Furanocoumarin compounds isolated from Dorstenia foetida potentiate irinotecan anticancer activity against colorectal cancer cells.

Although the anticancer activity of Dorstenia foetida was already observed, the chemical entity responsible for this activity remained unidentified. In this study, the cytotoxic activity of two furanocoumarin compounds, i.e., 5-methoxy--3-(3-methyl-2,3-dihydroxybutyl)-psoralen (1) and 5-methoxy-3-(3-methyl-2,3-dihydroxybutyl)-psoralen diacetate (2) isolated from ethyl acetate fraction of D. foetida (whole plant) was investigated in several cancer cell lines including HN22, MDA-MB-231, HCT116, and HT29. The results revealed that compound 2 exhibited cytotoxic activity, particularly against colorectal cancer cell lines HCT116 and HT29. The interplay between compound 2 and irinotecan (Iri) showed synergism against HCT116, which was analyzed by CompuSyn software. The simulation revealed that, at the molar ratio of Iri:2 of 1:40, the concentration predicted to achieve a 90 % inhibitory effect when used in the combination would be ~28- and ~4-fold lower than the concentration of compound 2 and Iri, resp., when used individually. Finally, the percentage of apoptotic cells in the HCT116 line treated with the combination was markedly higher than in the cells treated with the individual agent (60 % apoptotic cells for the combination compared to 17 and 45 % for Iri and compound 2 monotherapy, resp). In conclusion, our results identified compound 2 as a plant-derived compound exhibiting anticancer properties that can act synergistically with Iri and warranted further research to assess the potential of this synergism for colorectal cancer treatment.

A new acylated triterpene glycoside and cytotoxic constituents from Dolichandrone serrulata (Wall. ex DC.) Seem.

In this study, a new acylated triterpene glycoside, 3α-O-stearoyl-28-[2'-stearoyl-α-l-arabinopyranosyl]-olean-12-en-28-oic acid (1), was isolated from the flowers of Dolichandrone serrulata. In addition to this compound, eleven known compounds were also isolated, including a related pentacyclic triterpenoid: ursolic acid (2), two cycloartane triterpenoids: 24-methylenecycloartanol (3) and 24-methylenecycloartane-3,28-diol (4), three cyclohexylethane derivatives: (-)-rengyolone (5), (-)-cleroindicin C (6) and (-)-cleroindicin D (7), an iridoid: 6-O-trans-feruloyl catalpol (8), two phenylethanoid glycosides: salidroside (9) and verbascoside (10), and two steroids: ß-sitosterol (11) and ß-sitosterol-3-O-ß-d-glucopyranoside (12). The chemical structures of these compounds were determined by analysing their HRMS and NMR spectroscopic data. Additionally, their cytotoxic activities against NH22, HCT116, MCF7, MDA-MB-231, and HeLa cell lines were evaluated for all the compounds. Ursolic acid exhibited moderate cytotoxic activity against all cancer cell lines tested, particularly against HN22, MDA-MB-231, MCF-7, and HCT116 cells with IC50 values of approximately 19-34 µM.

Gamma-mangostin Protects S16Y Schwann Cells Against tert-Butyl Hydroperoxide-induced Apoptotic Cell Death.

BACKGROUND: Peripheral neuropathy is a common complication that affects individuals with diabetes. Its development involves an excessive presence of oxidative stress, which leads to cellular damage in various tissues. Schwann cells, which are vital for peripheral nerve conduction, are particularly susceptible to oxidative damage, resulting in cell death. MATERIALS AND METHODS: Gamma-mangostin (γ-mangostin), a xanthone derived from Garcinia mangostana, possesses cytoprotective properties in various pathological conditions. In this study, we employed S16Y cells as a representative Schwann cell model to investigate the protective effects of γ-mangostin against the toxicity induced by tert-Butyl hydroperoxide (tBHP). Different concentrations of γ-mangostin and tBHP were used to determine non-toxic doses of γ-mangostin and toxic doses of tBHP for subsequent experiments. MTT cell viability assays, cell flow cytometry, and western blot analysis were used for evaluating the protective effects of γ-mangostin. RESULTS: The results indicated that tBHP (50 µM) significantly reduced S16Y cell viability and induced apoptotic cell death by upregulating cleaved caspase-3 and cleaved PARP protein levels and reducing the Bcl- XL/Bax ratio. Notably, pretreatment with γ-mangostin (2.5 µM) significantly mitigated the decrease in cell viability caused by tBHP treatment. Furthermore, γ-mangostin effectively reduced cellular apoptosis induced by tBHP. Lastly, γ-mangostin significantly reverted tBHP-mediated caspase-3 and PARP cleavage and increased the Bcl-XL/Bax ratio. CONCLUSION: Collectively, these findings highlight the ability of γ-mangostin to protect Schwann cells from apoptotic cell death induced by oxidative stress.

