New Findings Regarding the Effects of Selected Blue Food Colorants (Genipin, Patent Blue V, and Brilliant Blue FCF) on the Hemostatic Properties of Blood Components In Vitro.

Natural and synthetic colorants present in food can modulate hemostasis, which includes the coagulation process and blood platelet activation. Some colorants have cardioprotective activity as well. However, the effect of genipin (a natural blue colorant) and synthetic blue colorants (including patent blue V and brilliant blue FCF) on hemostasis is not clear. In this study, we aimed to investigate the effects of three blue colorants-genipin, patent blue V, and brilliant blue FCF-on selected parameters of hemostasis in vitro. The anti- or pro-coagulant potential was assessed in human plasma by measuring the following coagulation times: thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (APTT). Moreover, we used the Total Thrombus formation Analysis System (T-TAS, PL-chip) to evaluate the anti-platelet potential of the colorants in whole blood. We also measured their effect on the adhesion of washed blood platelets to fibrinogen and collagen. Lastly, the cytotoxicity of the colorants against blood platelets was assessed based on the activity of extracellular lactate dehydrogenase (LDH). We observed that genipin (at all concentrations (1-200 µM)) did not have a significant effect on the coagulation times (PT, APTT, and TT). However, genipin at the highest concentration (200 µM) and patent blue V at the concentrations of 1 and 10 µM significantly prolonged the time of occlusion measured using the T-TAS, which demonstrated their anti-platelet activity. We also observed that genipin decreased the adhesion of platelets to fibrinogen and collagen. Only patent blue V and brilliant blue FCF significantly shortened the APTT (at the concentration of 10 µM) and TT (at concentrations of 1 and 10 µM), demonstrating pro-coagulant activity. These synthetic blue colorants also modulated the process of human blood platelet adhesion, stimulating the adhesion to fibrinogen and inhibiting the adhesion to collagen. The results demonstrate that genipin is not toxic. In addition, because of its ability to reduce blood platelet activation, genipin holds promise as a novel and valuable agent that improves the health of the cardiovascular system and reduces the risk of cardiovascular diseases. However, the mechanism of its anti-platelet activity remains unclear and requires further studies. Its in vivo activity and interaction with various anti-coagulant and anti-thrombotic drugs, including aspirin and its derivatives, should be examined as well.

IL-17A Drives Oxidative Stress and Cell Growth in A549 Lung Epithelial Cells: Potential Protective Action of Oleuropein.

IL-17A drives inflammation and oxidative stress, affecting the progression of chronic lung diseases (asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis). Oleuropein (OLP) is a polyphenolic compound present in olive oil and widely included in the Mediterranean diet. It exerts antioxidant and anti-inflammatory activities, oxidative stress resistance, and anticarcinogenic effects with a conceivable positive impact on human health. We hypothesized that OLP positively affects the mechanisms of oxidative stress, apoptosis, DNA damage, cell viability during proliferation, and cell growth in alveolar epithelial cells and tested its effect in a human alveolar epithelial cell line (A549) in the presence of IL-17A. Our results show that OLP decreases the levels of oxidative stress (Reactive Oxygen Species, Mitochondrial membrane potential) and DNA damage (H2AX phosphorylation-ser139, Olive Tail Moment data) and increases cell apoptosis in A549 cells exposed to IL-17A. Furthermore, OLP decreases the number of viable cells during proliferation, the migratory potential (Scratch test), and the single cell capacity to grow within colonies as a cancer phenotype in A549 cells exposed to IL-17A. In conclusion, we suggest that OLP might be useful to protect lung epithelial cells from oxidative stress, DNA damage, cell growth, and cell apoptosis. This effect might be exerted in lung diseases by the downregulation of IL-17A activities. Our results suggest a positive effect of the components of olive oil on human lung health.

Monotropein mitigates atopic dermatitis-like skin inflammation through JAK/STAT signaling pathway inhibition.

