Isorhamnetin: what is the in vitro evidence for its antitumor potential and beyond?

Isorhamnetin (ISO) is a phenolic compound belonging to flavonoid family, showcasing important in vitro pharmacological activities such as antitumor, anti-inflammation, and organ protection. ISO is predominantly extracted from Hippophae rhamnoides L. This plant is well-known in China and abroad because of its "medicinal and food homologous" characteristics. As a noteworthy natural drug candidate, ISO has received considerable attention in recent years owing to its low cost, wide availability, high efficacy, low toxicity, and minimal side effects. To comprehensively elucidate the multiple biological functions of ISO, particularly its antitumor activities and other pharmacological potentials, a literature search was conducted using electronic databases including Web of Science, PubMed, Google Scholar, and Scopus. This review primarily focuses on ISO's ethnopharmacology. By synthesizing the advancements made in existing research, it is found that the general effects of ISO involve a series of in vitro potentials, such as antitumor, protection of cardiovascular and cerebrovascular, anti-inflammation, antioxidant, and more. This review illustrates ISO's antitumor and other pharmacological potentials, providing a theoretical basis for further research and new drug development of ISO.

[Protective effect of salidroside on high fat-induced apoptosis in H9c2 cardiomyocytes through AMPK/mTOR/p70S6K pathway].

The study explored the effect of salidroside(SAL) on high fat-induced apoptosis in H9 c2 cardiomyocytes based on AMPK/mTOR/p70 S6 K pathway.H9 c2 cardiomyocytes were cultured in vitro and the lipotoxicity model of H9 c2 cardiomyocytes was constructed by 0.2 mmol·L~(-1) palmitic acid(PA) treatment for 24 hours.The cells were divided into control group, PA group, and SAL group(20 µmol·L~(-1)).Cell proliferation was detected with cell proliferation kit I(MTT) assay after SAL and PA treatment.Dihydroethidium(DHE) probe, Annexin V-FITC/PI kit, and JC-1 probe were used to estimate reactive oxygen species(ROS) level, cell apoptosis, and mitochondrial membrane potential(MMP) change, respectively.The expression levels of p-AMPK/AMPK, p-mTOR/mTOR, p-p70 S6 K/p70 S6 K and apoptosis-related proteins Bax, Bcl-2, and cleaved caspase-3 were investigated with Western blot.The mRNA levels of AMPK, mTOR and p70 S6 K were determined by quantitative reverse transcription-polymerase chain reaction(qRT-PCR).RESULTS:: showed that compared with control group, PA group had decreased cell proliferation ability, MMP, Bcl-2 protein expression and AMPK protein and mRNA expression, while increased ROS level, Bax and cleaved caspase-3 protein expression, and mTOR and p70 S6 K mRNA and protein expression, and the difference was statistically significant(P<0.05, P<0.01).Compared with PA group, SAL improved cell proliferation ability, MMP level, Bcl-2 protein expression, and AMPK mRNA and protein expression, while down-regulated ROS level, cell apoptosis, Bax and cleaved caspase-3 protein expression, and mTOR and p70 S6 K mRNA and protein expression, and the difference was statistically significant(P<0.05, P<0.01).In conclusion, SAL exerted protective effects on high fat-induced lipotoxicity of H9 c2 cardiomyocytes, alleviated the oxidative stress injury and reduced cell apoptosis via regulating AMPK/mTOR/p70 S6 K signaling pathway.

Examining impulsivity and risky decision making among school youth in balloon analogue risk task.

