Gambogic Acid Research Articles

Natural gambogic acid-tuned self-assembly of nanodrugs towards synergistic chemophototherapy against breast cancer.

Gambogic acid (GA) as a naturally derived chemotherapeutic agent is of increasing interest for antitumor therapy. However, current research mainly focuses on improving the pharmacological properties to overcome the shortcomings in clinical applications or as a synergistic anticancer agent in combination with chemotherapy and chemophototherapy. Yet, the material properties of GA (e.g., self-assembly) are often neglected. Herein, we validated the self-assembly function of GA and its huge potential as a single-component active carrier for synergistic delivery using pyropheophorbide-a (PPa) as a drug model. The results showed that self-assembled GA drives the formation of nano-GA/PPa mainly through noncovalent interactions such as π-π stacking, hydrophobic interactions, and hydrogen bonding. Additionally, although no significant differences in cytotoxicity were found between the individual in vitro chemotherapy and combined chemophototherapy, the as-prepared nano-GA/PPa exhibits remarkably improved water solubility and multiple favorable therapeutic features, leading to a prominent in vivo photochemotherapy efficiency of 89.3% inhibition rate with reduced hepatotoxicity of GA. This work highlights the potential of self-assembled GA as a drug delivery carrier for synergistic biomedical applications.

Emerging tendencies for the nano-delivery of gambogic acid: a promising approach in oncotherapy.

Despite the advancements in cancer therapies during the past few years, chemo/photo resistance, severe toxic effects, recurrence of metastatic tumors, and non-selective targeting remain incomprehensible. Thus, much effort has been spent exploring natural anticancer compounds endowed with biosafety and high effectiveness in cancer prevention and therapy. Gambogic acid (GA) is a promising natural compound in cancer therapy. It is the major xanthone component of the dry resin extracted from the Garcinia hanburyi Hook. f. tree. GA has significant antiproliferative effects on different types of cancer, and it exerts its anticancer activities through various pathways. Nonetheless, the clinical translation of GA has been hampered, partly due to its water insolubility, low bioavailability, poor pharmacokinetics, rapid plasma clearance, early degradation in blood circulation, and detrimental vascular irritation. Lately, procedures have been invented demonstrating the ability of nanoparticles to overcome the challenges associated with the clinical use of natural compounds both in vitro and in vivo. This review sheds light on the recent emerging trends for the nanodelivery of GA to cancer cells. To the best of our knowledge, no similar recent review described the different nanoformulations designed to improve the anticancer therapeutic activity and targeting ability of GA.

Naturally Occurring Xanthones; Biological Activities, Chemical Profiles and In Silico Drug Discovery.

Xanthones are widely distributed polyphenols, present commonly in higher plants; Garcinia, Calophyllum, Hypericum, Platonia, Mangifera, Gentiana</i> and Swertia</i>. Xanthone tricyclic scaffold is able to interact with different biological targets, showing antibacterial and cytotoxic effects, as well as potent effects against osteoarthritis, malaria, and cardiovascular diseases. Thus, in this article we focused on pharmacological effects, applications and preclinical studies with the recent updates of xanthon´s isolated compounds from 2017-2020. We found that only α-mangostin, gambogic acid, and mangiferin, have been subjected to preclinical studies with particular emphasis on the development of anticancer, diabetes, antimicrobial and hepatoprotective therapeutics. Molecular docking calculations were performed to predict the binding affinities of xanthone-derived compounds against SARS-CoV-2 M^pro. According to the results, cratoxanthone E and morellic acid demonstrated promising binding affinities towards SARS-CoV-2 M^pro with docking scores of -11.2 and -11.0 kcal/mol, respectively. Binding features manifested the capability of cratoxanthone E and morellic acid to exhibit nine and five hydrogen bonds, respectively, with the key amino acids of the M^pro active site. In conclusion, cratoxanthone E and morellic acid are promising anti-COVID-19 drug candidates that warrant further detailed in vivo</i> experimental estimation and clinical assessment.

