Natural Products Research Articles

Imidazo[1,2-A]Pyridine: Potent Biological Activity, SAR and Docking Investigations (2017-2022).

Regarding scientific research, Imidazo[1,2-a] pyridine derivatives are constantly being developed due to the scaffold's intriguing chemical structure and varied biological activity. They are distinctive organic nitrogen-bridged heterocyclic compounds that have several uses in medicines, organometallics and natural products. It has become a vital tool for medicinal chemists. In order to gather scientific information on Imidazo[1,2-a] pyridines derivative, Google, PubMed, Scopus, Google Scholar, and other databases were searched. In the current study, the medicinal value and therapeutic effect of Imidazo[1,2-a] pyridines were investigated using above mentioned databases. The current study analyzed the detailed pharmacological activities of Imidazo[1,2-a] pyridine analogs through literature from diverse scientific research works. Due to its wide range of biological activities, including antiulcer, anticonvulsant, antiprotozoal, anthelmintic, antiepileptic, antifungal, antibacterial, analgesic, antiviral, anticancer, anti-inflammatory, antituberculosis, and antitumor properties, imidazopyridine is one of the most significant structural skeletons in the field of natural and pharmaceutical products. An imidazopyridine scaffold serves as the basis for a number of therapeutically utilized medications, including zolpidem, alpidem, olprinone, zolimidine, and necopidem. This comprehensive study covers the period of the last five years, and it sheds light on the developments and emerging pharmacological actions of Imidazo[1,2-a] pyridines. Additionally, the structure-activity relationship and molecular docking studies are carefully documented throughout the paper, providing medicinal chemists with a clear picture for developing new drugs.

Marine Bacteria: A Source of Novel Bioactive Natural Products.

Marine natural products have great pharmacological potential due to their unique and diverse chemical structures. The marine bacterial biodiversity and the unique marine environment lead to a high level of complexity and ecological interaction among marine species. This results in the production of metabolic pathways and adaptation mechanisms that are different from those of terrestrial organisms, which has drawn significant attention from researchers in the field of natural medicine. This review provides an analysis of the distribution and frequency of keywords in the literature on marine bacterial natural products as well as an overview of the new natural products isolated from the secondary metabolites of marine bacteria in recent years. Finally, it discusses the current research hotspots in this field and speculates on future directions and limitations.

Natural products that alleviate depression: The putative role of autophagy.

Major depressive disorder (MDD) is a common mental disorder that severely disrupts psychosocial function and decreases the quality of life. Although the pathophysiological mechanism underlying MDD is complex and remains unclear, emerging evidence suggests that autophagy dysfunction plays a role in MDD occurrence and progression. Natural products serve as a major source of drug discovery and exert tremendous potential in developing antidepressants. Recently published reports are paying more attention on the autophagy regulatory effect of antidepressant natural products. In this review, we comprehensively discuss the abnormal changes occurred in multiple autophagy stages in MDD patients, and animal and cell models of depression. Importantly, we emphasize the regulatory mechanism of antidepressant natural products on disturbed autophagy, including monomeric compounds, bioactive components, crude extracts, and traditional Chinese medicine formulae. Our comprehensive review suggests that enhancing autophagy might be a novel approach for MDD treatment, and natural products restore autophagy homeostasis to facilitate the renovation of mitochondria, impede neuroinflammation, and enhance neuroplasticity, thereby alleviating depression.

Natural Products as Inhibitors of Coronavirus: An Update

Abstract: In the past couple of decades, several corona virus infections have alarmed the world claiming deaths of huge population over the globe. Effective anti-viral agents have been researched for treatment of COVID-19 infection. Vaccination has come up as an ultimate prevention against SARS-CoV-2virus as many vaccines have been recommended by WHO to be used for prevention from COVID-19. Alternative treatment strategies to combat infection include drug repurposing as well as supportive therapies. Traditional medicines being used from ancient times for different disease conditions provide a wealth of chemical diversity. Different classes of natural products are being utilized to study their antiviral properties and contributed in past for different viral diseases. The aim of current review is to enumerate different secondary metabolites and their pharmacophoric features against corona viruses that can be further optimized to develop more potent inhibitors specific to SARS-CoV-2. This review systematically evaluates natural products and their synthetic/ semisynthetic analogs belonging to terpenoids, polyphenols, saponins, and alkaloids having antiviral activity against coronaviruses. The information obtained from scope of Indian medicinal plants is also discussed which may be evaluated in future against SARS-CoV-2. Thus, it is proposed that the natural products may be used to develop potential inhibitors using the knowledge gained from similar studies to prevent morbidity and mortalities due to SARS-CoV-2.

