Showing papers in "Frontiers in Bioscience in 2015"

Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation.

Abstract: The kynurenine (Kyn) pathway is the major route for tryptophan (Trp) metabolism, and it contributes to several fundamental biological processes. Trp is constitutively oxidized by tryptophan 2, 3-dioxygenase in liver cells. In other cell types, it is catalyzed by an alternative inducible indoleamine-pyrrole 2, 3-dioxygenase (IDO) under certain pathophysiological conditions, which consequently increases the formation of Kyn metabolites. IDO is up-regulated in response to inflammatory conditions as a novel marker of immune activation in early atherosclerosis. Besides, IDO and the IDO-related pathway are important mediators of the immunoinflammatory responses in advanced atherosclerosis. In particular, Kyn, 3-hydroxykynurenine, and quinolinic acid are positively associated with inflammation, oxidative stress (SOX), endothelial dysfunction, and carotid artery intima-media thickness values in end-stage renal disease patients. Moreover, IDO is a potential novel contributor to vessel relaxation and metabolism in systemic infections, which is also activated in acute severe heart attacks. The Kyn pathway plays a key role in the increased prevalence of cardiovascular disease by regulating inflammation, SOX, and immune activation.

Matrix metalloproteinases as breast cancer drivers and therapeutic targets.

Abstract: Members of the matrix metalloproteinase (MMP) family have been identified as poor prognosis markers for breast cancer patients and as drivers of many facets of the tumor phenotype in experimental models. Early enthusiasm for MMPs as therapeutic targets was tempered following disappointing clinical trials that utilized broad spectrum, small molecule catalytic site inhibitors. However, subsequent research has continued to define key roles for MMPs as breast cancer promoters, to elucidate the complex roles that that these proteins play in breast cancer development and progression, and to identify how these roles are linked to specific and unique biochemical features of individual members of the MMP family. Here, we provide an overview of the structural features of the MMPs, then discuss clinical studies identifying which MMP family members are linked with breast cancer development and new experimental studies that reveal how these specific MMPs may play unique roles in the breast cancer microenvironment. We conclude with a discussion of the most promising avenues for development of therapeutic agents capable of targeting the tumor-promoting properties of MMPs.

The building process of the functional paraspeckle with long non-coding RNAs.

Abstract: Nuclei of mammalian cells are highly organized and composed of distinct subnuclear structures termed nuclear bodies. Paraspeckles are subnuclear structures that form around the long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) together with numerous RNA-binding proteins, many of which contain an RNA-binding domain and a prion-like domain and are related to specific neurodegenerative diseases. Paraspeckle formation proceeds in conjunction with NEAT1 lncRNA biogenesis and involves the cooperation of multiple paraspeckle-localized RNA-binding proteins. NEAT1 lncRNA likely sequesters these RNA-binding proteins in paraspeckle structures, which act as molecular sponges at which the nucleoplasmic activities of the sequestered proteins are modulated. This review presents, firstly, current knowledge regarding factors involved in the formation and function of paraspeckles. Secondly, the intracellular functions of all identified paraspeckle proteins, which are potentially controlled through their sequestration in paraspeckles, are categorized. Thirdly, recently identified nuclear bodies containing putative architectural lncRNAs are described and similarities among the architectures of lncRNA-dependent nuclear bodies are discussed.

Lactic dehydrogenase and cancer: an overview

Abstract: Despite the intense scientific efforts made, there are still many tumors that are difficult to treat and the percentage of patient survival in the long-term is still too low. Thus, new approaches to the treatment of cancer are needed. Cancer is a highly heterogeneous and complex disease, whose development requires a reorganization of cell metabolism. Most tumor cells downregulate mitochondrial oxidative phosphorylation and increase the rate of glucose consumption and lactate release, independently of oxygen availability (Warburg effect). This metabolic rewiring is largely believed to favour tumor growth and survival, although the underlying molecular mechanisms are not completely understood. Importantly, the correlation between the aerobic glycolysis and cancer is widely regarded as a useful biochemical basis for the development of novel anticancer strategies. Among the enzymes involved in glycolysis, lactate dehydrogenase (LDH) is emerging as a very attractive target for possible pharmacological approaches in cancer therapy. This review addresses the state of the art and the perspectives concerning LDH both as a useful diagnostic marker and a relevant molecular target in cancer therapy and management.