Therapeutic effect and metabolic fingerprinting of triple-negative breast cancer cells following exposure to a novel pH-responsive, gambogic acid-loaded micelle

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and lacks effective therapeutic targets. The use of gambogic acid (GA), a class of active ingredients in traditional Chinese medicine with anti-tumour potential, is limited in tumour therapy owing to its drawbacks and unclear organ toxicity. In this study, we used the pH-responsive amphiphilic block copolymer, PEOz-PCL, to create nanodrugs for GA delivery to MDA-MB-231 cells. The pH-responsive GA-loaded micelles were prepared through nanoprecipitation with a more homogeneous size. The average particle size was 42.29 ± 1.74 nm, and the zeta potential value was 9.88 ± 0.17 mV. The encapsulation rate was 85.06%, and the drug loading rate was 10.63%. The process was reproducible, and sustained release reached 80% in 96 h at acid pH 5.0. Furthermore, cellular tests using CCK-8, TUNEL, and flow cytometry revealed that pH-responsive GA-loaded micelles killed MDA-MB-231 cells more effectively and had much higher activity and targeting compared with free drugs. Metabolomic analysis of the changes in differential metabolites revealed that pH-responsive GA-loaded micelles may inhibit TNBC cells by causing amino acid anabolism, nucleotide metabolism, and glucose metabolism, as well as by affecting their energy sources. The study outcomes will help understand the mechanism of action and the therapeutic efficacy of pH-responsive GA-loaded micelles in vivo.

Natural Products Inhibition of Cytochrome P450 2B6 Activity and Methadone Metabolism.

Methadone is cleared predominately by hepatic cytochrome P450 (CYP) 2B6-catalyzed metabolism to inactive metabolites. CYP2B6 also catalyzes the metabolism of several other drugs. Methadone and CYP2B6 are susceptible to pharmacokinetic drug-drug interactions. Use of natural products such as herbals and other botanicals is substantial and growing, and concomitant use of prescription medicines and non-prescription herbals is common and may result in interactions, often precipitated by CYP inhibition. Little is known about herbal product effects on CYP2B6 activity, and CYP2B6-catalyzed methadone metabolism. We screened a family of natural product compounds used in traditional medicines, herbal teas, and synthetic analogs of compounds found in plants, including kavalactones, flavokavains, chalcones and gambogic acid, for inhibition of expressed CYP2B6 activity and specifically inhibition of CYP2B6-mediated methadone metabolism. An initial screen evaluated inhibition of CYP2B6-catalyzed 7-ethoxy-4-(trifluoromethyl) coumarin O-deethylation. Hits were further evaluated for inhibition of racemic methadone metabolism, including mechanism of inhibition and kinetic constants. In order of decreasing potency, the most effective inhibitors of methadone metabolism were dihydromethysticin (competitive, K i 0.074 µM), gambogic acid (noncompetitive, K i 6 µM), and 2,2'-dihydroxychalcone (noncompetitive, K i 16 µM). Molecular modeling of CYP2B6-methadone and inhibitor binding showed substrate and inhibitor binding position and orientation and their interactions with CYP2B6 residues. These results show that CYP2B6 and CYP2B6-catalyzed methadone metabolism are inhibited by certain natural products, at concentrations which may be clinically relevant. SIGNIFICANCE STATEMENT: This investigation identified several natural product constituents which inhibit in vitro human recombinant CYP2B6 and CYP2B6-catalyzed N-demethylation of the opioid methadone. The most potent inhibitors (K i) were dihydromethysticin (0.074 µM), gambogic acid (6 µM) and 2,2'-dihydroxychalcone (16 µM). Molecular modeling of ligand interactions with CYP2B6 found that dihydromethysticin and 2,2'-dihydroxychalcone bound at the active site, while gambogic acid interacted with an allosteric site on the CYP2B6 surface. Natural product constituents may inhibit CYP2B6 and methadone metabolism at clinically relevant concentrations.

