Mangiferin: A natural bioactive immunomodulating glucosylxanthone with potential against cancer and rheumatoid arthritis.

Mangiferin is a naturally occurring glucosylxanthone that has shown promising immunomodulatory effects. It is generally isolated from the leaves, peels, bark, and kernels of Mangifera indica Linn. Mangiferin is like a miraculous natural bioactive molecule that has an immunomodulatory function that makes it a potential therapeutic candidate for the treatment of rheumatoid arthritis (RA) and cancer. The anticancer activity of mangiferin acts by blocking NF-κB, as well as regulating the ß-catenin, EMT, MMP9, MMP2, LDH, ROS, and NO, and also by the activation of macrophages. It has no cytotoxic effect on grown chondrocytes and lowers matrix metalloproteinase levels. Additionally, it has a potent proapoptotic impact on synoviocytes. The precise molecular mechanism of action of mangiferin on RA and malignancies is still unknown. This comprehensive review elaborates on the immunomodulatory effect of mangiferin and its anticancer and anti-RA activity. This also explained the total synthesis of mangiferin and its in vitro and in vivo screening models.

Dicerandrol C Suppresses Proliferation and Induces Apoptosis of HepG2 and Hela Cancer Cells by Inhibiting Wnt/ß-Catenin Signaling Pathway.

Overwhelming evidence points to an aberrant Wnt/ß-catenin signaling as a critical factor in hepatocellular carcinoma (HCC) and cervical cancer (CC) pathogenesis. Dicerandrol C (DD-9), a dimeric tetrahydroxanthenone isolated from the endophytic fungus Phomopsis asparagi DHS-48 obtained from mangrove plant Rhizophora mangle via chemical epigenetic manipulation of the culture, has demonstrated effective anti-tumor properties, with an obscure action mechanism. The objective of the current study was to explore the efficacy of DD-9 on HepG2 and HeLa cancer cells and its functional mechanism amid the Wnt/ß catenin signaling cascade. Isolation of DD-9 was carried out using various column chromatographic methods, and its structure was elucidated with 1D NMR. The cytotoxicity of DD-9 on HepG2 and HeLa cells was observed with respect to the proliferation, clonality, migration, invasion, apoptosis, cell cycle, and Wnt/ß-catenin signaling cascade. We found that DD-9 treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in HepG2 and HeLa cells. The subsequent experiments in vitro implied that DD-63 could significantly suppress the tumor clonality, metastases, and induced apoptosis, and that it arrested the cell cycle at the G0/G1 phase of HepG2 and HeLa cells. Dual luciferase assay, Western blot, and immunofluorescence assay showed that DD-9 could dose-dependently attenuate the Wnt/ß-catenin signaling by inhibiting ß-catenin transcriptional activity and abrogating ß-catenin translocated to the nucleus; down-regulating the transcription level of ß-catenin-stimulated Wnt target gene and the expression of related proteins including p-GSK3-ß, ß-catenin, LEF1, Axin1, c-Myc, and CyclinD1; and up-regulating GSK3-ß expression, which indicates that DD-9 stabilized the ß-catenin degradation complex, thereby inducing ß-catenin degradation and inactivation of the Wnt/ß-catenin pathway. The possible interaction between DD-9 and ß-catenin and GSK3-ß protein was further confirmed by molecular docking studies. Collectively, DD-9 may suppress proliferation and induce apoptosis of liver and cervical cancer cells, possibly at least in part via GSK3-ß-mediated crosstalk with the Wnt/ß-catenin signaling axis, providing insights into the mechanism for the potency of DD-9 on hepatocellular and cervical cancer.

Xanthone Inhibitors of Unfolded Protein Response Isolated from Calophyllum caledonicum.

The unfolded protein response (UPR) is a key component of fungal virulence. The prenylated xanthone γ-mangostin isolated from Garcinia mangostana (Clusiaceae) fruit pericarp, has recently been described to inhibit this fungal adaptative pathway. Considering that Calophyllum caledonicum (Calophyllaceae) is known for its high prenylated xanthone content, its stem bark extract was fractionated using a bioassay-guided procedure based on the cell-based anti-UPR assay. Four previously undescribed xanthone derivatives were isolated, caledonixanthones N-Q (3, 4, 8, and 12), among which compounds 3 and 8 showed promising anti-UPR activities with IC50 values of 11.7 ± 0.9 and 7.9 ± 0.3 µM, respectively.

