hematological and biochemical indicators were also normalized after M.B administration. Outcomes of the study validated the anti-arthritic and immunomodulatory attributes of M.B probably through modulating oxidative stress, inflammatory, pro-inflammatory and anti-inflammatory biomarkers.

Integrating Chemical Profiling, In Vivo Study, and Network Pharmacology to Explore the Anti-inflammatory Effect of Pterocarpus dalbergioides Fruits and Its Correlation with the Major Phytoconstituents.

The purpose of this study is to explore the anti-inflammatory activity of Pterocarpus dalbergioides fruit extract (PFE) and the underlying mechanism. Chemical profiling using ultraperformance liquid chromatography/mass spectrometry identified 28 compounds in PFE (12 flavonoids, 5 fatty acids, 4 phenolic compounds, 3 alkaloids, 2 sesquiterpenes, and 2 xanthophylls). PFE (2 g/kg) significantly inhibited carrageenan-induced rat paw edema after 4 h of administration (42% inhibition). A network-based strategy and molecular docking studies were utilized to uncover the anti-inflammatory mechanism. Out of the identified compounds, 16 compounds with DL ≥ 0.18 and F ≥ 30% were selected using bioavailability (F) and drug-likeness (DL) metrics. The network analysis revealed that 90 genes are considered key targets for the selected compounds and linked to the anti-inflammatory effect. Among all compounds, linoleic acid was found to be the top-most active constituent as it targets maximum genes. Four targets (TNF, IL6, AKT1, and CCL2) among the top 10 genes were found to be the main target genes that may contribute to the anti-inflammatory potential of PFE. Furthermore, KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis revealed that PFE might regulate inflammation through five pathways: neuroactive ligand-receptor interaction, lipid and atherosclerosis, fluid shear stress and atherosclerosis, TNF signaling pathway, and rheumatoid arthritis. The docking study predicted the significant binding affinity between the top four active constituents (linoleic acid, 9-octadecenoic acid, 11,12,13-trihydroxy-9-octadecenoic acid, and rhamnetin-3-O-rhamnoside) and the selected target proteins (TNF and AKT1). The findings highlight PFE as a promising drug lead for controlling inflammation.

Appraisal of anti-inflammatory and immunomodulatory potential of ramipril against Freund's adjuvant-provoked arthritic rat model.

Because of evident role of renin-angiotensin system in the etiology of rheumatoid arthritis, the current study's objective was to assess the anti-arthritic efficacy of ramipril through CFA-instigated arthritic model. The drug has been shown to have anti-inflammatory potential. CFA-instigated arthritic model assessed the anti-arthritic efficacy of ramipril by estimating different parameters, including paw volume, arthritic index scoring, haematological and biochemical attributes, histological and radiographic analyses, and various cytokines level. Ramipril significantly (p < 0.001) reduced paw volume and the arthritic index especially at the dose of 4mg/kg. The biochemical and haematological changes were likewise restored to normal by ramipril administration with an increase in anti-inflammatory cytokines while reducing pro-inflammatory cytokines level. Ramipril's ability to prevent arthritis by preserving the normal architecture of arthritis-induced joints is further supported by radiographic and histological investigation. The study's findings demonstrated ramipril's considerable anti-arthritic activity. To identify the precise mechanism of action, however, thorough mechanistic studies are still needed.

Enalapril attenuated CFA provoked arthritic manifestation by modulating proinflammatory and anti-inflammatory cytokine network.

Enalapril with documented anti-inflammatory potential was evaluated in current investigation to explore its anti-arthritic efficacy. For anti-arthritic evaluation of enalapril, CFA-instigated arthritic model was employed after which various parameters comprising paw volume, body weight, arthritic index, hematological and biochemical parameters, radiographic analysis and level of various cytokines were estimated. Enalapril demonstrated significant (p˂0.001) anti-arthritic activity by suppressing paw volume, arthritic index while preserved CFA instigated weight loss. Likewise, enalapril also normalized the hematological and biochemical alterations, suppressed the level of proinflammatory cytokines with elevation of anti-inflammatory cytokines. Radiographic and histopathological analysis also further validates the anti-arthritic attribute of enalapril where enalapril preserved the normal architecture of arthritis induced joints. Outcomes of the study pointed out a notable anti-arthritic activity of enalapril. However detailed mechanistic studies are still required to point out the exact mechanism of action.