Novel Natural Inhibitors for Glioblastoma by Targeting Epidermal Growth Factor Receptor and Phosphoinositide 3-kinase.

Glioblastoma is an extensively malignant neoplasm of the brain that predominantly impacts the human population. To address the challenge of glioblastoma, herein, we have searched for new drug-like candidates by extensive computational and biochemical investigations. Approximately 950 compounds were virtually screened against the two most promising targets of glioblastoma, i.e., epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K). Based on highly negative docking scores, excellent binding capabilities and good pharmacokinetic properties, eight and seven compounds were selected for EGFR and PI3K, respectively. Among those hits, four natural products (SBEH-40, QUER, QTME-12, and HCFR) exerted dual inhibitory effects on EGFR and PI3K in our in-silico analysis; therefore, their capacity to suppress the cell proliferation was assessed in U87 cell line (type of glioma cell line). The compounds SBEH-40, QUER, and QTME-12 exhibited significant anti-proliferative capability with IC50 values of 11.97 ± 0.73 μM, 28.27 ± 1.52 μM, and 22.93 ± 1.63 μM respectively, while HCFR displayed weak inhibitory potency (IC50 = 74.97 ± 2.30 μM). This study has identified novel natural products that inhibit the progression of glioblastoma; however, further examinations of these molecules are required in animal and tissue models to better understand their downstream targeting mechanisms.

Knowledge-based In Silico Fragmentation and Annotation of Mass Spectra for Natural Products with MassKG

Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is a potent analytical technique utilized for identifying natural products from complex sources. However, due to the structural diversity, annotating LC-MS/MS data of natural products efficiently remains challenging, hindering the discovery process of novel active structures. Here, we introduce MassKG, an algorithm that combines a knowledge-based fragmentation strategy and a deep learning-based molecule generation model to aid in rapid dereplication and the discovery of novel NP structures. Specifically, MassKG has compiled 407,720 known NP structures and, based on this, generated 266,353 new structures using chemical language models for the discovery of potential novel compounds. Furthermore, MassKG demonstrates exceptional performance in spectra annotation compared to state-of-the-art algorithms. To enhance usability, MassKG has been implemented as a web server for annotating tandem mass spectral data (MS/MS, MS2) with a user-friendly interface, automatic reporting, and fragment tree visualization. Lastly, the interpretive capability of MassKG is comprehensively validated through composition analysis and MS annotation of Panax notoginseng, Ginkgo Biloba, Codonopsis pilosula, and Astragalus membranaceus. MassKG is now accessible at https://xomics.com.cn/masskg.

Resveratrol: Protective Agent Against Alzheimer's Disease.

Resveratrol is a biologically active natural phenolic plant product. It has several properties which make them useful to treat the disease. In this review, we have highlighted the neuroprotective effects of resveratrol. Several available animal models have been proven to help understand the disease pathway and mechanism of action by resveratrol. In this review, we have highlighted the neuroprotective activity of resveratrol in AD, which effectively counter the neurodegenerative disease by decreasing the formation of plaques. Resveratrol is a natural plant product that is easily available, cost-effective, and possesses neuroprotective activity, which is useful for treating neurodegenerative diseases. Resveratrol presents a promising avenue for AD treatment due to its diverse neuroprotective mechanisms. Given the ongoing global challenge in treating AD, researchers have increasingly focused on exploring the therapeutic potential of resveratrol.

Mechanism of Action and Related Natural Regulators of Nrf2 in Nonalcoholic Fatty Liver Disease.

