Cancer stem cells （CSCs） have been identified as rare cell populations in many cancers, including leukemia and solid tumors. Accumulating evidence has suggested that CSCs are capable of self-renewal and differentiation into various types of cancer cells. Aberrant regulation of gene expression and some signaling pathways has been observed in CSCs compared to other tumor cells. CSCs are thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug resistance. The CSC hypothesis has recently attracted much attention due to the potential for discovery and development of CSC-related therapies and the identification of key molecules involved in controlling the unique properties of CSC populations. Over the past several years, a tremendous amount of effort has been invested in the development of new drugs, such as nanomedicines, that can take advantage of the ＂Achilles＇ heel＂ of CSCs by targeting cell-surface molecular markers or various signaling pathways. Novel compounds and therapeutic strategies that selectively target CSCs have been identified, some of which have been evaluated in preclinical and clinical studies. In this article, we review new findings related to the investigation of the CSC hypothesis, and discuss the crucial pathways involved in regulating the development of CSC populations and the advances in studies of drug resistance. In addition, we review new CSC-targeted therapeutic strategies aiming to eradicate malignancies.
Amyloid beta peptide （Aβ） is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein （APP）, by β- and y-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer＇s disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer＇s disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer＇s disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer＇s disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ inhibitors or modulators of β- and y-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.
A pivotal role for excitotoxicity in neurodegenerative diseases is gaining increasingly more acceptance, but the underlying mechanisms through which it participates in neurodegeneration still need further investigation. Excessive activation of glu- tamate receptors by excitatory amino acids leads to a number of deleterious consequences, including impairment of calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxic- ity. Recent studies implicate excitotoxicity in a variety of neuropathological conditions, suggesting that neurodegenerative diseases with distinct genetic etiologies may share excitotoxicity as a common pathogenic pathway. Thus, understanding the pathways involved in excitotoxicity is of critical importance for the future clinical treatment of many neurodegenerative diseases. This review discusses the current understanding of excitotoxic mechanisms and how they are involved in the pathogenesis of neurodegenerative diseases.
Exosomes are nano-sized vesicles that serve as mediators for intercellular communication through the delivery of cargo, including protein, lipids, nucleic acids or other cellular components, to neighboring or distant cells. Exosomal cargo may vary in response to different physiological or pathological conditions. The endosomal sorting complex required for transport (ESCRT) family has been widely accepted as a key mechanism in biogenesis and cargo sorting. On the other hand, accumulating evidence show that ESCRT-independent pathways exist. Due to the critical role of exosomes in intercellular communications in delivering cargo to recipient cells, exosomes have been investigated as a vector for the delivery of endogenous or exogenous cargo for therapeutic purposes. But the number of exosomes produced by cells is limited, which hampers their application. Synthetic exosome-mimics have been fabricated and investigated as a therapeutic tool for drug delivery. This review focuses on ESCRT-independent regulation of cargo loading into exosomes, including lipid raft and ceramide-mediated mechanisms, and reported exosomes or exosome-mimics with therapeutic effects.
EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that methylates lysine 27 of histone 3. Overexpression of EZH2 has been found in a wide range of cancers, including those of the prostate and breast. In this review, we address the current understanding of the oncogenic role of EZH2, including its PRC2-dependent transcriptional repression and PRC2-independent gene activation. We also discuss the connections between EZH2 and other silencing enzymes, such as DNA methyltransferase and histone deacetylase. We comprehensively address the architecture of the PRC2 complex and the crucial roles of each subunit. Finally, we summarize new progress in developing EZH2 inhibitors, which could be a new epigenetic therapy for cancers.
Inflammation plays a critical role in mediating brain injury induced by neonatal hypoxic ischemic encephalopathy （HIE）. The mechanisms underlying inflammatory responses to ischemia may be shared by neonatal and adult brains; however, HIE exhibits a unique inflammation phenotype that results from the immaturity of the neonatal immune system. This review will discuss the current knowledge concerning systemic and local inflammatory responses in the acute and subacute stages of HIE. The key components of inflammation, including immune cells, adhesion molecules, cytokines, chemokines and oxidative stress, will be reviewed, and the differences between neonatal and adult inflammatory responses to cerebral ischemic injury will also be discussed.
