Progress 10/01/23 to 09/30/24
Outputs
PROGRESS REPORT Objectives (from AD-416): 1. Discover bioactive pesticides (fungicidal and herbicidal) that enhance quality and marketability of small fruits and specialty crops. 1.1. Discover novel biofungicides and bioherbicides from crude extract screening and bioassay-directed isolation approaches. 1.2. Isolation and identification of antifungal metabolites from actinomycete fermentation for control of important fungal plant pathogens. 1.3. Investigation of plant pathogenic fungi for phytotoxic and antifungal activities and synthetic modification of the isolated compounds to gain insights into structure-activity relationships. 2. Determine plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations. 2.1. Target medicinal and aromatic plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations. Approach (from AD-416): The long-term objectives of this project are to identify, chemically characterize, and develop new weed and plant pathogen managing biochemical biopesticides from natural sources and enhance or optimize commercially important bioactive compound concentrations. Plant and microbial extracts will be sourced using a variety of approaches and methods as evidenced through previous publications by the authors. These extracts will be subjected to in-house bioassays which include both antifungal and herbicidal based assays as described below. A bioassay-guided investigative approach will be performed on bioactive extracts in an effort to identify the specific natural compound(s) responsible for the activity of the extract(s). In-house high-throughput bioassays will be utilized to identify bioactive constituents with antifungal and herbicidal activities. A second component of this project pertains to natural products obtained from medicinal and aromatic crops which are low-volume high-value commodities that have numerous applications in various industries such as food, beverage, food supplement, flavor and fragrance, perfumery and cosmetics, pharmaceutical, aromatherapy, and various consumer products. Sourcing these and other natural compounds in an economical manner directly from plants is constantly evolving which creates an opportunity for small and mid-size farms. This is the fourth year of research for this project. This report also includes progress made as part of the outgoing agreement with the National Center for Natural Products Research (NCNPR) at the University of Mississippi in Oxford, Mississippi. This will also be the second year to report on progress made as part of the new outgoing agreement with Marshall University. For objective 1, discover bioactive pesticides (fungicidal and herbicidal) that enhance quality and marketability of small fruits and specialty crops, milestones have been met and significant progress has been made. Anthracnose, caused by a fungal pathogen Colletotrichum fragariae is an economically important disease affecting strawberries globally, causing substantial losses in yield and fruit quality. The study was conducted to identify essential oils (EOs) with antifungal properties against C. fragariae and other plant pathogenic fungi. We identified 20 plant EOs with antifungal activity against anthracnose pathogens. Among these, patchouli EO (Pogostemon cablin) was further explored, and the major constituent⿿s patchouli alcohol exhibited antifungal activity against C. fragariae (isolate cf63) as well as other two pathogens C. gloeosporioides (another Colletotrichum species that cause anthracnose) and Botrytis cinerea (gray mold). Both the whole patchouli EOs and its major constituent, patchouli alcohol, can be used to manage anthracnose disease in strawberries. Another minor constituents of patchouli EO called pogostone was also identified and exhibited a strong antifungal activity against C. fragariae, C. gloeosporioides, and B. cinerea. Pogostone also exhibited a strong phytotoxicity and therefore can be used as a herbicide. The mode of action for both herbicidal and fungicidal is underway. In an effort to discover alternatives to chemical fungicides, our unit is exploring beyond small fruits crop to field crops like sugarbeet. Our unit was funded with a FY 2024 National Plant Disease Recovery System (NPDRS) proposal fund that was submitted to the office of National Programs (ONP). The proposal has been approved for funding in the amount of $25,730. This funding will support research aimed at identifying natural products (non-chemical methods) to control postharvest pathogens in sugarbeet, contributing to improved crop management and sustainability. Soybean is one of the most economically important crops worldwide. However, soybean yield can be substantially decreased by many diseases. Soybean genotypes could have different reactions to pathogen infection. As a first step toward investigating the biochemical basis of soybean resistance and susceptibility to disease, phytochemicals in the seeds of 52 soybean genotypes previously reported to have different reactions to diseases of soybean rust (SBR), Phomopsis seed decay (PSD), and purple seed stain (PSS) were analyzed. This is a collaborative project with Dr. Shuxiang Li from CGRU, ARS, USDA in Stoneville, Mississippi. For objective 2, determine plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations, milestones have been met and significant progress has been made. Yerba Santa (Eriodictyon californicum) stands as a testament to the rich botanical diversity and medicinal heritage of the western United States. Its leaves are a potentially rich source of natural flavonoids with possible medical value. In collaboration with NCNPR, University of Mississippi, we have isolated 20 novel compounds and many known compounds. The medicinal properties for prevention and treatment of inflammatory diseases and metabolic disorders, along with antifungal and phytotoxicity against plants are currently under investigation. Moreover, in collaboration with Scientific Ecological Services (a private company in Ontario, OR), we are leveraging chemical analysis and quality standards set forth by NPURU at ARS, USDA, to enhance flavonoid content through optimized cultivation practices. This partnership aims to identify superior varieties suitable for potential use in herbal supplements, thereby harnessing the full therapeutic potential of Yerba Santa. Beyond its culinary prowess, scientific research has increasingly recognized the potential of turmeric (Curcuma longa) and curcumin in promoting overall health and well-being. Through collaborative efforts with the NCNPR, University of Mississippi, Alabama A&M University, and industry partners (such as doTERRA International LLC), a unique cultivar of Curcuma has been identified. This cultivar has significantly higher levels of turmerones and curcuminoids, up to double the usual amounts. Furthermore, it contains a specific class of volatiles derived from Curcuma, which act as efflux inhibitors, enhancing the bioavailability of curcuminoids. Despite its significant nutritional and economic value, peanut (Arachis hypogaea L.) confronts challenges in post-harvest storage. Research indicates that storage induces the formation of deleterious oxidation products, impacting viability and growth, and posing health concerns. The oxidation products also substantially modify peanuts⿿ chemical composition, affecting flavor, shelf life, and nutritional value. However, the specific identities of oxidation products remain elusive, and the relationship between storage duration, oxidation product formation, and their effects on cultivation and nutritional quality is not well understood. Collaborating with an ARS researcher in Griffin, Georgia, our investigation unveiled a direct correlation between the storage duration of peanuts and the accumulation of oxidation products. In addition, the oxidation products have also been identified. University of Mississippi Non-Assisted Cooperative Agreement: Eight hundred eight plant samples were added to our plant repository this year ⿿ one of which was a sample identified and collected in Oxford, Mississippi, and over 2,500 natural product crude extracts, semi-purified fractions, and purified compounds were screened for biological activities against specific molecular targets and whole-cell systems. As part of our continuing effort in the search for anti-infective, cancer chemopreventive, and immunomodulatory/anti-inflammatory leads from natural sources, more than 40 compounds were isolated from 11 extracts, with three showing promising activity against drug-resistant Enterococci, Streptococci, and Staphylococci strains and two exhibiting activities against Plasmodium falciparum, sans cytotoxicity to mammalian cells. Also, 16 compounds were tested against a panel of transcription factors involved in cancer signaling pathways, of which 4 had potent anticancer activity. Characterization and development of immunomodulatory natural products. A major focus of this research program is the continued evaluation of the botanical Limnospira/Arthrospira (common name spirulina) for enhancing host immune resilience to respiratory viral infection. Ongoing efforts support the development of Immulina®, a patented Arthrospira extract that was previously discovered at the NCNPR (commercially available as a dietary supplement). An awarded NIH Botanical Dietary Supplements Research Center grant (2020-2025, umbdsrc.org) and Administrative Supplement has allowed the formation of a multi-disciplinary team of investigators to perform in depth chemical analysis and biological studies (both in vitro and in vivo animal studies) on this botanical product. Preclinical data from mouse studies indicate that Immulina® is most effective at alleviating illness caused by influenza when administered as a prophylactic (before infection) and as a prodromal supplement (soon after initial infection during the asymptomatic period). However, it is not effective as a therapeutic agent (post-infection during the symptomatic phase). Additionally, our team continued with human clinical biomarker-based studies on Immulina® during this period, and these studies will continue through the remainder of the funded Botanical Center grant. Marshall University Non-assisted Cooperative agreement: A Director for the Appalachian Natural Products Research Program (ANPRP) has been hired, and she will start in September 2024. Efforts are currently underway to hire technical staff to support the project. Additional supplies and equipment to support the ANPRP are in the process of being ordered in consultation with the Director. The primary investigator also visited the National Center for Natural Products Research in Oxford, Mississippi, for additional advice on advancing this project. Plant material collection is continuing in FY24. We have collected over 10 species of plants this growing season from southern West Virginia and are still collecting plant material during this growing season. We anticipate having 25+ species on hand for extraction by the end of the growing season. We are in contact with a West Virginia native plant association and local individuals knowledgeable in medicinal plants to help guide our selection of plants for study. ACCOMPLISHMENTS 01 Glucose uptake enhancing property of capsiate from peppers. In support of a process ARS researchers at Oxford, Mississippi, patented two years ago to produce pure capsiate from peppers, we investigated the effects of a Capsicum annuum extract and pure capsiate on metabolic disorder important receptors. The findings from this study suggest that capsiate will enhance glucose uptake effect and prevent lipid accumulation. Additionally, capsiate could inhibit the adverse effect of blood glucose lowering drugs belonging to thiazolidinediones class without compromising their main effects. This is the first report to reveal the multiple nuclear receptors agonistic action and glucose uptake enhancing property of capsiate from C. annuum along with its antiadipogenic effect indicating its potential in preventing the undesired adipogenic effects of full PPAR gamma agonists such as the glitazone class of antidiabetic drugs. This study was published this year in the Journal of Agricultural Food and Chemistry. 02 Analytical method for detecting adulterated peppermint essential oil. Peppermint essential oil (EO) is extensively utilized in the food and beverage industry. Despite its wide acceptance and economic significance, peppermint EO stands out as one of the most commonly adulterated essential oils in the United States market. At the request of doTERRA International LLC, ARS researchers at Oxford, Mississippi, collaborated with the National Center for Natural Products Research (NCNPR) at the University of Mississippi to develop an integrated approach combining conventional and chiral gas chromatography⿿mass spectrometry with chemometrics for assessing the quality of peppermint EOs. Using this method, poor quality or adulterated peppermint EOs can be unambiguously identified in the commercial products sold in United States market. This study was published this year in the Journal of Agricultural Food and Chemistry.
