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Natural Products in Drug Discovery and Development
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Natural Products in Drug Discovery and Development

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 31 December 2025 | Viewed by 4170

Special Issue Editor

Dr. Tian-Le Gao

E-Mail Website
Guest Editor
Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China
Interests: innovative drugs; natural products; chronic pain

Special Issue Information

Dear Colleagues,

As traditional medicine continues to inspire modern pharmacology, researchers are increasingly turning to nature for solutions to pressing health challenges. In recent years, natural products have gained significant attention for their therapeutic potential. This Special Issue aims to compile research articles, reviews, and case studies that delve into various aspects of these topics. Through multidisciplinary approaches and innovative research methodologies, we aim to unlock the full potential of natural products in drug discovery and development.

Key areas of focus include:

  • Analysis and identification of natural product components.
  • Pharmacological actions of natural compounds.
  • Clinical efficacy and safety of natural products.
  • Neg-entropy mechanisms in disease treatment and prevention.
  • Pharmacological properties of aromatic drugs.
  • Effects of essential oils on human health.
  • Health benefits of probiotics.

Dr. Tian-Le Gao
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • natural product components
  • traditional medicine
  • biological entropy reduction
  • aromatic drugs
  • essential oils
  • gut microbiota modulation
  • probiotics
  • drug discovery

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Published Papers (6 papers)