Glioma accounts for the majority of human brain tumors. With prevailing treatment regimens, the patients have poor survival rates. In spite of current development in mainstream glioma therapy, a cure for glioma appears to be out of reach. The infiltrative nature of glioma and acquired resistance substancially restrict the therapeutic options. Better elucidation of the complicated pathobiology of glioma and proteogenomic characterization might eventually open novel avenues for the design of more sophisticated and effective combination regimens. This could be accomplished by individually tailoring progressive neuroimaging techniques, terminating DNA synthesis with prodrug-activating genes, silencing gliomagenesis genes (gene therapy), targeting miRNA oncogenic activity (miRNA-mRNA interaction), combining Hedgehog-Gli/Akt inhibitors with stem cell therapy, employing tumor lysates as antigen sources for efficient depletion of tumor-specific cancer stem cells by cytotoxic T lymphocytes (dendritic cell vaccination), adoptive transfer of chimeric antigen receptor-modified T cells, and combining immune checkpoint inhibitors with conventional therapeutic modalities. Thus, the present review captures the latest trends associated with the molecular mechanisms involved in glial tumorigenesis as well as the limitations of surgery, radiation and chemotherapy. In this article we also critically discuss the next generation molecular therapeutic strategies and their mechanisms for the successful treatment of glioma.
Aim: It is general believed that mitochondrial dysfunction and oxidative stress play critical roles in the pathology of Parkinson's disease (PD). Dihydromyricetin (DHM), a natural flavonoid extracted from Ampelopsis grossedentata, has recently been found to elicit potent anti-oxidative effects. In the present study, we explored the role of DHM in protecting dopaminergic neurons. Methods: Male C57BL/6 mice were intraperitoneally injected with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 d to induce PD. Additionally, mice were treated with either 5 or 10 mg/kg DHM for a total of 13 d (3 d before the start of MPTP, during MPTP administration (7 d) and 3 d after the end of MPTP). For the saline or DHM alone treatment groups, mice were injected with saline or DHM for 13 d. On d 14, behavioral tests (locomotor activity, the rotarod test and the pole test) were administered. After the behavioral tests, the mice were sacrificed, and brain tissue was collected for immunofluorescence staining and Western blotting. In addition, MES23.5 cells were treated with MPP+ and DHM, and evaluated using cell viability assays, reactive oxygen species (ROS) measurements, apoptosis analysis and Western blotting. Results: DHM significantly attenuated MPTP-induced mouse behavioral impairments and dopaminergic neuron loss. In the MES23.5 cells, DHM attenuated MPP+-induced cell injury and ROS production in a dose-dependent manner. In addition, DHM increased glycogen synthase kinase-3 beta phosphorylation in a dose-and time-dependent manner, which may be associated with DHM-induced dopaminergic neuronal protection. Conclusion: The present study demonstrated that DHM is a potent neuroprotective agent for DA neurons by modulating the Akt/GSK-3 beta pathway, which suggests that DHM may be a promising therapeutic candidate for PD.
The identification of the estrogen-related receptors (ERRs) as the first orphan nuclear receptors ignited a new era in molecular endocrinology, which led to the discovery of new ligand-dependent response systems. Although ERR subfamily members have yet to be associated with a natural ligand, the characterization of these orphan receptors has demonstrated that they occupy a strategic node in the transcriptional control of cellular energy metabolism. In particular, ERRs are required for the response to various environmental challenges that require high energy levels by the organism. As central regulators of energy homeostasis, ERRs may also be implicated in the etiology of metabolic disorders, such as type 2 diabetes and metabolic syndrome. Here, we review the recent evidence that further highlights the role of ERRs in metabolic control, particularly in liver and skeletal muscle, and their likely involvement in metabolic diseases. Consequently, we also explore the promises and pitfalls of ERRs as potential therapeutic targets.
Cardiac fibrosis is considered the initial change of diabetic cardiomyopathy （DCM）. We have shown that curcumin alleviates collagen deposition in DCM, but the mechanism remains unknown. In this study we sought to investigate the effects of curcumin on cardiac fibrosis in vivo and in vitro and to elucidate the underlying mechanisms. Experimental diabetes was induced in rats by injection of lowdose streptozotocin （STZ） combined with high energy diet. The rats were orally treated with curcumin （300 mg·kg^-1·d^-1） for 16 weeks. Curcumin administration significantly suppressed the deposition of type I and type III collagens in the heart tissues of diabetic rats, accompanied by markedly reduced TGF-β1 production, suppressed TβR II levels and Smad2/3 phosphorylation, and increased Smad7 expression. Similar effects were observed in human cardiac fibroblasts exposed to high glucose （HG, 30 mmol/L） or exogenous TGF-β1 （5 ng/mL）. Furthermore, TGF-β1 or HG treatment significantly increased the phosphorylation levels of AMPK and p38 MAPK in the fibroblasts. Application of curcumin （25 pmol/L） inhibited TGF-β1- or HG-induced AMPK/p38 MAPK activation and suppressed collagen synthesis in the fibroblasts. These effects were similar to those of the AMPK inhibitor compound C （10 pmol/L） but opposite to the effects of the AMPK activator metformin （2 mmol/L） in the fibroblasts. Our results demonstrate that curcumin suppresses diabetes- associated collagen synthesis in rat myocardium not only by inhibiting TGF-β1 production and canonical Smad signaling but also by blocking the non-canonical AMPK/p38 MAPK pathway.
