RESUMEN
The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.
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Cobre , Hidrogeles , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Activación de Linfocitos , Triterpenos Pentacíclicos , Especies Reactivas de Oxígeno , Linfocitos T , Microambiente Tumoral , Triterpenos Pentacíclicos/farmacología , Hidrogeles/química , Animales , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ratones , Activación de Linfocitos/efectos de los fármacos , Cobre/química , Microambiente Tumoral/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Humanos , Ratones Endogámicos C57BL , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/química , Femenino , Triterpenos/farmacología , Triterpenos/químicaRESUMEN
Inflammation involving adipose macrophages is an important inducer of obesity. Regulating macrophages polarization and improving the inflammatory microenvironment of adipose tissue is a new strategy for the treatment of obesity. An amphiphilic chondroitin sulfate phenylborate derivative (CS-PBE) was obtained by modifying the main chain of chondroitin sulfate with the hydrophobic small molecule phenylborate. Using CS-PBE self-assembly, macrophage targeting, reactive oxygen species (ROS) release and celastrol (CLT) encapsulation were achieved. The cytotoxicity, cellular uptake, internalization pathways and transmembrane transport efficiency of CS-PBE micelles were studied in Caco-2 and RAW264.7 cells. Hemolysis and organotoxicity tests were performed to assess the safety of the platform, while its therapeutic efficacy was investigated in high-fat diet-induced obese mice. Multifunctional micelles with macrophage targeting and ROS clearance capabilities were developed to improve the efficacy of CLT in treating obesity.In vitrostudies indicated that CS-PBE micelles had better ability to target M1 macrophages, better protective effects on mitochondrial function, better ability to reduce the number of LPS-stimulated M1 macrophages, better ability to reduce the number of M2 macrophages, and better ability to scavenge ROS in inflammatory macrophages.In vivostudies have shown that CS-PBE micelles improve inflammation and significantly reduce toxicity of CLT in the treatment of obesity. In summary, CS-PBE micelles could significantly improve the ability to target inflammatory macrophages and scavenge ROS in adipose tissue to alleviate inflammation, suggesting that CS-PBE micelles are a highly promising approach for the treatment of obesity.
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Macrófagos , Micelas , Mitocondrias , Obesidad , Especies Reactivas de Oxígeno , Animales , Especies Reactivas de Oxígeno/metabolismo , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Células RAW 264.7 , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacología , Células CACO-2 , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/química , Ratones Endogámicos C57BL , Masculino , Dieta Alta en Grasa/efectos adversos , Triterpenos/farmacología , Triterpenos/químicaRESUMEN
Mauritia flexuosa (M. flexuosa), commonly known as Aguaje or Moriche palm, is traditionally recognised in South America for its medicinal properties, particularly for its anti-inflammatory and antioxidant effects. However, the bioactive compounds responsible for these effects have not been thoroughly investigated. This study aims to isolate and characterise pentacyclic triterpenoid compounds from M. flexuosa and to evaluate their therapeutic potential. Using various chromatographic and spectroscopic techniques including Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS), three pentacyclic triterpenoid compounds were successfully isolated. Among them, compound 1 (3,11-dioxours-12-en-28-oic acid) exhibited notable bioactivity, significantly inhibiting the activation of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) (IC50 = 7.39-8.11 µM) and of Nitric Oxide (NO) (IC50 = 4.75-6.59 µM), both of which are key processes in inflammation. Additionally, compound 1 demonstrated potent antioxidant properties by activating the antioxidant enzyme Superoxide Dismutase (SOD) (EC50 = 1.87 µM) and the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) (EC50 = 243-547.59 nM), thus showing its potential in combating oxidative stress. This study is the first to isolate and characterise the three compounds from M. flexuosa, suggesting that compound 1 could be a promising candidate for the development of safer and more effective therapies for inflammatory and oxidative stress-related diseases.
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Antiinflamatorios , Antioxidantes , Triterpenos Pentacíclicos , Antioxidantes/farmacología , Antioxidantes/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/química , Animales , Ratones , Células RAW 264.7 , Óxido Nítrico/metabolismo , FN-kappa B/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
In the following study, a series of new lupeol-3-carbamate derivatives were synthesized, and the structures of all the newly derived compounds were characterized. The new compounds were screened to determine their anti-proliferative activity against human lung cancer cell line A549, human liver cancer cell line HepG2, and human breast cancer cell line MCF-7. Most of the compounds were found to show better anti-proliferative activity in vitro than lupeol. Among them, obvious anti-proliferation activity (IC50 = 5.39~9.43 µM) was exhibited by compound 3i against all three tumor cell lines. In addition, a salt reaction was performed on compound 3k (IC50 = 13.98 µM) and it was observed that the anti-proliferative activity and water solubility of compound 3k·CH3I (IC50 = 3.13 µM), were significantly enhanced subsequent to the salt formation process. The preliminary mechanistic studies demonstrated that apoptosis in HepG2 cells was induced by compound 3k·CH3I through the inhibition of the PI3K/AKT/mTOR pathway. In conclusion, a series of new lupeol-3-carbamate derivatives were synthesized via the structural modification of the C-3 site of lupeol, thus laying a theoretical foundation for the design of this new anticancer drug.