Atopic dermatitis (AD) is a globally increasing chronic inflammatory skin disease with limited and potentially side-effect-prone treatment options. Monotropein is the predominant iridoid glycoside in Morinda officinalis How roots, which has previously shown promise in alleviating AD symptoms. This study aimed to systematically investigate the pharmacological effects of monotropein on AD using a 2, 4-dinitrochlorobenzene (DNCB)/Dermatophagoides farinae extract (DFE)-induced AD mice and tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated keratinocytes. Oral administration of monotropein demonstrated a significant reduction in AD phenotypes, including scaling, erythema, and increased skin thickness in AD-induced mice. Histological analysis revealed a marked decrease in immune cell infiltration in skin lesions. Additionally, monotropein effectively downregulated inflammatory markers, encompassing pro-inflammatory cytokines, T helper (Th)1 and Th2 cytokines, and pro-inflammatory chemokines in skin tissues. Notably, monotropein also led to a considerable decrease in serum immunoglobulin (Ig)E and IgG2a levels. At a mechanistic level, monotropein exerted its anti-inflammatory effects by suppressing the phosphorylation of Janus kinase / signal transducer and activator of transcription proteins in both skin tissues of AD-induced mice and TNF-α/IFN-γ-stimulated keratinocytes. In conclusion, monotropein exhibited a pronounced alleviation of AD symptoms in the experimental models used. These findings underscore the potential application of monotropein as a therapeutic agent in the context of AD, providing a scientific basis for further exploration and development.

Effect of Oleuropein on Anti-Obesity and Uncoupling Protein 1 Level in Brown Adipose Tissue in Mild Treadmill Walking Rats with Diet-Induced Obesity.

Oleuropein aglycone (OA), which is the absorbed form of oleuropein, is a major phenolic compound in extra virgin olive oil. We analyzed the anti-obesity effect of OA intake combined with mild treadmill walking (MTW, 4 m/min for 20 min/d, 5-6 d/wk, without electric shocks and slope) in rats under a high-fat diet (HF). Four-week-old male Sprague-Dawley rats (n=28) were equally divided into four groups: control (HF), 0.08% oleuropein-supplemented HF (HFO), HF with MTW (HF+W), and HFO with MTW (HFO+W) groups. After 28 d, the inguinal subcutaneous fat content and weight gain were significantly lower in the HFO+W group than in the control group. The HFO+W group also had significantly higher levels of urinary noradrenaline secretion, interscapular brown adipose tissue, uncoupling protein 1, brain transient receptor potential ankyrin subtype 1 (TRPA1), vanilloid subtype 1 (TRPV1), and brain-derived neurotrophic factor (BDNF) than the control group. Especially, the HFO+W group showed a synergistic effect on noradrenaline secretion. Therefore, OA combined with MTW may accelerate the enhancement of UCP1 and BDNF levels in rats with HF-induced obesity by increasing noradrenaline secretion after TRPA1 and TRPV1 activation.

Concise Synthesis of 11-Noriridoids via Pauson-Khand Reaction.

Iridoids, which are a class of monoterpenoids, are attractive synthetic targets due to their diversely substituted cis-fused cyclopenta[c]pyran skeletons. Additionally, various biological activities of iridoids raise the value of synthetic studies on this class of compounds. Here, our synthetic efforts toward 11-noriridoids; (±)-umbellatolide B (6), (±)-10-O-benzoylglobularigenin (9) and 1-O-pentenylaucubigenin (34) are described. For the efficient synthesis of target compounds, common synthetic intermediates (tricyclic enones 17 and 26) were prepared by the Pauson-Khand reaction. The cleavage of the acetal bond on the tricyclic enones and 1,2-reduction introduced the two hydroxy groups on the cyclopentane ring of the core scaffold. Furthermore, the C3-C4 olefin part was constructed by the syn-elimination of a thiocarbonate moiety to obtain 34. The developed synthetic routes for 6, 9, and 34 will be useful for the preparation of iridoid analogs that have a polyfunctionalized core skeleton.

Oleuropein, a Component of Extra Virgin Olive Oil, Improves Liver Steatosis and Lobular Inflammation by Lipopolysaccharides-TLR4 Axis Downregulation.

