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Diabetic retinopathy (DR) is the leading cause of blindness and visual loss in people with diabetes. It has been suggested that the progression of DR is associated with chronic inflammation and oxidative stress. The aim of the present work was to evaluate the ability of the natural compound madecassic acid (MEA) to reverse the negative impact of streptozotocin (STZ) on retinal injury in rats. Diabetic rats induced by STZ were treated with MEA at the doses of 10 and 20 mg/kg bw for 8 weeks. The study compared the efficacy of the drug in controlling high blood sugar levels and its impact on therapeutic targets such as SOD, CAT, GPx, NF-κB, TNF-α, IL-6, IL-1β, VEGF, IGF, bFGF and Keap1/Nrf-2 pathway. The results showed that the treatment with MEA significantly restored the retinal SOD, CAT, and GPx levels in diabetic rats to the near-normal levels. Moreover, the level of inflammatory mediators (TNF-α, IL-1β, IL-6) and growth factors (VEGF, IGF, bFGF) was significantly lower in retinas of animals treated with MEA as compared to retinas of diabetic animals. The study also established that MEA administration reduced the NF-κB protein and altered the Nrf-2/Keap1 pathway thereby reducing oxidative stress and inflammation. Furthermore, the use of MEA prevented the progression of the retinal capillary basement membrane thickening. It has been found that MEA offers significant protection to the retina and therefore, the compound may be useful in the treatment of DR in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Celastrol, a pentacyclic triterpenoid found in Chinese herb Tripterygium wilfordii, is considered as one of the top-five natural medicinal compounds with high antioxidant property. However, celastrol has poor aqueous solubility and thereby low bioavailability, restricting its clinical application as drug. To overcome this problem, we nanonized celastrol by entrapping it within hydrophilic nanocarrier - calcium phosphate nanoparticle. The synthesized calcium phosphate celastrol nanoparticle (CPCN) had average size of 35 nm, spherical shape, significant stability with (-) 37 mV zeta potential, celastrol entrapment efficiency around 75 % and low celastrol release kinetics spanning over 7 days, as measured by different techniques like FESEM, AFM, DLS, and spectrophotometry. Studies on the antioxidant potency of CPCN by flow cytometry and fluorescence microscopy depicted that the toxicity developed in human neuroblastoma cells SH-SY5Y by treatment with the selective neurotoxin MPP + iodide (N-Methyl-4-phenylpyridinium iodide) got reduced by pretreatment of the cells with CPCN. Determination of cellular ROS content, depolarization level of mitochondrial membrane potential, cell cycle analysis and nuclear damage in MPP + -exposed cells demonstrated that CPCN had about 65 % more antioxidant efficacy over that of bulk celastrol. Thus, the nanonization process transformed hydrophobic celastrol into hydrophilic CPCN, having high potentiality to be developed as an effective antioxidant drug., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Prof. Tarakdas Basu has patent A PROCESS FOR SYNTHESIS OF CELASTROL-LOADED CALCIUM PHOSPHATE NANOPARTICLE AS A POTENT ANTIOXIDANT pending to UNIVERSITY OF KALYANI. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aspterric acid (AA) is a novel natural product herbicide that targets dihydroxyacid dehydratase in plants. In this study, we introduced two distinct AA biosynthesis-related gene clusters into Saccharomyces cerevisiae and screened the core biosynthetic enzyme, sesquiterpene cyclase, from various fungi. The combination of sesquiterpene cyclase from Aspergillus taichungensis IBT 19404 and two cytochrome P450s from Penicillium brasilianum resulted in the optimal AA synthesis efficiency in yeast, with the highest titer of 33.21 mg/L achieved by optimizing fermentation conditions in shake flasks. Moreover, the herbicidal effects of AA on weed germination and growth were evaluated. Notably, AA strongly inhibited the germination of Amaranthus tricolor , Portulaca oleracea , Bidens pilosa , Lolium perenne , and Leptochloa chinensis . Furthermore, AA could also inhibit the shoot and root growth of weeds with a superior inhibitory effect on roots relative to shoots. Our work not only provides a sustainable method for the biosynthesis of AA in yeast but also paves the way for the application of AA as a preemergence herbicide.

Ototoxicity is a common side effect of cisplatin cancer treatment, potentially leading to hearing loss. This study demonstrated the significant protective activity of Acanthopanax sessiliflorus ( A. sessiliflorus ) leaves against cisplatin-induced ototoxicity (CIO), investigated the active compounds, and elucidated their mechanisms in countering CIO. UPLC-Q/TOF-MS analysis identified 79 compounds. Network pharmacology and activity screening determined that chiisanoside (CSS) plays a crucial role in combating CIO. Transcriptomics combined with network pharmacology analysis and experiments revealed that CSS activates the Dock1/PIP5K1A pathway to suppress the actin-severing protein gelsolin, protecting hair cells from cisplatin-induced cytoskeleton damage. CSS also activates the SLC7A11/GPX4 pathway via TGFBR2, reducing lipid peroxidation and intracellular iron accumulation to suppress cisplatin-induced ferroptosis. This study discovers that the major component CSS in A. sessiliflorus leaves reverses CIO by regulating actin homeostasis via Dock1 and inhibiting ferroptosis through TGFBR2, providing a theoretical basis for expanding CIO treatment targets and related drug development.

It remains a challenge to effectively regulate the complicated microenvironment during the wound healing process. The optimization of synergistic action of angiogenesis and inflammation is considered critical for quicker scarless wound regeneration. Here, the silk nanofiber (SNF) acts as a multifunctional carrier to load hydrophobic asiaticoside (AC) and hydrophilic Mg 2+ , and also serves as an element to assemble injectable hydrogels, forming a bioactive matrix with improved angiogenic and anti-inflammatory capacities (SNF-AC-Mg). Mg 2+ and AC distributed homogeneously inside the silk nanofiber hydrogels without compromising the mechanical performance. Both Mg 2+ and AC released slowly to continuously tune both angiogenic and inflammatory behaviors. The hydrogels exhibited good biocompatibility, inflammation inhibition, and pro-angiogenic properties in vitro , suggesting the synergistic bioactivity of AC and Mg 2+ . In vivo analysis revealed that the synergistic action of AC and Mg 2+ resulted in better M2-type polarization of macrophages and angiogenesis during the inflammatory phase, while effectively achieving the inhibition of excessive accumulation of collagen and scar formation during the remodeling phases. The quicker scarless regeneration of the defects treated with SNF-AC-Mg implies the priority of SNFs in designing bioactive niches with complicated cues, which will favor the functional recovery of different tissues in the future.