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Antineoplásicos , Apoptosis , Carbamatos , Proliferación Celular , Triterpenos Pentacíclicos , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/síntesis química , Triterpenos Pentacíclicos/química , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Carbamatos/farmacología , Carbamatos/química , Carbamatos/síntesis química , Células Hep G2 , Relación Estructura-Actividad , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Células A549 , Células MCF-7 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , LupanosRESUMEN
Background: Dental pulp inflammation, often initiated by Gram-negative microorganisms and lipopolysaccharides (LPS), can lead to pulpitis and, subsequently, dental pulp necrosis, compromising tooth structure and increasing susceptibility to fracture. Asiatic acid, derived from Centella asiatica, has demonstrated pharmacological properties, including anti-inflammatory and antioxidant effects, making it a potential candidate for mitigating LPS-induced pulp inflammation. This in vivo study aims to investigate the impact of Asiatic acid on the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in Rattus norvegicus with LPS-induced pulp inflammation. Methods: This quasi-laboratory experimental in vivo study employed a post-test-only control group design to investigate the effects of Asiatic acid on LPS-induced pulp inflammation in Wistar rats. Thirty rats were randomly divided into six groups subjected to various interventions. LPS was administered to all groups for 6 h except the standard control group (CG, n = 5). The negative control group (NCG, n = 5) received only glass ionomer cement. The positive control group (PCG, n = 5) received Eugenol with glass ionomer cement. Intervention groups 1, 2, and 3 (IG1, IG2, IG3; n = 5 each) received Asiatic acid at concentrations of 0.5%, 1%, and 2%, respectively, with glass ionomer cement. Dental pulp inflammation was confirmed through immunological (tumor necrosis factor alpha (TNF-α) levels), histopathological (inflammatory parameters), and physiological (pain assessment using the rat grimace scale) analyses. Additionally, Nrf2 levels were examined using enzyme-linked immunosorbent assay (ELISA). Results: Asiatic acid administration significantly influenced Nrf2 levels in rats with LPS-induced pulp inflammation. Nrf2 levels were significantly higher in groups treated with 0.5% (IG1) (8.810 ± 1.092 ng/mL; p = 0.047), 1.0% (IG2) (9.132 ± 1.285 ng/mL; p = 0.020), and 2.0% (IG3) (11.972 ± 1.888 ng/mL; p = 0.000) Asiatic acid compared to NCG (7.146 ± 0.706). Notably, Nrf2 levels were also significantly higher in the 2.0% Asiatic acid group (IG3) compared to the PCG treated with Eugenol (8.846 ± 0.888 ng/mL; p = 0.001), as well as IG1 (p = 0.001) and IG2 (p = 0.002). However, no significant difference was observed between administering 0.5% Asiatic acid (IG1), 1.0% Asiatic acid (IG2), and Eugenol (PCG). Conclusion: This research showed that Asiatic acid significantly impacted the Nrf2 levels in rats with LPS-induced pulp inflammation. This suggests that it has the potential to be used as a therapeutic agent for reducing dental pulp inflammation. These findings support the need to further explore Asiatic acid as a promising intervention for maintaining dental pulp health.