Gut-dysbiosis-induced lipopolysaccharides (LPS) translocation into systemic circulation has been suggested to be implicated in nonalcoholic fatty liver disease (NAFLD) pathogenesis. This study aimed to assess if oleuropein (OLE), a component of extra virgin olive oil, lowers high-fat-diet (HFD)-induced endotoxemia and, eventually, liver steatosis. An immunohistochemistry analysis of the intestine and liver was performed in (i) control mice (CTR; n = 15), (ii) high-fat-diet fed (HFD) mice (HFD; n = 16), and (iii) HFD mice treated with 6 µg/day of OLE for 30 days (HFD + OLE, n = 13). The HFD mice developed significant liver steatosis compared to the controls, an effect that was significantly reduced in the HFD + OLE-treated mice. The amount of hepatocyte LPS localization and the number of TLR4+ macrophages were higher in the HFD mice in the than controls and were lowered in the HFD + OLE-treated mice. The number of CD42b+ platelets was increased in the liver sinusoids of the HFD mice compared to the controls and decreased in the HFD + OLE-treated mice. Compared to the controls, the HFD-treated mice showed a high percentage of intestine PAS+ goblet cells, an increased length of intestinal crypts, LPS localization and TLR4+ expression, and occludin downregulation, an effect counteracted in the HFD + OLE-treated mice. The HFD-fed animals displayed increased systemic levels of LPS and zonulin, but they were reduced in the HFD + OLE-treated animals. It can be seen that OLE administration improves liver steatosis and inflammation in association with decreased LPS translocation into the systemic circulation, hepatocyte localization of LPS and TLR4 downregulation in HFD-induced mouse model of NAFLD.

Transcriptome and metabolome analysis reveals mechanism of light intensity modulating iridoid biosynthesis in Gentiana macrophylla Pall.

Light intensity is a key factor affecting the synthesis of secondary metabolites in plants. However, the response mechanisms of metabolites and genes in Gentiana macrophylla under different light intensities have not been determined. In the present study, G. macrophylla seedlings were treated with LED light intensities of 15 µmol/m2/s (low light, LL), 90 µmol/m2/s (medium light, ML), and 200 µmol/m2/s (high light, HL), and leaves were collected on the 5th day for further investigation. A total of 2162 metabolites were detected, in which, the most abundant metabolites were identified as flavonoids, carbohydrates, terpenoids and amino acids. A total of 3313 and 613 differentially expressed genes (DEGs) were identified in the LL and HL groups compared with the ML group, respectively, mainly enriched in KEGG pathways such as carotenoid biosynthesis, carbon metabolism, glycolysis/gluconeogenesis, amino acids biosynthesis, plant MAPK pathway and plant hormone signaling. Besides, the transcription factors of GmMYB5 and GmbHLH20 were determined to be significantly correlated with loganic acid biosynthesis; the expression of photosystem-related enzyme genes was altered under different light intensities, regulating the expression of enzyme genes involved in the carotenoid, chlorophyll, glycolysis and amino acids pathway, then affecting their metabolic biosynthesis. As a result, low light inhibited photosynthesis, delayed glycolysis, thus, increased certain amino acids and decreased loganic acid production, while high light got an opposite trend. Our research contributed significantly to understand the molecular mechanism of light intensity in controlling metabolic accumulation in G. macrophylla.

Plumieride as a novel anti-fungal and anti-inflammatory iridoid against superficial candidiasis in mice.

In the past few decades, there has been a notable rise in the occurrence of several types of candidiasis. Candida albicans is the most common cause of superficial fungal infections in humans. In this study, plumieride, one of the major iridoids from Plumeria obtusa L. leaves, was isolated and investigated for its potential against Candida albicans (CA)-induced dermatitis in mice. qRT-PCR was done to assess the impact of plumieride on the expression of the major virulence genes of CA. Five groups (n = 7) of adult male BALB/c mice were categorized into: group I: non-infected mice; group II: mice infected intradermally with 107-108 CFU/mL of CA; group III: CA-infected mice treated with standard fluconazole (50 mg/kg bwt.); group IV and V: CA-infected mice treated with plumieride (25- and 50 mg/kg. bwt., respectively). All the treatments were subcutaneously injected once a day for 3 days. Skin samples were collected on the 4th day post-inoculation to perform pathological, microbial, and molecular studies. The results of the in vitro study proved that plumieride has better antifungal activity than fluconazole, manifested by a wider zone of inhibition and a lower MIC. Plumieride also downregulated the expression of CA virulence genes (ALS1, Plb1, and Hyr1). CA-infected mice showed extensive dermatitis, confirmed by strong iNOS, TNF-α, IL-1ß, and NF-κB genes or immune expressions. Whereas the treatment of CA-infected mice with plumieride significantly reduced the microscopic skin lesions and modulated the expression of all measured proinflammatory cytokines and inflammatory markers in a dose-dependent manner. Plumieride interfered with the expression of C. albicans virulence factors and modulated the inflammatory response in the skin of mice infected with CA.

