Antimicrobial and anti-virulence activities of 4-shogaol from grains of paradise against gram-negative bacteria: Integration of experimental and computational methods.

ETHNOPHARMACOLOGICAL RELEVANCE: Bacterial resistance to antibiotics is a growing global concern, highlighting the urgent need for new antimicrobial candidates. Aframomum melegueta was traditionally used for combating urinary tract and soft tissue infections, which implies its potential as an antimicrobial agent. AIM OF STUDY: This study was designed to explore the antibacterial and anti-virulence capabilities of 4-shogaol isolated from A. melegueta seeds versus gram-negative bacteria: Serratia marcescens, Klebsiella pneumoniae, Acinetobacter baumannii, and the clinically important pathogen Pseudomonas aeruginosa. MATERIALS AND METHODS: 4-Shogeol was isolated from A. melegueta seeds and its MICs were determined for Acinetobacter baumannii (ATCC-17978), Pseudomonas aeruginosa (ATCC-27853), Klebsiella pneumoniae (ATCC-700603), and Serratia marcescens clinical isolate. The anti-efflux activity and effect on the bacterial cell membrane for the compound were evaluated. Furthermore, the anti-virulence activities of the compound were evaluated. The effects of 4-shogeol at sub-MIC on bacterial motility, biofilm formation, and production of virulent enzymes and pigments were assessed. The anti-quorum sensing activities of 4-shogeol were evaluated virtually and by quantification its effect on the expression of quorum sensing encoding genes. The in vivo protection assay was conducted to evaluate the effect of 4-shogaol on the P. aeruginosa capacity to induce pathogenesis in mice. Finally, the effect of shogaol-antibiotics combination was assessed. RESULTS: The research revealed that 4-shogaol's antibacterial action primarily involves disrupting the bacterial cell membrane and efflux pumps. It also exhibited significant anti-virulence effects by reducing biofilm development and repressing virulence factors production, effectively protecting mice against P. aeruginosa infection. Furthermore, when combined with antibiotics, 4-shogaol demonstrated synergistic effects, leading to reduced minimum inhibitory concentrations (MICs) against P. aeruginosa. Its anti-virulence properties were linked to its ability to disrupt bacterial quorum sensing (QS) mechanisms, as evidenced by its interaction with QS receptors and downregulation of QS-related genes. Notably, in silico analysis indicated that 4-shogaol exhibited strong binding affinity to different P. aeruginosa QS targets. CONCLUSION: These findings suggest that 4-shogaol holds promise as an effective anti-virulence agent that can be utilized in combination with antibiotics for treating severe infections caused by gram-positive bacteria.

Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors.

The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6'-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of -7.526 kcal/mol, -7.438 kcal/mol, and -7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (-6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.

Ethnomedicinal uses, phytochemistry, and pharmacological relevance of Justicia procumbens (Oriental Water Willow) - A promising traditional plant.

ETHNOPHARMACOLOGICAL RELEVANCE: Justicia procumbens L. (JP) (Oriental Water Willow, Shrimp plant, Acanthaceae) is a herbaceous plant that is commonly found in India, Taiwan, Australia, Southern China, Vietnam, and Korea. The plant has been primarily used to treat fever, asthma, edema, cough, jaundice, urinary tract infection, and sore throat, as well as for snake bites and as a fish-killer. In the present review, the reported phyto-chemical, ethno-pharmacological, biological, and toxicological studies on J. procumbens were summarized. Special focus had been given to its reported lignans, regarding their isolation, characterization, quantitative estimation, and biosynthesis. MATERIALS AND METHODS: A survey of the literature was done using assorted databases and publishers; Scopus, Sci-Finder, Web of Science, PubMed, GoogleScholar, ScienceDirect, Wiley, Taylors&Francis, Bentham, Thieme, and Springer. RESULTS: Currently, 95 metabolites have been separated fromJ. procumbens. Lignans and their glycosides were reported as main phyto-constituents of J. procumbens. Various methods are mentioned for quantitative estimation of these lignans. These phyto-constituents possessed wide pharmacological effectiveness, such as antiplatelet aggregation, antimicrobial, antitumor, and antiviral. CONCLUSIONS: Many of the stated effects are harmonious with the reported traditional uses of this plant. This data could further support J. procumbens's utilization as a herbal remedy and drug lead. However, further study of J. procumbens toxicity, as well as preclinical and clinical investigation is required to ensure the safe usage of J. procumbens.