Impacts
(N/A)
Publications
- Chae, H., Cantrell, C.L., Khan, I.A., Jarret, R.L., Khan, S.I. 2023. Capsiate-rich fraction of Capsicum annuum induces muscular glucose uptake, ameliorates rosiglitazone-induced adipogenesis, and exhibits activation of NRs regulating multiple signaling pathways. Journal of Agricultural and Food Chemistry. https://doi.org/10.1021/acs.jafc.3c06148? urlappend=%3Fref%3DPDF&jav=VoR&rel=cite-as.
- Semerdjieva, I., Cantrell, C.L., Zheljazkov, V.D., Radoukova, T., Koleva- Valkova, L.H., Astatkie, T., Kacaniova, M., Borisova, D. 2023. Chemical profile, antioxidant and antimicrobial activity of Pinus heldreichii Christ. distributed in Bulgaria. Heliyon. 10:1-15. https://doi.org/10.1016/ j.heliyon.2023.e22967.
- Tan, L., He, Y., Li, S., Deng, J., Avula, B., Zhang, J., Nirmal, P.D., Solis-Sainz, J., Wang, M. 2023. Proximate composition and nutritional analysis of selected bananas cultivated in Hainan, China. Journal of Food Composition and Analysis. https://doi.org/10.1016/j.jfca.2023.105798.
- Liang, W., Wang, Q., Min, L., Han, L., Cantrell, C.L., Bajsa Hirschel, J.N. , Duke, S.0., Ye, P., Liu, X. 2023. Synthesis, herbicidal activity and in silico analysis of novel pyrido[2,3-d]pyrimidine compounds. Molecules. https://doi.org/10.3390/molecules28217363.
- Sun, N., Min, L., Sun, Z., Zhai, Z., Bajsa Hirschel, J.N., Wei, Z., Hua, X. , Cantrell, C.L., Xu, H., Duke, S.O., Liu, X. 2024. Novel pyrazole acyl(thio)urea derivatives containing a biphenyl scaffold as potential succinate dehydrogenase inhibitors: Design, synthesis, fungicidal activity and SAR. Journal of Agricultural and Food Chemistry. 72:2512-2525. https:// doi.org/10.1021/acs.jafc.3c07735.
- Sun, X., Yu, C., Li-Jing, M., Cantrell, C.L., Hua, X., Sun, N., Liu, X. 2023. Discovery of highly efficient novel antifungal leads targeting succinate dehydrogenase: pyrazole-4-carboxamide derivatives with an N- phenyl substituted amide fragment. Journal of Agricultural and Food Chemistry. 71:19312-19323. https://doi.org/10.1021/acs.jafc.3c04842.
- Adams, S.J., Lee, J., Avula, B., Katragunta, K., Wang, M., Parveen, I., Techen, N., Chittiboyina, A., Khab, I. 2023. Investigation of morpho- anatomical, molecular, GC/QToF, and LC/QToF characterization of Salvia mellifera (black sage), Saliva apiana (white sage) and their varieties. South African Journal of Botany. 164:77-90. https://doi.org/10.1016/j.sajb. 2023.11.038.
- Ribeiro, V., Bajsa Hirschel, J.N., Tamang, P., Meepagala, K.M., Duke, S. 2023. Antifungal and phytotoxic activities of isolated compounds from Helietta parvifolia stems. Molecules. 28(23):7930. https://doi.org/10.3390/ molecules28237930.
- Tamang, P., Upadhaya, A., Paudel, P., Meepagala, K.M., Cantrell, C.L. 2024. Mining Biosynthetic Gene Clusters of Pseudomonas vancouverensis Utilizing Whole Genome Sequencing. Microorganisms. 12:1-17. https://doi.org/10.3390/ microorganisms12030548.
- Paudel, P., Pandey, P., Paris, J.J., Ashpole, N.M., Mahdi, F., Tian, J., Lee, J., Wang, M., Xu, M., Chittiboyina, A.G., Khan, I.A., Ross, S.A., Li, X. 2023. Cannabinoid receptor type II ligands from sandalwood oil and synthetic alpha-santalol derivatives. Journal of Natural Products. https:// doi.org/10.1021/acs.jnatprod.3c00282.
- Moreau, T., Denning, S., Byrne, P., Volk, G.M. 2023. Climate change impacts agricultural productivity and food security. In: Volk, G.M., Moreau, T.L., Byrne, P.F., editors. Conserving and Using Climate-Ready Plant Collections. Fort Collins, Colorado: Colorado State University. Available: https://colostate.pressbooks.pub/climatereadyplantcollections/ chapter/agricultural-productivity-and-food-security/
- Cantrell, C.L., Travaini, M., Bajsa Hirschel, J.N., Svendsen, L.D., Reichley, A.C., Sosa, G.M., Kim, S., Tamang, P., Meepagala, K.M., Duke, S. O. 2023. Synthesis, Herbicidal Activity, and Structure-Activity Relationships of O-Alkyl Analogues of Khellin and Visnagin. Journal of Agriculture and Food Chemistry. 71:14593-14603. https://doi.org/10.1021/ acs.jafc.3c03254.
- Duke, S.O. 2023. Why are there no widely successful microbial bioherbicides for weed management in crops?. Pest Management Science. 80:56-94. https://doi.org/10.1002/ps.7595.
- Aydogan, F., Boga, M., Khan, S.I., Zulfiqar, F., Khan, I.A., Ali, Z. 2022. Phytochemical investigation of Teucrium pruinosum and biological potential assessment of the isolated diterpenoids. Biochemical Systematics and Ecology. 105:1-4. https://doi.org/10.1016/j.bse.2022.104545.
- Haron, M.H., Zhang, J., Chittiboyina, A.G., Khan, I.A., Pugh, N.D. 2023. Validation of a Toll-like receptor (TLR)2/TLR1 activation assay for biological standardization of Arthrospira/Limnospira immune-enhancing potency. Journal of Dietary Supplements. https://doi.org/10.1080/19390211. 2023.2263566.
- Parveen, I., Wang, M., Zhao, J., Zhu, Y., Chittiboyina, A.G., Khan, I.A., Pan, Z. 2024. Identification and functional characterization of oxidosqualene cyclases from medicinal plant Hoodia gordonii. Plants. 13(2) :231. https://doi.org/10.3390/plants13020231.
- Soltani, A., Ospanov, M., Ibrahim, Z.M., Bajsa Hirschel, J.N., Cantrell, C. L., Cizdziel, J.V., Khan, I.A., Ibrahim, M.A. 2024. Menthalactone from Mentha piperita L., a Monocot-Selective Bioherbicide. International Journal of Plant Biology. 15:293-303. https://doi.org/10.3390/ijpb15020025.
- Akins, N.S., Mohammed, S.F., Pandey, P., Kim, S., Mahdi, F., Khan, M.H., Moss, E., Worth, C.J., Keanne, M.M., Chittiboyina, A.G., Doerksen, R.J., Paris, J.J., Le, H.V. 2023. Alleviation of cocaine withdrawal and pertinent interactions between salvinorin-based antagonists and kappa opioid receptor. ACS Chemical Neuroscience. https://doi.org/10.1021/ acschemneuro.2c00806.
- Khan, M.H., Mahdi, F., Penformis, P., Akins, N.S., Hossain, M., Kim, S., Sulochana, S.P., Adam, A.T., Tran, T.D., Tan, C., Claudio, P., Paris, J.J., Hoang, L.V. 2022. Synthesis and biological evaluation of tert-butyl ester and ethyl ester prodrugs of L-gamma-methyleneglutamic acid amides for cancer. Bioorganic and Medicinal Chemistry. https://doi.org/10.1016/j.bmc. 2022.117137.
- Thoma, J., Cantrell, C.L., Tamang, P., Zheljazkov, V.D. 2023. Determining the optimum mixture of three essential oils for potato sprout suppression at room temperature storage. Frontiers in Plant Science. https://doi.org/ 10.3389/fpls.2023.1199117.
- Wang, M., Lee, J., Zhao, J., Lee, J., Chatterjee, S., Chittiboyina, A.G., Ali, Z., Khan, I.A. 2023. Comprehensive quality assessment of peppermint oils and commercial products: An integrated approach involving conventional and chiral GC/MS coupled with chemometrics. Journal of Chromatography B. 1232:123953. https://doi.org/10.1016/j.jchromb.2023. 123953.
