RESUMEN

Sophora flavescens Ait. (SFA), an extensively utilized herb for the treatment of fevers, inflammatory disorders, ulcers and skin diseases related to bur, contains oxymatrine (OMT) as its principal active constituent. OMT exerts regulatory effects over inflammation, oxidative stress and apoptosis. Neutrophils, critical regulators of the inflammation response, have not been thoroughly elucidated regarding the protective properties and underlying mechanisms of OMT-mediated anti-inflammation. This study was aim to explore the protective effect of OMT on neutrophils under inflammatory conditions and delve into its potential mechanism. Leveraging the advantages of zebrafish, an animal model with a real-time dynamic observation system, we established an in vivo caudal fin wound model and a copper sulfate induced-inflammation model in zebrafish line Tg (mpx:GFP). The result revealed that OMT significantly attenuated neutrophil migration, upregulated the mRNA expression levels of JNK, casp3, mapk14a, mapkapk2a and map2k1 damaged by zebrafish caudal fin wound model, and downregulated mRNA expression levels of JNK, casp3, mapk14a, mapkapk2a and map2k1 in the copper sulfate injury model. In vitro experiments demonstrated that OMT modulated the chemotaxis response of primary neutrophils from mice, enhanced phagocytosis, reduced oxidative stress and alleviated inflammation level. We hypothesize that the OMT may exert its anti-inflammatory effects by regulating primary neutrophils through the MAPK signaling pathway.

RESUMEN

OBJECTIVE: To investigate the involvement of the high mobility group box protein B1 (HMGB1)-Toll-like receptor 2 (TLR2)/TLR4-nuclear factor κB (NF-κB) pathway in the intestinal mucosal injury induced by Cryptosporidium parvum infection, and to examine the effect of oxymatrine (OMT) on C. parvum infection in mice. METHODS: Forty SPF 4-week-old BALB/c mice were randomly divided into four groups, including the control group, infection group, glycyrrhizin (GA) group and OMT group. Each mouse was orally administered with 1 × 105 C. parvum oocysts one week in the infection, GA and OMT groups following dexamethasone-induced immunosuppression to model C. parvum intestinal infections in mice. Upon successful modeling, mice in the GA group were intraperitoneally injected with GA at a daily dose of 25.9 mL/kg for successive two weeks, and animals in the OMT group were orally administered OMT at a daily dose of 50 mg/kg for successive two weeks, while mice in the control group were given normal food and water. All mice were sacrificed two weeks post-treatment, and proximal jejunal tissues were sampled. The pathological changes of mouse intestinal mucosal specimens were observed using hematoxylin-eosin (HE) staining, and the mouse intestinal villous height, intestinal crypt depth and the ratio of intestinal villous height to intestinal crypt depth were measured. The occludin and zonula occludens protein 1 (ZO1) expression was determined in mouse intestinal epithelial cells using immunohistochemistry, and the relative expression of HMGB1, TLR2, TLR4, myeloid differentiation primary response gene 88 (MyD88) and NF-κB p65 mRNA was quantified in mouse jejunal tissues using quantitative real-time PCR (qPCR) assay. RESULTS: HE staining showed that the mouse intestinal villi were obviously atrophic, shortened, and detached, and the submucosal layer of the mouse intestine was edematous in the infection group as compared with the control group, while the mouse intestinal villi tended to be structurally intact and neatly arranged in the GA and OMT groups. There were significant differences among the four groups in terms of the mouse intestinal villous height (F = 6.207, P = 0.000 5), intestinal crypt depth (F = 6.903, P = 0.000 3) and the ratio of intestinal villous height to intestinal crypt depth (F = 37.190, P < 0.000 1). The mouse intestinal villous height was lower in the infection group than in the control group [(321.9 ± 41.1) µm vs. (399.5 ± 30.9) µm; t = 4.178, P < 0.01] and the GA group [(321.9 ± 41.1) µm vs. (383.7 ± 42.7) µm; t = 3.130, P < 0.01], and the mouse intestinal crypt depth was greater in the infection group [(185.0 ± 35.9) µm] than in the control group [(128.4 ± 23.6) µm] (t = 3.877, P < 0.01) and GA group [(143.3 ± 24.7) µm] (t = 2.710, P < 0.05). The mouse intestinal villous height was greater in the OMT group [(375.3 ± 22.9) µm] than in the infection group (t = 3.888, P < 0.01), and there was no significant difference in mouse intestinal villous height between the OMT group and the control group (t = 1.989, P > 0.05). The mouse intestinal crypt depth was significantly lower in the OMT group [(121.5 ± 27.3) µm] than in the infection group (t = 4.133, P < 0.01), and there was no significant difference in mouse intestinal crypt depth between the OMT group and the control group (t = 0.575, P > 0.05). The ratio of the mouse intestinal villous height to intestinal crypt depth was significantly lower in the infection group (1.8 ± 0.2) than in the control group (3.1 ± 0.3) (t = 10.540, P < 0.01) and the GA group (2.7 ± 0.3) (t = 7.370, P < 0.01), and the ratio of the mouse intestinal villous height to intestinal crypt depth was significantly higher in the OMT group (3.1 ± 0.2) than in the infection group (t = 15.020, P < 0.01); however, there was no significant difference in the ratio of the mouse intestinal villous height to intestinal crypt depth between the OMT group and the control group (t = 0.404, P > 0.05). Immunohistochemical staining showed significant differences among the four groups in terms of occludin (F = 28.031, P < 0.000 1) and ZO1 expression (F = 14.122, P < 0.000 1) in mouse intestinal epithelial cells. The proportion of positive occluding expression was significantly lower in mouse intestinal epithelial cells in the infection group than in the control group [(14.3 ± 4.5)% vs. (28.3 ± 0.5)%; t = 3.810, P < 0.01], and the proportions of positive occluding expression were significantly higher in mouse intestinal epithelial cells in the GA group [(30.3 ± 1.3)%] and OMT group [(25.8 ± 1.5)%] than in the infection group (t = 7.620 and 5.391, both P values < 0.01); however, there was no significant differences in the proportion of positive occluding expression in mouse intestinal epithelial cells between the GA or OMT groups and the control group (t = 1.791 and 2.033, both P values > 0.05). The proportion of positive ZO1 expression was significantly lower in mouse intestinal epithelial cells in the infection group than in the control group [(14.4 ± 1.8)% vs. (24.2 ± 2.8)%; t = 4.485, P < 0.01], and the proportions of positive ZO1 expression were significantly higher in mouse intestinal epithelial cells in the GA group [(24.1 ± 2.3)%] (t = 5.159, P < 0.01) and OMT group than in the infection group [(22.5 ± 1.9)%] (t = 4.441, P < 0.05); however, there were no significant differences in the proportion of positive ZO1 expression in mouse intestinal epithelial cells between the GA or OMT groups and the control group (t = 0.037 and 0.742, both P values > 0.05). qPCR assay showed significant differences among the four groups in terms of HMGB1 (F = 21.980, P < 0.000 1), TLR2 (F = 20.630, P < 0.000 1), TLR4 (F = 17.000, P = 0.000 6), MyD88 (F = 8.907, P = 0.000 5) and NF-κB p65 mRNA expression in mouse jejunal tissues (F = 8.889, P = 0.000 7). The relative expression of HMGB1 [(5.97 ± 1.07) vs. (1.05 ± 0.07); t = 6.482, P < 0.05] 、TLR2 [(5.92 ± 1.29) vs. (1.10 ± 0.14); t = 5.272, P < 0.05] 、TLR4 [(5.96 ± 1.50) vs. (1.02 ± 0.03); t = 4.644, P < 0.05] 、MyD88 [(3.00 ± 1.26) vs. (1.02 ± 0.05); t = 2.734, P < 0.05] and NF-κB p65 mRNA [(2.33 ± 0.72) vs. (1.04 ± 0.06); t = 2.665, P < 0.05] was all significantly higher in mouse jejunal tissues in the infection group than in the control group. A significant reduction was detected in the relative expression of HMGB1 (0.63 ± 0.01), TLR2 (0.42 ± 0.10), TLR4 (0.35 ± 0.07), MyD88 (0.70 ± 0.11) and NF-κB p65 mRNA (0.75 ± 0.01) in mouse jejunal tissues in the GA group relative to the control group (t = 8.629, 5.830, 11.500, 4.729 and 6.898, all P values < 0.05), and the relative expression of HMGB1, TLR2, TLR4, MyD88 and NF-κB p65 mRNA significantly reduced in mouse jejunal tissues in the GA group as compared to the infection group (t = 7.052, 6.035, 4.084, 3.165 and 3.274, all P values < 0.05). In addition, the relative expression of HMGB1 (1.14 ± 0.60), TLR2 (1.00 ± 0.24), TLR4 (1.14 ± 0.07), MyD88 (0.96 ± 0.25) and NF-κ B p65 mRNA (1.12 ± 0.17) was significantly lower in mouse jejunal tissues in the OMT group than in the infection group (t = 7.059, 5.320, 3.510, 3.466 and 3.273, all P values < 0.05); however, there were no significant differences between the OMT and control groups in terms of relative expression of HMGB1, TLR2, TLR4, MyD88 or NF-κB p65 mRNA in mouse jejunal tissues (t = 0.239, 0.518, 1.887, 0.427 and 0.641, all P values > 0.05). CONCLUSIONS: C. parvum infection causes intestinal inflammatory responses and destruction of intestinal mucosal barrier through up-regulating of the HMGB1-TLR2/TLR4-NF-κB pathway. OMT may suppress the intestinal inflammation and repair the intestinal mucosal barrier through inhibiting the activity of the HMGB1-TLR2/TLR4-NF-κB pathway.