Assessments of Alpha-Amylase Inhibitory Potential of Tagetes Flavonoids through In Vitro, Molecular Docking, and Molecular Dynamics Simulation Studies.

Diabetes is a chronic fast-growing metabolic disorder that is characterized by high blood glucose levels. Tagetes minuta L. has been used as a traditional remedy for various illnesses for many years, and, furthermore, its oil is used in the perfume and flavor industries. T. minuta contains various metabolites, such as flavonoids, thiophenes, terpenes, sterols, and phenolics, with varied bioactivities. Flavonoids can inhibit carbohydrate-digesting enzymes, such as alpha-amylase, which is a convenient dietary strategy for controlling hyperglycemia. In the current investigation, the isolated flavonoids quercetagetin-6-O-(6-O-caffeoyl-ß-D-glucopyranoside), quercetagetin-7-O-ß-D-glucopyranoside, quercetagetin-6-O-ß-D-glucopyranoside, minutaside A, patuletin-7-O-ß-D-glucopyranoside, quercetagetin-7-methoxy-6-O-ß-D-glucopyranoside, tagenols A and B, quercetagetin-3,7-dimethoxy-6-O-ß-D-glucopyranoside, patuletin, quercetin-3,6-dimethyl ether, and quercetin-3-methyl ether from T. minuta were assessed for their alpha-amylase inhibition (AAI) efficacy using an in vitro assay, as well as molecular docking, dynamics simulation, and ADMET analyses. Our findings show that quercetagetin-6-O-(6-O-caffeoyl-ß-D-glucopyranoside) (1), quercetagetin-7-O-ß-D-glucopyranoside (2), quercetagetin-6-O-ß-D-glucopyranoside (3), minutaside A (4), patuletin-7-O-ß-D-glucopyranoside (5), and quercetagetin-7-methoxy-6-O-ß-D-glucopyranoside (6) had a notable AAI capacity (IC50s ranged from 7.8 to 10.1 µM) compared to acarbose (IC50 7.1 µM). Furthermore, these compounds with the highest binding affinity among the tested flavonoids revealed high docking scores for AA (ranging from -12.171 to 13.882 kcal/mol) compared to that of acarbose (-14.668 kcal/mol). In MDS, these compounds were observed to show maximum stability and the greatest binding free energy, suggesting that they may contend with native ligands. In addition, the ADMET analysis showed that these active compounds had a broad span of drug-like, pharmacokinetic, and physicochemical features and did not possess any considerable undesired effects. The current results suggest the potential of these metabolites as AAI candidates. However, further in vivo and mechanistic studies are warranted to specify the efficacy of these metabolites.

Computational Insights into Natural Antischistosomal Metabolites as SmHDAC8 Inhibitors: Molecular Docking, ADMET Profiling, and Molecular Dynamics Simulation.

Schistosomiasis is a neglected tropical disease with a significant socioeconomic impact. It is caused by several species of blood trematodes from the genus Schistosoma, with S. mansoni being the most prevalent. Praziquantel (PZQ) is the only drug available for treatment, but it is vulnerable to drug resistance and ineffective in the juvenile stage. Therefore, identifying new treatments is crucial. SmHDAC8 is a promising therapeutic target, and a new allosteric site was discovered, providing the opportunity for the identification of a new class of inhibitors. In this study, molecular docking was used to screen 13,257 phytochemicals from 80 Saudi medicinal plants for inhibitory activity on the SmHDAC8 allosteric site. Nine compounds with better docking scores than the reference were identified, and four of them (LTS0233470, LTS0020703, LTS0033093, and LTS0028823) exhibited promising results in ADMET analysis and molecular dynamics simulation. These compounds should be further explored experimentally as potential allosteric inhibitors of SmHDAC8.

Alpha-Mangostin as a New Therapeutic Candidate for Concanavalin A-Induced Autoimmune Hepatitis: Impact on the SIRT1/Nrf2 and NF-κB Crosstalk.

