Vascular calcification (VC) is increasingly recognized as an actively regulated pathological process rather than passive mineral deposition, strongly associated with aging, atherosclerosis, and chronic kidney disease. Sclerostin, a Wnt signalling antagonist primarily expressed in osteocytes, has recently been implicated in VC, although its precise vascular role remains debated. This review aims to integrate mechanistic and translational evidence on how hypoxia and hypoxia-inducible factor-1α (HIF-1α) regulate sclerostin and contribute to vascular mineralisation. Experimental studies demonstrate that HIF-1α activation links hypoxia to key osteogenic pathways, including BMP2, RUNX2, and Wnt/β-catenin signalling, thereby influencing phenotypic switching of vascular smooth muscle cells (VSMCs). Hypoxia exerts both stimulatory and suppressive effects on sclerostin depending on local tissue conditions, reflecting a context-dependent regulatory network. Preclinical and clinical data show that sclerostin can act as either a compensatory inhibitor or a pro-calcific mediator, depending on disease stage and metabolic environment. Emerging evidence further highlights natural products such as polyphenols, flavonoids, and marine-derived compounds that modulate sclerostin expression through oxidative, inflammatory, and Wnt-related pathways. Sclerostin sits at a critical intersection between bone and vascular systems, where hypoxia-driven HIF signalling orchestrates its dual effects on mineral metabolism. Understanding the HIF–sclerostin axis provides new insight into the bone–vascular continuum and identifies potential therapeutic targets. Natural bioactive compounds capable of restoring sclerostin–Wnt balance may represent safe, multi-targeted strategies to mitigate VC progression, warranting further mechanistic and translational evaluation.

Sclerostin (SOST) is traditionally regarded as an osteocyte-derived secreted glycoprotein that regulates bone mineralization. Recent studies reported that SOST is also released from non-skeletal sources, especially during inflammation. However, the cellular source and regulatory mechanisms governing SOST generation in inflammation remain unclear. This study investigated whether macrophages produce SOST in response to inflammatory stimuli and determined associated regulatory pathways. The effect of lipopolysaccharide (LPS)-induced inflammation in SOST generation and its underlying regulatory mechanism was examined on mouse macrophage RAW 264.7 by western blot and immunofluorescent staining. Transfection with miR-92a-3p mimic and inhibitor were used to validate its role in SOST production. The role of NF-κB and TLR4 were studied using pharmacological inhibitors BAY 11-7085 and TAK242, respectively. The involvement of NF-κB and TLR4 in LPS-induced SOST production was further validated through nuclear NF-κB p65 immunoprecipitation and TLR4 small interfering RNA (siRNA) experiments, respectively.GW4869 and manumycin A (extracellular vesicles (EV) biogenesis inhibitors) were used to examine the associated of SOST and EV. Finally, SOST expression and characteristics of the isolated EV were assessed by Western blot and nanoparticle tracking analysis (NTA). LPS significantly induced SOST protein expression and secretion in RAW 264.7. MiR-92a-3p was upregulated by LPS stimulation in macrophages. Transfection of miR-92a-3p mimic increased SOST generation in RAW 264.7. Inhibition of TLR4 and NF-κB signalling pathways using pharmacological inhibitors significantly suppressed LPS-induced SOST in RAW 264.7. Similarly, TLR4 siRNA effectively suppressed LPS-induced SOST level. However, the LPS-induced upregulation of miR-92a-3p was only regulated by TLR4, but not by NF-κB. NF-κB was found to directly bind to the mouse sost promoter, thereby activating sost transcription. Additionally, SOST secretion was found predominantly associated with EV from LPS-stimulated cells, and inhibition of EV biogenesis suppressed SOST production in RAW 264.7 cells. In conclusion, our study showed, for the first time, that LPS induced SOST generation and secretion via TLR4/miR-92a-3p/PTEN/NF-κB singling pathway in murine macrophage RAW 264.7 cells. Moreover, we showed that SOST is secreted from the RAW 264.7 cells in the form of extracellular vesicle. This study identified macrophage as a novel source of SOST, highlighting its potential role in inflammatory diseases.

