International Journal of Molecular Sciences

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13 pages, 1931 KiB

Open AccessArticle

Biotransformation of Xanthohumol by Entomopathogenic Filamentous Fungi

by Daniel Łój, Tomasz Janeczko, Agnieszka Bartmańska, Ewa Huszcza and Tomasz Tronina

Int. J. Mol. Sci. 2024, 25(19), 10433; https://doi.org/10.3390/ijms251910433 - 27 Sep 2024

Cited by 1 | Viewed by 589

Xanthohumol (1) is a major prenylated flavonoid in hops (Humulus lupulus L.) which exhibits a broad spectrum of health-promoting and therapeutic activities, including anti-inflammatory, antioxidant, antimicrobial, and anticancer effects. However, due to its lipophilic nature, it is poorly soluble in [...] Read more.

Xanthohumol (1) is a major prenylated flavonoid in hops (Humulus lupulus L.) which exhibits a broad spectrum of health-promoting and therapeutic activities, including anti-inflammatory, antioxidant, antimicrobial, and anticancer effects. However, due to its lipophilic nature, it is poorly soluble in water and barely absorbed from the gastrointestinal tract, which greatly limits its therapeutic potential. One method of increasing the solubility of active compounds is their conjugation to polar molecules, such as sugars. Sugar moiety introduced into the flavonoid molecule significantly increases polarity, which results in better water solubility and often leads to greater bioavailability. Entomopathogenic fungi are well known for their ability to catalyze O-glycosylation reactions. Therefore, we investigated the ability of selected entomopathogenic filamentous fungi to biotransform xanthohumol (1). As a result of the experiments, one aglycone (2) and five glycosides (3–7) were obtained. The obtained (2″E)-4″-hydroxyxanthohumol 4′-O-β-D-(4‴-O-methyl)-glucopyranoside (5) has never been described in the literature so far. Interestingly, in addition to the expected glycosylation reactions, the tested fungi also catalyzed chalcone–flavanone cyclization reactions, which demonstrates chalcone isomerase-like activity, an enzyme typically found in plants. All these findings undoubtedly indicate that entomopathogenic filamentous fungi are still an underexploited pool of novel enzymes. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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14 pages, 4196 KiB

Open AccessArticle

LcSAO1, an Unconventional DOXB Clade 2OGD Enzyme from Ligusticum chuanxiong Catalyzes the Biosynthesis of Plant-Derived Natural Medicine Butylphthalide

by Xueqing Chen, Xiaopeng Zhang, Wenkai Sun, Zhuangwei Hou, Bao Nie, Fengjiao Wang, Song Yang, Shourui Feng, Wei Li and Li Wang

Int. J. Mol. Sci. 2023, 24(24), 17417; https://doi.org/10.3390/ijms242417417 - 13 Dec 2023

Viewed by 1402

Abstract

Butylphthalide, a prescription medicine recognized for its efficacy in treating ischemic strokes approved by the State Food and Drug Administration of China in 2005, is sourced from the traditional botanical remedy Ligusticum chuanxiong. While chemical synthesis offers a viable route, limitations in [...] Read more.

Butylphthalide, a prescription medicine recognized for its efficacy in treating ischemic strokes approved by the State Food and Drug Administration of China in 2005, is sourced from the traditional botanical remedy Ligusticum chuanxiong. While chemical synthesis offers a viable route, limitations in the production of isomeric variants with compromised bioactivity necessitate alternative strategies. Addressing this issue, biosynthesis offers a promising solution. However, the intricate in vivo pathway for butylphthalide biosynthesis remains elusive. In this study, we examined the distribution of butylphthalide across various tissues of L. chuanxiong and found a significant accumulation in the rhizome. By searching transcriptome data from different tissues of L. chuanxiong, we identified four rhizome-specific genes annotated as 2-oxoglutarate-dependent dioxygenase (2-OGDs) that emerged as promising candidates involved in butylphthalide biosynthesis. Among them, LcSAO1 demonstrates the ability to catalyze the desaturation of senkyunolide A at the C-4 and C-5 positions, yielding the production of butylphthalide. Experimental validation through transient expression assays in Nicotiana benthamiana corroborates this transformative enzymatic activity. Notably, phylogenetic analysis of LcSAO1 revealed that it belongs to the DOXB clade, which typically encompasses genes with hydroxylation activity, rather than desaturation. Further structure modelling and site-directed mutagenesis highlighted the critical roles of three amino acid residues, T98, S176, and T178, in substrate binding and enzyme activity. By unraveling the intricacies of the senkyunolide A desaturase, the penultimate step in the butylphthalide biosynthesis cascade, our findings illuminate novel avenues for advancing synthetic biology research in the realm of medicinal natural products. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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11 pages, 1796 KiB

