Plant-derived Natural Products Research Articles

The benefit of combining curcumin, bromelain and harpagophytum to reduce inflammation in osteoarthritic synovial cells

BackgroundOsteoarthritis (OA) is the most common form of arthritis, affecting millions of people worldwide and characterised by joint pain and inflammation. It is a complex disease involving inflammatory factors and affecting the whole joint, including the synovial membrane. Since drug combination is widely used to treat chronic inflammatory diseases, a similar strategy of designing plant-derived natural products to reduce inflammation in OA joints may be of interest. In this study, we characterised the response of OA synovial cells to lipopolysaccharide (LPS) and investigated the biological action of the combination of curcumin, bromelain and harpagophytum in this original in vitro model of osteoarthritis.MethodsFirstly, human synovial cells from OA patients were stimulated with LPS and proteomic analysis was performed. Bioinformatics analyses were performed using Cytoscape App and SkeletalVis databases. Additionally, cells were treated with curcumin, bromelain and harpagophytum alone or with the three vegetal compounds together. The gene expression involved in inflammation, pain or catabolism was determined by RT-PCR. The release of the encoded proteins by these genes and of prostaglandin E2 (PGE2) were also assayed by ELISA.ResultsProteomic analysis demonstrated that LPS induces the expression of numerous proteins involved in the OA process in human OA synovial cells. In particular, it stimulates inflammation through the production of pro-inflammatory cytokines (Interleukin-6, IL-6), catabolism through an increase of metalloproteases (MMP-1, MMP-3, MMP-13), and the production of pain-mediating neurotrophins (Nerve Growth Factor, NGF). These increases were observed in terms of mRNA levels and protein release. LPS also increases the amount of PGE2, another inflammation and pain mediator. At the doses tested, vegetal extracts had little effect: only curcumin slightly counteracted the effects of LPS on NGF and MMP-13 mRNA, and PGE2, IL-6 and MMP-13 release. In contrast, the combination of curcumin with bromelain and harpagophytum reversed lots of effects of LPS in human OA synovial cells. It significantly reduced the gene expression and/or the release of proteins involved in catabolism (MMP-3 and -13), inflammation (IL-6) and pain (PGE2 and NGF).ConclusionWe have shown that the stimulation of human OA synovial cells with LPS can induce protein changes similar to inflamed OA synovial tissues. In addition, using this model, we demonstrated that the combination of three vegetal compounds, namely curcumin, bromelain and harpagophytum, have anti-inflammatory and anti-catabolic effects in synovial cells and may thus reduce OA progression and related pain.

Pharmacologic Activities of Plant-Derived Natural Products on Respiratory Diseases and Inflammations.

Respiratory inflammation is caused by an air-mediated disease induced by polluted air, smoke, bacteria, and viruses. The COVID-19 pandemic is also a kind of respiratory disease, induced by a virus causing a serious effect on the lungs, bronchioles, and pharynges that results in oxygen deficiency. Extensive research has been conducted to find out the potent natural products that help to prevent, treat, and manage respiratory diseases. Traditionally, wider floras were reported to be used, such as Morus alba, Artemisia indica, Azadirachta indica, Calotropis gigantea, but only some of the potent compounds from some of the plants have been scientifically validated. Plant-derived natural products such as colchicine, zingerone, forsythiaside A, mangiferin, glycyrrhizin, curcumin, and many other compounds are found to have a promising effect on treating and managing respiratory inflammation. In this review, current clinically approved drugs along with the efficacy and side effects have been studied. The study also focuses on the traditional uses of medicinal plants on reducing respiratory complications and their bioactive phytoconstituents. The pharmacological evidence of lowering respiratory complications by plant-derived natural products has been critically studied with detailed mechanism and action. However, the scientific validation of such compounds requires clinical study and evidence on animal and human models to replace modern commercial medicine.