Alpha-mangostin (α-MN) is a xanthone obtained from Garcinia mangostana that has diverse anti-oxidative and anti-inflammatory potentials. However, its pharmacological activity against autoimmune hepatitis (AIH) has not been investigated before. Concanavalin A (Con A) was injected into mice to induce AIH and two doses of α-MN were tested for their protective effects against Con A-induced AIH. The results demonstrated the potent hepatoprotective activity of α-MN evidenced by a remarkable decrease of serum indices of the hepatic injury and amendment of the histological lesions. α-MN significantly attenuated the level and immuno-expression of myeloperoxidase (MPO) indicating a decrease in the neutrophil infiltration into the liver. Additionally, the recruitment of the CD4+ T cell was suppressed in the α-MN pre-treated animals. α-MN showed a potent ability to repress the Con A-induced oxidative stress evident by the reduced levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and protein carbonyl (PC), as well as the enhanced levels of antioxidants as the reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (TAC). The ELISA, RT-PCR, and IHC analyses revealed that α-MN enhanced the sirtuin1/nuclear factor erythroid 2 related factor-2 (SIRT1/Nrf2) signaling and its downstream cascade genes concurrently with the inhibition of the nuclear factor kappa B (NF-κB) and the inflammatory cytokines (tumor necrosis factor-alpha and interleukine-6) signaling. Taken together, these results inferred that the hepatoprotective activity of α-MN could prevent Con A-induced AIH through the modulation of the SIRT1/Nrf2/NF-κB signaling. Hence, α-MN may be considered as a promising candidate for AIH therapy.

Bio-Guided Isolation of SARS-CoV-2 Main Protease Inhibitors from Medicinal Plants: In Vitro Assay and Molecular Dynamics.

Since the emergence of the pandemic of the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the discovery of antiviral phytoconstituents from medicinal plants against SARS-CoV-2 has been comprehensively researched. In this study, thirty-three plants belonging to seventeen different families used traditionally in Saudi Arabia were tested in vitro for their ability to inhibit the SARS-CoV-2 main protease (MPRO). Major constituents of the bio-active extracts were isolated and tested for their inhibition potential against this enzyme; in addition, their antiviral activity against the SARS-CoV-2 Egyptian strain was assessed. Further, the thermodynamic stability of the best active compounds was studied through focused comparative insights for the active metabolites regarding ligand-target binding characteristics at the molecular level. Additionally, the obtained computational findings provided useful directions for future drug optimization and development. The results revealed that Psiadia punctulata, Aframomum melegueta, and Nigella sativa extracts showed a high percentage of inhibition of 66.4, 58.7, and 31.5%, against SARS-CoV-2 MPRO, respectively. The major isolated constituents of these plants were identified as gardenins A and B (from P. punctulata), 6-gingerol and 6-paradol (from A. melegueta), and thymoquinone (from N. sativa). These compounds are the first to be tested invitro against SARS-CoV-2 MPRO. Among the isolated compounds, only thymoquinone (THY), gardenin A (GDA), 6-gingerol (GNG), and 6-paradol (PAD) inhibited the SARS-CoV-2 MPRO enzyme with inhibition percentages of 63.21, 73.80, 65.2, and 71.8%, respectively. In vitro assessment of SARS-CoV-2 (hCoV-19/Egypt/NRC-03/2020 (accession number on GSAID: EPI_ISL_430820) revealed a strong-to-low antiviral activity of the isolated compounds. THY showed relatively high cytotoxicity and was anti-SARS-CoV-2, while PAD demonstrated a cytotoxic effect on the tested VERO cells with a selectivity index of CC50/IC50 = 1.33 and CC50/IC50 = 0.6, respectively. Moreover, GNG had moderate activity at non-cytotoxic concentrations in vitro with a selectivity index of CC50/IC50 = 101.3/43.45 = 2.3. Meanwhile, GDA showed weak activity with a selectivity index of CC50/IC50 = 246.5/83.77 = 2.9. The thermodynamic stability of top-active compounds revealed preferential stability and SARS-CoV-2 MPRO binding affinity for PAD through molecular-docking-coupled molecular dynamics simulation. The obtained results suggest the treating potential of these plants and/or their active metabolites for COVID-19. However, further in-vivo and clinical investigations are required to establish the potential preventive and treatment effectiveness of these plants and/or their bio-active compounds in COVID-19.

Ethnobotanical Uses, Phytochemical Composition, Biosynthesis, and Pharmacological Activities of Carpesium abrotanoides L. (Asteraceae).