Near-infrared-II responsive ovalbumin functionalized gold-genipin nanosystem cascading photo-immunotherapy of cancer.

Synergistic cancer therapies have attracted wide attention owing to their multi-mode tumor inhibition properties. Especially, photo-responsive photoimmunotherapy demonstrates an emerging cancer treatment paradigm that significantly improved treatment efficiency. Herein, near-infrared-II responsive ovalbumin functionalized Gold-Genipin nanosystem (Au-G-OVA NRs) was designed for immunotherapy and deep photothermal therapy of breast cancer. A facile synthesis method was employed to prepare the homogeneous Au nanorods (Au NRs) with good dispersion. The nanovaccine was developed further by the chemical cross-linking of Au-NRs, genipin and ovalbumin. The Au-G-OVA NRs outstanding aqueous solubility, and biocompatibility against normal and cancer cells. The designed NRs possessed enhanced localized surface plasmon resonance (LSPR) effect, which extended the NIR absorption in the second window, enabling promising photothermal properties. Moreover, genipin coating provided complimentary red fluorescent and prepared Au-G-OVA NRs showed significant intracellular encapsulation for efficient photoimmunotherapy outcomes. The designed nanosystem possessed deep photothermal therapy of breast cancer and 90% 4T1 cells were ablated by Au-G-OVA NRs (80µg ml-1concentration) after 1064 nm laser irradiation. In addition, Au-G-OVA NRs demonstrated outstanding vaccination phenomena by facilitating OVA delivery, antigen uptake, maturation of bone marrow dendritic cells, and cytokine IFN-γsecretion for tumor immunosurveillance. The aforementioned advantages permit the utilization of fluorescence imaging-guided photo-immunotherapy for cancers, demonstrating a straightforward approach for developing nanovaccines tailored to precise tumor treatment.

Biofunctionalized hydrogel composed of genipin-crosslinked gelatin/hyaluronic acid incorporated with lyophilized platelet-rich fibrin for segmental bone defect repair.

Segmental bone defects can arise from trauma, infection, metabolic bone disorders, or tumor removal. Hydrogels have gained attention in the field of bone regeneration due to their unique hydrophilic properties and the ability to customize their physical and chemical characteristics to serve as scaffolds and carriers for growth factors. However, the limited mechanical strength of hydrogels and the rapid release of active substances have hindered their clinical utility and therapeutic effectiveness. With ongoing advancements in material science, the development of injectable and biofunctionalized hydrogels holds great promise for addressing the challenges associated with segmental bone defects. In this study, we incorporated lyophilized platelet-rich fibrin (LPRF), which contains a multitude of growth factors, into a genipin-crosslinked gelatin/hyaluronic acid (GLT/HA-0.5 % GP) hydrogel to create an injectable and biofunctionalized composite material. Our findings demonstrate that this biofunctionalized hydrogel possesses optimal attributes for bone tissue engineering. Furthermore, results obtained from rabbit model with segmental tibial bone defects, indicate that the treatment with this biofunctionalized hydrogel resulted in increased new bone formation, as confirmed by imaging and histological analysis. From a translational perspective, this biofunctionalized hydrogel provides innovative and bioinspired capabilities that have the potential to enhance bone repair and regeneration in future clinical applications.

Genipin's potential as an anti-cancer agent: from phytochemical origins to clinical prospects.

This comprehensive review delves into the multifaceted aspects of genipin, a bioactive compound derived from medicinal plants, focusing on its anti-cancer potential. The review begins by detailing the sources and phytochemical properties of genipin, underscoring its significance in traditional medicine and its transition into contemporary cancer research. It then explores the intricate relationship between genipin's chemical structure and its observed anti-cancer activity, highlighting the molecular underpinnings contributing to its therapeutic potential. This is complemented by a thorough analysis of preclinical studies, which investigates genipin's efficacy against various cancer cell lines and its mechanisms of action at the cellular level. A crucial component of the review is the examination of genipin's bioavailability and pharmacokinetics, providing insights into how the compound is absorbed, distributed, metabolized, and excreted in the body. Then, this review offers a general and updated overview of the anti-cancer studies of genipin and its derivatives based on its basic molecular mechanisms, induction of apoptosis, inhibition of cell proliferation, and disruption of cancer cell signaling pathways. We include information that complements the genipin study, such as toxicity data, and we differentiate this review by including commercial status, disposition, and regulation. Also, this review of genipin stands out for incorporating information on proposals for a technological approach through its load in nanotechnology to improve its bioavailability. The culmination of this information positions genipin as a promising candidate for developing novel anti-cancer drugs capable of supplementing or enhancing current cancer therapies.