In China, the Astragalus membranaceus root is used to treat chronic kidney disease. Astragaloside IV (AS-IV), the primary bioactive compound, exhibits anti-inflammatory and antioxidative properties; however, its renoprotective mechanism in diabetic kidney disease (DKD) remains unclear. The study aimed to investigate the protective effects of AS-IV on DKD revealing the underlying mechanisms. We established an early diabetic rat model by feeding a high-fat diet and administering low-dose streptozotocin. Twelve weeks post-treatment, renal function was evaluated using functional assays, histological analyses, immunohistochemistry, western blotting, and transmission electron microscopy. HK-2 cells exposed to high glucose conditions were used to examine the effect of AS-IV on oxidative stress, iron levels, reactive oxygen species (ROS), and lipid peroxidation. Network pharmacology, proteomics, molecular docking, and molecular dynamics simulation techniques were employed to elucidate the role of AS-IV in DKD. The results revealed that AS-IV effectively enhanced renal function and mitigated disease pathology, oxidative stress, and ferroptosis markers in DKD rats. In HK-2 cells, AS-IV lowered the levels of lipid peroxides, Fe 2+ , and glutathione, indicating the repair of ferroptosis-related mitochondrial damage. AS-IV reduced mitochondrial ROS while enhancing mitochondrial membrane potential and ATP production, indicating its role in combating mitochondrial dysfunction. Overall, in silico analyses revealed that AS-IV interacts with HMOX1, FTH1, and TFR1 proteins, supporting its efficacy in alleviating renal injury by targeting mitochondrial dysfunction and ferroptosis. AS-IV may play a renoprotective role by regulating mitochondrial dysfunction and inhibiting. HMOX1/FTH1/TFR1-induced ferroptosis. Accordingly, AS-IV could be developed for the clinical treatment of DKD-related renal injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacology Relevance: Ganoderma leucocontextum T.H. Li, W. Q. Deng M. Wang & H.P.Hu. is a highland herbal medicine that has been shown to nourish the nervesand prolong life. Nevertheless, there is no evidence to indicate that Ganoderma leucocontextum triterpenoids (GLTs) reduce the damage triggered by Alzheimer's disease (AD)., Aim of the Study: The aim of this investigation was to ascertain the protective effects of GLTs on AD mice models and cells, as well as to look into potential pathways., Materials and Methods: In this study, the phytochemical characterization of GLTs was performed by High Performance Liquid Chromatography (HPLC) and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). The AD mouse model was induced by injecting intraperitoneally with D-galactose (120 mg/kg) and administering orally with aluminum chloride (20 mg/kg) daily for 28 days. After that, donepezil (5 mg/kg) and GLTs (0.4, 0.8, and 1.6 g/kg) were administered orally for 35 days. During the treatment period, aluminum chloride (20 mg/kg) and D-galactose (120 mg/kg) were continuously administered. And the behavior of the animals and the molecular changes of the hippocampus were determined after the whole experimental procedure. Furthermore, BV-2 cells were employed to validate GLTs' anti-neuroinflammatory properties., Results: The total triterpenoids content was 443.12 ± 0.21 g/kg and was inferred to contain 19 classes of substances such as organic acids, amino acids, vitamins, flavonoids, and other chemicals in GLTs. Treatment of D-galactose/aluminum chloride-induced mouse with GLTs can ameliorate AD symptoms, counteract cognitive decline, improve Aβ1-42 deposition, reduce the expression level of pro-apoptotic proteins, and attenuate the activation of hippocampal microglia and astrocytes. GLTs significantly increased the expression of antioxidant enzymes and significantly reduced the expression of inflammatory factors. GLTs inhibits nuclear factor kappa B (NF-κB) nuclear translocation and preserves myd88/traf6-mediated mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, GLTs (2 and 5 mg/mL) inhibited the generation of nitric oxide and protected lipopolysaccharide (1 mg/L)-induced neuroinflammation in BV-2 cells., Conclusions: Taken together, Ganoderma leucocontextum triterpenoids can improve cognitive functions, including learning and memory, by reducing neuroinflammation and oxidative stress, preventing apoptosis, and controlling amyloid genesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Astragaloside IV (AS), a key active ingredient obtained from Chinese herb Astragalus mongholicus Bunge, exerts potent neuroprotective and anti-inflammatory effects for treating neurodegenerative diseases. However, mechanisms of AS on improvement of ischemic brain tissue repair remain unclear., Aim of the Study: This research aims at using magnetic resonance imaging (MRI) to noninvasively determine whether AS facilitates brain tissue repair, and investigating whether AS exerts brain remodeling through adenosine monophosphate-activated protein kinase (AMPK) metabolic signaling regulating key glycolytic enzymes and energy transporters, thereby impacting microglia polarization., Materials and Methods: Ischemic stroke model in male Sprague-Dawley rats were induced through permanent occlusion of the middle cerebral artery (MCAO). Infarct volume, the alterations of brain microstructure and nerve fibers reorganization were examined by multi-parametric MRI. The pathological damages of myelinated axons and microglia polarization surrounding infarct tissue were detected using pathological techniques. Furthermore, M1/M2 microglia polarization associated protein, glycolytic rate-limiting enzymes, energy transporters and AMPK/mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) signal were examined both in ischemic stroke rats and BV2 microglia treated with lipopolysaccharide (LPS) + interferon-γ (IFN-γ) by western blotting., Results: MRI revealed that AS obviously decreased infarct volume, relieved brain microstructure damage and improved nerve fibers reorganization in ischemic stroke rats. Histological tests supported MRI findings. Notably, AS promoted microglia M2 and reduced M1 polarization, induced the AMPK activation accompanied with decreased levels of phosphorylated mTOR and HIF-1α. Moreover, AS suppressed the expression of glycolytic rate-limiting enzymes and energy transporters in ischemic stroke rats and BV2 microglia. In contrast, these beneficial effects were greatly blocked by AMPK inhibitor compound C., Conclusion: Overall, these results collectively suggested that AS facilitated tissue remodeling that may be partially through modulating polarization of microglia in AMPK- dependent metabolic pathways after ischemic stroke., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The limitations of modern medicine in mitigating the pathological process of diabetic kidney disease (DKD) necessitate novel, precise, and effective prevention and treatment methods. Huangqi, the root of Astragalus membranaceus Fisch. ex Bunge has been used in traditional Chinese medicine for various kidney ailments. Astragaloside IV (AS-IV), the primary pharmacologically active compound in A. membranaceus, is involved in lipid metabolism regulation; however, its potential in ameliorating renal damage in DKD remains unexplored., Aim of the Study: To elucidate the specific mechanism by which AS-IV moderates DKD progression., Materials and Methods: A murine model of DKD and high glucose-induced HK-2 cells were treated with AS-IV. Furthermore, multiomics analysis, molecular docking, and molecular dynamics simulations were performed to elucidate the mechanism of action of AS-IV in DKD, which was validated using molecular biological methods., Results: AS-IV regulated glucose and lipid metabolism in DKD, thereby mitigating lipid deposition in the kidneys. Proteomic analysis identified 12 proteins associated with lipid metabolism regulated by AS-IV in the DKD renal tissue. Additionally, lipid metabolomic analysis revealed that AS-IV upregulated and downregulated 4 beneficial and 79 harmful lipid metabolites, respectively. Multiomics analysis further indicated a positive correlation between the top-ranked differential protein heme oxygenase (HMOX)1 and the levels of various harmful lipid metabolites and a negative correlation with the levels of beneficial lipid metabolites. Furthermore, enrichment of both ferroptosis and hypoxia-inducible factor (HIF)-1 signaling pathways during the AS-IV treatment of DKD was observed using proteomic analysis. Validation results showed that AS-IV effectively reduced ferroptosis in DKD-affected renal tubular epithelial cells by inhibiting HIF-1α/HMOX1 pathway activity, upregulating glutathione peroxidase-4 and ferritin heavy chain-1 expression, and downregulating acyl-CoA synthetase long-chain family member-4 and transferrin receptor-1 expression. Our findings demonstrate the potential of AS-IV in mitigating DKD pathology by downregulating the HIF-1α/HMOX1 signaling pathway, thereby averting ferroptosis in renal tubular epithelial cells., Conclusions: AS-IV is a promising treatment strategy for DKD via the inhibition of ferroptosis in renal tubular epithelial cells. The findings of this study may help facilitate the development of novel therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Synthesis, solubility and cytotoxicity evaluation of anionic phosphonates derived from betulin, betulinic acid, oleanolic acid and ursolic acid is reported. Phosphonate moieties were successfully installed at terpenoid C28 by carboxylic acid deprotonation/alkylation sequence using (dimethoxyphosphoryl)methyl trifluoromethanesulfonate as alkylation reagent. Also, betulin-derived and ether-linked bis-phosphonate is obtained and characterized. After demethylation in the presence of TMSI the resulting phosphonic acids were transformed into their disodium salts. All target compounds display excellent water solubility, which was determined by qNMR in D 2 O. Cytotoxicity tests were performed in different concentrations of each compound (10-50 µM) against human osteosarcoma cell line MG-63 and osteoblast precursor cell line MC3T3-E1. Improved aqueous solubility and low cytotoxicity profile of the newly designed triterpenoid phosphonates reveal high potential for various medicinal chemistry and pharmacological applications in the future., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Molecular staples or interfacial inhibitors are small molecules that exert their activity through co-association with macromolecules leading to various effects on target functions. Some molecules inhibit target activity, while others generate gain-of-function complexes. We and others have previously identified two structurally distinct classes of molecular staples, pateamine A and rocaglates. These molecules inhibit eukaryotic initiation factor (eIF) 4A, a critical RNA helicase required for translation initiation, by simultaneously interacting with both RNA and protein components. Structural insights from members of these two families indicate that they wedge themselves between RNA bases during engagement. To extend our understanding of rocaglates, we investigated the RNA-binding properties of silvestrol, a natural rocaglate distinguished by the presence of a unique dioxanyloxy ring. Our study demonstrates that silvestrol expands the RNA-binding repertoire of rocaglates due to this structural characteristic, providing a rationale for improving synthetic molecular staples targeting eIF4A., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

