International Journal of Molecular Sciences

34 pages, 2599 KiB

Open AccessReview

Recent Progress in Research on Mechanisms of Action of Natural Products against Alzheimer’s Disease: Dietary Plant Polyphenols

by Yi Wang, Kaiyue Wang, Junyuan Yan, Qian Zhou and Xiaoying Wang

Int. J. Mol. Sci. 2022, 23(22), 13886; https://doi.org/10.3390/ijms232213886 - 11 Nov 2022

Cited by 6 | Viewed by 2214

Abstract

Alzheimer’s disease (AD) is an incurable degenerative disease of the central nervous system and the most common type of dementia in the elderly. Despite years of extensive research efforts, our understanding of the etiology and pathogenesis of AD is still highly limited. Nevertheless, [...] Read more.

Alzheimer’s disease (AD) is an incurable degenerative disease of the central nervous system and the most common type of dementia in the elderly. Despite years of extensive research efforts, our understanding of the etiology and pathogenesis of AD is still highly limited. Nevertheless, several hypotheses related to risk factors for AD have been proposed. Moreover, plant-derived dietary polyphenols were also shown to exert protective effects against neurodegenerative diseases such as AD. In this review, we summarize the regulatory effects of the most well-known plant-derived dietary polyphenols on several AD-related molecular mechanisms, such as amelioration of oxidative stress injury, inhibition of aberrant glial cell activation to alleviate neuroinflammation, inhibition of the generation and promotion of the clearance of toxic amyloid-β (Aβ) plaques, inhibition of cholinesterase enzyme activity, and increase in acetylcholine levels in the brain. We also discuss the issue of bioavailability and the potential for improvement in this regard. This review is expected to encourage further research on the role of natural dietary plant polyphenols in the treatment of AD. Full article

(This article belongs to the Special Issue Research on Plant Bioactive Phytochemical)

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16 pages, 27359 KiB

Open AccessArticle

Discovery of Flavonoids as Novel Inhibitors of ATP Citrate Lyase: Structure–Activity Relationship and Inhibition Profiles

by Pan Wang, Tao Hou, Fangfang Xu, Fengbin Luo, Han Zhou, Fan Liu, Xiaomin Xie, Yanfang Liu, Jixia Wang, Zhimou Guo and Xinmiao Liang

Int. J. Mol. Sci. 2022, 23(18), 10747; https://doi.org/10.3390/ijms231810747 - 15 Sep 2022

Cited by 5 | Viewed by 2293

Abstract

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism and its aberrantly high expression is closely associated with various cancers, hyperlipemia and atherosclerotic cardiovascular diseases. Prospects of ACLY inhibitors as treatments of these diseases are excellent. To date, flavonoids have not [...] Read more.

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism and its aberrantly high expression is closely associated with various cancers, hyperlipemia and atherosclerotic cardiovascular diseases. Prospects of ACLY inhibitors as treatments of these diseases are excellent. To date, flavonoids have not been extensively reported as ACLY inhibitors. In our study, 138 flavonoids were screened and 21 of them were subjected to concentration–response curves. A remarkable structure–activity relationship (SAR) trend was found: ortho-dihydroxyphenyl and a conjugated system maintained by a pyrone ring were critical for inhibitory activity. Among these flavonoids, herbacetin had a typical structure and showed a non–aggregated state in solution and a high inhibition potency (IC₅₀ = 0.50 ± 0.08 μM), and therefore was selected as a representative for the ligand–protein interaction study. In thermal shift assays, herbacetin improved the thermal stability of ACLY, suggesting a direct interaction with ACLY. Kinetic studies determined that herbacetin was a noncompetitive inhibitor of ACLY, as illustrated by molecular docking and dynamics simulation. Together, this work demonstrated flavonoids as novel and potent ACLY inhibitors with a remarkable SAR trend, which may help design high–potency ACLY inhibitors. In–depth studies of herbacetin deepened our understanding of the interactions between flavonoids and ACLY. Full article

(This article belongs to the Special Issue Research on Plant Bioactive Phytochemical)

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33 pages, 1896 KiB

Open AccessReview

A Comprehensive Review on Beneficial Effects of Catechins on Secondary Mitochondrial Diseases

by Baoyi Chen, Wenting Zhang, Chuyuan Lin and Lingyun Zhang

Int. J. Mol. Sci. 2022, 23(19), 11569; https://doi.org/10.3390/ijms231911569 - 30 Sep 2022

Cited by 6 | Viewed by 2098

Abstract

Mitochondria are the main sites for oxidative phosphorylation and synthesis of adenosine triphosphate in cells, and are known as cellular power factories. The phrase “secondary mitochondrial diseases” essentially refers to any abnormal mitochondrial function other than primary mitochondrial diseases, i.e., the process caused [...] Read more.