Open AccessArticle

Identification of P450 Candidates Associated with the Biosynthesis of Physalin-Class Compounds in Physalis angulata

by Congkun Hua, Zhengqin Xu, Nan Tang, Yehan Xu, Yansheng Zhang and Changfu Li

Int. J. Mol. Sci. 2023, 24(18), 14077; https://doi.org/10.3390/ijms241814077 - 14 Sep 2023

Cited by 2 | Viewed by 1226

Abstract

The Physalis genus has long been used as traditional medicine in the treatment of various diseases. Physalins, the characteristic class of compounds in this genus, are major bioactive constituents. To date, the biogenesis of physalins remains largely unknown, except for the recently established [...] Read more.

The Physalis genus has long been used as traditional medicine in the treatment of various diseases. Physalins, the characteristic class of compounds in this genus, are major bioactive constituents. To date, the biogenesis of physalins remains largely unknown, except for the recently established knowledge that 24-methyldesmosterol is a precursor of physalin. To identify the genes encoding P450s that are putatively involved in converting 24-methyldesmosterol to physalins, a total of 306 P450-encoding unigenes were retrieved from our recently constructed P. angulata transcriptome. Extensive phylogenetic analysis proposed 21 P450s that might participate in physalin biosynthesis. To validate the candidates, we developed a virus-induced gene silencing (VIGS) system for P. angulata, and four P450 candidates were selected for the VIGS experiments. The reduction in the transcripts of the four P450 candidates by VIGS all led to decreased levels of physalin-class compounds in the P. angulata leaves. Thus, this study provides a number of P450 candidates that are likely associated with the biosynthesis of physalin-class compounds, forming a strong basis to reveal the unknown physalin biosynthetic pathway in the future. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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10 pages, 2036 KiB

Open AccessArticle

The Dipeptide Gly-Pro (GP), Derived from Hibiscus sabdariffa, Exhibits Potent Antifibrotic Effects by Regulating the TGF-β1-ATF4-Serine/Glycine Biosynthesis Pathway

by HaiVin Kim, YoungSu Jang, JaeSang Ryu, DaHye Seo, Sak Lee, SungSoo Choi, DongHyun Kim, SangHyun Moh and JungU Shin

Int. J. Mol. Sci. 2023, 24(17), 13616; https://doi.org/10.3390/ijms241713616 - 3 Sep 2023

Cited by 1 | Viewed by 1730

Abstract

TGF-β1, a key fibrotic cytokine, enhances both the expression and translocation of the activating transcriptional factor 4 (ATF4) and activates the serine/glycine biosynthesis pathway, which is crucial for augmenting collagen production. Targeting the TGF-β1-ATF4-serine/glycine biosynthesis pathway might offer a promising therapeutic approach for [...] Read more.

TGF-β1, a key fibrotic cytokine, enhances both the expression and translocation of the activating transcriptional factor 4 (ATF4) and activates the serine/glycine biosynthesis pathway, which is crucial for augmenting collagen production. Targeting the TGF-β1-ATF4-serine/glycine biosynthesis pathway might offer a promising therapeutic approach for fibrotic diseases. In this study, we aimed to identify a proline-containing dipeptide in Hibiscus sabdariffa plant cells that modulates collagen synthesis. We induced Hibiscus sabdariffa plant cells and screened for a proline-containing dipeptide that can suppress TGF-β1-induced collagen synthesis in fibroblasts. Analyses were conducted using LC-MS/MS, RT-qPCR, Western blot analysis, and immunocytochemistry. We identified Gly-Pro (GP) from the extract of Hibiscus sabdariffa plant cells as a dipeptide capable of suppressing TGF-β1-induced collagen production. GP inhibited the phosphorylation of Smad2/3 and reduced the expression of ATF4, which is upregulated by TGF-β1. Notably, GP also decreased the expression of enzymes involved in the serine/glycine biosynthesis and glucose metabolism pathways, such as PHGDH, PSAT1, PSPH, SHMT2, and SLC2A1. Our findings indicate that the peptide GP, derived from Hibiscus sabdariffa plant cells, exhibits potent anti-fibrotic effects, potentially through its regulation of the TGF-β1-ATF4-serine/glycine biosynthesis pathway. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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21 pages, 5833 KiB