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Progress 10/01/22 to 09/30/23
Outputs
PROGRESS REPORT Objectives (from AD-416): 1. Discover bioactive pesticides (fungicidal and herbicidal) that enhance quality and marketability of small fruits and specialty crops. 1.1. Discover novel biofungicides and bioherbicides from crude extract screening and bioassay-directed isolation approaches. 1.2. Isolation and identification of antifungal metabolites from actinomycete fermentation for control of important fungal plant pathogens. 1.3. Investigation of plant pathogenic fungi for phytotoxic and antifungal activities and synthetic modification of the isolated compounds to gain insights into structure-activity relationships. 2. Determine plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations. 2.1. Target medicinal and aromatic plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations. Approach (from AD-416): The long-term objectives of this project are to identify, chemically characterize, and develop new weed and plant pathogen managing biochemical biopesticides from natural sources and enhance or optimize commercially important bioactive compound concentrations. Plant and microbial extracts will be sourced using a variety of approaches and methods as evidenced through previous publications by the authors. These extracts will be subjected to in-house bioassays which include both antifungal and herbicidal based assays as described below. A bioassay-guided investigative approach will be performed on bioactive extracts in an effort to identify the specific natural compound(s) responsible for the activity of the extract(s). In-house high-throughput bioassays will be utilized to identify bioactive constituents with antifungal and herbicidal activities. A second component of this project pertains to natural products obtained from medicinal and aromatic crops which are low-volume high-value commodities that have numerous applications in various industries such as food, beverage, food supplement, flavor and fragrance, perfumery and cosmetics, pharmaceutical, aromatherapy, and various consumer products. Sourcing these and other natural compounds in an economical manner directly from plants is constantly evolving which creates an opportunity for small and mid-size farms. This is the third year of research for this project. This report also includes progress made as part of the NACA with the National Center for Natural Products Research (NCNPR) at the University of Mississippi in Oxford, Mississippi. This will also be the first year to report on progress made as part of the new NACA with Marshall University. For objective 1, discover bioactive pesticides (fungicidal and herbicidal) that enhance quality and marketability of small fruits and specialty crops, milestones have been met and significant progress has been made. Anthracnose is an economically important disease that affects strawberries globally and can lead to significant losses in both yield and fruit quality. The objective of this study is to identify EOs with antifungal properties against C. fragariae and other pathogenic fungi. We found 20 plant EOs has antifungal activity against anthracnose pathogens. Among these 20 EOs, the patchouli EOs (Pogostemon cablin) was further studied, and the major constituent⿿s patchouli alcohol exhibited antifungal activity against C. fragariae (isolate cf63) as well as other two pathogens C. gloesoporioides (one of the fungus that cause anthracnose in strawberries) and Botrytis cinerea that cause gray mold in strawberries. Either whole Patchouli EOs or its major constituent⿿s patchouli alcohol can be used to manage anthracnose disease in strawberries. Nicotine is a class of pyridine type natural products which was first found in tobacco. Nicotine has the effects of killing insects and regulating human physiological activities. Nicotine is also an important intermediate in the synthesis of the natural product niacin and niacinamide, which are essential vitamins for human. Nicotine acid derivatives can be found in many plant or microbial secondary metabolites. In order to discover lead compounds with high fungicidal or herbicidal activity, new niacinamide derivatives containing chiral flexible chains were designed and synthesized derived from the natural product niacinamide. The fungicidal and herbicidal activities of these compounds were tested. The fungicidal activity results demonstrated that the compound (S)-2-(2-chloronicotinamido)propyl-2-methylbenzoate exhibited good fungicidal activity (92.3% inhibition) against the plant pathogen Botryosphaeria berengriana at 50 µg/mL and the EC50 is 6.68±0.72 µg/mL, which is the same as the positive control (fluxapyroxad). This compound was not phytotoxic and could therefore be used as a fungicide on crops. Structure-activity relationships (SAR) were studied by molecular docking simulations with the succinate dehydrogenase of the fungal mitochondrial respiratory chain. Natural pesticides can provide an alternative approach for managing pests and diseases, as they often have different modes of action and lower toxicity to non-target organisms, such as beneficial insects, birds, and mammals. Yerba santa, meaning ⿿holy weed or ⿿sacred herb in Spanish, is a common name for several plant species in the Eriodictyon genus. The plants are native to western North America and their leaves have historically been used for centuries to treat various aliments among indigenous people of the region. Our studies on this plant species revealed that these plant species contain diverse groups of constituents, many of which have not been previously described. More than 10 novel compounds were isolated. Studies using germination and plant growth bioassays suggested that extracts and fractions of yerba santa possessed strong herbicidal activity against lettuce (Lactuca sativa), creeping bentgrass (Agrostis stolonifera), and ryegrass (Lolium multiflorum). These newly discovered activities from the extracts and fractions suggested the existence of desirable herbicidal compound(s) in yerba santa. In our previous work we have shown occurrence of antifungal and phytotoxic activities in the seeds of some Apiaceae plant family. We have investigated the antifungal constituents that can be used to control post- harvest decay of fruits and vegetables. Some of these constituents are essential oils and thus have high vapor pressure making them potential sources of fumigants. Most of the seeds we investigated have been used in culinary industry for long periods of time and ca be considered as non- toxic chemicals. We are making synthetic analogs of 4- isopropylbenzaldehyde, 4-isopropyl benzoic acid, 4-isopropylbenzyl alcohol, 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enone, apiol and elemicin that have been isolated from the seeds of the plants in Apiaceae family. For objective 2, determine plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations, milestones have been met and significant progress has been made. The non-pungent analogs of capsaicinoids, were first identified in fruit of Capsicum annuum. Recent studies have reported that various biological activity characteristics of capsaicinoids are also characteristic of capsinoids albeit with less of the adverse effects associated with pungency. In support of a process NPURU patented last year, we investigated the effects of a C. annuum extracts and pure capsiate on metabolic disorder important receptors. The findings from this study suggest that capsiate will enhance glucose uptake effect and prevent lipid accumulation. Additionally, capsiate could inhibit the adverse effect of blood glucose lowering drugs belonging to thiazolidinediones class without compromising their main effects. This is the first report to reveal the multiple nuclear receptors agonistic action and glucose uptake enhancing property of capsiate from C. annuum along with its antiadipogenic effect indicating its potential in preventing the undesired adipogenic effects of full PPAR¿ agonists such as the glitazone class of antidiabetic drugs. In recent years, the popularity of copaiba oil-resin has increased worldwide due to its medicinal value and wide applications in industry. Despite its popularity, the oil has not been standardized by industry or regulatory agencies. Product adulteration in order to maximize profits has become a problem. To address these issues the current study describes the chemical and chemometric characterization of forty copaiba oil-resin samples by GC/MS. The commercial samples detected as outliers were further subjected to analysis using an SFC/MS method. Product adulteration with soybean oil was clearly detected, with each individual triglyceride in soybean oil being unambiguously identified. By combining these analytical techniques, the overall quality of copaiba oil can be assessed. University of Mississippi NACA - This year 1,081 plant samples were tested for biological activity in high-throughput assays. From the initial results, 9 samples were selected for advanced testing. To probe their immunomodulatory potential, 126 (including microalgae, kelp, mushrooms and plants) were evaluated in cell-based assays to detect activation/inhibition of molecular pathways in innate immune cells and redox homeostasis. Additionally, by implementing high throughput signal transduction metabolic panel assays, more than 10 pure phytochemicals were screened specifically for anticancer properties. Over 100 compounds were evaluated in a mechanistic assay designed to identify agents that modify the fungal cell wall. Hit compounds will be confirmed in beta- glucan unmasking assays, and advanced to in vivo studies for investigating their effects on the fungal microbiome in a mouse model of diabetes. The goal of this project is to identify natural products that can prevent microbiome-derived fungal infections associated with metabolic diseases. Mechanistic assays evaluating the inhibition of rate-limiting steps of the glycolytic pathway enzymes viz., hexokinase, phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase, have been setup and over 10 lead compounds were screened for these enzyme(s) inhibitory potential. The goal of this project is to identify the mechanism responsible for the glycolytic inhibitory potential of these lead compounds and to use these enzymes as biomarkers in translational studies. Marshall University NACA - The initial approach of growing plants locally for study has been replaced by an approach of directly collecting or purchasing materials from qualified collectors of targeted plants/ trees in West Virginia with appropriate collecting permits. It was felt that the agricultural aspect of the project should be a later phase, once positive results were obtained from plants extracts/purified compounds. Artificial Intelligence (AI)/Machine Learning (ML) No artificial intelligence or machine learning methods were used. ACCOMPLISHMENTS 01 Melissa officinalis essential oil as an effective potato sprout inhibitor. Potato (Solanum tuberosum L.) is the most important noncereal staple crop in the world and is the main contributor toward improving food security and reducing hunger. Control of sprouting is critical for potato storage since the sprouting leads to alterations in weight, texture, nutritional value, softening, shrinkage, and formation of toxic alkaloids. The primary methods for controlling sprouting of stored potatoes are by using sprout-inhibiting chemicals that are effective. Chlorpropham (CIPC) is the most efficient and cost effective; however, ARS researchers in Oxford, Mississippi, have shown that CIPC and its degradation products are hazardous for consumer health and the environment. The goal of this project was to identify plant essential oils (EOs) as sprout inhibitors or suppressors in potato (Solanum tuberosum L.). The results indicated that Melissa officinalis L. EO inhibited sprouting. The pure isolated compounds, together with the major compound in M. officinalis EO (citral), were tested for sprout suppression on three potato cultivars (Ranger Russet, Terra Rosa, and Dakota TrailBlazer), which revealed that beta-citronellol reduced the sprout length and the number of sprouts in all three cultivars, while citral and (+)-alpha-terpineol reduced the sprout length and the number of sprouts in Ranger Russet relative to the two controls in all three cultivars. This is the first report on the use of Melissa officinalis L. EO as a sprouting inhibitor. Melissa officinalis whole EO can be utilized for the development of a new commercial products for sprout control of potatoes. Such products would reduce toxic chemical residues in potatoes and contribute to improved human and environmental health. 02 Establishment of quality control standards for Eriodictyon sp. Eriodictyon species, commonly known as yerba santa, are plants native to the Southwestern United States and northern Mexico. The plants are known for their medicinal properties and have been used by indigenous people for centuries to treat various ailments, particularly respiratory conditions. Despite a long history of traditional use, a full chemical characterization of many of the species is lacking. In addition, the constituent range of these species has not been comprehensively reported. ARS researchers in Oxford, Mississippi, initiated this investigation at the request of the American Herbal Pharmacopoeia (AHP) to develop analytical methods for the chemical characterization and quantitative determination of the primary constituents in yerba santa (Eriodictyon spp.). Over 100 plant samples were collected by 18 scientists/botanists and two companies from California, Arizona, Oregon, and New Mexico to give a comprehensive data set. Our study describes the development and validation of an UHPLC/DAD/MS method for the investigation of 111 samples belonging to six different Eriodictyon species, viz., E. californicum, E. angustifolium, E. trichocalyx, E. crassifolium, E. tomentosum, E. traskiae, and E. capitatum. Fourteen compounds, comprised of flavonoids and phenolic acids, were quantified. To the best of our knowledge, this work encapsulates the most comprehensive data set currently available for the chemical characterization and quantification of the primary constituents in Eriodictyon species. This work has been reported as part of the ⿿American Herbal Pharmacopoeia and Therapeutic Compendium- Yerba Santa Leaves & Tops Eriodictyon californicum and related species- Standards of Identity, Purity, Analysis, and Quality Control.