Carpesium abrotanoides L. (Asteraceae) is a medicinal plant with immense therapeutic importance and bioactivities. It is commonly encountered in various Asian regions. It has numerous ethnomedicinal uses for curing diverse ailments such as toothache, stomach ulcer, boils, tonsillitis, bronchitis, bacterial infection, bruises, swelling, virus infection, fever, and amygdalitis, as well as an anthelmintic versus round-, tape-, hook-, and pinworms. Different classes of phytoconstituents such as sesquiterpenes, sesquiterpene dimers, monoterpenes, and nitrogenous compounds have been reported from this plant. These phytoconstituents have proved to possess anti-inflammatory, cytotoxic, antimicrobial, and insecticidal capacities. The present review aims to summarize all published data on C. abrotanoides including traditional uses, phytoconstituents, bioactivities, and toxicological aspects, as well as the synthesis and biosynthesis of its metabolites through an extensive survey on various databases and various publishers. These reported data could draw the attention of various natural-metabolite-interested researchers and medicinal chemists towards the development of this plant and/or its metabolites into medicine for the prevention and treatment of certain illnesses. Despite the diverse traditional uses of C. abrotanoides, there is a need for scientific evidence to support these claims. Clinical trials are also required to further assure these data and validate this plant utilization in treating several diseases.

Phytoconstituents and Pharmacological Activities of Indian Camphorweed (Pluchea indica): A Multi-Potential Medicinal Plant of Nutritional and Ethnomedicinal Importance.

Pluchea indica (L.) Less. (Asteraceae) commonly known as Indian camphorweed, pluchea, or marsh fleabane has gained great importance in various traditional medicines for its nutritional and medicinal benefits. It is utilized to cure several illnesses such as lumbago, kidney stones, leucorrhea, inflammation, gangrenous and atonic ulcer, hemorrhoids, dysentery, eye diseases, itchy skin, acid stomach, dysuria, abdominal pain, scabies, fever, sore muscles, dysentery, diabetes, rheumatism, etc. The plant or its leaves in the form of tea are commonly used for treating diabetes and rheumatism. The plant is a rich source of calcium, vitamin C, dietary fiber, and ß-carotene. Various biomolecules have been isolated from P. indica, including thiophenes, terpenes, quinic acids, sterols, lignans, phenolics, and flavonoids. The current review reports detailed information about the phytoconstituents and pharmacological relevance of P. indica and the link to its traditional uses. The reported studies validated the efficacy and safety of P. indica, as well as supported its traditional uses for treating various ailments and promoting health and well-being. Thus, this could encourage the development of this plant into a healthy food supplement or medicine for the prevention and treatment of various diseases. However, further studies on the drug interactions, mechanism of action, pharmacokinetics, toxicology, and metabolism, as well as clinical trials, should be carried out.

Lansium domesticum-A Fruit with Multi-Benefits: Traditional Uses, Phytochemicals, Nutritional Value, and Bioactivities.

Lansium domesticum (Langsat, Meliaceae) is a tropical fruit mainly found in Southeast Asian countries, particularly in Thailand, Malaysia, Indonesia, and the Philippines. Traditionally, it is utilized as a folk treatment for eye inflammation, ulcers, diarrhea, dysentery, fever, spasms, flatulence, worms, insect bites, scorpion stings, and malaria. Additionally, it is utilized as a mosquito repellent, skin moisturizer and whitening agent. Pharmacological research showed that the plant has a wide array of bioactivities, including antimalarial, antifeedant, anti-aging, wound healing, antioxidant, cytotoxic, analgesic, antibacterial, antimutagenic, insecticidal, and larvicidal. The most commonly described activities were attributed to the presence of terpenoids and phenolics. Further, some studies reported the preparation of nanoparticles and pharmaceutical formulations from the plant. This review highlights the potential of L. domesticum as herbal medicine. It provides an overview about the reported data on L. domesticum from 1931 to November 2021, including nutritional value, traditional uses, phytoconstituents, and bioactivities, as well as nanoparticles and pharmaceutical formulations.