Open AccessArticle

Comparative Analysis of Water Extracts from Roselle (Hibiscus sabdariffa L.) Plants and Callus Cells: Constituents, Effects on Human Skin Cells, and Transcriptome Profiles

by Won Kyong Cho, Soo-Yun Kim, Sung Joo Jang, Sak Lee, Hye-In Kim, Euihyun Kim, Jeong Hun Lee, Sung Soo Choi and Sang Hyun Moh

Int. J. Mol. Sci. 2023, 24(13), 10853; https://doi.org/10.3390/ijms241310853 - 29 Jun 2023

Cited by 4 | Viewed by 2450

Abstract

Roselle (Hibiscus sabdariffa L.) is a plant that has traditionally been used in various food and beverage products. Here, we investigated the potential of water extracts derived from Roselle leaves and callus cells for cosmetic and pharmaceutical purposes. We generated calluses from [...] Read more.

Roselle (Hibiscus sabdariffa L.) is a plant that has traditionally been used in various food and beverage products. Here, we investigated the potential of water extracts derived from Roselle leaves and callus cells for cosmetic and pharmaceutical purposes. We generated calluses from Roselle leaves and produced two different water extracts through heat extraction, which we named Hibiscus sabdariffa plant extract (HSPE) and Hibiscus sabdariffa callus extract (HSCE). HPLC analysis showed that the two extracts have different components, with nucleic acids and metabolites such as phenylalanine and tryptophan being the most common components in both extracts. In vitro assays demonstrated that HSCE has strong anti-melanogenic effects and functions for skin barrier and antioxidant activity. Transcriptome profiling of human skin cells treated with HSPE and HSCE showed significant differences, with HSPE having more effects on human skin cells. Up-regulated genes by HSPE function in angiogenesis, the oxidation-reduction process, and glycolysis, while up-regulated genes by HSCE encode ribosome proteins and IFI6, functioning in the healing of radiation-injured skin cells. Therefore, we suggest that the two extracts from Roselle should be applied differently for cosmetics and pharmaceutical purposes. Our findings demonstrate the potential of Roselle extracts as a natural source for skincare products. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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25 pages, 6380 KiB

Open AccessArticle

Synthesis and Anticancer Activity of A-Ring-Modified Derivatives of Dihydrobetulin

by Irina Tolmacheva, Yulia Beloglazova, Mikhail Nazarov, Olga Gagarskikh and Victoria Grishko

Int. J. Mol. Sci. 2023, 24(12), 9863; https://doi.org/10.3390/ijms24129863 - 7 Jun 2023

Cited by 3 | Viewed by 1812

Abstract

Multidrug resistance (MDR) is a common phenomenon in clinical oncology, whereby cancer cells become resistant to chemotherapeutic drugs. A common MDR mechanism is the overexpression of ATP-binding cassette efflux transporters in cancer cells, with P-glycoprotein (P-gp) being one of them. New 3,4-seco-lupane [...] Read more.

Multidrug resistance (MDR) is a common phenomenon in clinical oncology, whereby cancer cells become resistant to chemotherapeutic drugs. A common MDR mechanism is the overexpression of ATP-binding cassette efflux transporters in cancer cells, with P-glycoprotein (P-gp) being one of them. New 3,4-seco-lupane triterpenoids, and the products of their intramolecular cyclization with the removed 4,4-gem-dimethyl group, were synthesized by the selective transformations of the A-ring of dihydrobetulin. Among the semi-synthetic derivatives, the MT-assay-enabled methyl ketone 31 (MK), exhibiting the highest cytotoxicity (0.7–16.6 µM) against nine human cancer cell lines, including P-gp overexpressing subclone HBL-100/Dox, is identified. In silico, MK has been classified as a potential P-gp-inhibitor; however, the Rhodamine 123 efflux test, and the combined use of P-gp-inhibitor verapamil with MK in vitro, showed the latter to be neither an inhibitor nor a substrate of P-gp. As the studies have shown, the cytotoxic effect of MK against HBL-100/Dox cells is, arguably, induced through the activation of the ROS-mediated mitochondrial pathway, as evidenced by the positive Annexin V-FITC staining of apoptotic cells, the cell cycle arrest in the G0/G1 phase, mitochondrial dysfunction, cytochrome c release, and the activation of caspase-9 and -3. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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16 pages, 7958 KiB

