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Thrombosis is a key process that determines acute coronary syndrome and ischemic stroke and is the leading cause of morbidity and mortality in the world, together with cancer. Platelet adhesion and subsequent activation and aggregation are critical processes that cause thrombus formation after endothelial damage. To date, high hopes are associated with compounds of natural origin, which show anticoagulant action without undesirable effects and can be proposed as supportive therapies. We investigated the effect of the new combination of four natural compounds, escin-bromelain-ginkgo biloba-sage miltiorrhiza (EBGS), on the initial process of the coagulation cascade, which is the adhesion of platelets to activated vascular endothelium. Our results demonstrated that EBGS pretreatment of endothelial cells reduces platelet adhesion even in the presence of the monocyte-lymphocyte population. Our data indicate that EBGS exerts its effects by inhibiting the transcription of adhesion molecules, including P-selectin, platelet membrane glycoprotein GP1b, integrins αV and ß3, and reducing the secretion of the pro-inflammatory cytokines interleukin 6, interleukin 8, and the metalloproteinases MMP-2 and MMP-9. Furthermore, we demonstrated that EBGS inhibited the expression of focal adhesion kinase (FAK), strictly involved in platelet adhesion, and whose activity is correlated with that of integrin ß3. The results shown in this manuscript suggest a possible inhibitory role of the new combination EBGS in the reduction in platelet adhesion to activated endothelium, thus possibly preventing coagulation cascade initiation.

Asunto(s)

Endotelio Vascular , Adhesividad Plaquetaria , Transducción de Señal , Factor de Necrosis Tumoral alfa , Humanos , Adhesividad Plaquetaria/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Plaquetas/metabolismo , Plaquetas/efectos de los fármacos , Salvia miltiorrhiza/química , Quinasa 1 de Adhesión Focal/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Extractos Vegetales/farmacología

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Natural products based on their significant anti-cancer potencies have been used in cancer treatment. A natural blend of triterpenoid saponins derived from the horse chestnut (Aesculus hippocastanum L.), has been investigated in various diseases based on its main active ingredient escin. Herein, we examined the potential antiproliferative, proapoptotic, and cytotoxic activities of escin on human skin melanoma (CHL-1) cells. Cytotoxicity of escin was determined by MTT assay. Morphological changes were detected by confocal microscopy and ultrastructural changes by transmission electron microscopy studies. Phosphatidylserine translocation assay, Bcl-2 activation assessment, and oxidative stress analysis were used to determine the cell death mode of the cells. The results showed that escin reduced cell viability in a dose-dependent manner within 24 h of exposure and was highly cytotoxic at lower concentrations (IC50 value 6 µg/mL). Escin inactivated Bcl-2 signaling and triggered apoptosis by increasing the reactive oxygen species and by causing morphological and ultrastructural changes that implicate to the proapoptotic activity. Escin has been found to exert high potential for an anti-cancer drug following further in vitro and in vivo investigations.

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Cerebral ischemia-induced systemic inflammation and inflammasome-dependent pyroptotic cell death in ileum, causing serious intestinal injury. Glucocorticoid receptor (GR) mediates the effects of glucocorticoids and participates in inflammation. Escin has corticosteroid-like, neuroprotective, and anti-intestinal dysfunction effects. This study aimed to investigate the effect of Escin on the intestinal barrier injury in rats subjected to middle cerebral artery occlusion (MCAO) and on Caco-2 cells exposed to lipopolysaccharides. The MCAO-caused brain injury was evaluated by assessing neurological function, cerebral infarct volume, and plasma corticosterone (Cort) levels. Intestinal injury was evaluated by observing the histopathological changes, assessing the intestinal barrier function, and determining blood FD4, endotoxin and IL-1ß levels. The levels of the tight-junction proteins such as claudin-1, occludin, and ZO-1, and proteins involved in the GR/p38 MAPK/NF-κB pathway and NLRP3-inflammasome activation were evaluated using western blotting or immunofluorescence. Administration of Escin suppressed the cerebral ischemia-induced increases in Garcia-test scores and infarct volume, alleviated the injury to the intestinal barrier, and decreased the levels of Cort, endotoxin, and IL-1ß. Additionally, Escin upregulated GR and downregulated phospho(p)-p65, p-p38MAPK, NLRP3, GSDMD-N, and cleaved-caspase-1 in the intestine. The effects of Escin could be suppressed by the GR antagonist RU486 or enhanced by the p38 MAPK antagonist SB203580. We revealed details how Escin improves cerebral ischemia-induced intestinal barrier injury by upregulating GR and thereby inhibiting the pyroptosis induced by NF-κB-mediated NLRP3 activation. This study will provide a experimental foundation for the features of glucocorticoid-like activity and the discovery of new clinical application for Escin.