The total xanthones extracted from Gentianella acuta alleviates HFpEF by activating the IRE1α/Xbp1s pathway.

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by pulmonary and systemic congestion resulting from left ventricular diastolic dysfunction and increased filling pressure. Currently, however, there is no evidence on effective pharmacotherapy for HFpEF. In this study, we aimed to investigate the therapeutic effect of total xanthones extracted from Gentianella acuta (TXG) on HFpEF by establishing an high-fat diet (HFD) + L-NAME-induced mouse model. Echocardiography was employed to assess the impact of TXG on the cardiac function in HFpEF mice. Haematoxylin and eosin staining, wheat germ agglutinin staining, and Masson's trichrome staining were utilized to observe the histopathological changes following TXG treatment. The results demonstrated that TXG alleviated HFpEF by reducing the expressions of genes associated with myocardial hypertrophy, fibrosis and apoptosis. Furthermore, TXG improved cardiomyocyte apoptosis by inhibiting the expression of apoptosis-related proteins. Mechanistic investigations revealed that TXG could activate the inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (Xbp1s) signalling pathway, but the knockdown of IRE1α using the IRE1α inhibitor STF083010 or siRNA-IRE1α impaired the ability of TXG to ameliorate cardiac remodelling in HFpEF models. In conclusion, TXG alleviates myocardial hypertrophy, fibrosis and apoptosis through the activation of the IRE1α/Xbp1s signalling pathway, suggesting its potential beneficial effects on HFpEF patients.

pH/GSH dual-responsive nanoparticle for auto-amplified tumor therapy of breast cancer.

Breast cancer remains a malignancy that poses a serious threat to human health worldwide. Chemotherapy is one of the most widely effective cancer treatments in clinical practice, but it has some drawbacks such as poor targeting, high toxicity, numerous side effects, and susceptibility to drug resistance. For auto-amplified tumor therapy, a nanoparticle designated GDTF is prepared by wrapping gambogic acid (GA)-loaded dendritic porous silica nanoparticles (DPSNs) with a tannic acid (TA)-Fe(III) coating layer. GDTF possesses the properties of near-infrared (NIR)-enhanced and pH/glutathione (GSH) dual-responsive drug release, photothermal conversion, GSH depletion and hydroxyl radical (·OH) production. When GDTF is exposed to NIR laser irradiation, it can effectively inhibit cell proliferation and tumor growth both in vitro and in vivo with limited toxicity. This may be due to the synergistic effect of enhanced tumor accumulation, and elevated reactive oxygen species (ROS) production, GSH depletion, and TrxR activity reduction. This study highlights the enormous potential of auto-amplified tumor therapy.

Mangiferin alleviated poststroke cognitive impairment by modulating lipid metabolism in cerebral ischemia/reperfusion rats.

INTRODUCTION: Mangiferin is a Chinese herbal extract with multiple biological activities. Mangiferin can penetrate the blood‒brain barrier and has potential in the treatment of nervous system diseases. These findings suggest that mangiferin protects the neurological function in ischemic stroke rats by targeting multiple signaling pathways. However, little is known about the effect and mechanism of mangiferin in alleviating poststroke cognitive impairment. METHODS: Cerebral ischemia/reperfusion (I/R) rats were generated via middle cerebral artery occlusion. Laser speckle imaging was used to monitor the cerebral blood flow. The I/R rats were intraperitoneally (i.p.) injected with 40 mg/kg mangiferin for 7 consecutive days. Neurological scoring, and TTC staining were performed to evaluate neurological function. Behavioral experiments, including the open field test, elevated plus maze, sucrose preference test, and novel object recognition test, were performed to evaluate cognitive function. Metabolomic data from brain tissue with multivariate statistics were analyzed by gas chromatography‒mass spectrometry and liquid chromatography‒mass spectrometry. RESULTS: Mangiferin markedly decreased neurological scores, and reduced infarct areas. Mangiferin significantly attenuated anxiety-like and depression-like behaviors and enhanced learning and memory in I/R rats. According to the metabolomics results, 13 metabolites were identified to be potentially regulated by mangiferin, and the differentially abundant metabolites were mainly involved in lipid metabolism. CONCLUSIONS: Mangiferin protected neurological function and relieved poststroke cognitive impairment by improving lipid metabolism abnormalities in I/R rats.