Antimicrobial and anti-biofilm properties of oleuropein against Escherichia coli and fluconazole-resistant isolates of Candida albicans and Candida glabrata.

BACKGROUND: Side effects associated with antimicrobial drugs, as well as their high cost, have prompted a search for low-cost herbal medicinal substances with fewer side effects. These substances can be used as supplements to medicine or to strengthen their effects. The current study investigated the effect of oleuropein on the inhibition of fungal and bacterial biofilm in-vitro and at the molecular level. MATERIALS AND METHODS: In this experimental study, antimicrobial properties were evaluated using microbroth dilution method. The effect of oleuropein on the formation and eradication of biofilm was assessed on 96-well flat bottom microtiter plates and their effects were observed through scanning electron microscopy (SEM). Its effect on key genes (Hwp1, Als3, Epa1, Epa6, LuxS, Pfs) involved in biofilm formation was investigated using the quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) method. RESULTS: The minimum inhibitory concentration (MIC) and minimum fungicidal/bactericidal concentration (MFC/MBC) for oleuropein were found to be 65 mg/ml and 130 mg/ml, respectively. Oleuropein significantly inhibited biofilm formation at MIC/2 (32.5 mg/ml), MIC/4 (16.25 mg/ml), MIC/8 (8.125 mg/ml) and MIC/16 (4.062 mg/ml) (p < 0.0001). The anti-biofilm effect of oleuropein was confirmed by SEM. RT-qPCR indicated significant down regulation of expression genes involved in biofilm formation in Candida albicans (Hwp1, Als3) and Candida glabrata (Epa1, Epa6) as well as Escherichia coli (LuxS, Pfs) genes after culture with a MIC/2 of oleuropein (p < 0.0001). CONCLUSIONS: The results indicate that oleuropein has antifungal and antibacterial properties that enable it to inhibit or destroy the formation of fungal and bacterial biofilm.

A validated high-performance liquid chromatography method for detecting geniposide, ellagic acid, piperine, costunolide and dehydrocostus lactone in Liuwei Muxiang capsules.

In this study, a sensitive high-performance liquid chromatography detector was established and validated for the simultaneous determination of geniposide, ellagic acid, piperine, costunolide and dehydrocostuslactone in Liuwei Muxiang Capsules. The analysis was achieved on CHANIN 100-5-C18-H column (5µm, 250 mm×4.6 mm) with the temperature of 30oC. Gradient elution was applied using 0.1% phosphoric acid solution-methanol-acetonitrile (50:50) as mobile phase at the flow rate of 1.0 mL/min. The determination was performed at the wavelength of 225 nm (detecting geniposide), 254 nm (detecting ellagic acid), 343 nm (detecting piperine) and 225 nm (detecting costunolide and dehydrocostuslactone) along with the sample volume of 10µL. The linear ranges of geniposide, ellagic acid, piperine, costunolide and dehydrocostuslactone demonstrated good linear relationships within their respective determination ranges. The average recoveries were 100.04%, 99.86%, 99.79%, 100.17% and 100.41%, respectively. RSD% was 1.3%, 1.2%, 1.2%, 1.2%, 1.5%, respectively. The developed method was proved to be simple, accurate and sensitive, which can provide a quantitative analysis method for the content determination of geniposide, ellagic acid, piperine, costunolide and dehydrocostuslactone in Liuwei Muxiang capsules.

Implications of the Propagation Method for the Phytochemistry of Nepeta cataria L. throughout a Growing Season.