Asunto(s)

Isquemia Encefálica , Escina , Inflamasomas , Piroptosis , Receptores de Glucocorticoides , Transducción de Señal , Animales , Humanos , Masculino , Ratas , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Células CACO-2 , Modelos Animales de Enfermedad , Escina/farmacología , Escina/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/inmunología , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Intestinos/patología , Intestinos/efectos de los fármacos , Intestinos/inmunología , Lipopolisacáridos , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Piroptosis/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Transducción de Señal/efectos de los fármacos

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<b>Introduction:</b> Hemorrhoidal disease is the most common disease treated in proctology ambulatories. Conservative treatment is the basic form of treatment for this disease. One of the elements of treatment may be preparations with myoand phlebotropic effects.<b>Aim:</b> To assess the effect of a multi-ingredient myophlebotropic dietary supplement used as an adjunct on the rate and effectiveness of symptom relief in patients with stage II and III hemorrhoidal disease.<b>Material and method:</b> Patients with stage II and III hemorrhoidal disease with clinical symptoms such as pain, burning, itching and bleeding were qualified for the study. The patients were divided into two groups. The control group (Group I) of 29 patients receiving standard local treatment plus placebo and the study group (Group II) of 32 patients receiving the same local treatment and a six-component myophlebotropic product. Symptoms were analyzed at the time of inclusion in the study (day 0), after 4 and 10 days of therapy. The severity of hemorrhoidal disease and the feeling of relief were assessed on the day of inclusion (W0) and after 30 days of therapy.<b>Results:</b> There were no statistical differences between the groups in terms of disease advancement, age, gender, and duration of symptoms. Compared to the moment of inclusion in the study (W0), after 4 days (W1), after 10 days (W2) of taking the multi- -component product, there was a statistically significant improvement in the VAS scale: spontaneous pain and pain during defecation. In the qualitative assessment (yes/no), there were statistically significantly fewer cases of burning in the anus and itching. The treatment did not affect the rate of spontaneous bleeding, which was low at the beginning of the study, but significantly reduced the rate of bleeding during defecation. After 30 days of observation, it was found that the improvement in the severity of hemorrhoidal disease symptoms was significantly higher in the group using the tested preparation. Relief after a month of the study (one-question method) was noted in the group of patients receiving the tested product.<b>Conclusions:</b> The tested six-component myophlebotropic product proved to be effective in reducing the severity of symptoms such as spontaneous pain, pain during defecation, burning/burning in the anus and bleeding during defecation. Statistical significance was demonstrated in the symptom's relief and reduction in the severity of hemorrhoidal disease.

Asunto(s)

Hemorroides , Humanos , Hemorroides/terapia , Femenino , Masculino , Persona de Mediana Edad , Adulto , Resultado del Tratamiento , Suplementos Dietéticos , Anciano