Engineered urolithin A-laden functional polymer-lipid hybrid nanoparticles prevent cisplatin-induced proximal tubular injury in vitro.

Functional polymer-lipid hybrid nanoparticles (H-NPs) are a promising class of nanocarriers that combine the benefits of polymer and lipid nanoparticles, offering biocompatibility, structural stability, high loading capacity, and, most importantly, superior surface functionalization. Here, we report the synthesis and design of highly functional H-NPs with specificity toward the transferrin receptor (TfR), using a small molecule ligand, gambogic acid (GA). A fluorescence study revealed the molecular orientation of H-NPs, where the lipid-dense core is surrounded by a polymer exterior, functionalized with GA. Urolithin A, an immunomodulator and anti-inflammatory agent, served as a model drug-like compound to prepare H-NPs via traditional emulsion-based techniques, where H-NPs led to smaller particles (132 nm) and superior entrapment efficiencies (70 % at 10 % drug loading) compared to GA-conjugated polymeric nanoparticles (P-NPs) (157 nm and 52 % entrapment efficiency) and solid lipid nanoparticles (L-NPs) (186 nm and 29 % entrapment efficiency). H-NPs showed superior intracellular accumulation compared to individual NPs using human small intestinal epithelial (FHs 74) cells. The in vitro efficacy was demonstrated by flow cytometry analysis, in which UA-laden H-NPs showed excellent anti-inflammatory properties in cisplatin-induced injury in healthy human proximal tubular cell (HK2) model by decreasing the TLR4, NF-κß, and IL-ß expression. This preliminary work highlights the potential of H-NPs as a novel functional polymer-lipid drug delivery system, establishing the foundation for future research on its therapeutic potential in addressing chemotherapy-induced acute kidney injury in cancer patients.

Mangiferin attenuates lipopolysaccharide-induced neuronal injuries in primary cultured hippocampal neurons.

Mangiferin, a naturally occurring potent glucosylxanthone, is mainly isolated from the Mangifera indica plant and shows potential pharmacological properties, including anti-bacterial, anti-inflammation, and antioxidant in sepsis-induced lung and kidney injury. However, there was a puzzle as to whether mangiferin had a protective effect on sepsis-associated encephalopathy. To answer this question, we established an in vitro cell model of sepsis-associated encephalopathy and investigated the neuroprotective effects of mangiferin in primary cultured hippocampal neurons challenged with lipopolysaccharide (LPS). Neurons treated with 20 µmol/L or 40 µmol/L mangiferin for 48 h can significantly reverse cell injuries induced by LPS treatment, including improved cell viability, decreased inflammatory cytokines secretion, relief of microtubule-associated light chain 3 expression levels and several autophagosomes, as well as attenuated cell apoptosis. Furthermore, mangiferin eliminated pathogenic proteins and elevated neuroprotective factors at both the mRNA and protein levels, showing strong neuroprotective effects of mangiferin, including anti-inflammatory, anti-autophagy, and anti-apoptotic effects on neurons in vitro.

12-O-deacetyl-phomoxanthone A inhibits ovarian tumor growth and metastasis by downregulating PDK4.