meta-Ureidophenoxy-1,2,3-triazole hybrid as a novel scaffold for promising HepG2 hepatocellular carcinoma inhibitors: Synthesis, biological evaluation and molecular docking studies.

Thirty-one meta-ureidophenoxymethyl-1,2,3-triazole derivatives were designed and synthesized via nucleophilic addition, nucleophilic substitution and copper-catalyzed azide-alkyne cycloaddition (CuAAC). The evaluation of their cytotoxicity using MTT assay indicated that almost all derivatives exhibited significantly superior inhibitory activity against hepatocellular carcinoma cell line HepG2 compared to the parental molecule sorafenib (1). Among the series, 5r was the most potent anti-HepG2 agent with IC50 = 1.04 µM, which was almost 5-fold more active than sorafenib (IC50 = 5.06 µM), while the cytotoxic activity against human embryonal lung fibroblast cell line MRC-5 remained comparable to sorafenib. The synthetic derivative 5r, thus, possessed 5.2-time higher selectivity index (SI) than that of sorafenib. Molecular docking studies revealed an efficient interaction of 5r at the same sorafenib's binding region in both B-Raf and VEGFR-2 with lower binding energies than those of sorafenib, consistent with its cytotoxic effect. Furthermore, 5r was proven to induce apoptosis in a dose-dependent manner similar to sorafenib. In addition, the prediction using SwissADME suggested that 5r possessed appropriate drug properties conforming to Veber's studies. These findings revealed that the newly designed meta-ureidophenoxy-1,2,3-triazole hybrid scaffold was a promising structural feature for an efficient inhibition of HepG2. Moreover, derivative 5r emerged as a promising candidate for further development as a targeted anti-cancer agent for hepatocellular carcinoma (HCC).

The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2.

Target cancer drug therapy is an alternative treatment for advanced hepatocellular carcinoma (HCC) patients. However, the treatment using approved targeted drugs has encountered a number of limitations, including the poor pharmacological properties of drugs, therapy efficiency, adverse effects, and drug resistance. As a consequence, the discovery and development of anti-HCC drug structures are therefore still in high demand. Herein, we designed and synthesized a new series of 1,2,3-triazole-cored structures incorporating aryl urea as anti-HepG2 agents. Forty-nine analogs were prepared via nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. Significantly, almost all triazole-cored analogs exhibited less cytotoxicity toward normal cells, human embryonal lung fibroblast cell MRC-5, compared to Sorafenib and Doxorubicin. Among them, 2m' and 2e exhibited the highest selectivity indexes (SI = 14.7 and 12.2), which were ca. 4.4- and 3.7-fold superior to that of Sorafenib (SI = 3.30) and ca. 3.8- and 3.2-fold superior to that of Doxorubicin (SI = 3.83), respectively. Additionally, excellent inhibitory activity against hepatocellular carcinoma HepG2, comparable to Sorafenib, was still maintained. A cell-cycle analysis and apoptosis induction study suggested that 2m' and 2e likely share a similar mechanism of action to Sorafenib. Furthermore, compounds 2m' and 2e exhibit appropriate drug-likeness, analyzed by SwissADME. With their excellent anti-HepG2 activity, improved selectivity indexes, and appropriate druggability, the triazole-cored analogs 2m' and 2e are suggested to be promising candidates for development as targeted cancer agents and drugs used in combination therapy for the treatment of HCC.

Melatonin Receptor as a Drug Target for Neuroprotection.