Roles of lncRNA in breast cancer.

Abstract: Recent systematic genomic studies have revealed a broad spectrum of lncRNAs that are involved in a variety of disease (diseases), including tumor progression, by regulating gene expression at epigenetic, transcriptional and post-transcriptional levels. However, their exact roles of physiological function and the mechanism (mechanisms) of action are yet to be clarified. In breast cancer research, several lncRNAs are identified as tumor driving oncogenic lncRNAs and few are identified as tumor suppressive lncRNAs. They are involved in cell growth, apoptosis, cell migration and invasiveness as well as cancer cell stemness. Therefore, this new class of RNAs may serve as biomarkers for diagnostic and prognostic purpose and also as potential therapeutic targets. This review summarizes the current information about lncRNAs that are particularly involved in breast cancer progression and also discusses the potential translational application of these newly discovered nucleic acids.

How fisetin reduces the impact of age and disease on CNS function.

Abstract: It is becoming increasingly clear that neurological diseases are multi-factorial involving disruptions in multiple cellular systems. Thus, while each disease has its own initiating mechanisms and pathologies, certain common pathways appear to be involved in most, if not all, neurological diseases. Thus, it is unlikely that modulating only a single factor will be effective at either preventing disease development or slowing disease progression. A better approach is to identify small (< 900 daltons) molecules that have multiple biological activities relevant to the maintenance of brain function. We have identified an orally active, novel neuroprotective and cognition-enhancing molecule, the flavonoid fisetin. Fisetin not only has direct antioxidant activity but it can also increase the intracellular levels of glutathione, the major intracellular antioxidant. Fisetin can also activate key neurotrophic factor signaling pathways. In addition, it has anti-inflammatory activity and inhibits the activity of lipoxygenases, thereby reducing the production of pro-inflammatory eicosanoids and their by-products. This wide range of actions suggests that fisetin has the ability to reduce the impact of age-related neurological diseases on brain function.

The role of microRNAs in skeletal muscle health and disease.

Abstract: Over the last decade non-coding RNAs have emerged as importance regulators of gene expression. In particular, microRNAs are a class of small RNAs of ∼ 22 nucleotides that repress gene expression through a post-transcriptional mechanism. MicroRNAs have been shown to be involved in a broader range of biological processes, both physiological and pathological, including myogenesis, adaptation to exercise and various myopathies. The purpose of this review is to provide a comprehensive summary of what is currently known about the role of microRNAs in skeletal muscle health and disease.

Chronic kidney disease alters vascular smooth muscle cell phenotype.

Abstract: Vascular access dysfunction associated with arteriovenous grafts and fistulas contributes to the morbidity and mortality of chronic kidney disease (CKD) patients receiving hemodialysis. We hypothesized that the uremic conditions associated with CKD promote a pathophysiological vascular smooth muscle cell (VSMC) phenotype that contributes to neointimal hyperplasia. We analyzed the effect of culturing human VSMC with uremic serum. Expression of VSMC contractile marker genes was reduced 50-80% in cells exposed to uremic serum and the decreased expression was accompanied by changes in histone marks. There was an increase in proliferation in cells exposed to uremic conditions, with no change in the levels of apoptosis. Interestingly, we found that uremic serum inhibited PDGF-induced migration of VSMC. Histomorphometric analysis revealed venous neointimal hyperplasia in veins from chronic kidney disease (CKD) patients prior to any surgical manipulation as compared to veins from patients with no kidney disease. We conclude that uremia associated with CKD alters VSMC phenotype in vitro and contributes to neointimal hyperplasia formation in vivo contributing to the pathogenesis of vascular access dysfunction in CKD patients.

Glioma: an overview of current classifications, characteristics, molecular biology and target therapies.