This study aims to identify potential targets and regulatory mechanisms of Astragaloside Ⅳ (AS-Ⅳ) in treating intervertebral disc degeneration (IDD) through network pharmacology analysis with experimental validation. Lumbar spine instability (LSI) mouse models were first established and treated with AS-Ⅳ. Micro-CT, safranin O-fast green staining, IDD score, RT-PCR and immunohistochemistry staining were employed to demonstrate the effect of AS-Ⅳ. Network pharmacology was used to predict the signaling pathways and potential targets of AS-Ⅳ in treating IDD. RT-PCR and immunohistochemistry staining were used to elucidate and validate the mechanism of AS-Ⅳ in vivo. Animal experiments showed that AS-Ⅳ maintained disc height and volume, improved matrix metabolism in LSI mice, and restored Col2α1, ADAMTS-5, Aggrecan, and MMP-13 expression in degenerated discs. Network pharmacology analysis identified 32 cross-targets between AS-Ⅳ and IDD, and PPI network analysis filtered out 11 core genes, including ALB, MAPK1, MAPK14 (p38 MAPK), EGFR, TGFBR1, MAPK8, MMP3, ANXA5, ESR1, CASP3, and IGF1. Enrichment analysis revealed that 7 of the 11 core target genes enriched in the MAPK signaling pathway, and AS-Ⅳ exhibited stable binding to them according to molecular docking results. Experimental validation indicated that AS-Ⅳ reversed mRNA levels of 7 core targets in degenerated disc tissues in LSI mice. Immunohistochemistry staining further revealed that AS-Ⅳ treatment mainly depressed IDD-elevated protein levels of EGFR, p38 MAPK and CASP3 in the annulus fibrosus. This study elucidates that AS-Ⅳ alleviates lumbar spine instability-induced IDD in mice, suggesting the mechanism may involve inhibition of the EGFR/MAPK signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and its prevention and treatment face severe challenges. It is crucial to improve the targeting of drugs on tumor cells and tissues. Celastrol (CeT), as an active ingredient of traditional Chinese medicine, possesses strong antitumor effects, especially in triggering apoptosis of HCC. However, due to its toxicity and lack of targeting, its application is greatly limited. HMCLPs, a nano-biomimetic platform carrying CeT with controllable drug release, enhanced targeting, and immunocompatibility, were developed for the first time, which can be used for the treatment of HCC. By utilizing homologous cell membranes and hyaluronic acid (HA), HMCLPs can precisely target tumor regions and release CeT in a controlled manner. Both in vitro and in vivo studies have demonstrated that HMCLPs loaded with CeT significantly increased the accumulation of reactive oxygen species (ROS), induced mitochondrial damage, and triggered apoptosis of HCC cells, resulting in effective treatment with minimal adverse reaction. The development of HMCLPs as a nanocarrier system for CeT delivery offers a promising therapeutic strategy for HCC. This innovative approach improves the targeted delivery and bioavailability of CeT, dramatically induces apoptosis in HCC cells, and exerts its powerful antitumor effects while minimizing systemic toxicity. The present study highlights the potential of combining innovative nanocarriers with powerful natural compounds such as CeT to enhance efficacy and reduce toxicity.

This study aimed to explore the pathogenesis of platycodin D and luteolin, which are both active components in Jiegeng (Platycodonis Radix), in the treatment of influenza virus pneumonia through network pharmacology analysis combined with experimental verification. The bioactive components of Jiegeng (Platycodonis Radix) were screened by TCMSP and literature mining, and the results were standardized via the UniProt database. The action targets for the disease were identified from databases including OMIM, GeneCards, TTD, DisGeNET, and PharmGKB. Then, the visualized key target regulatory network and protein-protein interaction (PPI) network for the active components were established using Cytoscape3.7.1 software. The findings were illustrated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The intervention concentrations of platycodin D and luteolin were screened by the CCK8 method, and the important signaling pathways of platycodin D and luteolin for treating influenza virus pneumonia were verified by RT-qPCR and Western blot tests. From data mining, 89 common drug-disease targets were screened out, and five major active components of Jiegeng (Platycodonis Radix), including platycodin D and luteolin, were obtained. Besides, 11 therapeutic targets including IL-17, IL-6, TNF-α, JUN, and MAKP1 were identified by PPI network analysis. GO and KEGG enrichment analyses showed that the pathways most related to the mechanisms of Jiegeng (Platycodonis Radix) against influenza virus pneumonia included the TNF and IL-17 signaling pathways and apoptosis. In vitro experiments demonstrated that the model group exhibited a notable elevation in mRNA levels of IL-6, IL-17, TNF-α, JUN, MAPK1, and the IL-17/-acting protein ratio, as compared to the control group (p < 0.05). In contrast to the model group, the IL-6, IL-17, TNF-α, JUN, MAPK1 mRNA expression levels, and the IL-17 protein ratio in both the platycodin D group and luteolin group were considerably decreased (p < 0.05). Combined with network pharmacology and experimental verification, this study revealed that platycodin D and luteolin in Jiegeng (Platycodonis Radix) may treat influenza virus pneumonia by regulating inflammation through the IL-17 signaling pathway., (© 2024 John Wiley & Sons Ltd.)

Acanthopanax senticosus belongs to Araliaceae family and is traditionally used as a tonic. The roots and stems are mainly used as treatments for hypodynamia, rheumatism, and hypertension, but their frequent use may lead to extinction. However, comprehensive and simultaneous analysis of the remaining parts were still limited. There is a need to reorganize them for standardization of functional foods. In this study, 50 phenolic compounds and 82 triterpenoid saponins from the shoots, leaves, fruits, and stems of were characterized using UPLC-QTOF-MS and UPLC-QTRAP-MS/MS. Among them, 52 compounds were newly determined as the cis and malonyl-bound phenolic acids and were found to be structural isomers of Acanthopanax flavonoids and saponins. All compounds were absolutely/relatively quantified, and shoots had the highest content. Peroxynitrite and α-glucosidase inhibitory activities were performed, followed by evaluation of structure-activity relationships. Particularly, hederasaponin B and ciwujianoside B showed remarkable efficacy, which were affected by the C-23 hydroxylation, the C-20(29) double bond, and the presence of rhamnose. These detailed profiling can be used as fundamental data for increasing the utilization of A. senticosus and developing them into functional foods., (© 2024. The Author(s).)

Triterpenes are structurally complex natural products with promising therapeutic properties. Recalcitrance to chemical synthesis has hindered their use in drug development. Recent advances now make it possible to access and harness triterpene structural diversity using engineering biology approaches, enabling the discovery and optimisation of a new generation of drug leads., Competing Interests: Declaration of interests A.O. is a cofounder and shareholder of HotHouse Therapeutics and serves as a consultant for this company. The remaining authors have no interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Heatstroke is a condition caused by overheating of the body that leads to severe central nervous system dysfunction. Although there have been numerous studies on the pathological process of heatstroke, effective treatment methods are lacking. Astragaloside IV can protect the brain from inflammation and brain damage in various inflammation-related diseases, but it has not yet been used clinically for the treatment of heatstroke. Therefore, the aim of this study was to explore the neuroprotective effect of Astragaloside IV on heatstroke-induced central nervous system damage and its mechanism. Brain injury model under heatstroke was established using artificial climate simulation cabin. By scoring neurological deficits, performing histological and immunofluorescence staining of microglia, and detecting cytokine levels, we determined that Astragaloside IV alleviated brain injury and neuroinflammation. To further explore the potential molecular mechanism, RNA sequencing was performed to investigate the differences in the brain. The results revealed that the PI3K/AKT pathway is involved. In vitro experiments further confirmed that Astragaloside IV can abrogate the phenotypic changes in microglia induced by heatstroke. Moreover, Astragaloside IV promotes the polarization of M2 microglia by activating the PI3K/AKT pathway. In summary, these results indicate that Astragaloside IV alleviates neuroinflammation and brain injury induced by heatstroke through the PI3K/AKT pathway. Astragaloside IV is a commonly used therapeutic agent in the clinic, but its use in the treatment of heatstroke-induced brain injury has not been explored. This study reveals that Astragaloside IV may be a new therapeutic agent for the treatment of heatstroke-induced brain injury., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024. Published by Elsevier Masson SAS.)

