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12 pages, 941 KiB

Open AccessArticle

Semisynthetic Abietic and Dehydroabietic Acid Derivatives and Triptoquinone Epimers Interfere with LPS-Triggered Activation of Dendritic Cells

by Jelver A. Sierra, Katherine Gilchrist, Jorge H. Tabares-Guevara, Liliana Betancur-Galvis, Jose R. Ramirez-Pineda and Miguel A. González-Cardenete

Molecules 2022, 27(19), 6684; https://doi.org/10.3390/molecules27196684 - 08 Oct 2022

Cited by 4 | Viewed by 1417

Abstract

Abietic acid (AA), dehydroabietic acid (DHA) and triptoquinones (TQs) are bioactive abietane-type diterpenoids, which are present in many edible vegetables and medicinal herbs with health-promoting properties. Evidence suggests that beneficial effects of diterpenes operate, at least in part, through effects on cells in [...] Read more.

Abietic acid (AA), dehydroabietic acid (DHA) and triptoquinones (TQs) are bioactive abietane-type diterpenoids, which are present in many edible vegetables and medicinal herbs with health-promoting properties. Evidence suggests that beneficial effects of diterpenes operate, at least in part, through effects on cells in the immune system. Dendritic cells (DCs) are a key type of leukocyte involved in the initiation and regulation of the immune/inflammatory response and natural or synthetic compounds that modulate DC functions could be potential anti-inflammatory/immunomodulatory agents. Herein, we report the screening of 23 known semisynthetic AA and DHA derivatives, and TQs, synthesized previously by us, in a multi-analyte DC-based assay that detects inhibition of pro-inflammatory cytokine production. Based on the magnitude of the inhibitory effect observed and the number of cytokines inhibited, a variety of activities among compounds were observed, ranging from inactive/weak to very potent inhibitors. Structurally, either alcohol or methyl ester substituents on ring A along with the introduction of aromaticity and oxidation in ring C in the abietane skeleton were found in compounds with higher inhibitory properties. Two DHA derivatives and two TQs exhibited a significant inhibition in all pro-inflammatory cytokines tested and were further investigated. The results confirmed their ability to inhibit, dose dependently, LPS-stimulated expression of the co-stimulatory molecules CD40 and/or CD86 and the production of the pro-inflammatory cytokines IL-1β, IL-6, IL-12 and TNFα. Our results demonstrate that DC maturation process can be targeted by semisynthetic DHA derivatives and TQ epimers and indicate the potential of these compounds as optimizable anti-inflammatory/immunomodulatory agents. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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18 pages, 2843 KiB

Open AccessArticle

Computer-Aided Screening of Phytoconstituents from Ocimum tenuiflorum against Diabetes Mellitus Targeting DPP4 Inhibition: A Combination of Molecular Docking, Molecular Dynamics, and Pharmacokinetics Approaches

by Harshit Sajal, Shashank M. Patil, Ranjith Raj, Abdullah M. Shbeer, Mohammed Ageel and Ramith Ramu

Molecules 2022, 27(16), 5133; https://doi.org/10.3390/molecules27165133 - 12 Aug 2022

Cited by 27 | Viewed by 2942

Abstract

Diabetes mellitus is a major global health concern in the current scenario which is chiefly characterized by the rise in blood sugar levels or hyperglycemia. In the context, DPP4 enzyme plays a critical role in glucose homeostasis. DPP4 targets and inactivates incretin hormones [...] Read more.

Diabetes mellitus is a major global health concern in the current scenario which is chiefly characterized by the rise in blood sugar levels or hyperglycemia. In the context, DPP4 enzyme plays a critical role in glucose homeostasis. DPP4 targets and inactivates incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) as physiological substrates, which are essential to regulate the amount of insulin that is secreted after eating. Since the inactivation of incretins occurs, the hyperglycemic conditions continue to rise, and result in adverse physiological conditions linked with diabetes mellitus. Hence, inhibition of DPP4 has been the center of focus in the present antidiabetic studies. Although few DPP4 inhibitor drugs, such as alogliptin, saxagliptin, linagliptin, and sitagliptin, are available, their adverse effects on human metabolism are undeniable. Therefore, it becomes essential for the phytochemical intervention of the disease using computational methods prior to performing in vitro and in vivo studies. In this regard, we used an in-silico approach involving molecular docking, molecular dynamics simulations, and binding free energy calculations to investigate the inhibitory potential of Ocimum tenuiflorum phytocompounds against DPP4. In this regard, three phytocompounds (1S-α-pinene, β-pinene, and dehydro-p-cymene) from O. tenuiflorum have been discovered as the potential inhibitors of the DPP4 protein. To summarize, from our in-silico experiment outcomes, we propose dehydro-p-cymene as the potential lead inhibitor of DPP4 protein, thereby discovering new a phytocompound for the effective management of hyperglycemia and diabetes mellitus. The reported compound can be taken for in vitro and in vivo analyses in near future. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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21 pages, 4732 KiB

