Class Of Secondary Metabolites Research Articles

Clerodendrum Glandulosum Lindl.: A Review of Ethnopharmacology, Pharmacological Potentials, and their Mechanism of Action.

Clerodendrum glandulosum Lindl. is popularly known for its traditional herbal remedies and therapeutic properties among the people of Northeast Indian communities, as well as Chinese traditional medicine. For the myriad pharmacological properties, viz., anti-hypertensive, hypolipidemic, hepatoprotective, anti-inflammatory, and neuroprotective, planting this species in kitchen gardens is a common practice to treat various ailments, especially hypertension, diabetes, and other metabolic complications. Different phytochemicals, representing the diverse classes of secondary metabolites comprising physiological and phytopharmaceutical significance, have been reported from C. glandulosum. Compounds with terpenoids, steroids, and phenolics are in demand in the pharmaceutical industry. An overview of the mechanism of action of the prominent compounds has also been collated for future research on C. glandulosum-based therapeutics. Current information focuses on this important medicinal plant's ethnomedicinal use, phytochemistry, pharmacology, associated mechanisms, and toxicology. This review will help explore this potential medicinal plant, which can pave the path for its application in the pharmaceutical industry.

Characterization of CYP82 genes involved in the biosynthesis of structurally diverse benzylisoquinoline alkaloids in Corydalis yanhusuo.

Benzylisoquinoline alkaloids (BIAs) represent a significant class of secondary metabolites with crucial roles in plant physiologyand substantial potential for clinical applications. CYP82 genes are involved in the formation and modification of various BIA skeletons, contributing to the structural diversity of compounds. In this study, Corydalis yanhusuo, a traditional Chinese medicine rich in BIAs, was investigated to identify the catalytic function of CYP82s during BIA formation. Specifically, 20 CyCYP82-encoding genes were cloned, and their functions were identified in vitro. Tenof these CyCYP82s were observed to catalyze hydroxylation, leading to the formation of protopine and benzophenanthridine scaffolds. Furthermore, the correlation between BIA accumulation and the expression ofCyCYP82s in different tissues of C. yanhusuo wasassessed their. The identification andcharacterization of CyCYP82s provide novel genetic elementsthatcan advance the synthetic biology of BIA compounds such as protopine and benzophenanthridine, and offer insights into the biosynthesis of BIAs with diverse structures in C. yanhusuo.

Jozimine A2, a Dimeric Naphthylisoquinoline (NIQ) Alkaloid, Shows In Vitro Cytotoxic Effects against Leukemia Cells through NF-κB Inhibition.

Naphthylisoquinoline (NIQ) alkaloids are rising as a promising class of secondary metabolites with pharmaceutical potential. NF-κB has already been recognized as a significant modulator of cancer proliferation and drug resistance. We have previously reported the mechanisms behind the cytotoxic effect of dioncophylline A, an NIQ monomer, in leukemia cells. In the current study, we have investigated the cytotoxic effect of jozimine A2, an NIQ dimer, on leukemia cells in comparison to a second, structurally unsymmetric dimer, michellamine B. To this end, molecular docking was applied to predict the binding affinity of the dimers towards NF-κB, which was then validated through microscale thermophoresis. Next, cytotoxicity assays were performed on CCRF-CEM cells and multidrug-resistant CEM/ADR5000 cells following treatment. Transcriptome analysis uncovered the molecular networks affected by jozimine A2 and identified the cell cycle as one of the major affected processes. Cell death modes were evaluated through flow cytometry, while angiogenesis was measured with the endothelial cell tube formation assay on human umbilical vein endothelial cells (HUVECs). The results indicated that jozimine A2 bound to NF-κB, inhibited its activity and prevented its translocation to the nucleus. In addition, jozimine A2 induced cell death through apoptosis and prevented angiogenesis. Our study describes the cytotoxic effect of jozimine A2 on leukemia cells and explains the interactions with the NF-κB signaling pathway and the anticancer activity.

A comparative untargeted metabolomic analysis and assessment of antiplasmodial potential of nine Albizia species.