Abstract: Glioma is the most common primary brain tumor, accounting for 30% to 40% of all intracranial tumors. About half of all gliomas in adults are glioblastomas. Patients with glioblastoma have a poor prognosis, with a median survival of one year despite aggressive therapy and a five year mortality of over 95%. Although considerable progress has been made in the technical proficiencies of surgical and radiation oncology, the overall impact of these advances on clinical outcomes has been disappointing. Recent elucidation of several biochemical and molecular markers associated with glioma may provide valuable insight into the underlying biological features of the disease, as well as illuminate possible new therapeutic targets. This review focuses on the current characteristics, classifications, and management of glioma.

MMP Inhibitors: Past, present and future.

Abstract: Development of inhibitors of matrix metalloproteinases (MMPs) has been fraught with challenges. Early compounds largely failed due to poor selectivity and bioavailability. Dose-limiting side effects, off-target interactions, and improperly designed clinical trials significantly impeded clinical success. As information becomes available and technology evolves, tools to combat these obstacles have been developed. Improved methods for high throughput screening and drug design have led to identification of compounds exhibiting high potency, binding affinity, and favorable pharmacokinetic profiles. Current research into MMP inhibitors employs innovative approaches for drug delivery methods and allosteric inhibitors. Such innovation is key for development of clinically successful compounds.

Aquaporins in the female reproductive system of mammals.

Abstract: Water and ion accumulation is the driving force for rapid expansion of the amnion and allantois of mammalian placentae during early gestation, and, therefore, essential for embryonic/fetal growth and survival. Aquaporins (AQP) are a family of small integral plasma membrane proteins that primarily transport water across the plasma membrane. To date, thirteen AQP isoforms (AQP 0-12) have been identified in mammals. AQP 1, 2, 3, 4, 5, 6, 7, 8, 9, and 11 are expressed in the female reproductive tract. Based on their structural and functional properties, AQPs are divided into three subgroups: classical aquaporins (AQP 0, 1, 2, 4, 5, 6, and 8), aquaglyceroporins (AQP 3, 7, 9, and 10), and superaquaporins (AQP 11 and 12). Expression of AQPs in the uterus and placenta is regulated by hormones and nutrients to maintain fluid homeostasis in the conceptus. The underlying mechanisms may involve signal transduction pathways mediated by cAMP, MAPK, PKC, and PI3K/Akt/mTOR. Such new knowledge will advance basic understanding of mammalian reproductive biology to enhance embryonic/fetal survival, growth and development in women and livestock.

Nutritional and regulatory roles of leucine in muscle growth and fat reduction.

Abstract: The metabolic roles for L-leucine, an essential branched-chain amino acid (BCAA), go far beyond serving exclusively as a building block for de novo protein synthesis. Growing evidence shows that leucine regulates protein and lipid metabolism in animals. Specifically, leucine activates the mammalian target of rapamycin (mTOR) signaling pathway, including the 70 kDa ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor (eIF) 4E-binding protein 1 (4EBP1) to stimulate protein synthesis in skeletal muscle and adipose tissue and to promote mitochondrial biogenesis, resulting in enhanced cellular respiration and energy partitioning. Activation of cellular energy metabolism favors fatty acid oxidation to CO2 and water in adipocytes, lean tissue gain in young animals, and alleviation of muscle protein loss in aging adults, lactating mammals, and food-deprived subjects. As a functional amino acid, leucine holds great promise to enhance the growth, efficiency of food utilization, and health of animals and humans.

Andrographolide and analogues in cancer prevention.

Abstract: Andrographis paniculata is a medicinal plant traditionally used for treatment of cough and cold, fever, laryngitis, and several infectious diseases. Extracts of A. paniculata have shown versatile potency against various diseases including cancer. The active biomolecules of A. paniculata mainly are lactone and diterpene. Andrographolide and analogues have been widely used for prevention of different diseases. Andrographolides have shown potent antiinflammatory and anticancer activities. It showed potentials as chemopreventive agents by suppressing growth of cancer cells by inhibiting NF-kappaB, PI3K/AKT and other kinase pathways and by inducing apoptosis. Andrographolide induced both intrinsic and extrinsic apoptosis pathway in different cancer cells via expression of different anti-apoptotic protein like Bax, p53, and activated caspases. Andrographolide was successfully used as an antineoplastic drug in cancer chemotherapy. Andrographolide inhibited the growth of human breast, prostate, and hepatoma tumors. Andrographolide and analogues need to be subjected to further clinical and biomedical studies in cancer chemoprevention. Andrographolide could be potent anticancer agent when used in combination with other chemotherapeutic agents.