Open AccessArticle

Caffeic Acid Phenethyl Ester and Caffeamide Derivatives Suppress Oral Squamous Cell Carcinoma Cells

by Yin-Hwa Shih, Chieh-Chieh Chen, Yueh-Hsiung Kuo, Lih-Jyh Fuh, Wan-Chen Lan, Tong-Hong Wang, Kuo-Chou Chiu, Thanh-Hien Vu Nguyen, Shih-Min Hsia and Tzong-Ming Shieh

Int. J. Mol. Sci. 2023, 24(12), 9819; https://doi.org/10.3390/ijms24129819 - 6 Jun 2023

Cited by 7 | Viewed by 1815

Abstract

Caffeic acid phenethyl ester (CAPE) contains antibiotic and anticancer activities. Therefore, we aimed to investigate the anticancer properties and mechanisms of CAPE and caffeamide derivatives in the oral squamous cell carcinoma cell (OSCC) lines SAS and OECM-1. The anti-OSCC effects of CAPE and [...] Read more.

Caffeic acid phenethyl ester (CAPE) contains antibiotic and anticancer activities. Therefore, we aimed to investigate the anticancer properties and mechanisms of CAPE and caffeamide derivatives in the oral squamous cell carcinoma cell (OSCC) lines SAS and OECM-1. The anti-OSCC effects of CAPE and the caffeamide derivatives (26G, 36C, 36H, 36K, and 36M) were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Cell cycle and total reactive oxygen species (ROS) production were analyzed using flow cytometry. The relative protein expression of malignant phenotypes was determined via Western blot analysis. The results showed that 26G and 36M were more cytotoxic than the other compounds in SAS cells. After 26G or 36M treatment for 48 h, cell cycle S phase or G2/M phase arrest was induced, and cellular ROS increased at 24 h, and then decreased at 48 h in both cell lines. The expression levels of cell cycle regulatory and anti-ROS proteins were downregulated. In addition, 26G or 36M treatment inhibited malignant phenotypes through mTOR-ULK1-P62-LC3 autophagic signaling activated by ROS generation. These results showed that 26G and 36M induce cancer cell death by activating autophagy signaling, which is correlated with altered cellular oxidative stress. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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36 pages, 3766 KiB

Open AccessArticle

Elaboration of the Effective Multi-Target Therapeutic Platform for the Treatment of Alzheimer’s Disease Based on Novel Monoterpene-Derived Hydroxamic Acids

by Yulia Aleksandrova, Aldar Munkuev, Evgenii Mozhaitsev, Evgenii Suslov, Dmitry Tsypyshev, Kirill Chaprov, Roman Begunov, Konstantin Volcho, Nariman Salakhutdinov and Margarita Neganova

Int. J. Mol. Sci. 2023, 24(11), 9743; https://doi.org/10.3390/ijms24119743 - 4 Jun 2023

Cited by 4 | Viewed by 2349

Abstract

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene [...] Read more.

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene moiety through aliphatic (hexa/heptamethylene) or aromatic linkers. An in vitro analysis of biological activity demonstrated that some of these molecules had powerful HDAC6 inhibitory activity, with the presence of a linker area in the structure of compounds playing a key role. In particular, it was found that hydroxamic acids containing a hexa- and heptamethylene linker and (-)-perill fragment in the Cap group exhibit excellent inhibitory activity against HDAC6 with IC₅₀ in the submicromolar range from 0.56 ± 0.01 µM to 0.74 ± 0.02 µM. The results of the study of antiradical activity demonstrated the presence of moderate ability for some hydroxamic acids to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2ROO^• radicals. The correlation coefficient between the DPPH radical scavenging activity and oxygen radical absorbance capacity (ORAC) value was R² = 0.8400. In addition, compounds with an aromatic linker based on para-substituted cinnamic acids, having a monocyclic para-menthene skeleton as a Cap group, 35a, 38a, 35b and 38b, demonstrated a significant ability to suppress the aggregation of the pathological β-amyloid peptide 1-42. The 35a lead compound with a promising profile of biological activity, discovered in the in vitro experiments, demonstrated neuroprotective effects on in vivo models of Alzheimer’s disease using 5xFAD transgenic mice. Together, the results obtained demonstrate a potential strategy for the use of monoterpene-derived hydroxamic acids for treatment of various aspects of Alzheimer’s disease. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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15 pages, 6747 KiB