Asunto(s)

Alcaloides , Criptosporidiosis , Cryptosporidium parvum , Proteína HMGB1 , Ratones Endogámicos BALB C , FN-kappa B , Quinolizinas , Receptor Toll-Like 2 , Receptor Toll-Like 4 , Animales , Criptosporidiosis/tratamiento farmacológico , Criptosporidiosis/parasitología , Quinolizinas/farmacología , Cryptosporidium parvum/efectos de los fármacos , Cryptosporidium parvum/fisiología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Ratones , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , FN-kappa B/metabolismo , FN-kappa B/genética , Alcaloides/farmacología , Alcaloides/administración & dosificación , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Transducción de Señal/efectos de los fármacos , Masculino , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/parasitología , Mucosa Intestinal/metabolismo , Matrinas

RESUMEN

Matrine (MT) and Oxymatrine (OMT) are two natural alkaloids derived from plants. These bioactive compounds are notable for their diverse pharmacological effects and have been extensively studied and recognized in the treatment of cardiovascular diseases in recent years. The cardioprotective effects of MT and OMT involve multiple aspects, primarily including antioxidative stress, anti-inflammatory actions, anti-atherosclerosis, restoration of vascular function, and inhibition of cardiac remodeling and failure. Clinical pharmacology research has identified numerous novel molecular mechanisms of OMT and MT, such as JAK/STAT, Nrf2/HO-1, PI3 K/AKT, TGF-ß1/Smad, and Notch pathways, providing new evidence supporting their promising therapeutic potential against cardiovascular diseases. Thus, this review aims to investigate the potential applications of MT and OMT in treating cardiovascular diseases, encompassing their mechanisms, efficacy, and safety, confirming their promise as lead compounds in anti-cardiovascular disease drug development.

