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Natural Products as Drug Candidates for Redox-Related Human Disease

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 40063

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Special Issue Editors

Dr. Jong Heon Kim

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Guest Editor

Foodborne Toxin Detection and Prevention Research Unit, Western Regional Research Center, USDA‐ARS, 800 Buchanan St., Albany, CA 94710, USA
Interests: antifungal intervention; drug repurposing; drug resistance; redox adjuvants; resistance management
Special Issues, Collections and Topics in MDPI journals

Dr. Kirkwood Land

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Co-Guest Editor

Department of Biological Sciences, University of the Pacific, Stockton, CA 95211, USA
Interests: control of microbial growth; drug discovery; treatment for infectious diseases; animal pathogens
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Canhua Huang

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Co-Guest Editor

1. School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
2. West China School of Basic Medical Sciences and Forensic Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Interests: redox regulation in tumorigenesis; the mechanism of virus-induced tumorigenesis
Special Issues, Collections and Topics in MDPI journals

Dr. Sarah Yuan-Yuan Zhang

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Co-Guest Editor

Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Interests: metabolic pharmacology

Special Issue Information

Dear Colleagues,

The disruption of cellular redox homeostasis results in the development of various human diseases/pathologies. For instance, interference of the normal mitochondrial function generates reactive oxygen species (ROS), thus triggering oxidative stress, which is responsible for cardiovascular/neurodegenerative diseases, metabolic disorder and aging. Further examples of oxidative-stress-associated human diseases include Parkinson’s disease, Huntington’s disease, inflammation (arthritis), ischemia–reperfusion injury, atherosclerosis, amyotrophic lateral sclerosis, stroke, red blood cell disorder, cancer, cataract, etc. Therefore, the precise regulation of cellular redox homeostasis is crucial for preventing human diseases.

Conversely, the disruption of cellular antioxidant systems has been used as an effective strategy for the control of infectious pathogens, such as the protozoan parasite Trichomonas vaginalis. Due to their anaerobic lifestyle, T. vaginalis and other protozoa are highly sensitive to ROS, for which thioredoxin-dependent peroxidases play key roles in pathogen defense against oxidative stress. Meanwhile, the invasive fungal pathogen Aspergillus terreus possesses intrinsically higher catalase activity compared to other fungal pathogens, thus exhibiting resistance to the oxidative stress drug amphotericin B. Therefore, disruption of the antioxidant systems of pathogens could serve as an effective method for the control of pathogens.

Natural products that do not pose any significant environmental impact are a potential source of drug candidates for redox-related human diseases, either in their nascent form or as template structures for more effective derivatives. Redox-active natural products, such as sulfur-containing compounds or phenolics, can serve as potent redox cyclers that function as antioxidants for preventing human diseases or prooxidants for inhibiting pathogen growth through destabilization of pathogens’ antioxidant systems.

This Special Issue invites both reviews and original articles elucidating recent progress on natural products that serve as drug candidates for redox-related human diseases. Topics include but are not limited to: cellular targets, drug repurposing, drug synergism, infectious diseases, metabolic diseases, modes of action, natural products, nutritional strategies, oxidative stress, redox molecules, and selective optimization. The collection of manuscripts will be published as a Special Issue of Pharmaceuticals.

Dr. Jong Heon Kim
Dr. Kirkwood Land
Prof. Dr. Canhua Huang
Dr. Sarah Yuan-Yuan Zhang
Guest Editors

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Keywords

cellular target
drug repurposing
drug synergism
infectious disease
metabolic disease
natural products
nutritional strategies
oxidative stress
redox modulation
selective optimization

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Published Papers (11 papers)

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Editorial

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5 pages, 220 KiB

Open AccessEditorial

Natural Products as Drug Candidates for Redox-Related Human Disease

by Jong H. Kim, Kirkwood M. Land, Canhua Huang and Yuan-Yuan Zhang

Pharmaceuticals 2023, 16(9), 1294; https://doi.org/10.3390/ph16091294 - 13 Sep 2023

