Two spurge species, Euphorbia resinifera O. Berg and Euphorbia officinarum subsp. echinus (Hook.f. & Coss.) Vindt inhibit colon cancer.

BACKGROUND: Colon cancer, a prominent contributor to global cancer-related deaths, prompts the need for innovative treatment strategies. Euphorbia resinifera O. Berg (E. resinifera) and Euphorbia officinarum subsp. echinus Hook. f. & Coss Vindt (E. echinus) and their bee-derived products have been integral to traditional Moroccan medicine due to their potential health benefits. These plants have historical use in addressing various health issues, including cancer. However, their effects against colon cancer remain unclear, and the specific mechanisms underlying their anti-cancer effects lack comprehensive investigation. METHODS: The study aimed to assess the potential anti-cancer effects of Euphorbia extract on colon cancer cell lines (DLD-1) through various techniques. The apoptosis, migration, and proliferation of DLD-1 cells were measured in DLD-1 cells. In addition, we conducted High-Performance Liquid Chromatography (HPLC) analysis to identify the profile of phenolic compounds present in the studied extracts. RESULTS: The extracts demonstrated inhibition of colon cancer cell migration. E. resinifera flower and E. echinus stem extracts show significant anti-migratory effects. Regarding anti-proliferative activity, E. resinifera flower extract hindered proliferation, whereas E. echinus flower extract exhibited dose-dependent inhibition. Apoptosis assays revealed E. resinifera flower extract inducing early-stage apoptosis and E. echinus flower extract promoting late-stage apoptosis. While apoptotic protein expression indicated, E. resinifera stem and propolis extracts had minimal impact on apoptosis. CONCLUSION: The findings provide evidence supporting the beneficial effects of E resinifera and E. echinus extracts on colon cancer and exerting anti-cancer properties.

Exploring the Therapeutic Effects of Atractylodes macrocephala Koidz against Human Gastric Cancer.

Atractylodes macrocephala Koidz (AMK) is a traditional herbal medicine used for thousands of years in East Asia to improve a variety of illnesses and conditions, including cancers. This study explored the effect of AMK extract on apoptosis and tumor-grafted mice using AGS human gastric adenocarcinoma cells. We investigated the compounds, target genes, and associated diseases of AMK using the Traditional Chinese Medical Systems Pharmacy (TCMSP) database platform. Cell viability assay, cell cycle and mitochondrial depolarization analysis, caspase activity assay, reactive oxygen species (ROS) assay, and wound healing and spheroid formation assay were used to investigate the anti-cancer effects of AMK extract on AGS cells. Also, in vivo studies were conducted using subcutaneous xenografts. AMK extract reduced the viability of AGS cells and increased the sub-G1 cell fraction and the mitochondrial membrane potential. Also, AMK extract increased the production of ROS. AMK extract induced the increased caspase activities and modulated the mitogen-activated protein kinases (MAPK). In addition, AMK extract effectively inhibited AGS cell migration and led to a notable reduction in the growth of AGS spheroids. Moreover, AMK extract hindered the growth of AGS xenograft tumors in NSG mice. Our results suggest that AMK has anti-cancer effects by promoting cell cycle arrest and inhibiting the proliferation of AGS cancer cells and a xenograft model through apoptosis. This study could provide a novel approach to treat gastric cancer.

Structure-Activity Relationship and Evaluation of Phenethylamine and Tryptamine Derivatives for Affinity towards 5-Hydroxytryptamine Type 2A Receptor.