The genus Albizia is one of the richest genera in phenolics besides other classes of secondary metabolites including saponins, terpenes, and alkaloids with promising medicinal applications. In the current study, UHPLC-PDA-ESI-MS/MS-based metabolic profiling of leaves of Albizia lebbeck, Albizia julibrissin, Albizia odoratissima, Albizia procera, Albizia anthelmintica, Albizia guachapele, Albizia myriophylla, Albizia richardiana, and Albizia lucidior resulted in the tentative identification of 64 metabolites, mainly flavonoids, phenolic acids, saponins, and alkaloids. Some metabolites were identified in Albizia for the first time and could be used as species-specific chemotaxonomic markers, including: apigenin 7-O-dihydroferuloyl hexoside isomers, apigenin 7-O-pentosyl hexoside, quercetin 3-O-rutinoside 7-O-deoxyhexoside, quercetin 3,7-di-O-hexoside deoxyhexoside, quercetin 7-O-feruloyl hexoside, methyl myricetin 7-O-deoxyhexoside, kaempferol di-3-O-di-deoxyhexoside-7-O-hexoside, and kaempferol 3-O-neohesperidoside 7-O-hexoside. Comparative untargeted metabolomic analysis was undertaken to discriminate between species and provide a chemotaxonomic clue that can be used together with morphological and genetic analyses for more accurate classification within this genus. Moreover, the in vitro antiplasmodial activity was assessed and correlated to the metabolic profile of selected species. This was followed by a molecular docking study and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction of the identified budmunchiamine alkaloids, revealing promising interactions with the active site of lactate dehydrogenase of Plasmodium falciparum and good pharmacokinetics and pharmacodynamics, which could help in designing novel antimalarial drugs.

Association of dietary flavonoid intakes with prevalence of chronic respiratory diseases in adults

Background and aimsFlavonoids are a class of secondary plant metabolites that have been shown to have multiple health benefits, including antioxidant and anti-inflammatory. This study was to explore the association between dietary flavonoid consumption and the prevalence of chronic respiratory diseases (CRDs) in adults.Methods and resultsThe six main types of flavonoids, including isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and flavonols, were obtained from the National Health and Nutrition Examination Survey (NHANES) 2007–2010 and 2017–2018 by the two 24-h recall interviews. The prevalence of CRDs, including asthma, emphysema, and chronic bronchitis, was determined through a self-administered questionnaire. The analysis included 15,753 participants aged 18 years or older who had completed a diet history interview. After adjustment for potential confounders, the inverse link was found with total flavonoids, anthocyanidins, flavanones, and flavones, with an OR (95%CI) of 0.86 (0.75–0.98), 0.84 (0.72–0.97), 0.80(0.69–0.92), and 0.85(0.73–0.98) for the highest group compared to the lowest group. WQS regression revealed that the mixture of flavonoids was negatively linked with the prevalence of CRDs (OR = 0.88 [0.82–0.95], P < 0.01), and the largest effect was mainly from flavanones (weight = 0.41). In addition, we found that flavonoid intake was negatively linked with inflammatory markers, and systemic inflammation significantly mediated the associations of flavonoids with CRDs, with a mediation rate of 12.64% for CRP (P < 0.01).ConclusionHigher flavonoid intake was related with a lower prevalence of CRDs in adults, and this relationship may be mediated through systemic inflammation.

Hirsutinolide- and Cadinanolide-type Sesquiterpene Lactones from Lessingianthus rubricaulis (Vernonieae, Asteraceae).

Sesquiterpene lactones are an important class of secondary metabolites frequently isolated from Lessingianthus genus that present a variety of biological properties, such as antimalarial, anti-inflammatory, antileishmanial, antitrypanosomal and anticancer. The limited phytochemical studies and the importance of this class of compounds isolated from Lessingianthus led us to study this genus. In this work, we focused on the phytochemical investigation and dereplication based on UHPLC-HRMS/MS and molecular networking of L. rubricaulis. Chemical investigation resulted in the isolation of several hirsutinolide-type sesquiterpene lactones including a new hirsutinolide derivative, 8,10α-hydroxy-1,13-bis-O-methylhirsutinolide, besides a cadinanolide and flavonoids. The dereplication study resulted in the identification of three known flavonoids, six known hirsutinolides and two known cadinanolides. Moreover, a fragmentation pathway for cadinanolide-type sesquiterpene lactones was proposed. These results contribute to chemotaxonomic studies and demonstrates the potential of Lessingianthus genus.