RESUMEN

Chronic pain often coincides with changes in gut microbiota composition. Yet, the role of gut microbiota in bone cancer pain (BCP) is still not fully understood. This study investigated the role of gut microbiota in BCP and the effect of oxymatrine (OMT) on gut microbiota in BCP. A BCP mice model was developed to assess gut microbiota composition, serum and brain tissue butyric acid levels, and blood-brain barrier (BBB) permeability. Microbiota transplantation was used to restore gut microbiota, and the effect of Clostridium butyricum or sodium butyrate (NaB) supplementation on pain-related behaviors and BBB integrity was evaluated. The potential benefits of OMT on gut microbiota composition, peroxisome proliferator-activated receptor gamma (PPARγ)/cyclooxygenase-2 (COX-2) signaling, BBB integrity, and pain-related behaviors were also explored. BCP significantly altered gut microbiota composition and reduced serum and brain tissue butyric acid levels. Additionally, BBB permeability increased considerably in the BCP group compared with sham and control mice. Microbiota transplantation, as well as C butyricum or NaB supplementation, ameliorated pain-related behaviors and BBB integrity; the supplementation of C butyricum or NaB boosted brain-tight-junction protein expression, potentially through modulating PPARγ/COX-2 signaling. OMT influenced gut microbiota composition and regulated PPARγ/COX-2 signaling in the BCP model, improving pain-related behaviors and BBB integrity. BCP affects gut microbiota composition and butyric acid levels. Modulating gut microbiota and butyric acid levels through transplantation or supplementation may alleviate BCP. OMT shows potential as a treatment by altering gut microbiota composition and regulating PPARγ/COX-2 signaling. These findings provide new insights into BCP pathophysiology and possible treatments. PERSPECTIVE: This study explores the impact of gut microbiota on BCP. Microbiota transplantation alleviates BCP and enhances BBB integrity. Also, C butyricum or NaB improves BBB via PPARγ/COX-2. OMT, a BCP treatment, modifies microbiota by regulating PPARγ/COX-2, in turn improving pain and BBB integrity. These findings suggest a therapeutic approach, emphasizing clinical relevance in targeting gut microbiota and restoring butyric acid levels.

Asunto(s)

Alcaloides , Microbioma Gastrointestinal , PPAR gamma , Quinolizinas , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Ratones , Alcaloides/farmacología , Alcaloides/administración & dosificación , PPAR gamma/metabolismo , Quinolizinas/farmacología , Quinolizinas/administración & dosificación , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/metabolismo , Dolor en Cáncer/terapia , Ciclooxigenasa 2/metabolismo , Ácido Butírico/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Femenino , Clostridium butyricum/efectos de los fármacos , Clostridium butyricum/fisiología , Manejo del Dolor/métodos , Matrinas

RESUMEN

Cryptosporidiosis is a worldwide zoonotic disease. Oxymatrine, an alkaloid extracted and isolated from the plant bitter ginseng, has been reported to have therapeutic effects on cryptosporidiosis. However, the underlying mechanism of its action remains unclear. In this study, we utilized network pharmacology and experimental validation to investigate the mechanism of oxymatrine in the treatment of cryptosporidiosis. First, the potential targets of drugs and diseases were predicted by TCMSP, Gene Cards, and other databases. Following the intersection of drug-disease targets, the DAVID database was used to implement the enrichment analysis of GO functions and KEGG pathways, and then the network diagram of "intersected target-KEGG" relationship was constructed. Autodock 4.2.6 software was used to carry out the molecular docking of core targets to drug components. Based on the establishment of a mouse model of cryptosporidiosis, the validity of the targets in the TNF/NF-κB signaling pathway was confirmed using Western blot analysis and Quantitative Rea-ltime-PCR. A total of 41 intersectional targets of oxymatrine and Cryptosporidium were generated from the results, and five core targets were screened out by network analysis, including RELA, AKT1, ESR1, TNF, and CASP3. The enrichment analysis showed that oxymatrine could regulate multiple gene targets, mediate TNF, Apoptpsis, IL-17, NF-κB and other signaling pathways. Molecular docking experiments revealed that oxymatrine was tightly bound to core targets with stable conformation. Furthermore, we found through animal experiments that oxymatrine could regulate the mRNA and protein expression of IL-6, NF-κB, and TNF-α in the intestinal tissues of post-infected mice through the TNF/NF-κB signaling pathway. Therefore, it can be concluded that oxymatrine can regulate the inflammatory factors TNF-α, NF-κB, and IL-6 through the TNF/NF-κB signaling pathway for the treatment of cryptosporidiosis. This prediction has also been validated by network pharmacology and animal experiments.

Asunto(s)

Alcaloides , Criptosporidiosis , Simulación del Acoplamiento Molecular , FN-kappa B , Farmacología en Red , Quinolizinas , Transducción de Señal , Quinolizinas/farmacología , Quinolizinas/química , Quinolizinas/uso terapéutico , Criptosporidiosis/tratamiento farmacológico , Criptosporidiosis/parasitología , Animales , Transducción de Señal/efectos de los fármacos , Alcaloides/farmacología , Alcaloides/uso terapéutico , Ratones , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Modelos Animales de Enfermedad , Humanos , Matrinas