RESUMEN

Chronic venous insufficiency (CVI) represents a risk factor for cardiovascular events. The first-line treatment includes the use of compression stockings and lifestyle changes. Natural products, such as flavonoids, could be used to improve the effects of compression therapy due to their anti-inflammatory and anti-oxidant properties. This study aims to evaluate the effects of a dietary supplement containing baicalin, bromeline and escin in CVI patients. A retrospective cohort study was performed by using the medical records of CVI affected outpatients. Patients treated with the dietary supplement were defined as "users". A modified Venous Clinical Severity Score (VCSS) was calculated, including pain, inflammation, vessels induration and skin pigmentation. All clinical variables were evaluated at baseline (T0), after 30 (T1) and 90(T2) days in "users" and "non-users". Out of 62 patients, 30 (48.4%) were "users". No difference was observed between groups at baseline. A lower VCSS value was recorded in "users" than that observed in "non-users" at T2 (7.0 (4.0-9.0) vs. 9.0 (5.0-10.0); p = 0.025). Vessels' induration and pain significantly reduced in 53.3% and 43.3% of "users" and in 18.8% and 9.4% of "non-users". Only "users" (33.3%) showed a reduction of the inflammatory signs as well as a decrease in malleolar circumference, from 29.0 (26.5-30.0) to 27.5 (26.0-28.5) (p < 000.1). A reduction of C-reactive Protein levels was found in "users" compared to "non-users" at T2 (1.0 (0.9-1.2) vs. 1.3 (1.0-1.5); p = 0.006). These findings suggest that implementation of a dietary supplement could improve the clinical outcomes of CVI patients.

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The cation channel Piezo1, a crucial mechanotransducer found in various organs and tissues, has gained considerable attention as a therapeutic target in recent years. Following this trend, several Piezo1 inhibitors have been discovered and studied for potential pharmacological properties. This review provides an overview of the structural and functional importance of Piezo1, as well as discussing the biological activities of Piezo1 inhibitors based on their mechanism of action. The compounds addressed include the toxin GsMTx4, Aß peptides, certain fatty acids, ruthenium red and gadolinium, Dooku1, as well as the natural products tubeimoside I, salvianolic acid B, jatrorrhzine, and escin. The findings revealed that misexpression of Piezo1 can be associated with a number of chronic diseases, including hypertension, cancer, and hemolytic anemia. Consequently, inhibiting Piezo1 and the subsequent calcium influx can have beneficial effects on various pathological processes, as shown by many in vitro and in vivo studies. However, the development of Piezo1 inhibitors is still in its beginnings, with many opportunities and challenges remaining to be explored.

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Canales Iónicos , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/metabolismo , Humanos , Animales , Estructura Molecular

RESUMEN

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common solid cancer and the leading cause of cancer deaths worldwide. Sorafenib is the first drug used to treat HCC but its effectiveness needs to be improved, and it is important to find ways to treat cancer that combine sorafenib with other drugs. Synergistic therapies lower effective drug doses and side effects while enhancing the anticancer effect. PURPOSE: In the present study, the therapeutic potential of sorafenib in combination with escin and its underlying mechanism in targeting liver cancer has been established. STUDY DESIGN/METHODS: The IC50 of sorafenib and escin against HepG2, PLC/PRF5 and Huh7 cell lines were determined using MTT assay. The combination index, dose reduction index, isobologram and concentrations producing synergy were evaluated using the Chou-Talaly algorithm. The sub-effective concentration of sorafenib and escin was selected to analyze cytotoxic synergistic potential. Cellular ROS, mitochondrial membrane potential, annexin V and cell cycle were evaluated using a flow-cytometer, and autophagy biomarkers were determined using western blotting. Moreover, autophagy was knocked down using ATG5 siRNA to confirm its role. A DEN-induced liver cancer rat model was developed to check the synergy of sorafenib and escin. RESULTS: Different concentrations of escin reduced the IC50 of sorafenib in HepG2, PLC/PRF5 and Huh7 cell lines. Chou-Talaly algorithm determined cytotoxic synergistic concentrations of sorafenib and escin in these cell lines. Mechanistically, this combination over-expressed p62 and LC-II, reflecting autophagy block and induced late apoptosis, further reconfirmed by ATG5 knockdown. Sorafenib and escin combination  reduced HCC serum biomarker α-feto protein (α-FP) by 1.5 folds. This combination restricted liver weight, tumor number and size, also, conserved morphological features of liver cells. The combination selectively targeted the G0 /G1 phase of cancer cells. CONCLUSION: Escin and sorafenib combination potentially up-regulates p62 to block autophagy to induce late apoptosis in liver cancer cells.