Therapeutic Potential of Pectin and Its Derivatives in Chronic Diseases.

Non-communicable diseases (NCDs) are described as a collection of chronic diseases that do not typically develop from an acute infection, have long-term health effects, and frequently require ongoing care and therapy. These diseases include heart disease, stroke, cancer, chronic lung disease, neurological diseases, osteoporosis, mental health disorders, etc. Known synthetic drugs for the treatment or prevention of NCDs become increasingly dangerous over time and pose high risks due to side effects such as hallucination, heart attack, liver failure, etc. As a result, scientists have had to look for other alternatives that are natural products and that are known to be less detrimental and contain useful bioactive compounds. The increasing understanding of the biological and pharmacological significance of carbohydrates has helped to raise awareness of their importance in living systems and medicine, given they play numerous biological roles. For example, pectin has been identified as a class of secondary metabolites found in medicinal plants that may play a significant role in the treatment and management of a variety of NCDs. Pectin is mainly made of homogalacturonan, which is a linear polymer composed primarily of D-galacturonic acid units (at least 65%) linked in a chain by α-(1,4)-glycosidic linkages. There are also modified pectins or derivatives that improve pectin's bioavailability. Pectin is found in the cell walls of higher plants (pteridophytes, angiosperms, and gymnosperms), particularly in the middle lamella of the plant material. Citrus pectin is used in various industries. This article compiles information that has been available for years about the therapeutic importance of pectin in chronic diseases, different modes of pectin extraction, the chemistry of pectin, and the potency of pectin and its derivatives.

Structural Revision of Tinotufolins from Tinospora crispa Leaves Guided by Empirical Rules and DFT Calculations.

Clerodane diterpenes are a class of secondary metabolites that can be classified into four types according to the configuration of the H3-19/H-10-H3-17/H3-20 fragment, i.e., trans-cis (TC), trans-trans (TT), cis-cis (CC), and cis-trans (CT). Tinotufolins A-C and E (1a-3a and 5a), isolated from the leaves of Tinospora crispa, were previously elucidated as CT-type clerodanes; however, our established 13C NMR-based empirical rules and density functional theory calculations suggested that these clerodanes belong to the CC type. Therefore, tinotufolins A-F (1-6) were reisolated from the leaves of T. crispa, along with an undescribed compound 7 and known compounds 8-11, and their structures were established by extensive spectroscopic analyses. The structures of tinotufolins A-C and E were revised to CC-type 1-3 and 5, and undescribed compound 7 was established as a CC-type clerodane. The present study demonstrates that empirical rules and calculations can efficiently identify and revise erroneous structures in clerodane diterpenes.

Deep learning-based quantification and transcriptomic profiling reveal a methyl jasmonate-mediated glandular trichome formation pathway in Cannabis sativa.

Cannabis glandular trichomes (GTs) are economically and biotechnologically important structures that have a remarkable morphology and capacity to produce, store, and secrete diverse classes of secondary metabolites. However, our understanding of the developmental changes and the underlying molecular processes involved in cannabis GT development is limited. In this study, we developed Cannabis Glandular Trichome Detection Model (CGTDM), a deep learning-based model capable of differentiating and quantifying three types of cannabis GTs with a high degree of efficiency and accuracy. By profiling at eight different time points, we captured dynamic changes in gene expression, phenotypes, and metabolic processes associated with GT development. By integrating weighted gene co-expression network analysis with CGTDM measurements, we established correlations between phenotypic variations in GT traits and the global transcriptome profiles across the developmental gradient. Notably, we identified a module containing methyl jasmonate (MeJA)-responsive genes that significantly correlated with stalked GT density and cannabinoid content during development, suggesting the existence of a MeJA-mediated GT formation pathway. Our findings were further supported by the successful promotion of GT development in cannabis through exogenous MeJA treatment. Importantly, we have identified CsMYC4 as a key transcription factor that positively regulates GTformation via MeJA signaling in cannabis. These findings provide novel tools for GT detection and counting, as well as valuable information for understanding the molecular regulatory mechanism of GT formation, which has the potential to facilitate the molecular breeding, targeted engineering, informed harvest timing, and manipulation of cannabinoid production.