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Research

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21 pages, 8307 KiB  
Article
Isochlorogenic Acid C Alleviates Allergic Asthma via Interactions Between Its Bioactive Form and the Gut Microbiome
by Jing-Yi Xu, Xiao-Juan Rong, Zhen Shen, Yun-Dan Guo, Yi-Xuan Zhang, Chen-Chen Ding, Yi Wang, Yan-Xing Han, Tian-Le Gao and Cai Tie
Int. J. Mol. Sci. 2025, 26(10), 4864; https://doi.org/10.3390/ijms26104864 - 19 May 2025
Viewed by 272
Abstract
The global prevalence of asthma is approximately 4.3%, and current asthma treatments focus on reducing symptoms, maintaining normal activity levels, and preventing the deterioration of lung function, rather than achieving a cure or complete prevention. We identified isochlorogenic acid C (ICGAC) as a [...] Read more.
The global prevalence of asthma is approximately 4.3%, and current asthma treatments focus on reducing symptoms, maintaining normal activity levels, and preventing the deterioration of lung function, rather than achieving a cure or complete prevention. We identified isochlorogenic acid C (ICGAC) as a potential natural medicine for the treatment of asthma. However, the bioavailability of ICGAC was low, ranging from 14.4% to 16.9%, suggesting the involvement of the gut microbiota. The full spectrum of ICGAC’s anti-asthmatic mechanism remains to be elucidated. This study investigated the mechanism by which ICGAC alleviates allergic asthma through the gut–lung axis. We discovered anti-asthma pathways and targets based on the selective regulation of lipid peroxidation and employed pharmacological tools to preliminarily validate their mechanisms and efficacy. To study the role of ICGAC in regulating the gut microbiota, we performed 16S rRNA gene sequencing and metabolite analysis. Furthermore, by combining molecular biology and lipid metabolomics, we elucidated the underlying anti-asthma mechanisms of ICGAC. The effective form of ICGAC varies between single and long-term administration. The oral administration of ICGAC enhances the gut-microbiota-derived production of short-chain fatty acids (SCFAs) as the active substances, modulates immune cell activity, influences the differentiation of T- and B-cells, and reduces airway inflammation. ICGAC also regulates the metabolic network of lipid mediators (LMs) and polyunsaturated fatty acids (PUFAs), thus exerting anti-inflammatory effects by modulating arachidonate lipoxygenase (ALOX) activity and LM levels. In addition, ICGAC enhanced the antioxidant response by upregulating the expression of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and nuclear factor erythroid 2-related factor 2 (Nrf2), while inhibiting the release of interleukin-4 (IL-4), thereby suppressing asthma inflammation and IgE production. The anti-asthmatic mechanism of oral ICGAC involves the inhibition of lipid peroxidation by chlorogenic acid (CGA) and SCFAs produced by the gut microbiota. ICGAC suppresses asthma-associated inflammatory and oxidative stress responses through the upregulation of GPX4, SLC7A11, and Nrf2 in lung tissue. This study not only provides a solid foundation for the potential clinical use of ICGAC in asthma treatment but also offers novel insights for future research and therapeutic strategies targeting asthma. Full article
(This article belongs to the Special Issue Natural Products in Drug Discovery and Development)
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18 pages, 3713 KiB  
Article
Exploring the Multi-Faceted Effects of Berberine in Ameliorating Diastolic Dysfunction in Rats with Heart Failure with Preserved Ejection Fraction
by Yu Mu, Jing Geng, Chilu Liu, Shuang Jiang, Yanxing Han, Jiandong Jiang and Yuhong Wang
Int. J. Mol. Sci. 2025, 26(10), 4847; https://doi.org/10.3390/ijms26104847 - 19 May 2025
Viewed by 240
Abstract
Heart failure with preserved ejection fraction (HFpEF), marked by cardiac diastolic dysfunction, contributes to half of all heart failure cases globally and poses a significant public health challenge. Effective therapies for HFpEF are rare, largely due to its complex and heterogeneous pathophysiology, which [...] Read more.
Heart failure with preserved ejection fraction (HFpEF), marked by cardiac diastolic dysfunction, contributes to half of all heart failure cases globally and poses a significant public health challenge. Effective therapies for HFpEF are rare, largely due to its complex and heterogeneous pathophysiology, which often involves multiple comorbidities. Berberine (BBR), an isoquinoline alkaloid, has demonstrated beneficial effects on multiple metabolic and cardiovascular disorders; however, its impact on cardiac diastolic dysfunction in HFpEF remains poorly understood. In this study, we utilized a rat model of HFpEF induced by a sustained high-fat/high-sucrose (HFHS) diet to explore the impact and mechanisms of BBR on diastolic dysfunction. The results revealed that BBR administration effectively alleviated cardiac diastolic dysfunction and alleviated extracardiac comorbidities, including increased weight, impaired glucose tolerance, hypercholesterolemia and hypertension, in rats fed an HFHS diet. Furthermore, BBR mitigated myocardial inflammation, oxidative stress, microvascular endothelial dysfunction, and notably restored the disturbed NO-cGMP-PKG pathway. Additionally, BBR reduced myocardial fibrosis and inhibited the abnormally activated TGF-β/Smads signaling. Moreover, BBR attenuated the systemic inflammation and corrected immune dysregulation in an HFHS diet-fed rats. Our study suggests that BBR exhibits multi-beneficial effects in the prevention and management of HFpEF, demonstrating its potential as a holistic therapeutic candidate for HFpEF. Full article