Pedunculoside (PE), a triterpenoid saponin isolated from Ilex rotunda Thunb., exhibits an anti-inflammatory effect; however, its hepatoprotective effects and pharmacokinetics are still unclear. Thus, an integrated strategy using network pharmacology and pharmacokinetics was used to investigate the hepatoprotective effects of PE. A simple, sensitive, and reliable LC-MS/MS method was established for the quantitative analysis of PE to elucidate its pharmacokinetics in normal rats and those with acute liver injury (ALI). LO2 cells and carbon tetrachloride-treated rats were used to evaluate the hepatoprotective effects and mechanism of PE in vitro and in vivo, respectively. The blood concentration curve demonstrated a decrease in clearance (CL) and an increase in the area under the curve (AUC(0-∞)) and mean residence time (MRT) in rats with ALI. Normal rats in the intravenous injection group had a CL of 36.80 L/h/kg, AUC(0-∞) of 1092.01 μg/L•h, and MRT(0-∞) of 0.93 h. In contrast, the CL of rats with ALI was 34.54 L/h/kg, AUC(0-∞) was 1170.01 μg/L•h, and MRT was 1.16 h. Similar results were obtained for rats in the intraperitoneal injection group. Qualitative studies of rat metabolites identified 19 metabolites, indicating that PE mainly undergoes phase I metabolism followed by phase II metabolism to a lesser extent. As rats with ALI showed a liver-targeting trend, network pharmacology was used to predict 20 potential ALI-related targets, among which the nuclear factor-kappa B (NF-κB) pathway had the strongest correlation. PE exhibited a protective effect on ALI by decreasing the levels of alanine transaminase, aspartate transaminase, and the pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, wherein the mechanism was related to the NF-κB pathway. Thus, PE exhibited a significant protective effect against ALI through the NF-κB pathway.

Medulla Tetrapanacis (MT) is traditionally consumed as herbal soup to manage mastitis. Although scientific evidence supports its anti-inflammatory effect, no study has investigated its effect on ulcerative colitis (UC). This study aimed to investigate the effect of MT water extract and its underlying mechanisms both in vitro and in vivo. Dextran sulfate sodium (DSS) was used to induce UC in zebrafish for assessing the effect of MT water extract on oxidative stress, inflammation, and migration of neutrophils. A DSS-induced UC mouse model was further employed to examine the effect of MT on oxidative stress, inflammation, macrophage phenotype, histopathology, and intestinal barrier integrity. Moreover, bone-marrow-derived macrophages (BMDMs) were used to elucidate the actions of MT on regulating polarization and energy metabolism. In vitro results showed that MT water extract significantly suppressed lipopolysaccharide and interferon-gamma-induced M1 polarization in BMDMs by reprogramming energy metabolism via suppressing hypoxia-inducible factor-1 alpha (HIF-1 alpha)/glycolysis. In zebrafish, MT water extract remarkably reduced neutrophil intestinal infiltration, reactive oxygen species generation, and expressions of pro-inflammatory genes (inducible nitric oxide synthase [iNOS], cyclooxygenase-2 [COX-2], interleukin [IL]-6, and IL-1 beta) in DSS-induced UC. Furthermore, MT treatment alleviated symptoms and histopathological damage in DSS-induced UC in mice, restored the balance of M1/M2 macrophages in the colon, attenuated inflammation and oxidative stress, and preserved intestinal barrier integrity. In conclusion, MT water extract ameliorated DSS-induced UC by regulating macrophage polarization through reprogramming of energy metabolism via suppressing HIF-1 alpha/glycolysis, suppressing oxidative stress, and maintaining intestinal barrier integrity. These findings support the application of MT for managing UC.