Mitochondria are the main sites for oxidative phosphorylation and synthesis of adenosine triphosphate in cells, and are known as cellular power factories. The phrase “secondary mitochondrial diseases” essentially refers to any abnormal mitochondrial function other than primary mitochondrial diseases, i.e., the process caused by the genes encoding the electron transport chain (ETC) proteins directly or impacting the production of the machinery needed for ETC. Mitochondrial diseases can cause adenosine triphosphate (ATP) synthesis disorder, an increase in oxygen free radicals, and intracellular redox imbalance. It can also induce apoptosis and, eventually, multi-system damage, which leads to neurodegenerative disease. The catechin compounds rich in tea have attracted much attention due to their effective antioxidant activity. Catechins, especially acetylated catechins such as epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), are able to protect mitochondria from reactive oxygen species. This review focuses on the role of catechins in regulating cell homeostasis, in which catechins act as a free radical scavenger and metal ion chelator, their protective mechanism on mitochondria, and the protective effect of catechins on mitochondrial deoxyribonucleic acid (DNA). This review highlights catechins and their effects on mitochondrial functional metabolic networks: regulating mitochondrial function and biogenesis, improving insulin resistance, regulating intracellular calcium homeostasis, and regulating epigenetic processes. Finally, the indirect beneficial effects of catechins on mitochondrial diseases are also illustrated by the warburg and the apoptosis effect. Some possible mechanisms are shown graphically. In addition, the bioavailability of catechins and peracetylated-catechins, free radical scavenging activity, mitochondrial activation ability of the high-molecular-weight polyphenol, and the mitochondrial activation factor were also discussed. Full article

(This article belongs to the Special Issue Research on Plant Bioactive Phytochemical)

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22 pages, 2785 KiB

Open AccessArticle

Methanolic Extracts of D. viscosa Specifically Affect the Cytoskeleton and Exert an Antiproliferative Effect on Human Colorectal Cancer Cell Lines, According to Their Proliferation Rate

by Chiara Anglana, Makarena Rojas, Chiara Roberta Girelli, Fabrizio Barozzi, Josefa Quiroz-Troncoso, Nicolás Alegría-Aravena, Anna Montefusco, Miriana Durante, Francesco Paolo Fanizzi, Carmen Ramírez-Castillejo and Gian-Pietro Di Sansebastiano

Int. J. Mol. Sci. 2023, 24(19), 14920; https://doi.org/10.3390/ijms241914920 - 05 Oct 2023

Viewed by 998

Abstract

Numerous studies have reported the pharmacological effects exhibited by Dittrichia viscosa, (D. viscosa) including antioxidant, cytotoxic, antiproliferative, and anticancer properties. In our research, our primary objective was to validate a prescreening methodology aimed at identifying the fraction that demonstrates the [...] Read more.

Numerous studies have reported the pharmacological effects exhibited by Dittrichia viscosa, (D. viscosa) including antioxidant, cytotoxic, antiproliferative, and anticancer properties. In our research, our primary objective was to validate a prescreening methodology aimed at identifying the fraction that demonstrates the most potent antiproliferative and anticancer effects. Specifically, we investigated the impact of various extract fractions on the cytoskeleton using a screening method involving transgenic plants. Tumors are inherently heterogeneous, and the components of the cytoskeleton, particularly tubulin, are considered a strategic target for antitumor agents. To take heterogeneity into account, we used different lines of colorectal cancer, specifically one of the most common cancers regardless of gender. In patients with metastasis, the effectiveness of chemotherapy has been limited by severe side effects and by the development of resistance. Additional therapies and antiproliferative molecules are therefore needed. In our study, we used colon-like cell lines characterized by the expression of gastrointestinal differentiation markers (such as the HT-29 cell line) and undifferentiated cell lines showing the positive regulation of epithelial–mesenchymal transition and TGFβ signatures (such as the DLD-1, SW480, and SW620 cell lines). We showed that all three of the D. viscosa extract fractions have an antiproliferative effect but the pre-screening on transgenic plants anticipated that the methanolic fraction may be the most promising, targeting the cytoskeleton specifically and possibly resulting in fewer side effects. Here, we show that the preliminary use of screening in transgenic plants expressing subcellular markers can significantly reduce costs and focus the advanced characterization only on the most promising therapeutic molecules. Full article