Asunto(s)

Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Ratas , Antineoplásicos/farmacología , Apoptosis , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular , Escina/farmacología , Neoplasias Hepáticas/patología , Proteínas Asociadas a Microtúbulos , Sorafenib/farmacología

RESUMEN

BACKGROUND: The tobacco use is one of the biggest public health threats worldwide. Cigarette smoke contains over 7000 chemicals among other aldehydes, regarded as priority toxicants. ß-escin (a mixture of triterpenoid saponins extracted from the Aesculus hippocastanum. L) is a potent activator of aldehyde dehydrogenase (ALDH) - an enzyme catalyzing oxidation of aldehydes to non-toxic carboxylic acids. PURPOSE: The aim of this study was to evaluate the effect of ß-escin on ALDH activity, ALDH isoforms mRNA expression and cytotoxicity in nasal epithelial cells exposed to cigarette smoke extract (CSE). METHODS: Nasal epithelial cells from healthy non-smokers were treated with ß-escin (1 µM) and exposed to 5% CSE. After 6- or 24-hours of stimulation cell viability, DNA damage, ALDH activity and mRNA expression of ALDH isoforms were examined. RESULTS: 24 h ß-escin stimulation revised CSE induced cytotoxicity and DNA damage. Cells cultured with ß-escin or exposed to CSE responded with strong increase in ALDH activity. This effect was more pronounced in cultures treated with combination of ß-escin and CSE. The strongest stimulatory effect on ALDH isoform mRNA expression was observed in cells cultured simultaneously with ß-escin and CSE: at 6 h for ALDH1A1 and ALDH3A1, and at 24 h for ALDH1A3, ALDH3A2, ALDH3B1, and ALDH18A1. Combined ß-escin and CSE treatment prevented the CSE-induced inhibition of ALDH2 expression at 24 h. CONCLUSIONS: ß-escin is an effective ALDH stimulatory and cytoprotective agent and might be useful in the prevention or supportive treatment of tobacco smoke-related diseases.

Asunto(s)

Aldehído Deshidrogenasa , Fumar Cigarrillos , Aldehído Deshidrogenasa/metabolismo , Escina/metabolismo , Escina/farmacología , Células Epiteliales , Aldehídos/farmacología , Aldehídos/metabolismo , Muerte Celular , ARN Mensajero/genética , ARN Mensajero/metabolismo , Isoformas de Proteínas/metabolismo , Supervivencia Celular , Productos de Tabaco

RESUMEN

Our study produced GO-TiO2-chitosan-escin nanocomposites (GTCEnc), characterized them using physical and biological methods, and evaluated their potential as cancer treatment candidates. Standard protocols were used to produce GTCEnc. Nanocomposites are created using XRD, FTIR, UV-Vis, and PL spectroscopy analysis. The morphology and ultrastructure of nanocomposites were investigated using SEM and TEM. Nanocomposites containing TiO2, GO, chitosan, and escin nanostructures were characterized using diffraction, microscopy, and spectroscopy; the antimicrobial activity of GTCEnc was investigated. Various methods were used to test the anticancer activity of GTCEnc against COLO 205 cell lines, including MTT, EtBr/AO, DAPI, JC-1, Annexin-V/FITC, cell cycle analysis, and activation of pro-apoptotic markers, such as caspase-3, -8, and -9. The nanocomposites were cytotoxic to COLO 205 cells, with an IC50 of 22.68 µg/mL, but not to 293T cells. In cells treated with nanomaterials, cytotoxicity, nuclear damage, apoptosis induction, and free radical production were significantly increased. Our finding suggests that GTCEnc has potent anticancer and antibacterial activity in vitro because of its unique nanocomposite properties and antibacterial and anticancer activity in vitro. Additional research is required to understand the clinical efficacy of these nanocomposites.