BACKGROUND: Impulsivity trait as a risk factor which typically displayed in risk decision among school youth. This study aims to examine behavioral and cognitive problems of risky decision among Chinese young people aged 15-25 years. The balloon analogue risk task (BART) and event-related potential (ERP) were combine used to explore the neural mechanism of risky decision process whether infected by impulsivity trait. METHODS: A total of 31 subjects were included, including 16 experimental subjects with risk behavior (RS), and 15 health control subjects with non-risk behavior (HC). BART were used to measure risk-taking propensity and ERP were to record in real time. RS vs. HC were compared to explain the relationship between impulsivity and risky decision. RESULTS: Behavioral data in BART task shown that the RS subjects tended to make risky decisions. ERP results illustrate that P300 in RS subjects is more significant positive-going than HC that means dysfunction of cognitive control, and FRN in RS subjects is more negative-going than HC in negative feedback condition, which means individual with high impulsive would be more sensitive to unexpected outcome. CONCLUSIONS: Impulsiveness is a risk factor for school adolescent, because RS subjects performed more risky decision than control group, the evidence indicate that individual with high impulsiveness would lead to be less sensitive to harmful consequences and more inclination to immediate rewards. Therefore, the inclination of risk taking can be powerfully informed by different levels of impulsiveness.

Cancer stem cells in esophageal squamous cell cancer.

Cancer stem cells (CSCs) are hypothesized to govern the origin, progression, drug resistance, recurrence and metastasis of human cancer. CSCs have been identified in nearly all types of human cancer, including esophageal squamous cell cancer (ESCC). Four major methods are typically used to isolate or enrich CSCs, including: i) fluorescence-activated cell sorting or magnetic-activated cell sorting using cell-specific surface markers; ii) stem cell markers, including aldehyde dehydrogenase 1 family member A1; iii) side population cell phenotype markers; and iv) microsphere culture methods. ESCC stem cells have been identified using a number of these methods. An increasing number of stem cell signatures and pathways have been identified, which have assisted in the clarification of molecular mechanisms that regulate the stemness of ESCC stem cells. Certain viruses, such as human papillomavirus and hepatitis B virus, are also considered to be important in the formation of CSCs, and there is a crosstalk between stemness and viruses-associated genes/pathways, which may suggest a potential therapeutic strategy for the eradication of CSCs. In the present review, findings are summarized along these lines of inquiry.

Molecular Mechanism for Selective Cytotoxicity towards Cancer Cells of Diselenide-Containing Paclitaxel Nanoparticles.

Diselenide-containing paclitaxel nanoparticles (SePTX NPs) indicated selectivity of cytotoxicity between cancerous and normal cells in our previous work. Herein, the mechanism is revealed by molecular biology in detail. Cancer cells and normal cells were treated with the SePTX NPs and cell proliferation was measured using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay and cell morphology. Measurement of reactive oxygen species (ROS) levels and biochemical parameters were employed to monitor oxidative stress of the cells. JC-1 assay was used to detect the mitochondrial dysfunction of the cells. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis was used to detect apoptosis of the cells. Immunofluorescence analysis and western blotting were employed to monitor changes in signaling pathway-related proteins. Compared with PTX, SePTX NPs has a good selectivity to cancer cells and can obviously induce the proliferation damage of cancer cells, but has no significant toxicity to normal cells, indicating that SePTX NPs has a specific killing effect on cancer cells. The results of mechanism research show that SePTX NPs can successfully inhibit the depolymerization of microtubules and induce cell cycle arrest, which is related to the upregulation of p53 and CyclinB1. Simultaneously, SePTX NPs can successfully induce oxidative stress, cause mitochondrial dysfunction, resulting in mitochondrial pathway-mediated apoptosis, which is related to the upregulation of autophagy-related protein LC3-II. On the other hand, lewis lung cancer C57BL/6 mice were used to evaluate the anti-tumor effects of SePTX NPs in vivo. Our data show that SePTX NPs exhibited high inhibiting efficiency against the growth of tumors and were able to reduce the side effects. Collectively, these data indicate that the high antitumor effect and selective cytotoxicities of SePTX NPs is promising in future cancer therapy.

Curcumin­loaded PEG­PDLLA nanoparticles for attenuating palmitate­induced oxidative stress and cardiomyocyte apoptosis through AMPK pathway.