Background Instead of completely suppressing blood vessels inside tumors, vascular normalization therapy is proposed to normalize and prune the abnormal vasculature in tumor microenvironment (TME) to acquire a normal and stable blood flow and perfusion. The theoretical basis for the use of “blood-activating and stasis-resolving” formulas in Traditional Chinese Medicine to treat cancer is highly consistent with the principle of vascular normalization therapy, suggesting the potential application of these traditional formulas in vascular normalization therapy. Purpose To study the underlying mechanisms of a classical “blood-activating and stasis-resolving” formula, Taohong Siwu decoction (TSD), in enhancing the efficacy of chemotherapy for breast cancer treatment. Study Design HUVECs and transgenic zebrafish embryos were used as the major model in vitro. A 4T1 mouse breast cancer model was applied to study tumor vasculature normalization of TSD and the combination effects with DOX. Results Our data showed that TSD exhibited anti-angiogenic potential in HUVECs and transgenic zebrafish embryos. After 20 days treatment, TSD significantly normalized the tumor vasculature by remodeling vessel structure, reducing intratumoral hypoxia and vessel leakage, and promoting vessel maturation and blood perfusion in 4T1 breast tumor-bearing mice. Moreover, the anti-tumor efficacy of doxorubicin liposome in 4T1 breast tumors was significantly improved by TSD, including the suppression of tumor cell proliferation, angiogenesis, hypoxia, and the increase of cell apoptosis, which is likely through the vascular normalization induced by TSD. TSD also shifted the macrophage polarization from M2 to M1 phenotype in TME during the combination therapy, as evidenced by the reduced number of CD206+ macrophages and increased number of CD86+ macrophages. Additionally, TSD treatment protected against doxorubicin-induced cardiotoxicity in animals, as evidenced by the reduced cardiomyocytes apoptosis and improved heart function. Conclusion This study demonstrated for the first time that TSD as a classical Chinese formula can enhance the drug efficacy and reduce the side effects of doxorubicin. These findings can support that TSD could be used as an adjuvant therapy in combination with conventional chemotherapy for the future breast cancer treatment.

While mangrove ecosystems are rich in biodiversity, they are increasingly impacted by climate change and urban pollutants. The current study provides first insights into the emergence of potentially pathogenic yeasts in Hong Kong’s mangroves. Sediment and water samples were collected from ten urban and rural mangroves sites. Initial CHROMagarTM Candida Plus screening, representing the first application of this differential medium for water and soil samples collected from a non-clinical environment, enabled the rapid, preliminary phenotypic identification of yeast isolates from mangroves. Subsequent molecular profiling (ITS and/or 28S nrDNA sequencing) and antifungal drug susceptibility tests were conducted to further elucidate yeast diversity and drug resistance. A diversity of yeasts, including 45 isolates of 18 distinct species across 13 genera/clades, was isolated from sediments and waters from Hong Kong mangroves. Molecular profiling revealed a dominance of the Candida/Lodderomyces clade (44.4%), a group of notorious opportunistic pathogens. The findings also reveal a rich biodiversity of non-Candida/Lodderomyces yeasts in mangroves, including the first reported presence of Apiotrichum domesticum and Crinitomyces flavificans. A potentially novel Yamadazyma species was also discovered. Remarkably, 14.3% of the ubiquitous Candida parapsilosis isolates displayed resistance to multiple antifungal drugs, suggesting that mangroves may be reservoirs of multi-drug resistance. Wildlife, especially migratory birds, may disseminate these hidden threats. With significant knowledge gaps regarding the environmental origins, drug resistance, and public health impacts of pathogenic yeasts, urgent surveillance is needed from a One Health perspective. This study provides an early warning that unrestrained urbanization can unleash resistant pathogens from coastal ecosystems globally. It underscores the necessity for enhanced surveillance studies and interdisciplinary collaboration between clinicians, ornithologists, and environmental microbiologists to effectively monitor and manage this environmental health risk, ensuring the maintenance of ‘One Health’.