Impacts
(N/A)
Publications
- Shi, H., Zhai, Z., Min, L., Han, L., Sun, N., Cantrell, C.L., Bajsa Hirschel, J.N., Duke, S.O., Liu, X. 2022. Synthesis and pesticidal activity of new 1,3,4-oxadiazole thioether compounds containing a trifluoro-methylpyrazoyl moiety. Research on Chemical Intermediates. https://doi.org/10.1007/s11164-022-04839-x.
- Semerdjieva, I.B., Radoukova, T., Cantrell, C.L., Astatkie, T., Kacanlova, M., Borisova, D., Zheljazkov, V.D. 2022. Essential oil composition of Pinus heldreichii Christ., P. peuce Griseb., and P. mugo Turra as a function of hydrodistillation time and evaluation of its antimicrobial activity. Industrial Crops and Products. 187(Part B). Article 115484. https://doi.org/10.1016/j.indcrop.2022.115484.
- Zhang, J., Agarwal, A., Feng, Q., Tripathi, S.K., Khan, I.A., Pugh, N.D. 2023. Identification of botanicals that unmask beta-glucan from the cell surface of an opportunistic fungal pathogen. Journal of Dietary Supplement. https://doi.org/10.1080/19390211.2023.2201355.
- Chae, H., Dale, O., Mir, T.M., Ashfaq, M.K., Avula, B., Walker, L.A., Khan, I.A., Khan, S.I. 2023. Juniper berry (Juniperus communis L.) extract regulates obesity markers through modulating PPAR-alpha, PPAR-gamma, and LXR: in vitro and in vivo effects. Journal of Medicinal Food. https://doi. org/10.1089/jmf.2022.0146.
- Sparks, T.C., Sparks, J.M., Duke, S.O. 2023. Natural product-based crop protection compounds - origins and future prospects. Journal of Agricultural and Food Chemistry. https://doi.org/10.1021/acs.jafc.2c06938.
- Husain, I., Dale, O.R., Martin, K., Gurley, B.J., Avula, B., Chittiboyina, A.G., Khan, I.A., Khan, S.I. 2022. Screening of medicinal plants for possible herb-drug interactions through modulating nuclear receptors, drug- metabolizing enzymes and transporters. Journal of Ethnopharmacology. https://doi.org/10.1016/j.jep.2022.115822.
- Pandey, P., Kumarihamy, M., Ibrahim, M.A., Ilias, M., Doerksen, R.J. 2023. In vitro and in silico studies of neolignans from Magnolia Grandiflora L. seeds against human cannabinoid and opioid receptors. Molecules. https:// doi.org/10.3390/molecules28031253.
- Avula, B., Katragunta, K., Osman, A.G., Ali, Z., Adams, S., Chittiboyina, A.G., Khan, I.A. 2023. Advances in the chemistry, analysis, and adulteration of anthocyanin rich-berries and fruits: 2000-2022. Molecules. https://doi.org/10.3390/molecules28020560.
- Cao, L., Wang, M., Zhao, J., Peng, L., Cheng, J., Qiu, S., Khan, I., Li, X. 2022. Comparative analysis of chemical profiles of Radix Astragali between ultrafine granular powder and traditional sliced mate-rials. Medicinal Plant Biology. https://doi.org/10.48130/MPB-2022-0004.
- Meepagala, K.M., Tamang, P. 2023. Antifungal activity of Poncirus trifoliata roots against Colletotrichum species. Agricultural Sciences. https://doi.org/10.4236/as.2023.143022.
- Drumond De Souza, L.M., Costa Barreto, D.L., Da Costa Coelho, L., Amancio Teixeira, E.A., Nicolau Goncalves, V., Muzetti Ribeiro, J.P., Gontijo Rabelo, N., De Oliveira Alves, S.E., Da Silva, L.M., Cantrell, C.L., Duke, S.O., Henrique Rosa, L. 2023. Fungal biosurfactants: applications in agriculture, medicine, industry and in environmental bioremediation processes. In: Marcelino, P.R.F., Da Silva, S.S., Lopez, A.O., editors. Biosurfactants and Sustainability: From Biorefineries Production to Versatile Applications. Hoboken, NJ:John Wiley & Sons Ltd. p 243-254.
- Costa Barreto, D., De Carvalho, C.R., De Almeida Alves, T., Zani, C., Cantrell, C.L., Duke, S.O., Rosa, L. 2023. Influence of genetics on the secondary metabolism of fungi. Natural Secondary Metabolites ⿿ from Nature, Through Science, to Industry. https://doi.org/10.1007/978-3-031-18587- 8_22.
- Matundura, J.O., Midiwo, J.O., Yenesew, A., Omosa, L., Kumarihamy, M., Zhao, J., Wang, M., Tripathi, S., Khan, S., Masila, V.M., Nchiozem- Ngnitedem, V., Muhammad, I. 2022. Antiplasmodial and antimicrobial activities of ent-abietane diterpenoids from the roots of Suregada zanzibariensis. Natural Product Research. https://doi.org/10.1080/14786419. 2022.2158463.
- Wang, M., Zhao, J., Avula, B., Lee, J., Upton, R., Khan, I. 2023. Chemical characterization and quantitative determination of flavonoids and phenolic acids in yerba santa (Eriodictyon spp.) using UHPLC/DAD/Q-ToF. Journal of Pharmaceutical and Biomedical Analysis. https://doi.org/10.1016/j.jpba. 2023.115570.
- Lee, J., Wang, M., Mondal, G., Khan, I.A., Yates, C.R. 2022. Development of a GC/Q-ToF method coupled with headspace solid-phase microextraction to evaluate the in vitro metabolism of ÿ-Caryophyllene. Molecules. https:// doi.org/10.3390/molecules27217441.
- Kumarihamy, M., Tripathi, S., Balachandran, P., Avula, B., Zhao, J., Wang, M., Bennett, M., Carr, M.A., Micheal, L., Ocean, W.I., Marquart, M.E., Nanayakkara, D., Muhammad, I. 2022. Synthesis and inhibitory activity of machaeridiol- based novel anti-MRSA and anti-VRE compounds and their profiling for cancer- related signaling pathways. Molecules. https://doi. org/10.3390/molecules27196604.
- Thoma, J., Cantrell, C.L., Zheljazkov, V.D. 2022. Evaluation of essential oils as sprout suppressants for potato (Solanum tuberosum) at room temperature storage. Plants. https://doi.org/10.3390/plants11223055.
- Thoma, J., Cantrell, C.L., Zheljazkov, V.D. 2022. Effects of essential oil fumigation on potato sprouting at room-temperature storage. Plants. https:/ /doi.org/10.3390/plants11223109.
- Lee, J., Wang, M., Zhao, J., Ali, Z., Hawwal, M., Khan, I. 2023. Chemical characterization and quality assessment of copaiba oil-resin using GS/MS and SFC/MS. Plants. https://doi.org/10.3390/plants12081619.
- Semerdjieva, I., Zheljazkov, V.D., Dincheva, I., Piperkova, N., Maneva, V., Cantrell, C.L., Astatkie, T., Stoyanova, A., Ivanova, T. 2023. Essential oil composition of seven Bulgarian Hypericum species and its potential as biopesticide. Plants. https://doi.org/10.3390/plants12040923.
- Min, L., Shen, Z., Bajsa Hirschel, J.N., Cantrell, C.L., Han, L., Hua, X., Liu, X., Duke, S.O. 2022. Synthesis, crystal structure, herbicidal activity and mode of action of new cyclopropane-1,1-dicarboxylic acid analogues. Pesticide Biochemistry and Physiology. https://doi.org/10.1016/ j.pestbp.2022.105228.
- Wei, Z., Wang, Q., Min, L., Bajsa Hirschel, J.N., Cantrell, C.L., Han, L., Tan, C., Weng, J., Liu, X., Duke, S.O. 2022. Synthesis and pesticidal activity of new niacinamide derivatives containing a flexible, chiral chain. Molecules. https://doi.org/10.3390/molecules28010047.
- Zheljazkov, V.D., Micalizzi, G., Yilma, S., Cantrell, C.L., Reichley, A.C., Mondello, L., Semerdjieva, I., Radoukova, T. 2022. Melissa officinalis L. as a sprout suppressor in Solanum tuberosum L. and an alternative to synthetic pesticides. Journal of Agriculture and Food Chemistry. https:// doi.org/10.1021/acs.jafc.2c05942.