Ageing, neuroinflammation and neurodegeneration.

Abstract: During ageing, different iron complexes accumulate in specific brain regions which are associated with motor and cognitive dysfunction. In neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in local iron homoeostasis result in altered cellular iron distribution and accumulation, ultimately inducing neurotoxicity. The use of iron chelators which are able to penetrate the blood brain barrier and reduce excessive iron accumulation in specific brain regions have been shown to reduce disease progression in both Parkinson's disease and Friedreich's Ataxia. Neuroinflammation often occurs in neurodegenerative diseases, which is mainly sustained by activated microglia exhibiting the M1 phenotype. Such inflammation contributes to the disease progression. Therapeutic agents which reduce such inflammation, e.g. taurine compounds, may ameliorate the inflammatory process by switching the microglia from a M1 to a M2 phenotype.

E3 ubiquitin ligase Skp2 as an attractive target in cancer therapy.

Abstract: E3 ubiquitin ligase Skp2 attaches ubiquitin to its target proteins and marks them for destruction by the 26S proteasome. This mechanism participates in a number of important cellular processes such as cell proliferation, DNA replication, V(D)J recombination, gene transcription, cellular metabolism and senescence. Skp2 is oncogenic. It is overexpressed in various solid tumors and hematological malignancies. Due to the antagonistic role Skp2 plays against p27, Skp2 overexpression is frequently associated with down-regulation of p27. Importantly, Skp2 overexpression in cancer cells is prognostic of cancer progression and overall survival. Recent studies have shown that Skp2 suppression might be an excellent strategy to inhibit tumorigenesis in tumors in which tumor suppressor genes such as VHL, RB or TP53 are mutated. In this review, we also summarize early efforts in the development of Skp2 inhibitors. The implications of continued, long-term Skp2 suppression is discussed.

Tumour-associated macrophage polarisation and re-education with immunotherapy.

Abstract: Monocytes/macrophages constitute important contributors of cancer-associated inflammation. Through their plasticity and capacity to become polarised by tumours towards less activatory and more immunosuppressive (M2) phenotypes, tumour-associated macrophages (TAM) are thought to support tumour progression. Orchestrated by T helper 2 (Th2)-biased stimuli, macrophage recruitment, activation and polarisation in tumour microenvironments is associated with poorer clinical outcomes. Their key roles in supporting tumour progression and their capacity for plasticity have focused targeted and immunotherapeutic strategies to counteract macrophage pro-tumourigenic activities and to re-ignite their tumour-cytotoxic power. Therapeutic approaches include blockade of macrophage recruitment into tumours, suppression of TAM survival, re-polarisation towards an M1-like phenotype and antibody therapies to enhance TAM anti-tumoural activities. Future immunotherapeutic directions may include monoclonal antibodies with enhanced effector functions. Antibodies of different classes, including those of the IgE class, shown to restrict tumour growth by harnessing monocyte/macrophage cytotoxic properties in pre-clinical cancer models, may synergise or re-educate these potent immune sentinels to destroy rather than support tumours. Opportunities for monitoring monocyte/macrophage polarisation or activatory signatures in patients may inform clinical management.

Gene therapy for hemophilia.

Abstract: Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors.

Pathological functions of hypoxia in endometriosis.