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Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , Triterpenos Pentacíclicos , Pulpitis , Ratas Wistar , Animales , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/uso terapéutico , Lipopolisacáridos/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Ratas , Pulpitis/tratamiento farmacológico , Pulpitis/patología , Pulpitis/metabolismo , Pulpitis/inducido químicamente , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Pulpa Dental/efectos de los fármacos , Pulpa Dental/metabolismo , Pulpa Dental/patología , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/inducido químicamenteRESUMEN
Pristimerin is a natural triterpenoid that has received much attention from medicinal chemists for its multiple biological activities. However, structural modifications of pristimerin, especially those aimed at discovering antitumor agents, are relatively limited. In this study, two series of pristimerin derivatives containing phenyloxazole and quinoxaline moieties, respectively, were designed via the scaffold hopping strategy. The target compounds were synthesized and analyzed for their cytotoxic activities in vitro using the MTT assay. The most potent cytotoxic compound (21o) significantly inhibited the proliferation of MCF-7 cells with an IC50 value of 2.0 µM, 1.5-fold more potent than pristimerin (IC50 = 3.0 µM). Compared with pristimerin, compound 21o displayed the greatest improvement in selectivity (25.7-fold) against the MCF-7 and MCF-10A cell lines. Transmission electron microscopy, monodansylcadaverine and DCFH-DA staining, Western blotting, and different inhibitor assays were performed to elucidate the mechanism of action of compound 21o. Compound 21o induced autophagy-mediated cell death in MCF-7 cells by activating the ROS/JNK signaling pathway. Therefore, incorporating a quinoxaline substructure into pristimerin could be advantageous for enhancing its cytotoxic activity. Compound 21o may serve as a lead compound for developing new therapies to treat breast cancer.
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Autofagia , Neoplasias de la Mama , Triterpenos Pentacíclicos , Quinoxalinas , Triterpenos , Femenino , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Autofagia/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células MCF-7 , Estructura Molecular , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/química , Quinoxalinas/farmacología , Quinoxalinas/química , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Triterpenos/farmacología , Triterpenos/químicaRESUMEN
Betulinic acid (BA) is a lupinane-type pentacyclic triterpenoid natural product derived from lupeol that has favorable anti-inflammatory and anti-tumor activities. Currently, BA is mainly produced via botanical extraction, which significantly limits its widespread use. In this study, we investigated the de novo synthesis of BA in Saccharomyces cerevisiae, and to facilitate the synthesis and storage of hydrophobic BA, we adopted a dual-engineering strategy involving peroxisomes and lipid droplets to construct the BA biosynthetic pathway. By expressing Betula platyphylla-derived lupeol C-28 oxidase (BPLO) and Arabidopsis-derived ATR1, we succeeded in developing a BA-producing strain and following multiple expression optimizations of the linker between BPLO and ATR1, the BA titer reached 77.53 mg/L in shake flasks and subsequently reached 205.74 mg/L via fed-batch fermentation in a 5-L bioreactor. In this study, we developed a feasible approach for the de novo synthesis of BA and its direct precursor lupeol in engineered S. cerevisiae.
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Ácido Betulínico , Triterpenos Pentacíclicos , Saccharomyces cerevisiae , Triterpenos , Saccharomyces cerevisiae/metabolismo , Triterpenos Pentacíclicos/metabolismo , Triterpenos Pentacíclicos/química , Triterpenos/metabolismo , Triterpenos/química , Estructura Molecular , Ingeniería MetabólicaRESUMEN
In situ vaccines that can stimulate tumor immune response have emerged as a breakthrough in antitumor therapy. However, the immunosuppressed tumor microenvironment and insufficient infiltration of immune cells lead to ineffective antitumor immunity. Hence, a biomimetic carrier-free nanosystem (BCC) to induce synergistic phototherapy/chemotherapy-driven in situ vaccines was designed. A carrier-free nanosystem was developed using phototherapeutic reagents CyI and celastrol as raw materials. In vitro and in vivo studies have shown that under NIR light irradiation, BCC-mediated photo/chemotherapy not only accelerates the release of drugs to deeper parts of tumors, achieving timing and light-controlled drug delivery to result in cell apoptosis, but also effectively stimulates the antitumor response to induce in situ vaccine, which could invoke long-lasting antitumor immunity to inhibit tumor metastasis and eliminate distant tumor. This therapeutic strategy holds promise for priming robust innate and adaptive immune responses, arresting cancer progression, and inducing tumor dormancy.
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Vacunas contra el Cáncer , Inmunoterapia , Animales , Ratones , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/inmunología , Humanos , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacología , Línea Celular Tumoral , Neoplasias/terapia , Neoplasias/inmunología , Microambiente Tumoral/efectos de los fármacos , Nanopartículas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Fototerapia , Apoptosis/efectos de los fármacos , Rayos InfrarrojosRESUMEN
Celastrol, a triterpenoid found in the root of the traditional medicinal plant Tripterygium wilfordii, is a potent anti-inflammatory and antiobesity agent. However, pharmacological exploitation of celastrol has been hindered by the limited accessibility of plant material, the co-existence of other toxic compounds in the same plant tissue, and the lack of an efficient chemical synthesis method. In this review, we highlight recent progress in elucidating celastrol biosynthesis and discuss how this knowledge can facilitate its scalable bioproduction using cell factories and its further development as an antiobesity and anti-inflammatory drug.
