Many neurological disorders, including neurodevelopmental disorders, report hypersynchrony of neuronal networks. These alterations in neuronal synchronization suggest a link to the function of inhibitory interneurons. In Fragile X Syndrome (FXS), it has been reported that altered synchronization may underlie hyperexcitability, cognitive dysfunction and provide a link to the increased incidence of epileptic seizures. Therefore, understanding the roles of inhibitory interneurons and how they control neuronal networks is of great importance in studying neurodevelopmental disorders such as FXS. Here, we present a review of how interneuron populations and inhibition are important contributors to the loss of excitatory/inhibitory balance seen in hypersynchronous and hyperexcitable networks from neurodevelopmental disorders, and specifically in FXS. FMR1) gene and the consequent loss of the gene product of FMR1—Fragile X Mental Retardation Protein  repeat located in the 5’ untranslated region of the gene expands to a length of more than 200 repeats. The loss of this protein is far reaching because FMRP interacts with approximately 4–8% of all synaptic mRNAs and regulates the translation of numerous synaptic proteins and receptor systems  is one of several disorders associated with autism spectrum disorders (ASDs)—a heterogeneous group of behaviorally identified neurodevelopmental disabilities. The prevalence rate of autism in FXS reportedly ranges from 25% to 52% , but not in the cornu ammonis area 1 (CA1) subregion  played by this large and heterogeneous cell population (Buzsáki et al., 2+-dependent spike initiation and/or propagation (Miles et al., As earlier stated, cortical networks in FXS are hyperexcitable and highly synchronous (Gonçalves et al., Fmr1 KO mouse model (Gibson et al., Fmr1 KO mice (Selby et al., Fmr1 KO mice compared to wild type animals (Paluszkiewicz et al., Fmr1 KO mice reduces inhibitory output which in turn alters the synchronization and spike output of excitatory neuronal networks in layer II/III (Paluszkiewicz et al., Fmr1 KO mice (Gibson et al., In FXS, EEG recordings show elevated relative theta power and reduced relative upper-alpha power (Van der Molen and Van der Molen, Fmr1 KO mouse model (Xu et al., There is additional evidence that suggest a role for interneurons in FXS with respect to specific activation via neuromodulators. Inhibitory interneurons have differential response to neuromodulators, among them, acetylcholine muscarinic receptors (Cea-del Rio et al., Interestingly, inhibitory neurotransmission dysfunction appears to be region selective. As stated above, studies in the cerebral cortex reveal interneuron specific problems. There is a clear lack of excitatory drive to FS interneurons in layer IV (Gibson et al., In summary, while enhanced excitatory neurotransmission leads to hyperexcitable phenotypes, inhibitory interneurons are not just contributing factors but are likely playing a major role in hyperexcitable, hyperresponsiveness and hypersynchronicity of neuronal networks in FXS (Gibson et al., Since many FXS patients also present with one or more features of ASDs, insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of the role of inhibitory interneurons in autism. At this point most of the evidence for interneuron participation is indirect in terms of neuromodulatory activation and downstream excitatory network activation, but very promising in terms of the relevance of their contribution. Thus, understanding how interneurons participate in neuronal network abnormalities seen in FXS lends to a greater understanding for neurodevelopmental disorders that fall in the autism spectrum.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Plants form the foundation for our global ecosystem and are essential for environmental and human health. With an increasing number of available plant genomes and tractable experimental systems, comparative and functional plant genomics research is greatly expanding our knowledge of the molecular basis of economically and nutritionally important traits in crop plants. Inferences drawn from comparative genomics are motivating experimental investigations of gene function and gene interactions. This special issue aims to highlight recent advances made in comparative and functional genomics research in plants. Nine original research articles in this special issue cover five important topics: (1) transcription factor gene families relevant to abiotic stress tolerance; (2) plant secondary metabolism; (3) transcriptome-based markers for quantitative trait locus; (4) epigenetic modifications in plant-microbe interactions; and (5) computational prediction of protein-protein interactions. The plant species studied in these articles include model species as well as nonmodel plant species of economic importance .Evolution of Transcription Factor Gene Families Relevant to Abiotic Stress Tolerance. The extant flowering plants have experienced multiple rounds of genome duplication and gene duplication is the primary source of gene family evolution. X.-L. Wang et al. in “Divergence of the bZIP Gene Family in Strawberry, Peach, and Apple Suggests Multiple Modes of Gene Evolution after Duplication” explored the evolutionary dynamics of the bZIP family, which contains transcription factors associated with plant tolerance to abiotic stress. They performed evolutionary analysis of the bZIP family in three rosaceous species in multiple aspects such as selection pressure on protein-coding sequences and genomic synteny. Another transcription factor gene family relevant to abiotic stress, the CCCH zinc finger family, was studied by W.-J. Chen et al. in “Significant Microsynteny with New Evolutionary Highlights Is Detected through Comparative Genomic Sequence Analysis of Maize CCCH IX Gene Subfamily.” They performed comparative analysis of the CCCH IX subfamily in three cereal grain species  and found that segmental duplication has played an important role in the expansion of this gene family. Their analysis also indicates that deletions, multiplications, inversions, and purifying selection have contributed to the evolution of the CCCH IX subfamily.Plant Secondary Metabolism. Plants produce a wide range of secondary metabolites that underpin functional diversity in plants. Gene expression profiling through transcriptome sequencing is a powerful approach for understanding the molecular basis of plant secondary metabolism. H. Tian et al. in “Analysis of Polygala tenuifolia Transcriptome and Description of Secondary Metabolite Biosynthetic Pathways by Illumina Sequencing” analyzed expression of secondary metabolite biosynthetic genes in P. tenuifolia, a well-known medicinal plant, using RNA-seq approach. Their analysis revealed candidate genes that are potentially involved in biosynthesis of several important secondary metabolites such as triterpene saponins and phenylpropanoid. Similarly, R. Li et al. in “De Novo Transcriptome Sequencing of the Orange-Fleshed Sweet Potato and Analysis of Differentially Expressed Genes Related to Carotenoid Biosynthesis” performed RNA-seq analysis of secondary metabolism in Ipomoea batatas, an important food crop. Through comparing the global gene expression profile in relation to the differences in the carotenoid content of two I. batatas cultivars, they identified more than 50 genes potentially involved in carotenoid biosynthesis. Also, Y. Wei et al. in “Genome-Wide Identification of Genes Probably Relevant to the Uniqueness of Tea Plant (Camellia sinensis) and Its Cultivars” performed comparative analysis of RNA-seq data in several species of the genus Camellia, an important source for tea production. They identified differentially expressed genes relevant to