Some skin wounds often have many exudate. Ordinary single layer electrospunning nanofiber wound dressings often don't have enough capacity to absorb them. Therefore, a separable double layer electrospunning nanofiber dressing was developed in this work. The dressing had a separable feature that allowed the upper layer to be separated and removed after it had absorbed a significant amount of wound exudate. This dressing consisted of an upper layer of super hydrophilic sodium polyacrylate nanofibers and a bottom layer of 3D-structure coaxial nanofibers with encapsulated Astragaloside (AS). The results showed that nanofibers had better morphology. The water absorption rate, water vapor transmission rate and free radical scavenging rate of the double-layer dressings were 1461.71 ± 39.72 %, 1193.63 ± 134 g·m -2 ·day -1 , and 63.35 ± 3.65 %, respectively. The double-layer nanofiber dressing achieved 65.69 ± 2.62 % and 75.10 ± 6.26 % inhibition against Staphylococcus aureus and Escherichia coli, respectively. The double-layer dressing had proliferative, migratory, and adhesive effects on L929 fibroblasts. And the double-layer dressing resulted in a 96.78 ± 1.0 % wound healing rate in rats after giving a 14 days treatment. Therefore, the 3D-structure separable double-layer wound dressing designed and prepared in this study was effective in promoting wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Low concentrations or limited residence times in tumor tissues, making celastrol (Cel) difficult to exert significant therapeutic effects. Thus, we developed Zein/hyaluronic acid core-shell nanoparticles (Cel/Zein@HA NPs) for active targeted delivery of Cel via CD44 receptor over-expression on cancer cells, which may strengthen the therapeutic efficacy of Cel and improve delivery targeting. Cel-loaded Zein nanoparticles (core), are elegantly enveloped by a hydrophilic HA coating that forms the shell, resulting in significantly improved encapsulation efficiency and ensured good stability. The cellular uptake of Cel/Zein@HA NPs in HepG2 cells was 1.57-fold higher than nontargeting Cel/Zein NPs. Near-infrared fluorescence imaging confirmed the accumulation of Cel/Zein@HA NPs in H22 liver cancer tumors in mice, resulting in effective antitumor effects and good biosafety. Besides, in vitro and in vivo experiments showed that compared with Cel/Zein NPs, Cel/Zein@HA NPs had more efficient inhibitory effect on tumor proliferation and lower systemic toxicity. Further studies revealed that Cel/Zein@HA NPs induced apoptosis in hepatocellular carcinoma cells by modulating Bax and Bcl-2 expression, while also inhibiting tumor angiogenesis by decreasing CD31 and VEGF levels. Overall, this study presents a promising strategy for enhancing targeted liver cancer therapy through the utilization of biopolymer nanoparticle-based nano-pharmaceuticals that facilitate CD44-mediated cellular uptake., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The species Ganoderma calidophilum represents a distinct variety within the genus Ganoderma and used by the indigenous Li ethnic group as a medicinal agent for the prevention and treatment of cancer. However, the precise biological activity and role of G. calidophilum in antitumor treatment remain largely unresolved. Several lanostane triterpenoids have been isolated from G. calidophilum. The enzyme activity analysis revealed that four lanostane triterpenoids exhibited PTP1B inhibition activity, with minimal inhibition towards SHP2, SHP1, PTPN5, PTPRA, STEP and TCPTP. Molecular docking analysis demonstrated that these compounds primarily bind to the substrate recognition and entry regions of PTP1B. Further analysis indicated that among them, ganoderic aldehyde A (GAA) is a selective and non-competitive PTP1B inhibitor. GAA inhibited the proliferation, colony formation and migration of C33A and MDA-MB-231 cells in a dose-dependent manner. GAA has the capacity to induce apoptosis in a cell-type-specific manner, both in a caspase-dependent and -independent manner. PTP1B siRNA significantly reduced the cytotoxic effect of GAA, while overexpression of PTP1B significantly increased cell growth after GAA treatment. These findings confirm that PTP1B is a functional target of GAA. Research into the mechanisms of action of GAA has revealed that it could inhibit the activation of AKT by inhibiting PTP1B, while simultaneously activating p38, which promotes cell death. It is possible to develop specific PTP1B inhibitors based on the lanosterol triterpene skeleton. G. calidophilum has the potential to be developed into functional foods or drugs with the aim of preventing and treating cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recently, the potential association between polycystic ovary syndrome (PCOS) development and progression and ferroptosis has garnered attention. Increasing evidence suggests that targeting ferroptosis may be an effective strategy for treating PCOS. First, we observed that the expression of the ferroptosis regulatory molecules SLC7A11, GPX4, and FTH1 was decreased in the granulosa cells (GCs) of patients with PCOS and ovarian tissues of rats with PCOS; in contrast, TFR1 expression was increased. This suggests that GC ferroptosis is involved in PCOS pathogenesis. Furthermore, bioinformatics analysis of GC datasets from patients with PCOS and PCOS clinical samples and animal model analysis revealed CD44 as a key molecule regulating ferroptosis in PCOS, which was down-regulated in GCs of PCOS patients and rats. Subsequently, molecular docking was performed to screen existing natural compounds for inhibiting ferroptosis. Dynamic simulation and cellular thermal shift assay identified platycodin D as a natural plant extract for inhibiting ferroptosis by targeting CD44 in GCs. Subsequently, a series of functional experiments revealed that platycodin D ameliorated ovarian damage in rats with PCOS. This was primarily owing to the protective effects achieved by promoting glutathione production, attenuating lipid accumulation and lipid peroxidation in GCs, inhibiting iron overload, and scavenging reactive oxygen species. In addition, western blotting and immunofluorescence staining revealed that platycodin D upregulated the expression of CD44 and SLC7A11 in GCs. Furthermore, by knocking down CD44 and SLC7A11 in vivo and in vitro, respectively, the ameliorative effect of platycodin D on ferroptosis in the GCs of rats with PCOS was reversed. Collectively, these findings suggest that platycodin D attenuates ferroptosis in GCs by activating CD44/SLC7A11 axis, thereby upregulating system X c - . In conclusion, platycodin D can attenuate ferroptosis in GCs by activating CD44, potentially ameliorating ovarian damage in PCOS., Competing Interests: Declaration of interest statement We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “Platycodin D ameliorates polycystic ovary syndrome-induced ovarian damage by upregulating CD44 to attenuate ferroptosis”., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common causes of respiratory failure in critically ill patients. There is still a lack of definitive and effective treatment options, and the mortality rate remains as high as 30% to 40%. Effective therapeutics for ALI/ARDS are greatly hindered by the side effects resulting from inefficient delivery to the disease lesions and off-targeting biodistribution of drugs. Macrophages play an integral role in maintaining the steady state of the immune system and are involved in inflammation processes. Thus, nanodrug to accurately target macrophages have the potential to transform disease treatment. Here, we developed an mannosylated drug delivery system to target and deliver celastrol (Cel) to the alveolar macrophages for enhanced alleviating the cytokines in LPS-induce ALI mice. In vitro data demonstrated that the as-synthesized Man@Cel-NPs significantly improved the targeting of Cel into the inflammatory macrophages via mannose receptor-mediated phagocytosis. In vivo experiments further showed that intratracheal delivery of Man@Cel-NPs can improve the dysregulation of inflammatory response in LPS-induced mice by inhibiting the release of inflammatory cytokines and increasing autophagy and decreasing apoptosis in lungs. This work provides a potential NP platform for the locally tracheal delivery of herbal ingredients and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including ALI/ARDS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Centella asiatica Linn Urban (C. asiatica), aka Mandukparni, is one of the flagship herbs used in traditional medicines to effectively manage neurological problems. Although this plant has a wealth of comprehensive preclinical pharmacological profiles, further clinical research and execution of its molecular mode of action are still required. We searched electronic databases (Google Scholar, SciFinder, MEDLINE, Scopus, EMBASE, Science Direct, and PubMed) using relevant key words to retrieve information pertaining to C. asiatica till June 2023 and performed network pharmacology to understand the mechanism related to their neurobiological roles. This study extensively analyses its pharmacological properties, nutritional profile, ethnomedical uses, safety, and mechanistic role in treating neurological and neurodegenerative disorders. Additionally, a network pharmacology study was performed which suggests that its phytomolecules are involved in different neuroactive ligand-receptor pathways, glial cell differentiation, gliogenesis, and astrocyte differentiation. Hopefully, this report will lead to a paradigm shift in medical practice, research, and the creation of phytopharmaceuticals derived from C. asiatica that target the central nervous system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Chronic myeloid leukemia (CML) is driven primarily by the constitutively active BCR-ABL fusion oncoprotein. Although the development of tyrosine kinase inhibitors has markedly improved the prognosis of CML patients, it remains a significant challenge to overcome drug-resistant mutations, such as the T315I mutation of BCR-ABL, and achieve treatment-free remission in the clinic., Purpose: The identification of new intervention targets beyond BCR-ABL could provide new perspectives for future research and therapeutic intervention. A network pharmacology analysis was conducted to identify the most promising natural product with anti-CML activity. Celastrol was selected for further analysis to gain insights into its mechanism of action (MoA), with the aim of identifying potential new intervention targets for BCR-ABL T315I-mutant CML., Methods: Transcriptomic and proteomic analyses were conducted to systematically investigate the molecular MoA of celastrol in K562 T315I cells. To identify the target proteins of celastrol, mass spectrometry-coupled cellular thermal shift assay (MS-CETSA) was carried out, followed by validations with genetic knockdown and overexpression, cell proliferation assay, comet assay, Western blotting, celastrol probe-based in situ labeling and pull-down assay, molecular docking, and biolayer interferometry., Results: Our multi-omics analyses revealed that celastrol primarily induces DNA damage accumulation and the unfolded protein response in K562 T315I cells. Among the twelve most potential celastrol targets, experimental evidence demonstrated that the direct interaction of celastrol with YY1 and HMCES increases the levels of DNA damage, leading to cell death., Conclusion: This study represents the first investigation utilizing a proteome-wide label-free target deconvolution approach, MS-CETSA, to identify the protein targets of celastrol. This study also develops a new systems pharmacology strategy. The findings provide new insights into the multifaceted mechanisms of celastrol and, more importantly, highlight the potential of targeting proteins in DNA damage and repair pathways, particularly YY1 and HMCES, to combat drug-resistant CML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