Toxicological Effects of Compounds from the Leaves of Schinus terebinthifolius Against Two Tetranychid Mites (Acari: Tetranychidae)

The use of synthetic acaricides is becoming increasingly hazardous to non-target organisms. Plant-derived natural products are alternative candidates with general low toxicity to human and environment. Two extracts and nine phenolic compounds (1-9) from the leaves of the Brazilian pepper tree (Schinus terebinthifolius Raddi) were investigated for their acaricidal effects against two tetranychid mites, Tetranychus cinnabarinus (carmine spider mite) and Tetranychus urticae (two-spotted spider mite). After 7-days of treatment, the ethyl acetate fraction demonstrated remarkable mortality against T. cinnabarinus (86.67%) while, the n-hexane fraction showed the highest mortality against T. urticae (96.67%) at 200 μg/mL. Among the tested compounds, afzelin (2) and protocatechuic acid (7) exhibited remarkable activity. Regarding T. cinnabarinus, afzelin showed the highest mortality (86.67%), toxic activity (LC50 22.32 μg/mL and toxicity index, Ti 0.972), and the fastest lethality by time. Whereas, protocatechuic acid achieved the highest mortality (96.67%), the lowest LC50 (0.232 μg/mL, Ti 73.71), and fastest lethality by time against T. urticae. This study reported a promising in vitro acaricidal activity of the phytoconstituents of the Brazilian pepper tree and suggested its isolated compounds, such as afzelin and chatechuic acid, as alternative leads for the development of echo-friendly acaricides.

Flavonoid-Coated Gold Nanoparticles as Efficient Antibiotics against Gram-Negative Bacteria-Evidence from In Silico-Supported In Vitro Studies.

Flavonoids are a class of bioactive plant-derived natural products that exhibit a broad range of biological activities, including antibacterial ones. Their inhibitory activity toward Gram-positive bacterial was found to be superior to that against Gram-negative ones. In the present study, a number of flavonoid-coated gold nanoparticles (GNPs) were designed to enhance the antibacterial effects of chrysin, kaempferol, and quercetin against a number of Gram-negative bacteria. The prepared GNPs were able to conjugate to these three flavonoids with conjugation efficiency ranging from 41% to 80%. Additionally, they were able to exert an enhanced antibacterial activity in comparison with the free flavonoids and the unconjugated GNPs. Quercetin-coated GNPs were the most active nano-conjugates and were able to penetrate the cell wall of E. coli. A number of in silico experiments were carried out to explain the conjugation efficiency and the antibacterial mechanisms of these flavonoids as follows: (i) these flavonoids can efficiently bind to the glutathione linker on the surface of GNPs via H-bonding; (ii) these flavonoids, particularly quercetin, were able to increase the bacterial membrane rigidity, and hence decrease its functionality; (iii) these flavonoids can inhibit E. coli’s DNA gyrase (Gyr-B) with IC50 values ranging from 0.9 to 3.9 µM. In conclusion, these bioactive flavonoid-based GNPs are considered to be very promising antibiotic candidates for further development and evaluation.

Antibacterial Activity, Mechanism and Application of Plant-Derived Natural Products in Food Preservation

Antibacterial Activity, Mechanism and Application of Plant-Derived Natural Products in Food Preservation

Potential Role of In Vitro-In Vivo Correlations (IVIVC) for the Development of Plant-Derived Anticancer Drugs.

Conventional medicines, along with herbal formulations of Chinese, serve as the primary source and hub of active new drugs where the initial research concentrates on the extraction and isolation of bioactive lead compound(s) to treat several diseases largely for cancer. Plant-derived natural products and their analogs reveal a significant source of several clinically useful anticancer agents. Herbs and herbal derived active compounds play an unavoidable role in the treatment, drug discovery and delivery for decades, as evidenced by numerous existing marked drugs and various cancer-related molecular targets in clinical development. Solubility, resistance and metabolic limitations of the drug can be overcome by suitable molecular modifications. Due to enhancements in tumor targeting technology, some agents who failed in earlier clinical studies are also stimulating renewed interest. In this connection, In Vitro-In Vivo Correlation (IVIVC) plays an important role in the development of dosage forms in the field of pharmaceutical technology. IVIVC tool fastens and improves the drug development process and product quality, which is also utilized in internal control for scale-up to improve formulations and alternative production processes. Most importantly, this IVIVC tool lessens the number of human studies during new pharmaceuticals developments. In this review, we would like to grab the attention of readers to the importance and significance of IVIVC for natural products of anticancer drugs examples such as Docetaxel, Etoposide phosphate, 6-Gingerol, Capsaicin, etc.