the biosynthesis of flavonoid, theanine, and caffeine. Furthermore, their sequence comparison revealed nonsynonymous mutations that are potentially related to the diversity between the two cultivars of C. sinensis.Transcriptome-Based Markers for Quantitative Trait Locus. Quantitative trait locus (QTL) analysis has been widely used for elucidating the genetic basis of complex traits in plants. Molecular makers are prerequisites for QTL analysis. QTL makers can be developed from either genome sequences or transcriptome sequences. Development of genome-based markers requires genome-sequencing data, which are available only in model plant species or major crop species. For nonmodel plant (crop) systems, transcriptome-based markers can be a better choice for QTL analysis with a limited budget. E. S. Seong et al. in “Expressed Sequence Tags Analysis and Design of Simple Sequence Repeats Markers from a Full-Length cDNA Library in Perilla frutescens (L.)” developed simple sequence repeats (SSR) markers based on approximately 1,000 expressed sequence tags (ESTs) derived from cDNA libraries for this member of the mint family used in traditional Asian medicine. They identified 18 SSR makers that could be very useful for understanding of genomic basis of medicinal function in P. frutescens. Recent advance in next-generation sequencing technology greatly enhances the capability for molecular marker development. Q. Ding et al. in “Characterization and Development of EST-SSRs by Deep Transcriptome Sequencing in Chinese Cabbage (Brassica rapa L. ssp. pekinensis)” identified 10,420 SSR markers from 51,694 nonredundant unigenes assembled from RNA-seq data. This large set of SSR makers could facilitate genome-wide discovery of QTLs in Chinese cabbage. Also, R. Li et al. in “De Novo Transcriptome Sequencing of the Orange-Fleshed Sweet Potato and Analysis of Differentially Expressed Genes Related to Carotenoid Biosynthesis” identified 1,725 SSR markers in the transcriptome data for sweet potato.Epigenetic Modifications in Plant-Microbe Interactions. While it is widely accepted that genetics governs plant growth, development, and response to environment, an increasing number of studies have showed that epigenetics also plays an important regulatory role in plants. The paper by K. Melmaiee et al. entitled “Quantification and Gene Expression Analysis of Histone Deacetylases in Common Bean during Rust Fungal Inoculation” revealed that epigenetic modification via histone deacetylases is involved in the response of common bean to rust fungal inoculation. The results from this paper provide new insight into the molecular mechanism underlying plant-microbe interactions.Computational Prediction of Protein-Protein Interactions. Protein-protein interaction (PPI) is an important molecular mechanism underlying various biological processes. Computational prediction of protein-protein interactions based on protein sequences is a straightforward approach to the utilization of whole-genome gene annotation for the global view of protein-protein interaction network in an organism. Various algorithms have been developed for protein sequence-based PPI prediction, though with limited success. J. Yao et al. in “PPCM: Combing Multiple Classifiers to Improve Protein-Protein Interaction Prediction” present a machine learning approach for PPI prediction based on various features derived from protein sequences. Their results demonstrated that integration of multiple features could significantly improve the PPI prediction accuracy as compared with prediction classifiers based on individual features. This novel approach has a great potential for PPI prediction in nonmodel organisms, including plant species.


Valero-Muñoz et al. showed that heart failure with preserved ejection fraction (HFpEF) induced beiging in adipose tissue. They reported that in HFpEF brown adipose tissue (BAT) reduced the expression of some browning markers, such as uncoupling protein 1 (ucp-1), cell death-inducing DFFA-like effector a (cidea), and epithelial V-like antigen (eva), which were yet expressed by white adipose tissue (WAT) during beiging  and further deepen the role of immune cells, particularly M1 and M2 macrophages (Liu et al., A complex machinery of interactions between bone marrow precursors, pre-adipocytes, mature adipocytes and de-differentiated/mesenchymal progenitors, strongly suggests that the “adipose” compartment is a complex dynamic system that acts on several physiological districts to regulate energy balance, survival and tissue renewal (Hausman and Hausman, Further markers and investigations are needed to elucidate the role of adipose tissue and its beiging in heart function and heart failure.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Assessments of climate change impacts on forests and their vitality are essential for semi-arid environments such as Central Asia, where the mountain regions belong to the globally important biodiversity hotspots. Alterations in species distribution or drought-induced tree mortality might not only result in a loss of biodiversity but also in a loss of other ecosystem services. Here, we evaluate spatial trends and patterns of the growth-climate relationship in a tree-ring network comprising 33 juniper sites from the northern Pamir-Alay and Tien Shan mountain ranges in eastern Uzbekistan and across Kyrgyzstan for the common period 1935–2011. Junipers growing at lower elevations are sensitive to summer drought, which has increased in intensity during the studied period. At higher elevations, juniper growth, previously favored by warm summer temperatures, has in the recent few decades become negatively affected by increasing summer aridity. Moreover, response shifts are observed during all seasons. Rising temperatures and alterations in precipitation patterns during the past eight decades can account for the observed increase in drought stress of junipers at all altitudes. The implications of our findings are vital for the application of adequate long-term measures of ecosystem conservation, but also for paleo-climatic approaches and coupled climate-vegetation model simulations for Central Asia. Uzbekistan (UZ) and Kyrgyzstan (KG) belong to a region commonly referred to as Central Asia. This largely semi-arid to arid mountainous region is particularly vulnerable to ongoing and predicted climate change , 2. TempObserved impacts of anthropogenic climate change include an increase in health risks , decreasJuniperus spp.) dominates with around 80% of the forested areas at mid-to high elevations in Central Asia ).et al [et al [2 concentrations have been related to increased intrinsic water-use efficiency, where increased drought stress can lead to reduced stomatal conductance to compensate water loss at the expense of secondary growth [Although changes in climate during the past eight decades were remarkable and comparatively rapid, trends in juniper growth are less obvious and uniform. Combining the obtained results, we can summarize that juniper trees at the sites in Karakol, KG, with humid growing season climate  seem to et al  found sil [et al , reviewiy growth –54. Howey growth  and 2) ty growth .Over the full 1935–2011 period, the growth-climate relationships of the juniper sites generally showed benefiting effects on tree growth from warm temperatures at high altitudes and abundant moisture supply at low elevation sites , agreeinJ. seravschanica in the Zaamin National Park, UZ [et al [et al [Conversely, junipers at lower altitudes showed distinct and persistent drought responses, which has previously been shown for Park, UZ . Liu et Z [et al  or Liangl [et al  noted all [et al , are likl [et al . Moreovel [et al .The identified growth-climate response