Viewed by 1365

Abstract

This Special Issue presented recent progress on natural products that serve as drug candidates for redox-related human diseases [...] Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

Research

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14 pages, 6669 KiB

Open AccessArticle

Ciclopirox Olamine Induces Proliferation Inhibition and Protective Autophagy in Hepatocellular Carcinoma

by Xinyan Wan, Junqi Xiang, Hui Fan, Ying Jiang, Yiting Lu, Chundong Zhang, Ying Zhang, Quanmei Chen and Yunlong Lei

Pharmaceuticals 2023, 16(1), 113; https://doi.org/10.3390/ph16010113 - 12 Jan 2023

Cited by 6 | Viewed by 3046

Abstract

Hepatocellular carcinoma is one of the most common fatal malignancies worldwide. Thus far, the hepatocellular carcinoma prognosis has been bleak due to deficiencies in the identification and diagnosis of early hepatocellular carcinoma. Ciclopirox olamine (CPX) is a synthetic antifungal agent and has been considered as an anti-cancer candidate drug recently, though the detailed mechanisms related to its anti-cancer effect in hepatocellular carcinoma have not yet been revealed. Here, we found that CPX could inhibit proliferation in HCC cells but not in intrahepatic cholangiocarcinoma cells by arresting the cell cycle. Moreover, the anti-cancer effects of CPX in HCC cells were also attributed to CPX-triggered ROS accumulation and DJ-1 downregulation. Additionally, CPX could promote complete autophagic flux, which alleviated the anti-cancer effect of CPX in HCC cells, whereas the ROS scavenger (NAC) would attenuate CPX-induced protective autophagy. Interestingly, CPX could also induce glycogen clustering in HCC cells. Altogether, this study provides a new insight into the detailed molecular mechanisms of CPX as an anti-cancer therapy and a strategy for treating hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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14 pages, 5057 KiB

Open AccessArticle

Targeting Annexin A1 as a Druggable Player to Enhance the Anti-Tumor Role of Honokiol in Colon Cancer through Autophagic Pathway

by Xi Wang, Gang Shao, Xiangyu Hong, Yue Shi, Yiting Zheng, Yucheng Yu and Caiyun Fu

Pharmaceuticals 2023, 16(1), 70; https://doi.org/10.3390/ph16010070 - 1 Jan 2023

Cited by 9 | Viewed by 3169

Abstract

Colon cancer is one of the most common digestive tract malignancies, having the second highest mortality rate among all tumors, with a five-year survival of advanced patients of only 10%. Efficient, targeted drugs are still lacking in treating colon cancer, so it is urgent to explore novel druggable targets. Here, we demonstrated that annexin A1 (ANXA1) was overexpressed in tumors of 50% of colon cancer patients, and ANXA1 overexpression was significantly negatively correlated with the poor prognosis of colon cancer. ANXA1 promoted the abnormal proliferation of colon cancer cells in vitro and in vivo by regulating the cell cycle, while the knockdown of ANXA1 almost totally inhibited the growth of colon cancer cells in vivo. Furthermore, ANXA1 antagonized the autophagic death of honokiol in colon cancer cells via stabilizing mitochondrial reactive oxygen species. Based on these results, we speculated that ANXA1 might be a druggable target to control colon cancer and overcome drug resistance. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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13 pages, 3086 KiB

Open AccessArticle

Gold Nanoparticles Encapsulated Resveratrol as an Anti-Aging Agent to Delay Cataract Development

by Qifang Chen, Peilin Gu, Xuemei Liu, Shaohua Hu, Hong Zheng, Ting Liu and Chongyi Li

Pharmaceuticals 2023, 16(1), 26; https://doi.org/10.3390/ph16010026 - 25 Dec 2022