Catnip (Nepeta cataria L.) plants produce a wide array of specialized metabolites with multiple applications for human health. The productivity of such metabolites, including nepetalactones, and natural insect repellents is influenced by the conditions under which the plants are cultivated. In this study, we assessed how field-grown catnip plants, transplanted after being propagated via either single-node stem cuttings or seeds, varied regarding their phytochemical composition throughout a growing season in two distinct environmental conditions (Pittstown and Upper Deerfield) in the state of New Jersey, United States. Iridoid terpenes were quantified in plant tissues via ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-QqQ-MS), and phenolic compounds (phenolic acids and flavonoids) were analyzed via UHPLC with diode-array detection (UHPLC-DAD). The highest contents of total nepetalactones in Pittstown were found at 6 weeks after transplanting (WAT) for both seedlings and cuttings (1305.4 and 1223.3 mg/100 g, respectively), while in Upper Deerfield, the highest contents for both propagules were at 11 WAT (1247.7 and 997.1 mg/100 g, respectively) for seed-propagated and stem cuttings). The highest concentration of nepetalactones was associated with floral-bud to partial-flowering stages. Because plants in Pittstown accumulated considerably more biomass than plants grown in Upper Deerfield, the difference in nepetalactone production per plant was striking, with peak productivity reaching only 598.9 mg per plant in Upper Deerfield and 1833.1 mg per plant in Pittstown. Phenolic acids accumulated in higher contents towards the end of the season in both locations, after a period of low precipitation, and flavone glycosides had similar accumulation patterns to nepetalactones. In both locations, rooted stem cuttings reached their maximum nepetalactone productivity, on average, four weeks later than seed-propagated plants, suggesting that seedlings have, overall, better agronomic performance.

[Content of secondary metabolites and antioxidant activities of Lonicera japonica flowers at different developmental stages from Shandong province].

This study established an ultrasound-assisted extraction-high performance liquid chromatography method for simulta-neously determinining the content of 11 bioactive compounds including iridoids, phenolic acids, and flavonoids in Lonicera japonica flowers. The flowers at six stages from the rice bud stage(ML) to the golden flower stage(JH) of L. japonica varieties 'Sijuhua' and 'Beihua No.1' in two planting bases in Shandong province were collected. The established method was employed to determine the content of 11 target compounds, on the basis of which the dynamics of active components in L. japonica sampels during different development stages was investigated. The correlation analysis was carried out to reveal the correlations of the content of iridoids, phenolic acids, and flavonoids. Furthermore, the antioxidant activities of samples at different developmental stages were determined, and the relationship between antioxidant activity and chemical components was analyzed by the correlation analysis. The results showed that the total content of the 11 components in 'Sijihua' changed in a "W" pattern from the ML to JH, being the highest at the ML and the second at the slight white stage(EB). The total content of 11 compounds in 'Beihua No.1' was the highest at the ML and decreased gra-dually from the ML to JH. The samples of 'Sijihua' had higher content of iridoids and lower content of phenolic acids than those of 'Beihua No.1'. The content of flavonoids and phenolic acids showed a positive correlation(R~2=0.90, P<0.05) in 'Sijihua' but no obvious correlation in 'Beihua No.1'. The antioxidant activity and phenolic acid content showed positive correlations, with the determination coefficients(R~2) of 0.84(P<0.05) in 'Beihua No.1' and 0.73(P<0.05) in 'Sijihua'. The antioxidant activity of both varieties was the strongest at the ML and the second at the EB. This study revealed that the content dynamics of iridoids, phenolic acids, and flavonoids in 'Sijihua' and 'Beihua No.1' cultivated in Shandong province during different developmental stages. The results indicated that the antioxidant activity of L. japonica flowers was significantly correlated with the content of phenolic acids at different deve-lopmental stages, which provided a basis for determining the optimum harvest time of L. japonica flowers.

Genipin improves obesity through promoting bile secretion and changing bile acids composition in diet-induced obese rats.

OBJECTIVES: Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats. METHODS: The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined. KEY FINDINGS: Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously. CONCLUSIONS: These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.

Genipin crosslinked quaternary ammonium chitosan hydrogels for wound dressings.

Bacterial infection can lead to various complications, such as inflammations on surrounding tissues, which can prolong wound healing and thus represent a significant clinical and public healthcare problem. Herein, a report on the fabrication of a novel genipin/quaternized chitosan (CS) hydrogel for wound dressing is presented. The hydrogel was prepared by mixing quaternized CS and genipin under 35 °C bath. The hydrogels showed porous structure (250-500 µm) and mechanical properties (3000-6000 Pa). In addition, the hydrogels displayed self-healing ability and adhesion performance on different substrates. Genipin crosslinked quaternized CS hydrogels showed antibacterial activities againstE. coliandS. aureus. The CCK-8 and fluorescent images confirmed the cytocompatibility of hydrogels by seeding with NIH-3T3 cells. The present study showed that the prepared hydrogel has the potential to be used as wound dressing.