shifts in our study, which occurred only within the past 40 to 50 years, most likely indicate impacts of the ongoing climate change on juniper growth in Central Asia. We therefore stress the importance of long-term conservation measures to counteract possible losses or reductions of the mountain juniper forest ecosystems in UZ and KG. Our findings also highlight the need of time-dependency analyses in paleo-climatological studies when using high elevation juniper trees, as well as the integration of growth-climate response shifts when assessing and predicting vegetation dynamics in Central Asia.Juniperus spp. and local drought-induced juniper die-backs in this biodiversity hotspot. Consequently, alterations in the floral composition of the temperate coniferous forest biome in Central Asia can be expected. We therefore stress the need to apply adequate long-term measures for ecosystem conservation and to consider this ongoing response shift in paleo-climate and model simulation approaches for this region.Using a unique and extensive juniper network established for the Tien Shan and northern Pamir-Alay mountain ranges, we detected changes in growth-climate responses during the past eight decades. Junipers at low elevation sites mainly increased their climate sensitivity to drought during summer and the entire growing season. At the highest elevation sites, however, juniper growth was favored by high summer temperatures during 1935–1964, but was limited by increasing drought conditions during the past ~30 years. This change in climate sensitivity of the junipers likely demonstrates the effect of the ongoing climate change, and also explains the low reconstruction skills of high elevation juniper sites in Central Asia. Across the study area, changes in climate response were detected at all regions during summer, but also during winter, spring and autumn. This may be the cause of the spatially non-uniform changes in growth trends across the study region. Finally, our results indicate that a further rise in temperature together with decreasing rainfall amounts, as predicted for the coming decades, will most likely increase the risk of altitudinal range shifts of S1 TableJuniperus sp. (JUSP), J. seravschanica (JUSE), J. semiglobosa (JUSM), and J. turkistanica (JUTU)), the number of trees (n) and TRW series (n), start and end year over the full and truncated (n(i) < 5 series) period, interseries correlation (Rbar), mean segment length (MSL), mean sensitivity (MS), Expressed Population Signal (EPS), and highest correlations with climate (rMAX) for the analyzed 1935–2011 period.Information include country code (CC), latitude , longitude , elevation , exposition (Exp), species ((EPS)Click here for additional data file.S2 TablePearson correlation results for all juniper sites and sites closest grid point data for monthly (current year January to December) and seasonal a) temperature means and b) precipitation sums for the full 1935–2011 period. Sites within the region are sorted based on increasing longitude and within the region from high to low elevation sites . Seasons include previous year December to current year February (pDJF), March–May (MAM), June–July (JJ), June–August (JJA), September–November (SON), May–September (M–S), April–October (A–O), and the entire year.(EPS)Click here for additional data file.S3 TableDifferences in climate response from 1935–1964 to 1982–2011 of all juniper sites for monthly (current year January to December) and seasonal a) temperature means and b) precipitation sums. Sites within the region are sorted based on increasing longitude and within the region from high to low elevation . Seasons include previous year December to current year February (pDJF), March–May (MAM), June–July (JJ), June–August (JJA), September–November (SON), May–September (M–S), April–October (A–O), and the entire year.(EPS)Click here for additional data file.S1 FigSee (EPS)Click here for additional data file.S1 File(XLSX)Click here for additional data file.


Loss of auditory sensory hair cells (HCs) is the most common cause of hearing loss. This review addresses the signaling pathways that are involved in the programmed and necrotic cell death of auditory HCs that occur in response to ototoxic and traumatic stressor events. The roles of inflammatory processes, oxidative stress, mitochondrial damage, cell death receptors, members of the mitogen-activated protein kinase (MAPK) signal pathway and pro- and anti-cell death members of the Bcl-2 family are explored. The molecular interaction of these signal pathways that initiates the loss of auditory HCs following acoustic trauma is covered and possible therapeutic interventions that may protect these sensory HCs from loss via apoptotic or non-apoptotic cell death are explored. Auditory hair cells (HCs) are important for the conversion of acoustic sound energy into electrical impulses that travel to the auditory centers of the brain for hearing. Sensorineural hearing loss (SNHL) is a form of hearing impairment that occurs most commonly from damagedHCs within the cochlea; it is a prevalent disability, affecting one in five people and more than 48 million Americans , endonuclease G (EndoG), apoptosis inducing factor (AIF), second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein binding protein with low pI (Smac/DIABLO), and mammalian homolog of bacterial high temperature requirement protein A2  and recruits pro-caspase-9 to form an apoptosome . XIAP is a cytosolic protein that has three baculoviral inhibitory repeat (BIR) domains—BIR1 and BIR2 specifically bind and inhibit caspase-3 and -7, while BIR3 is a specific inhibitor of caspase-9  binding of a death ligand to its complementary receptor; 2) recruitment of adaptor molecules such as FAS-associated death domain protein (FADD) and tumor necrosis factor receptor type 1-associated death domain protein (TRADD); (3) binding, dimerizing, and activation of initiator caspase-8 and -10; and (4) formation of a death-inducing signaling complex , respectively  are important regulators of cell survival and cell death. Necroptosis refers to a RIPK3-dependent molecular cascade of events that promotes regulated necrotic cell death  polymerase 1 (PARP1) dependent form of non-apoptotic death. PARP1 is recruited to sites of DNA damage where it is able to catalyze ADP ribosylation of various proteins and histones and generate negative charges by overconsumption of nicotinamide adenine dinucleotide (NAD) during the ADP ribosylation process. Ultimately, other factors important for DNA repair are recruited. However, when PARP1 becomes hyper-activated in situations of persistent DNA damage, there is a depletion of NAD and inhibition of mitochondrial ATP synthesis, which is essential in ATP-dependent apoptosis pathways , caspase-3 activation, and intrinsic cell death , and hydroxyl  expression of extracellular pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα) and recruited of neutrophils and macrophages to the cochlea; and 2) generation of oxidative stress in the form of ROS and reactive nitrogen species (RNS) such as superoxide  on the cell surface of auditory HCs and initiate a signaling cascade that can lead to cell death  that promotes mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFkB) signaling  have also been detected in OC and cochlea following various inner ear challenges such as exposure to gentamicin, electrode insertion trauma, and autoimmune responses mediated by inner ear tissues  1 and 2 (ERK1/2), c-Jun N-terminal kinases , and p38 kinases  and blocking transcription of anti-apoptotic genes (such as Bcl-2)  have demonstrated protection against HC and hearing losses following aminoglycoside, acoustic, and electrode insertion injury to