Abstract: Endometriosis is one of the most common gynecological diseases that significantly reduce the life quality of affected women. Research results from the past decade clearly demonstrated that aberrant production of estrogen and cyclooxygenase-2-derived prostaglandin E2 play indispensable roles in the pathogenesis of this disease. However, the etiology of endometriosis remains obscure. Recent evidence reveals a new facet of endometriotic pathogenesis by showing that hypoxia induces the expression of many important downstream genes to regulate the implantation, survival, and maintenance of ectopic endometriotic lesions. These new findings shed lights on future investigations of delineating the etiology of endometriosis and designing new therapeutic strategy for endometriosis.

Post-transcriptional inducible gene regulation by natural antisense RNA.

Abstract: Accumulating data indicate the existence of natural antisense transcripts (asRNAs), frequently transcribed from eukaryotic genes and do not encode proteins in many cases. However, their importance has been overlooked due to their heterogeneity, low expression level, and unknown function. Genes induced in responses to various stimuli are transcriptionally regulated by the activation of a gene promoter and post-transcriptionally regulated by controlling mRNA stability and translatability. A low-copy-number asRNA may post-transcriptionally regulate gene expression with cis-controlling elements on the mRNA. The asRNA itself may act as regulatory RNA in concert with trans-acting factors, including various RNA-binding proteins that bind to cis-controlling elements, microRNAs, and drugs. A novel mechanism that regulates mRNA stability includes the interaction of asRNA with mRNA by hybridization to loops in secondary structures. Furthermore, recent studies have shown that the functional network of mRNAs, asRNAs, and microRNAs finely tunes the levels of mRNA expression. The post-transcriptional mechanisms via these RNA-RNA interactions may play pivotal roles to regulate inducible gene expression and present the possibility of the involvement of asRNAs in various diseases.

L-arginine improves DNA synthesis in LPS-challenged enterocytes.

Abstract: The neonatal small intestine is susceptible to damage by endotoxin, and this cytotoxicity may involve intracellular generation of reactive oxygen species (ROS), resulting in DNA damage and mitochondrial dysfunction. L-Arginine (Arg) confers a cytoprotective effect on lipopolysaccharide (LPS)-treated enterocytes through activation of the mammalian target of the rapamycin (mTOR) signaling pathway. Arg improves DNA synthesis and mitochondrial bioenergetics, which may also be responsible for beneficial effects of Arg on intestinal mucosal cells. In support of this notion, results of recent studies indicate that elevated Arg concentrations enhances DNA synthesis, cell-cycle progression, and mitochondrial bioenergetics in LPS-treated intestinal epithelial cells through mechanisms involving activation of the PI3K-Akt pathway. These findings provide a biochemical basis for dietary Arg supplementation to improve the regeneration and repair of the small-intestinal mucosa in both animals and humans.

Critical analysis of Alzheimer's amyloid-beta toxicity to mitochondria.

Abstract: Amyloid-beta peptide (Abeta) is believed to be a central player in the Alzheimer disease (AD) pathogenesis. However, its mechanisms of toxicity to the central nervous system are unknown. To explore this area, investigators have recently focused on Abeta-induced cellular dysfunction. Extensive research has been conducted to investigate Abeta monomers and oligomers, and these multiple facets have provided a wealth of data from specific models. Abeta appears to be accumulated in neuronal mitochondria and mediates mitochondrial toxicity. Mitochondrial dysfunction became a hallmark of Abeta-induced neuronal toxicity. Mitochondria are currently considered as primary targets in the pathobiology of neurodegeneration. This review provides an overview of the Abeta toxicity to isolated mitochondria, mitochondria in different tissues and cells in vitro and in vivo. Full texts and abstracts from all 530 biomedical articles listed in PubMed and published before January 2014 were analysed. The mechanisms underlying the interaction between Abeta and mitochondrial membranes and resulting mitochondrial dysfunction are most disputed issues. Understanding and discussing this interaction is essential to evaluating Abeta effects on various intracellular metabolic processes.

Respiratory supercomplexes: plasticity and implications.

Abstract: The plasticity model of the electron transport chain has slowly begun to replace both the liquid model of free complexes and the solid model of supercomplexes. The plasticity model predicts that respiratory complexes exist and function both as single complexes and as supercomplexes. The advantages of this system is an electron transport train which is able to adapt to changes in its environment. This review will investigate the current body of work on supercomplexes including their assembly, regulation, and plasticity, and particularly their role in the generation of reactive oxygen species and aging.