Decoding the alpha-amylase inhibitory activity of Garcinia indica Choisy by computational and experimental studies

Garcinia indica Choisy is traditionally used to manage diabetes mellitus, also used in various herbal formulations, and is indicated as an insulin sensitizer. The present study investigates the hydroalcoholic extract of G. indica Choisy rind as an α-amylase inhibitor, followed by the identification of the probable lead hits via a computational approach. LC-MS analyse were carried out. In vitro assays for alpha amylase were performed at concentrations of G. indica ranging from (1000–125 µg/mL) and acarbose (25–1.56 µg/mL) with inhibition times ranging from 5th to 30th min. In silico study was performed based upon the bioactives traced from LC-MS data retrieved from the PubChem database and predicted for probable targets of diabetes mellitus, followed by a drug-likeness score, probable side effects, and an ADMET profile. In addition, molecular docking and the dynamics of the representative complex were explored using AutoDock Vina and Gromac. In vitro study revealed IC50 values of 400.5, 526.07, 728.05, 792.7, 848.3, and 897.5 µg/mL and acarbose displayed IC50 values of <1.56, 6.6, 10.46, 12.6, 14.14, and 15.24 µg/mL respectively. LC-MS analysis identified 17 bioactives, of which 13 showed positive druglikness; among them, 5 bioactives were predicted to modulate AMY2A. The gene set enrichment analysis revealed that AMY2A and gambogic acid possessed high edge counts, with the lowest binding energy of gambogic acid- AMY2A (-11.7 kcal/mol), followed by amentoflavone (-10.6 kcal/mol), volkensiflavone (-9.3 kcal/mol), fukugcide (-8.8 kcal/mol), and garcinol (-7.7 kcal/mol) when compared with acarbose- AMY2A (-7.7 kcal/mol), which also indicates high stability up to 100 ns in molecular simulation. Hydroalcoholic extract of G. indica rind α-amylase inhibitory activity, may be due to the presence of gambogic acid and other bioactives. Thus, it can be speculated that G. indica may possess anti-diabetic activity by reducing the post prandial glucose level. This needs to be further confirmed via enriched fractions or pure substances with inhibitory activity to develop Traditional medicine based new drugs

Gambogic acid inhibits HBx-mediated hepatitis B virus replication by targeting the DTX1-Notch signaling pathway

Background & AimsCurrent antiviral drugs, including nucleoside analogs and interferon, fail to eliminate the HBV covalently closed circular DNA (cccDNA), which serves as a transcript template in infected hepatocytes. Silencing the HBV X protein, which plays a crucial role in cccDNA transcription, is a promising approach to inhibit HBV replication. Therefore, the identification of novel compounds that can inhibit HBx-mediated cccDNA transcription is critical. MethodsInitially, a compound library consisting of 715 monomers derived from traditional Chinese medicines known for their liver-protecting properties was established. Then, MTT assays were used to determine the cytotoxicity of each compound. The effect of candidates on Flag-HBx expression was examined by real-time PCR and western blotting in Flag-HBx transfected HepG2-NTCP cells. Ultimately, the antiviral effect of gambogic acid (GA) on HBV was observed in HBV-infected HepG2-NTCP cells. Mechanistically, the functional role of DTX1 in GA-induced HBV inhibition was examined using RNA-seq. Finally, the antiviral effect of GA was estimated in vivo. ResultsGambogic acid (GA), a natural bioactive compound with a myriad of biological activities, markedly reduced Flag-HBx expression. Potent and dose-dependent reductions in extracellular HBV RNAs, HBV DNA, HBsAg, HBeAg and HBc protein were discovered three days after GA treatment in HBV-infected cells, accompanied by the absence of significant cytotoxicity. Furthermore, our research revealed that GA exhibited a dose-dependent inhibition of HBx expression, which is a pleiotropic protein required for HBV infection in vivo. We explored the mechanisms underlying GA-mediated inhibition of HBV and confirmed that this inhibition is accomplished by upregulating the expression of the DTX1 gene and boosting the Notch signaling pathway. Finally, the inhibitory effect of GA on HBV replication was tested in vivo using a mouse model of hepatitis B virus recombinant cccDNA. ConclusionsHerein, we discovered GA, which is a natural bioactive compound that targets HBx to inhibit hepatitis B virus replication by activating the DTX1-Notch signaling pathway.

Retraction: gambogic acid affects high glucose-induced apoptosis and inflammation of retinal endothelial cells through the NOX4/NLRP3 pathway.