Cited by 11 | Viewed by 3428

Abstract

Nanoparticle-based drug delivery systems, which can overcome the challenges associated with poor aqueous solubility and other harmful side effects of drugs, display potent applications in cataract treatment. Herein, we designed a nanosystem of gold nanoparticles containing resveratrol (RGNPs) as an anti-aging agent to delay cataracts. The spherical RGNPs had a superior ability to inhibit hydrogen peroxide-mediated oxidative stress damage, including reactive oxygen species (ROS) production, malondialdehyde (MDA) generation, and glutathione (GSH) consumption in the lens epithelial cells. Additionally, the present data showed that RGNPs could delay cellular senescence induced by oxidative stress by decreasing the protein levels of p16 and p21, reducing the ratio of BAX/BCL-2 and the senescence-associated secretory phenotype (SASP) in vitro. Moreover, the RGNPs could also clearly relieve sodium selenite-induced lens opacity in a rat cataract model. Our data indicated that cell senescence was reduced and cataracts were delayed upon treatment with RGNPs through activating the Sirt1/Nrf2 signaling pathway. Our findings suggested that RGNPs could serve as an anti-aging ingredient, highlighting their potential to delay cataract development. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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15 pages, 1593 KiB

Open AccessArticle

Pharmacological Properties of Jaeumgeonbi-Tang on Redox System and Stress-Related Hormones in Chronic Subjective Dizziness: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial

by Chan-young Kim, Hyeong-Geug Kim, Hye Won Lee, In-Chan Seol, Yoon-Sik Kim, Hyung Il Choi, Miso S. Park and Ho-Ryong Yoo

Pharmaceuticals 2022, 15(11), 1375; https://doi.org/10.3390/ph15111375 - 9 Nov 2022

Cited by 3 | Viewed by 1802

Abstract

Jaeumgeonbi-Tang (JGT), a traditional herbal medicine, has been used to treat dizziness and vertigo in Korea and China for hundreds of years. The purpose of this study was to evaluate the pharmacological properties of JGT in chronic subjective dizziness (CSD) patients. A randomized, double-blind, parallel-group and placebo-controlled trial was performed with a total of 50 CSD patients. The patients were randomly assigned to one of two groups: JGT or placebo (n = 25 for each). All participants received the treatment (placebo or JGT, 24 g/day) for 4 weeks. We analyzed the serum levels of oxidative stressors, antioxidants, and stress hormones. Serum levels of lipid peroxidation, but not nitric oxide, were significantly decreased in the JGT group. JGT not only prevented the decline of serum total glutathione contents and total antioxidant capacity, but it also increased superoxide dismutase and catalase activities. Serum levels of stress hormones including cortisol, adrenaline, and serotonin were notably normalized by JGT treatment, but noradrenaline levels were not affected. Regarding the safety and tolerability of JGT, we found no allergic, adverse, or side effects in any of the participants. JGT showed beneficial effects on CSD patients by improving redox status and balancing psycho-emotional stress hormones. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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18 pages, 44922 KiB

Open AccessArticle

Biotransformation of (–)-Isopulegol by Rhodococcus rhodochrous

by Irina B. Ivshina, Natalia A. Luchnikova, Polina Yu. Maltseva, Irina V. Ilyina, Konstantin P. Volcho, Yurii V. Gatilov, Dina V. Korchagina, Nadezhda A. Kostrikina, Vladimir V. Sorokin, Andrey L. Mulyukin and Nariman F. Salakhutdinov

Pharmaceuticals 2022, 15(8), 964; https://doi.org/10.3390/ph15080964 - 3 Aug 2022