Genipin Activates Autophagy and Promotes Myoblast Differentiation by Activating AMPK Pathway.

Cultured meat technology is expected to solve problems such as resource shortages and environmental pollution, but the muscle fiber differentiation efficiency of cultured meat is low. Genipin is the active compound derived from Gardenia jasminoides Ellis, which has a variety of activities. Additionally, genipin serves as a noncytotoxic agent for cross-linking, which is suitable as a foundational scaffold for in vitro tissue regeneration. However, the impact of genipin on myoblast differentiation remains to be studied. The research revealed that genipin was found to improve the differentiation efficiency of myoblasts. Genipin improved mitochondrial membrane potential by activating the AMPK signaling pathway of myoblasts, promoting mitochondrial biogenesis, and mitochondrial network remodeling. Genipin activated autophagy in myoblasts and maintained cellular homeostasis. Autophagy inhibitors blocked the pro-differentiation effect of genipin. These results showed that genipin improved the differentiation efficiency of myoblasts, which provided a theoretical basis for the development of cultured meat technology.

Discovery, optimization and biological activity evaluation of genipin derivatives as potential KRAS G12D inhibitors.

A series of genipin derivatives were designed and synthesized as potential inhibitors targeted KRAS G12D mutation. The majority of these compounds demonstrated potential antiproliferative effects against KRAS G12D mutant tumor cells (CT26 and A427). Notably, seven compounds exhibited the anticancer effects with IC50 values ranging from 7.06 to 9.21 µM in CT26 (KRASG12D) and A427 (KRASG12D) cells and effectively suppressed the colony formation of CT26 cells. One representative compound SK12 was selected for further investigation into biological activity and action mechanisms. SK12 markedly induced apoptosis in CT26 cells in a concentration-dependent manner. Moreover, SK12 elevated the levels of reactive oxygen species (ROS) in tumor cells and exhibited a modulatory effect on the KRAS signaling pathway, thereby inhibiting the activation of downstream phosphorylated proteins. The binding affinity of SK12 to KRAS G12D protein was further confirmed by the surface plasmon resonance (SPR) assay with a binding KD of 157 µM. SK12 also exhibited notable anticancer efficacy in a nude mice tumor model. The relative tumor proliferation rate (T/C) of the experimental group (50 mg/kg) was 31.04 % (P < 0.05), while maintaining a commendable safety profile.

Renewable Electroconductive Hydrogels for Accelerated Diabetic Wound Healing and Motion Monitoring.

Diabetic foot ulcers (DFUs), a prevalent complication of diabetes mellitus, may result in an amputation. Natural and renewable hydrogels are desirable materials for DFU dressings due to their outstanding biosafety and degradability. However, most hydrogels are usually only used for wound repair and cannot be employed to monitor motion because of their inherent poor mechanical properties and electrical conductivity. Given that proper wound stretching is beneficial for wound healing, the development of natural hydrogel patches integrated with wound repair properties and motion monitoring was expected to achieve efficient and accurate wound healing. Here, we designed a dual-network (chitosan and sodium alginate) hydrogel embedded with lignin-Ag and quercetin-melanin nanoparticles to achieve efficient wound healing and motion monitoring. The double network formed by the covalent bond and electrostatic interaction confers the hydrogel with superior mechanical properties. Instead of the usual chemical reagents, genipin extracted from Gardenia was used as a cross-linking agent for the hydrogel and consequently improved its biosafety. Furthermore, the incorporation of lignin-Ag nanoparticles greatly enhanced the mechanical strength, antibacterial efficacy, and conductivity of the hydrogel. The electrical conductivity of hydrogels gives them the capability of motion monitoring. The motion sensing mechanism is that stretching of the hydrogel induced by motion changes the conductivity of the hydrogel, thus converting the motion into an electrical signal. Meanwhile, quercetin-melanin nanoparticles confer exceptional adhesion, antioxidant, and anti-inflammatory properties to the hydrogels. The system ultimately achieved excellent wound repair and motion monitoring performance and was expected to be used for stretch-assisted safe and accurate wound repair in the future.