the cochlea  contains two unpaired electrons. Superoxide anion -mediated apoptosis; however there is some recent evidence that oxidative stress can turn on extrinsic cell death signaling. This again demonstrates the many levels of communication that occur both upstream and downstream in events of programmed cell death. ROS can activate apoptosis signal-regulating kinase-1 (ASK-1), which is a MAPKKK that can phosphorylate and activate mediators of the JNK and p38 pathways of extrinsic programmed cell death  that can trigger up regulation of genes important for cell death such as Bim and Bcl-6 . Acoustic trauma can also initiate inflammation and edema of the stria vascularis and compromise the blood supply to the cochlea (Smith et al., Acoustic trauma can lead to ROS release by the marginal cells of the stria vascularis as a result of reductions in cochlear blood flow and cochlear hypoxia (Yamane et al., c (Wang et al., When TNFα binds to its complementary receptor TNFR1, TRADD and FADD are recruited along with caspase-8. Caspase-8 can activate executioner caspase-3 to promote extrinsic cell death through DNA fragmentation and chromatin condensation via CAD, ACINUS, and HELI-CARD or it can cleave BID into tBID, which can activate Bax-mediated intrinsic, mitochondrial cell death (Liu et al., c into the cytoplasm, generation of apoptosomes, and activation of caspase-3 dependent cell death. AIF and EndoG are also released into the cytosol, translocate into the nucleus, and can initiate chromatin condensation and DNA fragmentation of auditory HCs (Nicotera et al., Oxidative stress from noise exposure can also initiate intrinsic apoptotic cell death in auditory HCs, resulting in mitochondrial release of cyt In addition to apoptosis, acoustic trauma can result in regulated necrosis through RIPK3/RIPK1 activation in rats, that was reversed with necrosis inhibitor necrostatin-1 (Zheng et al., Acoustic trauma can also promote swelling and rupture of dendritic terminals of cochlear nerve afferent fibers (Spoendlin, Furthermore, intense noise exposure can increase intracellular calcium in auditory HCs and activate calcium-dependent calpains—cysteine proteases that promote proteolysis and breakdown of cytoskeletal and membrane proteins, kinases, phosphatases, and transcription factors (Wang et al., Otoprotective drugs can target different levels in apoptosis and necrosis signaling pathways following acoustic trauma Figure . GlucocoNumerous diverse insults to the inner ear can cause auditory HC damage and hearing loss. The evolutionarily conserved apoptotic and necrotic cell death signaling that occurs in auditory HCs is shared among many ototoxic and traumatic stressor events. The most well studied molecular mechanisms behind cell death in auditory HCs involve TNFα signaling, JNK and p38 activation and the effect of high levels of oxidative stress. Although their effects on intrinsic and extrinsic pathways of apoptosis have been studied extensively, there are likely many levels of cross communication between signaling cascades that are still undiscovered. Research in this area is becoming more prevalent, as well as research into mechanisms of regulated necrosis in auditory HCs. A number of otoprotective drug therapies target different levels along this pro-inflammatory pro-death signaling cascade to block downstream events that lead to cell death and promote auditory HC viability and hearing protection.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


CYP3A2) mRNA expression and DNA fragmentation, as well as on contents of different cholesterol fractions and protein thiol groups in rat testes. Wistar albino male rats were divided into two groups: I – control , II – chronic alcoholism (15% ethanol self-administration during 150 days). Following 150 days of alcohol consumption, testicular free amino acid content was found to be significantly changed as compared with control. The most profound changes were registered for contents of lysine (–53%) and methionine (+133%). The intensity of DNA fragmentation in alcohol-treated rat testes was considerably increased, on the contrary CYP3A2 mRNA expression in testis cells was inhibited, testicular contents of total and etherified cholesterol increased by 25% and 45% respectively, and protein SH-groups decreased by 13%. Multidirectional changes of the activities of testicular dehydrogenases were detected. We thus obtained complex assessment of chronic alcoholism effects in male gonads, affecting especially amino acid, protein, ATP and NADPH metabolism. Our results demonstrated profound changes in testes on the level of proteome and genome. We suggest that the revealed metabolic disorders can have negative implication on cellular regulation of spermatogenesis under long-term ethanol exposure.There is good evidence for impairment of spermatogenesis and reductions in sperm counts and testosterone levels in chronic alcoholics. The mechanisms for these effects have not yet been studied in detail. The consequences of chronic alcohol consumption on the structure and/or metabolism of testis cell macromolecules require to be intensively investigated. The present work reports the effects of chronic alcoholism on contents of free amino acids, levels of cytochrome P450 3A2 ( Spermatet al., et al., et al., Ethanol can cause disturbance in the main metabolic pathways Zakhari, . AlcoholCYP3A2) mRNA expression and DNA fragmentation, as well as on contents of different cholesterol fractions and proteins thiol groups in rat testes.Based on these facts and considering that alcoholism is a chronic disease highly prevalent in the world population, the present work reports the effects of chronic ethanol consumption on free amino acids, levels of cytochrome P450 3A2 , relative humidity of 40% to 70%, lighting (12 h light-dark cycle), and on a standard pellet feed diet . The study was performed in accordance with the recommendations of the European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes and approved by the Institutional Animal Care and Use Committee. For the experimental  model, reproducing male rats were selected according to the method for measuring voluntary alcohol self-administration in rats, which provides a continuous choice between an alcohol solution and water (two-bottle preference test)  were used as controls. From the beginning of the experiment, they were kept in the same conditions as the experimental animals, but were given only water After 150 days, both the experimental and control rats were sacrificed under a mild diethyl ether anesthesia by decapitation. The right testis was used for histochemical analysis and the left testis for other investigations.et al.  activity in the testes was demonstrated by the method of Nachlas et al.  was histochemically detected according to the technique of Hess g, 10 min, 4 °C)  equal volumes of 3% sulfa-salicylic acid were added and the obtained mixtures were left for 10 minutes in the refrigerator at 4 °C. The formed sediments were removed by centrifugation  and then fractionated through 2% agarose gels . After electrophoresis, the gels were stained with ethidium bromide and visualized under a UV transilluminator . Analysis of electrophoresis data was carried out with Quantity One Software (USA).The DNA from the testes was isolated by a modified method from Current Protocols in Toxicology . Data were compared using Student's t-test. Differences were considered to be statistically significant at Investigation of chronic alcoholism effects on rat testis pools of free amino acids  showed tInvestigation of rat testes DNA fragmentation demonstrated its essential intensification following 150 days of ethanol administration in comparison with control . In the In testes of