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Fármacos Antiobesidad , Triterpenos Pentacíclicos , Triterpenos , Triterpenos/metabolismo , Tripterygium/metabolismo , Biotecnología/métodosRESUMEN
BACKGROUND: Celastrol is a natural triterpene exhibiting significant and extensive antitumor activity in a wide range of cancer. Due to unfavorable toxicity profile and undefined mechanism, Celastrol's application in clinical cancer therapy remains limited. Herein, we elucidate the pharmacological mechanism of Celastrol's anticancer effects, with a focus on STAT3 signaling pathway in cancers with high incidence of metastasis. METHODS: The safety profile of Celastrol were assessed in mice. In vitro analysis was performed in gastric cancer and ovarian cancer to assess the cytotoxicity, induction of reactive oxygen species (ROS) of Celastrol using STAT3 knockout cancer cells. Effects of Celastrol on STAT3 activation and transcription activity, JAK2/STAT3 signaling protein expression were assessed. Additionally, proteomic contrastive analysis was performed to explore the molecular association of Celastrol with STAT3 deletion in cancer cells. RESULTS: Celastrol has no obvious toxic effect at 1.5 mg/kg/day in a 15 days' administration. Celastrol inhibits tumor growth and increases ROS in a STAT3 dependent manner in gastric and ovarian cancer celllines. On molecular level, it downregulates IL-6 level and inhibits the JAK2/STAT3 signaling pathway by suppressing STAT3' activation and transcription activity. Proteomic contrastive analysis suggests a similar cellular mechanism of action between Celastrol and STAT3 deletion on regulating cancer progression pathways related to migration and invasion. CONCLUSION: Our research elucidates the anti-cancer mechanism of Celastrol through targeting the JAK2/STAT3 signaling pathway in cancer with high incidence of metastasis. This study provides a solid theoretical basis for the application of Celastrol in cancer therapy.
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Janus Quinasa 2 , Neoplasias Ováricas , Triterpenos Pentacíclicos , Factor de Transcripción STAT3 , Transducción de Señal , Neoplasias Gástricas , Triterpenos , Janus Quinasa 2/metabolismo , Femenino , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/genética , Animales , Humanos , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Línea Celular Tumoral , Ratones , Antineoplásicos/farmacología , Ratones Desnudos , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Betulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) is highly overexpressed on the CRC cell membrane. A single-stranded short oligonucleotide sequence, aptamer (Apt), that folds into a 3D-defined architecture can be used as a targeting ligand for its specific binding to a target protein. EpCAM targeting aptamer was designed for site-specific homing of aptamer-conjugated-2c-loaded nanoparticles (Apt-2cNP) at the CRC tumor site to enhance therapeutic potential and reduce off-target toxicity in normal cells. We investigated the in vitro and in vivo therapeutic efficacy and anti-tumorigenic immune response of aptamer conjugated nanotherapy in CRC-TME. METHODS: After the characterization of nanoengineered aptamer conjugated betulinic acid nanotherapy, we evaluated therapeutic efficacy, tumor targeting efficiency, and anti-tumorigenic immune response using cell-based assays and mouse and rat models. RESULTS: We found that Apt-2cNP improved drug bioavailability, enhanced its biological half-life, improved antiproliferative activity, and minimized off-target cytotoxicity. Importantly, in an in vivo TME, Apt-2cNP showed promising signs of anti-tumorigenic immune response (increased mDC/pDC ratio, enhanced M1 macrophage population, and CD8 T-cells). Furthermore, in vivo upregulation of pro-apoptotic while downregulation of anti-apoptotic genes and significant healing efficacy on cancer tissue histopathology suggest that Apt-2cNP had predominantly greater therapeutic potential than the non-aptamer-conjugated nanoparticles and free drug. Moreover, we observed greater tumor accumulation of the radiolabeled Apt-2cNP by live imaging in the CRC rat model. CONCLUSIONS: Enhanced therapeutic efficacy and robust anti-tumorigenic immune response of Apt-2cNP in the CRC-TME are promising indicators of its potential as a prospective therapeutic agent for managing CRC. However, further studies are warranted.