Phytochemical and Over-The-Counter Drug Interactions: Involvement of Phase I and II Drug-Metabolizing Enzymes and Phase III Transporters.

Consumption of plant-derived natural products and over-the-counter (OTC) drugs is increasing on a global scale, and studies of phytochemical-OTC drug interactions are becoming more significant. The intake of dietary plants and herbs rich in phytochemicals may affect drug-metabolizing enzymes (DMEs) and transporters. These effects may lead to alterations in pharmacokinetics and pharmacodynamics of OTC drugs when concomitantly administered. Some phytochemical-drug interactions benefit patients through enhanced efficacy, but many interactions cause adverse effects. This review discusses possible mechanisms of phytochemical-OTC drug interactions mediated by phase I and II DMEs and phase III transporters. In addition, current information is summarized for interactions between phytochemicals derived from fruits, vegetables, and herbs and OTC drugs, and counseling is provided on appropriate and safe use of OTC drugs.

Modular metabolic engineering for production of phloretic acid, phloretin and phlorizin in Escherichia coli

Phloretic acid, phloretin and phlorizin (phloretin 2′-O-glucoside), plant-derived natural products, are well known for human health benefits and medical application. Here, we construct an artificial biosynthetic pathway of phlorizin by modular engineering strategy and realize the production of phloretic acid, phloretin and phlorizin in Escherichia coli. Extending from L-tyrosine biosynthetic pathway, we firstly established the phloretic acid module comprised of heterologous TAL and ER enzymes, and highest titer of phloretic acid was achieved from glucose. Then, through biochemical screening of functional microbial Aa4CL and structure-based mutagenesis of MdCHS3 in phloretin module, we successfully constructed the phloretin biosynthetic pathway. Finally, we tested several glycosyltransferases in phlorizin module, and phloretic acid was bioconverted to phlorizin. This is the first report on biosynthesis of phloretin and phlorizin in engineered E. coli, indicating the promising potential of microbial cell factories to produce natural and unnatural dihydrochalcones.

Synthetic biology for the synthesis of aromatic natural products: a review

Plant-derived aromatic natural products have important medicinal value and can be made into pharmaceutical and healthcare products with antibacterial, anti-inflammatory, analgesic, anti-oxidative, insecticidal and anthelmintic, expectorant and cough suppressant, tranquilizer and antitumor effects. However, the low content of aromatic natural products in plants and the difficulty and high costs in extraction and purification hampered its large-scale production and application. Recent advances in synthetic biology and metabolic engineering have enabled the tailor-made production of aromatic natural products using engineered microbial cell factories. This review summarizes the categories, the synthetic pathways, the key enzymes and the synthetic biology strategies for production of aromatic natural products, and discusses the challenges and opportunities in this area.

Synthetic biology of plants-derived medicinal natural products

Medicinal natural products derived from plants are usually of low content and difficult to extract and isolate. Moreover, these compounds are structurally complex, making it difficult to obtain them by environmental unfriendly chemical synthesis. Biosynthesis of medicinal natural products through synthetic biology is a novel, environment-friendly and sustainable approach. Taking terpenoids (ginsenosides, paclitaxel, artemisinin, tanshinones), alkaloids (vincristine and morphine), and flavonoids (breviscapine) as examples, this review summarizes the advances of the biosynthetic pathways and synthetic biology strategies of plant-derived medicinal natural products. Moreover, we introduce the key technologies and methods of synthetic biology used in the research of medicinal natural products, and provide future prospects in this area.