alcohol-treated rats 8 fractions of DNA fragments with weights over 1000 (4 different fractions), 700, 550, 30 and 20 b.p. were present. Main of high-weighted DNA fragments were fractions with weights over 1000 b.p., while among low-weighted DNA fragments fractions were approximately equal (by peak intensity).CYP3A2 mRNA expression was indicated in testes of rats with chronic alcoholism  and reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), both at the stage of glycolysis (changes of glycine and serine) and in the citric acid cycle (changes of methionine) , with superoxide anions, oxygen molecules, hydroperoxide, organic peroxides and peroxide radicals Stepuro, . Thus, cet al., et al., et al., et al., Changes of methionine in testicular pools deserve special attention. This amino acid can act as antioxidant and immunomodulator Pavlov, . Methionet al., et al., et al., et al., It is reasonable to propose that biosynthesis of S-adenosylhomocysteine and homocysteine could be also broken due to excessive alcohol intake. Changes in contents of methionine, glycine and serine – amino acids involved in the synthesis of these compounds , changes in its contents can cause changes in free amino acid contents .Changes of such amino acids as glycine in the testis pool are of special importance because of the involvement  in glutathione biosynthesis  Marks, . Such chet al., et al., et al., DNA is an important molecular target for toxicants  by mitochondria, driven by acetaldehyde metabolism, is a common trigger of both mechanisms . In our previous study, we showed CYP2E1 mRNA expression and protein content elevation in alcohol-treated rat testes with simultaneous spermatogenesis violations , which are involved in testosterone biosynthesis , a member of the nuclear receptor superfamily, regulating gene transcription in a ligand-dependent manner   and much of this function is attributed to the thiol groups present on them. One or more reduced thiol (-SH) groups are essential for the function of many proteins (Topçuoglu et al., Our results on the decrease of protein SH-groups in testes of alcohol-treated rats are in good accordance with data of clinical studies on the decrease of total thiol in alcohol abusers (Prakash Our results suggest that the self-administration of 15% alcohol in rats during 150 days led to multidirectional changes of the activity of testicular dehydrogenases, which play a crucial role in supplying energy needed for various metabolic functions in germ cells Mathur, . Dehydroet al., Forming part of complex II of the respiratory chain, SDH, is situated at the intersection of the citric acid cycle and oxidative phosphorylation. This combination of functions places SDH at the center of two essential energy-producing metabolic processes of the cell (Cervera et al., It is well known that spermatogonia may utilize glucose as the major energy substrate, but spermatocytes and spermatids suffer a rapid decline in their ATP content in glucose-supplemented media and require lactate/pyruvate for the maintenance of their ATP concentrations (Jutte et al., et al., Glucose transport into the cell and the lactate LDH isoenzyme system, which reversibly catalyzes the inter-conversion of pyruvate and lactate, are biochemical steps which participate in the regulation of lactate production (Riera Chemically induced stress causes elevated LDH activity, which can be used as a good diagnostic tool in toxicology (Ksheerasagar & Kaliwal, CYP3A2 mRNA expression and DNA fragmentation processes, as well as changes in cholesterol and protein thiol group contents allowed us to obtain complex estimation of this pathologic influence in male gonads, especially on the metabolism of amino acids, proteins, ATP and NADPH. Our results demonstrated profound changes in testes on the level of proteome and genome. We suggest that the revealed testicular metabolic disorders could have negative implications on cellular regulation of spermatogenesis under long-term ethanol exposure.Thus investigation of chronic alcoholism effects on testicular levels of free amino acids, rates of


Cilia are whip-like projections that are widely conserved in eukaryotes and function as a motile propeller and/or sensory platform to detect various extracellular stimuli. In vertebrates, cilia are ubiquitously found in most cells, showing structural and functional diversities depending on the cell type. In this review, we focus on the structure and function of cilia in choroid plexus epithelial cells (CPECs). CPECs form one or two dozen non-motile 9+0 cilia, which display transient acquisition of motility during development. Genetic malfunction of cilia can lead to failure of multiple organs including the brain. Especially, several groups have demonstrated that the defects in CPEC cilia cause the communicating form of hydrocephalus. In order to elucidate the molecular mechanisms underlying the hydrocephalus, we have previously demonstrated that the cilia possess an NPFF receptor for autocrine signaling to regulate transepithelial fluid transport. In this perspective, we also discuss the potential involvement of cilia in the other aspects of choroid plexus functions, such as the regulation of brain development and neuroinflammation. Cilia are hair-like projections on the cell surface with a diameter of ~250 nm and various lengths of typically 5–10 μm Figure . Their sFor example, ependyma (ependymocytes) lining brain ventricles form hundreds of motile cilia to circulate the cerebrospinal fluid (CSF). The axoneme of this ciliary subtype has a central pair of singlet microtubules (termed “9+2”), and is heavily equipped with axonemal dyneins and their regulatory complexes, which collectively drive the back-and-forth movement of cilia Figure . In contGenetic defects leading to ciliary malfunctions cause disorders with clinically variable phenotypes. Such disorders are called ciliopathies and include primary ciliary dyskinesia, polycystic kidney disease, Leber congenital amaurosis, nephronophthisis, Senior-Løken syndrome, Joubert syndrome, Bardet-Biedl syndrome, and Meckel Gruber syndrome  carries tubulin and other materials along the axoneme  that produce CSF with high efficiency (Damkier et al., As described above, mature ependyma form hundreds of motile 9+2 cilia that beat in a concerted manner to circulate CSF. In mouse, the multiciliogenesis initiates after birth and requires about 2 weeks for full maturation Figure . In contCelsr2, an ortholog of the planar cell polarity gene Flamingo, an impairment of ciliogenesis is observed in ependyma but not in CPECs (Tissir et al., Genetically modified mouse models have also shown differences in the mechanism of ciliary formation and/or the maintenance of cilia in CPECs and ependyma. In a knockout mouse for Tg737RpwIft88 mouse that has defects in IFT88 expression and function, Banizs et al. observed a communicating form of the hydrocephalus at neonatal periods, when most ependyma lack mature motile cilia. During these stages, CPEC cilia show an accumulation of polycystin-1, the defects of which cause autosomal dominant polycystic kidney disease, in a bulb-like structure at the tip. This abnormal ciliary structure and protein localization coincide with an increase in cellular cAMP levels and aberrant regulation of intracellular pH and ion transport activities in CPECs (Banizs et al., Pkd1 knockout mice, which encodes polycystin-1, and observed hydrocephalus at perinatal periods in both mouse lines.Regarding the unique function of CPEC cilia, several groups including ours have reported the potential involvement of CPEC cilia in the regulation of CSF production. Analysis of CPEC cilia in relation to the hydrocephalus was first described by Yoder et al. (Banizs