Among 14 subtypes of serotonin receptors (5-HTRs), 5-HT2AR plays important roles in drug addiction and various psychiatric disorders. Agonists for 5-HT2AR have been classified into three structural groups: phenethylamines, tryptamines, and ergolines. In this study, the structure-activity relationship (SAR) of phenethylamine and tryptamine derivatives for binding 5-HT2AR was determined. In addition, functional and regulatory evaluation of selected compounds was conducted for extracellular signal-regulated kinases (ERKs) and receptor endocytosis. SAR studies showed that phenethylamines possessed higher affinity to 5-HT2AR than tryptamines. In phenethylamines, two phenyl groups were attached to the carbon and nitrogen (R3) atoms of ethylamine, the backbone of phenethylamines. Alkyl or halogen groups on the phenyl ring attached to the ß carbon exerted positive effects on the binding affinity when they were at para positions. Oxygen-containing groups attached to R3 exerted mixed influences depending on the position of their attachment. In tryptamine derivatives, tryptamine group was attached to the ß carbon of ethylamine, and ally groups were attached to the nitrogen atom. Oxygen-containing substituents on large ring and alkyl substituents on the small ring of tryptamine groups exerted positive and negative influence on the affinity for 5-HT2AR, respectively. Ally groups attached to the nitrogen atom of ethylamine exerted negative influences. Functional and regulatory activities of the tested compounds correlated with their affinity for 5-HT2AR, suggesting their agonistic nature. In conclusion, this study provides information for designing novel ligands for 5-HT2AR, which can be used to control psychiatric disorders and drug abuse.

Potential Functional Role of Phenethylamine Derivatives in Inhibiting Dopamine Reuptake: Structure-Activity Relationship.

Numerous psychotropic and addictive substances possess structural features similar to those of ß-phenethylamine (ß-PEA). In this study, we selected 29 ß-PEA derivatives and determined their structure-activity relationship (SAR) to their ability to inhibit dopamine (DA) reuptake; conducted docking simulation for two selected compounds; and identified their potential functionals. The compounds were subdivided into arylethylamines, 2-(alkyl amino)-1-arylalkan-1-one derivatives and alkyl 2-phenyl-2-(piperidin-2-yl)acetate derivatives. An aromatic group, alkyl group, and alkylamine derivative were attached to the arylethylamine and 2-(alkyl amino)-1-arylalkan-1-one derivatives. The inhibitory effect of the compounds on dopamine reuptake increased in the order of the compounds substituted with phenyl, thiophenyl, and substituted phenyl groups in the aromatic position; compounds with longer alkyl groups and smaller ring-sized compounds at the alkylamine position showed stronger inhibitory activities. Docking simulation conducted for two compounds, 9 and 28, showed that the (S)-form of compound 9 was more stable than the (R)-form, with a good fit into the binding site covered by helices 1, 3, and 6 of human dopamine transporter (hDAT). In contrast, the (R, S)-configuration of compound 28 was more stable than that of other isomers and was firmly placed in the binding pocket of DAT bound to DA. DA-induced endocytosis of dopamine D2 receptors was inhibited when they were co-expressed with DAT, which lowered extracellular DA levels, and uninhibited when they were pretreated with compound 9 or 28. In summary, this study revealed critical structural features responsible for the inhibition of DA reuptake and the functional role of DA reuptake inhibitors in regulating D2 receptor function.

The lysosome as a novel therapeutic target of EGFR-mediated tumor inflammation.

EGFR-mediated tumors have been targeted to overcome several different malignant cancers. EGFR overexpression and mutations are directly related to the malignancy, which makes the therapy more complicated. One reason for the malignancy is the induction of AP1 followed by inflammation via IL-6 secretion. Current therapeutic strategies to overcome EGFR-mediated tumors are tyrosine kinase inhibitors (TKIs), anti-EGFR monoclonal antibodies, and the combination of these two agents with classic chemotherapy or immune checkpoint inhibitors (ICIs). Although the strategies are straightforward and have shown promising efficacy in several studies, there are still hurdles to overcoming the adverse effects and limited efficacy. This study reviews the current therapeutic strategies to target EGFR family members, how they work, and their effects and limitations. We also suggest developing novel strategies to target EGFR-mediated tumors in a novel approach. A lysosome is the main custodial staff to discard unwanted amounts of EGFR and other receptor tyrosine kinase molecules. Targeting this organelle may be a new approach to overcoming EGFR-mediated cancers.