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Ácido Betulínico , Neoplasias Colorrectales , Molécula de Adhesión Celular Epitelial , Triterpenos Pentacíclicos , Microambiente Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Animales , Microambiente Tumoral/efectos de los fármacos , Ratones , Triterpenos Pentacíclicos/farmacología , Molécula de Adhesión Celular Epitelial/metabolismo , Humanos , Nanopartículas/química , Línea Celular Tumoral , RatasRESUMEN
This study aims to further elucidate the efficacy targets of celastrol(CEL) intervention in central inflammation in mice with obesity-depression comorbiditiy, based on the differential mRNA expression in the amygdala(AMY) and dorsal raphe nucleus(DRN) after CEL intervention. C57BL/6J mice were randomly divided into a normal diet group(Chow), a obesity-depression comorbidity(COM) group, and low-, medium-, and high-dose CEL groups(CEL-L, CEL-M, CEL-H, 0.5, 1.0, 2.0 mg·kg~(-1)). The Chow group received a normal diet, while the COM group and CEL-L, CEL-M, CEL-H groups received a high-fat diet combined with chronic stress from wet bedding. After 10 weeks of feeding, the mice were orally administered CEL for three weeks. Subsequently, the AMY and DRN of mice in the Chow, COM, and CEL-H groups were subjected to transcriptome analysis, and the intersection of target differentially expressed genes in both nuclei was visualized using a Venn diagram. The intersected genes were then imported into STRING for protein-protein interaction(PPI) analysis, and Gene Ontology(GO) analysis was performed using DAVID to identify the core targets regulated by CEL in the AMY and DRN. Independent samples were subjected to quantitative real-time PCR(qPCR) to validate the intersection genes. The results revealed that the common genes regulated by CEL in the AMY and DRN included chemokine family genes Ccl2, Ccl5, Ccl7, Cxcl10, Cxcr6, and Hsp70 family genes Hspa1a, Hspa1b, as well as Myd88, Il2ra, Irf7, Slc17a8, Drd2, Parp9, and Nampt. GO analysis showed that the top 5 nodes Ccl2, Cxcl10, Myd88, Ccl5, and Irf7 were all involved in immune-inflammation regulation(P<0.01). The qPCR results from independent samples showed that in the AMY, compared with the results in the Chow group, chemokine family genes, Hsp70, Myd88, Il2ra, Irf7, Slc17a8, Parp9, and Nampt were significantly up-regulated in the COM group, with Drd2 showing a decreasing trend; these pathological changes were significantly improved in the CEL-H group compared to the COM group. In the DRN, compared with the results in the Chow group, chemokine family genes, Hsp70, Myd88, Il2ra, Irf7, Parp9, and Nampt were significantly down-regulated, while Slc17a8 was significantly up-regulated in the COM group; compared with those in the COM group, Cxcr6, Irf7, and Drd2 were significantly up-regulated, while Slc17a8 was significantly down-regulated in the CEL-H group. In both the AMY and DRN, the expression of Irf7 by CEL showed both inhibition and activation in a dose-dependent manner(R~2 were 0.709 8 and 0.917 2, respectively). These findings suggest that CEL can effectively improve neuroinflammation by regulating bidirectional expression of the same target proteins, thereby intervening in the immune activation of the AMY and immune suppression of the DRN in COM mice.
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Amígdala del Cerebelo , Depresión , Núcleo Dorsal del Rafe , Ratones Endogámicos C57BL , Obesidad , Triterpenos Pentacíclicos , Triterpenos , Animales , Ratones , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Masculino , Depresión/tratamiento farmacológico , Depresión/genética , Depresión/metabolismo , Obesidad/genética , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Triterpenos/farmacología , Núcleo Dorsal del Rafe/metabolismo , Núcleo Dorsal del Rafe/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/genética , HumanosRESUMEN
Four previously unreported triterpenoid saponins named 3ß-hydroxy-23-oxours-12-en-28-oic acid 28-O-ß-D-glucopyranosyl ester (mannioside G) (1), 23-O-acetyl-3ß-hydroxyurs-12-en-28-oic acid 28-O-ß-D-glucopyranosyl ester (mannioside H) (2), ursolic acid 28-O-[α-L-rhamnopyranosyl-(1â4)-ß-D-glucopyranosyl-(1â6)-ß-D-glucopyranosyl] ester (mannioside I) (3), and 3ß-hydroxy-23-oxolup-20(29)-en-28-oic acid 28-O-ß-D-glucopyranosyl ester (mannioside J) (4) were isolated as minor constituents from the EtOAc soluble fraction of the MeOH extract of the leaves of Schefflera mannii along with the known compounds 23-hydroxyursolic acid 28-O-ß-D-glucopyranosyl ester (5), ursolic acid 28-O-ß-D-glucopyranosyl ester (6), pulsatimmoside B (7) betulinic acid 28-O-[α-L-rhamnopyranosyl-(1â4)-ß-D-glucopyranosyl-(1â6)-ß-D-glucopyranosyl] ester (8), 23-hydroxy-3-oxo-urs-12-en-28-oic acid (9), hederagenin (10), ursolic acid (11), betulinic acid (12), and lupeol (13). Their structures were elucidated by a combination of 1D and 2D NMR analysis and mass spectrometry. The MeOH extract, the EtOAc and n-BuOH fractions, and some of the isolated compounds were evaluated for their antibacterial activity against four bacteria: Staphylococcus aureus ATCC1026, Staphylococcus epidermidis ATCC 35984, Escherichia coli ATCC10536, and Klepsiella pnemoniae ATCC13882. They were also screened for their antioxidant properties, but no significant results were obtained.