[This retracts the article DOI: 10.21037/atm-22-6591.].

XPO2 Is Essential for a Subset of AML Cells and Is a Biomarker for Poor Response and Survival in Pediatric and AYA AML

Importins &amp; exportins regulate protein transport across the nuclear membrane. Twenty nuclear transport receptors (NTRs) have been identified; six are involved in nuclear export. NTRs contribute to cancer development, through abnormal localization of protein cargos. The exportin, XPO1, is associated with high risk AML &amp; shorter survival times. However, little is known regarding the functional importance of the related exportin, XPO2 (alias CSE1L). We analyzed a public database of CRISPR/Cas9 depletion screens in 26 AML cell lines. XPO2 ranked in the top 1.4% of essential genes, along with XPO1 (top 1.3%) (DepMap 22Q2 Public+Score, Chronos). An RNAi depletion screen confirmed this, with XPO2 ranked in the top 0.2% of AML genes. Leukemia cells were more dependent on XPO2 vs solid tumors (P = 0.0394) &amp; gene dependency scores indicated a greater reliance on XPO2 vs XPO1 (P &amp;lt;0.0001). Increased expression of XPO2 mRNA was associated with decreased event free survival (EFS) (P = 0.0014) &amp; overall survival (OS) (P = 0.00091) in pediatric &amp; adolescent/young adult (AYA) AML patients (TARGET dataset). In the BeatAML dataset, increased XPO2 mRNA expression was associated with decreased OS in patients &amp;lt;40 years, but not in patients &amp;gt;40 years (P &amp;lt;0.0001). We analyzed protein expression databases &amp; identified XPO2 as the highest expressed exportin in AML cells lines &amp; patient samples. Increased XPO2 expression was detected in 7/7 primary AML samples &amp; 9 AML cell lines by immunoblot (HL60, MV4-11, MOML13, NB4, OCI-AML2, OCI-M2, TEX, U937 &amp; 1254 cells), compared to normal hematopoietic cells. Expression of XPO2 was increased in younger (&amp;lt;40 years) vs older patients (&amp;gt;70 years) (P = 0.0454). Genetic silencing of XPO2 decreased growth &amp; viability of OCI-AML2, TEX, NB4 &amp; 1254 cells. Gambogic acid is an inhibitor of XPO2-mediated nuclear transport. In OCI-AML2, TEX &amp; NB4 cell lines, gambogic acid decreased viability of AML cells (TEX IC50 = 369nM, OCI-AML2 IC50 = 433nM, NB4 IC50 = 161nM). Next, we interrogated a BioID database (PXD007976) &amp; performed gene set enrichment analysis on XPO2 targets. Processes related to ribosome biogenesis were enriched in XPO2 cargo, whereas XPO1 cargo were enriched for snRNA transcription processes (P &amp;lt;0.05). A gene expression signature encompassing XPO2 &amp; its associated cargo genes was enriched in functionally defined LSCs (P = 0.001, in patients with more primitive AML subtypes (P &amp;lt; 2.22 x 10 -16), in more primitive AML blasts as defined by FAB subtype and in high risk subsets, including WT1 mutated pediatric AML. Additionally, the XPO2 gene signature was associated with minimal-residual-disease (MRD) positive disease after induction cycle I (P &amp;lt; 5.1x 10 -6) and II (P = 0.0013), decreased complete remission (CR) rates after cycle I (P = 0.00025) and II (P = 0.02), worse EFS (P = 0.019) and worse OS (P = 0.02) in pediatric and AYA AML patients. In summary, we identified XPO2 as an essential gene for AML . XPO2 is increased in AML cells &amp; primary samples from younger patients. Increased XPO2 expression &amp; increased expression of XPO2 mediated processesare associated with worse outcomes in pediatric AML &amp; correlate with LSC enrichment &amp; primitive AML subtypes. XPO2 may function to enhance ribosomal biogenesis, demonstrating a critical role in leukemogenesis. Thus, this work demonstrates a new dependency of pediatric AML on XPO2 highlighting a new target and biomarker for this disease.