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Quitosano , Neoplasias del Colon , Grafito , Nanocompuestos , Humanos , Escina , Quitosano/farmacología , Quitosano/química , Titanio/farmacología , Titanio/química , Antibacterianos/química , Grafito/farmacología , Grafito/química , Neoplasias del Colon/tratamiento farmacológico , Nanocompuestos/química

RESUMEN

[Formula: see text]-Escin is an oleanane-type pentacyclic triterpenoid saponin extracted from the seeds of Aesculus hippocastanum (AH), which is more widely distributed. [Formula: see text]-Escin sodium has been approved by the American FDA for clinical usage. This paper is intended to summarize an updated and comprehensive review of the pharmacological activities, pharmacokinetic properties, toxicity, and analytical methods of [Formula: see text]-escin. Studies have shown that [Formula: see text]-escin has significant antitumor, antiviral, anti-inflammatory, and other activities alongside less adverse effects and higher safety than other compounds. The review shows that the pharmacological effects of [Formula: see text]-escin involve mechanisms such as ATM/[Formula: see text]H2AX, RhoA/Rock, GSK-3[Formula: see text]/[Formula: see text]-Catenin, HER2/HER3/Akt, and PI3K/Akt signaling pathways, and Cyclin A, p21[Formula: see text], survivin, Bcl-2, Mcl-1, Caspases, TGF-[Formula: see text], MMPs, and TNF-[Formula: see text] among other inflammatory factors. [Formula: see text]-Escin has significant cytotoxicity; the use of the chitosan/xanthan gum-based polyelectrolyte complexes PA1 and PC-11 to modify it not only to reduces its toxicity, but also improves its drug efficacy. Because of this, these compounds may become a new research hotspot. [Formula: see text]-Escin in vivo metabolism can be converted by the CYP1A2 enzyme in the intestinal flora to produce [Formula: see text]-escin, deacylated, deglycosylated, and 21[Formula: see text]-[Formula: see text]-crotonoyl-protoescin, and the binding rate of the plasma proteins is higher than 90%. These are mainly metabolized by the liver, kidneys, and other organs, and excreted in the form of urine and feces. The number of reports on the specific mediators of the metabolism of [Formula: see text]-escin and their mechanisms and metabolites is relatively small; furthermore, the results are vague. Therefore, a complete and in-depth exploration of the pharmacokinetic characteristics of [Formula: see text]-escin is needed to provide a more complete and effective theoretical reference for the study of its pharmacodynamic activity.

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Escina , Extractos Vegetales , Escina/farmacología , Extractos Vegetales/farmacología , Glucógeno Sintasa Quinasa 3 , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt

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BACKGROUND: Hemorrhagic transformation (HT) seriously affects the clinical application of recombinant tissue plasminogen activator (rt-PA). The main strategy for combating HT is to keep the blood-brain barrier (BBB) stable. Escin is the active ingredient of Aesculus hippocastanum and a natural mixture of triterpene saponins, and may play a part in mitigation of HT. PURPOSE: This study sought to investigate the effect of Escin in improving rt-PA-induced HT, explore possible mechanisms, and provide new ideas for the treatment of clinical HT. STUDY DESIGN AND METHODS: In in vivo experiments, transient middle cerebral artery occlusion (tMCAO) was undertaken in 6-week-old and 12-month-old mice, and rt-PA was administered to induce HT injury. The inhibitory effect of Escin on HT and its protective effect on neurobehavior, the BBB, and cerebrovascular endothelial cells was determined. In in vitro experiments, bEnd.3 cells were injured by oxygen-glucose deprivation/reperfusion (OGD/R) and rt-PA. The protective effect of Escin was measured by the CCK8 assay, release of lactate dehydrogenase (LDH), and expression of tight junction (TJ) proteins. In mechanistic studies, the effect of Escin on the adenosine monophosphate-activated kinase / caveolin-1 / matrix metalloprotease-9 (AMPK/Cav-1/MMP-9) pathway was investigated by employing AMPK inhibitor and Cav-1 siRNA. RESULTS: In mice suffering from ischemia, rt-PA caused HT as well as damage to the BBB and cerebrovascular endothelial cells. Escin reduced the infarct volume, cerebral hemorrhage, improved neurobehavioral deficits, and maintained BBB integrity in rt-PA-treated tMCAO mice while attenuating bEnd.3 cells damage caused by rt-PA and OGD/R injury. Under physiological and pathological conditions, Escin increased the expression of p-AMPK and Cav-1, leading to decreased expression of MMP-9, which further attenuated damage to cerebrovascular endothelial cells, and these effects were verified with AMPK inhibitor and Cav-1 siRNA. CONCLUSION: We revealed important details of how Escin protects cerebrovascular endothelial cells from HT, these effects were associated with the AMPK/Cav-1/MMP-9 pathway. This study provides experimental foundation for the development of new drugs to mitigate rt-PA-induced HT and the discovery of new clinical application for Escin.