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Antibacterianos , Saponinas , Triterpenos , Triterpenos/química , Triterpenos/farmacología , Triterpenos/aislamiento & purificación , Saponinas/química , Saponinas/farmacología , Saponinas/aislamiento & purificación , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/química , Extractos Vegetales/farmacología , Estructura Molecular , Hojas de la Planta/química , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/aislamiento & purificación , Staphylococcus aureus/efectos de los fármacos , Araliaceae/químicaRESUMEN
OBJECTIVES: Celastrol has widespread therapeutic applications in various pathological conditions, including chronic inflammation. Previous studies have demonstrated the potent cardioprotective effects of celastrol. Nevertheless, limited attention has been given to its potential in reducing ventricular arrhythmias (VAs) following myocardial infarction (MI). Hence, this study aimed to elucidate the potential mechanisms underlying the regulatory effects of celastrol on VAs and cardiac electrophysiological parameters in rats after MI. METHODS: Sprague-Dawley rats were divided at random: the sham, MI, and MI + celastrol groups. The left coronary artery was occluded in the MI and MI + Cel groups. Electrocardiogram, heart rate variability (HRV), ventricular electrophysiological parameters analysis, histology staining of ventricles, Enzyme-linked immunosorbent assay (ELISA), western blotting and Quantitative real-time polymerase chain reaction (qRT-PCR) were performed to elucidate the underlying mechanism of celastrol. Besides, H9c2 cells were subjected to hypoxic conditions to create an in vitro model of MI and then treated with celastrol for 24â¯hours. Nigericin was used to activate the NLRP3 inflammasome. RESULTS: Compared with that MI group, cardiac electrophysiology instability was significantly alleviated in the MI + celastrol group. Additionally, celastrol improved HRV, upregulated the levels of Cx43, Kv.4.2, Kv4.3 and Cav1.2, mitigated myocardial fibrosis, and inhibited the NLRP3 inflammasome pathway. In vitro conditions also supported the regulatory effects of celastrol on the NLRP3 inflammasome pathway. CONCLUSIONS: Celastrol could alleviate the adverse effects of VAs after MI partially by promoting autonomic nerve remodeling, ventricular electrical reconstruction and ion channel remodeling, and alleviating ventricular fibrosis and inflammatory responses partly by through inhibiting the NLRP3/Caspase-1/IL-1ß pathway.
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Antiarrítmicos , Arritmias Cardíacas , Caspasa 1 , Insuficiencia Cardíaca , Interleucina-1beta , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Triterpenos Pentacíclicos , Ratas Sprague-Dawley , Transducción de Señal , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Triterpenos Pentacíclicos/farmacología , Caspasa 1/metabolismo , Antiarrítmicos/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Ratas , Interleucina-1beta/metabolismo , Arritmias Cardíacas/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Triterpenos/farmacología , Enfermedad Crónica , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Línea Celular , Frecuencia Cardíaca/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
The investigation of the leaves of Pittosporum elevaticostatum Chang et Yan led to the isolation of fifteen pentacyclic triterpenoids (1-15), including five previously undescribed ones (1-5), and nine others (16-24). The structures of compounds 1-5 were elucidated based on comprehensive spectroscopic techniques, including one dimension (1D) and 2D nuclear magnetic resonance (NMR), high resolution electrospray ionization mass spectroscopy (HR-ESI-MS), and other methods. Compounds 2 and 13 demonstrated significant inhibitory activity against Listeria monocytogenes (L. monocytogenes) with minimum inhibitory concentration (MIC) values of 32 µM. Scanning electron microscopy (SEM) observations revealed insights into the antibacterial mechanism, indicating that compounds 2 and 13 either prevent biofilm formation of dispersed the preformed cell membranes. Additionally, compounds 1, 5, 7, and 12 exhibited anti-inflammatory activity on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells with IC50 values ranging from 11.27 to 17.80 µM.