A multiplexed time-resolved fluorescence resonance energy transfer ultrahigh-throughput screening assay for targeting the SMAD4-SMAD3-DNA complex.

The transforming growth factor-beta (TGFβ) signaling pathway plays crucial roles in the establishment of an immunosuppressive tumor microenvironment, making anti-TGFβ agents a significant area of interest in cancer immunotherapy. However, the clinical translation of current anti-TGFβ agents that target upstream cytokines and receptors remains challenging. Therefore, the development of small-molecule inhibitors specifically targeting SMAD4, the downstream master regulator of the TGFβ pathway, would offer an alternative approach with significant therapeutic potential for anti-TGFβ signaling. In this study, we present the development of a cell lysate-based multiplexed time-resolved fluorescence resonance energy transfer (TR-FRET) assay in an ultrahigh-throughput screening (uHTS) 1536-well plate format. This assay enables simultaneous monitoring of the protein‒protein interaction between SMAD4 and SMAD3, as well as the protein‒DNA interaction between SMADs and their consensus DNA-binding motif. The multiplexed TR-FRET assay exhibits high sensitivity, allowing the dynamic analysis of the SMAD4-SMAD3-DNA complex at single-amino acid resolution. Moreover, the multiplexed uHTS assay demonstrates robustness for screening small-molecule inhibitors. Through a pilot screening of an FDA-approved bioactive compound library, we identified gambogic acid and gambogenic acid as potential hit compounds. These proof-of-concept findings underscore the utility of our optimized multiplexed TR-FRET platform for large-scale screening to discover small-molecule inhibitors that target the SMAD4-SMAD3-DNA complex as novel anti-TGFβ signaling agents.

Gambogenic Acid Inhibits Invasion and Metastasis of Melanoma through Regulation of lncRNA MEG3.

Cutaneous melanoma is an aggressive cancer, which is the most common type of melanoma. In our previous studies, gambogenic acid (GNA) inhibited the proliferation and migration of melanoma cells. Maternally expressed gene 3 (MEG3) is a long noncoding RNA (lncRNA) that has been shown to have inhibitory effects in a variety of cancers. However, the mechanisms in melanoma progression need to be further investigated. In the current study, we investigated the inhibitory effect of GNA on melanoma and its molecular mechanism through a series of cell and animal experiments. We found that GNA could improve epithelial mesenchymal transition by up-regulating the expression of the lncRNA MEG3 gene, thereby inhibiting melanoma metastasis in vitro and in vivo.

Preparation of acid-sensitive polymeric oncology drug carriers and analysis of effectiveness

Gambogic acid (GA) and combretastatin A-4 (CA-4) were used as antitumor drugs to prepare three-armed polymers (TPs) by reversible addition–fragmentation chain-transfer polymerization, atom-transfer radical polymerization and click polymerization. Gel permeation chromatography characterization showed that the molecular weights of glucose cyanine 7.5 (Cy7.5), carboxyl-terminated chain transfer agent (C7A) and polyethylene glycol (PEG) in CTA-PEG5k-Lys-AzMA-Cy7.5-C7A TP were 5000. The grain size of GA and CA-4 embedded in 10 mg TP and linear polymer (LP) is 3.2 mg. The toxicity of CA-4 is low, while the toxicity of GA is high. For the LP and TP, a higher apoptosis rate is produced under laser irradiation. The polymers are aggregated at the tumor site, which indicates that the polymer system has a better in vivo distribution effect, and the aggregation effect of the TP is better than that of the LP. The TP prepared by this research has good antitumor effect and biological effect and can be popularized and applied in the targeted treatment of tumor diseases.

Carrier-Free Gambogic Acid Dimer Self-Assembly Nanomedicines for Rheumatoid Arthritis Treatment.