Open AccessArticle

Biosynthesis of Novel Ascorbic Acid Esters and Their Encapsulation in Lignin Nanoparticles as Carriers and Stabilizing Systems

by Eliana Capecchi, Davide Piccinino, Chiara Nascimben, Elisabetta Tomaino, Natalia Ceccotti Vlas, Sofia Gabellone and Raffaele Saladino

Int. J. Mol. Sci. 2023, 24(10), 9044; https://doi.org/10.3390/ijms24109044 - 20 May 2023

Cited by 3 | Viewed by 2504

Abstract

A dual-target strategy was designed for the application of lignin nanoparticles in the lipase mediated biosynthesis of novel 3-O-ethyl-L-ascorbyl-6-ferulate and 3-O-ethyl-L-ascorbyl-6-palmitate and in their successive solvent-shift encapsulation in order to improve stability and antioxidant activity against temperature and pH-dependent [...] Read more.

A dual-target strategy was designed for the application of lignin nanoparticles in the lipase mediated biosynthesis of novel 3-O-ethyl-L-ascorbyl-6-ferulate and 3-O-ethyl-L-ascorbyl-6-palmitate and in their successive solvent-shift encapsulation in order to improve stability and antioxidant activity against temperature and pH-dependent degradation. The loaded lignin nanoparticles were fully characterized in terms of kinetic release, radical scavenging activity and stability under pH 3 and thermal stress (60 °C), showing improved antioxidant activity and high efficacy in the protection of ascorbic acid esters from degradation. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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14 pages, 1532 KiB

Open AccessArticle

Acacia senegal Budmunchiamines as a Potential Adjuvant for Rejuvenating Phenicol Activities towards Escherichia coli-Resistant Strains

by René Dofini Magnini, François Pedinielli, Julia Vergalli, Noufou Ouedraogo, Simon Remy, Adama Hilou, Jean-Michel Brunel, Jean-Marie Pagès and Anne Davin-Regli

Int. J. Mol. Sci. 2023, 24(10), 8790; https://doi.org/10.3390/ijms24108790 - 15 May 2023

Cited by 1 | Viewed by 2072

Abstract

The continuous emergence of bacterial resistance alters the activities of different antibiotic families and requires appropriate strategies to solve therapeutic impasses. Medicinal plants are an attractive source for researching alternative and original therapeutic molecules. In this study, the fractionation of natural extracts from [...] Read more.

The continuous emergence of bacterial resistance alters the activities of different antibiotic families and requires appropriate strategies to solve therapeutic impasses. Medicinal plants are an attractive source for researching alternative and original therapeutic molecules. In this study, the fractionation of natural extracts from A. senegal and the determination of antibacterial activities are associated with molecular networking and tandem mass spectrometry (MS/MS) data used to characterize active molecule(s). The activities of the combinations, which included various fractions plus an antibiotic, were investigated using the “chessboard” test. Bio-guided fractionation allowed the authors to obtain individually active or synergistic fractions with chloramphenicol activity. An LC-MS/MS analysis of the fraction of interest and molecular array reorganization showed that most identified compounds are Budmunchiamines (macrocyclic alkaloids). This study describes an interesting source of bioactive secondary metabolites structurally related to Budmunchiamines that are able to rejuvenate a significant chloramphenicol activity in strains that produce an AcrB efflux pump. They will pave the way for researching new active molecules for restoring the activity of antibiotics that are substrates of efflux pumps in enterobacterial-resistant strains. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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16 pages, 3005 KiB

Open AccessArticle

Uncovering the Cryptic Gene Cluster ahb for 3-amino-4-hydroxybenzoate Derived Ahbamycins, by Searching SARP Regulator Encoding Genes in the Streptomyces argillaceus Genome

by Suhui Ye, Brian Molloy, Ignacio Pérez-Victoria, Ignacio Montero, Alfredo F. Braña, Carlos Olano, Sonia Arca, Jesús Martín, Fernando Reyes, José A. Salas and Carmen Méndez

Int. J. Mol. Sci. 2023, 24(9), 8197; https://doi.org/10.3390/ijms24098197 - 3 May 2023

Cited by 5 | Viewed by 1955

Abstract

Genome mining using standard bioinformatics tools has allowed for the uncovering of hidden biosynthesis gene clusters for specialized metabolites in Streptomyces genomes. In this work, we have used an alternative approach consisting in seeking “Streptomyces Antibiotic Regulatory Proteins” (SARP) encoding genes and [...] Read more.