Open AccessArticle

Antibacterial Potential of Bacopa monnieri (L.) Wettst. and Its Bioactive Molecules against Uropathogens—An In Silico Study to Identify Potential Lead Molecule(s) for the Development of New Drugs to Treat Urinary Tract Infections

by Jyoti Mehta, Kumar Utkarsh, Shivkanya Fuloria, Tejpal Singh, Mahendran Sekar, Deeksha Salaria, Rajan Rolta, M. Yasmin Begum, Siew Hua Gan, Nur Najihah Izzati Mat Rani, Kumarappan Chidambaram, Vetriselvan Subramaniyan, Kathiresan V. Sathasivam, Pei Teng Lum, Subasini Uthirapathy, Olatomide A. Fadare, Oladoja Awofisayo and Neeraj Kumar Fuloria

Molecules 2022, 27(15), 4971; https://doi.org/10.3390/molecules27154971 - 05 Aug 2022

Cited by 16 | Viewed by 3552

Abstract

Urinary tract infections (UTIs) are becoming more common, requiring extensive protection from antimicrobials. The global expansion of multi-drug resistance uropathogens in the past decade emphasizes the necessity of newer antibiotic treatments and prevention strategies for UTIs. Medicinal plants have wide therapeutic applications in [...] Read more.

Urinary tract infections (UTIs) are becoming more common, requiring extensive protection from antimicrobials. The global expansion of multi-drug resistance uropathogens in the past decade emphasizes the necessity of newer antibiotic treatments and prevention strategies for UTIs. Medicinal plants have wide therapeutic applications in both the prevention and management of many ailments. Bacopa monnieri is a medicinal plant that is found in the warmer and wetlands regions of the world. It has been used in Ayurvedic systems for centuries. The present study aimed to investigate the antibacterial potential of the extract of B. monnieri leaves and its bioactive molecules against UTIs that are caused by Klebsiella pneumoniae and Proteus mirabilis. This in vitro experimental study was conducted by an agar well diffusion method to evaluate the antimicrobial effect of 80% methanol, 96% ethanol, and aqueous extracts of B. monnieri leaves on uropathogens. Then, further screening of their phytochemicals was carried out using standard methods. To validate the bioactive molecules and the microbe interactions, AutoDock Vina software was used for molecular docking with the Klebsiella pneumoniae fosfomycin resistance protein (5WEW) and the Zn-dependent receptor-binding domain of Proteus mirabilis MR/P fimbrial adhesin MrpH (6Y4F). Toxicity prediction and drug likeness were predicted using ProTox-II and Molinspiration, respectively. A molecular dynamics (MD) simulation was carried out to study the protein ligand complexes. The methanolic leaves extract of B. monnieri revealed a 22.3 mm ± 0.6 mm to 25.0 mm ± 0.5 mm inhibition zone, while ethanolic extract seemed to produce 19.3 mm ± 0.8 mm to 23.0 mm ± 0.4 mm inhibition zones against K. pneumoniae with the use of increasing concentrations. In the case of P. mirabilis activity, the methanolic extracts showed a 21.0 mm ± 0.8 mm to 24.0 mm ± 0.6 mm zone of inhibition and the ethanol extract produced a 17.0 mm ± 0.9 mm to 23.0 mm ± 0.7 mm inhibition zone with increasing concentrations. Carbohydrates, flavonoids, saponin, phenolic, and terpenoid were common phytoconstituents identified in B. monnieri extracts. Oroxindin showed the best interactions with the binding energies with 5WEW and 6Y4F, −7.5 kcal/mol and −7.4 kcal/mol, respectively. Oroxindin, a bioactive molecule, followed Lipinski’s rule of five and exhibited stability in the MD simulation. The overall results suggest that Oroxindin from B. monnieri can be a potent inhibitor for the effective killing of K. pneumoniae and P. mirabilis. Additionally, its safety has been established, indicating its potential for future drug discovery and development in the treatment for UTIs. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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15 pages, 1003 KiB

Open AccessArticle

Cancer and Traditional Plant Knowledge, an Interesting Field to Explore: Data from the Catalan Linguistic Area

by Airy Gras, Montse Parada, Jaume Pellicer, Joan Vallès and Teresa Garnatje

Molecules 2022, 27(13), 4070; https://doi.org/10.3390/molecules27134070 - 24 Jun 2022

Viewed by 1737

Abstract

Cancer is the second cause of death in the world and is foreseen to be responsible for about 16 million deaths in 2040. Approximately, 60% of the drugs used to treat cancer are of natural origin. Besides the extensive use of some of [...] Read more.