et al., We used a primary culture system for swine CPECs to analyze ciliary function and showed that deciliation by chloral hydrate increases both intracellular cAMP levels and basolateral-to-apical transepithelial fluid transcytosis, which is consistent with the above observations by Banizs et al. (Narita et al., Bbs1, Bbs2, Bbs4, and Bbs6 mutant mice (Swiderski et al., Swiderski et al. investigated the mechanism of ventriculomegaly that is common in ciliopathy models of Kif3a in cranial neural crest cells, using a Wnt1 promoter-driven Cre recombinase (Liu et al., cre expression in E16.5 choroid plexuses, they concluded that the hydrocephalus is due to overproduction of CSF (Liu et al., Recently, Liu et al. generated a conditional knockout of Rfx3 knockout mouse also exhibits corpus callosum agenesis (Benadiba et al., The above studies implicate defects in CPEC cilia as a cause of the communicating form of hydrocephalus. However, reports by Durand et al. suggest additional mechanisms. They generated mice deficient for Rfx3, a transcription factor that regulates ciliogenesis, and demonstrated marked inhibition of ciliogenesis in both CPECs and ependyma, which is associated with the communicating form of hydrocephalus (Baas et al., A growing body of evidence suggests that the choroid plexus functions as a selective and educative gate for circulating immune cells in the immune surveillance of the CNS to resolve neuroinflammation under pathological conditions (Schwartz and Baruch, Recently, we performed proteomic analysis of CPEC cilia from swine and identified >800 proteins (Narita et al., According to the traditional view, CPECs have been regarded as solely responsible for the production of CSF. However, based on our current understanding of CSF production, we should re-interpret or re-evaluate the traditional views of CSF homeostasis (Iliff et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The most common diseases resulting in irreversible blindness or vision impairment include age-related macular degeneration (AMD), glaucoma, diabetic retinopathy, cataract, and dry eye. These diseases seriously affect the quality of life in elderly people worldwide. Therefore, understanding their pathogenesis and the development of strategies allowing earlier detection and treatment demands more effort and attention from both basic and clinical fields. This issue focuses on different aspects of these diseases in elderly population.β, IL-18, or IL-17” by S. Chen et al., the authors investigated the responses of multipotent retinal stem cells (RSCs), isolated from mice, to the proinflammatory signaling molecules including IL-1β, IL-18, and IL-17A. They found that the addition of IL-1β, IL-18, or IL-17A in the cultured cell decreased RSC viability but increased pyroptotic and/or necroptotic cells. The study is innovative and unique, because, instead of RPE19, a new cell type was used as the model system. Additionally, the results fill gaps in understanding immunological mechanism of AMD pathogenesis.AMD is one of the most common diseases resulting in irreversible blindness worldwide in the elderly population. Among multifactorial pathogenesis, immune dysregulations are leading theories of AMD pathogenesis. Recently IL-17 pathway was reported to be involved in AMD pathogenesis. In the original article “Responses of Multipotent Retinal Stem Cells to IL-1Like AMD, glaucoma and diabetic retinopathy are common causes of blindness in older adults. Glaucoma is often caused by damage to the optic nerve due to an abnormally high pressure in your eye, while diabetic retinopathy is a diabetes complication, caused by damage to the retinal blood vessels. However, both of them have no symptoms or warning signs at early stage. Thus, it is important to have regular eye exams to measure intraocular pressure and ocular blood flow. In the review paper “Ocular Blood Flow Autoregulation Mechanisms and Methods” by X. Luo et al., the authors summarized the methods for ocular blood flow evaluating and discussed mechanism and treatment of ocular blood flow regulation, particular in glaucoma and diabetic retinopathy.Cataract is one of the major causes of visual impairment of elderly people. Although recent bioinformatics studies revealed susceptibility genes, such as EPHA2, for age-related cataract, the mechanism underlying its pathogenesis remains elusive. In the original paper “The Polymorphisms with Cataract Susceptibility Impair the EPHA2 Receptor Stability and Its Cytoprotective Function” by J. Yang et al., the authors found that EPHA2 signaling can protect the lens epithelial cells from oxidative stress-induced cell death. In the original paper “Epigenetic Regulation of Werner Syndrome Gene in Age-Related Cataract” by X. Zhu et al., the authors investigated the promotor methylation and histone medication of Werner syndrome gene (WRN). They found that both mRNA and protein levels of WRN were significantly decreased only in anterior lens capsules in age-related cataract, suggesting that the strategies to intervene epigenetic alteration in this disease should aim to anterior lens capsules. By investigating very large cataract patient population in rural China, X. Cao et al. presented a normative ocular biometry of adult cataract patients in rural China. They found that the axial length is normally distributed with a positive skew and a big kurtosis and corneal astigmatism may affect rural Chinese vision acuity.Dry eye is a multifactorial disorder of the tears and ocular surface and is a common and often unrecognized disease affecting tens of millions of individuals worldwide. Q. Long et al. evaluated the biomechanical behavior of the cornea in dry eye using, for the first time, Corneal Visualization Scheimpflug Technology (CorVis ST), a new noncontact tonometry system. Their results provide insight into its full usefulness for dry eye patients. B. Wang et al. compared dry eye disease that resulted from two refractive surgeries [small-incision lenticule extraction (SMILE) versus femtosecond laser in situ keratomileusis (FS-LASIK)] in high myopia. They found that SMILE is a safe and successful alternative for the correction of refractive error and may provide a more superior and safer refractive outcome than FS-LASIK in the first six months following surgery. CorVis ST, the very latest technology, has been used by J. Wang et al. to assess the biomechanical parameters of the cornea in myopic and emmetropic eyes.Vitreous hemorrhage (VH) is one of the ophthalmologic emergency situations. In the paper contributed by D. Y. Kim and colleagues, the authors analyzed causes and prognosis of acute-onset preoperatively unknown origin VH in 169 eyes and found that retinal vein occlusion, retinal break, and AMD are the most common causes. In addition, aging may be an important factor for influencing visual prognosis following vitrectomy.Optic neuritis is one of the common optic neuropathies and is highly associated with multiple sclerosis. In the original paper “Evaluation of Retinal Nerve Fiber Layer and Ganglion Cell Complex in Patients with Optic Neuritis or Neuromyelitis Optica Spectrum Disorders Using Optical Coherence Tomography in a Chinese Cohort” by G. Tian et al., the authors reported that spectral-domain optical coherence tomography, SD-OCT, is a very useful and objective method to evaluate the thickness of the peripapillary retinal nerve fiber layer and macular ganglion cell complex in optic neuritis and neuromyelitis optica.Common age-related ocular diseases demand attention as a global health problem. This special issue covered pathogenesis, diagnosis, and treatment of most of these diseases.Jun ZhangJun ZhangJingsheng TuoJingsheng TuoZhongfeng WangZhongfeng WangAiqin ZhuAiqin ZhuAnna MachalińskaAnna MachalińskaQin LongQin Long