Genome mining using standard bioinformatics tools has allowed for the uncovering of hidden biosynthesis gene clusters for specialized metabolites in Streptomyces genomes. In this work, we have used an alternative approach consisting in seeking “Streptomyces Antibiotic Regulatory Proteins” (SARP) encoding genes and analyzing their surrounding DNA region to unearth cryptic gene clusters that cannot be identified using standard bioinformatics tools. This strategy has allowed the unveiling of the new ahb cluster in Streptomyces argillaceus, which had not been retrieved before using antiSMASH. The ahb cluster is highly preserved in other Streptomyces strains, which suggests a role for their encoding compounds in specific environmental conditions. By combining overexpression of three regulatory genes and generation of different mutants, we were able to activate the ahb cluster, and to identify and chemically characterize the encoded compounds that we have named ahbamycins (AHBs). These constitute a new family of metabolites derived from 3-amino-4-hydroxybenzoate (3,4-AHBA) known for having antibiotic and antitumor activity. Additionally, by overexpressing three genes of the cluster (ahbH, ahbI, and ahbL2) for the synthesis and activation of 3,4-AHBA, a new hybrid compound, AHB18, was identified which had been produced from a metabolic crosstalk between the AHB and the argimycin P pathways. The identification of this new BGC opens the possibility to generate new compounds by combinatorial biosynthesis. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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16 pages, 1225 KiB

Open AccessArticle

Synthesis and Evaluation of Hypoglycemic Activity of Structural Isomers of ((Benzyloxy)phenyl)propanoic Acid Bearing an Aminobornyl Moiety

by Sergey O. Kuranov, Darya A. Pon`kina, Yulia V. Meshkova, Mariya K. Marenina, Mikhail V. Khvostov, Olga A. Luzina, Tatiana G. Tolstikova and Nariman F. Salakhutdinov

Int. J. Mol. Sci. 2023, 24(9), 8022; https://doi.org/10.3390/ijms24098022 - 28 Apr 2023

Cited by 1 | Viewed by 1526

Abstract

Free fatty acid receptor-1 (FFAR1) agonists are promising candidates for therapy of type 2 diabetes because of their ability to normalize blood sugar levels during hyperglycemia without the risk of hypoglycemia. Previously, we synthesized compound QS-528, a FFA1 receptor agonist with a [...] Read more.

Free fatty acid receptor-1 (FFAR1) agonists are promising candidates for therapy of type 2 diabetes because of their ability to normalize blood sugar levels during hyperglycemia without the risk of hypoglycemia. Previously, we synthesized compound QS-528, a FFA1 receptor agonist with a hypoglycemic effect in C57BL/6NCrl mice. In the present work, structural analogs of QS-528 based on (hydroxyphenyl)propanoic acid bearing a bornyl fragment in its structure were synthesized. The seven novel compounds synthesized were structural isomers of compound QS-528, varying the positions of the substituents in the aromatic fragments as well as the configuration of the asymmetric center in the bornyl moiety. The studied compounds were shown to have the ability to activate FFAR1 at a concentration of 10 μM. The cytotoxicity of the compounds as well as their effect on glucose uptake in HepG2 cells were studied. The synthesized compounds were found to increase glucose uptake by cells and have no cytotoxic effect. Two compounds, based on the meta-substituted phenylpropanoic acid, 3-(3-(4-(((1R,2R,4R)-1,7,7-trimethylbicyclo-[2.2.1]heptan-2-ylamino)methyl)benzyloxy)phenyl)propanoic acid and 3-(3-(3-(((1R,2R,4R)-1,7,7-trimethylbicyclo [2.2.1]heptan-2-ylamino)methyl)benzyloxy)phenyl)propanoic acid, were shown to have a pronounced hypoglycemic effect in the oral glucose tolerance test with CD-1 mice. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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11 pages, 1917 KiB