RESUMEN

Ulcerative colitis (UC) is difficult to cure and easy to relapse, leading to poor quality of life for patients. Oxymatrine (OMT) is one of the main alkaloids of Sophora flavescens Aiton, which has many effects, such as anti-inflammation, anti-oxidative stress, and immunosuppression. This study aimed to investigate whether OMT could attenuate ulcerative colitis by inhibiting the NOD-like receptor family pyrin domain containing three (NLRP3) inflammasome-mediated pyroptosis. In this study, the UC rat models were established by 2,4,6-Trinitrobenzenesulfonic acid (TNBS) in vivo, while RAW264.7 cells and peritoneal macrophages were stimulated with Lipopolysaccharides/Adenosine Triphosphate (LPS/ATP) in vitro to simulate pyroptosis models, and Western blotting (WB) and other detection techniques were applied to analyze proteins involved in the NLRP3 inflammasome pathway. Our results showed that OMT alleviated colitis ulcers and pathological damage in the TNBS-induced UC rats and exhibited an inhibitory effect on pyroptosis at the early stage of UC. In the model group, the pyroptosis reached the peak at 24 h after modeling with the contents of active-cysteine-aspartic proteases-1 (caspase-1), Gasdermin D (GSDMD)-N, and cleaved-interleukin-1 beta (IL-1ß) to the highest expression level. Meanwhile, we found that OMT (80 mg kg-1) remarkably decreased the expression levels of NLRP3, active-caspase-1, and cleaved-IL-1ß at 24 h in the lesion tissue from UC rats. Further experiments on cells demonstrated that OMT at concentrations of 100 and 250 µM significantly inhibited cell death caused by NLRP3 inflammasome activation (p < 0.05), downregulated caspase-1, GSDMD, and decreased the levels of active-caspase-1, GSDMD-N, cleaved-IL-1ß in RAW326.7 cells, and peritoneal macrophages. In summary, these results indicated that OMT could attenuate ulcerative colitis through inhibiting pyroptosis mediated by the NLRP3 inflammasome. The inhibition of the NLRP3 inflammasome may be a potential strategy for UC.

Asunto(s)

Alcaloides , Colitis Ulcerosa , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Quinolizinas , Animales , Quinolizinas/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Alcaloides/farmacología , Piroptosis/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratones , Ratas , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Células RAW 264.7 , Masculino , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Ácido Trinitrobencenosulfónico , Lipopolisacáridos , Matrinas

RESUMEN

Sepsis is a life-threatening organ dysfunction that endangers patient lives and is caused by an imbalance in the host defense against infection. Sepsis continues to be a significant cause of morbidity and mortality in critically sick patients. Oxymatrine (OMT), a quinolizidine alkaloid derived from the traditional Chinese herb Sophora flavescens Aiton, has been shown to have anti-inflammatory effects on a number of inflammatory illnesses according to research. In this study, we aimed to evaluate the therapeutic effects of OMT on sepsis and explore the underlying mechanisms. We differentiated THP-1 cells into THP-1 macrophages and studied the anti-inflammatory mechanism of OMT in a lipopolysaccharide (LPS)-induced THP-1 macrophage sepsis model. Activation of the receptor for advanced glycation end products (RAGE), as well as NF-κB, was assessed by Western blot analysis and immunofluorescence staining. ELISA was used to measure the levels of inflammatory factors. We found that OMT significantly inhibited HMGB1-mediated RAGE/NF-κB activation and downstream inflammatory cytokine production in response to LPS stimulation. Finally, an in vivo experiment was performed on septic mice to further study the effect of OMT on injured organs. The animal experiments showed that OMT significantly inhibited HMGB1-mediated RAGE/NF-κB activation, protected against the inflammatory response and organ injury induced by CLP, and prolonged the survival rate of septic mice. Herein, we provide evidence that OMT exerts a significant therapeutic effect on sepsis by inhibiting the HMGB1/RAGE/NF-κB signaling pathway.

Asunto(s)

Alcaloides , Proteína HMGB1 , Inflamación , Lipopolisacáridos , FN-kappa B , Quinolizinas , Receptor para Productos Finales de Glicación Avanzada , Sepsis , Transducción de Señal , Alcaloides/farmacología , Alcaloides/uso terapéutico , Quinolizinas/farmacología , Quinolizinas/uso terapéutico , Animales , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/metabolismo , FN-kappa B/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB1/antagonistas & inhibidores , Humanos , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Células THP-1 , Ratones Endogámicos C57BL , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Matrinas

RESUMEN

In our research, we explored a natural substance called Oxymatrine, found in a traditional Chinese medicinal plant, to fight against a common bird flu virus known as H9N2. This virus not only affects birds but can also pose a threat to human health. We focused on how this natural compound can help in stopping the virus from spreading in cells that line the lungs of birds and potentially humans. Our findings show that Oxymatrine can both directly block the virus and boost the body's immune response against it. This dual-action mechanism is particularly interesting because it indicates that Oxymatrine might be a useful tool in developing new ways to prevent and treat this type of bird flu. Understanding how Oxymatrine works against the H9N2 virus could lead to safer and more natural ways to combat viral infections in animals and humans, contributing to the health and well-being of society. The H9N2 Avian Influenza Virus (AIV) is a persistent health threat because of its rapid mutation rate and the limited efficacy of vaccines, underscoring the urgent need for innovative therapies. This study investigated the H9N2 AIV antiviral properties of Oxymatrine (OMT), a compound derived from traditional Chinese medicine, particularly focusing on its interaction with pulmonary microvascular endothelial cells (PMVECs). Employing an array of in vitro assays, including 50% tissue culture infectious dose, Cell Counting Kit-8, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot, we systematically elucidated the multifaceted effects of OMT. OMT dose-dependently inhibited critical antiviral proteins (PKR and Mx1) and modulated the expression of type I interferons and key cytokines (IFN-α, IFN-ß, IL-6, and TNF-α), thereby affecting TLR3 signaling and its downstream elements (NF-κB and IRF-3). OMT's antiviral efficacy extended beyond TLR3-mediated responses, suggesting its potential as a versatile antiviral agent. This study not only contributes to the growing body of research on the use of natural compounds as antiviral agents but also underscores the importance of further investigating the broader application of OMT for combating viral infections.