Cucurbitacin E glucoside alleviates concanavalin A-induced hepatitis through enhancing SIRT1/Nrf2/HO-1 and inhibiting NF-ĸB/NLRP3 signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Cucurbitacins are highly oxygenated tetracyclic triterpenoids, that represent the major metabolites reported from C. colocynthis (L.) Schrad.. Cucurbitacin E glucoside (CuE) is a tetracyclic triterpene glycoside separated from Cucurbitaceae plants. CuE has potent anti-inflammatory, immunomodulatory, and anti-tumor properties. AIM OF THE STUDY: The current study aimed at examining the hepatoprotective effect of CuE against concanavalin A (Con A)-produced hepatitis. MATERIALS AND METHODS: Mice were intravenously administered Con A (15 mg/kg) to induce AIH. CuE was orally administered at two different doses for five days preceding Con A injection. RESULTS: The results revealed that CuE pretreatment markedly attenuated the serum indices of hepatotoxicity and the severity of hepatic lesions. CuE depressed Con A-provoked increment in CD4+ T-cells in hepatic tissue. The antioxidant activity of CuE was evident through its ability to decrease markers of Con A-induced oxidative stress (malondialdehyde, 4-hydroxyenonanal, and protein carbonyl) and intensified the antioxidants in the hepatic tissue (SOD, GSH, and TAC). CuE increased mRNA expression of SIRT1 and Nrf2 as well as its binding capacity. Subsequently, CuE augmented mRNA expression of Nrf2 targeted genes as NQO1, GCL, and HO-1 and recovered its normal level. CuE inhibited the activation of NF-κB/downstream pro-inflammatory mediators signaling. Furthermore, CuE attenuated the mRNA expression of NLRP3 and its associated genes. CONCLUSION: Collectively, these results demonstrated the remarkable hepatoprotective potential of CuE towards Con A-induced AIH which was mediated via suppression of oxidative stress, enhancing SIRT1/Nrf2/HO-1, and prohibition of the NF-κB/NLRP3 signaling. CuE could be a candidate for hepatitis patients.

Kirenol: A promising bioactive metabolite from siegesbeckia species: A detailed review.

ETHNOPHARMACOLOGICAL RELEVANCE: Kirenol (Kr) is an ent-pimarane type diterpenoid that has been reported from Siegesbeckiaorientalis, S. pubescens, and S. glabrescens (family Asteraceae). These plants have been used traditionally for treating various ailments such as hypertension, neurasthenia, rheumatoid arthritis, asthma, snakebites, allergic disorders, paralysis, soreness, cutaneous disorders, rubella, menstrual disorders, numbness of limbs, dizziness, headache, and malaria. Importantly, in recent years, Kr has received great attention due to its diversified pharmacological activities. AIM OF THE STUDY: The current work aims to give an overview on the reported pharmacological activities of Kr. Furthermore, the findings regarding its methods for extraction, quantitative analysis, purification, pharmacokinetics, pharmaceutical and food preparations, biosynthesis, identification, semisynthetic analogues, and toxicity are highlighted to provide a reference and perspective for its further investigation. METHODS: Electronic databases including ScienceDirect, Web of Knowledge, SCOPUS, Wiley Online Library, Taylor & Francis, PubMed, Springer, JACS, and Google Scholar were searched up to the beginning of 2021 to identify the reported studies. RESULTS: A total of 93 articles have been reviewed. The reported data suggested that Kr possessed various bioactivities including cytotoxic, apoptotic, anticancer, anti-inflammatory, cardio-protective, anti-photo-aging, anti-adipogenic, antimicrobial, muscle function improvement, fracture and wound healing, and anti-arthritic. In addition, studies revealed that the antioxidative and anti-inflammatory activities of Kr may mediate many of its therapeutic potentials as confirmed by several in-vitro and in-vivo studies. CONCLUSION: This review provides an updated summary of the recent studies on Kr, including methods for extraction, quantitative analysis, purification, pharmacokinetics, pharmaceutical and food preparations, biosynthesis, and identification, as well as semisynthetic analogues, pharmacological activities, and toxicity. Thus, this work can provide useful considerations for planning and design future research on Kr.

Major flavonoids from Psiadia punctulata produce vasodilation via activation of endothelial dependent NO signaling.

Vasodilators are important pharmacologic agents for managing and/or treating hypertension. Medicinal plants are considered as valuable source of bioactive compounds. We used a bioguided approach to isolate, identify, and investigate the possible vasodilation activities and mechanism(s) of the prepared methanol extract from aerial parts of Psiadia punctulata (MAPP), its bioactive fraction and active compounds. Vascular effects of MAPP were studied using isolated artery technique in the presence or absence of specific candidate pathways inhibitors, and found to produce a significant vasodilation of phenylephrine preconstricted rat aortae. The bioactive chloroform fraction yielded five methoxylated flavonoids: umuhengerin (1), gardenin A (2), gardenin B (3), luteolin-3',4' -dimethyl ether (4), and 5,3'-dihydroxy-6,7,4',5'-tetramethoxyflavone (5). Metabolites 1, 4, and 5 produced a significant vasodilation. Removal of the endothelium significantly inhibited MAPP vasodilation. Nitric oxide synthase inhibition and not prostacycline inhibition or K+ channel blocking, was found to cause the observed vasodilation inhibition. Both guanylate cyclase and adenylate cyclase inhibitions markedly inhibited MAPP vasodilation. In conclusion MAPP possesses vasodilation activities that is mediated through endothelial nitric oxide pathway, calcium dependent endothelial nitric oxide synthase activation, and interference with the depolarization process through calcium channel blocking activity.