With the acceleration of people's pace of life, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world, which greatly threatens people's health and safety. Therefore, there is still an urgent need for higher-quality research and treatment in this area. Nuclear factor Red-2-related factor 2 (Nrf2), as a key transcription factor in the regulation of oxidative stress, plays an important role in inducing the body's antioxidant response. Although there are no approved drugs targeting Nrf2 to treat NAFLD so far, it is still of great significance to target Nrf2 to alleviate NAFLD. In recent years, studies have reported that many natural products treat NAFLD by acting on Nrf2 or Nrf2 pathways. This article reviews the role of Nrf2 in the pathogenesis of NAFLD and summarizes the currently reported natural products targeting Nrf2 or Nrf2 pathway for the treatment of NAFLD, which provides new ideas for the development of new NAFLD-related drugs.

Important Regulatory Guidelines on Natural Products

Abstract: Ayurvedic cosmeceuticals are alluded to as products of various passable magnificence substances to shape the base in which one or more ayurvedic parts are utilized to give benefits and various ailments. The Drugs and Cosmetics Act of 1940 controls the approaches concerning the making, dealing, amassing, allotment, and importing of drugs in essentially a comparable manner to radiance care things in India. Quality control and assessment of Ayurvedic drugs must ensure the effectiveness of the drug. Given their crucial role, it involves evaluating their physical, chemical, and physiochemical qualities, as well as conducting in-vitro and in-vivo tests. Natural ingredients have consistently been our primary source of medicines, and dosage forms determine how drug molecules or plant components are delivered to the site of action within the body. Good agricultural and collection practices (GACP) rules have been given by the WHO (World Health Organization) for the differentiation and planning of regular items. There are primarily two legal regulatory bodies within the AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy) sector i.e., Central Council of Indian Medicine (CCIM) and the Central Council of Homeopathy.

Adenanthin Exhibits Anti-Inflammatory Effects by Covalently Targeting the p65 Subunit in the NF-κB Signaling Pathway

Adenanthin is a structurally unique ent-kaurane diterpenoid isolated from Rabdosia adenantha, a traditional Chinese medicinal plant with potent anti-cancer and anti-inflammatory activities. However, its anti-inflammatory molecular mechanism remains largely elusive to date. Here, we developed an affinity-based label-free protein profiling (ALFPP) to identify potential covalent targets of electrophilic natural products with ketone or aldehyde groups. Using ALFPP, we identified 27 potential covalent targets of adenanthin, among which p65 (RelA) has been associated with its anti-inflammatory activities. Through a series of experiments, including LC-MS/MS, molecular docking, electrophoretic mobility shift assays (EMSA), and genome editing, we demonstrated that adenanthin could covalently modify the Cys38 residue of p65 to affect the binding of DNA to p65, thereby inhibiting the NF-κB signaling pathway. ALFPP will facilitate the target identification of electrophilic carbonylated natural products, especially those containing α, β-unsaturated keto groups. Furthermore, the elucidation of the molecular mechanism of adenanthin will contribute to new drug development of adenanthin to treat inflammations and cancers, enhancing the possibility for its clinical application.

Insights into the anticancer effects of galangal and galangin: A comprehensive review

BackgroundsCancer continues to be the leading cause of death worldwide, significantly impacting both health and the economy. Natural products have emerged as promising sources for the development of new anticancer drugs, with galangal and their active ingredient, galangin, garnering substantial interest. PurposeThis study summarizes recent findings on the anticancer properties of galangal and galangin, highlighting their potential to target various cancer types. MethodsWe systematically searched the literature across PubMed, Web of Science, and Google Scholar, using keywords such as “Alpinia officinarum,” “Alpinia galanga”, “galangal,” and “galangin.” This thorough approach allowed us to gather and compile a comprehensive collection of existing research on the topic. ResultsThis article provided a thorough analysis of the distribution of galangal, the methods used to extract the active compounds of galangal, and the anticancer properties of both galangin and galangal. It is important to note that galangal and galangin primarily function by regulating the signaling pathways of PI3K/Akt, MAPK, AMPK, p53, NF-κB, and Ras/RAF/MEK/ERK, which in turn triggers apoptosis, autophagy, and ROS while preventing the migration and invasion of cancer cells. We also discussed their toxicity, bioavailability, and clinical uses. ConclusionIn conclusion, galangal extract and galangin have a lot of promise for treating cancer. It is anticipated that this review will further advance the use of galangal extract and galangin as potential cancer treatment medications. Moreover, the discovery and development of drugs based on galangal has enormous potential for the therapy of cancer.