Asunto(s)

Antivirales , Subtipo H9N2 del Virus de la Influenza A , Gripe Aviar , Matrinas , Transducción de Señal , Receptor Toll-Like 3 , Animales , Perros , Humanos , Antivirales/farmacología , Subtipo H9N2 del Virus de la Influenza A/efectos de los fármacos , Gripe Aviar/tratamiento farmacológico , Gripe Aviar/inmunología , Células de Riñón Canino Madin Darby , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 3/metabolismo

RESUMEN

INTRODUCTION: The management of erythrodermic psoriasis (EP), a rare but severe type of psoriasis, is challenging, especially in patients with concomitant chronic hepatitis B (CHB). We previously demonstrated that oxymatrine treatment alleviated severe plaque psoriasis, but its therapeutic potential in treating EP remains unexplored. This study was to assess the efficacy and safety of oxymatrine for the treatment of EP, with attention to concomitant CHB. METHODS: In this investigator-initiated clinical trial, four consecutive patients with EP, including two (A and B) with concomitant CHB, were treated with intravenous administration of oxymatrine as monotherapy for 8 weeks, and scheduled to be followed up for a minimum of 24 weeks. The primary outcome was at least 75% improvement in the psoriasis area and severity index (PASI 75) at week 32. Secondary outcomes included the body surface area (BSA) score, dermatology life quality index (DLQI)], and safety. RESULTS: Patients A, B, and C achieved PASI 75 at treatment completion and week 32, demonstrating improvements of 77.4%, 97.2%, and 100% in PASI, respectively. Their BSA and DLQI were also improved significantly at week 32 and throughout follow-up of 37, 57, and 105 weeks, respectively. The viral loads in patients A and B with CHB decreased modestly. Patient D discontinued after follow-up for 19 weeks, and the primary outcome could not be analyzed. No adverse events were reported during treatment and follow-up. CONCLUSION: Oxymatrine appears to be efficacious and safe for the treatment of patients with EP, including those with concomitant CHB. TRIAL REGISTRATION: This study was registered at the Chinese Clinical Trial Registry ( www.chictr.org.cn ; Registration number ChiCTR-TRC-14004301).

RESUMEN

Daruqi is a Traditional Mongolian medicine with anti-inflammatory, anti-bacterial, and immune-regulatory effects. However, the mechanisms of its activity were unclear. In the present study, we confirmed the anti-inflammation effect of Daruqi on inflammation induced by LPS using animal models. Then, THP-1 cells treated with LPS was used as a positive control to explore the effective component of Daruqi on inflammation. We identified that Oxymatrine was the essential effector of Daruqi. Furthermore, the mechanism of Oxymatrine on inflammation was verified through proteomics analyses and validation assays. Our results demonstrated that Oxymatrine significantly reduced the levels of inflammatory cytokine, including IL-8, IL-1α, and IL-1ß, in LPS induced THP-1 cells. Based on tandem mass tag -labeled quantitative proteomics, 428 differentially expressed proteins were screened, involved in TNF signaling pathway, Ferroptosis, IL-17 signaling pathway, etc. Among these differential expressed proteins (DEPs), 23 proteins were verified with parallel reaction monitoring analysis. The results showed that LPS treatment potentiated the protein level of PLEK, ACSL5 and CYBB, which could be reversed by Oxymatrine. By contrast, the protein expression of SPRYD4 and EMR2 was suppressed after LPS treatment, which could be rescued by Oxymatrine. In summary, Oxymatrine has excellent protective effects in LPS induced THP-1 cells. The five proteins, including PLEK, ACSL5, CYBB, SPRYD4 and EMR2, might serve as the targets of Oxymatrine, and as candidates regulating inflammation in future therapies.

Asunto(s)

Alcaloides , Antiinflamatorios , Inflamación , Lipopolisacáridos , Medicina Tradicional Mongoliana , Quinolizinas , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Animales , Lipopolisacáridos/farmacología , Alcaloides/farmacología , Antiinflamatorios/farmacología , Quinolizinas/farmacología , Células THP-1 , Proteómica/métodos , Citocinas/metabolismo , Ratones , Masculino , Transducción de Señal/efectos de los fármacos , Matrinas

RESUMEN

Sophora flavescens Aiton, a traditional Chinese medicine that was supposed to predominantly play an anti-inflammatory role, has been used to treat multiple diseases, including cancer, for over two thousand years. Recently, it has attracted increasing attention due to the anti-tumor properties of Oxymatrine, one of the most active alkaloids extracted from S. flavescens. This study aims to explore it's anti-tumor effects in non-small cell lung cancer (NSCLC) and the underlying mechanisms. We first investigated the effects of oxymatrine on cell apoptosis in lung cancer cell lines A549 and PC9 as well as explored related genes in regulating the apoptosis by transcriptome analysis. Subsequently, to further study the role of TRIM46, we constructed two types of TRIM46 over-expression cells (A549TRIM46+ and PC9TRIM46+ cells) and then investigated the effect of TRIM46 on oxymatrine-induced apoptosis. Moreover, we explored the effect of TRIM46 on downstream signaling pathways. Transcriptome analysis suggested that shared differentially expressed genes (DEGs) in A549 and PC9 cells treated with oxymatrine were CACNA1I, PADI2, and TRIM46. According to TCGA database analysis, the abundance of TRIM46 expression was higher than CACNA1I, and PADI2 in lung cancer tissues, then was selected as the final DEG for subsequent studies. We observed that oxymatrine resulted in down-expression of TRIM46 as well as induced the apoptosis of the cancer cells in a dose- and time-dependent manner. Meanwhile, we found that apoptosis induced by oxymatrine was inhibited by over-expressing TRIM46. Furthermore, our study indicated that the NF-κB signaling pathway was involved in apoptosis suppressed by TRIM46. We conclude that TRIM46 is the direct target of oxymatrine to induce anti-tumor apoptosis and may activate the downstream NF-κB signaling pathway.

