Mesenchymal stem cells （MSCs）, the major stem cells for cell therapy, have been used in the clinic for approximately 10 years. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. In this review, we summarize the recent opinions on methods, timing and cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC-mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinic.
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.
Androgens and androgen receptors （AR） play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome （AIS） and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2-3 years as the patients develop castration-resistant prostate cancer （CRPC）. In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain （DBD） and ligand binding domain （LBD） provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.
Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases （PTPs） are considered next-generation drug targets. For instance, PTPIB is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type I diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTPIB, Src homology phosphotyrosyl phosphatase 2 （SHP2）, lymphoid-specific tyrosine phosphatase （LYP）, CD45, Fas associated phosphatase-1 （FAP-1）, striatal enriched tyrosine phosphatases （STEP）, mitogen-activated protein kinase/dual-specificity phosphatase 1 （MKP-1）, phosphatases of regenerating liver-1 （PRL）, low molecular weight PTPs （LMWPTP）, and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs.
Exosomes, a subgroup of extracellular vesicles (EVs), have been recognized as important mediators of long distance intercellular communication and are involved in a diverse range of biological processes. Because of their ideal native structure and characteristics, exosomes are promising nanocarriers for clinical use. Exosomes are engineered at the cellular level under natural conditions, but successful exosome modification requires further exploration. The focus of this paper is to summarize passive and active loading approaches, as well as specific exosome modifications and examples of the delivery of therapeutic and imaging molecules. Examples of exosomes derived from a variety of biological origins are also provided. The biocompatible characteristics of exosomes, with suitable modifications, can increase the stability and efficacy of imaging probes and therapeutics while enhancing cellular uptake. Challenges in clinical translation of exosome-based platforms from different cell sources and the advantages of each are also reviewed and discussed.
is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lyso- some. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.
Korean Panax ginseng C A Meyer is mainly used to maintain the homeostasis of the body, and the pharmacological efficacy of Korean ginseng identified by modem science includes improved brain function, pain-relieving effects, preventive effects against tumors as well as anti-tumor activity, enhanced immune system function, anti-diabetic effects, enhanced liver function, adjusted blood pressure, anti-fatigue and anti-stress effects, improved climacteric disorder and sexual functions, as well as anti-oxidative and anti-aging effects. Further clinical studies of these pharmacological efficacies will continue to be carried out. Korean ginseng is found to have such main properties as ginsenoside, ployacetylene, acid polysaccharide, anti-oxidative aromatic compound, and insulin-like acid peptides. The number of ginsenoside types contained in Korean ginseng （38 ginsenosides） is substantially more than that of ginsenoside types contained in American ginseng （19 ginsenosides）. Furthermore, Korean ginseng has been identified to contain more main non-saponin compounds, phenol compounds, acid polysaccharides and polyethylene compounds than American ginseng and Sanchi ginseng.
G-protein-coupled receptors （GPCRs） mediate many important physiological functions and are considered as one of the most success- ful therapeutic targets for a broad spectrum of diseases. The design and implementation of high-throughput GPCR assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates are critical in early drug discovery. Early functional GPCR assays depend primarily on the measurement of G-protein-mediated 2nd messenger generation. Taking advantage of the continuously deepening understanding of GPCR signal transduction, many G-protein-independent pathways are utilized to detect the activity of GPCRs, and may provide additional information on functiona~ selectivity of candidate compounds. With the combination of automated imaging systems and label-free detection systems, such assays are now suitable for high-throughput screening （HTS）. In this review, we summarize the most widely used GPCR assays and recent advances in HTS technologies for GPCR drug discovery.
Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis It was approved by the FDA for the treatment of advanced renal cell carcinoma in 2006, and as a unique target drug for advanced hepatocellular carcinoma （HCC） in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies to the primary resistance, mechanisms are underying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients.
As autophagy is involved in cell growth, survival, development and death, impaired autophagic flux has been linked to a variety of human pathophysiological processes, including neurodegeneration, cancer, myopathy, cardiovascular and immune-mediated disorders. There is a growing need to identify and quantify the status of autophagic flux in different pathological conditions. Given that autophagy is a highly dynamic and complex process that is regulated at multiple steps, it is often assessed accurately. This perspective review article will focus on the autophagic flux defects in different human disorders and update the current methods of monitoring autophagic flux. This knowledge is essential for developing autophagy-related therapeutics for treating the diseases.
This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented.
Systemic lupus erythematosus （SLE） is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Accumulating evidence shows that Toll-like receptors （TLRs）, previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules. Genome-wide association studies, experimental mouse models and clinical sample studies have provided evidence for the involvement of TLRs, including TLR2/4, TLR5, TLR3 and TLR7/8/9, in SLE pathogenesis. A number of downstream proteins in the TLR signaling cascade （such as MyD88, IRAKs and IFN-a） are identified as potential therapeutic targets for SLE treatment. Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment. Moreover, the emerging new manipulation of TLR signaling by microRNA （miRNA） regulation shows promise for the future treatment of SLE.