Cancer is an extremely diverse and complex disease that results from various genetic and epigenetic changes such as DNA copy-number variations, mutations, and aberrant mRNA and/or protein expression caused by abnormal transcriptional regulation. The expression profiles of certain microRNAs （miRNAs） and messenger RNAs （mRNAs） are closely related to cancer progression stages. In the past few decades, DNA microarray and next-generation sequencing techniques have been widely applied to identify miRNA and mRNA signatures for cancers on a genome-wide scale and have provided meaningful insights into cancer diagnosis, prognosis and personalized medicine. In this review, we summarize the progress in genome-wide analysis of miRNAs and mRNAs as cancer biomarkers, highlighting their diagnostic and prognostic roles.
Diterpene ginkgolides meglumine injection (DGMI) is a therapeutic extract of Ginkgo biloba L, which has been used for the treatment of cerebral ischemic stroke in China. Ginkgolides A, B and C are the main components of DGMI. This study was designed to investigate the neuroprotective effects of DGMI components against ischemic stroke in vivo and in vitro. Acute cerebral ischemic injury was induced in rats by occlusion of the middle cerebral artery (MCA) for 1.5 h followed by 24 h reperfusion. The rats were treated with DGMI (1, 3 and 10 mg/kg, iv) at the onset of reperfusion and 12 h after reperfusion. Administration of DGMI significantly decreased rat neurological deficit scores, reduced brain infarct volume, and induced protein kinase B (Akt) phosphorylation, which prompted the nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and phosphorylation of the survival regulatory protein cyclic AMP-responsive element binding protein (CREB). Nrf2 activation led to expression of the downstream protein heme oxygenase-1 (HO-1). In addition, PC12 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) in vitro, treatment with DGMI (1, 10 and 20 mu g/mL) or ginkgolides A, B or C (10 mu mol/L for each) significantly reduced PC12 cell death and increased phosphorylation of Akt, nuclear translocation of Nrf2 and activation of CREB. Activation of Nrf2 and CREB could be reversed by co-treatment with a phosphoinositide-3-kinase (PI3K) inhibitor LY294002. These observations suggest that ginkgolides act as novel extrinsic regulators activating both Akt/Nrf2 and Akt/CREB signaling pathways, protecting against cerebral ischemia/reperfusion (I/R) damage in vivo and in vitro.
Guanxinjing capsules (GXJCs) are used in traditional Chinese medicine as a common therapy for coronary heart disease (CHD) complicated with depression. In this study, we aimed to identify the main active constituents in GXJCs and to investigate the mechanisms of GXJC action on CHD complicated with depression. The chemical constituent profile of the GXJC was identified by UHPLC-LTQ-Orbitrap assay, and oral bioavailability was evaluated to screen the GXJC drug-like chemical constituents. A total of 16 GXJC drug-like chemical constituents were identified. Then, putative targets of the GXJC drug-like chemical constituents were predicted using MedChem Studio, with 870 genes found to be the putative targets of these molecules. After that, a GXJC putative target-known CHD/depression therapeutic target network was constructed, and four topological features, including degree, betweenness, closeness and K-coreness, were calculated. According to the topological feature values of the GXJC putative targets, 14 main active constituents were identified because their corresponding putative targets had topological importance in the GXJC putative target-known CHD/depression therapeutic target network, which were defined as the candidate targets of GXJC against CHD complicated with depression. Functionally, these candidate targets were significantly involved in several CHD/depression-related pathways, including repairing pathological vascular changes, reducing platelet aggregation and inflammation, and affecting patient depression. This study identified a list of main active constituents of GXJC acting on CHD complicated with depression using an integrative pharmacology-based approach that combined active chemical constituent identification, drug target prediction and network analysis. This method may offer an efficient way to understand the pharmacological mechanisms of traditional Chinese medicine prescriptions.