Classification and Identification of Essential Oils from Herbs and Fruits Based on a MOS Electronic-Nose Technology

The frequent occurrence of adulterated or counterfeit plant products sold in worldwide commercial markets has created the necessity to validate the authenticity of natural plant-derived palatable products, based on product-label composition, to certify pricing values and for regulatory quality control (QC). The necessity to confirm product authenticity before marketing has required the need for rapid-sensing, electronic devices capable of quickly evaluating plant product quality by easily measurable volatile (aroma) emissions. An experimental MAU-9 electronic nose (e-nose) system, containing a sensor array with 9 metal oxide semiconductor (MOS) gas sensors, was developed with capabilities to quickly identify and classify volatile essential oils derived from fruit and herbal edible-plant sources. The e-nose instrument was tested for efficacy to discriminate between different volatile essential oils present in gaseous emissions from purified sources of these natural food products. Several chemometric data-analysis methods, including pattern recognition algorithms, principal component analysis (PCA), and support vector machine (SVM) were utilized and compared. The classification accuracy of essential oils using PCA, LDA and QDA, and SVM methods was at or near 100%. The MAU-9 e-nose effectively distinguished between different purified essential oil aromas from herbal and fruit plant sources, based on unique e-nose sensor array responses to distinct, essential-oil specific mixtures of volatile organic compounds (VOCs).

Potent antioxidant and anticancer activities of the methanolic extract of Calligonum comosum (L'Her) fruit hairs against human hepatocarcinoma cells.

Cancer is a devastating and aggressive disease that is globally ranked as the second-leading cause of deaths despite the relentless efforts being directed towards the discovery of novel chemotherapeutic drugs. Plants naturally produce a plethora of secondary metabolites that play a crucial role as effective therapeutic agents. Cancer treatment rely primarily on chemo- and radio-therapeutic strategies that suffers from known side effects. Recently, the strategy of controlling cancer progression by use of plant-derived natural products have extensively attracted research interests. In this study, the antioxidant and anticancer activities of the methanolic extract of Calligonum comosum (MeCc) fruit hairs were investigated. According to DPPH and ABTS assays, MeCc exhibited potent antioxidant capacity as it displayed significant free-radical scavenging activity. Results of the MTT cytotoxicity assay revealed that the MeCc exhibited potent anti-proliferation activity (IC50 = 10.4 µg/ml) that is specific against human hepatocarcinoma cells (HepG2), as only marginally harmful effect against non-cancerous control BJ-1 cells was detected. Results of the RT-qPCR gene expression analyses indicated that MeCc resulted in significant overexpression of mRNA transcript levels of the pro-apoptotic genes p53, caspase-3 and Bax, while downregulating the level of Bcl-2, an anti-apoptotic marker gene. Immunoblotting of the protein expression levels for the same markers showed similar pattern to that observed in RT-qPCR profiling. While the levels of p53, caspase-3 and Bax proteins exhibited significant increase, the protein level of Bcl-2 was significantly reduced. In conclusion, it is proposed that the observed specific anticancer activity of MeCc against HepG2 cells takes place via the engagement of apoptosis. This highlights the value of C. comosum as a source of potent natural anticancer agents and warrants further investigation to identify the active principals involved.

Inhibitory Effects of the Natural Product Esculetin on Phytophthora capsici and Its Possible Mechanism.

Esculetin is an important plant-derived natural product that has multiple bioactivities and applications. Phytophthora capsici is a notorious plant pathogen capable of infecting a broad range of hosts. In this study, we evaluated the antifungal activity of esculetin against P. capsici. The baseline sensitivity of P. capsici to esculetin was established using 108 isolates collected from various geographical regions in the Jiangsu and Shandong Provinces of China. The median effective concentration (EC50) values for esculetin ranged from 2.08 to 16.46 μg/ml (mean, 6.87 ± 2.70 μg/ml) and were normally distributed. Furthermore, both zoospore production and germination were strongly inhibited by esculetin. Importantly, esculetin exhibited protective as well as curative activities against P. capsici on tomato and was capable of restricting the early infection of P. capsici on Nicotiana benthamiana. We found that the esculetin treatment led to cell membrane damage of P. capsici, as revealed by morphological observations and measurements of relative conductivity and malondialdehyde (MDA). Finally, our results also suggested that esculetin may adversely affect P. capsici by inhibiting its DNA and protein synthesis. These findings will contribute to the broader evaluation of the use of esculetin to control diseases caused by P. capsici and toward a better understanding of its mode of action as a potential fungicide.