Structural, optical, luminescent and magnetic properties of Gd2O3 nanoparticles: A comparative study on the effect of different green fuels in the sol–gel synthesis tactics

In this study, five samples of Gd2O3 NPs (size range: 4–33 nm) were synthesized by five different green facile and diverse natural products acting as reducing & stabilizing agents such as: fresh juices of sugarcane, lemon, tomato & orange fruits and citric acid via self combustion sol–gel tactics. Powder X-ray diffraction (PXRD), High resolution transmission electron microscopy (HRTEM), Fourier transform infrared (FTIR) and Raman analysis affirmed cubic-C type crystal structure of Gd2O3 NPs prepared using citric acid, lemon juice and sugarcane juice. Mixed cubic and monoclinic phases were observed in Gd2O3 NPs prepared using tomato and orange juices. Notably, NPs of Gd2O3 in quantum dot regime (size: 6 ± 2 nm) were produced in the fresh sugarcane juice mediated synthesis protocol. Fresh lemon juice and sugarcane juice were appeared to be the most efficient green fuel for producing quality samples of Gd2O3 NPs. Optical absorption studies showed that bandgap in these Gd2O3 NPs is strongly dependent on the preparation protocol and type of green fuel. Interestingly, highest and lowest band gap of 4.91 eV and 4.43 eV were obtained for Gd2O3 NPs fabricated with orange and lemon juices, respectively. Photoluminescence (PL) and electron spin resonance (ESR) analysis affirmed formation of Schottky and Frenkel surface defects along with self trapped excitons and oxygen vacancies in these Gd2O3 NPs. Paramagnetic character of these Gd2O3 NPs at 300 K is validated by dc-magnetization and ESR studies. Present study demonstrated that microstructural, optical absorption and photoluminescence properties of Gd2O3 NPs can be easily customized by choice of natural products in the synthesis tactics.

Chitosan-coated nanoemulsions of a terpene-based natural deep eutectic solvent and lemongrass essential oil to control coffee leaf rust: Two alternatives based on natural products

Coffee production is negatively affected by coffee leaf rust, a disease caused by the fungus Hemileia vastatrix. As a natural product-based alternative to chemically control the disease, this study evaluated the effect of two chitosan-coated nanoemulsions prepared from Cymbopogon citratus essential oil (EO) and the thymol: pyruvic acid (1:1) natural deep eutectic solvent (NADES) on the in vitro germination of H. vastatrix urediospores and on the in vivo control of the disease in Coffea arabica plants under greenhouse conditions. Both nanoformulations inhibited urediospores in vitro germination but only that prepared with EO did it significantly more than its free form active ingredient (the observed reduction was around 60 %). On the other hand, the in vivo experiment showed that the EO and NADES chitosan-coated nanoemulsions offered similar and significant protection for Coffea arabica plants against leaf rust; the disease severity level was found to be less than 2.6 % after 81 days from the application of the treatments to the plants (comparable to the cooper oxychloride, which is one of the commercial fungicides traditionally used), while the free components did not (9.0–13.3 % of severity level by day 81, such as the control). This is the first report demonstrating that chitosan-coated nanoemulsions, containing NADES or EO, protect coffee plants against H. vastatrix infection and can be two alternatives for sustainable pest management. Furthermore, this study contributes to broadening the prospects for using hydrophobic NADES in the design of biopesticides.

Synthesis and Anti-gastric Cancer Activity by Targeting FGFR1 Pathway of Novel Asymmetric Bis-chalcone Compounds.

Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities. The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity. The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Western Blotting, shRNA, and MTT assays. Finally, the in vivo anti-tumor activity and mechanism of J3 were studied through nude mice xenograft assay, western blotting. 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R2 = 0.851627) by applying random forest algorithms. The optimal compound J3, which had better activity, concentration-dependently inhibited the formation of gastric cancer cell colonies and led to cell apoptosis by inducing the expression of the pro-apoptotic protein cleaved PARP in a dose-dependent manner. J3 may exert anti-gastric cancer effects by inhibiting the activation of FGFR1/ERK pathway. Moreover, at a dose of 10 mg/kg/day, J3 inhibited tumor growth in nude mice by nearly 70% in vivo with no significant toxic effect on body weight and organs. In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug.