Structural Requirements for Modulating 4-Benzylpiperidine Carboxamides from Serotonin/Norepinephrine Reuptake Inhibitors to Triple Reuptake Inhibitors.

8K: and a serotonin/norepinephrine reuptake inhibitor. 7J: showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound. 8K: bound tightly to the binding pocket of all three monoamine reuptake transporters; however. 7J: showed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with. 8F: , which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.

A novel molecular mechanism involved in the crosstalks between homologous and PKC-mediated heterologous regulatory pathway of dopamine D2 receptor.

Protein kinase C (PKC) is one of the major effectors involved in the heterologous regulatory pathways of G protein-coupled receptors (GPCRs). On the other hand, GRK2 and ß-arrestins are the players of homologous regulatory pathway of GPCRs that affect the receptor functions in agonist-selective manner. Even though two pathways can occur independently, crosstalks between two pathways add more diverse modes of regulations on GPCR functions. Even if extensive studies have been conducted, a commonly applicable molecular mechanism involved in the crosstalks between two regulatory pathways has yet to be elucidated. Here we show that PKCßII was phosphorylated at its activation loop of kinase domain (T500) through constitutive interaction with phosphoinositide-dependent kinase 1 (PDK1) that is phosphorylated at S214. With agonist stimulation, dopamine D2 receptor interacted with 14-3-3η in GRK2/ß-arrestin2-dependent manner, resulting in the recruitment of PDK1. The PDK1 recruited to 14-3-3η was dephosphorylated at S241 and dissociated from PKCßII, abrogating the phosphorylation of PKCßII at T500. This signaling cascade resulted in the inhibition of PKCßII functions, including its phosphorylation in the C-terminal tail, intracellular translocation, and kinase activity. Thus, this study revealed a novel and commonly applicable molecular mechanism involved in the inhibition of PKCßII functions through GRK2/ß-arrestin2-mediated homologous pathway of GPCRs. The results obtained in this study could be expanded to other GPCRs and provide new strategies for the treatment of PKCßII-related disorders.

Effects of simvastatin and taurine on delayed cerebral vasospasm following subarachnoid hemorrhage in rabbits.

The aim of the current study was to observe the effects of simvastatin and taurine on delayed cerebral vasospasm (DCVS) following experimental subarachnoid hemorrhage (SAH) in rabbits. A total of 48 New Zealand white rabbits were allocated at random into four groups (control, SAH, SAH + simvastatin and SAH + taurine groups; n=12 each). The rabbit model of DCVS was established using a double hemorrhage method, which involved injecting autologous arterial blood into the cisterna magna in the SAH groups. The SAH + simvastatin group was administered oral simvastatin (5 mg/kg) daily between days 0-6. The SAH + taurine group was administered oral taurine (50 mg/kg) daily between days 0-6. Starch (50 mg/kg) was administered orally to the animals in the other two groups (control and SAH groups). The control group were not subjected to any other injections or treatment. The internal diameter and internal diameter/wall thickness of the basilar artery (BA) were measured. The expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were determined using immunohistochemical and quantitative polymerase chain reaction methods following the sacrifice of all animals on day 7. The activity of nuclear factor (NF)-κB in the BA was also measured using an electrophoretic mobility shift assay. The BA walls in the SAH + simvastatin and SAH + taurine groups exhibited reduced narrowing and corrugation of the tunica elastica interna compared with the SAH group. At the protein and cDNA levels, it was found that cerebral vasospasm of the BA in the SAH + simvastatin and SAH + taurine groups was alleviated, as indicated by the reduced expression of TNF-α, IL-1ß, IL-6 and NF-κB compared with the SAH group (P<0.05). In conclusion, simvastatin and taurine reduced DCVS following SAH in rabbits, which suggests that these compounds may exert anti-inflammatory effects.