(This article belongs to the Special Issue Natural Products in Drug Discovery and Development)
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18 pages, 7539 KiB  
Article
Identification of a Novel Antagonist of BRS-3 from Natural Products and Its Protective Effects Against H2O2-Induced Cardiomyocyte Injury
by Jihong Lu, Lehao Wu, Jianzheng Zhu, Han Zhou, Mingzhu Fang, Hongshuo Liang, Miao Guo, Mo Chen, Yuhang Zhu, Jixia Wang, Hua Xiao and Yan Zhang
Int. J. Mol. Sci. 2025, 26(6), 2745; https://doi.org/10.3390/ijms26062745 - 18 Mar 2025
Viewed by 454
Abstract
The identification of exogenous ligands from natural products is an alternative strategy to explore the unrevealed physiological functions of orphan G-protein-coupled receptors (GPCRs). In this study, we have successfully identified and pharmacologically characterized licoisoflavone A (LIA) as a novel selective antagonist of BRS-3, [...] Read more.
The identification of exogenous ligands from natural products is an alternative strategy to explore the unrevealed physiological functions of orphan G-protein-coupled receptors (GPCRs). In this study, we have successfully identified and pharmacologically characterized licoisoflavone A (LIA) as a novel selective antagonist of BRS-3, an orphan GPCR. Functional studies showed that pretreatment with LIA ameliorated hydrogen peroxide (H2O2)-induced cardiomyocyte injury. Furthermore, LIA pretreatment significantly restored the activities of malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT), as well as lactate dehydrogenase (LDH) levels, in H9c2 cells following H2O2 exposure. The protective effect of LIA was also evident in primary cardiomyocytes from rats and mice against H2O2-induced cell injury but was absent in primary cardiomyocytes derived from bombesin receptor subtype-3 knockout (Brs3−/y) mice, strongly confirming the mechanism of LIA’s action through BRS-3 antagonism. Proteomics studies further revealed that LIA exerted its protective effects via activating the integrin/ILK/AKT and ERK/MAPK signaling pathways. Complementary findings from Bantag-1, a well-recognized antagonist of BRS-3, in human embryonic kidney 293 mBRS-3 (HEK293-mBRS-3) stable cells and B16 cell lines, which demonstrated resistance to H2O2-induced damage, further supported the pivotal role of BRS-3 in oxidative stress-induced cell injury. Our study contributes to expanding our understanding of the potential pharmacological functions of BRS-3, unveiling previously unknown pharmacological functionality of this orphan receptor. Full article
(This article belongs to the Special Issue Natural Products in Drug Discovery and Development)
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24 pages, 10350 KiB  
Article
Using Integrated Network Pharmacology and Metabolomics to Reveal the Mechanisms of the Combined Intervention of Ligustrazine and Sinomenine in CCI-Induced Neuropathic Pain Rats
by Zhaoyue Yuan, Xiaoliang Zhao, Yan Zhang, Yue Jiao, Yang Liu, Chang Gao, Jidan Zhang, Yanyan Ma, Zhiguo Wang and Tao Li
Int. J. Mol. Sci. 2025, 26(6), 2604; https://doi.org/10.3390/ijms26062604 - 13 Mar 2025
Viewed by 566
Abstract
Neuropathic pain (NP) is a type of chronic pain resulting from injury or dysfunction of the nerves or spinal cord. Previous studies have shown that the combination of ligustrazine (LGZ) and sinomenine (SIN) exerts a synergistic antinociceptive effect in peripheral and central NP [...] Read more.
Neuropathic pain (NP) is a type of chronic pain resulting from injury or dysfunction of the nerves or spinal cord. Previous studies have shown that the combination of ligustrazine (LGZ) and sinomenine (SIN) exerts a synergistic antinociceptive effect in peripheral and central NP models. On this basis, a comprehensive analgesic evaluation was performed in a chronic constriction injury (CCI)-induced NP model in rats. Sciatic nerve histopathological changes were observed, and 22 cytokines and chemokines levels were analyzed. We also combined network pharmacology and metabolomics to explore their molecular mechanisms. Results showed that the combination of LGZ and SIN significantly alleviated the pain-like behaviors in CCI rats in a time- and dose-dependent manner, demonstrating superior therapeutic effects compared to LGZ or SIN alone. It also improved pathological damage to sciatic nerves and regulated inflammatory cytokine levels. Network pharmacology identified shared and distinct pain-related targets for LGZ and SIN, while metabolomics revealed 54 differential metabolites in plasma, and 17 differential metabolites in CSF were associated with the combined intervention of LGZ and SIN. Finally, through an integrated analysis of the core targets and differential metabolites, tyrosine metabolism, phenylalanine metabolism, and arginine and proline metabolism were identified as potential key metabolic pathways underlying the therapeutic effects of LGZ and SIN in CCI treatment. In conclusion, our study provides evidence to support the clinical application of LGZ and SIN in the treatment of NP. Full article