Cancer is the second cause of death in the world and is foreseen to be responsible for about 16 million deaths in 2040. Approximately, 60% of the drugs used to treat cancer are of natural origin. Besides the extensive use of some of these drugs in therapies, such as those derived from the genus Taxus, a significant number of plants have revealed themselves as useful against cancer in recent years. The field of ethnobotany focuses on documenting traditional knowledge associated with plants, constituting a starting point to uncover the potential of new plant-based drugs to treat or prevent, in this case, tumour diseases and side effects of chemotherapy and radiotherapy. From a series of extensive ethnobotanical prospections across the Catalan linguistic area (CLA), we have recorded uses for 41 taxa with antitumour effects. The two most quoted botanical families are Asteraceae and Ranunculaceae, and the most frequently reported species is Ranunculus parnassifolius, a high-mountain species, which is widely collected for this purpose. The reported species have been used to treat an important number of cancer types, focusing on preventive, palliative, and curative uses, as well as to deal with the side effects of conventional treatments. Comparing our results in CLA with previous data available in the most comprehensive databases of pharmacology and a review of cytotoxicity assays revealed that for the several species reported here, there was no previous evidence of traditional uses against cancer. Despite the need for further analyses to experimentally validate the information presented here, combining traditional uses and phylogenetically-informed strategies to phytochemical and pharmacological research would represent new avenues to establish more integrative approaches, hence improving the ability to select new candidate taxa in cancer research. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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18 pages, 1794 KiB

Open AccessArticle

Phytochemical Study and Antiglioblastoma Activity Assessment of Plectranthus hadiensis (Forssk.) Schweinf. ex Sprenger var. hadiensis Stems

by Eva María Domínguez-Martín, Mariana Magalhães, Ana María Díaz-Lanza, Mário P. Marques, Salvatore Princiotto, Ana M. Gómez, Thomas Efferth, Célia Cabral and Patricia Rijo

Molecules 2022, 27(12), 3813; https://doi.org/10.3390/molecules27123813 - 14 Jun 2022

Cited by 4 | Viewed by 2370

Abstract

Glioblastoma (GB) is the most malignant form of primary astrocytoma, accounting for more than 60% of all brain tumors in adults. Nowadays, due to the development of multidrug resistance causing relapses to the current treatments and the development of severe side effects resulting [...] Read more.

Glioblastoma (GB) is the most malignant form of primary astrocytoma, accounting for more than 60% of all brain tumors in adults. Nowadays, due to the development of multidrug resistance causing relapses to the current treatments and the development of severe side effects resulting in reduced survival rates, new therapeutic approaches are needed. The genus Plectranthus belongs to the Lamiaceae family and is known to be rich in abietane-type diterpenes, which possess antitumor activity. Specifically, P. hadiensis (Forssk.) Schweinf. ex Sprenger has been documented for the use against brain tumors. Therefore, the aim of this work was to perform the bioguided isolation of compounds from the acetonic extract of P. hadiensis stems and to investigate the in vitro antiglioblastoma activity of the extract and its isolated constituents. After extraction, six fractions were obtained from the acetonic extract of P. hadiensis stems. In a preliminary biological screening, the fractions V and III showed the highest antioxidant and antimicrobial activities. None of the fractions were toxic in the Artemia salina assay. We obtained different abietane-type diterpenes such as 7α-acetoxy-6β-hydroxyroyleanone (Roy) and 6β,7β-dihydroxyroyleanone (DiRoy), which was also in agreement with the HPLC-DAD profile of the extract. Furthermore, the antiproliferative activity was assessed in a glioma tumor cell line panel by the Alamar blue assay. After 48 h treatment, Roy exerted strong antiproliferative/cytotoxic effects against tumor cells with low IC₅₀ values among the different cell lines. Finally, we synthesized a new fluorescence derivative in this study to evaluate the biodistribution of Roy. The uptake of BODIPY-7α-acetoxy-6β-hydroxyroyleanone by GB cells was associated with increased intracellular fluorescence, supporting the antiproliferative effects of Roy. In conclusion, Roy is a promising natural compound that may serve as a lead compound for further derivatization to develop future therapeutic strategies against GB. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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16 pages, 29619 KiB

Open AccessArticle

New Potential Pharmacological Targets of Plant-Derived Hydroxyanthraquinones from Rubia spp.

by Petko Alov, Merilin Al Sharif, Hristo Najdenski, Tania Pencheva, Ivanka Tsakovska, Maya Margaritova Zaharieva and Ilza Pajeva

Molecules 2022, 27(10), 3274; https://doi.org/10.3390/molecules27103274 - 19 May 2022

Cited by 1 | Viewed by 1506

Abstract

The increased use of polyphenols nowadays poses the need for identification of their new pharmacological targets. Recently, structure similarity-based virtual screening of DrugBank outlined pseudopurpurin, a hydroxyanthraquinone from Rubia cordifolia spp., as similar to gatifloxacin, a synthetic antibacterial agent. This suggested the bacterial [...] Read more.