Plectrabarbene, a New Abietane Diterpene from Plectranthus barbatus Aerial Parts.

A new abietane diterpene namely plectrabarbene (2), together with two known compounds: sugiol (1) and 11,14-dihydroxy-8,11,13-abietatrien-7-one (3) have been isolated from the aerial parts of Plectranthus barbatus Andr. (Labiatae). The structures of these compounds were determined by various spectral techniques (e.g., UV, IR, NMR, and FAB) and by comparison with the literature data. A molecular docking study of the isolated diterpenes (1-3) was performed with AChE to gain an insight into their AChE inhibition mechanism. The results of docking experiments revealed that the all tested compounds showed binding affinity at the active site of AchE in comparison to donepezil.

Natural Peroxisome Proliferator-Activated Receptor γ (PPARγ) Activators for Diabetes.

CONTEXT: Metabolic syndrome (MetS) represents a worldwide problem. Drugs used in MetS target different symptoms, like excessive body weight, insulin resistance, hyperglycemia, dyslipidemia, or hypertension. Peroxisome proliferator-activated receptors (PPAR) regulate the gene expression involved in lipid metabolism, inflammation, and adipogenesis. Activation of PPARγ has become a target of interest to counter hyperglycemia linked with MetS and type 2 diabetes (T2DM). OBJECTIVE: The current review intended to summarize reported research on medicinal plants, or their bioactive constituents, with PPARγ-activating potential. DESIGN: The research team searched the literature up to 2016 using electronic databases- ScienceDirect, PubMed, Google-Scholar, SpringerLink, Scopus, and Wiley-for publications on medicinal plants with promising PPARγ modulators using keywords diabetes mellitus, natural products, peroxisome proliferator-activated receptors, metabolic syndrome, adipogenesis. SETTING: This study was conducted in the Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia, Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Cairo, Egypt, and Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al Madinah, Al Munawwarah, Saudi Arabia. RESULTS: Several natural products were considered to be good ligands for PPARγ. The PPARγ agonistic activity of over 100 plants covered in this review was supported by experimental evidence. Some of the plants and their constituents had been studied for their possible mechanisms of action. CONCLUSIONS: Findings discussed in this review highlighted PPARγ's role as an organizer of lipid metabolism and glucose homeostasis, thus supporting its function as a target for antidiabetic agents. The discovery that some natural compounds and plants could activate PPARγ opens up the prospect for future development of strategies to take advantage of its therapeutic potential in diabetes. Therefore, the current review could provide significant information for biotechnological or pharmaceutical applications in targeted drug delivery and design.

Tagetnoic acid, a new lipoxygenase inhibitor peroxy fatty acid from Tagetes minuta growing in Saudi Arabia.

A new peroxy fatty acid, tagetnoic acid (5) [4-((3S,6S)-6-((3E,8E)-octadeca-3,8-dien-1-yl)-3,6-dihydro-1,2-dioxin-3-yl)butanoic acid] and four known metabolites: ecliptal (5-formyl-α-terthiophene) (1), 5-(4-hydroxybut-1-ynyl)-2,2'-bithiophene (2), 22,23-dihydrospinasterone (3), and stigmasterol (4) were separated from the n-hexane fraction of the aerial parts of Tagetes minuta L. (Asteraceae). Their chemical structures were verified using IR, UV, 2D and 1D NMR, and HRMS. Compounds 3-5 displayed potent lipoxygenase inhibitory potential with IC50s 2.26, 1.83, and 1.17 µM, respectively compared to indomethacin (IC50 0.89 µM). Moreover, molecular docking study revealed that the potent activity of 5 is due to H-bonding and hydrophobic interaction. The results of this study suggested that Tagetes minuta dietary consumption would be useful for the individuals at risk of acute and chronic inflammatory disorders.

Perisomalien A, a new cytotoxic scalarane sesterterpene from the fruits of Periploca somaliensis.