Network pharmacology and molecular docking study for biological pathway detection of cytotoxicity of the yellow jasmine flowers.

BACKGROUND: The yellow jasmine flower (Jasminum humile L.) is a fragrant plant belonging to the Oleaceae family with promising phytoconstituents and interesting medicinal uses. The purpose of this study was to characterize the plant metabolome to identify the potential bioactive agents with cytotoxic effects and the underlying mechanism of cytotoxic activity. METHODS: First, HPLC-PDA-MS/MS was used to identify the potential bioactive compounds in the flowers. Furthermore, we assessed the cytotoxic activity of the flower extract against breast cancer (MCF-7) cell line using MTT assay followed by the cell cycle, DNA-flow cytometry, and Annexin V-FITC analyses alongside the effect on reactive oxygen species (ROS). Finally, Network pharmacology followed by a molecular docking study was performed to predict the pathways involved in anti-breast cancer activity. RESULTS: HPLC-PDA-MS/MS tentatively identified 33 compounds, mainly secoiridoids. J. humile extract showed a cytotoxic effect on MCF-7 breast cancer cell line with IC50 value of 9.3 ± 1.2 µg/mL. Studying the apoptotic effect of J. humile extract revealed that it disrupts G2/M phase in the cell cycle, increases the percentage of early and late apoptosis in Annexin V-FTIC, and affects the oxidative stress markers (CAT, SOD, and GSH-R). Network analysis revealed that out of 33 compounds, 24 displayed interaction with 52 human target genes. Relationship between compounds, target genes, and pathways revealed that J. humile exerts its effect on breast cancer by altering, Estrogen signaling pathway, HER2, and EGFR overexpression. To further verify the results of network pharmacology, molecular docking was performed with the five key compounds and the topmost target, EGFR. The results of molecular docking were consistent with those of network pharmacology. CONCLUSION: Our findings suggest that J. humile suppresses breast cancer proliferation and induces cell cycle arrest and apoptosis partly by EGFR signaling pathway, highlighting J. humile as a potential therapeutic candidate against breast cancer.

Designing Click One-Pot Synthesis and Antidiabetic Studies of 1,2,3-Triazole Derivatives.

In the present study, a new series of 1,2,3-triazole derivatives was synthesized via a click one-pot reaction. The synthesized compounds were found to be active during molecular docking studies against targeted protein 1T69 by using the Molecular Operating Environment (MOE) software. The designed and synthesized compounds were characterized by using FT-IR, 1H-NMR and LC-MS spectra. The synthesized triazole moieties were further screened for their α-amylase and α-glucosidase inhibitory activities. The preliminary activity analysis revealed that all the compounds showed good inhibition activity, ranging from moderate to high depending upon their structures and concentrations and compared to the standard drug acarbose. Both in silico and in vitro analysis indicated that the synthesized triazole molecules are potent for DM type-II. Out of all the compounds, compound K-1 showed the maximum antidiabetic activity with 87.01% and 99.17% inhibition at 800 µg/mL in the α-amylase and α-glucosidase inhibition assays, respectively. Therefore these triazoles may be further used as promising molecules for development of antidiabetic compounds.

Revealing the Underlying Mechanism of Acacia Nilotica against Asthma from a Systematic Perspective: A Network Pharmacology and Molecular Docking Study.