(This article belongs to the Special Issue Research on Plant Bioactive Phytochemical)

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15 pages, 4965 KiB

Open AccessReview

Lavandula Species, Their Bioactive Phytochemicals, and Their Biosynthetic Regulation

by Miroslav Habán, Joanna Korczyk-Szabó, Simona Čerteková and Katarína Ražná

Int. J. Mol. Sci. 2023, 24(10), 8831; https://doi.org/10.3390/ijms24108831 - 16 May 2023

Cited by 4 | Viewed by 1966

Abstract

Lavandula species are one of the most useful aromatic and medicinal plants and have great economic potential. The phytopharmaceutical contribution of the secondary metabolites of the species is unquestionable. Most recent studies have been focusing on the elucidation of the genetic background of [...] Read more.

Lavandula species are one of the most useful aromatic and medicinal plants and have great economic potential. The phytopharmaceutical contribution of the secondary metabolites of the species is unquestionable. Most recent studies have been focusing on the elucidation of the genetic background of secondary metabolite production in lavender species. Therefore, knowledge of not only genetic but especially epigenetic mechanisms for the regulation of secondary metabolites is necessary for the modification of those biosynthesis processes and the understanding of genotypic differences in the content and compositional variability of these products. The review discusses the genetic diversity of Lavandula species in relation to the geographic area, occurrence, and morphogenetic factors. The role of microRNAs in secondary-metabolites biosynthesis is described. Full article

(This article belongs to the Special Issue Research on Plant Bioactive Phytochemical)

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15 pages, 8525 KiB

Open AccessArticle

Saikosaponin A and Saikosaponin C Reduce TNF-α-Induced TSLP Expression through Inhibition of MAPK-Mediated EGR1 Expression in HaCaT Keratinocytes

by Sung Shin Ahn, Young Han Lee, Hyunjin Yeo, Euitaek Jung, Yoongho Lim and Soon Young Shin

Int. J. Mol. Sci. 2022, 23(9), 4857; https://doi.org/10.3390/ijms23094857 - 27 Apr 2022

Cited by 5 | Viewed by 2294

Abstract

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide, characterized by intense pruritus and eczematous lesions. Aberrant expression of thymic stromal lymphopoietin (TSLP) in keratinocytes is associated with the pathogenesis of AD and is considered a therapeutic target [...] Read more.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide, characterized by intense pruritus and eczematous lesions. Aberrant expression of thymic stromal lymphopoietin (TSLP) in keratinocytes is associated with the pathogenesis of AD and is considered a therapeutic target for the treatment of this disease. Saikosaponin A (SSA) and saikosaponin C (SSC), identified from Radix Bupleuri, exert anti-inflammatory effects. However, the topical effects of SSA and SSC on chronic inflammatory skin diseases are unclear. In this study, we investigated the effects of SSA and SSC on TSLP suppression in an AD-like inflammatory environment. We observed that SSA and SSC suppressed tumor necrosis factor-α-induced TSLP expression by downregulating the expression of the transcription factor early growth response 1 (EGR1) via inhibition of the extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase 1/2, and p38 mitogen-activated protein kinase pathways. We also confirmed that topical application of SSA or SSC reduced AD-like skin lesions in BALB/c mice challenged with 2,4-dinitrochlorobenzene. Our findings suggest that suppression of EGR1-regulated TSLP expression in keratinocytes might be attributable to the anti-inflammatory effects of SSA and SSC in AD-like skin lesions. Full article