This manuscript describes the isolation of nine new nor-3,4-seco-dammarane triterpenoids, norqingqianliusus A-I (1-9) and one known nortriterpenoid (10) from Cyclocarya paliurus leaves. Norqingqianliusus A and B (1 and 2) possess a unique 3,4-seco-dammarane-type C 26 tetranortriterpenoid skeleton. The compounds were structurally characterized through modern spectroscopic techniques. Moreover, the potential mechanism of hypoglycemic activity was further explored by studying the effects on glucosamine-induced insulin resistant HepG2 cells. In vitro hypoglycemic effects of all of the isolates were investigated using insulin resistant HepG2 cells. The glucose consumption was significantly promoted by compound 10, in a dose-dependent manner, thus alleviating damage in IR-HepG2 cells. Besides, it reduced the PEPCK and GSK3β gene expression, involved in glucose metabolism. The anti-diabetic effects of the plant, utilized traditionally, can hence be attributed to the presence of nor-3,4-seco-dammarane triterpenoids in the leaves., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Renal tubular injury induced by free fatty acid bound to albumin is the key pathological basis for the progression of diabetic kidney disease. However, effective interventions are limited. Astragaloside IV, as a major bioactive component purified from Astragalus membranaceus (Fisch.) Bunge, possesses pharmacological properties of lowering blood glucose and proteinuria, and renal tubular protection in diabetic kidney disease. Further work is needed to understand the underlying molecular mechanisms., Purpose: This study was designed to investigate the mechanism of renal tubular protection by astragaloside IV in diabetic kidney disease., Methods: Rats receiving high-fat diet combined with streptozotocin (30 mg/kg, i.p.) were gavaged with astragaloside IV (10 mg/kg/d or 20 mg/kg/d) or empagliflozin (1.72 mg/kg/d) for 8 weeks. In vitro, the NRK-52E cells were treated with free fatty acid-deleted BSA or palmitic acid-bound BSA in the presence or absence of astragaloside IV (5 μM, 10 μM, 20 μM) or 5 μM of mcc950. The effects of astragaloside IV on mitochondrial function, NLRP3/ASC/IL-18/IL-1β inflammatory cascade, and renal tubular injury were detected by pathological staining, immunoblotting, MitoSOX Red staining. Next, to investigate the mechanism of renal tubular protection by astragaloside IV, we transfected Fatp2 siRNA into BSA-PA-treated NRK-52E cells and injected lipofermata (a FATP2 inhibitor) intraperitoneally into free fatty acid-bound BSA overloaded rats with concomitant astragaloside IV treatment., Results: Treatment with astragaloside IV for 8 weeks dose-dependently attenuated the blood glucose, ratio of urinary albumin to creatinine, disorder of lipid metabolism, and pathological injury in diabetic kidney disease rats. In addition, astragaloside IV dose-dependently attenuated mitochondrial-derived reactive oxygen species and subsequent inhibiting NLRP3-mediated inflammatory cascade in diabetic kidney disease rats and palmitic acid-bound BSA-treated NRK-52E cells, thereby exerting renal tubular protection. More importantly, the effects of astragaloside IV on restoration of mitochondrial function, inhibition of inflammatory response and amelioration of renal tubular injury in vivo and in vitro were further enhanced when used in combination with Fatp2 siRNA or lipofermata., Conclusion: Astragaloside IV exerts antioxidant and anti-inflammatory effects in diabetic kidney disease by inhibiting FATP2-mediated fatty acid transport, thereby attenuating renal tubular injury., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Two new cucurbitane-type triterpenoid saponins, 2,20 β ,22 β -trihydroxy-16 α ,23( R )-epoxycucurbita-1,5,24-triene-3,11-dione 2- O - β -D-glucopyranoside ( 1 ), 2,20 β ,22 α -trihydroxy-16 α ,23( S )-epoxycucurbita-1,5,11,24-tetraene-3-one 2- O - β -D-glucopyranoside ( 2 ) were isolated from the fruit of Citrullus colocynthis (L.) Schrad. Their structures were elucidated by mass spectrometry, IR, 1D, and 2D NMR spectroscopy, etc. Besides, both of the compounds showed significant hepatoprotective activities at 10  μ M against paracetamol-induced HepG2 cell damage.

One promising approach to overcome drug resistance in asthma treatments involves dual-target therapy, specifically targeting the β2 adrenergic receptor (β 2 -AR) and muscarinic-3 acetylcholine receptor (M 3 R). This study investigated the anti-asthma effects and dual-target mechanisms of glycyrrhizic acid, hesperidin, and platycodin D (GHP) from Zhisou San. GHP administration effectively attenuated OVA-induced inflammatory infiltration and overproduction of mucus in asthmatic mice. Additionally, GHP treatment significantly suppressed M 3 R and promoted β 2 -AR activation, resulting in the relaxation of tracheal smooth muscle. These findings concluded that GHP mitigated asthma by targeting β 2 -AR and M 3 R to ameliorate airway inflammation and modulate airway smooth muscle relaxation.

Non-small cell lung cancer (NSCLC) is the primary inducer of cancer-related death worldwide. Asiaticoside (ATS) is a triterpenoid saponin that has been indicated to possess an antitumor activity in several malignancies. Nonetheless, its detailed functions in NSCLC remain unclarified. In this study, NSCLC cells were exposed to various doses of ATS. Functional experiments were employed to estimate the ATS effect on NSCLC cell behaviors. Western blotting was implemented for protein expression evaluation. A xenograft mouse model was established to assess the ATS effect on NSCLC in vivo. The results showed that ATS restrained NSCLC cell proliferation, cell cycle progression, migration, and invasiveness. ATS reversed TGF-β-induced promotion in epithelial-mesenchymal transition (EMT). Mechanistically, ATS inhibited Wnt/β-catenin signaling in NSCLC. Upregulating β-catenin restored ATS-mediated suppression of NSCLC cell aggressiveness. Moreover, ATS administration repressed tumorigenesis in tumor-bearing mice. In conclusion, ATS represses growth and metastasis in NSCLC by blocking EMT via the inhibition of Wnt/β-catenin signaling., (© 2024 Wiley Periodicals LLC.)

Bone marrow mesenchymal stem cells (BMECs)-derived exosomes (MSC-Exo) can improve acute myocardial infarction (AMI). Astragaloside IV (AS-IV) has also been reported to have cardioprotective pharmacological effects. However, it is not entirely clear whether AS-IV can improve AMI by inducing MSC-Exo. BMSCs and MSC-Exo were isolated and identified, and we also established the AMI rat model and the OGD/R model with H9c2 cells. After MSC-Exo or AS-IV-mediated MSC-Exo treatment, cell angiogenesis, migration, and apoptosis were evaluated by tube formation, wound healing, and TUNEL staining. The cardiac function of the rats was measured by echocardiography. The pathological changes and collagen deposition in rats were also assessed with Masson and Sirius red staining. The levels of α-SMA, CD31 and inflammatory factors were determined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). In vitro , AS-IV-mediated MSC-Exo can significantly enhance the angiogenesis and migration of H9c2 cells induced by OGD/R, and significantly reduce their apoptosis. In vivo , AS-IV-mediated MSC-Exo can improve the cardiac function of rats, and attenuate pathological damage and collagen deposition in AMI model rats. In addition, AS-IV-mediated MSC-Exo can also promote angiogenesis and reduce inflammatory factors in rats with AMI. AS-IV-stimulated MSC-Exo can improve myocardial contractile function, myocardial fibrosis and angiogenesis, reduce inflammatory factors and induce apoptosis in rats after AMI.