BACKGROUND: Melatonin, a neurohormone secreted from the pineal gland, circulates throughout the body and then mediates several physiological functions. The pharmacological effects of melatonin can be mediated through its direct antioxidant activity and receptor-dependent signaling. OBJECTIVE: This article will mainly review receptor-dependent signaling. Human melatonin receptors include melatonin receptor type 1 (MT1) and melatonin receptor type 2 (MT2), which are widely distributed throughout the brain. RESULT: Several lines of evidence have revealed the involvement of the melatonergic system in different neurodegenerative diseases. Alzheimer's disease pathology negatively affects the melatonergic system. Melatonin effectively inhibits ß-amyloid (Aß) synthesis and fibril formation. These effects are reversed by pharmacological melatonin receptor blockade. Reductions in MT1 and MT2 expression in the amygdala and substantia nigra pars compacta have been reported in Parkinson's disease patients. The protective roles of melatonin against ischemic insults via its receptors have also been demonstrated. Melatonin has been reported to enhance neurogenesis through MT2 activation in cerebral ischemic/reperfusion mice. The neurogenic effects of melatonin on mesenchymal stem cells are particularly mediated through MT2. CONCLUSION: Understanding the roles of melatonin receptors in neuroprotection against diseases may lead to the development of specific analogs with specificity and potency greater than those of the original compound. These successfully developed compounds may serve as candidate preventive and disease-modifying agents in the future.

Miliusins; cytotoxic neolignans from the leaves of Miliusa sessilis.

Eight undescribed neolignans and an undescribed propanoid dimer were isolated from the leaves of Miliusa sessilis, together with two known compounds, dehydrodieugenol A and dehydrodieugenol B. All structures were elucidated by extensive spectroscopic data analysis and the structure of (7S,8R)-5'-hydroxy-3,4-dimethoxy-4',7-epoxy-8,3'-neolign-8'-en-9-acetate (miliusin A) was further confirmed by X-ray crystallographic analysis. The absolute configurations were determined using circular dichroism (CD) data analysis and the modified Mosher's method. All isolated compounds were evaluated for their cytotoxic activities against four human cancer cell lines (HeLa, HN22, HepG2, and HCT116), including one normal-type cell line (HaCaT) using MTT assay. (7S,8R)-5'-hydroxy-3,4-dimethoxy-4',7-epoxy-8,3'-neolign-8'-en-9-ol (miliusin B) was found to exhibit the most promising cytotoxic effect against Hela cells with the lowest IC50 value of 0.04 µM and the highest selective index of 187.8, highlighting miliusin B as an attractive candidate for cervical cancer drug development.

Melatonin as a mitochondrial protector in neurodegenerative diseases.

Mitochondria are crucial organelles as their role in cellular energy production of eukaryotes. Because the brain cells demand high energy for maintaining their normal activities, disturbances in mitochondrial physiology may lead to neuropathological events underlying neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Melatonin is an endogenous compound with a variety of physiological roles. In addition, it possesses potent antioxidant properties which effectively play protective roles in several pathological conditions. Several lines of evidence also reveal roles of melatonin in mitochondrial protection, which could prevent development and progression of neurodegeneration. Since the mitochondrial dysfunction is a primary event in neurodegeneration, the neuroprotection afforded by melatonin is thereby more effective in early stages of the diseases. This article reviews mechanisms which melatonin exerts its protective roles on mitochondria as a potential therapeutic strategy against neurodegenerative disorders.

Melatonin Protects SH-SY5Y Neuronal Cells Against Methamphetamine-Induced Endoplasmic Reticulum Stress and Apoptotic Cell Death.

Methamphetamine (METH), a psychostimulant with highly neurotoxic effects, has been known to induce neuronal apoptosis in part through an endoplasmic reticulum (ER) stress pathway. Melatonin is an endogenous antioxidant compound that exerts protective effects against several neurodegenerative conditions, including METH-induced neurotoxicity, via various mechanisms. However, the role of melatonin in ER stress is still relatively unclear. In the present study, we investigated ER stress and neuronal apoptosis following METH treatment and the role of melatonin in METH-mediated ER stress-induced cell death in the SH-SY5Y neuroblastoma cell line. We found that METH caused the overexpression of ER stress-related genes, including C/EBP homologous protein and spliced X-box binding protein 1, in dose- and time-dependent manners. Moreover, METH time-dependently activated caspase-12 and -3, leading to cellular apoptosis. Furthermore, we demonstrated that pretreatment with melatonin attenuated the overexpression of ER stress-related genes and the cleavages of caspase-12 and -3 caused by METH exposure. Flow cytometry revealed that METH-mediated neuronal apoptosis was also prevented by melatonin. These findings suggest the protective effects of melatonin against ER stress and apoptosis caused by METH and other harmful agents.