Amauroderma rugosum (AR), also known as “Blood Lingzhi” in Chinese, is a basidiomycete belonging to the Ganodermataceae family. Four polysaccharide fractions were systematically isolated and purified from AR. Subsequently, their compositions were examined and analyzed via high-performance gel permeation chromatography (HPGPC), analysis of the monosaccharide composition, Fourier-transform infrared spectroscopy (FT-IR), and 1H nuclear magnetic resonance (NMR). The zebrafish model was then used to screen for proangiogenic activities of polysaccharides by inducing vascular insufficiency with VEGF receptor tyrosine kinase inhibitor II (VRI). The third fraction of AR polysaccharides (PAR-3) demonstrated the most pronounced proangiogenic effects, effectively ameliorating VRI-induced intersegmental vessel deficiency in zebrafish. Concurrently, the mRNA expression levels of vascular endothelial growth factor (VEGF)-A and VEGF receptors were upregulated by PAR-3. Moreover, the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) were also stimulated by PAR-3, consistently demonstrating that PAR-3 possesses favorable proangiogenic properties. The activation of the Akt, ERK1/2, p38 MAPK, and FAK was most likely the underlying mechanism. In conclusion, this study establishes that PAR-3 isolated from Amauroderma rugosum exhibits potential as a bioresource for promoting angiogenesis.

AbstractMedulla Tetrapanacis (MT) is a commonly used herbal ingredient in soup to promote lactation and management of mastitis among lactating mothers worldwide, particularly in Asian countries. However, scientific evidence to support its usage in the management of mastitis is limited. This study aimed to investigate the effects of MT water extract and its underlying mechanisms in Staphylococcus aureus (SA)–induced mastitis in human mammary epithelial cells (HuMEC) and lipopolysaccharide (LPS)–induced mastitis in lactating Sprague–Dawley (SD) rats. The anti‐inflammatory and antibacterial effects of MT water extract were examined in SA‐infected HuMEC by ELISA and plate counting, respectively. The effects of MT water extract on blood‐milk barrier and the underlying mechanism of action of the MT water extract were also investigated by transendothelial electrical resistance assay and western blot. The effects and mechanisms of MT water extract on alleviating mastitis on SD rats were evaluated using LPS‐induced mastitis rat model. Our results showed that MT water extract could suppress SA‐induced mastitis by reducing SA internalization and growth, protecting blood‐milk barrier integrity, and attenuating release of cytokines (interleukin 6 [IL‐6] and tumor necrosis factor‐alpha [TNF‐α]) in HuEMC. Furthermore, the antibacterial effect might be related to the increase of antimicrobial peptides transcription, and the anti‐inflammatory effect is at least partly mediated by inactivation of p38 and JNK signaling pathways. Finally, our in vivo results showed that MT water extract ameliorated LPS‐induced mastitis in SD rats via suppressing inflammatory cytokine release (TNF‐α, IL‐6, and interleukin‐1 beta), myeloperoxidase, and alleviating pathohistological damage by downregulation of JNK signaling pathway.

Background: Amauroderma rugosum (AR) is a medicinal mushroom commonly used to treat inflammation, gastric disorders, epilepsy, and cancers due to its remarkable anti-inflammatory and anti-oxidative properties. This study was designed to evaluate the pharmacological effects of AR and its underlying mechanism of action against ulcerative colitis (UC) in vitro and in vivo. Methods: A UC mouse model was established by administration of dextran sulfate sodium (DSS). AR extract was administered intragastrically to mice for 7 days. At the end of the experiment, histopathology, macrophage phenotype, oxidative stress, and inflammatory status were examined in vivo. Furthermore, RAW 264.7, THP-1, and Caco-2 cells were used to elucidate the mechanism of action of AR in vitro. Results: AR extract (0.5-2 mg/mL) significantly suppressed lipopolysaccharide (LPS) and interferon-gamma (IFN gamma)-induced M1 macrophage (pro-inflammatory) polarization in both RAW 264.7 and THP-1 cells. LPS-induced pro-inflammatory mediators (nitric oxide, TNF-alpha, IL-1 beta, MCP-1, and IL-6) were reduced by AR extract in a concentration-dependent manner. Similarly, AR extract downregulated MAPK signaling activity in LPSstimulated RAW 264.7 cells. AR extract elicited a concentration-dependent increase in the mRNA expression of M2 (anti-inflammatory) phenotype markers (CD206, Arg-1, Fizz-1, and Ym-1) in RAW 264.7 cells. Moreover, AR extract suppressed DSS-induced ROS generation and mitochondrial dysfunction in Caco-2 cells. The in vivo experiment revealed that AR extract (200 mg/kg) increased colon length compared to the DSS-treated group. In addition, disease activity index, spleen ratio, body weight, oxidative stress, and colonic inflammation were markedly improved by AR treatment in DSS-induced UC mice. Finally, AR suppressed M1 and promoted M2 macrophage polarization in UC mice. Conclusion: The AR extract protected against DSS-induced UC by regulating macrophage polarization and suppressing oxidative stress. These valuable findings suggest that adequate intake of AR can prevent and/or treat UC.

