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Background: Hypercholesterolemia, characterized by elevated low-density lipoprotein (LDL) cholesterol levels, is a significant risk factor for cardiovascular diseases. Familial and behavioral factors contribute to its onset, and while lifestyle changes offer some benefits, medical interventions are essential to manage this condition effectively. Statins, the primary medications used to lower LDL cholesterol, have limitations, including the unintended upregulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). Therefore, exploring alternative approaches to enhance LDL receptor expression while targeting PCSK9 is crucial, with herbal medicine showing promise in this endeavor. Objective: This study investigates the potential of pomegranate peel extract and punicalagin, a key pomegranate component, in lowering LDL cholesterol in HepG2 cells. The research explores their effects on LDL receptor (LDLR) expression, LDL uptake, and proprotein convertase subtilisin/kexin type 9 (PCSK9) gene expression. Methods: HepG2 cells were treated with different concentrations of pomegranate peel extract (37.5, 75, 150, and 300 µg/ml) and punicalagin (12.5, 25, 50, and 100 µg/ml). Next, the viability of HepG2 cells, the protein levels of LDL receptors and LDL uptake, and the expression levels of PCSK9 were measured. Results: Pomegranate peel extract (37.5, 75, 150, and 300 µg/ml) and punicalagin (12.5, 25, 50, and 100 µg/ml) did not exhibit significant cytotoxicity and significantly increased LDLR protein levels (P-value= 0.00, after 24 hours) and LDL cholesterol uptake (P-value= 0.00, after 24 hours). Furthermore, they exhibited a dose-dependent reduction in the expression of PCSK9 (pomegranate: P-value= 0.01; punicalagin: P-value= 0.00). Conclusion: These findings suggest that pomegranate peel extract and punicalagin have the potential to serve as effective agents in managing hypercholesterolemia by enhancing LDL receptor expression and reducing PCSK9 expression in HepG2 cells. Further research is required to explore their effects on transcription factors and PCSK9 function. [ABSTRACT FROM AUTHOR]

The proprotein convertases family is involved in several physiological processes such as cell growth, migration, and angiogenesis, and also in different pathological conditions. Evolocumab, an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), has recently been approved for treatment of hypercholesterolemia. This study aimed to investigate the effect of evolocumab on angiogenesis in human umbilical vein endothelial cells (HUVECs). Cell proliferation and migration were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell methods. In vitro angiogenesis was assessed by tube formation assay. Vascular endothelial growth factor (VEGF) secretion by HUVECs was also determined using an enzyme-linked immunosorbent assay kit. Evolocumab significantly increased HUVECs viability at 100[micro]g/mL. Significant enhancement in cell migration, and mean tubules length and size was observed at the concentrations of 10 and 100[micro]g/mL and also in mean number of junctions at the concentration of 100[micro]g/mL. Administration of evolocumab at the concentration of 10[micro]g/mL increased VEGF release into supernatants of HUVECs. Findings of this investigation provided in vitro evidence for pro-angiogenic activity of evolocumab through promoting cell proliferation, migration, tubulogenesis, and VEGF secretion in HUVECs. Key words: angiogenesis, cell proliferation, cell migration, HUVEC, PCSK9, evolocumab, VEGF. La famille des proproteine convertases joue un role dans plusieurs processus physiologiques comme la croissance cellulaire, la migration cellulaire et l'angiogenese, ainsi que dans differents etats pathologiques. L'evolocumab, un inhibiteur de la proproteine convertase subtilisine/kexine de type 9 (PCSK9), a recemment ete approuve dans le traitement de l'hypercholesterolemie. Ces travaux visaient a etudier l'effet de l'evolocumab sur l'angiogenese dans les cellules endotheliales des veines ombilicales chez l'humain (HUVEC). Nous avons evalue la proliferation et la migration cellulaires a l'aide des methodes dubromure de (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium et de Transwell. Nous avons evalue l'angiogenese in vitro a l'aide de l'epreuve de formation de tubes. Nous avons aussi evalue la secretion du VEGF (pour << vascular endothelial growth factor>>) par les cellules HUVEC a l'aide d'un kit d'ELISA (pour<< enzyme-linked immunosorbent assay>>). L'evolocumab a 100[micro]g/mL permettait d'augmenter la vitalite des cellules HUVEC de facon marquee. Nous avons observe une nette augmentation de la migration des cellules et des longueurs et des tailles moyennes des tubules a des concentrations de 10 et de 100[micro]g/mL, avec une augmentation du nombre moyen de jonctions a la concentration de 100[micro]g/mL. A la concentration de 10[micro]g/mL, l'administration d'evolocumab entrainait une augmentation de la liberation de VEGF dans le liquide surnageant les cellules HUVEC. Les resultats de cette etude ont permis d'obtenir des donnees in vitro temoignant de l'activite proangiogenique de l'evolocumab par l'intermediaire de l'augmentation de la proliferation, de la migration, de la tubulogenese et de la secretion de VEGF avec les cellules HUVEC. [Traduit par la Redaction] Mots-cles: angiogenese, proliferation cellulaire, migration cellulaire, HUVEC, PCSK9, evolocumab, VEGF., Introduction Angiogenesis is the formation and growing of new blood vessels from pre-existing vasculature during several normal and pathological situations (Goodwin 2007). This process involves a sequence of organized steps [...]

