Pimenta dioica (L.) Merr. Bioactive Constituents Exert Anti-SARS-CoV-2 and Anti-Inflammatory Activities: Molecular Docking and Dynamics, In Vitro, and In Vivo Studies

In response to the urgent need to control Coronavirus disease 19 (COVID-19), this study aims to explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological responses to the viral infection could lead to acute respiratory distress which is considered a critical and life-threatening complication associated with the infection. Therefore, the anti-viral and anti-inflammatory agents can be key to the management of patients with COVID-19. Four bioactive compounds, namely ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were isolated from the leaves of Pimenta dioica (L.) Merr (ethyl acetate extract) and identified using spectroscopic evidence. Furthermore, molecular docking and dynamics simulations were performed for the isolated and identified compounds (1–4) against SARS-CoV-2 main protease (Mpro) as a proposed mechanism of action. Furthermore, all compounds were tested for their half-maximal cytotoxicity (CC50) and SARS-CoV-2 inhibitory concentrations (IC50). Additionally, lung toxicity was induced in rats by mercuric chloride and the effects of treatment with P. dioca aqueous extract, ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were recorded through measuring TNF-α, IL-1β, IL-2, IL-10, G-CSF, and genetic expression of miRNA 21-3P and miRNA-155 levels to assess their anti-inflammatory effects essential for COVID-19 patients. Interestingly, rutin 2, gallic acid 3, and chlorogenic acid 4 showed remarkable anti-SARS-CoV-2 activities with IC50 values of 31 µg/mL, 108 μg/mL, and 360 µg/mL, respectively. Moreover, the anti-inflammatory effects were found to be better in ferulic acid 1 and rutin 2 treatments. Our results could be promising for more advanced preclinical and clinical studies especially on rutin 2 either alone or in combination with other isolates for COVID-19 management.

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An Appraisal of Current Pharmacological Perspectives of Sesamol: A Review

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200313120419 ◽

2020 ◽

Vol 20 (11) ◽

pp. 988-1000 ◽

Cited By ~ 1

Author(s):

Bellamkonda Bosebabu ◽

Sri Pragnya Cheruku ◽

Mallikarjuna Rao Chamallamudi ◽

Madhavan Nampoothiri ◽

Rekha R. Shenoy ◽

...

Keyword(s):

Molecular Mechanisms ◽

Biological Effects ◽

Hepatoprotective Activity ◽

In Vivo Studies ◽

Therapeutic Effects ◽

Pharmacological Effects ◽

Bioactive Constituents ◽

Anti Inflammatory

Sesame (Sesamum indicum L.) seeds have been authenticated for its medicinal value in both Chinese and Indian systems of medicine. Its numerous potential nutritional benefits are attributed to its main bioactive constituents, sesamol. As a result of those studies, several molecular mechanisms are emerging describing the pleiotropic biological effects of sesamol. This review summarized the most interesting in vitro and in vivo studies on the biological effects of sesamol. The present work summarises data available from Pubmed and Scopus database. Several molecular mechanisms have been elucidated describing the pleiotropic biological effects of sesamol. Its major therapeutic effects have been elicited in managing oxidative and inflammatory conditions, metabolic syndrome and mood disorders. Further, compelling evidence reflected the ability of sesamol in inhibiting proliferation of the inflammatory cell, prevention of invasion and angiogenesis via affecting multiple molecular targets and downstream mechanisms. Sesamol is a safe, non‐toxic chemical that mediates anti‐inflammatory effects by down‐regulating the transcription of inflammatory markers such as cytokines, redox status, protein kinases, and enzymes that promote inflammation. In addition, sesamol also induces apoptosis in cancer cells via mitochondrial and receptor‐mediated pathways, as well as activation of caspase cascades. In the present review, several pharmacological effects of sesamol are summarised namely, antioxidant, anti-cancer, neuroprotective, cardioprotective, anti-inflammatory, hypolipidemic, radioprotective, anti-aging, anti-ulcer, anti-dementia, anti-depressant, antiplatelet, anticonvulsant, anti-anxiolytic, wound healing, cosmetic (skin whitening), anti-microbial, matrix metalloproteinase (MMPs) inhibition, hepatoprotective activity and other biological effects. Here we have summarized the proposed mechanism behind these pharmacological effects.