The Hippophae rhamnoides L. pomace was generated in the production process for juice, wine of food industry. To expand the application of pomace, the extraction process optimization, enrichment and identification of triterpene acids were performed in this study. The extraction yield was 14.87% under optimal ultrasound-assisted extraction techniques performed via response surface methodology. The extract was subsequently purified to obtain the triterpenoid acid enrichment fraction (TPF) with the content of 75.23% ± 1.45%. 13 triterpenoid acids were identified via UPLC-Triple-TOF MS/MS and further semi-quantified through comparison with triterpenoid acid standards. TPF exhibited a strong inhibitory effect on α-glucosidase with IC 50 value of 5.027 ± 0.375 μg/mL, as determined via enzyme inhibition experiment and molecular docking. Additionally, the TPF significantly reduced postprandial glucose levels, as revealed via carbohydrate tolerance tests, as well as ameliorate serum lipid profiles. Therefore, pomace may be a promising resource of functional food components with therapeutic and commercial values., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The aim of this study was to examine the effects of triterpenes from Pleiocarpa pycnantha leaves on the induction of apoptotic signalling in human cells. The molecular mechanisms of triterpenes isolated from P. pycnantha leaves were investigated in vitro on HeLa, MCF-7, HT-29, and KMST-6 cells. The compounds activated several markers associated with apoptosis, viz., phosphatidylserine translocation, caspase activation, oxidative stress, and topoisomerase I inhibition. Compounds 1 and 5 were non-selective, whereas compounds 2, 3, and 4 showed potential as cancer-specific agents by selectively inducing apoptosis only on cancer cells. Theoretical studies on the interactions of compound 1 with caspases -3 and -9 and topoisomerase I were carried out through a molecular docking study and illustrated that compound 1 had an equal binding affinity with the caspases and topoisomerase I comparable to that of camptothecin. The cellular pathway activated by these compounds was dependent on the compound and the cell type.

Mastic is a natural resin produced by Pistacia lentiscus L. (Anacardiaceae) with high medicinal value and have been traditionally used as Uighur imported medicine for centuries. In this study, 16 triterpenoids including seven new noroleanane triterpenoids (1-7), along with nine known oleanane triterpenoids (8-16), were isolated from the mastic. Their chemical structures were determined on the basis of extensive spectroscopic analyses (including IR, UV, ESI-HR-MS and NMR spectroscopy) and singlecrystal X-ray diffraction. Compounds 4-7, 11, 14 and 16 showed strong inhibitory NO production in LPS-induced RAW264.7 cells with IC 50 values 7.44-9.76 μM, respectively (positive control dexamethasone, 9.93±1.17 μM). Furthermore, compounds 3 and 12 significantly inhibited the growth of SW480 cells, compound 3 showed the most pronounced inhibitory effect with an IC 50 of 2.30±0.38 μM., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Hepatocellular carcinoma (HCC) is identified as a common cancer type across the world and needs novel and efficient treatment. Tripterine, a well-known compound, exerts suppressive role in HCC development. However, the related molecular mechanism of tripterine in HCC remains unclear. The expression of MBNL1-AS1in HCC tissues and cells was measured via qRT-PCR assay. MTT assay was employed to estimate cell viability. Besides, cell migration as well as invasion was determined through transwell assay. Additionally, the binding ability of miR-708-5p and MBNL1-AS1or HK2 was proved by starBase database and luciferase reporter gene assay. Moreover, the HK2 level was detected by immunoblotting. MBNL1-AS1 was reduced in HCC tissues and cells. Overexpression of MBNL1-AS1 decreased the sensitivity of HCC cells to tripterine while MBNL1-AS1 silence played opposite effect. In addition, miR-708-5p was the target of MBNL1-AS1 and was down-regulated through MBNL1-AS1 in HCC cells. Moreover, miR-708-5p suppressed glycolysis rate and reduced the expression of vital glycolytic enzyme (HK2, LDHA and PKM2) in HCC cells. Furthermore, miR-708-5p reduced HK2 expression by binding to it directly. In this investigation, we proved that LncRNA MBNL1-AS1 increased the tripterine resistance of HCC cells at least partly by mediating miR-708-5p-related glycolysis. These findings revealed a potent therapeutic target for the treatment of HCC.

A crude methanol extract of the roots of Allochrusa gypsophiloides (syn. Acanthophyllum gypsophiloides ) (collected from the Tashkent region of Uzbekistan) was chemically characterised by UHPLC-ESI-QTOF-MS/MS analysis. The results indicate the presence of six major bisdesmosidic saponins derived from gypsogenin, gypsogenic and quillaic acids, including five compounds reported for the first time for this species. The chloroform, methanol and water extracts of A. gypsophiloides showed weak antioxidant and anthelmintic activities. Among the tested extracts, the water extract exhibited the highest level of cytotoxicity in CCRF-CEM and CEM/ADR5000 cell lines with IC50 values of 23.6 and 31.9 µg/mL, respectively.

A new triterpene saponin, 2, 3, 21, 23-tetrahydroxyolean-12-en-28-oic-acid-28- O -β-D- glucosyl-(2''→1')-β-D-glucoside ( 1 ), was isolated from the n -butanol extract of dried aerial parts of Salvia argentea L. (Lamiaceae) in addition to two known flavonoids, apigenin 7- O -β-D-glucoside ( 2 ), threo-guaiacylglycerol 3- O -[6- O - p -hydroxybenzoyl]-β-D-glucoside ( 3 ), luteolin 7- O -β-D-glucoside ( 4 ), verbascoside ( 5 ) and rosmarinic acid ( 6 ). The structure elucidation of these compounds was based on analyses of spectroscopic data including 1D-, 2D-NMR and HR-ESI-MS techniques and by comparing their NMR data with those reported in the literature. Compound 6 exhibited the highest antioxidant activity in DPPH assay (IC 50 <3.00 µg/mL) which was better than the standards BHA, BHT, Trolox and ascorbic acid.

Gut microbiota dysbiosis and gut barrier disruption are key events associated with high-fat diet (HFD)-induced systemic metabolic disorders. Gymnemic acid (GA) has been reported to have an important role in alleviating HFD-induced disorders of glycolipid metabolism, but its regulatory role in HFD-induced disorders of the gut microbiota and gut barrier function has not been elucidated. Here we showed that GA intervention in HFD-induced hamsters increased the relative abundance of short-chain fatty acid (SCFA)-producing microbes including Lactobacillus (P<.05) and Lachnoclostridium (P<.01) in the gut, and reduced the relative abundance of lipopolysaccharide (LPS)-producing microbes including Enterococcus (P<.05) and Bacteroides (P<.05), subsequently improving HFD-induced intestinal barrier dysfunction and systemic inflammation. Specifically, GA intervention reduced mRNA expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α (P<.01), increased mRNA expression of antioxidant-related genes, including Nfe2l2, Ho-1, and Nqo1 (P<.01), and increased mRNA expression of intestinal tight junction proteins, including Occludin and Claudin-1 (P<.01), thereby improving gut barrier function of HFD hamsters. This ameliorative effect of GA on the gut of HFD hamsters may further promote lipid metabolic balance in liver and adipose tissue by regulating the Toll-like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) signaling pathway. Taken together, these results systematically revealed the important role of GA in regulating HFD-induced gut microbiota disturbance and gut barrier function impairment, providing a potential clinical theoretical basis for targeted treatment of HFD-induced microbiota dysbiosis., Competing Interests: Declaration of competing interests The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Inflammation induced by angiotensin II (Ang II) is a key event in the progression of numerous cardiovascular diseases. Astragaloside IV (AS-IV), a glycoside extracted from Astragalus membranaceus Bunge , has been shown to inhibit Ang II-induced inflammatory responses in vivo. However, the mechanisms underlying the beneficial effects are still unclear. This study investigated whether AS-IV attenuates endothelial inflammation induced by Ang II via the activation of endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) pathway. Human umbilical vein endothelial cells (HUVECs) were cultured in the presence of AS-IV with or without the specific inhibitor of NOS or Ca 2+ - and phosphatidylinositol 3-kinase (PI3K)/Akt-dependent cascade prior to Ang II exposure. Incubation of HUVECs with AS-IV enhanced NO production and eNOS ser1177 phosphorylation. These responses were abrogated by the inhibition of NOS or Ca 2+ - and PI3K/Akt-dependent pathway. In addition, preincubation of HUVECs with AS-IV inhibited Ang II-induced cytokine and chemokine production, adhesion molecule expression, monocyte adhesion, and nuclear factor kappa B (NF-κB) activation as evidenced by the attenuation of inhibitor of kappa B alpha phosphorylation and subsequent NF-κB DNA binding. These effects of AS-IV were abolished by the suppression of NOS or Ca 2+ - and PI3K/Akt-dependent cascade. Our findings indicate that AS-IV attenuates inflammatory responses triggered by Ang II possibly via the activation of Ca 2+ /PI3K/Akt/eNOS/NO pathway in endothelial cells., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Shiyu Zhang et al.)