The increased use of polyphenols nowadays poses the need for identification of their new pharmacological targets. Recently, structure similarity-based virtual screening of DrugBank outlined pseudopurpurin, a hydroxyanthraquinone from Rubia cordifolia spp., as similar to gatifloxacin, a synthetic antibacterial agent. This suggested the bacterial DNA gyrase and DNA topoisomerase IV as potential pharmacological targets of pseudopurpurin. In this study, estimation of structural similarity to referent antibacterial agents and molecular docking in the DNA gyrase and DNA topoisomerase IV complexes were performed for a homologous series of four hydroxyanthraquinones. Estimation of shape- and chemical feature-based similarity with (S)-gatifloxacin, a DNA gyrase inhibitor, and (S)-levofloxacin, a DNA topoisomerase IV inhibitor, outlined pseudopurpurin and munjistin as the most similar structures. The docking simulations supported the hypothesis for a plausible antibacterial activity of hydroxyanthraquinones. The predicted docking poses were grouped into 13 binding modes based on spatial similarities in the active site. The simultaneous presence of 1-OH and 3-COOH substituents in the anthraquinone scaffold were emphasized as relevant features for the binding modes’ variability and ability of the compounds to strongly bind in the DNA-enzyme complexes. The results reveal new potential pharmacological targets of the studied polyphenols and help in their prioritization as drug candidates and dietary supplements. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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18 pages, 7511 KiB

Open AccessArticle

In Silico Molecular Docking Analysis of Karanjin against Alzheimer’s and Parkinson’s Diseases as a Potential Natural Lead Molecule for New Drug Design, Development and Therapy

by Charles Gnanaraj, Mahendran Sekar, Shivkanya Fuloria, Shasank S. Swain, Siew Hua Gan, Kumarappan Chidambaram, Nur Najihah Izzati Mat Rani, Tavamani Balan, Sarah Stephenie, Pei Teng Lum, Srikanth Jeyabalan, M. Yasmin Begum, Vivek Chandramohan, Lakshmi Thangavelu, Vetriselvan Subramaniyan and Neeraj Kumar Fuloria

Molecules 2022, 27(9), 2834; https://doi.org/10.3390/molecules27092834 - 29 Apr 2022

Cited by 24 | Viewed by 5877

Abstract

Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that have emerged as among the serious health problems of the 21st century. The medications currently available to treat AD and PD have limited efficacy and are associated with side effects. Natural products [...] Read more.

Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that have emerged as among the serious health problems of the 21st century. The medications currently available to treat AD and PD have limited efficacy and are associated with side effects. Natural products are one of the most vital and conservative sources of medicines for treating neurological problems. Karanjin is a furanoflavonoid, isolated mainly from Pongamia pinnata with several medicinal plants, and has been reported for numerous health benefits. However, the effect of karanjin on AD and PD has not yet been systematically investigated. To evaluate the neuroprotective effect of karanjin, extensive in silico studies starting with molecular docking against five putative targets for AD and four targets for PD were conducted. The findings were compared with three standard drugs using Auto Dock 4.1 and Molegro Virtual Docker software. Additionally, the physiochemical properties (Lipinski rule of five), drug-likeness and parameters including absorption, distribution, metabolism, elimination and toxicity (ADMET) profiles of karanjin were also studied. The molecular dynamics (MD) simulations were performed with two selective karanjin docking complexes to analyze the dynamic behaviors and binding free energy at 100 ns time scale. In addition, frontier molecular orbitals (FMOs) and density-functional theory (DFT) were also investigated from computational quantum mechanism perspectives using the Avogadro-ORCA 1.2.0 platform. Karanjin complies with all five of Lipinski’s drug-likeness rules with suitable ADMET profiles for therapeutic use. The docking scores (kcal/mol) showed comparatively higher potency against AD and PD associated targets than currently used standard drugs. Overall, the potential binding affinity from molecular docking, static thermodynamics feature from MD-simulation and other multiparametric drug-ability profiles suggest that karanjin could be considered as a suitable therapeutic lead for AD and PD treatment. Furthermore, the present results were strongly correlated with the earlier study on karanjin in an Alzheimer’s animal model. However, necessary in vivo studies, clinical trials, bioavailability, permeability and safe dose administration, etc. must be required to use karanjin as a potential drug against AD and PD treatment, where the in silico results are more helpful to accelerate the drug development. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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16 pages, 3836 KiB

Open AccessArticle

The Role of Cannabis sativa L. as a Source of Cannabinoids against Coronavirus 2 (SARS-CoV-2): An In Silico Study to Evaluate Their Activities and ADMET Properties

by Ahmed E. Altyar, Fadia S. Youssef, Maram M. Kurdi, Renad J. Bifari and Mohamed L. Ashour

Molecules 2022, 27(9), 2797; https://doi.org/10.3390/molecules27092797 - 27 Apr 2022

Cited by 11 | Viewed by 2967

Abstract

Cannabis sativa L. is an annual herbaceous plant that belongs to the family Cannabinaceae. In this study, the potential use of forty-five cannabinoids, previously identified from Cannabis sativa to alleviate COVID-19 infection via prohibition of crucial SARS-CoV-2 proteins using molecular docking, was examined. [...] Read more.