Curcumin (CUR) has the ability to attenuate oxidative stress in the myocardium and to protect the myocardium from lipotoxic injury owing to its lipid­reducing properties. However, the use of CUR is limited due to its hydrophobicity and instability. In this study, CUR­loaded nanoparticles (CUR NPs) were developed using an amphiphilic copolymer, monomethoxy poly (ethylene glycol)­b­poly (DL­lactide), as a vehicle material. CUR NPs with high drug loading and small size were prepared under optimized conditions. The effects of CUR NPs on palmitate­induced cardiomyocyte injury were investigated and the possible protective mechanism of CUR NPs was also examined. It was found that CUR NPs were able to control the release of CUR and to deliver CUR to H9C2 cells, and they could prevent palmitate­treated H9C2 cells from apoptosis. In addition, CUR NPs could regulate the Bax and Bcl­2 levels of palmitate­treated H9C2 cells back to their respective normal levels. A prospective mechanism for the function of CUR NPs is that they may activate the AMP­activated protein kinase (AMPK)/mammalian target of rapamycin complex­1/p­p70 ribosomal protein S6 kinase signaling pathway, regulate the expression of downstream proteins and resist the palmitate­induced cardiomyocyte injury. Results suggest that CUR NPs can attenuate palmitate­induced oxidative stress in cardiomyocytes and protect cardiomyocytes from apoptosis through the AMPK pathway. In view of the safety and efficiency of these CUR NPs, they have potential for application in protecting the myocardium from lipotoxic injury.

Inotodiol suppresses proliferation of breast cancer in rat model of type 2 diabetes mellitus via downregulation of ß-catenin signaling.

Breast cancer is amongst the most common cancers causing death of women worldwide. Breast cancer occurrence is more prominent in people with diabetes. A recent trend is management of diabetes and cancer has evolved to be natural remedy including single molecule therapy or combination. In this study, we investigated the effect of inotodiol on breast cancer growth in diabetic conditions. Inotodiol is a lanostane triterpenoid found in natural resources like edible mushroom Inonotus obliquus. We established a rat model of diabetic-breast cancer by treating female Sprague-Dawley rats with streptazotocin (STZ) at 35 mg/kg followed by induction of breast cancer by administration of 7,12-dimethylbenz(a)anthracene (DMBA) at 10 mg/kg. Diabetes development in experimental rats was confirmed by measuring fasting blood glucose levels and oral glucose tolerance test (OGTT), and other biochemical assays were performed. Histological evaluation of pancreas was performed. The proliferation of breast tumor was measured by immunohistochemical staining for PCNA, cleaved-caspase-3 and TUNEL staining for apoptosis, and ß-catenin. Results of the study demonstrate that inotodiol lowered the blood glucose levels in SD rats as well as reduced plasma levels of cholesterol, triglyceride, and high-density lipoprotein. The tumor proliferation marker PCNA was reduced by inotodiol. It downregulated the expression of ß-catenin and its downstream targets (c-Myc and Cyclin D1) followed by apoptosis induction. Conclusively, results suggest that inotodiol regulates blood glucose levels in diabetic rats and then controls proliferation of breast tumor progression by inducing apoptosis via downregulation of ß-catenin signaling. It further suggests that inotodiol can be a preventive approach in managing dietary chronic conditions like diabetic-breast cancer.

Relief of oxidative stress and cardiomyocyte apoptosis by using curcumin nanoparticles.