Investigating Metabolic Plant Response toward Deoxynivalenol Accumulation in Four Winter Cereals.

Deoxynivalenol (DON) is a phytotoxic agent supporting the spread of fungal diseases in cereals worldwide, i.e., fusarium head blight. It is known that DON accumulation may elicit changes in plant secondary metabolites in response to pathogen attack. This study maps the changes in selected secondary metabolite classes upon DON contamination occurring in fifteen Triticum spp. genotypes, among them emmer, spelt, and soft wheat, and 2 tritordeum varieties, cultivated in two different sites and over two harvest years. The main phenolic classes (i.e., alkylresorcinols, soluble, and cell-wall bound phenolic acids) were targeted analyzed, while changes in the lipidome signature were collected through untargeted HRMS experiments. The results, obtained across multiple Triticum species and in open fields, confirmed the modulation of first-line biological pathways already described in previous studies involving single cereal species or a limited germplasm, thus reinforcing the involvement of nonspecific chemical defenses in the plant response to pathogen attack.

An Insight into the Role of Phenolics in Abiotic Stress Tolerance in Plants: Current Perspective for Sustainable Environment

Phenolic compounds (PCs) are a prominent class of secondary metabolites produced by plants and are essential for the natural role of the entire plant life cycle. PCs are formed in plants under both favorable and unfavorable conditions and have essential functions in signaling pathways, such as cell division, nutrient mineralization, hormone control, and reproduction. Under abiotic stress conditions, plants produce more polyphenols, which aid them in adapting to their environment. The phenylpropanoid biosynthetic pathway is activated under various environmental stress conditions, such as drought, heavy metal toxicity, salinity, and high/low temperatures, resulting in the deposition of compounds. These compounds can neutralize reactive oxygen species (ROS) produced in excessive amounts in crops under stressful conditions and adversely affect plants. It is imperative to investigate the functions of PCs in response to several abiotic stresses, as the phenylpropanoid pathway plays a crucial role in the metabolic pathway in crop plants, leading to the biosynthesis of a wide range of PCs. These compounds play various roles in plant growth, development, and response to environmental stress. Therefore, this review provides a comprehensive understanding of PCs and their exchanges with other cellular components, which is crucial for harnessing their potential to improve crop resilience to environmental stresses.

Anticancer Potential of Biologically Active Diosgenin and its Derivatives: An Update

Abstract: Diosgenin (1) is an important steroidal metabolite often used as a precursor material for the synthesis of a broad array of steroidal drugs. Recent studies have indicated that compound (1) and many diosgenyl derivatives such as (1→9) possess both in vivo and in vitro biological activities like antioxidant, hypolipidemic, antithrombotic, immuno-modulatory, and estrogenic including anticancer activities. This steroidal sapogenin is of increasing interest in the pharmaceutical industry as it is being explored as an important starting material for the synthesis of oral contraceptives, sex hormones, and many other steroidal drugs having anticancer potential. Naturally occurring diosgenin, and its glucoside derivatives are quite abundant in several plant sources, but very little is known about the biogenesis of this class of secondary plant metabolites. Hence, designing a semi-synthetic protocol for the improved anticancer potential with enhanced efficacy of diosgenin and its derivatives is always a challenging field of cutting-edge research in pharmaceutical chemistry. The present review highlights some of the recent research findings and applications of this group of triterpenoids as a potential anticancer agent.

Inhibitory Activity of Flavonoid Scaffolds on SARS-CoV-2 3CLpro: Insights from the Computational and Experimental Investigations.

The emergence of the COVID-19 situation has become a global issue due to the lack of effective antiviral drugs for treatment. Flavonoids are a class of plant secondary metabolites that have antiviral activity against SARS-CoV-2 through inhibition of the main protease (3CLpro). In this study, 22 flavonoids obtained from natural sources and semisynthetic approaches were investigated for their inhibitory activity against SARS-CoV-2 3CLpro, along with cytotoxicity on Vero cells. The protein-ligand interactions were examined using molecular dynamics simulation. Moreover, QSAR analysis was conducted to clarify the structural effects on bioactivity. Accordingly, the in vitro investigation demonstrated that four flavonoids, namely, tectochrysin (7), 6″,6″-dimethylchromeno-[2″,3″:7,8]-flavone (9), panduratin A (19), and genistein (20), showed higher protease inhibitory activity compared to the standard flavonoid baicalein. Finally, our finding suggests that genistein (20), an isoflavone discovered in Millettia brandisiana, has potential for further development as a SARS-CoV-2 3CLpro inhibitor.