Morphine and other opioids are used to manage cancer-related pain; however, the role of these drugs in cancer progression remains controversial. Emerging evidence indicates that morphine can activate Toll-like receptor 4 (TLR4) and its signaling pathways, by the way the activation and expression of TLR4 can promote melanoma. In this study, we investigated the effects of morphine on the expression of TLR4 and promotion of melanoma in mice. Mice melanoma cells (B16F10) were cultured with morphine (0.1, 1 and 10 µM) for 24 h. In the other experiment, cells were treated with morphine with or without TLR4 agonist (LPS) or antagonist (TAK-242). In in-vivo model, B16F10 cells were subcutaneously injected to C57BL/6 mice, and morphine was administrated in three different treatment protocols after developing palpable tumors (acute treatment, chronic daily injections, escalating doses of morphine). In another set of experiments, B16F10 cells were pretreated with LPS (5 µg/ml) 24 h before injection into mice. Control group received normal saline. We measured cell proliferation, the expression level of Tlr4, Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (Nf-κb1) genes, TLR4 protein expression, and tumor volume. Chronic, acute, and escalating doses of morphine increased tumor. Morphine increased the expression of Tlr4 and Nf-κb1 regardless of the treatment protocol used. Morphine increases the progression of melanoma cancer and may be related to the increased expression of TLR4. Our results suggest that morphine should be used with caution in patients with melanoma. Morphine increases the expression of TLR4 in melanoma. Morphine increases melanoma progression. These effects are mostly observed with chronic and escalating morphine administration [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the effect of aerobic exercise with detraining in different phases of prevention on BCL2 Associated X (BAX) and B-cell lymphoma 2 (BCl-2) gene expression and proteins. Methods: For this purpose, 32 female Balb-c mice (18-20 g) were purchased and randomly assigned to primordial prevention (A), primary prevention (B), secondary prevention (C), and control (D). A group performed aerobic exercise for 4 weeks, after 4T1 cells injection detrained for 8 weeks. Group B performed aerobic exercise for 4 weeks immediately after injecting 4T1 cells and then detrained for 4 weeks. In C group, the 4T1 cells were first injected and did not perform any activity for 4 weeks, followed by 4 weeks of aerobic exercise. Forty-eight hours after the last training session and detraining courses, after anesthesia, sacrificing, and tissue removal, were performed. Reverse transcription polymerase chain reaction (RT PCR) was used to measure gene expression and Western blot (WB) was used to measure protein content. One-way Analysis of variance (ANOVA) test was used to analyze data. Results: The results showed that aerobic exercise in A, B, and C groups compared to D group reduced BCl-2 gene expression and protein and increased BAX gene expression and protein. Conclusions: Therefore, exercise can cause apoptosis in tumor cells by increasing pre-apoptotic factors and decreasing antiapoptotic factors in tumor cells, and consequently improving the disease status. [ABSTRACT FROM AUTHOR]

Vascular cell adhesion molecule 1 (VCAM-1) plays an important role in tumour cell adhesion to endothelial cells. Some tumour cells also show aberrant expression of VCAM‐1. Toll-like receptor 4 (TLR4) agonists can increase VCAM-1 expression. Morphine, an opioid receptor agonist, is also a TLR4 agonist. In this study, we aimed to evaluate whether morphine increase VCAM-1 expression in a TLR4 dependent manner. A549 Lung cancer cells were treated with different doses of morphine and TLR4 antagonist for 24 and 48 h. TLR4 gene expression was evaluated by real-time PCR and VCAM-1 protein was measured by the enzyme-linked immunosorbent assay (ELISA). Morphine enhanced mRNA expression of TLR4 and protein level of VCAM-1. TLR4 antagonist returned VCAM-1expression to the normal level. Morphine effects VCAM-1expressions via TLR4 in lung cancer cell line. [ABSTRACT FROM AUTHOR]

Opioids are available for the management of severe and chronic pain. However, long-term use of high-dose opioids could lead to physiologic tolerance, hyperalgesia, gastrointestinal immobility, addiction, respiratory depression, tumor progression, and inhibition of the immune system. It seems some of these adverse effects of opioids might be induced by TLR-4 signaling. The review aims to investigate the potential interplay between opioids and TLR-4 in CNS, gastrointestinal, cancer, and immune system. The search of PubMed, Embase, Scopus, web of sciences, and Google scholar was performed for all relevant studies published. From a total of 513 papers obtained at the initial database search, publications including in silico, in vitro, and in vivo studies were selected for the review. A comprehensive review of studies indicated that using opioids for the reduction of pain might induce adverse effects such as analgesic tolerance, hyperalgesia, cancer progression, and suppression of the immune system. Some studies have indicated these effects may be due to a change in the level of expression and signaling pathway of TLR-4. The generalizability of the results was limited due to the inconsistency of findings. More studies are needed to clarify TLR-4-mediated opioid effects on the biology or stages of the disease as well as the role of different types of opioids, appropriate dosage, and exposure in various contexts. Designing the drug candidate and doing many formulation studies for different diseases and various stages of disease could be associated with effective treatment and pain management. [ABSTRACT FROM AUTHOR]