Hypoxia is an important micro-environmental characteristic of rheumatoid arthritis (RA). Hypoxia-inducible factors (HIF) are key transcriptional factors that are highly expressed in RA synovium to regulate the adaptive responses to this hypoxic milieu. Accumulating evidence supports hypoxia and HIFs in regulating a number of important pathophysiological characteristics of RA, including synovial inflammation, angiogenesis, and cartilage destruction. Experimental and clinical data have confirmed the upregulation of both HIF-1α and HIF-2α in RA. This review will focus on the differential expression of HIFs within the synovial joint and its functional behavior in different cell types to regulate RA progression. Potential development of new therapeutic strategies targeting HIF-regulated pathways at sites of disease in RA will also be addressed. It is an autoimmune and polyarthritic condition, characterized by inflammation of the synovium (synovitis), progressive cartilage destruction, and bone erosion, which ultimately results in loss of integrity of the affected joints  are activated as an adaptive mechanism. HIFs are considered the “master regulators”  and macrophage-like synoviocytes  and an underlying loose connective tissue called the sub-lining (sub-intima) layer Smith, . The arcInflammatory factors are known to upregulate the expression HIF-1α and HIF-2α in RA. Pro-inflammatory cytokines such as IL-1, TNF-α, and IL-33 have previously been reported to increase the expression of HIF isoforms in synovial fibroblasts  are pattern recognition receptors that are mainly expressed in immune cells and RASF cells in RA to regulate inflammatory responses (Brentano et al., Immune cells also play an important role in synovial inflammation. HIF-1α and HIF-2α are highly expressed in immune cells, in particular macrophages, in the RA synovium (Hollander et al., Synovial angiogenesis is likely a consequence of synovial hypoxia in RA (Konisti et al., The articular cartilage is an avascular, aneural, and alymphatic tissue, which is composed primarily of chondrocytes. The role of HIFs in cartilage destruction in RA is not yet fully characterized, with the majority of the work conducted in healthy articular cartilage. Cells in the articular cartilage normally reside in a hypoxic environment, with oxygen tension varying from 6–10% at the joint surface to 1% in the deeper layers (Gibson et al., in vitro on cells derived from RA synovium, further ex vivo and in vivo studies are warranted to assist in strengthening our understanding of the complex role of HIF in cartilage degradation in RA.Hypoxia has been demonstrated to upregulate the levels of MMPs in cells derived from RA synovium, although additional pathways independent of HIF may also be involved (Canning et al., Studies to date suggest that HIFs are promising targets for novel RA treatments. Approaches that may be considered for targeting hypoxia in RA cells include the use of hypoxia-activated prodrugs, specific HIF inhibitors, gene therapy, or targeting indirect pathways important in hypoxic cells. The majority of these targeted therapies have come from research on the effects of hypoxia on the growth of tumors (Phillips, A number of HIF inhibitors have been developed that possess inhibitory activity against cancer and HIF-related diseases (Ban et al., in vivo model of RA (del Rey et al., The use of delivery carriers may improve the efficacy of HIF-related therapeutic agents following systemic administration, by overcoming the pharmacokinetic and stability issues. The best example of this is in the delivery of gene therapy targeting HIFs, which have previously been shown to modulate cellular responses in hypoxia-related diseases (Post et al., Indirect strategies to target downstream HIF signaling pathways have also been investigated in RA. For example, many therapeutic approaches have successfully resolved angiogenesis in preclinical animal models of RA by administering antibodies targeting VEGF or small molecule inhibitors targeting the VEGF receptor (Maruotti et al., Accumulating evidence supports hypoxia and HIFs in regulating a number of important pathophysiological characteristics of RA, including synovial inflammation, angiogenesis, and cartilage destruction. Therefore, HIF inhibitors are likely to target multiple important RA processes. Experimental and clinical data have confirmed the upregulation of both HIF-1α and HIF-2α in RA. At this time, the relative importance of each isoform in RA pathology and disease severity is still unclear. These two isoforms show different sensitivity to oxygen tension and display distinct, and sometimes opposing, cellular activities. In addition, further studies are required to clarify the interrelationship between HIFs and other simultaneous pathways in perpetuating RA disease. This will allow us to determine whether specific HIF-1α or HIF-2α inhibition is likely to be required for successful clinical outcomes in RA. To optimize their effects, HIF inhibitors may require encapsulation within delivery vehicles directed toward affected RA tissue to improve therapeutic accumulation and stability following systemic administration, as well as reduce off-target effects.SH was responsible for assembling, drafting and revising the manuscript, and preparing the associated figure and table. TD contributed to the drafting of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The liver is famous for its strong regenerative capacity, employing different modes of regeneration according to type and extent of injury. Mature liver cells are able to proliferate in order to replace the damaged tissue allowing the recovery of the parenchymal function. In more severe scenarios hepatocytes are believed to arise also from a facultative liver progenitor cell compartment. In human, severe acute liver failure and liver cirrhosis are also both important clinical targets in which regeneration is impaired, where the role of this stem cell compartment seems more convincing. In animal models, the current state of ambiguity regarding the identity and role of liver progenitor cells in liver physiology dampens the enthusiasm for the potential use of these cells in regenerative medicine. The aim of this review is to give the basics of liver progenitor cell biology and discuss recent results vis-à-vis their identity and contribution to liver regeneration. The liver has the amazing potential to regenerate when mild liver damage occurs. During this process, remnant resting hepatocytes will re-enter the cell cycle and efficiently replenish the liver through proliferation. A good example of the capacity of adult hepatocytes and bile epithelial cells to proliferate is seen during recovery from partial hepatectomy in rats and mice, when two-third of the liver is removed , liver stem cells (LSCs), atypical ductal cells (ADCs), or intermediate hepatobiliary cells, it is sometimes difficult to deducewhether researchers are studying the same cell. While it is desirable to come to a nomenclature and classification of these -maybe different- cells, in this review we will use the term HSPCs to encompass the various liver stem/progenitor cell populations irrespective of species or injury model.Liver regeneration can be broadly characterized into hepatocellular or biliary regeneration, which is dependent on the type of injury. Adaptive, but flexible crosstalk between the microenvironment (i.e. extracellular matrix (ECM) and neighboring cells, like Kupffer cells, myofibroblasts and hepatic stellate cells) and the stem-cells themselves are required to allow the activation of HSPCs . Differin vitro for their cell renewal and differentiation capacity or in vivo