A Critical Review on Antiurolithiatic Activity of Bioactive Phytoconstituents

New drugs are introduced in the market every year and new diseases are emerging every year and there is no cure for existing diseases. Though new drugs are being approved by the FDA every year, controlling emerging infections is a global concern. Due to increased side effects and toxicity the modern world is turning towards herbal medicine. Due to few reasons like global warming, food habits and modern life style disease like Urolithiasis places a significant economic burden on the healthcare system, especially in developed and developing countries where, owing to changes in food habits and lifestyle, the prevalence of stone disease has significantly increased over the last few decades; unfortunately, it will probably continue to increase for a number of reasons. Despite considerable improvements in the development of new herbal therapies for the management of urinary stones, the incidence of urolithiasis is increasing worldwide. However, it is evident that crystal retention, cell apoptosis, renal cell injury, and associated stone promoters or inhibitors play important roles for kidney stone formation. In addition, the identification of novel phytoconstituents on the basis of molecular and cellular alterations in relation to stone formation will help develop better herbal remedies. Moreover, better understanding of the mechanisms of urolithiasis associated with stone inhibitors or promoters will be critical for stone-removing medications. This review encompasses different medicinal plants, polyherbal formulations and phytoconstituents used in the treatment of Kidney stones. More interdisciplinary research is needed to develop new plant-derived high-quality natural products to treat and prevent the formation of kidney stones.

Environmental toxicants, oxidative stress and health adversities: interventions of phytochemicals

Oxidative stress is the most common factor mediating environmental chemical-induced health adversities. Recently, an exponential rise in the use of phytochemicals as an alternative therapeutics against oxidative stress-mediated diseases has been documented. Due to their free radical quenching property, plant-derived natural products have gained substantial attention as a therapeutic agent in environmental toxicology. The present review aimed to describe the therapeutic role of phytochemicals in mitigating environmental toxicant-mediated sub-cellular and organ toxicities via controlling cellular antioxidant response. The present review has covered the recently related studies, mainly focussing on the free radical scavenging role of phytochemicals in environmental toxicology. In vitro and in vivo studies have reported that supplementation of antioxidant-rich compounds can ameliorate the toxicant-induced oxidative stress, thereby improving the health conditions. Improving the cellular antioxidant pool has been considered as a mode of action of phytochemicals. However, the other cellular targets of phytochemicals remain uncertain. Knowing the therapeutic value of phytochemicals to mitigate the chemical-induced toxicity is an initial stage; mechanistic understanding needs to decipher for development as therapeutics. Moreover, examining the efficacy of phytochemicals against mixer toxicity and identifying the bioactive molecule are major challenges in the field.

The Most Competent Plant-Derived Natural Products for Targeting Apoptosis in Cancer Therapy.

Cancer is a challenging problem for the global health community, and its increasing burden necessitates seeking novel and alternative therapies. Most cancers share six basic characteristics known as “cancer hallmarks”, including uncontrolled proliferation, refractoriness to proliferation blockers, escaping apoptosis, unlimited proliferation, enhanced angiogenesis, and metastatic spread. Apoptosis, as one of the best-known programmed cell death processes, is generally promoted through two signaling pathways, including the intrinsic and extrinsic cascades. These pathways comprise several components that their alterations can render an apoptosis-resistance phenotype to the cell. Therefore, targeting more than one molecule in apoptotic pathways can be a novel and efficient approach for both identifying new anticancer therapeutics and preventing resistance to therapy. The main purpose of this review is to summarize data showing that various plant extracts and plant-derived molecules can activate both intrinsic and extrinsic apoptosis pathways in human cancer cells, making them attractive candidates in cancer treatment.