AIMS: The xanthone dimer 12-O-deacetyl-phomoxanthone A (12-ODPXA) was extracted from the secondary metabolites of the endophytic fungus Diaporthe goulteri. The 12-ODPXA compound exhibited anticancer properties in murine lymphoma; however, the anti-ovarian cancer (OC) mechanism has not yet been explored. Therefore, the present study evaluated whether 12-ODPXA reduces OC cell proliferation, metastasis, and invasion by downregulating pyruvate dehydrogenase kinase (PDK)4 expression. METHODS: Cell counting kit-8, colony formation, flow cytometry, wound healing, and transwell assays were performed to examine the effects of 12-ODPXA on OC cell proliferation, apoptosis, migration, and invasion. Transcriptome analysis was used to predict the changes in gene expression. Protein expression was determined using western blotting. Glucose, lactate, and adenosine triphosphate (ATP) test kits were used to measure glucose consumption and lactate and ATP production, respectively. Zebrafish xenograft models were constructed to elucidate the anti-OC effects of 12-ODPXA. RESULTS: The 12-ODPXA compound inhibited OC cell proliferation, migration, invasion, and glycolysis while inducing cell apoptosis via downregulation of PDK4. In vivo experiments showed that 12-ODPXA suppressed tumor growth and migration in zebrafish. CONCLUSION: Our data demonstrate that 12-ODPXA inhibits ovarian tumor growth and metastasis by downregulating PDK4, revealing the underlying mechanisms of action of 12-ODPXA in OC.

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.

Nucleobase-Coupled Xanthones with Anti-ROS Effects from Marine-Derived Fungus Aspergillus sydowii.

A MS/MS-based molecular networking approach compared to the Global Natural Product Social Molecular Networking library, in association with genomic annotation of natural product biosynthetic gene clusters within a marine-derived fungus, Aspergillus sydowii, identified a suite of xanthone metabolites. Chromatographic techniques applied to the cultured fungus led to the isolation of 11 xanthone-based alkaloids, dubbed sydoxanthones F-M. The structures of these alkaloids were elucidated using extensive spectroscopic data, including electronic circular dichroism and single-crystal X-ray diffraction data for configurational assignments. Among these analogues, sydoxanthones F-K exhibit structure features typical of nucleobase-coupled xanthones, with sydoxanthone H being an N-bonded xanthone dimer. Notably, (±)sydoxanthones F (1a/1b), (±)sydoxanthones H (3b/3a), and (±)sydoxanthones J (5b/5a) are enantiomeric pairs, while sydoxanthones G (2), I (4), and K (6) are stereoisomers of 1, 3, and 5, respectively. Furthermore, (+)sydoxanthone H (3a) demonstrated significant rescue of cell viability in H2O2-injuried SH-SY5Y cells by inhibiting reactive oxygen species production, suggesting its potential for neuroprotection.

Development of a manganese complex hyaluronic acid hydrogel encapsulating stimuli-responsive Gambogic acid nanoparticles for targeted Intratumoral delivery.

Gambogic acid is a natural compound with anticancer properties and is effective for many tumors. But its low water solubility and dose-dependent side effects limit its clinical application. This study aims to develop a novel drug delivery system for intratumoral delivery of gambogic acid. In our experimental study, we propose a new method for encapsulating gambogic acid nanoparticles using a manganese composite hyaluronic acid hydrogel as a carrier, designed for targeted drug delivery to tumors. The hydrogel delivery system is synthesized through the coordination of hyaluronic acid-dopamine (HA-DOPA) and manganese ions. The incorporation of manganese ions serves three purposes:1.To form cross-linked hydrogels, thereby improving the mechanical properties of HA-DOPA.2.To monitor the retention of hydrogels in vivo in real-time using magnetic resonance imaging (MRI).3.To activate the body's immune response. The experimental results show that the designed hydrogel has good biosafety, in vivo sustained release effect and imaging tracking ability. In the mouse CT26 model, the hydrogel drug-loaded group can better inhibit tumor growth. Further immunological analysis shows that the drug-loaded hydrogel group can stimulate the body's immune response, thereby better achieving anti-tumor effects. These findings indicate the potential of the developed manganese composite hyaluronic acid hydrogel as an effective and safe platform for intratumoral drug delivery. The amalgamation of biocompatibility, controlled drug release, and imaging prowess positions this system as a promising candidate for tumor treatment.

A Multifunctional Hydrogel Fabricated by Direct Self-Assembly of Natural Herbal Small Molecule Mangiferin for Treating Diabetic Wounds.