This study investigated the therapeutic effects of astragaloside IV (AST) on spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), a neurodegenerative disorder. Human neuroblastoma SK-N-SH cells expressing mutant ataxin-3 protein with 78 CAG repeats (MJD78) were employed as an in vitro model. Protein expression analysis demonstrated that AST treatment reduced mutant ataxin-3 protein expression and aggregation by enhancing the autophagic process in MJD78 cells. Elevated oxidative stress levels in MJD78 cells were significantly reduced following AST treatment, which also enhanced antioxidant capacity, as evidenced by flow cytometry and antioxidant enzyme activity assays. Furthermore, AST treatment ameliorated mitochondrial dysfunction in MJD78 cells, including improvements in mitochondrial membrane potential, respiration, and mitochondrial dynamics. In conclusion, AST administration increased antioxidant capacity, reduced both cellular and mitochondrial oxidative stress, and improved mitochondrial quality control processes through fusion, fission, and autophagy. These mechanisms collectively reduced intracellular mutant ataxin-3 protein aggregation, thereby achieving therapeutic efficacy in the SCA3 model., (© 2024. The Author(s).)

Dysregulated chondrocyte metabolism is an essential risk factor for osteoarthritis (OA) progression. Maintaining cartilage homeostasis represents a promising therapeutic strategy for the treatment of OA. However, no effective disease-modifying therapy is currently available to OA patients. To discover potential novel drugs for OA, we screened a small-molecule natural product drug library and identified deapi-platycodin D3 (D-PDD3), which was subsequently tested for its effect on extracellular matrix (ECM) properties and on OA progression. We found that D-PDD3 promoted the generation of ECM components in cultured chondrocytes and cartilage explants and that intra-articular injection of D-PDD3 delayed disease progression in a trauma-induced mouse model of OA. To uncover the underlying molecular mechanisms supporting these observed functions of D-PDD3, we explored the targets of D-PDD3 via screening approach integrating surface plasmon resonance with liquid chromatography-tandem mass spectrometry. The results suggested that D-PDD3 targeted tyrosine-protein phosphatase non-receptor type 1 (PTP1B), deletion of which restored chondrocyte homeostasis and markedly attenuated destabilization of the medial meniscus induced OA. Further cellular and molecular analyses showed that D-PDD3 maintained cartilage homeostasis by directly binding to PTP1B and consequently suppressing the PKM2/AMPK pathway. These findings demonstrated that D-PDD3 was a potential therapeutic drug for the treatment of OA and that PTP1B served as a protein target for the development of drugs to treat OA. This study provided significant insights into the development of therapeutics for OA treatment, which, in turn, helped to improve the quality of life of OA patients and to reduce the health and economic burden., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pre-clinical studies suggest that extracts prepared from the fruits of Vitex agnus castus (VAC) interact with dopamine D2 receptors, leading to reduced prolactin secretion. In previous experiments, dopaminergic activity was mostly evaluated using radioligand binding assays or via the inhibition of prolactin release from rat pituitary cells. Diterpenes featuring a clerodadienol scaffold were identified as major active compounds, but no conclusive data regarding their potency and intrinsic activity are available. Utilising advances in chromatography, we re-examined this topic using HPLC-based tracking of bioactivity via microfractionation of the VAC extract Ze 440. Using a cAMP-based assay, we measured dopaminergic activity in CHO-K1 cells that overexpress the human D2 receptor. Six diterpenes were isolated from two active HPLC microfractions. Viteagnusin I emerged as the most potent diterpene (EC 50 : 6.6 µM), followed by rotundifuran (EC 50 : 12.8 µM), whereas vitexilactone was inactive (EC 50 : >50 µM). Interestingly, triterpenes were also identified as active, with 3- epi -maslinic acid being the most active compound (EC 50 : 5.1 µM). To better understand these interactions at the molecular level, selected diterpenes and triterpenes were analysed through molecular docking against D2 receptor structures. Our data show that the dopaminergic activity of VAC diterpenes seems to depend on the configuration and on ring substitution in the side chain. This study also highlights for the first time the dopaminergic contribution of triterpenes such as 3-epi-maslinic acid.

Programmed cell death protein-1 (PD-1) inhibitors are increasingly utilized in the treatment of lung cancer (LC). Combination therapy has recently gained popularity in treating LC. This study aimed to assess the efficacy of combining Astragaloside IV (AS-IV) and anti-PD-1 in LC. C57BL/6J mice were subcutaneously injected with Lewis lung carcinoma (LLC) cells. After 3 weeks, the animals were sacrificed, and the tumors were harvested for analysis. Ki-67 immuno-labeling and TUNEL assay were used for evaluating cell proliferation and apoptosis in tumor tissues. In addition, anti-cleaved caspase 3 was used for immunolabelling of apoptotic cells. Immune cell infiltration (macrophages and T cells) and gene expression in tumor tissues were also investigated by using immunofluorescence staining. Compared to treatment with anti-PD-1 or AS-IV, the combination of AS-IV and anti-PD-1 notably reduced tumor volume and weight of LLC-bearing mice. Additionally, the combination treatment strongly induced the apoptosis and suppressed the proliferation in tumor tissues through inactivating PI3K/Akt and ERK signaling pathways, compared to single treatment group. Moreover, the combination treatment elevated levels of the M1 macrophage marker mCD86, reduced levels of the M2 macrophage marker mCD206, as well as upregulated levels of the T cell activation marker mCD69 in tumor tissues. Collectively, the combination treatment effectively inhibited tumor growth in LLC mice through promoting M1 macrophage polarization and T cell activation. These findings showed that combining AS-IV with anti-PD-1 therapy could be a promising therapeutic approach for LC.

Buddlejasaponin IVb (BJP-IVb), a triterpenoid saponin derived from Pleurotus ostreatus , is abundant in bioactive constituents. However, its potential therapeutic benefits and underlying mechanism of action against ulcerative colitis (UC) remain elusive. Studies performed using a mouse model of colitis caused by dextran sulfate sodium showed that BJP-IVb helped reduce symptoms of UC, such as weight loss, a higher disease activity index, shorter colon length, and colon damage. It also repaired the intestinal barrier function and suppressed inflammation. BJP-IVb activated the Nrf2/HO-1 antioxidant pathway, inhibited ferroptosis, and affected protein expression and oxidative indicators. The combined use of BJP-IVb and Nrf2 inhibitor ML385 negated the effects of BJP-IVb. In Nrf2-KO mice, the protective effects of BJP-IVb were reversed. BJP-IVb inhibited ferroptosis via the Nrf2/GPX4 axis and alleviated gut microbiota dysbiosis. In conclusion, our research validates the therapeutic and protective efficacy of BJP-IVb on ulcerative colits. Additionally, it offers new perspectives on preventing colitis by focusing on the metabolism of gut microbiota using natural substances.

Increasing evidence suggests that the mononuclear/macrophage system is vital in amplifying the inflammatory cascade in IgA Nephropathy (IgAN). However, the pathogenic mechanism of macrophages in IgAN and targeted treatment strategies still need to be explored. This study found that botanical triterpene celastrol (CLT) effectively alleviated renal lesions, M1-like macrophage infiltration, inflammatory factors production, and improved renal function in IgAN mice. We found that the renal macrophages of IgAN patients had high expression of ECM1, a crucial molecule involved in macrophage inflammatory polarization, positively correlated with the IgAN clinical severity. In murine macrophage Raw 264.7 cells, CLT inhibited macrophage M1-like polarization and the output of TNF-α and IL-6 by downregulating the ECM1/STAT5 pathway. Mechanistically, molecular docking, CESTA, and immunoprecipitation verified that CLT directly bound to ECM1 and increased the ubiquitination of ECM1. Collectively, these results illustrated that CLT inhibited proinflammatory macrophage in IgAN by directly targeting ECM1 to promote ubiquitination degradation of ECM1. Therefore, this study may provide a theoretical basis for exploring the pathogenesis of IgAN and identifying new perspectives for targeted therapy of IgAN., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Subarachnoid hemorrhage (SAH) is a life -threatening cerebrovascular disease, where early brain injury (EBI) stands as a primary contributor to mortality and unfavorable patient outcomes. Neuronal ferroptosis emerges as a key pathological mechanism underlying EBI in SAH. Targeting ferroptosis for therapeutic intervention in SAH holds significant promise as a treatment strategy., Methods: SAH model was induced via intravascular puncture and quantitatively assessed the presence of neuronal ferroptosis in the early phase of SAH using FJC staining, Prussian blue staining, as well as malondialdehyde (MDA) and glutathione (GSH) measurements. Hyaluronic acid-coated ursolic acid nanoparticles (HA-PEG-UA NPs) were prepared using the solvent evaporation method. We investigated the in vivo distribution of HA-PEG-UA NPs in SAH model through IVIS and fluorescence observation, and examined their impact on short-term neurological function and cortical neurological injury. Finally, we assessed the effect of UA on the Nrf-2/SLC7A11/GPX4 axis via Western Blot analysis., Results: We successfully developed self-assembled UA NPs with hyaluronic acid to target the increased CD44 expression in the SAH-afflicted brain. The resulting HA-PEG-UA NPs facilitated delivery and enrichment of UA within the SAH-affected region. The targeted delivery of UA to the SAH region can effectively inhibit neuronal ferroptosis, improve neurological deficits, and prognosis in mice. Its mechanism of action is associated with the activation of the Nrf-2/SLC7A11/GPX4 signaling pathway., Conclusions: Brain-targeted HA-PEG-UA NPs was successfully developed and hold the potential to enhance SAH prognosis by limiting neuronal ferroptosis via modulation of the Nrf-2/SLC7A11/GPX4 signal., (© 2024. The Author(s).)