In this work, the influence of curcumin nanoparticles (CUR-NPs) on NADPH oxidase-related reactive oxygen species (ROS) production and cardiac apoptosis, together with the modulation of protein signaling pathways, were investigated in detail by using cardiomyocytes. The exposure of cardiomyocytes to palmitate (PA) led to an increase in both cell apoptosis and intracellular ROS levels, which were strongly inhibited by CUR-NPs. CUR-NPs treatment remarkably suppressed the increased activity of Rac1, as well as the enhanced expression of p22phox, p47phox, p67phox and gp91phox induced by PA. Lipid peroxidation and SOD were reversed in the presence of CUR-NPs. Furthermore, CUR-NPs treatment markedly inhibited the reduced Bcl-2/Bax ratio elicited by PA exposure. CUR-NPs significantly increased GRP78 and CHOP expression in cardiomyocytes. Pravastatin (a known ERS inhibitor) blocked the effects of CUR-NPs on cardiomyocytes exposure to PA. These results demonstrated that CUR-NPs attenuated PA-induced cardiomyocyte apoptosis by inhibiting NADPH-mediated oxidative stress, and this protective effect is possibly mediated by endoplasmic reticulum stress (ERS)-related signaling pathway.

Inhibition of cyclooxygenase-2 reduces hypothalamic excitation in rats with adriamycin-induced heart failure.

BACKGROUND: The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the progression of heart failure (HF). We investigated whether cyclooxygenase-2 (COX-2) inhibition in the PVN attenuates the activities of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in rats with adriamycin-induced heart failure. METHODOLOGY/PRINCIPAL FINDING: Heart failure was induced by intraperitoneal injection of adriamycin over a period of 2 weeks (cumulative dose of 15 mg/kg). On day 19, rats received intragastric administration daily with either COX-2 inhibitor celecoxib (CLB) or normal saline. Treatment with CLB reduced mortality and attenuated both myocardial atrophy and pulmonary congestion in HF rats. Compared with the HF rats, ventricle to body weight (VW/BW) and lung to body weight (LW/BW) ratios, heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular peak systolic pressure (LVPSP) and maximum rate of change in left ventricular pressure (LV±dp/dtmax) were improved in HF+CLB rats. Angiotensin II (ANG II), norepinephrine (NE), COX-2 and glutamate (Glu) in the PVN were increased in HF rats. HF rats had higher levels of ANG II and NE in plasma, higher level of ANG II in myocardium, and lower levels of ANP in plasma and myocardium. Treatment with CLB attenuated these HF-induced changes. HF rats had more COX-2-positive neurons and more corticotropin releasing hormone (CRH) positive neurons in the PVN than did control rats. Treatment with CLB decreased COX-2-positive neurons and CRH positive neurons in the PVN of HF rats. CONCLUSIONS: These results suggest that PVN COX-2 may be an intermediary step for PVN neuronal activation and excitatory neurotransmitter release, which further contributes to sympathoexcitation and RAS activation in adriamycin-induced heart failure. Treatment with COX-2 inhibitor attenuates sympathoexcitation and RAS activation in adriamycin-induced heart failure.

Enhancement of the survival of engrafted mesenchymal stem cells in the ischemic heart by TNFR gene transfection.

Autologous or allogeneic mesenchymal stem cells (MSCs) have been used as one of the potential cell sources for cellular cardiomyoplasty. The adverse microenvironment in acute myocardial infarction, however, is considered a deleterious factor for MSC transplantation and cell survival. Tumor necrosis factor (TNF)-alpha is an inflammatory mediator produced during ischemia that may affect the survival of MSCs. In this study, we investigated the enhancement of MSC survival by transfecting cells with the TNF receptor (TNFR) gene, leading to the overproduction of TNFR and the binding of TNF-alpha. Rats with acute myocardial infarction, induced by the occlusion of the left coronary artery, were transplanted with MSC or MSC-TNFR. After 2 weeks of acute myocardial infarction, cardiac function was assessed. Engrafted MSC survival and localization of TNF-alpha protein in infarction myocardium were evaluated. The levels of TNF-alpha and TNFR in the infarction zone were assessed. The results indicate that MSC-TNFR transplantation (1) improved left ventricular function; (2) enhanced engrafted MSC survival in the infarcted myocardium; (3) attenuated the level of TNF-alpha in serum and cardiac tissue; and (4) increased TNFR protein production in the infarcted myocardium. Our results showed that MSC modified by the TNFR gene improved cell viability and thereby has the potential to improve the efficiency of MSC transplantation therapy in the ischemic heart.