Asunto(s)

Alcaloides , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Regulación hacia Abajo , Neoplasias Pulmonares , Quinolizinas , Quinolizinas/farmacología , Humanos , Alcaloides/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Línea Celular Tumoral , Células A549 , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Transducción de Señal/efectos de los fármacos , Matrinas

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Sophora flavescens is often used in traditional Chinese medicine for skin issues, diarrhea, and vaginal itching (Plant names have been checked with http://www.the/plant/list.org on Feb 22nd, 2024). Oxymatrine (OY), a major bioactive compound from Sophora flavescens, is commonly used in China to treat ulcerative colitis, but its mechanisms are still unclear. AIM OF THE STUDY: Recent studies have found that the crosstalk between ferroptosis and inflammation is an important mechanism in the pathogenesis of UC. The aim of this study was to investigate the potential underlying mechanisms of OY treatment on DSS-induced ulcerative colitis, specifically focusing on the processes of ferroptosis and inflammation. MATERIALS AND METHODS: Bioinformatics methods were used to identify key targets of OY for ferroptosis and inflammation in ulcerative colitis, based on GEO data and FerrDb database. Then, 4% DSS solution was used to induce UC model. OY's impact on morphological changes was assessed using colon views, Hematoxylin and eosin (HE) staining, and transmission electron microscopy (TEM). Ferroptosis phenotype index and inflammations factors were detected by ELISA or chem-bio detection kits. The screen out hub related genes about ferroptosis and inflammation were verified by RT-PCR, immunohistochemistry (IHC), and western blotting (WB) respectively. RESULTS: Bioinformatics results show that there are 16 key target genes involved in ferroptosis and inflammation interaction of OY treatment for UC, such as IL6, NOS2, IDO1, SOCS1, and DUOX. The results of animal experiments show that OY could depress inflammatory factors (IL-1ß, IL-6, TNF-α, HMGB1, and NLRP3) and reduce iron deposition (Fe2+, GSH). Additionally, OY suppressed the hub genes or proteins expression involved in ferroptosis and inflammation, including IL-1ß, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2. CONCLUSION: This present study combines bioinformatics, molecular biology, and animal experimental research evidently demonstrated that OY attenuates UC by improving ferroptosis and inflammation, mainly target to the expression of IL-1ß, IL-6, NOS2, HIF1A, IDO1, TIMP1, and DUOX2.

Asunto(s)

Alcaloides , Colitis Ulcerosa , Sulfato de Dextran , Ferroptosis , Quinolizinas , Sophora , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Quinolizinas/farmacología , Quinolizinas/uso terapéutico , Sophora/química , Ferroptosis/efectos de los fármacos , Animales , Alcaloides/farmacología , Alcaloides/uso terapéutico , Ratones , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ratones Endogámicos C57BL , Masculino , Modelos Animales de Enfermedad , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Sophora flavescens , Matrinas

RESUMEN

Background and aim: Solid organ transplantation remains a life-saving therapeutic option for patients with end-stage organ dysfunction. Acute cellular rejection (ACR), dominated by dendritic cells (DCs) and CD4+ T cells, is a major cause of post-transplant mortality. Inhibiting DC maturation and directing the differentiation of CD4+ T cells toward immunosuppression are keys to inhibiting ACR. We propose that oxymatrine (OMT), a quinolizidine alkaloid, either alone or in combination with rapamycin (RAPA), attenuates ACR by inhibiting the mTOR-HIF-1α pathway. Methods: Graft damage was assessed using haematoxylin and eosin staining. Intragraft CD11c+ and CD4+ cell infiltrations were detected using immunohistochemical staining. The proportions of mature DCs, T helper (Th) 1, Th17, and Treg cells in the spleen; donor-specific antibody (DSA) secretion in the serum; mTOR-HIF-1α expression in the grafts; and CD4+ cells and bone marrow-derived DCs (BMDCs) were evaluated using flow cytometry. Results: OMT, either alone or in combination with RAPA, significantly alleviated pathological damage; decreased CD4+ and CD11c+ cell infiltration in cardiac allografts; reduced the proportion of mature DCs, Th1 and Th17 cells; increased the proportion of Tregs in recipient spleens; downregulated DSA production; and inhibited mTOR and HIF-1α expression in the grafts. OMT suppresses mTOR and HIF-1α expression in BMDCs and CD4+ T cells in vitro. Conclusions: Our study suggests that OMT-based therapy can significantly attenuate acute cardiac allograft rejection by inhibiting DC maturation and CD4+ T cell responses. This process may be related to the inhibition of the mTOR-HIF-1α signaling pathway by OMT.

RESUMEN

Following the publication of the above article, a concerned reader drew to the Editor's attention that certain of the cell migration and invasion assay data featured in Figs. 2B, 5C, 6B and C were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been submitted elsewhere prior to the submission of this paper to Oncology Reports, or were under consideration for publication at around the same time (one of which has been retracted). In view of the fact that certain of these data had already apparently been submitted for publication prior to the submission of this article to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 39: 967­976, 2018; DOI: 10.3892/or.2018.6204].