IntroductionVibrio alginolyticus is a Gram-negative, rod-shaped bacterium belonging to the family of Vibrionaceae, a common pathogen in aquaculture animals, However, studies on its impact on Scylla serrata (mud crabs) are limited. In this study, we isolated V. alginolyticus SWS from dead mud crab during a disease outbreak in a Hong Kong aquaculture farm, which caused up to 70% mortality during summer.MethodsExperimental infection and histopathology were used to investigate the pathogenicity of V. alginolyticus SWS in S. serrata and validate Koch’s postulates. Comprehensive whole-genome analysis and phylogenetic analysis antimicrobial susceptibility testing, and biochemical characterization were also performed. ResultsOur findings showed that V. alginolyticus SWS caused high mortality (75%) in S. serrata with infected individuals exhibiting inactivity, loss of appetite, decolored and darkened hepatopancreas, gills, and opaque muscle in the claw. Histopathological analysis revealed tissue damage and degeneration in the hepatopancreas, gills, and claw muscle suggesting direct and indirect impacts of V. alginolyticus SWS infection.ConclusionsThis study provides a comprehensive characterization of V. alginolyticus SWS as an emerging pathogen in S. serrata aquaculture. Our findings underscore the importance of ongoing surveillance, early detection, and the development of targeted disease management strategies to mitigate the economic impact of vibriosis outbreaks in mud crab aquaculture.

AGS-30, a new andrographolide derivative, showed significant anticancer and anti-angiogenic characteristics. However, its role in controlling macrophage polarization and tumor immune response is unknown. Thus, the main goals of this study are to investigate how AGS-30 regulates macrophage polarization and how it suppresses breast cancer metastasis. AGS-30 inhibited IL-4 and IL-13-induced RAW 264.7 and THP-1 macrophages into M2-like phenotype. However, AGS-30 did not affect the LPS and IFN-γ-induced polarization of M1-like macrophages. AGS-30 reduced the mRNA expressions of CD206, Arg-1, Fizz-1, Ym-1, VEGF, IL-10, MMP2, and MMP9 in M2-like macrophages in a concentration-dependent manner. In contrast, andrographolide treatment at 5 μM did not affect M1-like and M2-like macrophage polarization. The conditioned medium from M2-like macrophages increased 4T1 breast cancer cell migration and invasion, whereas AGS-30 inhibited these effects. In the 4T1 breast tumor xenograft mice, the tumor volume and weight were reduced without affecting body weight after receiving AGS-30. AGS-30 treatment also reduced lung and liver metastasis, with reduced STAT6, CD31, VEGF, and Ki67 protein expressions. Moreover, the tumors had considerably fewer M2-like macrophages and Arg-1 expression, but the proportion of M1-like macrophages and iNOS expression increased after AGS-30 treatment. Same results were found in the tail vein metastasis model. In conclusion, this study shows that AGS-30 inhibits breast cancer growth and metastasis, probably through inhibiting M2-like macrophage polarization. Our findings suggest that AGS-30 may be a potential immunotherapeutic alternative for metastatic breast cancer.