(This article belongs to the Special Issue Natural Products in Drug Discovery and Development)
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24 pages, 17079 KiB  
Article
Enhancing the Therapeutic Efficacy of Berberine and Quercetin Through Salt Formulation for Liver Fibrosis Treatment
by Yangyang Cheng, Haoyang Yu, Sitong Yang, Xiaolian Tian, Mengyu Zhao, Ling Ren, Xiuping Guo, Chujuan Hu, Jiandong Jiang and Lulu Wang
Int. J. Mol. Sci. 2025, 26(5), 2193; https://doi.org/10.3390/ijms26052193 - 28 Feb 2025
Viewed by 838
Abstract
Liver fibrosis, caused by chronic hepatic injury, is a major threat to human health worldwide, as there are no specific drugs available for its treatment. Natural compounds, such as berberine (BBR) and quercetin (QR), have shown the ability to regulate energy metabolism and [...] Read more.
Liver fibrosis, caused by chronic hepatic injury, is a major threat to human health worldwide, as there are no specific drugs available for its treatment. Natural compounds, such as berberine (BBR) and quercetin (QR), have shown the ability to regulate energy metabolism and protect the liver without significant adverse effects. Additionally, combination therapy (the cocktail therapy approach), using multiple drugs, has shown promise in treating complicated conditions, including liver injury. In this study, we prepared a salt formulation of BBR and QR (BQS) to enhance their combined effect on liver fibrosis. The formation of BQS was confirmed using various analytical techniques, including nuclear magnetic resonance spectroscopy (NMR), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), powder X-ray diffractometry (PXRD), and scanning electron microscopy (SEM). The results demonstrated that the dissolution efficiency and bioavailability of QR significantly increased in the BQS form, aligning with that of BBR, compared to the physically mixed (BQP) form. Moreover, BQS exhibited a superior inhibitory effect on fibrosis compared to BQP in the human hepatic stellate cell line LX-2 by modulating lipid accumulation, inflammation, apoptosis, and the cell cycle. Furthermore, in a mouse model of hepatic fibrosis induced by methionine and choline-deficient (MCD) diets, BQS demonstrated enhanced anti-fibrotic activities compared to BQP. These findings suggest that BQS holds promise as a potential alternative treatment for liver fibrosis. Importantly, this study provides novel insights into achieving a cocktail effect through the salt formation of two or more drugs. The results highlight the potential of salt formulations in enhancing the therapeutic efficacy and consistent biological processes of drug combinations. Full article
(This article belongs to the Special Issue Natural Products in Drug Discovery and Development)
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10 pages, 1702 KiB  
Brief Report
Synergistic Effects of a Novel Combination of Natural Compounds Prevent H2O2-Induced Oxidative Stress in Red Blood Cells
by Giuditta Benincasa, Paola Bontempo, Ugo Trama and Claudio Napoli
Int. J. Mol. Sci. 2025, 26(3), 1334; https://doi.org/10.3390/ijms26031334 - 5 Feb 2025
Viewed by 1162
Abstract
Novel strategies to prevent the “storage lesions” of red blood cells (RBCs) are needed to prevent the risk of adverse effects after blood transfusion. One option could be the supplementation of stored blood bags with natural compounds that may increase the basal load [...] Read more.
Novel strategies to prevent the “storage lesions” of red blood cells (RBCs) are needed to prevent the risk of adverse effects after blood transfusion. One option could be the supplementation of stored blood bags with natural compounds that may increase the basal load of antioxidant protection and the shelf life of RBCs. In this pilot study, we investigated for the first time potential synergistic effects of a triple combination of well-known anti-oxidant compounds curcumin (curc), vitamin E (vit E), and vitamin C (vit C). Briefly, we established an ex vivo model of H2O2-induced oxidative stress and measured the hemolysis ratio (HR) (%) and thiobarbituric acid reactive substances (TBARS) levels in RBCs with or without pre-exposure for 30 min with increasing concentrations of curc, vit E, and vit C and then exposed to 10 mM H2O2. for 60 min. Exposure of RBCs to a triple combination of curc, vit E, and vit C at the highest concentration (100 µM) completely prevented H2O2-induced hemolysis. Surprisingly, we found that pre-treatment of RBCs with curc 100 µM alone completely prevented hemolysis as compared to vit E and vit C alone or in combination at the same concentration. On the other hand, pre-treatment with the triple combination of curc, vit E, and vit C 100 µM was required to totally prevent lipid peroxidation, as compared to curc 100 µM alone, supporting their synergistic effects in preventing RBCs membrane peroxidation. Further experiments are ongoing to investigate the anti-aging effects of the triple combination of curc, vit E, and vit C on cold-stored bags. Full article
(This article belongs to the Special Issue Natural Products in Drug Discovery and Development)
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