Chemical Characterization and Biological Activities of Jandaíra Stingless Bee Products (Melipona subnitida, Ducke, 1911): A Brief Review.

Melipona subnitida (Ducke, 1911), a species of stingless bee, popularly known as Jandaíra, has a wide distribution in the Brazilian Northeast region, being an important pollinator of the Caatinga biome. This bee produces products such as honey, geopropolis, pollen (saburá) and wax that are traditionally used for therapeutic purposes and some studies report the biological properties, as well as its chemical composition. This review aimed to select, analyze and gather data published in the literature focusing on the chemical profile and bioactivities described for M. subnitida products. Data collection was carried out through the Capes Journal Portal platform, using the following databases: Web of Science, Scopus, and PubMed. Original articles published in English and Portuguese were included, with no time limitation. The chemical composition of M. subnitida products has been investigated through chromatographic analysis, demonstrating the presence of a variety of phenolic compounds, such as flavonoids and phenylpropanoids, among other classes of secondary metabolites. These products also have several biological activities, including antioxidant, healing, antinociceptive, anti-inflammatory, antidepressant, antidyslipidemic, antiobesity, antifungal, antibacterial and prebiotic. Among the biological activities reported, the antioxidant activity was the most investigated. These data show that products derived from the stingless bee M. subnitida have promising bioactive compounds. This review provides useful information about the bioactivities and chemical profile of Melipona subnitida bee products, and a direction for future research, which should focus on understanding the mechanisms of action associated with the already elucidated pharmacological activities, as well as the bioactive properties of the main isolate's constituents identified in the chemical composition of these products.

A Study on Anti-oxidant and Anti-cancer Perspectives of Rutin

Introduction: The purpose of this study was to extract, isolate, and evaluate in vitro the antioxidant and anticancer properties of rutin from Citrus reticulata and Citrus limon. Background: Bioflavonoids are a class of polyphenolic secondary metabolites that give plants their distinctive organoleptic properties. Rutin, also known as rutoside, is a citrus flavonoid that is found in a variety of plants, including citrus fruits, and has a wide range of pharmacological effects. Objective: This investigation's goal was to extract, isolate, and test the antioxidant and anti-cancer properties of rutin in vitro. Methods: By incorporating the appropriate solvent system, the Soxhlet apparatus was used to extract C. reticulata (R2) and C. limon (R3) from dried peel powder. Column chromatography was used in the isolation process. Various solvent systems on the basis of their polarity were used to isolate rutin, which further was evaluated for anti-oxidant and anti-cancer action by the use of in vitro tests. Results: Successful extraction and isolation of rutin from two sources were achieved. Additionally, their antioxidant and anticancer activity was also evaluated by in vitro methods. Both isolated rutins (R2 and R3) possessed optimal antioxidants in the range of 31.64 to 76.28 g/ml and anticancer activity with IC50 values of 4 to 7 g/ml, when compared to standard doxorubicin with an IC50 value of 3g/ml. In the comparison of rutin isolated from C. reticulata with rutin isolated from C. limon, rutin isolated from C. reticulata was found to be more abundant and more potent in terms of yield and activity. Conclusion: The study's findings are clear; Citrus reticulata species have a higher flavonoid and phenolic content, and the rutin extracted from them is an effective anti-oxidant and anti-cancer agent against lung cancer. The study can be used as a model for future studies on rutin’s role in cancer.

Exploring natural chalcones: innovative extraction techniques, bioactivities, and health potential

Chalcones, a class of secondary metabolites within the flavonoid family, are characterized by a distinct C6-C3-C6 structure.

Flavonoid diversity and roles in the lipopolysaccharide-mediated inflammatory response of monocytes and macrophages.