Aim： Berberine （BBR）, an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum （ER） stress plays a pivotal role in myocardial ischemia/reperfusion （MI/R）-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process. Methods： Male rats were treated with BBR （200 mg.k-1.d-1, ig） for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion （SIR）. The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses.Results： Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and elF2a and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR （50 pmol/L） markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA. Conclusion： BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.
Aim: To investigate whether curcumin (Cur) suppressed lipopolysaccharide (LPS)-induced inflammation in vascular smooth muscle cells (VSMCs) of rats, and to determine its molecular mechanisms. Methods: Primary rat VSMCs were treated with LPS (1 mu g/L) and Cur (5, 10, or 30 mu mol/L) for 24 h. The levels of MCP-1, TNF-alpha, and iNOS were measured using ELISA and real-time RT-PCR. NO level was analyzed with the Griess reaction. Western-blotting was used to detect the activation of TLR4, MAPKs, I kappa B alpha, NF-kappa B p65, and the p47(phox) subunit of NADPH oxidase in the cells. Results: Treatment of VSMCs with LPS dramatically increased expression of inflammatory cytokines MCP-1 and TNF-alpha, expression of TLR4 and iNOS, and NO production. LPS also significantly increased phosphorylation of I kappa B alpha, nuclear translocation of NF-kappa B (p65) and phosphorylation of MAPKs in VSMCs. Furthermore, LPS significantly increased production of intracellular ROS, and decreased expression of p47(phox) subunit of NADPH oxidase. Pretreatment with Cur concentration-dependently attenuated all the aberrant changes in LPS-treated VSMCs. The LPS-induced overexpression of MCP-1 and TNF-alpha, and NO production were attenuated by pretreatment with the ERK inhibitor PD98059, the p38 MAPK inhibitor SB203580, the NF-kappa B inhibitor PDTC or anti-TLR4 antibody, but not with the JNK inhibitor SP600125. Conclusion: Cur suppresses LPS-induced overexpression of inflammatory mediators in VSMCs in vitro via inhibiting the TLR4-MAPK/NF-.B pathways, partly due to block of NADPH-mediated intracellular ROS production.
The rapid advancement of nanotechnology in recent years has fuelled a burgeoning interest in the field of nanoparticle research, in particular, its application in the medical arena. A constantly expanding knowledge based on a better understanding of the properties of gold nanoparticles （AuNPs） coupled with relentless experimentation means that the frontiers of nanotechnology are constantly being challenged. At present, there seems to be heightened interest in the application of AuNPs to the management of cancer, encompass- ing diagnosis, monitoring and treatment of the disease. These efforts are undertaken in the hope of revolutionizing current methods of treatment and treatment strategies for a multifactodal disease such as cancer. This review will focus on the current applications of AuNPs in cancer management.
It has been widely recognized that inflammation, particularly chronic inflammation, can increase the risk of cancer and that the simultaneous treatment of inflammation and cancer may produce excellent therapeutic effects. Berberine, an alkaloid isolated from Rhizoma coptidis, has broad applications, particularly as an antibacterial agent in the clinic with a long history. Over the past decade, many reports have demonstrated that this natural product and its derivatives have high activity against both cancer and inflammation In this review, we sqmmarize the advances in studing berberine and its derivatives as anti-inflammatory and anti-tumor agents in the digestive system; we also discuss their structure-activity relationship. These data should be useful for the development of this natural product as novel anticancer drugs with anti-inflammation activity.
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.
Depression is one of the most prevalent and life-threatening forms of mental illnesses and the neural circuitry underlying depression remains incompletely understood. Most attention in the field has focused on hippocampal and frontal cortical regions for their roles in depression and antidepressant action. While these regions no doubt play important roles in the mental illness, there is compelling evidence that other brain regions are also involved. Brain-derived neurotrophic factor （BDNF） is broadly expressed in the developing and adult mammalian brain and has been implicated in development, neural regeneration, synaptic transmission, synaptic plasticity and neurogenesis. Recently BDNF has been shown to play an important role in the pathophysiology of depression, however there are controversial reports about the effects of BDNF on depression. Here, we present an overview of the current knowledge concerning BDNF actions and associated intraceilular signaling in hippocampus, prefrontal cortex, nucleus accumbens （NAc） and amygdala as their relation to depression.
Recent studies have revealed extensive genetic and non-genetic variation across different geographical regions of a tumor or throughout different stages of tumor progression, which is referred to as intra-tumor heterogeneity. Several causes contribute to this phenomenon, including genomic instability, epigenetic alteration, plastic gene expression, signal transduction, and microenvironmental differences. These variables may affect key signaling pathways that regulate cancer cell growth, drive phenotypic diversity, and pose challenges to cancer treatment. Understanding the mechanisms underlying this heterogeneity will support the development of effective therapeutic strategies.
Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress （ERS） is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response （UPR） to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.