Separation of salidroside from the fermentation broth of engineered Escherichia coli using macroporous adsorbent resins

Abstract Salidroside (8-O-β- d -glucoside of tyrosol), a plant-derived natural product, is used for treatment of hypoxia, fatigue and aging diseases. The availability of salidroside is restricted since it is extracted from 3-5 years old Rhodiola roots, which grow very slowly in the cold region of northern hemisphere of Earth. Our laboratory has constructed an engineered Escherichia coli and established a fermentation process to produce salidroside from glucose. In this article, nine macroporous resins from polarity to non-polarity, including NKA-9, S-8, AB-8, SP825, D101, LSA-8, LX-12, LX-18 and LX-68 resins, were tested to separate salidroside from fermentation broth. After static and dynamic experiments, the weakly polar SP825 resin had a better separation efficiency among nine resins. The adsorption kinetic and isotherm of salidroside on the SP825 resin were determined, and the pseudo-second-order kinetic model and Langmuir model could be fitted well. The effects of the pH on adsorption and ethanol concentration on desorption were investigated, and an optimal separation process was established. The adsorption for salidroside in the SP825 resin column was conducted with loading 150 ml at pH 7, and desorpted by washing 50 ml of 80% ethanol solution. Under the best process conditions, the purity and yield of salidroside in the final product were 91.6% and 74.0%, respectively. The results showed that the macroporous SP825 resin would be feasible and effective to prepare salidroside and has promising application in the downstream process of microbial fermentation. © 2020 The Chemical Industry and Engineering Society of China, and Chemical Industry Press Co., Ltd.. All rights reserved.

Temperate Zone Plant Natural Products-A Novel Resource for Activity against Tropical Parasitic Diseases.

The use of plant-derived natural products for the treatment of tropical parasitic diseases often has ethnopharmacological origins. As such, plants grown in temperate regions remain largely untested for novel anti-parasitic activities. We describe here a screen of the PhytoQuest Phytopure library, a novel source comprising over 600 purified compounds from temperate zone plants, against in vitro culture systems for Plasmodium falciparum, Leishmania mexicana, Trypanosoma evansi and T. brucei. Initial screen revealed 6, 65, 15 and 18 compounds, respectively, that decreased each parasite’s growth by at least 50% at 1–2 µM concentration. These initial hits were validated in concentration-response assays against the parasite and the human HepG2 cell line, identifying hits with EC50 < 1 μM and a selectivity index of >10. Two sesquiterpene glycosides were identified against P. falciparum, four sterols against L. mexicana, and five compounds of various scaffolds against T. brucei and T. evansi. An L. mexicana resistant line was generated for the sterol 700022, which was found to have cross-resistance to the anti-leishmanial drug miltefosine as well as to the other leishmanicidal sterols. This study highlights the potential of a temperate plant secondary metabolites as a novel source of natural products against tropical parasitic diseases.

Aspergillus oryzae Biosynthetic Platform for de Novo Iridoid Production.

The iridoids and their derivatives monoterpene indole alkaloids (MIAs) are two broad classes of plant-derived natural products with valuable pharmaceutical properties. However, the poor source limited their application. Nepetalactol, a common iridoid scaffold of MIAs, was heterologously produced in Saccharomyces cerevisiae. Although the optimization of nepetalactol production in S. cerevisiae was achieved by metabolic engineering, the inherent metabolic constraints impose a restriction on the production. Herein, we developed a high nepetalactol-producing Aspergillus oryzae platform strain. First, the co-expression of 5 nepetalactol biosynthetic genes, in a high isopentenyl pyrophosphate (IPP)-producing strain A. oryzae AK2, succeeded in the biosynthesis of nepetalactol. Second, the improvement of the IPP supply and the suppression of the byproduct citronellol formation were simultaneously achieved. Finally, the highest titer of nepetalactol of 7.2 mg/L was obtained with the engineered strain, after the optimization of the carbon source. To the best of our knowledge, this is the highest reported titer of nepetalactol in microbial cells. The developed A. oryzae strain represents an attractive biosynthetic platform host for the de novo production of iridoids and MIAs.

Systems Biology and Multi‐Omics

Systems Biology and Multi‐Omics