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Antibacterianos , Antiinflamatorios , Listeria monocytogenes , Pruebas de Sensibilidad Microbiana , Triterpenos Pentacíclicos , Hojas de la Planta , Hojas de la Planta/química , Antibacterianos/farmacología , Antibacterianos/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Estructura Molecular , Ratones , Animales , Listeria monocytogenes/efectos de los fármacos , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/aislamiento & purificación , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Microglía/efectos de los fármacos , Línea Celular , ChinaRESUMEN
Leishmaniosis is a tropical neglected parasitic disease that is endemic in many countries, including Middle East, with no existing effective vaccines. The bite of female sand-fly transmits the causative agent, Leishmania spp., to humans. High toxicity, resistance and treatment failure of the available chemotherapy against visceral leishmaniosis demands the investigation of new anti-leishmanial compounds. Lupeol is a form of triterpene isolated from several medicinal plants and possesses an antimicrobial property. In this study, cytotoxic effect of lupeol was screened against the mammalian amastigotes form and insect promastigote form of Leishmania donovani, following three cycles of incubation at different concentrations by MTT assay. Results revealed the in vitro anti-leishmanial effect of lupeol on both forms of the parasite where significant decline in promastigotes and amastigotes growth was observed. This was conducted along three times of follow up (24, 48, 72) hours, in comparison to the classical sodium stibogluconate treatment. Cell viability was calculated and the minimum IC50 was detected after 48 hours for amastigotes and 24 hours for promastigotes, 12.125 µM, 102.78 µM, respectively. Given the severity of visceral leishmaniosis and the toxicity of conventional chemotherapies, the anti-leishmanial activity of lupeol suggested a promising compound for additional clinical trials.
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Antiprotozoarios , Leishmania donovani , Triterpenos Pentacíclicos , Triterpenos Pentacíclicos/farmacología , Leishmania donovani/efectos de los fármacos , Antiprotozoarios/farmacología , Animales , Relación Dosis-Respuesta a Droga , LupanosRESUMEN
Obesity has emerged as a significant global health burden, exacerbated by serious side effects associated with existing anti-obesity medications. Celastrol (CLT) holds promise for weight loss but encounters challenges related to poor solubility and systemic toxicity. Here, we present chondroitin sulfate (CS)-derived micelles engineered for adipocyte-specific targeting, aiming to enhance the therapeutic potential of CLT while minimizing its systemic toxicity. To further enhance adipocyte affinity, we introduced a biguanide moiety into a micellar vehicle. CS is sequentially modified with hydrophilic metformin and hydrophobic 4-aminophenylboronic acid pinacol ester (PBE), resulting in the self-assembly of CLT-encapsulated micelles (MET-CS-PBE@CLT). This innovative design imparts amphiphilicity via the PBE moieties while ensuring the outward exposure of hydrophilic metformin moieties, facilitating active interactions with adipocytes. In vitro studies confirmed the enhanced uptake of MET-CS-PBE@CLT micelles by adipocytes, while in vivo studies demonstrated increased distribution within adipose tissues. In a diet-induced obese mouse model, MET-CS-PBE@CLT exhibited remarkable efficacy in weight loss without affecting food intake. This pioneering strategy offers a promising, low-risk, and highly effective solution to address the global obesity epidemic.
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Adipocitos , Micelas , Obesidad , Triterpenos Pentacíclicos , Animales , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacología , Ratones , Adipocitos/efectos de los fármacos , Obesidad/tratamiento farmacológico , Biguanidas/química , Biguanidas/farmacología , Biguanidas/uso terapéutico , Ratones Endogámicos C57BL , Células 3T3-L1 , Sistemas de Liberación de Medicamentos , Masculino , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/química , Tamaño de la Partícula , Sulfatos de Condroitina/química , Portadores de Fármacos/química , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
BACKGROUND: Betulinic acid (BA), which is a pentacyclic triterpenoid found in the bark of plane, birch, and eucalyptus trees, has emerged as a compound of significant interest in scientific research due to its potential therapeutic applications. BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities. Although numerous research studies have explored the potential anticancer effects of BA, there is a noticeable gap in the literature, highlighting the need for a more up-to-date and comprehensive evaluation of BA's anticancer potential. PURPOSE: The aim of this work is to critically assess the reported cellular and molecular mechanisms underlying the cancer preventive and therapeutic effects of BA. METHODS: Relevant research on the inhibitory effects of BA against cancerous cells was searched using Science Direct, Scopus, Web of Science, and PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: The anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling. Emerging evidence also underscores the combined anticancer effects of BA with other natural bioactive compounds or approved drugs. Notably, several novel BA nanoformulations have been found to exhibit encouraging antineoplastic activities. CONCLUSION: BA, whether used alone or in combination, or as a form of nanoformulation, shows significant potential for cancer prevention and treatment. Nevertheless, further detailed studies are necessary to confirm the therapeutic effectiveness of this natural compound.