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Synthesis of new hexahydropyrimido[1,2-a]azepine derivatives bearing functionalized aryl and heterocyclic moieties as anti-inflammatory agents

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0298 ◽

2021 ◽

Author(s):

Hassanein H Hassanein ◽

Doaa E Abdel Rahman ◽

Marwa A Fouad ◽

Rehab F Ahmed

Keyword(s):

Molecular Docking ◽

Binding Sites ◽

Docking Study ◽

In Vivo Studies ◽

Molecular Docking Study ◽

Cox 2 ◽

Anti Inflammatory ◽

Cox 1

New hexahydropyrimido[1,2- a]azepine derivatives bearing functionalized aryl and heterocyclic moieties were synthesized as anti-inflammatory agents with better safety profiles. All synthesized compounds were assessed in vitro for their COX-1 and COX-2 inhibition activities. The most selective compounds, 2f, 5 and 6, were further evaluated for their in vivo anti-inflammatory activity and PGE2 inhibitory activity. To rationalize their selectivity, molecular docking within COX-1 and COX-2 binding sites was performed. Their physicochemical properties and drug-like nature profile were also calculated. The good activity and selectivity of compounds 2f, 5 and 6 were rationalized using a molecular docking study and supported by in vivo studies. These promising findings are encouraging for performing future investigations of these derivatives.

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Development of a High Throughput In Vitro Fecal Fermentation Method to Screen for TMA Production Inhibitors

Current Developments in Nutrition ◽

10.1093/cdn/nzab054_015 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1160-1160

Author(s):

Lisard Iglesias-Carres ◽

Lauren Essenmacher ◽

Kathryn Racine ◽

Andrew Neilson

Keyword(s):

Chlorogenic Acid ◽

Gallic Acid ◽

Cell Density ◽

High Throughput ◽

Positive Control ◽

In Vivo Studies ◽

Fermentation Conditions ◽

Fermentation Method

Abstract Objectives Choline is metabolized by gut bacteria to trimethylamine (TMA), which is further metabolized by the host into trimethylamine N-oxide (TMAO). There is significant interest in reducing TMAO formation to reduce atherosclerosis risk. Our objective was to develop an in vitro fermentation methodology to screen for bioactives able to reduce TMA formation. Methods Choline (5–100 µM) fermentation was optimized under anaerobic conditions at 37°C with the presence of human fecal slurry (OpenBiome) diluted 1:10 in PBS 1X (5–45%) over 36 h. Common dietary phenolics (gallic acid and chlorogenic acid, 0.1–10 mM) were evaluated as TMA production inhibitors under optimal fermentation conditions. 3,3-dimethyl-1-butanol (DMB, 10 mM) was used as a positive control. TMA and choline levels were monitored and analyzed by UPLC-ESI-MS/MS. Cell density (O.D. at 600 nm) was evaluated to account potential cytotoxicity. Results TMA kinetic production curves from choline at >25 µM were statistically different from background (no choline added), suggesting its potential to be used to assay inhibition of TMA production. Fecal slurry concentration of 5% did not reach a TMA plateau within 36 h of fermentation, while the kinetics reported by 45% were fast, reaching a plateau at 12 h, suggesting the need for intermediate fecal concentrations. Optimal fermentation conditions were 100 µM choline and 20%. fecal slurry Under those conditions, exogenous choline was consumed within the first 12 h of fermentation, during which TMA formation plateaued. Under optimal conditions plus gallic acid or chlorogenic acid, TMA formation was significantly reduced, reaching 50% of inhibitor-free control at concentrations >5 mM at 8 h. Also, >2 mM reported higher inhibition potential than DMB 10 mM. Of note, no reductions in cell density were reported due to treatment administration, suggesting a lack of cytotoxicity. Conclusions Our results suggest that gallic acid and chlorogenic acid are promising compounds for in vivo studies. Moreover, our fermentation method can be used to screen for TMA production inhibitors in a high-throughput fashion. Funding Sources Supported by through startup funding from North Carolina State University and the Hatch Program of the National Institute of Food and Agriculture, U.S. Department of Agriculture.

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In vitro anti-diabetic activity, bioactive constituents, and molecular modeling studies with sulfonylurea receptor1 for insulin secretagogue activity of seed extract of Syzygium cumini (L.)