Colorectal endometriosis and pregnancy wish: why doing primary surgery.

Abstract: One of the most interesting debates surrounding deep endometriosis concerns the management of patients with colorectal lesions and pregnancy intention, for which no strong first level of evidence data exists to recommend performing surgical excision of colorectal endometriosis or ART. Studies assessing the policy of primary IVF have recorded pregnancy rates inferior to 45% and estimated cumulative pregnancy rates after up to 3 cycles or IVF as high as 68%. Other authors have reported pregnancy rates over 60% in patients undergoing primary surgery for colorectal endometriosis, with spontaneous conception representing up to 60% of pregnancies. Although overall pregnancy rates appear roughly comparable in patients undergoing either IVF followed by surgery or surgery followed if required by IVF, questions remain as to whether delaying surgery for months or years impairs health. Delaying surgery may lead to bowel occlusion, higher rates of radical colorectal procedures, increased postoperative morbidity and prolonged painful complaints. To provide definitive answers requires a randomized trial on an international scale with a sample size exceeding 400 patients and follow up averaging 4 years.

Heparin defends against the toxicity of circulating histones in sepsis.

Abstract: Although circulating histones were demonstrated as major mediators of death in septic mice models, their roles in septic patients are not clarified. The present study sought to evaluate the clinical relevance of the circulating histone levels in septic children, and the antagonizing effects of heparin on circulating histones. Histone levels in the plasma of septic children were significantly higher than healthy controls, and positively correlated with disease severity. Histone treatment could activate NF-κB pathway of the endothelial cells and induce the secretion of large amount of cytokines that further amplify inflammation, subsequently leading to organ damage. Co-injection of low dose heparin with lethal dose histones could protect mouse from organ damage and death by antagonizing circulating histones, and similar effects were also observed in other septic models. Collectively, these findings indicated that circulating histones might serve as key factors in the pathogenesis of sepsis and their levels in plasma might be a marker for disease progression and prognosis. Furthermore, low dose heparin might be an effective therapy to hamper sepsis progression and reduce the mortality.

Object recognition test for studying cognitive impairments in animal models of Alzheimer's disease.

Abstract: Animal models are essential resources in basic research and drug discovery in the field of Alzheimer's disease (AD). As the main clinical feature in AD is cognitive failure, the ultimate readout for any interventions or the ultimate goal in research should be measures of learning and memory. Although there is a wealth of genetic and biochemical studies on proposed AD pathogenic pathways, the aetiology of the illness remains unsolved. Therefore, assessment by cognitive assays should target relevant memory systems without assumptions about pathogenesis. The description of several tests that are available for assessing cognitive functioning in animal models can be found in literature. Among the behavioural test, the novel object recognition (NOR) task is a method to measure a specific form of recognition memory. It is based on the spontaneous behaviour of rodents and offers the advantage of not needing external motivation, reward or punishment. Therefore, the NOR test has been increasingly used as an experimental tool in assessing drug effects on memory and investigating the neural mechanisms underlying learning and memory. This review describes the basic procedure, modifications, practical considerations, and the requirements and caveats of this behavioural paradigm to be considered as appropriate for the study of AD. Altogether, NOR test could be considered as a very useful instrument that allows researchers to explore the cognitive status of rodents, and hence, for studying AD related pathological mechanisms or treatments.

The role of mitochondrial fusion and fission in skeletal muscle function and dysfunction.

Abstract: Classic textbook depictions of mitochondria portray these organelles to be static bean-shaped structures. However the mitochondrial population is quite heterogeneous, and can form small individual organelles or extended reticula throughout muscle. This morphological plasticity is controlled by fission and opposing fusion events. Skeletal muscle mitochondrial morphology has been demonstrated to be altered under various disease conditions, including diabetes, denervation, as well as during development, aging, and exercise. This implies that mitochondrial fission and fusion machinery components are involved in regulating the architecture of the organelle during various states of muscle use and disuse. Furthermore, disruptions in either of these opposing processes have been demonstrated to result in diseases, suggesting that proper maintenance of mitochondrial morphology is critical for proper cell function.