Cited by 5 | Viewed by 2692

Abstract

The ability of actinobacteria of the genus Rhodococcus to biotransform the monoterpenoid (–)-isopulegol has been established for the first time. R. rhodochrous strain IEGM 1362 was selected as a bacterium capable of metabolizing (–)-isopulegol to form new, previously unknown, 10-hydroxy (2) and 10-carboxy (3) derivatives, which may presumably have antitumor activity and act as respiratory stimulants and cancer prevention agents. In the experiments, optimal conditions were selected to provide the maximum target catalytic activity of rhodococci. Using up-to-date (TEM, AFM-CLSM, and EDX) and traditional (cell size, roughness, and zeta potential measurements) biophysical and microbiological methods, it was shown that (–)-isopulegol and halloysite nanotubes did not negatively affect the bacterial cells. The data obtained expand our knowledge of the biocatalytic potential of rhodococci and their possible involvement in the synthesis of pharmacologically active compounds from plant derivatives. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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Review

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24 pages, 9486 KiB

Open AccessReview

Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases: Expanding the Therapeutic Approaches by Plant-Derived Natural Products

by Xiaoyue Zhang, Longqin Wang, Bowen Li, Jiayan Shi, Jia Xu and Minlan Yuan

Pharmaceuticals 2023, 16(2), 277; https://doi.org/10.3390/ph16020277 - 13 Feb 2023

Cited by 14 | Viewed by 6264

Abstract

Mitochondria are the primary source of energy production in neurons, supporting the high energy consumption of the nervous system. Inefficient and dysfunctional mitochondria in the central nervous system have been implicated in neurodegenerative diseases. Therefore, targeting mitochondria offers a new therapeutic opportunity for neurodegenerative diseases. Many recent studies have proposed that plant-derived natural products, as pleiotropic, safe, and readily obtainable sources of new drugs, potentially treat neurodegenerative diseases by targeting mitochondria. In this review, we summarize recent advances in targeting mitochondria in neurotherapeutics by employing plant-derived natural products. We discuss the mechanism of plant-derived natural products according to their mechanism of action on mitochondria in terms of regulating biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability, as well as repairing damaged mitochondria. In addition, we discuss the potential perspectives and challenges in developing plant-derived natural products to target mitochondria, highlighting the clinical value of phytochemicals as feasible candidates for future neurotherapeutics. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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23 pages, 2177 KiB

Open AccessReview

Distinct Role of Lycium barbarum L. Polysaccharides in Oxidative Stress-Related Ocular Diseases

by Yali Niu, Guoheng Zhang, Xiaojia Sun, Shikun He and Guorui Dou

Pharmaceuticals 2023, 16(2), 215; https://doi.org/10.3390/ph16020215 - 31 Jan 2023

Cited by 11 | Viewed by 3759

Abstract

Oxidative stress is an imbalance between the increased production of reactive species and reduced antioxidant activity, which can cause a variety of disturbances including ocular diseases. Lycium barbarum polysaccharides (LBPs) are complex polysaccharides isolated from the fruit of L. barbarum, showing distinct roles in antioxidants. Moreover, it is relatively safe and non-toxic. In recent years, the antioxidant activities of LBPs have attracted remarkable attention. In order to illustrate its significance and underlying therapeutic value for vision, we comprehensively review the recent progress on the antioxidant mechanisms of LBP and its potential applications in ocular diseases, including diabetic retinopathy, hypertensive neuroretinopathy, age-related macular degeneration, retinitis pigmentosa, retinal ischemia/reperfusion injury, glaucoma, dry eye syndrome, and diabetic cataract. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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23 pages, 1883 KiB

Open AccessReview

Nano-Based Drug Delivery of Polyphenolic Compounds for Cancer Treatment: Progress, Opportunities, and Challenges

by Wenhui Jia, Li Zhou, Lei Li, Ping Zhou and Zhisen Shen

Pharmaceuticals 2023, 16(1), 101; https://doi.org/10.3390/ph16010101 - 10 Jan 2023