Journal of Herbmed Pharmacology ◽

10.34172/jhp.2021.35 ◽

2021 ◽

Vol 10 (3) ◽

pp. 304-312

Author(s):

Meharban Assan Aliyar ◽

Pratibha Nadig ◽

Nagakumar Bharatham

Keyword(s):

Molecular Docking ◽

Glucose Uptake ◽

Gallic Acid ◽

Insulin Release ◽

Ellagic Acid ◽

Enzyme Linked Immunosorbent Assay ◽

Preparative Hplc ◽

Syzygium Cumini ◽

Bioactive Constituents

Introduction: Syzygium cumini (L.) has been known to be used for diabetes treatment in traditional Indian and Chinese medicine. The present study focuses on the evaluation for glucose uptake and insulin release in vitro and characterization of phytoconstituents of the hydro-ethanolic extract of Syzygium cumini seed (SCE). Further, this report covers the molecular docking findings of the bioactive constituents on the sulfonylurea receptor 1 (SUR1). Methods: A glucose uptake assay of SCE was used to estimate the glucose uptake from the cell lysates and the cell culture supernatants using insulin as the reference standard. Insulin release activity of SCE from RIN-5F cells was estimated using enzyme-linked immunosorbent assay. The phytoconstituents were isolated by preparative HPLC and characterized by mass spectrometry, nuclear magnetic resonance (NMR) and infrared spectroscopy. The molecular docking of bioactive constituents was carried on repaglinide bound to the SUR1. Results: In the presence of SCE, the glucose uptake through L6 myoblast cells increased by 19.91% at 40 µg/mL in comparison with the vehicle control (P < 0.05). Moreover, SCE showed 2.8-fold enhancement of insulin release at 40 µg/mL as compared to the vehicle controls (P < 0.05). Gallic and ellagic acids were the key phytoconstituents isolated from SCE. Molecular docking studies revealed that both gallic acid and ellagic acid bind to the repaglinide binding pocket of SUR1. Conclusion: SCE increases the release of insulin and enhances glucose uptake in vitro, which may contribute to its in vivo anti-diabetic activity. The presence of ellagic acid and gallic acid in SCE may be the cause for enhanced insulin release observed with SCE following binding to SUR1.

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The Immunomodulatory Effects of Honey and Associated Flavonoids in Cancer

Nutrients ◽

10.3390/nu13041269 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1269

Author(s):

Razan J. Masad ◽

Shoja M. Haneefa ◽

Yassir A. Mohamed ◽

Ashraf Al-Sbiei ◽

Ghada Bashir ◽

...

Keyword(s):

Immune Responses ◽

Antioxidant Properties ◽

In Vivo Studies ◽

Immunomodulatory Effects ◽

Bioactive Constituents ◽

Cancer Cell Growth ◽

Cancer Types ◽

Immunomodulatory Properties

Honey has exerted a high impact in the field of alternative medicine over many centuries. In addition to its wound healing, anti-microbial and antioxidant properties, several lines of evidence have highlighted the efficiency of honey and associated bioactive constituents as anti-tumor agents against a range of cancer types. Mechanistically, honey was shown to inhibit cancer cell growth through its pro-apoptotic, anti-proliferative and anti-metastatic effects. However, the potential of honey to regulate anti-tumor immune responses is relatively unexplored. A small number of in vitro and in vivo studies have demonstrated the ability of honey to modulate the immune system by inducing immunostimulatory as well as anti-inflammatory effects. In the present review, we summarize the findings from different studies that aimed to investigate the immunomodulatory properties of honey and its flavonoid components in relation to cancer. While these studies provide promising data, additional research is needed to further elucidate the immunomodulatory properties of honey, and to enable its utilization as an adjuvant therapy in cancer.

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Efficacy of Posidonia oceanica Extract against Inflammatory Pain: In Vivo Studies in Mice

Marine Drugs ◽

10.3390/md19020048 ◽

2021 ◽

Vol 19 (2) ◽

pp. 48

Author(s):

Laura Micheli ◽

Marzia Vasarri ◽

Emanuela Barletta ◽

Elena Lucarini ◽

Carla Ghelardini ◽

...