The insufficient targeting delivery of therapeutic agents greatly impeded the treatment outcomes of rheumatoid arthritis (RA). Despite the recognized therapeutic advantages of gambogic acid (GBA) in inflammatory diseases, its high delivery efficiency to inflammatory site still limits its clinical application. Self-assembly of drug dimers into carrier-free nanoparticles (NPs) has become a straightforward and attractive approach to develop nanomedicines for RA treatment. Herein, homodimers of GBA were designed to form the carrier-free NPs by self-assembly for RA treatment. The synthetic gambogic acid dimers (GBA2) were self-assembled into NPs using a one-step solvent evaporation method. The size distribution, morphology, drug-loading efficiency (DLE) and storage stability were evaluated. A molecular dynamic simulation was conducted to gain further insight into the self-assembly mechanisms of GBA2/NPs. Besides, we investigated the cytotoxicity, apoptosis and cellular uptake profiles of GBA2/NPs in macrophages and osteoclasts. Finally, the specific biodistribution on the ankles of adjuvant-induced arthritis (AIA) mice, and the anti-RA efficacy of the AIA rat model were assessed. GBA2/NPs exhibited the uniform spherical structure, possessing excellent colloidal stability, high self-assembly stability, high drug loading and low hemolytic activity. Comparing with GBA, GBA2/NPs showed higher cytotoxicity, cellular uptake and apoptosis rate against osteoclasts. In addition, GBA2/NPs exhibited much higher accumulation in ankle joints in vivo. As expected, the systematic administration of GBA2/NPs resulted in the greater alleviation of arthritic symptoms, cartilage protection, and inflammation, notably the reduced systemic toxicity compared to free GBA. GBA2/NPs formed GBA dimers exhibited the superior accumulation in the inflamed joint and anti-RA activity, potentially attributing to the similar extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration ("ELVIS") effects in inflamed joint and the enhanced cellular uptake in macrophages and osteoclasts. Our findings provide substantial evidence that self-assembly of GBA2/NPs would be a promising therapeutic alternative for RA treatment.

Mechanism of anticancer effect of gambogic acid on gastric signet ring cell carcinoma.

Gambogic acid has demonstrated inhibitory effects on the growth of various cancer cell types, such as breast cancer, pancreatic cancer, prostate cancer, lung cancer, and osteosarcoma. This study aims to investigate the antiproliferative activity of Gambogic acid on SNU-16 cells derived from gastric signet ring cell carcinoma and elucidate the underlying mechanisms. The cytotoxic effect of gambogic acid was evaluated in SNU-16 cells by treating them with different concentrations of the compound, and the XTT cell viability assay was employed to assess cell viability. ELISA was used to measure bax, BCL-2, caspase 3, PARP, and 8-oxo-dG levels. Additionally, immunofluorescence staining was applied to assess 8-oxo-dG and LC3β levels in SNU-16 cells. It was observed that gambogic acid exerted a dose-dependent and statistically significant antiproliferative effect on SNU-16 cells. The IC50 value of gambogic acid in SNU-16 cells was found to be 655.1nM for 24h. Subsequent investigations conducted using the IC50 dose revealed a significant upregulation of apoptotic proteins including cleaved caspase 3, Bax, and cleaved PARP (p < 0.001), along with a downregulation of BCL-2 (p < 0.001), an anti-apoptotic protein. Moreover, the administration of this drug led to an upregulation of 8-oxo-dG (p < 0.001), a widely acknowledged biomarker indicating oxidative damage in DNA, as well as an increase in LC3β levels (p < 0.05), a marker associated with autophagy. The antiproliferative effect of gambogic acid against gastric signet ring cell carcinoma is attributed to its ability to induce apoptosis and autophagy. This discovery highlights the promising potential of gambogic acid as a treatment option for gastric signet ring cell carcinoma.

Gambogic Acid Inhibits Gastric Cancer Cell Proliferation through Necroptosis.

Gambogic acid (GA) is a natural xanthonoid secreted by Garcinia hanburyi tree. It possesses anti-cancer activity in various types of cancers. In gastric cancer, it inhibits cell proliferation through increasing apoptosis. However, whether necroptosis is involved in the GA-induced proliferation inhibited in gastric cancer is unknown. In the present study, we found that RIPK1 specific inhibitor necrostatin-1 (Nec-1) attenuated GA-induced proliferation inhibition. GA treatment increased the phosphorylation of necroptosis-related proteins, RIPK1, RIPK3, and MLKL, and their interactions to form the necrosome complex. The effector protein Drp-1 was dephosphorylated by GA treatment. Inhibition of necroptosis by different inhibitors and PGAM5 knockdown attenuated GA-induced cell death in gastric cancer cell lines, thereby attenuating GA-caused cell proliferation inhibition. All the data supported the conclusion that GA could inhibit gastric cancer cell proliferation by inducing necroptosis.