Recent Advances in Total Synthesis of Tetrahydroisoquinoline Alkaloids Quinocarcin and Lemonomycin

Abstract: Tetrahydroisoquinoline natural products are a kind of alkaloids containing various pharmacological activities. These structurally diverse alkaloids mainly consist of two subclasses, monotetrahydroisoquinolines (MTHI) and bistetrahydroisoquinolines (BTHI). Since its family member, Ecteinascidin-743 (INN: Trabectedin, trade name: Yondelis®), has been approved by European Union in 2007 and the FDA in 2015 for the treatment of advanced soft tissue tumors, the research on this kind of natural product is full of new vitality. Quinocarcin and lemonomycin share a common diazabicyclo[3.2.1]octane framework that belongs to the subclass of MTHI, and their excellent antitumor activity and challenging architecture have made them an ideal target for total synthesis. In this short review, the progress in the total synthesis of quinocarcin and lemonomycin is summarized.

Effect of bioactive extracts from Eucalyptus globulus leaves in experimental models of Alzheimer's disease.

Current therapies for Alzheimer's disease (AD) do not delay its progression, therefore, novel disease-modifying strategies are urgently needed. Recently, an increasing number of compounds from natural origin with protective properties against AD have been identified. Mixtures or extracts obtained from natural products containing several bioactive compounds have multifunctional properties and have drawn the attention because multiple AD pathways can be simultaneously modulated. This study evaluated the in vitro and in vivo effect of the essential oil (EO) obtained from the hydrodistillation of Eucalyptus globulus leaves, and an extract obtained from the hydrodistillation residual water (HRW). It was observed that EO and HRW have anti-inflammatory effect in brain immune cells modeling AD, namely lipopolysaccharide (LPS)- and amyloid-beta (Aβ)-stimulated microglia. In cell models that mimic AD-related neuronal dysfunction, HRW attenuated Aβ secretion and Aβ-induced mitochondrial dysfunction. Since the HRW's major components did not cross the blood-brain barrier, both EO and HRW were administered to the APP/PS1 transgenic AD mouse model by an intranasal route, which reduced cortical and hippocampal Aβ levels, and to rescue memory deficits and anxiety-like behaviors. Finally, HRW and EO were found to regulate cholesterol levels in aged mice after intranasal administration, suggesting that these extracts can reduce hypercholesterolemia and avoid risk for AD development. Overall, findings support a protective role of E. globulus extracts against AD‑like pathology and cognitive impairment highlighting the underlying mechanisms. These extracts obtained from underused forest biomass could be useful to develop nutraceutical supplements helpful to avoid AD risk and to prevent its progression.

The Influence of Phytoconstituents for the Management of Antipsoriatic Activity in Various Animal Models.

It is possible for psoriasis to manifest at any point in a person's life, regardless of their age, gender, or geographic location. It is a chronic immune-linked inflammatory skin ill-ness that affects individuals of various racial and ethnic origins. It is recognized to be a long-lasting condition. Because of the significant contribution that natural products have made, there has been a significant advancement in the treatment of skin illnesses such as psoriasis. The biggest number of phytochemicals derived from a wide range of plants and herbs are now being used in a variety of applications throughout the whole world. Additionally, a number of phyto-chemicals, including aloe-emodin, psoralen, curcumin, and others, have been effectively ex-tracted in pure or clear form, and they have shown a great deal of efficacy in the treatment of psoriasis illness. There is evidence that a few herbal remedies are effective, and the occurrence of these phytochemicals provides more proof. When synthetic medications are used for chronic therapy, they may cause a variety of adverse consequences; hence, the exploration of natural pharmaceuticals can give a successful natural treatment with a minimal amount of adverse ef-fects. Within the scope of this concise review, a number of plant sources that possess anti-pso-riatic activity are investigated, and the antipsoriatic effects of these plant sources are shown on a number of animal models using particular pathways.