Keyword(s):

Inflammatory Pain ◽

Ex Vivo ◽

Antioxidant Properties ◽

Posidonia Oceanica ◽

In Vivo Studies ◽

Myeloperoxidase Activity ◽

Intraplantar Injection ◽

Hot Plate Test ◽

Anti Inflammatory

Posidonia oceanica (L.) Delile is traditionally used for its beneficial properties. Recently, promising antioxidant and anti-inflammatory biological properties emerged through studying the in vitro activity of the ethanolic leaves extract (POE). The present study aims to investigate the anti-inflammatory and analgesic role of POE in mice. Inflammatory pain was modeled in CD-1 mice by the intraplantar injection of carrageenan, interleukin IL-1β and formalin. Pain threshold was measured by von Frey and paw pressure tests. Nociceptive pain was studied by the hot-plate test. POE (10–100 mg kg−1) was administered per os. The paw soft tissue of carrageenan-treated animals was analyzed to measure anti-inflammatory and antioxidant effects. POE exerted a dose-dependent, acute anti-inflammatory effect able to counteract carrageenan-induced pain and paw oedema. Similar anti-hyperalgesic and anti-allodynic results were obtained when inflammation was induced by IL-1β. In the formalin test, the pre-treatment with POE significantly reduced the nocifensive behavior. Moreover, POE was able to evoke an analgesic effect in naïve animals. Ex vivo, POE reduced the myeloperoxidase activity as well as TNF-α and IL-1β levels; further antioxidant properties were highlighted as a reduction in NO concentration. POE is the candidate for a new valid strategy against inflammation and pain.

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Relevance and Standardization of In Vitro Antioxidant Assays: ABTS, DPPH, and Folin–Ciocalteu

Journal of Chemistry ◽

10.1155/2018/4608405 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 17

Author(s):

Helena Abramovič ◽

Blaž Grobin ◽

Nataša Poklar Ulrih ◽

Blaž Cigić

Keyword(s):

Ascorbic Acid ◽

Chlorogenic Acid ◽

Gallic Acid ◽

Caffeic Acid ◽

Sulfonic Acid ◽

Epigallocatechin Gallate ◽

The Other ◽

Oh Groups ◽

Standard Compound

Trolox, gallic acid, chlorogenic acid, caffeic acid, catechin, epigallocatechin gallate, and ascorbic acid are antioxidants used as standards for reaction with chromogenic radicals, 2,2-diphenyl-1-picrylhydrazyl (DPPH⋅) and 2,2′-azino-bis-3-ethylbenzotiazolin-6-sulfonic acid (ABTS⋅+), and Folin–Ciocalteu (FC) reagent. The number of exchanged electrons has been analyzed as function of method and solvent. A majority of compounds exchange more electrons in FC assay than in ABTS and DPPH assays. In reaction with chromogenic radicals, the largest number of electrons was exchanged in buffer (pH 7.4) and the lowest reactivity was in methanol (DPPH) and water (ABTS). At physiological pH, the number of exchanged electrons of polyphenols exceeded the number of OH groups, pointing to the important contribution of partially oxidized antioxidants, formed in the course of reaction, to the antioxidant potential. For Trolox, small impact on the number of exchanged electrons was observed, confirming that it is more suitable as a standard compound than the other antioxidants.

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STRUCTURE-BASED MULTITARGETED MOLECULAR DOCKING ANALYSIS OF PYRAZOLE-CONDENSED HETEROCYCLICS AGAINST LUNG CANCER

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2021v13i6.42801 ◽

2021 ◽

pp. 157-169

Author(s):

JAINEY P. JAMES ◽

AISWARYA T. C. ◽

SNEH PRIYA ◽

DIVYA JYOTHI ◽

SHESHAGIRI R. DIXIT

Keyword(s):

Lung Cancer ◽

Molecular Docking ◽

Binding Mode ◽

Pharmacophore Modeling ◽

In Vivo Studies ◽

Spectral Studies ◽

Pyrazole Derivatives ◽

Anticancer Activities

Objective: The significant drawbacks of chemotherapy are that it destroys healthy cells, resulting in adverse effects. Hence, there is a need to adopt new techniques to develop cancer-specific chemicals that target the molecular pathways in a non-toxic fashion. This study aims to screen pyrazole-condensed heterocyclics for their anticancer activities and analyse their enzyme inhibitory potentials EGFR, ALK, VEGFR and TNKS receptors. Methods: The structures of the compounds were confirmed by IR, NMR and Mass spectral studies. The in silico techniques applied in this study were molecular docking and pharmacophore modeling to analyse the protein-ligand interactions, as they have a significant role in drug discovery. Drug-likeness properties were assessed by the Lipinski rule of five and ADMET properties. Anticancer activity was performed by in vitro MTT assay on lung cancer cell lines. Results: The results confirm that all the synthesised pyrazole derivatives interacted well with the selected targets showing docking scores above-5 kcal/mol. Pyrazole 2e interacted well with all the four lung cancer targets with its stable binding mode and was found to be potent as per the in vitro reports, followed by compounds 3d and 2d. Pharmacophore modeling exposed the responsible features responsible for the anticancer action. ADMET properties reported that all the compounds were found to have properties within the standard limit. The activity spectra of the pyrazoles predicted that pyrazolopyridines (2a-2e) are more effective against specific receptors such as EGFR, ALK and Tankyrase. Conclusion: Thus, this study suggests that the synthesised pyrazole derivatives can be further investigated to validate their enzyme inhibitory potentials by in vivo studies.