Acacia Nilotica (AN) has long been used as a folk cure for asthma, but little is known about how AN could possibly modulate this disease. Thus, an in-silico molecular mechanism for AN's anti-asthmatic action was elucidated utilizing network pharmacology and molecular docking techniques. DPED, PubChem, Binding DB, DisGeNET, DAVID, and STRING were a few databases used to collect network data. MOE 2015.10 software was used for molecular docking. Out of 51 searched compounds of AN, eighteen compounds interacted with human target genes, a total of 189 compounds-related genes, and 2096 asthma-related genes were found in public databases, with 80 overlapping genes between them. AKT1, EGFR, VEGFA, and HSP90AB were the hub genes, whereas quercetin and apigenin were the most active components. p13AKT and MAPK signaling pathways were found to be the primary target of AN. Outcomes of network pharmacology and molecular docking predicted that AN might exert its anti-asthmatic effect probably by altering the p13AKT and MAPK signaling pathway.

A Network Pharmacology Analysis of Cytotoxic Triterpenes Isolated from Euphorbia abyssinica Latex Supported by Drug-likeness and ADMET Studies.

Euphorbia plants have been identified as potential sources of antitumor lead compounds. The current study aimed to isolate and identify the main active constituents of Euphorbia abyssinica latex followed by a cytotoxic evaluation. A network pharmacology approach was employed to predict the underlying mechanism. Finally, drug-likeness and ADMET studies were conducted for active compounds. The phytochemical investigation of the latex of E. abyssinica resulted in the isolation of two triterpenes, 3-acetyloxy-(3α)-urs-12-en-28-oic methyl ester (1) and lup-20(29)-en-3α,23-diol (2). The dichloromethane extract displayed potent cytotoxic activity against the MCF7 cell line with an IC50 value of 4.27 ± 0.12 µg/mL but weak activity against HepG2 and HeLa cell lines (IC50 = 20.47 ± 1.17 and 26.73 ± 2.99 µg/mL, respectively) compared to doxorubicin. Compound 1 showed an encouraging cytotoxic effect against MCF7 with IC50 = 4.20 ± 0.20 µg/mL, followed by compound 2 (IC50 = 5.8 ± 0.35 µg/mL). The network analysis revealed that the two isolated compounds are linked to 68 targets of human nature, among which 51 genes are linked to breast carcinomas and 5 targets (AR, CYP19A1, EGFR, PGR, and PTGS2) might be the top therapeutic targets of isolated compounds on breast cancer. Furthermore, the gene-enrichment analysis revealed that E. abyssinica could play a role in the treatment of breast cancer by striking 51 potential targets via mainly three signaling pathways: P13K-AKT, Wnt, and VEGF. Therefore, isolated triterpenes could be considered effective antitumor agents for breast cancer by elucidating their candidate target to alleviate breast cancer and related signaling pathways of the targets.

Assessment of Ferula hermonis Boiss fertility effects in immature female rats supported by quantification of ferutinin via HPLC and molecular docking.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferula hermonis is a small shrub renowned for its aphrodisiac abilities. Middle East herbalists have utilized Ferula hermonis seed and root as an aphrodisiac folk medicine to treat women's frigidity and male erectile and sexual dysfunction. AIM OF THE STUDY: Assessment of follicle-stimulating hormone-like (FSH), luteinizing hormone-like (LH), and estrogenic activities of the methanolic extract (ME) of the roots of Ferula hermonis on female reproductive function. MATERIALS AND METHODS: The methanolic extract was prepared from the root of F. hermonis and studied at dose level 6 mg/kg in immature female rats for FSH-like, LH-like, and estrogenic activities. These activities were determined by analyzing gross anatomical features, relative organ weight, and serum level of FSH, LH, progesterone and estrogen hormones, and histopathological characteristics. Quantification of the main phytoestrogenic component ferutinin carried out by HPLC. In addition, molecular docking for the binding affinity of ferutinin inside active sites of both estrogen receptor alpha (ERα) and FSH receptor (FSHR) was performed to predict the potential role of ferutinin in regulating the female reproductive process. RESULTS: Ferula hermonis (ME) showed potent FSH-like, LH-like activities and moderate estrogenic effect at the dose of 6 mg/kg. The content of ferutinin in F. hermonis was estimated to be 92 ± 1.33 mg/g of the methanolic extract. Molecular docking of ferutinin with ERα and FSHR displayed strong interaction with target proteins. CONCLUSIONS: Based on results, it can be concluded that Ferula hermonis can be considered as a suitable female fertility improving agent.