Melatonin Attenuates Methamphetamine-Induced Neurotoxicity.

Methamphetamine (METH), an illegal psycho-stimulant, is widely known as a recreational drug. In addition to its addictive effect, METH induces neurotoxicity via multiple mechanisms. The major contributors to METH-induced neurotoxicity are reactive oxygen species, which lead to cell death through apoptotic pathway and disturbances in mitochondria, the generation of neuroinflammation, and autophagy. Melatonin, a neurohormone secreted by the pineal gland, is a potent antioxidant compound that plays a beneficial role by protecting against the oxidative stress caused by METH. Melatonin also plays a role in maintaining mitochondrial homeostasis. Nanomolar concentrations of melatonin have been shown to protect against the inflammation caused by METH and to prevent the decrease in neurogenesis caused by METH in progenitor cells obtained from adult rat hippocampal tissue. The intent of this review is to describe the underlying mechanisms involving melatonin that protect against the neurodegeneration caused by METH.

Melatonin attenuates methamphetamine-induced neuroinflammation through the melatonin receptor in the SH-SY5Y cell line.

Methamphetamine is a well-known psychostimulant drug, the abuse of which is a serious worldwide public health issue. In addition to its addictive effect, methamphetamine exposure has been shown to be associated with neuroinflammation in several brain areas. Several lines of evidence indicate that TNFα plays an important role in the methamphetamine-induced neuroinflammatory processes that result in apoptotic cell death. Many investigators have demonstrated the anti-neuroinflammatory effects of melatonin, but the mechanism by which this occurs still needs to be explored. In this study, we investigated the effect of methamphetamine on TNFα expression and NFκB activation in the neuroblastoma cell line SH-SY5Y. We demonstrated the time-dependent effect of methamphetamine on the induction of TNFα expression as well as IκB degradation and NFκB nuclear translocation. Furthermore, we investigated the effect of melatonin on methamphetamine-induced TNFα overexpression and NFκB activation. The results showed that pretreatment with 100nM melatonin could prevent the TNFα overexpression caused by methamphetamine exposure. This attenuating effect was prevented by pre-incubation with luzindole, an antagonist of the melatonin MT1/MT2 receptors. Furthermore, methamphetamine-induced IκB degradation and NFκB nuclear translocation were also suppressed by pretreatment with melatonin, and pretreatment with luzindole diminished these protective effects. MT2 knockdown by siRNA abrogated the anti-inflammatory effect exerted by melatonin. From these findings, we propose that melatonin exerts its protective effects on methamphetamine-induced neuroinflammation through the membrane receptor, at least in part MT2 subtype, in the SH-SY5Y neuroblastoma cell line.

Differential effects of binge methamphetamine injections on the mRNA expression of histone deacetylases (HDACs) in the rat striatum.

Methamphetamine use disorder is characterized by recurrent binge episodes. Humans addicted to methamphetamine experience various degrees of cognitive deficits and show evidence of neurodegenerative processes in the brain. Binge injections of METH to rodents also cause significant toxic changes in the brain. In addition, this pattern of METH injections can alter gene expression in the dorsal striatum. Gene expression is regulated, in part, by histone deacetylation. We thus tested the possibility that METH toxic doses might cause changes in the mRNA levels of histone deacetylases (HDACs). We found that METH did produce significant decreases in the mRNA expression of HDAC8, which is a class I HDAC. METH also decreased expression of HDAC6, HDAC9, and HDAC10 that are class II HDACs. The expression of the class IV HDAC, HDAC11, was also suppressed by METH. The expression of Sirt2, Sirt5, and Sirt6 that are members of class III HDACs was also downregulated by METH injections. Our findings implicate changes in HDAC expression may be an early indicator of impending METH-induced neurotoxicity in the striatum. This idea is consistent with the accumulated evidence that some HDACs are involved in neurodegenerative processes in the brain.