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Effect of Harmine against Parkinson’s Disease Protein (PARK7) through Molecular Docking Studies

International Journal for Research in Applied Science and Engineering Technology ◽

10.22214/ijraset.2021.36192 ◽

2021 ◽

Vol 9 (VI) ◽

pp. 5479-5485

Author(s):

Love Kumar

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Docking ◽

Neurodegenerative Disorder ◽

Docking Studies ◽

In Vivo Studies ◽

Receptor Protein ◽

Unknown Etiology

Parkinson’s disease (PD) is a common known neurodegenerative disorder with unknown etiology. It was estimated about 0.3% prevalence in the U.S population and enhance to 4 to 5% in older than 85 years. All studies were depending on the molecular docking where all ligands and protein PARK7 (PDB ID: 2RK3) were interacted by docked process. Some natural compounds was selected such as Harmine, Alloxan, Alpha spinasterol, Myrcene, and Vasicinone and PARK7 (PDB ID: 2RK3) protein. According to the PyRx and SWISS ADME result, Harmine was the only ligand which was showing minimum binding affinity. AutoDock Vina software was used for docking process between ligand (Harmine) and receptor protein PARK7 (PDB ID: 2RK3). The result was visualized under PyMol. Harmine was inhibiting the activity of PARK7 (PDB ID: 2RK3) and it may be used for the treatment of PD in future prospect after its in vitro and in vivo studies.

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Anti-Inflammatory Potential of Daturaolone from Datura innoxia Mill.: In Silico, In Vitro and In Vivo Studies

Pharmaceuticals ◽

10.3390/ph14121248 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1248

Author(s):

Muhammad Waleed Baig ◽

Humaira Fatima ◽

Nosheen Akhtar ◽

Hidayat Hussain ◽

Mohammad K. Okla ◽

...

Keyword(s):

In Silico ◽

Therapeutic Potential ◽

In Vivo Studies ◽

Metabolic Reaction ◽

Datura Innoxia ◽

In Vivo Models ◽

Immobility Time ◽

Anti Inflammatory

Exploration of leads with therapeutic potential in inflammatory disorders is worth pursuing. In line with this, the isolated natural compound daturaolone from Datura innoxia Mill. was evaluated for its anti-inflammatory potential using in silico, in vitro and in vivo models. Daturaolone follows Lipinski’s drug-likeliness rule with a score of 0.33. Absorption, distribution, metabolism, excretion and toxicity prediction show strong plasma protein binding; gastrointestinal absorption (Caco-2 cells permeability = 34.6 nm/s); no blood–brain barrier penetration; CYP1A2, CYP2C19 and CYP3A4 metabolism; a major metabolic reaction, being aliphatic hydroxylation; no hERG inhibition; and non-carcinogenicity. Predicted molecular targets were mainly inflammatory mediators. Molecular docking depicted H-bonding interaction with nuclear factor kappa beta subunit (NF-κB), cyclooxygenase-2, 5-lipoxygenase, phospholipase A2, serotonin transporter, dopamine receptor D1 and 5-hydroxy tryptamine. Its cytotoxicity (IC50) value in normal lymphocytes was >20 µg/mL as compared to cancer cells (Huh7.5; 17.32 ± 1.43 µg/mL). Daturaolone significantly inhibited NF-κB and nitric oxide production with IC50 values of 1.2 ± 0.8 and 4.51 ± 0.92 µg/mL, respectively. It significantly reduced inflammatory paw edema (81.73 ± 3.16%), heat-induced pain (89.47 ± 9.01% antinociception) and stress-induced depression (68 ± 9.22 s immobility time in tail suspension test). This work suggests a possible anti-inflammatory role of daturaolone; however, detailed mechanistic studies are still necessary to corroborate and extrapolate the findings.

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