Cold-pressed raspberry seeds oil ameliorates high-fat diet triggered non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is considered one of the most serious public health problems affecting liver. The reported beneficial impact of raspberries on obesity and associated metabolic disorder makes it a suitable candidate against NAFLD. In the current study, the chemical profile of raspberry seed oil (RO) was characterized by analysis of fatty acid and tocopherol contents using high-performance liquid chromatography (HPLC) in addition to the determination of total phenolic and flavonoids. High levels of unsaturated fatty acids, linoleic acid (49.9%), α-linolenic acid (25.98%), and oleic acid (17.6%), along with high total tocopherol content (184 mg/100 gm) were detected in oil. The total phenolic and flavonoid contents in RO were estimated to be 22.40 ± 0.25 mg gallic acid equivalent (GAE)/100 mg oil and 1.34 ± 0.15 mg quercetin (QU)/100 mg, respectively. Anti-NAFLD efficacy of RO at different doses (0.4 and 0.8 mL) in a model of a high-fat diet (HFD) fed rats was assessed by estimating lipid profile, liver enzyme activity, glucose and insulin levels as well as adipokines and inflammatory marker. Peroxisome proliferator-activated receptor γ (PPARγ), which is a molecular target for NAFLD was also tested. Liver histopathology was carried out and its homogenate was used to estimate oxidative stress markers. Consumption of RO significantly improved lipid parameters and hepatic enzyme activities, reduced insulin resistance and glucose levels, significantly ameliorated inflammatory and oxidative stress markers. Furthermore, RO treatment significantly modulated adipokines activities and elevated PPARγ levels. Raspberry seed oil administration significantly improved these HFD induced histopathological alterations. Moreover, a molecular docking study was performed on the identified fatty acids and tocopherols. Among the identified compounds, oleic acid, α-linolenic acid and γ-tocopherol exhibited the highest docking score as PPARγ activator posing them as a potential anti-NAFLD drug leads. Study findings suggest RO as an effective therapeutic candidate for ameliorating NAFLD.

Ethyl-acetate extract of tara mira (Eruca sativa) alleviates the inflammation and rheumatoid arthritis in rats.

Eruca sativa, member of family Brassicaceae, was evaluated for its anti-arthritic potential. Both in vitro and in vivo models were used to bring out a safe, effective and economical remedy. In vitro tests included egg albumin denaturation suppression, bovine serum albumin assay and human red blood cells maintenance assay. While in vivo formaldehyde-induced arthritic model was initiated to check effect on paw volume. Similarly, carrageenan produced inflammation was applied to check anti-inflammatory ability of the plant. Acute toxicity studies showed safety margin at 2000mg/kg. The plant showed concentration dependent denaturation protection and membrane stability in vitro assays. Likewise, the carrageenan and formaldehyde investigations revealed visible paw volume reduction in dose attributed manner, with maximum outcome at dose of 500mg/kg. Hence, it may be established on the ground of presented results that ethyl-acetate extract of Eruca sativa has significant anti-inflammatory and anti-arthritic effects and may be considered for further research to reveal the core mechanism.

Evaluation of phytochemical, anti-oxidant and cardiac depressant effect of Rumex dentatus by using Langendorff's isolated heart apparatus.