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Progress 10/01/21 to 09/30/22
Outputs
PROGRESS REPORT Objectives (from AD-416): 1. Discover bioactive pesticides (fungicidal and herbicidal) that enhance quality and marketability of small fruits and specialty crops. 1.1. Discover novel biofungicides and bioherbicides from crude extract screening and bioassay-directed isolation approaches. 1.2. Isolation and identification of antifungal metabolites from actinomycete fermentation for control of important fungal plant pathogens. 1.3. Investigation of plant pathogenic fungi for phytotoxic and antifungal activities and synthetic modification of the isolated compounds to gain insights into structure-activity relationships. 2. Determine plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations. 2.1. Target medicinal and aromatic plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations. Approach (from AD-416): The long-term objectives of this project are to identify, chemically characterize, and develop new weed and plant pathogen managing biochemical biopesticides from natural sources and enhance or optimize commercially important bioactive compound concentrations. Plant and microbial extracts will be sourced using a variety of approaches and methods as evidenced through previous publications by the authors. These extracts will be subjected to in-house bioassays which include both antifungal and herbicidal based assays as described below. A bioassay-guided investigative approach will be performed on bioactive extracts in an effort to identify the specific natural compound(s) responsible for the activity of the extract(s). In-house high-throughput bioassays will be utilized to identify bioactive constituents with antifungal and herbicidal activities. A second component of this project pertains to natural products obtained from medicinal and aromatic crops which are low-volume high-value commodities that have numerous applications in various industries such as food, beverage, food supplement, flavor and fragrance, perfumery and cosmetics, pharmaceutical, aromatherapy, and various consumer products. Sourcing these and other natural compounds in an economical manner directly from plants is constantly evolving which creates an opportunity for small and mid-size farms. This is the second year of research for this project. For Objective 1, discover bioactive pesticides (fungicidal and herbicidal) that enhance quality and marketability of small fruits and specialty crops, milestones have been met and significant progress has been made. This report also includes progress made as part of the NACA with the National Center for Natural Products Research (NCNPR) at the University of Mississippi in Oxford, Mississippi. The genus Salvia includes around 900 species distributed throughout the world and is the largest genus in the economically and medicinally important plants of the Lamiaceae family. The secondary compounds of Salvia species have been extensively studied for numerous biological activities. The genus Salvia contains several allelopathic species and extracts from three of these species, Salvia miltiorrhiza, S. hispanica and S. columbariae, were tested in this study for phytotoxicity. Although there are several reports of phytotoxins from Salvia, there are no reports of phytotoxins against higher plants from Salvia miltiorrhiza. The abietane diterpenes tanshinone I and tanshinone IIA were identified as the compounds responsible for phytotoxicity. Natural products are a promising source for the development of new pesticides with alternative mechanisms of action. Sesquiterpene lactones (SLs) are one of the largest families of natural products and a broad range of bioactivities have already been reported. SLs are mainly isolated from the aerial parts of the family of the Compositae although they can also be found in other plant families, such as Umbelliferae, Lauraceae, and Magnoliaceae. Recent isolation studies have led to the discovery of a novel family of sesquiterpene lactones commonly named C17- sesquiterpenoids. In this study, we evaluated the phytotoxic and antifungal activity of a novel family of natural C17-sesquiterpenoids and examined the relationship between chemical structure and activity. Many tested compounds exhibited a strong, phytotoxic activity. Lappalone and pertyolide B were the most potent molecules from the tested group. Regarding the antifungal activity, pertyolide B presented significant activity against Colletotrichum fragareae and Fusarium oxysporum. Pesticides and fertilizers play crucial roles in modern agriculture. Due to the rapid evolution and spread of pesticide resistance, discovery and development of new pesticides with new structures and/or mechanisms of actions is needed. Heterocycles with nitrogen atoms are important structural units in many pesticides. Among them, 1,2,4-triazole is an important five-membered nitrogen-containing heterocycle which has led to the discovery of many agricultural fungicides used for crop protection such as propiconazole, tebuconazole, propiconazole, and cyproconazole. In a study in collaboration with colleagues in China, a series of 1,2,4- triazole derivatives containing dioxolane ring motif were designed and synthesized. Some of the synthetic 1,2,4-triazole derivatives exhibited good fungicidal and plant growth regulation activity. These new fungicides are structurally different from existing fungicides that act through inhibition of ergosterol synthesis. The antifungal activity of bacteria Psuedomonas vancouverensis isolated from a Farkleberry (Vaccinium arboreum) is being investigated. The bacterium Pseudomonas showed antifungal activity against the plant pathogenic fungi Colletotrichum fragariae, Botrytis cinerea, and Phomopsis obscurans on the PDA plate assay. The crude extracts also showed antifungal activity against C. fragariae in bioautography assay and now fractionation of the crude compound is under the way. Similarly, the antifungal constituents from a fungus Westerdykella multispora extracted from Sardis Lake are being investigated. The crude extracts from this fungus showed antifungal activity against C. fragariae in a bioautography assay and further fractionation and testing of the compounds responsible for the activity is underway. Approximately 176 crude extracts samples from NCPNR have been subjected to bioautography assay and six of them (Rhamnus beautifolia, Prunus pensylvanica, Senna obtusifolia, Eupatorium purpureum, Chamaecrista fasciculata, and Amphiachyris dracunculoides) showed antifungal activity against C. fragariae. Further fractionation and isolation process will be done. This is collaborative work with NCPNR, U. of Mississippi. For Objective 2, determine plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations, milestones have been met and significant progress has been made. Finalizing a collaboration with Alabama A&M University, and Samford University. The overall goal of this project is to understand how Ocimum extracts modulate the biological actions of insulin and the molecular mechanisms of insulin resistance as they relate to the pathophysiology of diabetes while determining the bioactive compound(s) associated with antihyperglycemic activity. Sixteen Ocimum accessions consisting of five different species, viz. O. africanum, O. americanum, O. basilicum, O. campechianum, O. gratissimum, and O. tenuiflorum were cultivated by Alabama A&M University. An UHPLC/DAD/QToF method was developed for the quantitative analysis of 14 bioactive compounds present in Ocimum species. Meanwhile, methanol extracts of the 16 plant species were evaluated for a-glucosidase inhibitory activities. Several samples demonstrated comparable IC50 inhibitory concentrations as acarbose, a widely- prescribed anti-diabetic medication. A collaborative project between the USDA, ARS, NPURU and Alabama A&M University to develop high curcumin turmeric (Curcuma spp.) varieties for high tunnel production to sustain small farms in Alabama is underway. The project is funded by National Institute of Food and Agriculture, USDA. The goal for this project is to evaluate the growth, development and yield, and curcumin levels in response to techniques and production conditions that are known to potentially increase curcumin accumulation. An UHPLC/UV/MS method has been developed for the quantification of bisdemethoxycurcumin, demethoxycurcumin, curcumin, and aR-tumerone. About 400 samples collected in 2018-2020 have been analyzed, and samples collected in 2021-2022 are under investigation. Chemical Analysis of Eriodictyon Species: Method Development and Validation. This investigation was initiated at the request of American Herbal Pharmacopoeia (AHP) to develop and validate a reliable and efficient analytical method for the quantitative analysis of major constudents in different Eriodictyon species. In a separate focus on Eriodictyon, the antifungal constituents are being investigated. Eriodictyon crassifolium demonstrated antifungal activity against C. fragariae. B4. Peppermint and Copaiba Essential Oil Analysis. These are collaborative projects between the USDA, ARS, NPURU and NCNPR, University of Mississippi. The goal for these two projects is to develop simple. economical analytical methods which will allow anyone in the peppermint oil or copaiba supply chain to quickly and cheaply evaluate the authenticity and quality of the oils. ACCOMPLISHMENTS 01 Process for producing capsinoids from Capsicum sp.. Capsinoids, the non- pungent analogs of capsaicinoids (e.g. capsaicin), were first identified in fruit of the sweet pepper (Capsicum annuum) cultivar CH- 19. Numerous subsequent studies have reported that many (but not all) of the types and degrees of biological activity characteristic of capaicinoids are also characteristic of capsinoids. The fruit of high- capsiate genotypes represent a commercial source of these compounds. To date, no method has been published that efficiently extracts and purifies capsinoids from Capsicum fruit in a rapid and simple bulk process. ARS researchers in Oxford, Mississippi, evaluated the efficacy of various organic solvents for the extraction of capsinoids from dried pepper fruit. Among the organic solvents evaluated, pentane appeared to provide a good combination of both recovery and purity. A subsequent liquid/liquid extraction step, utilizing pentane and acetonitrile, resulted in 26.3 % (wt/wt) capsiate and 19.4 % (wt/wt) dihydrocapsiate for a combined capsinoids yield of 45.7 % (wt/wt). This method and the associated patent provide a process to be utilized in producing ample quantities of capsiate for a growing market. 02 Antidiabetic activity of basil (Ocimum Species). The use of natural products as potential preventive and therapeutic interventions for diabetes has drawn worldwide attention. The Ocimum genus, collectively called basil, has been used historically as a medicinal herb for a myriad of ailments and diseases including diabetes. As part of an ongoing research project (partially funded by NIFA) to identify bioactive compound(s) associated with the anti-diabetic activity of basil, and to develop a sustainable organic production system for potential commercial cultivation, an in-depth chemical and biological study was performed by ARS researchers in Oxford, Mississippi, on sixteen Ocimum accessions consisting of six different species cultivated by Alabama A&M University (AAMU). Fourteen compounds, including terpenoids, phenolics, and flavonoids in the crude methanol extracts of the plant samples were quantitatively determined. The enzymatic inhibition activity study revealed that one accession, O. gratissimum from Zambia, strongly inhibited a-glucosidase. Moreover, two bioactive compounds, rosmarinic acid and caffeic acid that may be best associated with anti-diabetic properties of O.gratissimum species were identified. To the best of our knowledge, this is the first report of the anti-diabetic activity of these two compounds in basil species. The reported analytical and biological methods could be employed to evaluate the chemical composition and agronomic performance of Ocimum. Overall, this project provided scientific information necessary for the development of sustainable organic production systems, which enable commercial cultivation of Ocimum varieties with known bioactivity. With the right startup support, it is possible for farmers to produce a high- value crop for the national and world marketplace. A manuscript pertaining to this work has been accepted in the Journal of Food Science and Technology.
Impacts
(N/A)
Publications
- Zheljazkov, V.D., Cantrell, C.L., Jeliazkova, E.L., Astatkie, T., Schlegel, V. 2022. Sagebrush species of the U.S. Bighorn Mountains: essential oil content, composition, and bioactivity. Plants. https://doi.org/10.3390/ plants11091228.
- Maciel, G., Aparecida Lopes, A., Cantrell, C.L., De Castro Franca, S., Waleria Bertoni, B., Verginia Lourenco, M. 2021. Jasmonates promote enhanced production of bioactive caffeoylquinic acid derivative in Eclipta prostrata (L.) L. hairy roots. Plant Cell Tissue and Organ Culture. https:/ /doi.org/10.1007/s11240-021-02201-4.
- Zheljazkov, V.D., Semerdjieva, I.B., Stevens, J.F., Wu, W., Cantrell, C.L., Yankova-Tsvetkova, E., Koleva-Valkova, L.H., Stoyanova, A., Astatkie, T. 2021. Phytochemical investigation and reproductive capacity of the Bulgarian endemic plant species Marrubium friwaldskyanum Boiss. (Lamiaceae) . Journal of Agricultural and Food Chemistry. https://doi.org/10.3390/ plants11010114.
- Cantrell, C.L., Jarret, R.L. 2022. Bulk process for enrichment of capsinoids from capsicum fruit. Processes. 10(2):305. https://doi.org/10. 3390/pr10020305.