The CHCl3 fraction of MeOH extract of Periploca somaliensis (family Asclepiadaceae) fruits afforded a new scalarane sesterterpene, namely perisomalien A (1), along with lupeol acetate (2), ß-amyrin (3), cycloart-23Z-ene-3ß,25-diol (4), and ß-sitosterol-3-O-ß-D-glucopyranoside (5). Their chemical structures were established by various spectroscopic analyses, in addition to comparison with the formerly reported data. Moreover, the cytotoxic activity of these metabolites was assessed towards MCF-7, HepG2, and HCT-116 tumour cell lines using sulforhodamine B (SRB) assay. Compound 4 showed the most potent cytotoxic profile with IC50 9.0 µM towards MCF-7, compared to doxorubicin (IC50 0.18 µM). Also, 1 and 4 possessed the most potent effect towards HepG2 with IC50s 26.7 and 25.9 µM, respectively. In addition, all tested compounds showed cytotoxic effects with IC50 values ranging from 19.9 to 39.3 µM against HCT-116.

Mangostanaxanthone VIII, a new xanthone from Garcinia mangostana and its cytotoxic activity.

A new prenylated xanthone, mangostanaxanthone VIII (7) and six known metabolites: gartanin (1), 1,3,8-trihydroxy-2-(3-methyl-2-butenyl)-4-(3-hydroxy-3-methylbutanoyl)-xanthone (2), rubraxanthone (3), 1,3,6,7-tetrahydroxy-8-prenylxanthone (4), garcinone C (5), and xanthone I (9-hydroxycalabaxanthone) (6) were separated from the EtOAc-soluble fraction of the air-dried pericarps of Garcinia mangostana (Clusiaceae). Their structures have been verified on the basis of spectroscopic data analysis as well as comparison with the literature. The cytotoxic activity of 7 was assessed against MCF7, A549, and HCT116 cell lines using sulforhodamine B (SRB) assay. Compound 7 showed significant cytotoxic potential against MCF7 and A549 cell lines with IC50s 3.01 and 1.96 µM, respectively compared to doxorubicin (0.06 and 0.44 µM, respectively). However, it exhibited moderate activity towards HCT116 cell line.

Protective activity of tovophyllin A, a xanthone isolated from Garcinia mangostana pericarps, against acetaminophen-induced liver damage: role of Nrf2 activation.

Garcinia mangostana L. (GM, family Guttiferae) is one of the most widely recognized tropical fruits. GM is a wealthy pool of xanthones that exhibit a wide range of bioactivities. Tovophyllin A (TA) separated from GM pericarps was tested for its efficacy to ameliorate acetaminophen (APAP)-induced liver injury. Mice were injected with a single dose of APAP with or without TA pretreatment. The protective effects of TA against APAP-induced liver damage were evident through amelioration of serum indices of hepatotoxicity and improvement of hepatic histopathologic lesions. TA has antioxidant activity because it inhibited APAP-induced lipid peroxidation and improved the antioxidant capacity of the liver. Also, TA enhanced the mRNA expression of nuclear erythroid-related factor 2 (Nrf2) and its target genes. Protein expression of Nrf2 and heme oxygenase-1 was enhanced remarkably in TA-pretreated groups. TA suppressed activation of nuclear factor-kappa B (NF-κB) and the subsequent release of pro-inflammatory cytokines. In conclusion, TA has a marked protective activity against APAP-induced hepatotoxicity which may be linked to its ability to activate Nrf2 and inhibit the NF-κB signaling pathway.

Biologically active fungal depsidones: Chemistry, biosynthesis, structural characterization, and bioactivities.

Fungi produce a wide range of structurally unique metabolites. Depsidones represent one of the most interesting classes of metabolites, consisting of two 2,4-dihydroxybenzoic acid rings linked together by both ether and ester bonds. Naturally occurring depsidones are produced by lichen, fungi, and plants. They possessed a wide array of bioactivities, including antioxidant, antiproliferative, antimalarial, cytotoxic, antibacterial, radical scavenging, antihypertensive, anti-inflammatory, antifungal, and aromatase and protein kinase inhibitory. In order to point out the potential of this class of compounds, the present review focuses only on the depsidones that have been isolated from fungal source and published from 1978 to 2018. This review outlined the research on the biosynthesis, source, isolation, spectral and physical data, and bioactivities of the naturally occurring fungal depsidones. On the basis of 88 references, > 80 compounds have been described.