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Antineoplásicos Fitogénicos , Ácido Betulínico , Neoplasias , Triterpenos Pentacíclicos , Triterpenos , Triterpenos Pentacíclicos/farmacología , Humanos , Neoplasias/prevención & control , Neoplasias/tratamiento farmacológico , Triterpenos/farmacología , Antineoplásicos Fitogénicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacosRESUMEN
Celastrol, a bioactive molecule extracted from the plant Tripterygium wilfordii Hook F., possesses anti-inflammatory, anti-obesity and anti-tumour properties. Despite its efficacy in improving erythema and scaling in psoriatic mice, the specific therapeutic mechanism of celastrol in atopic dermatitis (AD) remains unknown. This study aims to examine the role and mechanism of celastrol in AD using TNF-α-stimulated HaCaT cells and DNCB-induced Balb/c mice as in vitro and in vivo AD models, respectively. Celastrol was found to inhibit the increased epidermal thickness, reduce spleen and lymph node weights, attenuate inflammatory cell infiltration and mast cell degranulation and decrease thymic stromal lymphopoietin (TSLP) as well as various inflammatory factors (IL-4, IL-13, TNF-α, IL-5, IL-31, IL-33, IgE, TSLP, IL-17, IL-23, IL-1ß, CCL11 and CCL17) in AD mice. Additionally, celastrol inhibited Ezrin phosphorylation at Thr567, restored mitochondrial network structure, promoted translocation of Drp1 to the cytoplasm and reduced TNF-α-induced cellular reactive oxygen species (ROS), mitochondrial ROS (mtROS) and mitochondrial membrane potential (MMP) production. Interestingly, Mdivi-1 (a mitochondrial fission inhibitor) and Ezrin-specific siRNAs lowered inflammatory factor levels and restored mitochondrial reticular formation, as well as ROS, mtROS and MMP production. Co-immunoprecipitation revealed that Ezrin interacted with Drp1. Knocking down Ezrin reduced mitochondrial fission protein Drp1 phosphorylation and Fis1 expression while increasing the expression of fusion proteins Mfn1 and Mfn2. The regulation of mitochondrial fission and fusion by Ezrin was confirmed. Overall, celastrol may alleviate AD by regulating Ezrin-mediated mitochondrial fission and fusion, which may become a novel therapeutic reagent for alleviating AD.
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Citocinas , Proteínas del Citoesqueleto , Dermatitis Atópica , Ratones Endogámicos BALB C , Dinámicas Mitocondriales , Triterpenos Pentacíclicos , Triterpenos , Animales , Dinámicas Mitocondriales/efectos de los fármacos , Triterpenos Pentacíclicos/farmacología , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Dermatitis Atópica/metabolismo , Humanos , Triterpenos/farmacología , Ratones , Citocinas/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/genética , Linfopoyetina del Estroma Tímico , Modelos Animales de Enfermedad , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Células HaCaT , Fosforilación/efectos de los fármacosRESUMEN
Uvaol (UV), a pentacyclic triterpene found in olives and virgin olive oil, is known for its anti-inflammatory and antioxidant effects in various disease models. While olive oil is reported to reduce obesity and insulin resistance, the specific impact of UV on liver lipid metabolism and its molecular mechanisms are not fully understood. In this study, hepatic lipid accumulation was measured using oil red O staining, and protein expression levels in liver cells were assessed via Western blot analysis. Apoptosis was evaluated through cell viability and caspase 3 activity assays. UV treatment reduced lipid accumulation, fatty acid uptake, apoptosis, and ER stress in palmitate-treated liver cells. Additionally, UV enhanced fatty acid oxidation. Mechanistically, increased SIRT6 expression and autophagy were observed in UV-treated cells. SIRT6-targeted siRNA or 3-methyladenine blocked the effects of UV in hyperlipidemic cells. In conclusion, UV improves SIRT6/autophagy signaling, reducing lipid deposition and apoptosis in liver cells under high lipid conditions. This in vitro study provides strong evidence for potential therapeutic strategies for hepatic steatosis.