Rumex dentatus has been used traditionally for ailment of cardiovascular diseases. The aim of the present study was to assess cardiovascular effects in isolated perfused rabbit heart. Aqueous and n-butanolic fractions were assessed for their effect on perfusion pressure (PP), force of contraction (FC) and heart rate (HR) of rabbit heart using Langendorff's method. The possible mechanisms of action of extracts/fraction were assessed with and without application of different agonist/antagonist. Phytochemical, toxicity and anti-oxidant activities were also determined. Both extracts at 1mg/mL dose produced a highly significant decrease in FC and HR but PP remained unchanged. Moreover, aqueous fraction of Rumex dentatus at 0.001mg/mL dose produced a highly significant decrease in FC and HR but no significant change in PP was observed. Atropine 10-5 M did not inhibit the cardiac depressant response of both fractions. Furthermore, both fractions blocked the positive ionotropic and chronotropic effects of adrenaline and calcium chloride. Phytochemical studies have shown the presence of some phytochemicals. Acute and sub-chronic toxicity studies demonstrated that test extracts are safe and produced no significant changes in haematological and biochemical parameters. Crude extract showed significant antioxidant activity like ascorbic acid. This study revealed that this plant have good cardiac depressant effect.

Antihypertensive and safety studies of Cydonia oblonga M.

Antihypertensive studies on aqueous-methanolic extract prepared from seeds of Cydonia oblonga M. were carried out. The test extract in 200, 400 and 600 mg/kg doses was investigated in normotensive, high cholesterol and glucose fed hypertensive rats through non-invasive blood pressure measuring technique. Acute and sub-chronic toxicity studies were conducted in mice and rats, respectively. The test extract significantly decreased dose dependently the systolic, diastolic and mean arterial pressures. The test extract in 600mg/kg dose produced maximum effect and prevented rise in blood pressure of high cholesterol diet and glucose fed rats as compare to control in 21 days studies. The extract was found safe up to 4g/kg dose in mice. In sub-chronic toxicity study, no significant alteration in blood chemistry of extract treated rats was observed except reduction in the low density cholesterol levels. It is concluded that Cydonia oblonga seeds extract possess antihypertensive effect which supports its use in folklore.

Appraisal of hypotensive effect of natural monoterpene: Bornyl acetate and in-silico molecular docking analysis.

The modern trend of research is highly focused on finding new bioactive molecules from medicinal plants. As a functional bicyclic monoterpene, Bornyl acetate (BA) has displayed antioxidant and anti-inflammatory properties in different types of cells and tissues. The purpose of this research was to evaluate the probable hypotensive effect of BA, an underlying mechanism(s) backboned by in-silico studies. Mean arterial pressure and heart rate were recorded via invasive blood pressure measuring technique in normotensive Sprague-Dawley rats following the administration of BA (1-80mg/kg). Docking studies were carried out with various targets involved in the pathophysiology of hypertension.RO5 and ADMET properties were also evaluated. In the current study dose-dependent reduction in systolic, diastolic and mean arterial pressure was observed. Pretreatment with atropine and captopril significantly (p<0.001) reduced the hypotensive effect produced by BA. On the other hand docking studies showed pronounced interactions with M2 mAch receptor in an agonistic way and ACE protein in an antagonistic way. BA justified all cut-off limits of RO5 and had an acceptable predicted computational toxicity profile. Results postulate that dose-dependent hypotensive effect of BA is mediated through the muscarinic pathway and ACE inhibitory activity corresponding well with findings of in-silico studies.

Endothelium independent calcium channel blocking pathways mediate antihypertensive effect of morus nigra.

Present study was conducted to validate the folkloric claims of morus nigra l. (moraceae) using invasive blood pressure measuring and ex vivo vasorelaxant experimental techniques. Intravenous administration of mn. Aq in 0.01-30 mg/kg doses caused significant decrease in mean arterial pressure and heart rate in fructose-induced hypertensive rats. It also showed relaxation in high k+ [80 mm] and pe (1µm) mediated aortic contraction with ec50 1.25 and 3.72mg/ml values, respectively. Vaso-relaxant effect of mn.aq was partially blocked in presence of l-name with ec50, 5.32mg/ml value, but showed concentration dependent significant inhibition of ligand gated and voltage gated ca+2 channels and intracellular ca+2 release, similar to verapamil. Findings of current study designate that aqueous fraction of m. Nigra possesses antihypertensive activity with concentration-dependent vaso-relaxant effect predominantly mediated through endothelial-independent calcium channel blocking pathways accompanied by partial involvement of endothelium-dependent nos mediated relaxation.