The root of Polygonum multiflorum Thunb （PM） has been used in China to treat a variety of diseases, such as constipation, early graying of the hair and hyperlipemia. Recent evidence shows that PM causes idiosyncratic drug-induced liver injury （IDILI） in humans. In this study, we investigated the molecular basis of PM-induced liver injury in a rat model of IDILI based on a non-hepatotoxic dose of LPS. SD rats were orally administered 3 potentially hepatotoxic compounds of PM： cis-stilbene glucoside （cis-SG, 50 mg/kg）, trans-SG （50 mg/kg） or emodin （5 mg/kg）, followed by injection of LPS （2.8 mg/kg, iv）. Serum and liver histology were evaluated 7 h after LPS injection. Among the 3 compounds tested, cis-SG, but not emodin or trans-SG, induced severe liver injury in rats when combined with LPS. The levels of AST and ALT in plasma and inflammatory cytokines in both plasma and liver tissues were markedly elevated. The liver tissues showed increased injury, hepatocyte apoptosis, and macrophage infiltration, and decreased cell proliferation. Microarray analysis revealed a negative correlation between peroxisome proliferator-activated receptor-y （PPAR-y） and LPS/cis-SG-induced liver injury. Immunohistochemical staining and RT-PCR results further confirmed that cis-SG significantly inhibited activation of the PPAR-~ pathway in the liver tissues of LPS/cis-SG-treated rats. Pre-treatment with a PPAR-y agonist pioglitazone （500 g/kg, ig） reversed LPS/ cis-SG-induced liver injury, which was associated with inhibiting the nuclear factor kappa B （NF-KB） pathway. These data demonstrate that c/s-stilbene glucoside induces immunological idiosyncratic hepatotoxicity through suppressing PPAR-γ in a rat model of IDILl.
Diabetes mellitus is currently a major public health problem. A common complication of diabetes is cardiac dysfunction, which is recognized as a microvascular disease that leads to morbidity and mortality in diabetic patients. While ischemic events are commonly observed in diabetic patients, the risk for developing heart failure is also increased, independent of the severity of coronary artery disease and hypertension. This diabetes-associated clinical entity is considered a distinct disease process referred to as "diabetic cardiomyopathy". However, it is not clear how diabetes promotes cardiac dysfunction. Vascular endothelial dysfunction is thought to be one of the key risk factors. The impact of diabetes on the endothelium involves several alterations, including hyperglycemia, fatty acid oxidation, reduced nitric oxide (NO), oxidative stress, inflammatory activation, and altered barrier function. The current review provides an update on mechanisms that specifically target endothelial dysfunction, which may lead to diabetic cardiomyopathy.
Medical application of Panax ginseng was first found in ＂Shen-Nong Herbal Classic＂ around 200 AD Panax quinquefolium was first introduced in ＂Essential of Materia Medica＂ in 1694 in China. The most important bioactive components contained in P ginseng and P quinquefolium are ginseng saponins （GS）. The contents of ginsenoside Rb 1, Re, and Rd in P quinquefolium are higher than they are in P ginseng. In P ginseng, the contents of Rg 1,Rb2, and Rc are higher than they are in P quinquefolium. P ginseng had a higher ratio of Rgl： Rbl, and which was lower in P quinquefolium. After steaming for several hours, the total GS will decrease. However, some ginsenosides （Rg2, 20R-Rg2, Rg3, Rhl and Rh2） increase, while others （Rbl, Rb2, Rb3, Rc, Rd, Re, and Rg1） decrease. However, variation, especially in P quinquefolium, is high. P ginseng and P quinquefolium are general tonics and adaptogens. Rgl and Rbl enhance central nervous system （CNS） activities, but the effect of the latter is weaker. Thus, for the higher contents of Rgl, P ginseng is a stimulant, whereas the Rbl contents of P quinquefolium are mainly calming to the CNS. Re, Rg1, panaxan A and B from P ginseng are good for diabetes. Re and Rgl enhance angiogenesis, whereas Rb1, Rg3 and Rh2 inhibit it. Rh2, an antitumor agent, can be obtained from Rbl by steaming. The content of Re in P quinquefolium are higher than in P ginseng by 3-4 times. The vasorelax, antioxidant, antihyperlipidemic, and angiogenic effects of Re are reported. Thus, for the CNS ＂hot,＂ wound healing and hypoglycemic effects, P ginseng is better than P quinquefolium. For anticancer effects, P quinquefolium is better.