Clinical studies have continually referred to the involvement of drug carrier having dramatic negative influences on the biocompatibility, biodegradability, and loading efficacy of hydrogel. To overcome this deficiency, researchers have proposed to directly self-assemble natural herbal small molecules into a hydrogel without any structural modification. However, it is still a formidable challenge due to the high requirements on the structure of natural molecules, leading to a rarity of this type of hydrogel. Mangiferin (MF) is a natural polyphenol of C-glucoside xanthone with various positive health benefits, including the treatment of diabetic wounds, but its poor hydrosolubility and low bioavailability significantly restrict the clinical application. Inspired by these, with heating/cooling treatment, a carrier-free hydrogel (MF-gel) is developed by assembling the natural herbal molecule mangiferin, which is mainly governed through hydrogen bonds and intermolecular π-π stacking interactions. The as-prepared hydrogel has injectable and self-healing properties and shows excellent biocompatibility, continuous release ability, and reversible stimuli-responsive performances. All of the superiorities enable the MF-based hydrogel to serve as a potential wound dressing for treating diabetic wounds, which was further confirmed by both the vitro and vivo studies. In vitro, the MF-gel could promote the migration of healing-related cells from peripheral as well as the angiogenesis and displays the capacity of mediating inflammation response by scavenging the intracellular ROS. In vivo, the MF-gel accelerates wound contraction and healing via inflammatory adjustment, collagen deposition, and angiogenesis. This study provides a facile and effective method for diabetic wound management and emphasizes the direct self-assembly hydrogel from natural herbal small molecule.

Gambogic acid exhibits promising anticancer activity by inhibiting the pentose phosphate pathway in lung cancer mouse model.

BACKGROUND: The pentose phosphate pathway (PPP) plays a crucial role in the material and energy metabolism in cancer cells. Targeting 6-phosphogluconate dehydrogenase (6PGD), the rate-limiting enzyme in the PPP metabolic process, to inhibit cellular metabolism is an effective anticancer strategy. In our previous study, we have preliminarily demonstrated that gambogic acid (GA) induced cancer cell death by inhibiting 6PGD and suppressing PPP at the cellular level. However, it is unclear whether GA could suppress cancer cell growth by inhibiting PPP pathway in mouse model. PURPOSE: This study aimed to confirm that GA as a covalent inhibitor of 6PGD protein and to validate that GA suppresses cancer cell growth by inhibiting the PPP pathway in a mouse model. METHODS: Cell viability was detected by CCK-8 assays as well as flow cytometry. The protein targets of GA were identified using a chemical probe and activity-based protein profiling (ABPP) technology. The target validation was performed by in-gel fluorescence assay, the Cellular Thermal Shift Assay (CETSA). A lung cancer mouse model was constructed to test the anticancer activity of GA. RNA sequencing was performed to analyze the global effect of GA on gene expression. RESULTS: The chemical probe of GA exhibited high biological activity in vitro. 6PGD was identified as one of the binding proteins of GA by ABPP. Our findings revealed a direct interaction between GA and 6PGD. We also found that the anti-cancer activity of GA depended on reactive oxygen species (ROS), as evidenced by experiments on cells with 6PGD knocked down. More importantly, GA could effectively reduce the production of the two major metabolites of the PPP in lung tissue and inhibit cancer cell growth in the mouse model. Finally, RNA sequencing data suggested that GA treatment significantly regulated apoptosis and hypoxia-related physiological processes. CONCLUSION: These results demonstrated that GA was a covalent inhibitor of 6PGD protein. GA effectively suppressed cancer cell growth by inhibiting the PPP pathway without causing significant side effects in the mouse model. Our study provides in vivo evidence that elucidates the anticancer mechanism of GA, which involves the inhibition of 6PGD and modulation of cellular metabolic processes.

GSH-Responsive Liposomes with Heat Shock Protein Regulatory Ability for Efficient Photodynamic/Photothermal Combined Therapy of Tumors.