Rosuvastatin Attenuates Rheumatoid Arthritis-Associated Manifestations via Modulation of the Pro- and Anti-inflammatory Cytokine Network: A Combination of In Vitro and In Vivo Studies.

The current investigation employed rosuvastatin for evaluation as an antiarthritic agent by in vitro and in vivo studies. In vitro studies comprised egg albumin and bovine serum albumin protein denaturation assays along with membrane stabilization assays, while in vivo studies comprised formaldehyde and complete Freund's adjuvant (CFA)-provoked arthritis. The antioxidant potential was estimated via DPPH free radical scavenging and ferric reducing assays. Rosuvastatin significantly inhibited heat-provoked protein denaturation of egg albumin and bovine serum in a concentration-dependent way with the highest inhibition of 1225 ± 9.83 and 82.80 ± 4.03 at 6400 µg/mL. The percentage protection of the RBC membrane from hypotonicity-prompted lysis was found to be 80.67 ± 2.7. Rosuvastatin promisingly subdued formaldehyde-provoked arthritis, with maximum reduction (65.47%) of the paw volume being observed at a dose of 40 mg/kg. Rosuvastatin also significantly (p < 0.001) attenuated arthritis induced by CFA injection by reducing the paw volume and arthritic index. The reduction in the body weight due to CFA injection was also preserved by rosuvastatin treatment. Hematological and biochemical changes due to arthritis induction by CFA injection were also maintained near normal values by rosuvastatin. The histopathological and radiographic investigation also revealed the protective effect of rosuvastatin on preventing structural changes. Gene expression of IL-1ß, TNF-α, and IL-6 was reduced, while IL-4 and IL-10 levels were elevated by rosuvastatin in comparison to those for the disease control group. Concentration-dependent antioxidant potential was shown by rosuvastatin. Thus, rosuvastatin possesses a notable antiarthritic potential as evidenced via in vitro and in vivo studies.

Appraisal of the Antiarthritic Potential of Prazosin via Inhibition of Proinflammatory Cytokine TNF-α: A Key Player in Rheumatoid Arthritis.

Prazosin, a selective α1 adrenergic receptor antagonist, with documented anti-inflammatory potential, was evaluated for its antiarthritic efficacy by targeting specifically TNF-α. The antiarthritic attribute of prazosin validated through in vitro screening comprised thermally provoked denaturation of bovine serum albumin (BSA) and egg albumin along with membrane stabilization evaluation at a concentration of 100-6400 µg/mL, while in vivo screening comprised formaldehyde-instigated arthritis at the doses of 5, 10, and 20 mg/kg and complete Freund's adjuvant (CFA)-induced arthritis at 20 mg/kg dose. Paw swelling, body weight, arthritic score, hematological parameters, and histological and radiographic examination of ankle joints were assessed for a period of 28 days after CFA immunization. Moreover, the proinflammatory cytokine TNF-α level was also assessed through quantitative real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Prazosin revealed significant antiarthritic effect evident through protein denaturation inhibition in the egg albumin and the BSA model, stabilization of red blood cell membrane in the membrane stabilizing assay, and reduction in paw volume in formaldehyde-induced arthritis. Likewise, prazosin exhibited propitious antiarthritic effects in the CFA-provoked arthritis model manifested by paw volume and arthritic score alleviation, substantial weight loss prevention, and preservation of the normal hematological and biochemical profile. Histological and X-ray investigation unveiled no substantive structural alterations in treated rat's ankle joints. The TNF-α expression level was also reduced. Thus, the current study is suggestive that prazosin exhibits a strong antiarthritic potential possibly through inhibition of TNF-α.

Correction to: Appraisal of disease-modifying potential of amlodipine as an anti-arthritic agent: new indication for an old drug.

Unfortunately, the 4th author name was incorrectly published in the original publication.