- Wang, M., Cantrell, C.L., Matthews, S.T., Paudel, P., Lee, J., Mentreddy, S.R. 2022. Agronomy, chemical analysis, and antidiabetic activity of basil (Ocimum species). Journal of Agricultural and Food Chemistry. https://doi. org/10.1021/acsfoodscitech.2c00100?urlappend=%3Fref%3DPDF&jav=VoR&rel=cite- as.
- Zheljazkov, V.D., Semerdjieva, I.B., Cantrell, C.L., Astatkie, T., Acimovic, ¿. 2022. Phytochemical variability of essential oils of two Balkan endemic species Satureja pilosa Velen. and S. kitaibelii Wierzb. ex Heuff. (Lamiaceae). Molecules. https://doi.org/10.3390/molecules27103153.
- Avula, B., Bae, J., Chittiboyina, A.G., Wang, Y., Wang, M., Zhao, J., Zulfiqar, A., Li, J., Wu, C., Khan, I.A. 2022. Chemometric analysis and chemical characterization for the botanical identification of Glycyrrhiza species (G. glabra, G. uralensis, G. inflata, G. echinata and G. lepidota) using liquid chromatography-quadrupole time of flig. Journal of Agricultural and Food Chemistry. https://doi.org/10.1016/j.jfca.2022. 104679.
- Shankara, V., Wang, M., Ajjarapua, S., Kolimi, P., Avula, B., Murthy, R., Khan, I., Naraisimha, M. 2021. Analysis of docosanol using GC/MS: Method development, validation, and application to ex vivo human skin permeation studies. Journal of Pharmaceutical and Biomedical Analysis. https://doi. org/10.1016/j.jpha.2021.08.004.
- Zhao, J., Wang, M., Saroja, S.G., Khan, I.A. 2021. NMR technique and methodology in botanical health product analysis and quality control. Journal of Pharmaceutical and Biomedical Analysis. https://doi.org/10.1016/ j.jpba.2021.114376.
- Ameen, G., Solanki, S., Sager-Bittara, L., Richards, J., Tamang, P., Friesen, T.L., Brueggeman, R.S. 2021. Mutations in a barley cytochrome P450 gene enhances pathogen induced programmed cell death and cutin layer instability. PLoS Genetics. 17(12). Article e1009473. https://doi.org/10. 1371/journal.pgen.1009473.
- Kumairhamy, M., Ilias, M., Siddharth, T.K., Shabana, K. 2021. Schottiin, a new prenylated isoflavones from Psorothamnus schottii and antibacterial synergism studies between methicillin and fremontone against methicillin- resistant Staphylococcus aureus ATCC 1708. Natural Product Research. https://doi.org/10.1080/14786419.2021.1937157.
- Akins, N.S., Mishra, N., Harris, H.M., Dudhipala, N., Kim, S., Keasling, A. W., Zjawiony, J.K., Ashpole, N.M., Le, H.V. 2022. 6,5-fused ring, C2- salvinorin ester, dual kappa and mu opioid receptor agonists as analgesics devoid of anxiogenic effects.. ChemMedChem. https://doi.org/10.1002/cmdc. 202100684.
- Avula, B., Bae, J., Chittiboyinaa, A.A., Wang, Y., Wang, M., Srivedavyasasri, R., Ali, Z., Li, J., Wu, C., Khan, I.A. 2021. Comparative analysis of five salvia species using LC-DAD-QToF. Journal of Pharmaceutical and Biomedical Analysis. https://doi.org/10.1016/j.jpba. 2021.114520.
- Sparks, T.C., Duke, S.O. 2021. Structure simplification of natural products as a lead generation approach in crop protection compound discovery. Journal of Agricultural and Food Chemistry. 69(30):8324-8346. https://doi.org/10.1021/acs.jafc.1c02616.
- Sarfare, S., Khan, S.I., Zulfiqar, F., Radhakrishnan, S., Ali, Z., Khan, I. A. 2022. Undescribed C-Glycosylflavones from corn silk and potential anti- inflammatory activity evaluation of isolates. Planta Medica. https://doi. org/10.1055/a-1728-1347.
- Avula, B., Katragunta, K., Wang, Y., Upton, R., Khan, I.A. 2022. Analysis of Crocetins and Saffanal variations in Saffron(Crocus sativus) stigma samples and dietary supplements using HPLC-UHPLC-PDA-MS: Chemical profiling and chemometric analysis using LC-QToF. Food Analytical Methods. https://doi.org/10.1007/s12161-022-02268-5.
- Avula, B., Katragunta, K., Wang, Y., Ali, Z., Khan, I.A. 2022. Simultaneous determination and characterization of flavonoids, sesquiterpene lactone, and other phenolics from centaurea benedicta and dietary dupplements using UHPLC-PDA-MS and LC-DAD-QToF. Journal of Pharmaceutical and Biomedical Analysis. https://doi.org/10.1016/j.jpba. 2022.114806.
- Avula, B., Katragunta, K., Wang, Y., Ali, Z., Srivedavyasasri, R., Gafner, S., Slimestad, R., Khan, I.A. 2022. Chemical profiling and UHPLC-QToF analysis for the simultaneous determination of anthocyanins and flavonoids in Sambucus berries and authentication and detection of adulteration in elderberry dietary supplements using UHPLC-PDA-MS. Journal of Pharmaceutical and Biomedical Analysis. https://doi.org/10.1016/j.jfca. 2022.104584.
- Balkisu, A., Fadime, A., Zulfiqar, F., Zhao, J., Khan, I. 2022. A novel cyclohexane carboxylic acid derivative from Black Turtle Bean (Phaseolus vulgaris L.). Records of Natural Products. http://doi.org/10.25135/rnp.325. 2202.2361.
- Da Cruz-Silva, C.T., Cantrell, C.L., Nobrega, L.P., Ali, A., Duke, S. 2021. Bioassay-guided isolation of phytotoxins from three salvia species. Allelopathy Journal. 54(1):13-24. https://doi.org/10.26651/allelo.j/2021- 54-1-1344.
- Min, L., Wang, H., Bajsa Hirschel, J.N., Yu, C., Wang, B., Yao, M., Han, L. , Cantrell, C.L., Duke, S.O., Sun, N., Liu, X. 2022. Novel dioxolane ring compounds for the management of phytopathogen diseases as ergosterol biosynthesis inhibitors: synthesis, biological activities and molecular docking. Journal of Agricultural and Food Chemistry. https://doi.org/10. 1021/acs.jafc.2c00541.
- Cárdenas, D.M., Bajsa Hirschel, J.N., Cantrell, C.L., Rial, C., Varela, R. M., Molinillo, J.G., Macías, F.A. 2022. Evaluation of the phytotoxic and antifungal activity of C17-sesquiterpenoids as potential biopesticides. Pest Management Science. https://doi.org/10.1002/ps.7042.
- Huijuan, Q., Lin, K., Li, X., Ou, H., Tan, Y., Wang, M., Wei, N. 2021. Chemical constituents and anti-gastric ulcer activity of essential oils of Alpinia officinarum (Zingiberaceae), Cyperus rotundus (Cyperaceae), and their herbal pair. Chemistry and Biodiversity. https://doi.org/10.1002/ cbdv.202100214.
- Kamau, R.W., Midiwo, J.O., Mgani, Q.A., Masila, V.M., Kumarihamy, M., Wang, M., Zhao, J., Muhamma, I. 2022. A new gnidiflavanone-flavonol dimer and other constituents from Gnidia apiculata. Natural Product Research. https:/ /doi.org/10.1080/14786419.2022.2062349.
- Chae, H., Dale, O., Maqbool, M., Zhao, J., Avula, B., Khan, I.A., Khan, S. I. 2022. A multitarget approach to evaluate the efficacy of Aquilaria sinensis flower extract against metabolic syndrome. Molecules. https://doi. org/10.3390/molecules27030629.
- Lee, J., Wang, M., Jianping, Z., Avula, B., Chittiboyinaa, A.G., Khan, I.A. 2022. Chemical authentication and speciation of Salvia botanicals: an investigation utilizing GC/Q-ToF and chemometrics. Foods. https://doi.org/ 10.3390/foods11142132.
- Ravu, R., Jacob, M.R., Khan, S.I., Wang, M., Cao, L., Agarwal, A.K., Clark, A.M., Li, X. 2021. Synthesis and antifungal activity evaluation of phloeodictine analogues. Journal of Natural Products. 84,2129-2137. https:/ /doi.org/10.1021/acs.jnatprod.1c00116.