RESUMEN

BACKGROUND: Gastric carcinoma (GC) remains a significant therapeutic challenge, garnering widespread attention. Oxymatrine (OMT), an active component of the traditional Chinese medicine compound Kushen injection (CKI), has shown promising results in combination with chemotherapy for the treatment of GC. However, the molecular mechanisms underlying OMT's therapeutic effects in GC have yet to be elucidated. METHODS: The transcriptomic expression data of HGC-27 post-OMT intervention were obtained through microarray sequencing, while the miRNA and mRNA sequencing data for GC patients were sourced from the TCGA database. The mechanism of OMT intervention in GC is analyzed in multiple aspects, including Protein-Protein Interactions (PPI), Competitive Endogenous RNA (ceRNA) networks, correlation and co-expression analyses, immune infiltration, and clinical implications. RESULTS: By analyzing key modules, five critical mRNAs were identified, and their interacting miRNAs were predicted to construct a ceRNA network. Among these, TGFBR2 and hsa-miR-107 have correlations or co-expression relationships with other genes in the network. They are differentially expressed in most other cancers, associated with prognosis, and have diagnostic value. TGFBR2 also exhibits immune infiltration phenomena, and its high expression is linked to poor patient prognosis. Low expression of hsa-miR-107 is associated with poor patient prognosis. OMT may act on the TGFß/Smad signaling pathway or negatively regulate the WNT signaling pathway through the hsa-miR-107/BTRC axis, thereby inhibiting the onset and progression of GC. CONCLUSION: The mechanisms of OMT intervention in GC are diverse, TGFBR2 and hsa-miR-107 may serve as prognostic molecular biomarkers or potential therapeutic targets.

Asunto(s)

MicroARNs , Neoplasias Gástricas , Humanos , Biología Computacional/métodos , MicroARNs/genética , MicroARNs/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , ARN Mensajero/genética , Neoplasias Gástricas/genética

RESUMEN

BACKGROUND: Osteoarthritis (OA) is a common degenerative joint disease characterized by persistent articular cartilage degeneration and synovitis. Oxymatrine (OMT) is a quinzolazine alkaloid extracted from the traditional Chinese medicine, matrine, and possesses anti-inflammatory properties that may help regulate the pathogenesis of OA; however, its mechanism has not been elucidated. This study aimed to investigate the effects of OMT on interleukin-1ß (IL-1ß)-induced damage and the potential mechanisms of action. METHODS: Chondrocytes were isolated from Sprague-Dawley rats. Toluidine blue and Collagen II immunofluorescence staining were used to determine the purity of the chondrocytes. Thereafter, the chondrocytes were subjected to IL-1ß stimulation, both in the presence and absence of OMT, or the autophagy inhibitor 3-methyladenine (3-MA). Cell viability was assessed using the MTT assay and SYTOX Green staining. Additionally, flow cytometry was used to determine cell apoptosis rate and reactive oxygen species (ROS) levels. The protein levels of AKT, mTOR, LC3, P62, matrix metalloproteinase-13, and collagen II were quantitatively analyzed using western blotting. Immunofluorescence was used to assess LC3 expression. RESULTS: OMT alleviated IL-1ß-induced damage in chondrocytes, by increasing the survival rate, reducing the apoptosis rates of chondrocytes, and preventing the degradation of the cartilage matrix. In addition, OMT decreased the ROS levels and inhibited the AKT/mTOR signaling pathway while promoting autophagy in IL-1ß treated chondrocytes. However, the effectiveness of OMT in improving chondrocyte viability under IL-1ß treatment was limited when autophagy was inhibited by 3-MA. CONCLUSIONS: OMT decreases oxidative stress and inhibits the AKT/mTOR signaling pathway to enhance autophagy, thus inhibiting IL-1ß-induced damage. Therefore, OMT may be a novel and effective therapeutic agent for the clinical treatment of OA.

Asunto(s)

Alcaloides , Cartílago Articular , Matrinas , Osteoartritis , Ratas , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Condrocitos/metabolismo , Interleucina-1beta/toxicidad , Interleucina-1beta/metabolismo , Osteoartritis/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ratas Sprague-Dawley , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Cartílago Articular/metabolismo , Alcaloides/farmacología , Alcaloides/uso terapéutico , Alcaloides/metabolismo , Autofagia , Colágeno/metabolismo , Apoptosis

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) represents a complex complication of type 2 diabetes mellitus (T2DM). Oxymatrine (OMT) is an alkaloid extracted from Sophora flavescens with broad pharmacological effects. However, there is currently a lack of research on OMT in the field of NAFLD. The present study aimed to explore the effects and underlying mechanisms of oxymatrine in treating T2DM with NAFLD. The T2DM mice model was induced by high-fat diet (HFD) combined with streptozotocin (STZ) injection in male C57BL/6 J mice. Animals were randomly divided into four groups (n = 8): Control group, DC group, OMT-L group (45 mg/kg i.g.), and OMT-H group (90 mg/kg, i.g.). The drug was administered once a day for 8 weeks. In addition, HepG2 hepatocytes were incubated with palmitic acid (PA) to establish a fatty liver cell model. Treated with OMT, the body weight and fasting blood glucose (FBG) of DC mice were reduced and the liver organ coefficient was significantly optimized. Meanwhile, OMT markedly enhanced the activities of key antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and also reduced malondialdehyde (MDA) levels. These biochemical alterations were accompanied by noticeable improvements in liver histopathology. Furthermore, OMT down-regulated the expression of NOD-like receptor protein 3 (NLRP3), interleukin-1ß (IL-1ß), transforming growth factor-ß1 (TGF-ß1) and collagen I significantly, highlighting its potential in modulating inflammatory and fibrotic pathways. In conclusion, OMT improved liver impairment effectively in diabetic mice by suppressing oxidative stress, inflammation and fibrosis. These results suggest that OMT may represent a novel therapy for NAFLD with diabetes.