Development and validation of biomarkers related to PANoptosis in osteoarthritis.

Osteoarthritis (OA) is a high-incidence disease of the orthopedic system. However, studies on the molecular mechanisms of OA and pyroptosis, apoptosis, and necroptosis (PANoptosis) at the transcriptome level remain scarce. Therefore, this study purposed to detect biomarkers in OA and explore their relationship to the immune microenvironment. OA-related expression data was sourced from the Gene Expression Omnibus (GEO) database. Subsequently, differentially expressed analysis and a Venn diagram were performed to obtain differentially expressed PANoptosis-related genes (DEPGs). Furthermore, the least absolute shrinkage and selection operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and random forest (RF) were implemented to screen diagnostic genes. Receiver operating characteristic (ROC) curves were performed to verify the diagnostic ability of the diagnostic genes. Next, immune infiltration analysis was performed to find the relationships between differential immune cells (OA vs. normal) and diagnostic genes. Finally, drug prediction analysis was also carried out, and the expression of diagnostic genes was verified in external datasets. A total of 62 DEPGs were identified, which were enriched for regulating apoptotic signaling pathways, tumor necrosis factor (TNF) signaling pathways, and other related pathways. Three feature genes, nuclear factor-kappa-B inhibitor-alpha (NFKBIA), RING finger protein 34 (RNF34), and serine incorporator 3 (SERINC3) were obtained by intersecting genes obtained by the LASSO regression algorithm, SVM algorithm, and RF algorithm and showed excellent diagnostic efficacy with the Area under the curve (AUC) values of individual genes were all greater than 0.7, indicating that the model was more effective. Immuno-infiltration analysis showed that RNF34 was positively correlated with CD56dim natural killer cells, type 17 helper T cells, and NFKBIA was positively correlated with plasmacytoid dendritic cells. Additionally, 12 drugs were predicted by NFKBIA, such as gambogic acid and dioscin. In addition, NFKBIA and SERINC3 were significantly downregulated, and RNF34 was upregulated in OA samples. Three genes (NFKBIA, RNF34, and SERINC3) related to PANoptosis, were obtained by bioinformatics analysis, which would provide a new direction for the diagnosis and treatment of OA.

NIR laser-activated multifunctional nanocomposites for cascade low-temperature photothermal and oxygen-irrelevant thermodynamic therapy

Osteosarcoma, occurring most frequently in adolescents, are highly malignant bone tumor and prone to develop local recurrence and long-distance metastasis. Therefore, new comprehensive therapeutic strategies for osteosarcoma are urgently needed. Different from traditional photothermal therapy (PTT), low temperature PTT (LTPTT) not only brings less heat damages to the surrounding normal tissues but also prevent tumor metastasis. Nevertheless, its therapeutic effects are severely attenuated due to the tumor thermo-resistance induced by the overexpression of heat shock protein (HSP). In our work, an acid-responsive core–shell nanocomposite was fabricated for cancer therapy. The nanoplatform can independently encapsulate alkyl radical initiator 2,2-azobis[2-(2-imidazolin-2-yl) propane]-dihydroch-loride (AIPH) in the mesoporous polydopamine (MPDA) core and HSP inhibitor (gambogic acid, GA) in the zeolite imidazolate framework-8 (ZIF-8) microporous shell, called MPDA/AIPH@ZIF-8/GA (MAZG), which could achieve the combined functions of LTPTT and thermodynamic therapy (TDT). After endocytosing by tumor cells, the pH-responsive degradation of the ZIF-8 coating stimulates the rapid release of GA, which can effectively inhibit HSP expression in advance, and then simultaneously enhanced the therapeutic efficacy of LTPTT. Further, both in vitro and in vivo experiments have demonstrated that the as-synthesized MAZG nanocomposite exhibited favorable biosafety and remarkable tumor growth inhibition.