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Progress 10/01/20 to 09/30/21
Outputs
Progress Report Objectives (from AD-416): 1. Discover bioactive pesticides (fungicidal and herbicidal) that enhance quality and marketability of small fruits and specialty crops. 1.1. Discover novel biofungicides and bioherbicides from crude extract screening and bioassay-directed isolation approaches. 1.2. Isolation and identification of antifungal metabolites from actinomycete fermentation for control of important fungal plant pathogens. 1.3. Investigation of plant pathogenic fungi for phytotoxic and antifungal activities and synthetic modification of the isolated compounds to gain insights into structure-activity relationships. 2. Determine plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations. 2.1. Target medicinal and aromatic plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations. Approach (from AD-416): The long-term objectives of this project are to identify, chemically characterize, and develop new weed and plant pathogen managing biochemical biopesticides from natural sources and enhance or optimize commercially important bioactive compound concentrations. Plant and microbial extracts will be sourced using a variety of approaches and methods as evidenced through previous publications by the authors. These extracts will be subjected to in-house bioassays which include both antifungal and herbicidal based assays as described below. A bioassay-guided investigative approach will be performed on bioactive extracts in an effort to identify the specific natural compound(s) responsible for the activity of the extract(s). In-house high-throughput bioassays will be utilized to identify bioactive constituents with antifungal and herbicidal activities. A second component of this project pertains to natural products obtained from medicinal and aromatic crops which are low-volume high-value commodities that have numerous applications in various industries such as food, beverage, food supplement, flavor and fragrance, perfumery and cosmetics, pharmaceutical, aromatherapy, and various consumer products. Sourcing these and other natural compounds in an economical manner directly from plants is constantly evolving which creates an opportunity for small and mid-size farms. This is the first year of research for this new project. For Objective 1, discover bioactive pesticides (fungicidal and herbicidal) that enhance quality and marketability of small fruits and specialty crops, milestones have been met and significant progress has been made. This 3 researcher project hired two scientists, a plant pathologist and an additional research chemist, during this year. This report also includes progress made as part of the NACA with the National Center for Natural Products Research (NCNPR) at the University of Mississippi in Oxford, Mississippi. Progress Report will be divided into sections based on in-house and Non Assistant Cooperator Agreement (NACA). As part of the antifungal discovery subobjective, the new plant pathologist has been developing an improved high throughput screening (HTS) bioassay. This method is very effective, time-efficient, and provides quantitative data as well, over the traditional bioautography utilized in the past. We are optimizing and developing the HTS assay protocol for the targeted fungi. In our search for antifungal compounds from natural sources, the ethanol extract of the roots of Gentiana crassicaulis showed potent in vitro antifungal activities against the fungal pathogens Crypococcus neoformans and Aspergillus fumigatus. Given the fact that our previous antifungal screening of plant extracts generated an extremely low hit rate against A. fumigatus, this extract appeared to be a good subject for follow-up bioassay-guided fractionation. In this study, the bisphosphocholine compound irlbacholine was identified as the primary constituent of G. crassicaulis responsible for the observed antifungal activity, along with three new irlbacholine analogues, gentianalines A, B and C. Identification of the bisphosphocholines, a rare class of antifungal natural products, in these medicinal plants provides scientific evidence to complement their medicinal use. Nicotinic acid (niacin or vitamin B3) is a natural product first extracted from tobacco (Nicotiana spp.) and its derivatives can be found in many plants, such as tobacco, Areca catechu, seeds of Ricinus communis, and seed coats of cereal grains. Niacin contains an important pyridine motif and derivatives of such have been used in the synthetic design of agrochemicals, with many pesticides containing this pyridine motif such as the herbicide nicosulfuron. Fifteen niacin derivatives were synthesized in the aim of uncovering a new leading compound with phytotoxic activity. Some of the compounds displayed excellent herbicidal activity against both bentgrass and duckweed. A novel furanocoumarin was isolated and identified as a phytotoxic constituent from Amyris elimifrea a plant in the Rutaceae family and determined he absolute stereochemistry of the asymmetric center by X-ray diffraction spectroscopy. We have also refined the structure of a previously published furanocumarin isolated form a Rutaceae plant. Under the Subobjective 1.3, we have investigated a plant pathogenic fungus infecting dollarweed, a weed predominantly found in golf courses. While isolating the fungus we also isolated a bacterium associated with it. These two microbes were isolated and identified by DNA analysis. The fungus was identified as a Diaporthe species and cultured in potato- dextrose broth (PDB) in the presence and absence of Dianion HP-20. We observed about threefold increase in metabolite production when using Dianion HP-20 compared to the culturing without the resin. Bioassay guided fractionation led to the isolation of two known azaphilones and a novel azaphilone with antifungal activity against Colletotrichum species. The bacterium was identified as a Pantoea species and we have demonstrated it to have plant growth promoting activity when tested in Lemna, cucumber and sorghum plants. This bacterium is being evaluated as a fertilizer substitute for organic farming at Marrone Bio Innovations (MBI) in Davis, California, and we have signed an MTA with MBI. For Objective 2, determine plant growth and post-harvest processing conditions to enhance or optimize commercially important bioactive compound concentrations, milestones have been met and significant progress has been made. Concluding a collaboration with Alabama A&M University, and Samford University. The overall goal of this project is to understand how Ocimum extracts modulate the biological actions of insulin and the molecular mechanisms of insulin resistance as they relate to the pathophysiology of diabetes while determining the bioactive compound(s) associated with antihyperglycemic activity. Sixteen Ocimum accessions consisting of five different species, viz. O. africanum, O. americanum, O. basilicum, O. campechianum, O. gratissimum, and O. tenuiflorum were cultivated by Alabama A&M University. An UHPLC/DAD/QToF method was developed for the quantitative analysis of 14 bioactive compounds present in Ocimum species. Meanwhile, methanol extracts of the 16 plant species were evaluated for a-glucosidase inhibitory activities. Several samples demonstrated comparable IC50 inhibitory concentrations as acarbose, a widely- prescribed anti-diabetic medication. Weed interference in sugarcane (Saccharum officinarum L.) can reduce crop yield by up to 97%. However, interference is not a phenomenon caused only by weeds, as the crop has the potential to limit the growth and development of weeds. Allelopathy is one of the factors involved in interference between plants. Allelopathy is the chemical inhibition of one plant by another, due to the release into the environment of phytotoxic compounds that inhibit germination and/or growth. Plants may adversely affect growth and development of each other through the production and release of compounds into the environment. Sugarcane cultivars that are currently planted are the result of genetic improvement focused on increased crop yield. However, this selection and genetic alteration reduced the competitive potential of sugarcane, as well as its allelopathic capabilities. Many members of the Poaceae family are highly allelopathic. Thus, the objective of this study was to characterize the allelopathic potential of two sugarcane cultivars (CTC 2 and IAC 91109) by bioassay-guided isolation and identification of potential allelochemicals. For both leaves and roots, alpha-linolenic and linoleic acid were found to be the most phytotoxic compounds found with this approach. NACA with University of Mississippi: The researchers continued to source plant materials for screening from our plant collections and numerous collaborators. Eight hundred eight plant samples were added to our inventory this year and over 2,500 natural product crude extracts, semi- purified fractions, and purified compounds were screened for biological activities against specific molecular targets and whole-cell systems. As part of our continuing effort in the search for anti-infective, cancer chemopreventive, and immunomodulatory/anti-inflammatory leads from natural sources, more than 40 compounds were isolated from 11 extracts, with three showing promising activity against drug-resistant Enterococci, Streptococci, and Staphylococci strains and two exhibiting activity against Plasmodium falciparum, sans cytotoxicity to mammalian cells. Also, 16 compounds were tested against a panel of transcription factors involved in cancer signaling pathways, of which 4 had potent anticancer activity. New collaborations with the countries of Kazakhstan, Egypt, Nigeria, and Kenya were implemented for the acquisition of several plant sources. Among these extracts, 15 purified phytochemicals were tested for antimicrobial and antimalarial activity, with two exhibiting good antifungal activity as well as efficacy towards methicillin-resistant Staphylococcus aureus (MRSA). A new project has been initiated to identify pure compounds and extracts that could inhibit the binding of the spike protein of SARS-CoV-2 and ACE2, the host receptor protein. The binding of spike protein and ACE2 receptor has been reported as the pathogenic mechanism for virus entry into the cell. More than 60 pure compounds and 15 extracts were screened at various concentrations through this assay. This project aims to identify the mechanism of action of these compounds/extracts for the inhibition of COVID-19 infection, and the confirmed hits will be subjected to various mechanistic testing. From the 100 plant extracts screened for their antidiabetic and cardiovascular pharmacological activity, during the previous funding cycle, 13 were studied further to determine their adipogenic, antiadipogenic, and glucose uptake effects. Their effect on insulin sensitivity and glucose transport as well as lipid metabolism was determined through Liver X Receptor (LXR) agonism assays. Ten medicinal plants were screened for anti-inflammatory activity mediated through modulation of two pathways, namely inducible nitric oxide synthase activity, which leads to excessive generation of intracellular nitrates, and activation of the NRF2-ARE signaling pathway, which regulates the cellular antioxidant response. High throughput cell-based assays utilized for this purpose employed mouse macrophage (RAW 264.7) and human hepatic (HepG2) cell lines. In addition to the above scientific activities, the Medicinal Plant Garden at the University of Mississippi continues to expand its renowned collection of living medicinal plants. New demonstration beds and field plots were developed. Here NCNPR cultivates and processes medicinal plants to be used in the discovery program, emphasizing new acquisitions from other countries. The new research wing will expand and enhance the research capabilities of NCNPR with a second plant specimen repository, herbarium, and laboratories for plant tissue cultures, cellular cultures, scale-up isolation, and synthetic chemistry. Record of Any Impact of Maximized Teleworking Requirement: The maximized telework situation has directly impacted the productivity of this project but fallen short of preventing us from meeting milestones. Meeting attendance has been reduced, international collaborations are reduced, and new MTA�s and other agreements are reduced. ACCOMPLISHMENTS 01 A novel approach for lavender essential oil authentication and quality assessment. Lavandula angustifolia Mill., commonly known as English lavender or true lavender, is an important agricultural plant which has been used to produce lavender essential oil (LEO). The oil is one of the most frequently adulterated essential oils, primarily due to the plants low oil production and high commercial value. Currently, the quality of LEO is defined and regulated based on the standards and methods established by various authoritative organizations. Due to the complexity of LEO, these existing standards and methods are not sufficient for quality control and to protect LEO from adulteration. The goal for ARS researchers in Oxford, Mississippi, was to develop an efficient and reliable method for LEO quality assessment and adulteration detection. After a comprehensive investigation, involving a large set of LEO samples analyzed by multiple techniques (GC/MS, GC/Q- ToF, NMR, and chemometric analysis), a new approach named Q-Index was proposed. Q-Index provided superior results compared to the ISO method, and successfully detected poor- quality LEO and LEO adulterated by addition of lavandin oil, ho leaf oil, cooking oil, and synthetic compounds. The results from this study demonstrated the feasibility and simplicity of the proposed Q-Index method as an efficient and reliable tool for routine analysis and quality control of LEOs, the international herbal products, cosmetic, and essential oil industries, and the extended natural products community in general. 02 Natural products as antimicrobial agents with a novel mechanism of actions. In an ongoing effort to develop antimicrobial agents from natural products, ARS researchers in Oxford, Mississippi, performed studies in collaboration with Kings College London, United Kingdom, on the inhibitory activities and synergism studies of machaeriols and machaeridiols against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. In addition, they were evaluated against permeabilized Gram-negative pathogens, which showed promising leads. A grant pre-proposal, followed by a full proposal, was submitted to the Wellcome Trust, United Kingdom. 03 Identify dietary or botanical products with cancer chemopreventive potential. This program identifies the most promising lead natural product extracts/pure compounds, using our battery of 15 cancer signaling pathway luciferase assays, to determine their cytotoxic potential against various cells in vitro and characterizes their mechanism(s) of action. A potent formulation with a unique mechanism of action containing a mixture of pure compounds and extracts has been identified through this extensive screening process. The PCT application that was filed last year on this formulation entered into a national phase, and a patent application has been filed. Preclinical studies are underway. Molecular assays have been carried out by ARS researchers in Oxford, Mississippi, to identify the enzyme(s) responsible for their mechanism of action. These enzymes could be possible molecular targets and could also serve as biomarkers when advancing to translational studies. Various combinations of this formulation have been tested in murine colon cancer models to establish its in vivo potential. Both biological and analytical methods have been developed to evaluate the pharmacokinetic properties of this formulation within mice, and target organs have been identified from bio-distribution patterns. To maximize the solubility and to increase bioavailability, various modifications of pure compounds were tested for intravenous administration. Optimal efficacy in target organs and maximum tolerated dosage studies are ongoing. This formulation might serve as a candidate for translational research and product development. To overcome the supply issue of the test article, an efficient synthetic strategy has been proposed and is being evaluated for feasibility. Thirty-five herbal extracts/pure compounds were also evaluated in various cancer cell lines (glioblastoma, colon cancer, and leukemia) for their synergistic interactions.