Cannabis sativa L. is an annual herbaceous plant that belongs to the family Cannabinaceae. In this study, the potential use of forty-five cannabinoids, previously identified from Cannabis sativa to alleviate COVID-19 infection via prohibition of crucial SARS-CoV-2 proteins using molecular docking, was examined. In silico studies were performed on three vital enzymes that serve as principle therapeutic targets to prevent SARS-CoV-2 replication. These enzymes are the main protease SARS-CoV-2 M^Pro, papain-like protease SARS-CoV-2 PL^pro and angiotensin-converting enzyme 2 (ACE2). Regarding SARS-CoV-2 M^Pro, cannabichromanon (32) showed the best fitting within its active centers, followed by cannabinolic acid (22) and cannabinol (21), displaying ∆G of −33.63, −23.24, and −21.60 kcal/mol, respectively. Concerning SARS-CoV-2 PL^pro, cannabichromanon (32) followed by cannabinolic acid (22) and cannabicyclolic acid (41) revealed the best binding within its active pockets owing to multiple bond formation with ∆G values of −28.36, −22.81, and −19.89 kcal/mol. Furthermore, cannabichromanon (32), cannabinolic acid (22), and cannabinol (21) showed considerable fitting within the active sites of angiotensin-converting enzyme 2 (ACE2) evidenced by their significant ∆G values that were estimated as −41.77, −31.34, and −30.36 kcal/mol, respectively. ADME/TOPKAT (absorption, distribution, metabolism, excretion, and toxicity) evaluation was performed on the tested cannabinoids to further explore their pharmacokinetics, pharmacodynamics, and toxicity properties. The results indicated the considerable pharmacokinetic, pharmacodynamic, and toxicity properties of cannabinol (21), cannabinolic acid (22), cannabichromanon (32), and cannabicyclolic acid (41) that showed best fitting scores within the active sites of the tested enzymes. Multivariate data analysis revealed that cannabichromanon and cannabinolic acid showed a discriminant nature and hence can be incorporated in pharmaceutical dosage forms to alleviate COVID-19 infection. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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16 pages, 4493 KiB

Open AccessArticle

Silibinin and Naringenin against Bisphenol A-Induced Neurotoxicity in Zebrafish Model—Potential Flavonoid Molecules for New Drug Design, Development, and Therapy for Neurological Disorders

by Geethanjali Thayumanavan, Srikanth Jeyabalan, Shivkanya Fuloria, Mahendran Sekar, Monica Ravi, Logesh Kumar Selvaraj, Logeshwari Bala, Kumarappan Chidambaram, Siew Hua Gan, Nur Najihah Izzati Mat Rani, M. Yasmin Begum, Vetriselvan Subramaniyan, Kathiresan V. Sathasivam, Dhanalekshmi U. Meenakshi and Neeraj Kumar Fuloria

Molecules 2022, 27(8), 2572; https://doi.org/10.3390/molecules27082572 - 15 Apr 2022

Cited by 16 | Viewed by 3082

Abstract

Bisphenol A (BPA), a well-known xenoestrogen, is commonly utilised in the production of polycarbonate plastics. Based on the existing evidence, BPA is known to induce neurotoxicity and behavioural issues. Flavonoids such as silibinin and naringenin have been shown to have biological activity against [...] Read more.

Bisphenol A (BPA), a well-known xenoestrogen, is commonly utilised in the production of polycarbonate plastics. Based on the existing evidence, BPA is known to induce neurotoxicity and behavioural issues. Flavonoids such as silibinin and naringenin have been shown to have biological activity against a variety of illnesses. The current research evaluates the neuropharmacological effects of silibinin and naringenin in a zebrafish model against neurotoxicity and oxidative stress caused by Bisphenol A. In this study, a novel tank diving test (NTDT) and light–dark preference test (LDPT) were used in neurobehavioural investigations. The experimental protocol was planned to last 21 days. The neuroprotective effects of silibinin (10 μM) and naringenin (10 μM) in zebrafish (Danio rerio) induced by BPA (17.52 μM) were investigated. In the brine shrimp lethality assay, the 50% fatal concentrations (LC₅₀) were 34.10 μg/mL (silibinin) and 91.33 μg/mL (naringenin) compared to the standard potassium dichromate (13.15 μg/mL). The acute toxicity investigation found no mortality or visible abnormalities in the silibinin- and naringenin-treated groups (LC₅₀ > 100 mg/L). The altered scototaxis behaviour in LDPT caused by BPA was reversed by co-supplementation with silibinin and naringenin, as shown by decreases in the number of transitions to the light zone and the duration spent in the light zone. Our findings point to BPA’s neurotoxic potential in causing altered scototaxis and bottom-dwelling behaviour in zebrafish, as well as the usage of silibinin and naringenin as potential neuroprotectants. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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16 pages, 3747 KiB

Open AccessArticle

Methyl Jasmonate Effect on Betulinic Acid Content and Biological Properties of Extract from Senna obtusifolia Transgenic Hairy Roots

by Tomasz Kowalczyk, Przemysław Sitarek, Anna Merecz-Sadowska, Monika Szyposzyńska, Aleksandra Spławska, Leslaw Gorniak, Michał Bijak and Tomasz Śliwiński

Molecules 2021, 26(20), 6208; https://doi.org/10.3390/molecules26206208 - 14 Oct 2021

Cited by 7 | Viewed by 1881

Abstract

It is known that Senna obtusifolia has been used in medicine since ancient times due to the content of many valuable compounds with a pro-health effect. One of them is betulinic acid, which is a pentacyclic triterpene with antimalarial, antiviral, anti-inflammatory and anticancer [...] Read more.