Asunto(s)

Accidente Cerebrovascular Isquémico , Animales , Ratones , Escina , Proteínas Quinasas Activadas por AMP , Células Endoteliales , Metaloproteinasa 9 de la Matriz , Activador de Tejido Plasminógeno , Barrera Hematoencefálica

RESUMEN

Escin, a naturally derived material isolated from horse chestnut, is used as an anti-inflammatory and anti-edema agent. This study aimed to evaluate its effects on lymphedema in a rat tail model. We divided the rats into five groups. The treatment groups received topical application of escin gel at concentrations of 20%, 10%, 2%, and 0.5% for 4 weeks. The fifth group served as a control. We performed volumetric (water displacement) tests, H&E staining, and LYVE-1 immunohistochemical staining, followed by statistical evaluation. All treatment groups showed significant volumetric reductions compared with the control group, but no significant differences were observed between the treatment groups. H&E staining showed a significant reduction in dermal thickness in the 20%, 10%, and 2% escin treatment groups compared to the control group. Within the treatment groups, the 2% escin group showed a significant difference compared with the 20% and 10% escin groups (p = 0.021 for both). LYVE-1 immunohistochemical staining revealed a significantly higher mean lymphatic vessel count in the 2% escin group compared with the 20%, 10%, and 0.5% escin-treated groups and the control group (p = 0.019, p = 0.025, p = 0.019, and p = 0.032 respectively). Topical escin applied to a rat tail model of acute lymphedema resulted in a significant reduction in tail volume, reduced dermal thickness, and increased lymphatic structures. The 2% escin concentration may be the optimal dose for improving lymphedema in this model. Further research is warranted to explore the clinical application of escin in patients with lymphedema.

RESUMEN

Escin is an active ingredient used in the treatment of phlebitis. However, the pharmacological mechanism of escin remains largely unclear. Here, we aimed to determine the molecular basis for the therapeutic effect of escin. Human umbilical vein endothelial cells (HUVECs) were subjected to shear-stress assays with or without escin. Intracellular Ca2+ levels, inflammatory factors and the activity of NF-κB were measured in endothelial cells (ECs) after mechanical-stretch or Yoda1 activation. Isometric tensions in aortic rings were identified. In addition, murine liver endothelial cells (MLECs) isolated from Piezo1 endothelial specific knockout mice (Piezo1△ EC) were used to explore the role of Piezo1. Our results showed that escin inhibited inflammatory factors, intracellular Ca2+ levels and Yoda1-evoked relaxation of thoracic aorta rings. Cell alignment induced by shear stress was inhibited by escin in HUVECs, and Piezo1 siRNA was used to show that this effect was dependent on Piezo1 channels. Moreover, escin reduced the inflammation and inhibited the activity of NF-κB in ECs with mechanical-stretch, which were insensitive to Piezo1 deletion. SN50, an NF-κB antagonist, significantly inhibited the mechanical stretch-induced inflammatory response. In addition, escin reduced inflammation in ECs subjected to mechanical-stretch, which was insensitive after using NF-κB antagonist. Collectively, our results demonstrate that escin inhibits the mechanical stretch-induced inflammatory response via a Piezo1-mediated NF-κB pathway. This study improves our understanding of a molecular target of escin that mediates its effect on chronic vascular inflammation.