Impacts
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Publications
- Perera, W.H., Meepagala, K.M., Duke, S.O. 2020. Sesquiterpene-a-amino acid quaternary ammonium hybrids from Stereum complicatum (Steraceae). Biochemical Systematics and Ecology. 93,104176. https://doi.org/10.1016/j. bse.2020.104176.
- Eliwa, D., Albadry, M.A., Ibrahim, A.S., Kabbash, A., Meepagala, K.M., Khan, I.A., El-Aasr, M., Ross, S.A. 2020. Biotransformation of papaverine and in silico docking studies of the metabolites on human phosphodiesterase 10a.. Phytochemistry. https://doi.org/10.1016/j. phytochem.2020.112598.
- Zhai, C., Zhao, J., Chittiboyina, A.G., Meng, Y., Wang, M., Khan, S.I., Khan, I.A. 2020. Newly generated Atractylon derivatives in the processed rhizomes of Atractylodes macrocephala Koidz. Molecules. https://doi.org/10. 3390/molecules25245904.
- Wei, N., Wang, M., Adams, S.J., Yu, P., Avula, B., Wang, Y., Pan, K., Wang, Y., Khan, I.A. 2020. Comparative Study and Quality Evaluation Regarding Morphology Characters, Volatile Constituents and Triglycerides in Seeds of Five Species Used in Traditional Chinese Medicine . Journal of Pharmaceutical and Biomedical Analysis. 194/113801. https://doi.org/10. 1016/j.jpba.2020.113801.
- Wang, M., Zhao, J., Ali, Z., Avonto, C., Khan, I. 2021. A Novel Approach for Lavender Essential Oil Authentication and Quality Assessment. Journal of Pharmaceutical and Biomedical Analysis. 199. https://doi.org/10.1016/j. jpba.2021.114050.
- Muhammad, I., Jacob, M.R., Ibrahim, M.A., Raman, V., Kumarihamy, M., Wang, M., Al-Adhami, T., Hind, C., Clifford, M., Martin, B., Sutton, M., Rahman, M., Zhao, J. 2020. Antimicrobial constituents from Machaerium Pers.: Inhibitory activities and synergism of machaeriols and machaeridiols against methicillin-resistant Staphylococcus aureus and Vancomycin- resistant Enterococcus faecium and perm. Molecules. 25/6000. https://doi. org/10.3390/molecules25246000.
- Balachandran, P., Ibrahim, M.A., Zhang, J., Wang, M., Pasco, D.S., Muhammad, I. 2021. Cross talk of cancer signaling pathways by cyclic hexapeptides and anthraquinones from Rubia cordifolia. Molecules. 26/735. https://doi.org/10.3390/molecules26030735.
- Avula, B., Bae, J., Zhao, J., Wang, Y., Wang, M., Zhang, Z., Ali, Z., Khan, I. 2021. Quantitative Determination and Characterization of Polyphenols from Cissus quadrangularis L. and Dietary Supplements using UHPLC-PDA-MS, LC-QToF and HPTLC. Journal of Pharmaceutical and Biomedical Analysis. https://doi.org/10.1016/j.jpba.2021.114036.
- Abdelmalek, E.M., Zulfiqar, F., Albadry, M.A., Khan, S.I., Meepagala, K.M., Ramadan, M.A., Darwish, F.M., Assaf, M.H., Ross, S.A. 2021. In silico and in vitro studies of isolated constituents from Callistemon citrinus leaves: Anti-microbial potential and inhibition of iNOS activity. Phytochemistry. 185. https://doi.org/10.1016/j.phytochem.2021.112745.
- Barreto, D.L., Nogueira De Azevedo, R., Carvalho, C., Ferreira, M.C., Cantrell, C.L., Duke, S.O., Rosa, L.H. 2021. Bioactive compounds produced by Neotropical endophytic fungi applied to agriculture. In: Rosa L.H. editors. Neotropical Endophytic Fungi. Springer, Cham: Springer International Publishing. p. 257-295.
- Meepagala, K.M., Bracken, A.K., Fronczek, F.R., Johnson, R.D., Wedge, D.E., Duke, S.O. 2020. A novel furanocoumarin with phytotoxic activity from the leaves of Amyris elemifera (Rutaceae). Journal of Agricultural and Food Chemistry. https://www.doi.org/10.1021/acsomega.0c04778.
- Ren, S., Deng, K., Qiu, S., Wang, M., Avula, B., Tripathi, S.K., Jacob, M. R., Gong, L., Wang, W., Khan, I.A., Li, X. 2020. Identification of antifungal Bisphosphocholines from medicinal Gentiana species. Journal of Natural Products. 2020, 83, 10, 3207�3211. https://doi.org/10.1021/acs. jnatprod.0c00584.
- De Oliveira, T.L., Fontana, P.D., Bavia, L., Cruz, L., Crisma, A.R., Sassaki, G.L., Menezes, L.R., Wang, M., Beltrame, F., Messias-Reason, I.J. 2020. Effects of Euphorbia umbellata extracts on complement activation and chemotaxis of neutrophils. Journal of Ethnopharmacology. 265/113348. https://doi.org/10.1016/j.jep.2020.113348.
- Avula, B., Parveen, I., Zhao, J., Wang, M., Techen, N., Wang, Y., Riaz, M., Bae, J., Shami, A.A., Chittiboyina, A.G., Khan, I.A., Sharp, J.S. 2021. A comprehensive workflow for the analysis of Bio-Macromolecular supplements: Case Study of 20 Whey protein products. Journal of Dietary Supplement. https://doi.org/10.1080/19390211.2021.1897724.
- Avula, B., Bae, J., Wang, Y., Wang, M., Ali, Z., Khan, I.A. 2021. Chemical profiling and characterization of anthraquinones from two Bulbine species and dietary supplements using liquid chromatography-high resolution mass spectrometry. Nature Product Communications. https://doi.org/10.1093/ jaoacint/qsab075.
- Stefenoni, H., R�is�nen, S., Cueva Welchez, S., Wasson, D., Lage, C., Melgar, A., Fetter, M., Smith, P., Hennessy, M., Vecchiarelli, B., Bender, J., Pitta, D., Cantrell, C.L., Yarish, C., Hristov, A. 2021. Effects of the macroalga Asparagopsis taxiformis and oregano leaves on methane emission, rumen fermentation, and lactational performance of dairy cows.. Journal of Dairy Science. 104/4157-4173. https://doi.org/10.3168/jds.2020- 19686.
- Yu, C., Wang, Q., Min, L., Bajsa Hirschel, J.N., Hua, X., Cantrell, C.L., Duke, S., Liu, X. 2021. Synthesis, crystal structure, herbicidal activity, and SAR study of Novel N-(Arylmethoxy)-2-chloronicotinamides derived from nicotinic acid. Journal of Agricultural and Food Chemistry. https://doi. org/10.1021/acs.jafc.0c07538.
- Zheljazkov, V.D., Cantrell, C.L., Semerdjieva, I., Radoukova, T., Stoyanova, A., Maneva, V., Kacaniova, M., Astatkie, T., Borisova, D., Dincheva, I., Salamon, I. 2021. Essential oil and bioactivity of two juniper species from Bulgaria and Slovakia. Molecules. 2021, 26, 3659.
- Hijano, N., Nepomuceno, M.P., Cantrell, C.L., Duke, S.O., Alves, P.L. 2021. Characterization of the allelopathic potential of sugarcane leaves and roots. Journal of Agricultural Chemistry and Environment. https://doi.org/ 10.4236/jacen.2021.103016.
- Hawwal, M.F., Ali, Z., Wang, M., Zhao, J., Lee, J., Fantoukh, O.I., Khan, I.A. 2021. (E)-2,6,10-Trimethyldodec-8-en-2-ol: An undescribed sesquiterpenoid from copaiba oil. Molecules. 2021, 26, 4456. https://doi. org/10.3390/molecules26154456.
- Avonto, C., Chittiboyina, A.G., Khan, S.I., Dale, O.R., Parcher, J.F., Wang, M., Khan, I.A. 2020. Are atranols the only skin sensitizers in oakmoss? A systematic investigation using non-animal methods.. Toxicology In Vitro. 70/105053. https://doi.org/10.1016/j.tiv.2020.105053.
- Shaukat, U., Ahemad, S., Wang, M., Khan, S.I., Ali, Z., Muhammad I, T.I., Abdallah, H.H., Khan, I.A., Saleem, M., Mahomoodally, M.F. 2021. Phenolic contents, chemical profiling, in silico and in vitro antiinflammatory and anticancer properties of Alnus nitida (Spach) Endl.. South African Journal of Botany. 138/148-155. https://doi.org/10.1016/j.sajb.2020.12.010.
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