Whole-pathway stimulation of anthocyanin biosynthesis by UDP-glycose: flavonoid glycosyltransferase gene (UFGT) providing new insights into natural product development based on plant cell factory

Anthocyanins are a type of plant natural products (PNPs) that play a crucial role in various fields, including food, medicine, cosmetics, and dyes. However, their primary source is plant extraction, leading to significant ecological damage and resource wastage issues. To address the challenge of achieving ecologically sustainable high-throughput anthocyanin production, this study proposes a plant cell factory (PCF) strategy based on suspension cell culture (SCC). In this study, the key gene VdUFGT involved in anthocyanin biosynthesis was cloned from Vitis davidii, and gene overexpression was conducted using Agrobacterium-mediated methods. Notably, the vgt3 transgenic cell line exhibited 4.4-fold increase in anthocyanin content, reaching 286.9 μg/g (FW) in solid medium, along with enhanced levels of flavonoids and proanthocyanidins. Integrative analysis of transcriptomics and metabolomics demonstrated that VdUFGT significantly promoted the expression of genes involved in anthocyanin biosynthesis, leading to the enhanced accumulation of various flavonoids, including anthocyanins. A small-scale plant cell factory was established, achieving an impressive production of 4.11 mg/g (DW) of anthocyanin within just 12 days, which is 8.5 times higher than that of the WT cell line, with the yield of purified freeze-dried anthocyanin powder reaching 3.17%. The plant cell factory, employing genetic engineering and suspension cell culture, offers a safe, ecological, economical, and efficient approach for the high-throughput production of plant natural products such as anthocyanins.

Effectiveness of Novel Drug Delivery System using Curcumin in Alzheimer's Disease.

Alzheimer's disease (AD) is a form of brain degeneration that gradually impairs a person's memory and cognitive skills, eventually making it harder for them to perform everyday activities. Its pathophysiology has been attributed to the deposition of amyloid β (Aβ), neurofibrillary tangles (NFT), and α-synuclein (A-s) in some cases. Presently, 4 drugs have been approved for the treatment. They are Donepezil, Rivastigmine, Galantamine and Memantine. The first three are acetylcholinesterase inhibitors, while memantine is an NMDA receptor antagonist. Even though these medications are successful in treating mild to moderate Alzheimer's disease, they have not been able to reverse the disease or even slow its progression completely. Hence, natural products are gaining more popularity due to the advantage of the multitarget intervention effect. The most investigated spice, Curcuma longa's bioactive component, curcumin, has demonstrated anti-amyloid, anti-NFT, and anti-Lewy body properties and substantial antiinflammatory, antioxidant, and antiapoptotic properties. However, its proven neuroprotective activity is hampered by many factors, such as poor water solubility and bioavailability. Therefore, many novel formulations have been designed to improve its bioavailability with methods such as 1) Micellar Solubilization, 2) Cyclodextrin Complexation, 3) Crystal Modification, and 4) Particle Size Reduction, etc. The current chapter aims to summarize various novel formulations of curcumin and their effectiveness in treating AD.

The sugar moiety in protopanaxadiol ginsenoside affects its ability to target glucocorticoid receptor to regulate lipid metabolism

Ginsenosides are natural products with hydrophobic rings adorned with sugar molecules. The elucidation of the impact of ginsenosides structure on their activity is crucial for facilitating precision-oriented modifications, thereby enhancing their suitability for drug development. Here, utilizing an ob/ob mouse model, we demonstrated that as the number of sugar moiety on the protopanaxadiol-type ginsenosides decreased, the hypolipidemic potency increased, while the aglycon exhibited negligible activity. Mechanistically, we demonstrated the dependency of ginsenosides on the glucocorticoid receptor (GR) for the regulation of lipid metabolism. Interestingly, ginsenoside CK was found to promote the transcription of lipid metabolism-related genes via GR contrast to the effects of glucocorticoids, suggesting a unique mode of action. Furthermore, we observed that a reduction in the number of sugar molecules strengthened the binding affinity of ginsenosides to GR, as determined by microscale thermophoresis. These findings highlight the critical role of the sugar moiety in modulating the lipid-regulating capacity of ginsenosides, providing valuable insights for the development of these compounds as potential therapeutic agents.