Asunto(s)

Alcaloides , Dieta Alta en Grasa , Matrinas , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Estrés Oxidativo , Quinolizinas , Estreptozocina , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Quinolizinas/farmacología , Alcaloides/farmacología , Dieta Alta en Grasa/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Masculino , Humanos , Ratones , Células Hep G2 , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Glucemia/efectos de los fármacos , Glucemia/metabolismo

RESUMEN

The aim of the study was to develop an oral targeting drug delivery system (OTDDS) of oxymatrine (OMT) to effectively treat ulcerative colitis (UC). The OTDDS of OMT (OMT/SA-NPs) was constructed with OMT, pectin, Ca2+, chitosan (CS) and sialic acid (SA). The obtained particles were characterized in terms of particle size, zeta potential, morphology, drug loading, encapsulation efficiency, drug release and stability. The average size of OMT/SA-NPs was 255.0 nm with a zeta potential of -12.4 mV. The loading content and encapsulation efficiency of OMT/SA-NPs were 14.65% and 84.83%, respectively. The particle size of OMT/SA-NPs changed slightly in the gastrointestinal tract. The nanoparticles can delivery most of the drug to the colon region. In vitro cell experiments showed that the SA-NPs had excellent biocompatibility and anti-inflammation, and the uptake of SA-NPs by RAW 264.7 cells was time and concentration-dependent. The conjugated SA can help the internalization of NPs into target cells. In vivo experiments showed that OMT/SA-NPs had a superior anti-inflammation effect and the effect of reducing UC, which was attributed to the delivery most of OMT to the colonic lumen, the specific targeting and retention in colitis site and the combined anti-inflammation of OMT and NPs.

Asunto(s)

Colitis Ulcerosa , Matrinas , Nanopartículas , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Ácido N-Acetilneuramínico , Pectinas , Sistemas de Liberación de Medicamentos , Antiinflamatorios/farmacología

RESUMEN

Fungal keratitis (FK) is a refractory keratitis caused by excessive inflammation and fungal damage. Excessive inflammation can lead to tissue damage and corneal opacity, resulting in a poor prognosis for FK. Oxymatrine (OMT) is a natural alkaloid, which has rich pharmacological effects, such as antioxidant and anti-inflammation. However, its antifungal activity and the mechanism of action in FK have not been elucidated. This study confirmed that OMT suppressed Aspergillus fumigatus growth, biofilm formation, the integrity of fungal cell and conidial adherence. OMT not only effectively reduced corneal fungal load but also inflammation responses. OMT lessened the recruitment of neutrophils and macrophages in FK. In addition, OMT up-regulated the expression of Nrf2 and down-regulated the expression of IL-18, IL-1ß, caspase-1, NLRP3 and GSDMD. Pre-treatment with Nrf2 inhibitor up-regulated the expression of IL-1ß, IL-18, caspase-1, NLRP3 and GSDMD supressed by OMT. In conclusion, OMT has efficient anti-inflammatory and antifungal effects by suppressing fungal activity and restricting pyroptosis via Nrf2 pathway. OMT is considered as a potential option for the treatment of FK.

Asunto(s)

Aspergilosis , Úlcera de la Córnea , Infecciones Fúngicas del Ojo , Queratitis , Matrinas , Animales , Ratones , Aspergillus fumigatus/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR , Interleucina-18 , Aspergilosis/tratamiento farmacológico , Aspergilosis/metabolismo , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Piroptosis , Factor 2 Relacionado con NF-E2 , Queratitis/microbiología , Inflamación , Infecciones Fúngicas del Ojo/tratamiento farmacológico , Infecciones Fúngicas del Ojo/metabolismo , Caspasa 1/metabolismo , Ratones Endogámicos C57BL

RESUMEN

This study aimed to provide irrefutable evidence of the preventive effects of oxymatine (OMT) on a model of endotoxin induced glaucoma in Wistar rats which can be attributed to its anti-inflammatory, antioxidant, and TNF-α antagonistic properties. To assess the impact of OMT on uveitic glaucoma, the normal group received 100 µL distilled water topically for 15 days, while the glaucoma control group was induced with uveitic glaucoma by applying 10 µL of 10 µg/mL lipopolysaccharide (LPS) topically for 3 consecutive days. The treatment groups were then given OMT solution at a volume of 50 µL with varying doses of 0.25%, 0.5%, and 1% once a day via topical administration for 15 days. In addition, as a standard, the animals were also given 100 µL of 1% dorzolamide topically for 15 days. All ophthalmic dosing was carried out by pulling the lower eye-lid of the experimental animals and administration of the respective solutions. The study uses cutting-edge real-time imaging of the retinal vasculature in anesthetized animals, postsacrifice lenticular picturization and biochemical evidence to support the changes in the retinal layers. LPS induced animals demonstrated increased IOP, disrupted antioxidant systems, massive lipid damage, enhanced TNF-α activity and changes in intracellular ATPase and ionic activities. The damaged retinal vasculature and lenticular opacification further supported the biochemical evidence. However, using OMT at a 1% dosage effectively enhanced the antioxidant levels, regulated intracellular ion concentration and ATPases, decreased TNF-α activity, and counteracted mechanobiological changes in the visual front and retina. Moreover, OMT can successfully normalize intraocular pressure, making it a highly beneficial treatment option for glaucoma.

Asunto(s)

Glaucoma , Lipopolisacáridos , Matrinas , Ratas , Animales , Lipopolisacáridos/toxicidad , Endotoxinas , Factor de Necrosis Tumoral alfa/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Ratas Wistar , Glaucoma/inducido químicamente , Glaucoma/tratamiento farmacológico , Oxidación-Reducción