Alcoholic beverages are among the most widely enjoyed leisure drinks around the world. However, irresponsible drinking habits can have detrimental effects on human health. Therefore, exploring strategies to alleviate discomfort following alcohol consumption would be beneficial for individuals who inevitably need to consume alcohol. In this study, three different models were used to determine the efficacy of a patented alcohol degradation protein (ADP) extracted from Bos taurus on ethanol metabolism. In an ethanol-challenged HepG2 cell model, ADP significantly protected the cell from ethanol-induced toxicity. Subsequently, results demonstrated that ADP significantly alleviated the effect of ethanol, as reflected by the increased distance and activity time of zebrafish during the testing period. Additionally, in a rat model, ADP promoted ethanol degradation at 1 and 2 h after ethanol consumption. Mechanistic studies found that ADP treatment increased ADH and ALDH activity in the gastrointestinal tract. ADP also exhibited potent antioxidation effects by lowering HO-1 expression in the liver. In conclusion, we believe that ADP is a promising product for relieving hangover symptoms after ethanol consumption, with demonstrated safety and effectiveness at the recommended dosage.

Cancer metastasis remains the most common cause of death in breast cancer patients. Tumor-associated macrophages (TAMs) are a novel therapeutic target for the treatment of metastatic breast cancer. Despite the good anti-cancer activity of garcinone E (GE), there are no reports on its therapeutic effects on breast cancer metastasis. The objective of this study was to examine the anti-cancer effects of GE on metastatic breast cancer. RAW 264.7 and THP-1 cells were polarized to M2 macrophages by IL-4/IL-13 in vitro. A 4T1 mouse breast cancer model and the tail vein breast cancer metastasis model were used to explore the effect of GE on breast cancer growth and metastasis in vivo. In vitro studies showed that GE dose-dependently suppressed IL-4 + IL-13-induced expression of CD206 in both RAW 264.7 cells and differentiated THP-1 macrophages. However, GE did not affect the LPS + IFN-gamma-induced polarization to the M1-like macrophages in vitro. GE inhibited the expression of the M2 macrophage specific genes in RAW 264.7 cells, and simultaneously impaired M2 macrophage-induced breast cancer cell proliferation and migration, and angiogenesis. In animal studies, GE significantly suppressed tumor growth, angiogenesis, and lung metastasis in 4T1 tumor-bearing mice, without causing toxicity. In both tumor and lung tissues, the proportion of M2-like TAMs was significantly decreased while the proportion of M1-like TAMs was markedly increased by GE treatment. Mechanistically, GE inhibited phosphorylation of STAT6 in vitro and in vivo. Our results demonstrate for the first time that GE suppresses breast cancer growth and pulmonary metastasis by modulating M2-like macrophage polarization through the STAT6 signaling pathway.

Despite the acknowledged advantages of combined immunochemotherapy for tumor treatment, the high efficiency of co-delivery of these combined agents into the targeted tumor tissue is still challenging. Herein, based on a "three-birds-with-one-stone" strategy, a facile glycyrrhizic acid (GL)-lipid hybrid nanoplatform loading triptolide (TP/GLLNP) is designed to better address the dilemma. Differing from the traditional liposomes with dual-drug co-delivery NPs, GL with a cholesterol-like structure is primarily employed to construct the lipid membrane skeleton of the GL-based lipid nanoparticle (GLLNP), and then triptolide (TP) is readily loaded in the lipid bilayer of GLLNP. The fabricated GLLNP possessed similar drug loading efficacy, particle size, and storage stability; none of the hemolysis; even higher membrane fluidity; and lower absorbed opsonin proteins compared with the conventional liposomes. Compared to TP-loaded traditional liposomes (TP/Lipo), TP/GLLNP exhibits significantly enhanced cellular uptake, cytotoxicity, and apoptosis of HepG2 cells. In addition, GLLNP could ameliorate tumor immunosuppression by promoting tumor-associated macrophage polarization from M2 to M1 phenotype. Furthermore, enhanced retention and accumulation in the tumor area of GLLNP could be found. As expected, TP/GLLNP displayed synergistic anti-hepatocellular carcinoma efficacy in vivo. In conclusion, this study provides an inspirational strategy to combine the anti-HCC benefits of GL and TP using a novel dual-drug co-delivery nanosystem.