Asunto(s)

Escina , Canales Iónicos , Ratones , Humanos , Animales , Canales Iónicos/metabolismo , FN-kappa B/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Ratones Noqueados , Inflamación/tratamiento farmacológico

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Abnormal inactivation of the Wnt/ß-catenin signaling pathway is involved in skin diseases like androgenetic alopecia, vitiligo and canities, but small-molecule activators are rarely described. In this study, we investigated the stimulatory effects of escin on the canonical Wnt/ß-catenin signaling pathway in cultured human dermal papilla cells (hDPCs). Escin stimulated Wnt/ß-catenin signaling, resulting in increased ß-catenin and lymphoid enhancer-binding factor 1 (LEF1), the accumulation of nuclear ß-catenin and the enhanced expression of Wnt target genes in cultured hDPCs. Escin drastically reduced the protein level of glycogen synthase kinase (GSK)-3ß, a key regulator of the Wnt/ß-catenin signaling pathway, while the presence of the proteasome inhibitor MG-132 fully restored the GSK-3ß protein level. The treatment of secreted frizzled-related proteins (sFRPs) 1 and 2 attenuated the activity of escin in Wnt reporter assays. Our data demonstrate that escin is a natural agonist of the canonical Wnt/ß-catenin signaling pathway and downregulates GSK-3ß protein expression by facilitating the proteasomal degradation of GSK-3ß in cultured hDPCs. Our data suggest that escin likely stimulates Wnt signaling through direct interactions with frizzled receptors. This study underscores the therapeutic potential of escin for Wnt-related diseases such as androgenetic alopecia, vitiligo and canities.

RESUMEN

Combining anti-cancer drugs has been exploited as promising treatment strategy to target lung cancer. Synergistic chemotherapies increase anti-cancer effect and reduce effective drug doses and side effects. In this study, therapeutic potential of escin in combination with sorafenib has been explored. 3-(4,5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide assay was used to calculate IC50 values. The synergy was evaluated using Chou-Talaly algorithm. Cellular reactive oxygen species, mitochondrial membrane potential, annexin V, and cell-cycle studies were done by flow-cytometer, and autophagy biomarkers expression were determined using western blotting. Moreover, autophagy was knocked down using ATG5 siRNA to confirm its role, diethylnitrosamine-induced lung cancer model was used to check the synergy of sorafenib/escin. Escin significantly reduced the IC50 of sorafenib in A549 and NCIH460 cells. The combination of sorafenib/escin produced a 2.95 and 5.45 dose reduction index for sorafenib in A549 and NCI-H460 cells. The combination of over-expressed p62 and LC3-II reflects autophagy block-mediated late apoptosis. This phenomenon was reconfirmed by ATG5 knockdown. This combination also selectively targeted G0/G1 phase of cancer cells. In in vivo study, the combination reduced tumour load and lower elevated serum biochemical parameters. The combination of sorafenib/escin synergistically inhibits autophagy to induce late apoptosis in lung cancer cells' G0/G1 phase.

RESUMEN

Nowadays, the increase in antimicrobial-resistant fungi (AMR) is certainly a major health concern, and the development of alternative therapeutic strategies has become crucial. Natural products have been used to treat various infections, and their chemical properties contribute to the performance of their biological activities, such as antifungal action. The various virulence factors and mechanisms of resistance to antifungals contribute to making Candida glabrata one of the most frequent agents of candidiasis. Here we investigate the in vitro and in vivo activity of ß-escin against Candida glabrata. The ß-escin MICs were determined for a reference strain and two clinical isolates of C. glabrata. Furthermore, growth kinetics assays and biofilm inhibition/eradication assays (crystal violet) were performed. The differences in the expression of some anti-biofilm-associated genes were analyzed during biofilm inhibition treatment so that reactive oxygen species could be detected. The efficacy of ß-escin was evaluated in combination with fluconazole, ketoconazole, and itraconazole. In addition, a Galleria mellonella infection model was used for in vivo treatment assays. Results have shown that ß-escin had no toxicity in vitro or in vivo and was able to inhibit or destroy biofilm formation by downregulating some important genes, inducing ROS activity and affecting the membrane integrity of C. glabrata cells. Furthermore, our study suggests that the combination with azoles can have synergistic effects against C. glabrata biofilm. In summary, the discovery of new antifungal drugs against these resistant fungi is crucial and could potentially lead to the development of future treatment strategies.