It is known that Senna obtusifolia has been used in medicine since ancient times due to the content of many valuable compounds with a pro-health effect. One of them is betulinic acid, which is a pentacyclic triterpene with antimalarial, antiviral, anti-inflammatory and anticancer properties. In this work, a continuation of our previous research, an attempt was made to increase the level of betulinic acid accumulation by the cultivation of transgenic hairy roots that overexpress the squalene synthase gene in a 10 L sprinkle bioreactor with methyl jasmonate elicitation. We present that the applied strategy allowed us to increase the content of betulinic acid in hairy root cultures to the level of 48 mg/g dry weight. The obtained plant extracts showed a stronger cytotoxic effect on the U87MG glioblastoma cell line than the roots grown without elicitors. Additionally, the induction of apoptosis, reduction of mitochondrial membrane potential, chromosomal DNA fragmentation and activation of caspase cascades are demonstrated. Moreover, the tested extract showed inhibition of topoisomerase I activity. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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Review

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27 pages, 3234 KiB

Open AccessReview

Functional Diversification and Structural Origins of Plant Natural Product Methyltransferases

by Audrey Lashley, Ryan Miller, Stephanie Provenzano, Sara-Alexis Jarecki, Paul Erba and Vonny Salim

Molecules 2023, 28(1), 43; https://doi.org/10.3390/molecules28010043 - 21 Dec 2022

Cited by 2 | Viewed by 2567

Abstract

In plants, methylation is a common step in specialized metabolic pathways, leading to a vast diversity of natural products. The methylation of these small molecules is catalyzed by S-adenosyl-l-methionine (SAM)-dependent methyltransferases, which are categorized based on the methyl-accepting atom ( [...] Read more.

In plants, methylation is a common step in specialized metabolic pathways, leading to a vast diversity of natural products. The methylation of these small molecules is catalyzed by S-adenosyl-l-methionine (SAM)-dependent methyltransferases, which are categorized based on the methyl-accepting atom (O, N, C, S, or Se). These methyltransferases are responsible for the transformation of metabolites involved in plant defense response, pigments, and cell signaling. Plant natural product methyltransferases are part of the Class I methyltransferase-superfamily containing the canonical Rossmann fold. Recent advances in genomics have accelerated the functional characterization of plant natural product methyltransferases, allowing for the determination of substrate specificities and regioselectivity and further realizing the potential for enzyme engineering. This review compiles known biochemically characterized plant natural product methyltransferases that have contributed to our knowledge in the diversification of small molecules mediated by methylation steps. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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33 pages, 5956 KiB

Open AccessReview

Chemistry, Biosynthesis and Pharmacology of Viniferin: Potential Resveratrol-Derived Molecules for New Drug Discovery, Development and Therapy

by Shivkanya Fuloria, Mahendran Sekar, Farrah Syazana Khattulanuar, Siew Hua Gan, Nur Najihah Izzati Mat Rani, Subban Ravi, Vetriselvan Subramaniyan, Srikanth Jeyabalan, M. Yasmin Begum, Kumarappan Chidambaram, Kathiresan V. Sathasivam, Sher Zaman Safi, Yuan Seng Wu, Rusli Nordin, Mohammad Nazmul Hasan Maziz, Vinoth Kumarasamy, Pei Teng Lum and Neeraj Kumar Fuloria

Molecules 2022, 27(16), 5072; https://doi.org/10.3390/molecules27165072 - 09 Aug 2022

Cited by 15 | Viewed by 3873

Abstract

Viniferin is a resveratrol derivative. Resveratrol is the most prominent stilbenoid synthesized by plants as a defense mechanism in response to microbial attack, toxins, infections or UV radiation. Different forms of viniferin exist, including alpha-viniferin (α-viniferin), beta-viniferin (β-viniferin), delta-viniferin (δ-viniferin), epsilon-viniferin (ε-viniferin), gamma-viniferin [...] Read more.

Viniferin is a resveratrol derivative. Resveratrol is the most prominent stilbenoid synthesized by plants as a defense mechanism in response to microbial attack, toxins, infections or UV radiation. Different forms of viniferin exist, including alpha-viniferin (α-viniferin), beta-viniferin (β-viniferin), delta-viniferin (δ-viniferin), epsilon-viniferin (ε-viniferin), gamma-viniferin (γ-viniferin), R-viniferin (vitisin A), and R2-viniferin (vitisin B). All of these forms exhibit a range of important biological activities and, therefore, have several possible applications in clinical research and future drug development. In this review, we present a comprehensive literature search on the chemistry and biosynthesis of and the diverse studies conducted on viniferin, especially with regards to its anti-inflammatory, antipsoriasis, antidiabetic, antiplasmodic, anticancer, anti-angiogenic, antioxidant, anti-melanogenic, neurodegenerative effects, antiviral, antimicrobial, antifungal, antidiarrhea, anti-obesity and anthelminthic activities. In addition to highlighting its important chemical and biological activities, coherent and environmentally acceptable methods for establishing vinferin on a large scale are highlighted to allow the development of further research that can help to exploit its properties and develop new phyto-pharmaceuticals. Overall, viniferin and its derivatives have the potential to be the most effective nutritional supplement and supplementary medication, especially as a therapeutic approach. More researchers will be aware of viniferin as a pharmaceutical drug as a consequence of this review, and they will be encouraged to investigate viniferin and its derivatives as pharmaceutical drugs to prevent future health catastrophes caused by a variety of serious illnesses. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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26 pages, 4852 KiB