Medulla Tetrapanacis (MT) is a commonly used herb to promote lactation and manage mastitis in lactating mothers. However, its anti-inflammatory and anti-bacterial effects are currently unknown. We hypothesized that MT water extract possesses anti-inflammatory and anti-bacterial effects by modulating macrophage polarization to reduce the release of inflammatory mediators and phagocytosis via inactivation of MAPKs pathways. The chemical composition of the MT water extract was analyzed by UPLC-Orbitrap-mass spectrometry. The anti-inflammatory and anti-bacterial properties of the MT water extract were examined using LPS-stimulated inflammation and Staphylococcus aureus infection model in RAW 264.7 cells, respectively. The underlying mechanism of action of the MT water extract was also investigated. We identified eight compounds by UPLC-Orbitrap-mass spectrometry that are abundant within the MT water extract. MT water extract significantly suppressed LPS-induced nitric oxide, TNF-α and IL-6 secretion in RAW 264.7 cells which was accompanied by the promotion of macrophage polarization from pro-inflammatory towards anti-inflammatory phenotypes. MT water extract significantly suppressed the LPS-induced MAPK activation. Finally, MT water extract decreased the phagocytic capacity of the RAW 264.7 cells against S. aureus infection. MT water extract could suppress LPS-induced inflammation by promoting macrophages towards an anti-inflammatory phenotype. In addition, MT also inhibited the growth of S. aureus.

Crocins (CRs) and the related active constituents derived from Crocus sativus L. (Saffron) have demonstrated protective effects against cerebral ischemia and ischemic stroke, with various bioactivities including neuroprotection, anti-neuroinflammation, antioxidant, and cardiovascular protection. Among CRs, crocin (CR) has been shown to act on multiple mechanisms and signaling pathways involved in ischemic stroke, including mitochondrial apoptosis, nuclear factor kappa light chain enhancer of B cells pathway, S100 calcium-binding protein B, interleukin-6 and vascular endothelial growth factor-A. CR is generally safe and well-tolerated. Pharmacokinetic studies indicate that CR has poor bioavailability and needs to convert to crocetin (CC) in order to cross the blood-brain barrier. Clinical studies have shown the efficacy of saffron and CR in treating various conditions, including metabolic syndrome, depression, Alzheimer's disease, and coronary artery disease. There is evidence supporting CR as a treatment for ischemic stroke, although further studies are needed to confirm their efficacy and safety in clinical settings.

EDITORIAL article Front. Pharmacol., 30 November 2022Sec. Experimental Pharmacology and Drug Discovery https://doi.org/10.3389/fphar.2022.1101742

BACKGROUND:Nucleoside transporters are crucial in regulating the functions of adenosine. This study investigated the contribution of equilibrative nucleoside transporter (ENT) type 4 to adenosine transport in cardiomyocytes under simulated ischemic conditions and whether the inhibition of ENT4 could protect cardiomyocytes against ischemia-reperfusion injury.METHODS:AC16 human cardiomyocytes were used to create a model to simulate ischemia/reperfusion injury. ENT4 activity was inhibited by decynium-22 or specific siRNA against ENT4. The protein expressions of nucleoside transporters were measured by western blot analysis. The transport activity was studied by [3?H]adenosine uptake. The cell injury was studied by biochemical assays.RESULTS:The [3?H]adenosine uptake in AC16 cells was predominantly mediated by ENTs. ENT1 to ENT4 were present in AC16 cells and their protein expression levels were comparable in normal and ischemic conditions. Decynium-22 or siRNA against ENT4 did not affect the adenosine uptake in AC16 cells under normal conditions but could inhibit the adenosine uptake in AC16 cells by 28% under ischemic conditions. In addition, the cell viability and lactate dehydrogenase release of AC16 cells under ischemia conditions could be reduced by decynium-22 or siRNA against ENT4.CONCLUSION:The cell culture model has suggested that ENT4 may play a role in adenosine transport in cardiomyocytes under ischemic conditions. Inhibition or downregulation of ENT4 may be a potential approach for cardioprotection but this notion should be further validated using animal model.