Cited by 20 | Viewed by 5287

Abstract

Polyphenols and their derivates, a kind of natural product distributed in herb plants, vegetables, and fruits, are the most abundant antioxidants in the human diet and have been found to display cancer-preventative effects in several epidemiological studies. The scientific community has also validated the anti-cancer bioactivities and low toxicities of polyphenolic compounds, including flavones, tannins, phenolic acids, and anthocyanins, through in vitro and in vivo studies. However, the low stability, weak targeting ability, poor solubility, and low bioavailability of pure polyphenolic agents have significantly impaired their treatment efficacy. Nowadays, nano-based technology has been applied to surmount these restrictions and maximize the treatment efficacy of polyphenols. In this review, we summarize the advantages and related mechanisms of polyphenols in cancer treatment. Moreover, aiming at the poor solubility and low bioavailability of pure polyphenols in vivo, the advantages of nano-based delivery systems and recent research developments are highlighted. Herein, particular emphasis is mainly placed on the most widely used nanomaterials in the delivery of natural products, including liposomes, micelles, and nanogels. Finally, we present an overview and the challenges of future implementations of nano-based delivery systems of polyphenolic compounds in the cancer therapeutic field. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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25 pages, 1178 KiB

Open AccessReview

Targeting the Interplay of Autophagy and ROS for Cancer Therapy: An Updated Overview on Phytochemicals

by Lixia Dong, Jingqiu He, Li Luo and Kui Wang

Pharmaceuticals 2023, 16(1), 92; https://doi.org/10.3390/ph16010092 - 8 Jan 2023

Cited by 32 | Viewed by 4572

Abstract

Autophagy is an evolutionarily conserved self-degradation system that recycles cellular components and damaged organelles, which is critical for the maintenance of cellular homeostasis. Intracellular reactive oxygen species (ROS) are short-lived molecules containing unpaired electrons that are formed by the partial reduction of molecular oxygen. It is widely known that autophagy and ROS can regulate each other to influence the progression of cancer. Recently, due to the wide potent anti-cancer effects with minimal side effects, phytochemicals, especially those that can modulate ROS and autophagy, have attracted great interest of researchers. In this review, we afford an overview of the complex regulatory relationship between autophagy and ROS in cancer, with an emphasis on phytochemicals that regulate ROS and autophagy for cancer therapy. We also discuss the effects of ROS/autophagy inhibitors on the anti-cancer effects of phytochemicals, and the challenges associated with harnessing the regulation potential on ROS and autophagy of phytochemicals for cancer therapy. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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21 pages, 2146 KiB

Open AccessReview

Exploiting Polyphenol-Mediated Redox Reorientation in Cancer Therapy

by Lei Li, Ping Jin, Yueyue Guan, Maochao Luo, Yu Wang, Bo He, Bowen Li, Kai He, Jiangjun Cao, Canhua Huang, Jingquan Li and Zhisen Shen

Pharmaceuticals 2022, 15(12), 1540; https://doi.org/10.3390/ph15121540 - 12 Dec 2022

Cited by 11 | Viewed by 2674

Abstract

Polyphenol, one of the major components that exert the therapeutic effect of Chinese herbal medicine (CHM), comprises several categories, including flavonoids, phenolic acids, lignans and stilbenes, and has long been studied in oncology due to its significant efficacy against cancers in vitro and in vivo. Recent evidence has linked this antitumor activity to the role of polyphenols in the modulation of redox homeostasis (e.g., pro/antioxidative effect) in cancer cells. Dysregulation of redox homeostasis could lead to the overproduction of reactive oxygen species (ROS), resulting in oxidative stress, which is essential for many aspects of tumors, such as tumorigenesis, progression, and drug resistance. Thus, investigating the ROS-mediated anticancer properties of polyphenols is beneficial for the discovery and development of novel pharmacologic agents. In this review, we summarized these extensively studied polyphenols and discussed the regulatory mechanisms related to the modulation of redox homeostasis that are involved in their antitumor property. In addition, we discussed novel technologies and strategies that could promote the development of CHM-derived polyphenols to improve their versatile anticancer properties, including the development of novel delivery systems, chemical modification, and combination with other agents. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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