Phototherapy, represented by photodynamic therapy (PDT) and photothermal therapy (PTT), has great potential in tumor treatment. However, the presence of antioxidant glutathione (GSH) and the heat shock proteins (HSPs) expression caused by high temperature can weaken the effects of PDT and PTT. Here, a multifunctional nanocomplex BT&GA@CL is constructed to realize enhanced synergistic PDT/PTT. Cinnamaldehyde liposomes (CLs) formed by cinnamaldehyde dimer self-assembly were loaded with in gambogic acid (GA) and an aggregation-induced emission molecule BT to obtain BT&GA@CL. As a drug carrier, CL can consume glutathione (GSH) and release drugs responsively. The released BT aggregates can simultaneously act as both a photothermal agent and photosensitizer to achieve PDT and PTT under 660 nm laser irradiation. Specifically, GA as an HSP90 inhibitor can attenuate PTT-induced HSP90 protein expression, thereby weakening the tolerance of tumor cells to high temperatures and enhancing PTT. Such a multifunctional nanocomplex simultaneously modulates the content of GSH and HSP90 in tumor cells, thus enhancing both PDT and PTT, ultimately achieving the goal of efficient combined tumor suppression.

Tumor vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Suppresses macrophage capping protein beyond STING activation.

The vascular disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) induces apoptosis in vascular endothelial cells and leads to tumor hemorrhagic necrosis. While DMXAA has been proven to be a potent agonist of murine stimulator of interferon genes (mSTING), it has little effect on human-STING (hSTING). This species selectivity of DMXAA may explain its effectiveness against solid tumors in mice and its failure in clinical trials. However, DMXAA did reduce tumor volume in some patients during clinical trials. These paradoxical results have prompted us to investigate the anti-tumor mechanism of DMXAA beyond STING in the destruction of tumor vasculature in humans. In this study, we demonstrated that DMXAA binds to both human and mouse macrophage capping protein (CapG), with a KD of 5.839 µM for hCapG and a KD of 2.867 µM for mCapG, as determined by surface plasmon resonance (SPR) analysis. Homology modeling and molecular docking analysis of hCapG indicated that the critical residues involved in the hydrogen bond interaction of DMXAA with hCapG were Arg153, Thr151, and GLN141, Asn234. In addition, electrostatic pi-cation interaction occurred between DMXAA and hCapG. Further functional studies revealed that CapG protein plays a crucial role in the effects of DMXAA on human umbilical endothelial vein cell (HUEVC) angiogenesis and migration, as well as the expression of cytoskeletal proteins actin and tubulin, and the invasion of A549 lung adenocarcinoma cells. Our study has originally uncovered a novel cross-species pathway underlying the antitumor vascular disruption of DMXAA extends beyond STING activation. This finding deepens our understanding of the multifaceted actions of flavonoid VDAs in animal models and in clinical settings, and may provide insights for the precise therapy of DMXAA based on the biomarker CapG protein.

A differential-targeting core-shell microneedle patch with coordinated and prolonged release of mangiferin and MSC-derived exosomes for scarless skin regeneration.

Microneedles for skin regeneration are conventionally restricted by uncontrollable multi-drug release, limited types of drugs, and poor wound adhesion. Here, a novel core-shell microneedle patch is developed for scarless skin repair, where the shell is composed of hydrophilic gelatin methacryloyl (GelMA) loaded with mangiferin, an anti-inflammatory small molecule, and the core is composed of hydrophobic poly (lactide-co-propylene glycol-co-lactide) dimethacrylates (PGLADMA) loaded with bioactive macromolecule and human mesenchymal stromal cell (hMSC)-derived exosomes. This material choice provides several benefits: the GelMA shell provides a swelling interface for tissue interlocking and rapid release of mangiferin at an early wound healing stage for anti-inflammation, whereas the PGLADMA core offers long-term encapsulation and release of exosomes (30% release in 3 weeks), promoting sustained angiogenesis and anti-inflammation. Our results demonstrate that the core-shell microneedle possesses anti-inflammatory properties and can induce angiogenesis both in vitro in terms of macrophage polarization and tube formation of human umbilical vein endothelial cells (HUVECs), and in vivo in terms of anti-inflammation, re-epithelization, and vessel formation. Importantly, we also observe reduced scar formation in vivo. Altogether, the degradation dynamics of our hydrophilic/hydrophobic materials enable the design of a core-shell microneedle for differential and prolonged release, promoting scarless skin regeneration, with potential for other therapies of long-term exosome release.

Inhibition of macrophage MAPK/NF-κB pathway and Th2 axis by mangiferin ameliorates MC903-induced atopic dermatitis.