Synergistic effects of trastuzumab and gambogic acid on MDA-MB-453 breast cancer cell line

Trastuzumab is one of the most commonly used monoclonal antibodies in the treatment of breast cancer. It is effective because it binds to the HER2 receptor and inhibits the signaling pathways for proliferation and metastasis. However, intrinsic or acquired resistance resulting from the various signaling pathways of heterogeneous breast cancer reduces its efficacy. To increase its efficacy, it is combined with different agents in the treatment. In this study, the synergistic effect of the combination of trastuzumab and gambogic acid on the breast cell line MDA-MB -453 was investigated in vitro. At the end of 12-, 24-, 48-, and 72-hour incubation, their antiproliferative effects were determined by XTT method. Combination Index (CI) values of the study were calculated using CompuSyn.exe software. The highest synergistic effect was obtained with 12.5 µg/mL trastuzumab + 1.25 µM gambogic acid (CI-4) at the 72nd hour. The activity of the antioxidant enzyme catalase (CAT) was also measured for the applications. We observed that combination of trastuzumab and gambogic acid decreased CAT activity at 24, 48 and 72nd hours. It was concluded that gambogic acid may be a good candidate for combination with other agents in targeted drug design.

Lactoferrin-Modified Gambogic Acid Liposomes for Colorectal Cancer Treatment.

Colorectal cancer (CRC) therapy is a big challenge, and seeking an effective and safe drug is a pressing clinical need. Gambogic acid is a potent antineoplastic agent without the drawback of bone marrow suppression. To improve its druggability (e.g., poor water solubility and tumor delivery), a lactoferrin-modified gambogic acid liposomal delivery system (LF-lipo) was developed to enhance the treatment efficacy of CRC. The LF-lipo can specifically bind LRP-1 expressed on colorectal cancer cells to enhance drug delivery to the tumor cells and yield enhanced therapeutic efficacy. The LF-lipo promoted tumor cell apoptosis and autophagy, reduced reactive oxygen species (ROS) levels in tumor cells, and inhibited angiogenesis; moreover, it could also repolarize tumor-associated macrophages from the M2 to M1 phenotype and induce ICD to activate T cells, exhibiting the capability of remodeling the tumor immune microenvironment. The liposomal formulation yielded an efficient and safe treatment outcome and has potential for clinical translation.

Gambogenic acid inhibits proliferation and ferroptosis by targeting the miR-1291/FOXA2 and AMPKα/SLC7A11/GPX4 axis in colorectal cancer.

The present study aims to investigate the mechanism of the nature compound gambogenic acid (GNA) on the apoptosis and ferroptosis in colorectal cancer (CRC).The effect of GNA on the proliferation of CRC cell lines were detected by MTT and clonogenic assay. The xenograft tumor model was established, and the inhibition effect of GNA were evaluated by observing the tumor growth. The endoplasmic reticulum (ER) of HCT116 was observed by using the ER tracker. The TargrtScan database was used to predict the miRNA binding sites. The level of miRNA with GNA treatment was explored by real-time quantitative PCR. The effect of ferroptosis were evaluated by detect the expression of reactive oxygen species (ROS), intracellular ferrous iron (Fe2+ ), malondialdehyde (MDA), glutathione (GSH), subunit solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase (GPX)4, transferrin, and ferritin by Western blot.GNA isolated from gamboge can inhibit the growth and proliferation of CRC cell lines in a concentration-dependent manner. GNA activated ER stress by upregulating miR-1291, and miR-1291 targeted the forkhead box protein A2 (FOXA2). GNA also induced ROS production and mediated the Fenton reaction by activating transferrin to increase Fe2+ , thus inducing ferroptosis. In addition, GNA could induce ferroptosis through the depletion of GSH and GPX4. Furthermore, GNA treatment regulated iron metabolism by activating AMPKα/SLC7A11/GPX4 signaling. In conclusion, GNA activated ER stress via miR-1291 and induced ferroptosis in CRC cells and might be a new inducer of ferroptosis, which can expand the efficacy of chemotherapy drugs.