Open AccessReview

Chemistry, Biosynthesis and Pharmacology of Sarsasapogenin: A Potential Natural Steroid Molecule for New Drug Design, Development and Therapy

by Nur Hanisah Mustafa, Mahendran Sekar, Shivkanya Fuloria, M. Yasmin Begum, Siew Hua Gan, Nur Najihah Izzati Mat Rani, Subban Ravi, Kumarappan Chidambaram, Vetriselvan Subramaniyan, Kathiresan V. Sathasivam, Srikanth Jeyabalan, Subasini Uthirapathy, Sivasankaran Ponnusankar, Pei Teng Lum, Vijay Bhalla and Neeraj Kumar Fuloria

Molecules 2022, 27(6), 2032; https://doi.org/10.3390/molecules27062032 - 21 Mar 2022

Cited by 9 | Viewed by 3761

Abstract

Sarsasapogenin is a natural steroidal sapogenin molecule obtained mainly from Anemarrhena asphodeloides Bunge. Among the various phytosteroids present, sarsasapogenin has emerged as a promising molecule due to the fact of its diverse pharmacological activities. In this review, the chemistry, biosynthesis and pharmacological potentials [...] Read more.

Sarsasapogenin is a natural steroidal sapogenin molecule obtained mainly from Anemarrhena asphodeloides Bunge. Among the various phytosteroids present, sarsasapogenin has emerged as a promising molecule due to the fact of its diverse pharmacological activities. In this review, the chemistry, biosynthesis and pharmacological potentials of sarsasapogenin are summarised. Between 1996 and the present, the relevant literature regarding sarsasapogenin was obtained from scientific databases including PubMed, ScienceDirect, Scopus, and Google Scholar. Overall, sarsasapogenin is a potent molecule with anti-inflammatory, anticancer, antidiabetic, anti-osteoclastogenic and neuroprotective activities. It is also a potential molecule in the treatment for precocious puberty. This review also discusses the metabolism, pharmacokinetics and possible structural modifications as well as obstacles and opportunities for sarsasapogenin to become a drug molecule in the near future. More comprehensive preclinical studies, clinical trials, drug delivery, formulations of effective doses in pharmacokinetics studies, evaluation of adverse effects and potential synergistic effects with other drugs need to be thoroughly investigated to make sarsasapogenin a potential molecule for future drug development. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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18 pages, 4205 KiB

Open AccessReview

Kirenol: A Potential Natural Lead Molecule for a New Drug Design, Development, and Therapy for Inflammation

by Naurah Nabihah Nasir, Mahendran Sekar, Shivkanya Fuloria, Siew Hua Gan, Nur Najihah Izzati Mat Rani, Subban Ravi, M. Yasmin Begum, Kumarappan Chidambaram, Kathiresan V. Sathasivam, Srikanth Jeyabalan, Arulmozhi Dhiravidamani, Lakshmi Thangavelu, Pei Teng Lum, Vetriselvan Subramaniyan, Yuan Seng Wu, Abul Kalam Azad and Neeraj Kumar Fuloria

Molecules 2022, 27(3), 734; https://doi.org/10.3390/molecules27030734 - 23 Jan 2022

Cited by 12 | Viewed by 4412

Abstract

Kirenol, a potential natural diterpenoid molecule, is mainly found in Sigesbeckia species. Kirenol has received a lot of interest in recent years due to its wide range of pharmacological actions. In particular, it has a significant ability to interact with a wide range [...] Read more.

Kirenol, a potential natural diterpenoid molecule, is mainly found in Sigesbeckia species. Kirenol has received a lot of interest in recent years due to its wide range of pharmacological actions. In particular, it has a significant ability to interact with a wide range of molecular targets associated with inflammation. In this review, we summarise the efficacy and safety of kirenol in reducing inflammation, as well as its potential mechanisms of action and opportunities in future drug development. Based on the preclinical studies reported earlier, kirenol has a good therapeutic potential against inflammation involved in multiple sclerosis, inflammatory bowel disorders, diabetic wounds, arthritis, cardiovascular disease, bone damage, and joint disorders. We also address the physicochemical and drug-like features of kirenol, as well as the structurally modified kirenol-derived molecules. The inhibition of pro-inflammatory cytokines, reduction in the nuclear factor kappa-B (NF-κB), attenuation of antioxidant enzymes, stimulation of heme-oxygenase-1 (HO-1) expression, and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation are among the molecular mechanisms contributing to kirenol’s anti-inflammatory actions. Furthermore, this review also highlights the challenges and opportunities to improve the drug delivery of kirenol for treating inflammation. According to the findings of this review, kirenol is an active molecule against inflammation in numerous preclinical models, indicating a path to using it for new drug discovery and development in the treatment of a wide range of inflammations. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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20 pages, 42298 KiB