TNFR gene-modified mesenchymal stem cells attenuate inflammation and cardiac dysfunction following MI.

OBJECTIVES: To investigate the protective effect of tumor necrosis factor receptor (TNFR) gene modified mesenchymal stem cells (MSCs) transplantation against inflammation and cardiac dysfunction following acute myocardial infarction (AMI). DESIGN: MSCs were extracted from the tibias and femurs of rats and transfected with recombinant adeno-associated viral (rAAV) expressing EGFP (enhanced green fluorescent protein) or p75 (human 75 kilodalton) TNFR at multiplicity of infection of 10(5) particles/cell. Rats with AMI induced by occlusion of the left coronary artery were randomized to MSCs-TNFR transplantation group, MSCs-EGFP transplantation group and MI control group. RESULTS: The effects of MSCs-TNFR transplantation on cardiac inflammation and left ventricular dysfunction were observed after 2 weeks of MI. We found that: 1) MSCs-TNFR transplantation attenuated protein production and gene expression of inflammatory cytokines TNF-, IL-1beta and IL-6; 2) MSCs-TNFR transplantation inhibited cardiomyocytes apoptosis and 3) MSCs-TNFR transplantation improved left ventricular function. CONCLUSIONS: The experimental data show that transplantation with rAAV-TNFR transfected MSCs improves left ventricular function following MI through anti-apoptotic and anti-inflammatory mechanisms.

Insulin-like growth factor 1 improves the efficacy of mesenchymal stem cells transplantation in a rat model of myocardial infarction.

BACKGROUND: Previous study demonstrated the improvement of cardiac function was proportional to the number of cells implanted. Therefore, increasing cell survival in the infarcted myocardium might contribute to the improvement of the functional benefit of cell transplantation. METHODS AND RESULTS: MSCs were treated with IGF-1 in vitro and infused into the acute myocardial infarction rats via the tail vein. After treatment of MSCs with IGF-1 for 48 h, flow cytometric analysis showed marked enhancement of expression of CXCR4 in the cell surface. After 4 weeks of transplantation, we found 1) a greater number of engrafted MSCs arrived and survived in the peri-infarct region; 2) TnT protein expression and capillary density were enhanced; 3) LV cavitary dilation, transmural infarct thinning, deposition of total collagen in the peri-infarct region and cardiac dysfunction were attenuated. CONCLUSION: 1) IGF-1 treatment has time-dependent and dose-dependent effects on CXCR4 expression in MSCs in vitro. 2) IGF-1 improves the efficacy of MSCs transplantation in a rat model of myocardial infarction mainly via enhancement of the number of cells attracted into the infarcted heart. These findings provide a novel stem cell therapeutic avenue against ischemic heart disease.

Anti-inflammation role for mesenchymal stem cells transplantation in myocardial infarction.

The aim of the present study was to investigate the role of anti-inflammation for MSCs transplantation in rat models of myocardial infarction. Rats with AMI induced by occlusion of the left coronary artery were randomized to MSCs transplantation group, MI group and sham operated group. The effects of MSCs transplantation on cardiac inflammation and left ventricular remodeling in non-infarcted zone were observed after 4 weeks of MI. We found that MSC transplantation (1) decreased protein production and gene expression of inflammation cytokines TNF-alpha, IL-1beta and IL-6, (2) inhibited deposition of type I and III collagen, as well as gene and protein expression of MMP-1 and TIMP-1, (3) attenuated LV cavitary dilation and transmural infarct thinning, thus prevent myocardial remodeling after myocardial infarction, and (4) increased EF, FS, LVESP and dp/dtmax (P < 0.01), decreased LVDd, LVEDV, LVEDP (P < 0.05). Anti-inflammation role for MSCs transplantation might partly account for the cardiac protective effect in ischemic heart disease.