(This article belongs to the Special Issue Research on Plant Bioactive Phytochemical)

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22 pages, 1897 KiB

Open AccessReview

Pentacyclic Triterpenoid Phytochemicals with Anticancer Activity: Updated Studies on Mechanisms and Targeted Delivery

by Madalina Nistor, Dumitrita Rugina, Zorita Diaconeasa, Carmen Socaciu and Mihai Adrian Socaciu

Int. J. Mol. Sci. 2023, 24(16), 12923; https://doi.org/10.3390/ijms241612923 - 18 Aug 2023

Cited by 3 | Viewed by 1267

Abstract

Pentacyclic triterpenoids (TTs) represent a unique family of phytochemicals with interesting properties and pharmacological effects, with some representatives, such as betulinic acid (BA) and betulin (B), being mainly investigated as potential anticancer molecules. Considering the recent scientific and preclinical investigations, a review of [...] Read more.

Pentacyclic triterpenoids (TTs) represent a unique family of phytochemicals with interesting properties and pharmacological effects, with some representatives, such as betulinic acid (BA) and betulin (B), being mainly investigated as potential anticancer molecules. Considering the recent scientific and preclinical investigations, a review of their anticancer mechanisms, structure-related activity, and efficiency improved by their insertion in nanolipid vehicles for targeted delivery is presented. A systematic literature study about their effects on tumor cells in vitro and in vivo, as free molecules or encapsulated in liposomes or nanolipids, is discussed. A special approach is given to liposome-TTs and nanolipid-TTs complexes to be linked to microbubbles, known as contrast agents in ultrasonography. The production of such supramolecular conjugates to deliver the drugs to target cells via sonoporation represents a new scientific and applicative direction to improve TT efficiency, considering that they have limited availability as lipophilic molecules. Relevant and recent examples of in vitro and in vivo studies, as well as the challenges for the next steps towards the application of these complex delivery systems to tumor cells, are discussed, as are the challenges for the next steps towards the application of targeted delivery to tumor cells, opening new directions for innovative nanotechnological solutions. Full article

(This article belongs to the Special Issue Research on Plant Bioactive Phytochemical)

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16 pages, 2753 KiB

Open AccessReview

Impact of Rutin and Other Phenolic Substances on the Digestibility of Buckwheat Grain Metabolites

by Ivan Kreft, Mateja Germ, Aleksandra Golob, Blanka Vombergar, Francesco Bonafaccia and Zlata Luthar

Int. J. Mol. Sci. 2022, 23(7), 3923; https://doi.org/10.3390/ijms23073923 - 01 Apr 2022

Cited by 18 | Viewed by 3381

Abstract

Tartary buckwheat (Fagopyrum tataricum Gaertn.) is grown in eastern and central Asia (the Himalayan regions of China, Nepal, Bhutan and India) and in central and eastern Europe (Luxemburg, Germany, Slovenia and Bosnia and Herzegovina). It is known for its high concentration of [...] Read more.

Tartary buckwheat (Fagopyrum tataricum Gaertn.) is grown in eastern and central Asia (the Himalayan regions of China, Nepal, Bhutan and India) and in central and eastern Europe (Luxemburg, Germany, Slovenia and Bosnia and Herzegovina). It is known for its high concentration of rutin and other phenolic metabolites. Besides the grain, the other aboveground parts of Tartary buckwheat contain rutin as well. After the mixing of the milled buckwheat products with water, the flavonoid quercetin is obtained in the flour–water mixture, a result of rutin degradation by rutinosidase. Heating by hot water or steam inactivates the rutin-degrading enzymes in buckwheat flour and dough. The low buckwheat protein digestibility is due to the high content of phenolic substances. Phenolic compounds have low absorption after food intake, so, after ingestion, they remain for some time in the gastrointestinal tract. They can act in an inhibitory manner on enzymes, degrading proteins and other food constituents. In common and Tartary buckwheat, the rutin and quercetin complexation with protein and starch molecules has an impact on the in vitro digestibility and the appearance of resistant starch and slowly digestible proteins. Slowly digestible starch and proteins are important for the functional and health-promoting properties of buckwheat products. Full article

(This article belongs to the Special Issue Research on Plant Bioactive Phytochemical)

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