Breast cancer is the most prevalent form of cancer in women worldwide. Triple-negative breast cancer is the most unfavorable for patients, but it is also the most sensitive to chemotherapy. Triterpene glycosides from sea cucumbers possess a high therapeutic potential as anticancer agents. This study aimed to identify the pathways triggered and regulated in MDA-MB-231 cells (triple-negative breast cancer cell line) by the glycosides cucumarioside A 0 -1 (Cuc A 0 -1) and djakonovioside A (Dj A), isolated from the sea cucumber Cucumaria djakonovi . Using flow cytometry, fluorescence microscopy, immunoblotting, and ELISA, the effects of micromolar concentrations of the compounds on cell cycle arrest, induction of apoptosis, the level of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), and expression of anti- and pro-apoptotic proteins were investigated. The glycosides caused cell cycle arrest, stimulated an increase in ROS production, and decreased Δψm in MDA-MB-231 cells. The depolarization of the mitochondrial membrane caused by cucumarioside A 0 -1 and djakonovioside A led to an increase in the levels of APAF-1 and cytochrome C. This, in turn, resulted in the activation of caspase-9 and caspase-3 and an increase in the level of their cleaved forms. Glycosides also affected the expression of Bax and Bcl-2 proteins, which are associated with mitochondria-mediated apoptosis in MDA-MB-231 cells. These results indicate that cucumarioside A 0 -1 and djakonovioside A activate the intrinsic apoptotic pathway in triple-negative breast cancer cells. Additionally, it was found that treatment with Cuc A 0 -1 resulted in in vivo inhibition of tumor growth and metastasis of murine solid Ehrlich adenocarcinoma.

Covering mainly from 2013 up to 2023 with relevant references to work done before 2013First reported in 1995, the dichapetalins and analogous compounds constitute a novel class of natural dammarane-type merotriterpenoids characterized by their unique 2-phenylpyrano moiety annellated to ring A of the dammarane skeleton. They have been reported from only two genera: Dichapetalum (Dichapetalaceae) and Phyllanthus (Phyllanthaceae). About 100 novel dichapetalins and dichapetalin-type compounds, including the acutissimatriterpenes and their antitumour and other bioactivities have been reported. In the present review, we cover the distribution, ethnobotanical and medicinal importance and the diversity of secondary metabolites reported from the two genera Dichapetalum and Phyllanthus from 2013 to date, with appropriate reference to relevant information prior to 2013. We also propose and discuss possible biosynthetic pathways, antitumour activity against a broad range of human and murine cancer cell lines, structure activity relationships, and other biological activities and mechanisms of action. Finally, the review deals with future perspectives which include expansion of the structural diversity and bioactivity scope, possible simplification of the structural complexity of the compounds to enhance their drug-likeness, in silico studies, and continuation of the search for new dichapetalins and dichapetalin-type compounds from the over 200 Dichapetalum and over 1200 Phyllanthus species yet to be investigated. It is envisaged that the present review will stimulate further multidisciplinary and interdisciplinary studies.

New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 and C-28. This resulted in the targeted molecules being produced in good yields. Some of the synthesized conjugates showed significantly relevant bioactivity against mammalian cells and in animal models of cancers. Selected UA conjugates were tested against bladder and breast cancer cell lines. The conjugates showed moderate to significantly enhanced antiproliferative activities against Triple Negative Breast Cancer (TNBC; MDA-MB 231), which is an aggressive tumor making up about 10-15 % of all breast cancers and bladder (T24 and 5637) cancer cell lines. These properties were superior to the parent UA. Among all the synthesized compounds, 18 c and 18 d have exhibited promising antiproliferative and cytotoxic properties against all tested cancer cell lines. However, 18 d has proved to be exceptionally selective for cancer cell lines, showing more cytotoxicity towards them than normal epithelial cells (MCF-12A). Compound 18 d has demonstrated cytotoxicity against tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy., (© 2024 Wiley-VCH GmbH.)

Taraxasterol is one of the bioactive ingredients from traditional Chinese herb Taraxacum, which exhibits multiple pharmacological activities and protective effects. However, the underlying influence and mechanism of its use against kidney damage caused from zearalenone (ZEA) remain unexplored. The ZEA-induced kidney damage model of mice was established by feeding diets containing ZEA (2 mg/kg), and taraxasterol (5 and 10 mg/kg) was administered by gavage for 28 days. Results demonstrated taraxasterol increased average daily gain (ADG) and average daily feed intake (ADFI), reduced feed-to-gain ratio (F/G) and kidney index of mice induced by ZEA. Taraxasterol alleviated histopathological changes of kidney, reduced ZEA residue and the levels of blood urea nitrogen (BUN), uric acid (UA), and creatinine (CRE). Concurrently, taraxasterol reduced the contents of oxidative stress indicator reactive oxygen species (ROS) and malondialdehyde (MDA), and increased the activities of antioxidant enzymes catalase (CAT), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px). Further, taraxasterol up-regulated the mRNA and protein expression of nuclear factor erythroid-2-related factor 2 (Nrf2), GSH-Px, NAD(P)H quinone oxidoreductase 1 (NQO1), and heme oxygenase-1 (HO-1), and down-regulated the mRNA and protein expression of KELCH like ECH associated protein (Keap1) in Nrf2/Keap1 pathway. Taraxasterol down-regulated the mRNA and protein expression of immunoglobulin binding protein (Bip), C/EBP homologous protein (CHOP), Bcl-2 associated X (Bax), cysteine protease (Caspase)-12, and Caspase-3, and up-regulated B-cell lymphoma 2 (Bcl-2) expression in endoplasmic reticulum stress pathway. This study suggests that taraxasterol attenuates ZEA-induced mouse kidney damage through the modulation of Nrf2/Keapl pathway to play antioxidant role and endoplasmic reticulum stress pathway to enhance anti-apoptotic ability. It will provide a basis for taraxasterol as a potential drug to prevent and treat ZEA-induced kidney damage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ursolic acid (UA), a pentacyclic triterpene, exhibits diverse pharmacological effects, including potential treatment for allergic diseases. It downregulates thymic stromal lymphopoietin (TSLP) and disrupts mast cell signaling pathways. However, the exact molecular mechanism by which UA interferes with mast cell action remains unclear. Therefore, the current study aimed to uncover molecular entities underlying the effect of UA on mast cells and its potential antipruritic effect, specifically investigating its modulation of key molecules such as TRPV4, PAR2, and MRGPRX2, which are involved in TSLP regulation and sensation. Calcium imaging experiments revealed that UA pretreatment significantly suppressed MRGPRX2 activation (and its mouse orthologue MrgprB2), a G protein-coupled receptor predominantly expressed in mast cells. Molecular docking predictions suggested potential interactions between UA and MRGPRX2/MrgprB2. UA pretreatment also reduced mast cell degranulation through MRGPRX2 and MrgprB2-dependent mechanisms. In a dry skin mouse model, UA administration decreased tryptase and TSLP production in the skin, and diminished TSLP response in the sensory neurons. While PAR2 and TRPV4 activation enhances TSLP production, UA did not inhibit their activity. Notably, UA attenuated compound 48/80-induced scratching behaviors in mice and suppressed spontaneous scratching in a dry skin model. The present study confirms the effective inhibition of UA on MRGPRX2/MrgprB2, leading to reduced mast cell degranulation and suppressed scratching behaviors. These findings highlight the potential of UA as an antipruritic agent for managing various allergy- or itch-related conditions., Competing Interests: Declaration of competing interest The authors state no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)