Functions and characteristics of PINK1 and Parkin in cancer.

Abstract: Most of the Parkinson disease (PD) linked genes are also associated with cancers. In particular, phosphatase and tensin homologue-induced kinase 1 (PINK1) and Parkin, both of which are involved in recessively inherited familial forms of PD linked to mitochondrial dysfunction, appear to be abnormally expressed in cancers. Functional studies have revealed that PINK1 recruits Parkin to mitochondria to initiate mitophagy, an important autophagic quality control mechanism that rids the cell of damaged mitochondria. Although PD and cancer are obviously disparate human disorders, there is an evidence for low cancer rates in patients with PD. The relationship between cancer rates and PD might be related to the involvement of common pathways in both diseases. This paper provides a concise overview on the cellular functions of the PINK1 and Parkin.

N-acetylcysteine and intestinal health: a focus on its mechanism of action.

Abstract: The integrity of the intestinal epithelium ensures its normal physiological function. Consequently, damage to the mucosal epithelium can impair the absorption of nutrients, thereby reducing the growth performance and compromising the health of animals. N-acetylcysteine (NAC) is pharmaceutically available either intravenously, orally, or by inhalation for reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage erosion, acetaminophen detoxification, and transplant prolongation. NAC is rapidly metabolized by the small intestine to produce glutathione and can not be detected in animals without supplementation. The physiologic functions and therapeutic effects of NAC are largely associated with maintaining intracellular concentrations of reduced glutathione. Results from recent studies indicate that NAC reduces inflammation, alleviates oxidative stress, improves energy status, and ameliorates tissue damage in the intestine of lipopolysaccharide-challenged piglets. Moreover, dietary supplementation with NAC ameliorates acetic acid-induced colitis in a porcine model. The effects of NAC are associated with some intestinal cell signaling pathways, such as EGFR, TLR4, apoptosis and tight junction signaling. The current review focuses on the protective effects of NAC on intestinal health and the molecular mechanisms of its action.

Cilia/Ift protein and motor -related bone diseases and mouse models.

Abstract: Primary cilia are essential cellular organelles projecting from the cell surface to sense and transduce developmental signaling. They are tiny but have complicated structures containing microtubule (MT)-based internal structures (the axoneme) and mother centriole formed basal body. Intraflagellar transport (Ift) operated by Ift proteins and motors are indispensable for cilia formation and function. Mutations in Ift proteins or Ift motors cause various human diseases, some of which have severe bone defects. Over the last few decades, major advances have occurred in understanding the roles of these proteins and cilia in bone development and remodeling by examining cilia/Ift protein-related human diseases and establishing mouse transgenic models. In this review, we describe current advances in the understanding of the cilia/Ift structure and function. We further summarize cilia/Ift-related human diseases and current mouse models with an emphasis on bone-related phenotypes, cilia morphology, and signaling pathways.

Inflammation in the pathogenesis of ischemic stroke.

Abstract: Ischemic stroke is a common cause of permanent disability in adults worldwide. Inflammation plays a significant role in the pathogenesis of ischemic stroke and its mechanism is complex. Both pro-inflammatory and anti-inflammatory mediators are involved in the pathogenesis of ischemic stroke, an imbalance of which leads to inflammation. Inflammatory cells from both the innate and acquired immune systems are involved in ischemic stroke-related inflammation; processes that are linked by the action of interleukin-17A (IL-17A). Although most inflammatory cells promote inflammation, T regulatory cells (Tregs) may have a protective function at the early stages of an ischemic injury, but a negative role during later stages. However, the precise mechanism of inflammation in ischemic stroke remains elusive; further understanding of it may provide new ideas for the prevention and treatment of ischemic stroke. In this review, we discuss the role of pro-inflammatory and anti-inflammatory mediators and related immune cells in the pathogenesis of ischemic stroke.