Open AccessReview

Tilianin: A Potential Natural Lead Molecule for New Drug Design and Development for the Treatment of Cardiovascular Disorders

by Farrah Syazana Khattulanuar, Mahendran Sekar, Shivkanya Fuloria, Siew Hua Gan, Nur Najihah Izzati Mat Rani, Subban Ravi, Kumarappan Chidambaram, M. Yasmin Begum, Abul Kalam Azad, Srikanth Jeyabalan, Arulmozhi Dhiravidamani, Lakshmi Thangavelu, Pei Teng Lum, Vetriselvan Subramaniyan, Yuan Seng Wu, Kathiresan V. Sathasivam and Neeraj Kumar Fuloria

Molecules 2022, 27(3), 673; https://doi.org/10.3390/molecules27030673 - 20 Jan 2022

Cited by 10 | Viewed by 3409

Abstract

Cardiovascular disorders (CVDs) are the leading risk factor for death worldwide, and research into the processes and treatment regimens has received a lot of attention. Tilianin is a flavonoid glycoside that can be found in a wide range of medicinal plants and is [...] Read more.

Cardiovascular disorders (CVDs) are the leading risk factor for death worldwide, and research into the processes and treatment regimens has received a lot of attention. Tilianin is a flavonoid glycoside that can be found in a wide range of medicinal plants and is most commonly obtained from Dracocephalum moldavica. Due to its extensive range of biological actions, it has become a well-known molecule in recent years. In particular, numerous studies have shown that tilianin has cardioprotective properties against CVDs. Hence, this review summarises tilianin’s preclinical research in CVDs, as well as its mechanism of action and opportunities in future drug development. The physicochemical and drug-likeness properties, as well as the toxicity profile, were also highlighted. Tilianin can be a natural lead molecule in the therapy of CVDs such as coronary heart disease, angina pectoris, hypertension, and myocardial ischemia, according to scientific evidence. Free radical scavenging, inflammation control, mitochondrial function regulation, and related signalling pathways are all thought to play a role in tilianin’s cardioprotective actions. Finally, we discuss tilianin-derived compounds, as well as the limitations and opportunities of using tilianin as a lead molecule in drug development for CVDs. Overall, the scientific evidence presented in this review supports that tilianin and its derivatives could be used as a lead molecule in CVD drug development initiatives. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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22 pages, 2128 KiB

Open AccessReview

Genistein: A Potential Natural Lead Molecule for New Drug Design and Development for Treating Memory Impairment

by Shivkanya Fuloria, Muhamad Azrul Amir Yusri, Mahendran Sekar, Siew Hua Gan, Nur Najihah Izzati Mat Rani, Pei Teng Lum, Subban Ravi, Vetriselvan Subramaniyan, Abul Kalam Azad, Srikanth Jeyabalan, Yuan Seng Wu, Dhanalekshmi Unnikrishnan Meenakshi, Kathiresan V. Sathasivam and Neeraj Kumar Fuloria

Molecules 2022, 27(1), 265; https://doi.org/10.3390/molecules27010265 - 01 Jan 2022

Cited by 18 | Viewed by 3524

Abstract

Genistein is a naturally occurring polyphenolic molecule in the isoflavones group which is well known for its neuroprotection. In this review, we summarize the efficacy of genistein in attenuating the effects of memory impairment (MI) in animals. Scopus, PubMed, and Web of Science [...] Read more.

Genistein is a naturally occurring polyphenolic molecule in the isoflavones group which is well known for its neuroprotection. In this review, we summarize the efficacy of genistein in attenuating the effects of memory impairment (MI) in animals. Scopus, PubMed, and Web of Science databases were used to find the relevant articles and discuss the effects of genistein in the brain, including its pharmacokinetics, bioavailability, behavioral effects, and some of the potential mechanisms of action on memory in several animal models. The results of the preclinical studies highly suggested that genistein is highly effective in enhancing the cognitive performance of the MI animal models, specifically in the memory domain, including spatial, recognition, retention, and reference memories, through its ability to reduce oxidative stress and attenuate neuroinflammation. This review also highlighted challenges and opportunities to improve the drug delivery of genistein for treating MI. Along with that, the possible structural modifications and derivatives of genistein to improve its physicochemical and drug-likeness properties are also discussed. The outcomes of the review proved that genistein can enhance the cognitive performance and ameliorate MI in different preclinical studies, thus indicating its potential as a natural lead for the design and development of a novel neuroprotective drug. Full article

(This article belongs to the Special Issue Drug Development Inspired by Natural Products)

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