Available online Atopic dermatitis (AD) is a chronic, persistent inflammatory skin disease characterized by eczema-like lesions and itching. Although topical steroids have been reported for treating AD, they are associated with adverse effects. Thus, safer medications are needed for those who cannot tolerate these agents for long periods. Mangiferin (MAN) is a flavonoid widely found in many herbs, with significant anti-inflammatory and immunomodulatory activities. However, the potential modulatory effects and mechanisms of MAN in treating Th2 inflammation in AD are unknown. In the present study, we reported that MAN could reduce inflammatory cell infiltration and scratching at the lesion site by decreasing MC903-induced levels of Th2-type cytokines, Histamine, thymic stromal lymphopoietin, Leukotriene B4, and immunoglobulin E. The mechanism may be related to reductions in MAPK and NF-κB-associated protein phosphorylation by macrophages. The results suggested that MAN may be a promising therapeutic agent for AD.

The discovery of an anti-Candida xanthone with selective inhibition of Candida albicans GAPDH.

OBJECTIVES: This study aimed to discover novel antifungals targeting Candida albicans glyceraldehyde-3-phosphate dehydrogenase (CaGAPDH), have an insight into inhibitory mode, and provide evidence supporting CaGAPDH as a target for new antifungals. METHODS: Virtual screening was utilized to discover inhibitors of CaGAPDH. The inhibitory effect on cellular GAPDH was evaluated by determining the levels of ATP, NAD, NADH, etc., as well as examining GAPDH mRNA and protein expression. The role of GAPDH inhibition in C. albicans was supported by drug affinity responsive target stability and overexpression experiments. The mechanism of CaGAPDH inhibition was elucidated by Michaelis-Menten enzyme kinetics and site-specific mutagenesis based on docking. Chemical synthesis was used to produce an improved candidate. Different sources of GAPDH were used to evaluate inhibitory selectivity across species. In vitro and in vivo antifungal tests, along with anti-biofilm activity, were carried out to evaluate antifungal potential of GAPDH inhibitors. RESULTS: A natural xanthone was identified as the first competitive inhibitor of CaGAPDH. It demonstrated in vitro anti-C. albicans potential but also caused hemolysis. XP-W, a synthetic side-chain-optimized xanthone, demonstrated a better safety profile, exhibiting a 50-fold selectivity for CaGAPDH over human GAPDH. XP-W also exhibited potent anti-biofilm activity and displayed broad-spectrum anti-Candida activities in vitro and in vivo, including multi-azole-resistant C. albicans. CONCLUSIONS: These results demonstrate for the first time that CaGAPDH is a valuable target for antifungal drug discovery, and XP-W provides a promising lead.

Unlocking the anticancer activity of gambogic acid: a shift towards ferroptosis via a GSH/Trx dual antioxidant system.

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in ferroptosis by regulating the cellular antioxidant response and maintaining redox balance. However, compounds that induce ferroptosis through dual antioxidant pathways based on Nrf2 have not been fully explored. In our study, we investigated the impact of Gambogic acid (GA) on MCF-7 cells and HepG2 cells in vitro. The cytotoxicity, colony formation assay and cell cycle assay demonstrated potent tumor-killing ability of GA, while its effect was rescued by ferroptosis inhibitors. Furthermore, RNA sequencing revealed the enrichment of ferroptosis pathway mediated by GA. In terms of ferroptosis indicators detection, evidences for GA were provided including reactive oxygen species (ROS) accumulation, alteration in mitochondrial membrane potential (MMP), disappearance of mitochondrial cristae, lipid peroxidation induction, malondialdehyde (MDA) accumulation promotion, iron ion accumulation as well as glutathione (GSH)/thioredoxin (Trx) depletion. Notably, Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) successfully rescued GA-induced MDA accumulation. In terms of mechanism, Nrf2 was found to play a pivotal role in GA-induced ferroptosis by inducing protein alterations through the iron metabolism pathway and GSH/Trx dual antioxidant pathway. Furthermore, GA exerted good antitumor activity in vivo through GSH/Trx dual antioxidant pathway, and Fer-1 significantly attenuated its efficacy. In conclusion, our findings first provided new evidence for GA as an inducer of ferroptosis, and Nrf2-mediated GSH/Trx dual antioxidant system played an important role in GA-induced ferroptosis.