Targeting lipopolysaccharide (LPS)/toll-like receptor4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a few key targets have been translated into clinical applications. Flavonoids, a class of ubiquitous plant secondary metabolites, possess a privileged scaffold which serves as a valuable template for designing pharmacologically active compounds directed against diseases with inflammatory components. This perspective provides a general overview of the diversity of flavonoids and their multifaceted mechanisms that interfere with LPS-induced signaling in monocytes and macrophages. Focus is placed on flavonoids targeting MD-2, IκB kinases, c-Jun N-terminal kinases, extracellular signal-regulated kinase, p38 MAPKand PI3K/Akt or modulating LPS-related gene expression.

A novel approach for the synthesis of the cyclic lipopeptide globomycin.

Cyclic lipopeptides (CLiPs) are a highly diverse class of secondary metabolites produced by bacteria and fungi. Examples of CLiPs have been found that possess potent antimicrobial activity against multidrug-resistant Gram-negative bacteria. Globomycin is a 19-membered CLiP that kills both Gram-positive and Gram-negative bacteria through inhibition of lipoprotein signal peptidase II (Lsp). It can only be obtained in small quantities from its Streptomyces producer strain, so there has been much interest in development of synthetic methods to access globomycin and analogues. Globomycin contains an N-terminal anti-α-methyl-β-hydroxy nonanoyl lipid tail, whose hydroxyl group forms an ester with the C-terminal carboxylate. Constructing the anti-arrangement between the α-methyl and β-hydroxy is synthetically challenging and previous globomycin syntheses are not compatible with diversification of the lipid tail after the stereocenters have been installed. Herein, we describe a new approach for the synthesis of globomycin that allows for facile lipid diversification. Using an anti-Evans Aldol condensation, a common intermediate is obtained that allows different "lipid swapping" through Grubbs-catalyzed cross-metathesis. Upon auxiliary cleavage, the resulting lipid can then be utilized in solid-phase peptide synthesis. Given the plethora of lipopeptides that contain β-hydroxy lipids, this method offers a convenient approach for convergent generation of lipopeptide analogues.

Molecular docking and molecular dynamic simulation studies to identify potential terpenes against Internalin A protein of Listeria monocytogenes.

Ever since the outbreak of listeriosis and other related illnesses caused by the dreadful pathogen Listeria monocytogenes, the lives of immunocompromised individuals have been at risk. The main goal of this study is to comprehend the potential of terpenes, a major class of secondary metabolites in inhibiting one of the disease-causing protein Internalin A (InlA) of the pathogen via in silico approaches. The best binding affinity value of -9.5kcal/mol was observed for Bipinnatin and Epispongiadiol according to the molecular docking studies. The compounds were further subjected to ADMET and biological activity estimation which confirmed their good pharmacokinetic properties and antibacterial activity. Molecular dynamic simulation for a timescale of 100ns finally revealed Epispongiadiol to be a promising drug-like compound that could possibly pave the way to the treatment of this disease.

A newly isolated intestinal bacterium involved in the C-ring cleavage of flavan-3-ol monomers and the antioxidant activity of the metabolites.

Flavan-3-ols are an important class of secondary metabolites in many plants. Their bioavailability and bioactivity are largely determined by the metabolism of intestinal microbiota. However, little is known about the intestinal bacteria involved in the metabolism of flavan-3-ols and the activities of the metabolites. C-ring cleavage is the initial and key step in the metabolism of flavan-3-ol monomers. Here, we isolated a strain from porcine cecum content, which is capable of cleaving the heterocyclic C-ring to form 1-(3',4'-dihydroxyphenyl)-3-(2'',4'',6''-trihydroxyphenyl)propan-2-ol from (+)-catechin and (-)-epicatechin, and 1-(3',4',5'-trihydroxyphenyl)-3-(2'',4'',6''-trihydroxyphenyl) propan-2-ol from (-)-epigallocatechin. The strain was identified as Streptococcus pasteurianus (Streptococcus gallolyticus subsp. Pasteurianus, designated as F32-1) based on 16S rDNA similarity and MALDI-TOF-MS identification. The formation of the C-ring cleavage structural unit by the F32-1 strain enhanced the chemical antioxidant ability and altered the cellular antioxidant activity of (+)-catechin, (-)-epicatechin and (-)-epigallocatechin. Overall, in this study we isolated a new intestinal bacterium involved in the C-ring cleavage of flavan-3-ol monomers and elucidated the bioactivity of their metabolites.