Open AccessArticle

Inhibitory Effects of Thermolysis Transformation Products of Rotenone on Nitric Oxide Production

by Gyeong Han Jeong, Hanui Lee, Seung Sik Lee, Byung Yeoup Chung, Hyoung-Woo Bai and Tae Hoon Kim

Int. J. Mol. Sci. 2023, 24(7), 6095; https://doi.org/10.3390/ijms24076095 - 23 Mar 2023

Cited by 1 | Viewed by 1480

Abstract

Rotenone, isolated from Derris, Lonchocarpus, and Tephrosia from the family Fabaceae, has been shown to have a variety of biological properties and is used in various agricultural industries as a potent biopesticide. However, recent reports have demonstrated that rotenone has the [...] Read more.

Rotenone, isolated from Derris, Lonchocarpus, and Tephrosia from the family Fabaceae, has been shown to have a variety of biological properties and is used in various agricultural industries as a potent biopesticide. However, recent reports have demonstrated that rotenone has the potential to cause several adverse effects such as a neurodegenerative disease. This study aimed to induce thermolysis of the biopesticide rotenone and enhance the functionality of the degraded products. Rotenone (1) was degraded after autoclaving for 12 h, and the thermolytic reactants showed enhanced anti-inflammatory capacity against nitric oxide (NO) production. The structures of the newly modified products were spectroscopically determined. The thermal reaction products included various isoflavonoid derivatives 2–6, whose structures were characterized as being produced via chemical reactions in rotenone at the C-12 positions. Among the degraded products, (−)-tubaic acid (6) exhibited significantly improved anti-inflammatory effects compared to the original rotenone. Quantitative LC-MS analysis of the major thermolysis products generated in Derris extract containing rotenone was performed using isolate 2–5 purified from autoclaved rotenone. These results suggest that the thermal transformation of rotenone can improve the functionality of anti-inflammatory agents. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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13 pages, 1944 KiB

Open AccessArticle

New Data on Anti-Inflammatory and Wound Healing Potential of Transgenic Senna obtusifolia Hairy Roots: In Vitro Studies

by Tomasz Kowalczyk, Przemysław Sitarek, Tomasz Śliwiński, Sophia Hatziantoniou, Nikolitsa Soulintzi, Rafal Pawliczak and Joanna Wieczfinska

Int. J. Mol. Sci. 2023, 24(6), 5906; https://doi.org/10.3390/ijms24065906 - 21 Mar 2023

Cited by 2 | Viewed by 2002

Abstract

Asthma is an inflammatory disease whose etiology remains unclear. Its characteristics encompass a wide range of clinical symptoms, inflammatory processes, and reactions to standard therapies. Plants produce a range of constitutive products and secondary metabolites that may have therapeutic abilities. The aim of [...] Read more.

Asthma is an inflammatory disease whose etiology remains unclear. Its characteristics encompass a wide range of clinical symptoms, inflammatory processes, and reactions to standard therapies. Plants produce a range of constitutive products and secondary metabolites that may have therapeutic abilities. The aim of this study was to determine the effects of Senna obtusifolia transgenic hairy root extracts on virus-induced airway remodeling conditions. Three cell lines were incubated with extracts from transformed (SOA4) and transgenic (SOPSS2, with overexpression of the gene encoding squalene synthase 1) hairy roots of Senna obtusifolia in cell lines undergoing human rhinovirus-16 (HRV-16) infection. The effects of the extracts on the inflammatory process were determined based on the expression of inflammatory cytokines (IL-8, TNF-α, IL-1α and IFN-γ) and total thiol content. The transgenic Senna obtusifolia root extract reduced virus-induced expression of TNF, IL-8 and IL-1 in WI-38 and NHBE cells. The SOPSS2 extract reduced IL-1 expression only in lung epithelial cells. Both tested extracts significantly increased the concentration of thiol groups in epithelial lung cells. In addition, the SOPPS2 hairy root extract yielded a positive result in the scratch test. SOA4 and SOPPS2 Senna obtusifolia hairy root extracts demonstrated anti-inflammatory effects or wound healing activity. The SOPSS2 extract had stronger biological properties, which may result from a higher content of bioactive secondary metabolites. Full article

(This article belongs to the Special Issue Biosynthesis and Application of Natural Compound)

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