RESUMEN

In this study, we investigated the properties of human varicose vein (VV) endothelial cells (HVVEC) in comparison to the human umbilical vein endothelial cells (HUVEC). The cells were treated with three bioactive compounds with proven beneficial effects in the therapy of patients with VV, diosmin, escin, and bromelain. Two concentrations of tested drugs were used (1, 10 mg/mL), which did not affect the viability of either cell type. Escin led to a slight generation of reactive oxygen species in HUVEC cells. We observed a slight release of superoxide in HVVEC cells upon treatment with diosmin and escin. Diosmin and bromelain showed a tendency to release nitric oxide in HUVEC. Using membrane fluorescent probes, we demonstrated a reduced fluidity of HVVEC, which may lead to their increased adhesion, and, consequently, a much more frequent occurrence of venous thrombosis. For the first time, we show the mechanism of action of drugs used in VV therapy on endothelial cells derived from a VV. Studies with HVVEC have shown that tested drugs may lead to a reduction in the adhesive properties of these cells, and thus to a lower risk of thrombosis.

RESUMEN

Breast cancer (BC) has threatened women worldwide for a long time, and novel treatments are needed. Ferroptosis is a new form of regulated cell death that is a potential therapeutic target for BC. In this study, we identified Escin, a traditional Chinese medicine, as a possible supplement for existing chemotherapy strategies. Escin inhibited BC cell growth in vitro and in vivo, and ferroptosis is probable to be the main cause for Escin-induced cell death. Mechanistically, Escin significantly downregulated the protein level of GPX4, while overexpression of GPX4 could reverse the ferroptosis triggered by Escin. Further study revealed that Escin could promote G6PD ubiquitination and degradation, thus inhibiting the expression of GPX4 and contributing to the ferroptosis. Moreover, proteasome inhibitor MG132 or G6PD overexpression could partially reverse Escin-induced ferroptosis, when G6PD knockdown aggravated that. In vivo study also supported that downregulation of G6PD exacerbated tumor growth inhibition by Escin. Finally, our data showed that cell apoptosis was dramatically elevated by Escin combined with cisplatin in BC cells. Taken together, these results suggest that Escin inhibits tumor growth in vivo and in vitro via regulating the ferroptosis mediated by G6PD/GPX4 axis. Our findings provide a promising therapeutic strategy for BC.

Asunto(s)

Neoplasias de la Mama , Ferroptosis , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Cisplatino/farmacología , Cisplatino/uso terapéutico , Escina , Ferroptosis/genética , Apoptosis

RESUMEN

Nanotechnology has been recognized as a highly interdisciplinary field of the twenty-first century, with diverse applications in biotechnology, healthcare, and material science. One of the most commonly employed non-toxic nanoparticles, magnesium oxide nanoparticles (MgO NPs), is simple, inexpensive, biocompatible, and biodegradable. Several researchers are interested in the biosynthesis process of MgO NPs through chemical and physical approaches. This is because of their simplicity, affordability, and environmental safety. In the current study, green MgO-Chitosan-Pluronic F127-Escin (MCsPFE) NPs have been synthesized and characterized via various techniques like UV-visible, Fourier-transform infrared spectroscopy, Energy dispersive X-ray composition analysis, Transmission electron microscopy, field emission scanning electron microscopy, X-ray Diffraction, Photoluminescence, and Dynamic light scattering analyses. The average crystallite size of MCsPFE NPs was 46 nm, and a face-centered cubic crystalline structure was observed. Further, the antimicrobial effectiveness of NPs against diverse pathogens has been assessed. The cytotoxic potential of the nanoparticles against MDA-MB-231 cell lines was evaluated using the MTT test, dual AO/EB, JC-1, DCFH-DA, and DAPI staining procedures. High antimicrobial efficacy of MCsPFE NPs against Gram-positive and Gram-negative bacterial strains as well as Candida albicans was observed. The findings concluded that the NPs augmented the ROS levels in the cells and altered the Δψm, leading to the initiation of the intrinsic apoptotic cell death pathway. Thus, green MCsPFE NPs possess immense potential to be employed as an effective antimicrobial and anticancer treatment option.