for their ability to repopulate an injured liver with HSPC-derived hepatocytes and cholangiocytes ), Prom1 Figure 2.The problem with the aforementioned markers is that they are also expressed on regular biliary epithelial cells. The current view is that, once awakened by signals from the surrounding liver tissue, HSPCs become transit amplifying cells expressing some proteins not expressed by regular biliary epithelial cells such as Foxl1 (Forkhead Box l1), TACSTD2/Trop2  or LGR5 ((leucine-rich-repeat-containing G protein-coupled receptor 5) -like weak inducer of apoptosis (TWEAK), which is produced by monocytes, T lymphocytes and macrophages whose expression increases in contexts of acute injury, inflammatory disease and cancer. The expression of its receptor Fn14, normally expressed by epithelial and mesenchymal cells, is also relatively low in healthy tissue but is dramatically induced in injured and diseased tissue, such as in livers following a DDC treatment. HSPC activation by DDC was significantly reduced in Fn14-null mice and by the use of an anti-TWEAK antibody while overexpression of TWEAK in hepatocytes  or exogal., 2005). Indeedal., 2005; Murakamal., 2005; Steilinal., 2005). FGF7-dal., 2013). Obvioual., 2013). Contraal., 2013). This sin vivo /c-MET and Epidermal growth factor (EGF)/EGF receptor (EGFR) are key regulatory elements to determine HSPC activation and differentiation. In c-MET knockout mice, HSPC response was significantly less upon DDC injury al., 2012) suggestal., 2012). Wnt3a al., 2012, 20137]in vivo  ).+/EpCAM+ cells are defined as hepatoblasts expressing albumin and they are capable of differentiating into hepatocytes (EpCAM-/Dlk1-/Alb+/CK19-) and cholangiocytes (EpCAM+/Dlk1-/Alb-/CK19+) . These ductal plate derived YFP positive cells co-expressed SOX9, OPN and other oval cell markers , the caal., 2012; Tanaka al., 2012). Only o4. This was in contrast to a later study that showed that lineage tracing of LGR5-CRE positive cells yielded hepatocyte-like cells after one single injection of CCl4 or the DDC and MCDE diets   Figure. Until ral., 2013). None oal., 2013; Schaub al., 2013) or regual., 2013) and appal., 2013; Feil etal., 2013). Severaal., 1989) and traal., 1989). If theal., 2011). Carpenal., 2011) showed al., 2011) is likeal., 2011; Yanger al., 2011). The real., 2011), ~ 28.7al., 2011), ~ 10.5al., 2011) to 7 % al., 2011); the fiAn alternate hypothesis that might at least partially explain the obtained results from these studies, is that the low hepatocyte repopulation from HSPCs is a matter of hepatobiliary linkage but not of massive hepatocyte production . In thide novo formation of mature hepatobiliary cells  An overarching mechanism by which an aberrant microbiota negatively impacts health is by driving chronic inflammation  Gut-derived endotoxins play a central role in the initiation of acute liver injury and progression to chronic liver disease ; (iii) An imbalanced intestinal homeostasis results in a breach of the gut barrier and subsequent microbial translocation ; (iv) Selective intestinal decontamination with antibiotics is beneficial for patients and prevents experimental liver injury ; (v) Mice with genetic deletions in the lipopolysaccharide (LPS) signaling pathway are resistant to experimental liver injury and fibrosis  Transplantation of microbiota from diseased mice to germfree mice transfers some aspects of diseased phenotypes, indicating that altered microbiota plays a role in disease establishment and manifestation . Thus, α,β)  into hepatocytes. Many research efforts are focused on ways to expand hepatocytes or have perfect differentiation conditions of stem cells towards functional hepatocytes. Both are not current practice; hepatocytes in culture lose their functionality very quickly while stem cell differentiation towards hepatocytes often only reaches the hepatocyte-like cell level . Currenal., 2012; Snykersal., 2012; Takase al., 2012) and manal., 2012) ). The seid, 2000). CurrenIn vivo, HSPCs are not only influenced by growth factors and cytokines, changes in the extracellular matrix (ECM) seem to effect the proliferation and differentiation as well. The ECM is a complex structure made up of protein fibers that serve as a dynamic substrate that supports tissue repair and regeneration . Changeal., 2011; Kallis al., 2011; Van Hulal., 2011) and Lamal., 2011; Espanolal., 2011) deposital., 2011; Shupe eal., 2011). Uygun al., 2011) successal., 2011).Similar decellularized matrixes also increased hepatocyte differentiation of human fetal HSPCs when used as a coating substrate for regular tissue culture plates . ClearlIn these last couple of years we have learned much about the pathways and conditions involved in HSPC activation thanks to sophisticated genetically modified mouse models. These same models are currently in conflict about the existence and function of HSPCs during liver injury and regeneration. Perhaps novel mouse liver injury models, more representative of human disease, need to be developed to fully unravel the existence, identity and function of HSPCs.LD & LvG: Interuniversity Attraction Poles (IAP) - phase VII - contract P7/47  (10/2012-09/2017); SV: Flemish Government Agency for Innovation by Science and Technology, IWT/SB/121548 (2013-2016).Leo A. van Grunsven and Laurent Dollé contributed equally to this publication.


In continuation of the last year's special issue “TCM Zheng Classification and Clinical Trials,” the time for 2014 issue has come. Now we are on the way from TCM Zheng classification in clinical trial to development of clinical practice guideline. Clinical effectiveness is what matters most in any treatment, including traditional Chinese medicine (TCM). Many clinical trials have been conducted in China to evaluate the effectiveness of TCM, but many of the studies are with poor quality and may be inaccessible to non-Chinese scientists. As shown in This 2014 special issue contains 9 articles accepted from a total of 19 submissions consisting of 6 research articles, 1 systematic review (SR) article, and 2 narrative review articles.Two cohort studies were gathered, “Chinese Herbal Decoction Based on Syndrome Differentiation as Maintenance Therapy in Patients with Extensive-Stage Small-Cell Lung Cancer: An Exploratory and Small Prospective Cohort Study”; 357 herbal decoctions were prescribed for 29 patients based on Zheng classification to observe the treatment effect and treatment length of herbal decoctions. Another cohort study “The Functional Difference of Dendritic Cells in HBeAg Negative Chronic Hepatitis B Patients with Three Different Spleen Deficiency Syndromes and the Therapeutic Evaluation of Chinese Medicine Intervention Based on Syndrome Differentiation” by H. Song et al. suggested that Chinese medicine intervention according to Zheng classification could advance the maturity and function of dendritic cells and improve the therapeutic effect.One case analysis study, “Study on TCM Syndrome Differentiation of Primary Liver Cancer Based on the Analysis of Latent Structural Model” by X. Yue et al., analyzed 559 inpatients records to provide evidences for TCM Zheng classification of primary liver cancer.Another paper focuses on clinical practice guideline; “Enhanced Evidence-Based Chinese Medicine Clinical Practice Guidelines in Hong Kong: A Study Protocol for Three Common Diseases” by A. Lu et al. presented a novel of three-phases clinical practice guidelines research protocol for insomnia, chronic gastritis, and cerebral infarction. This study may serve as model for future guidelines development in the area.To answer the question of what are the differences between different types of Zheng? “The Th17/Treg Immune Balance in Ulcerative Colitis Patients with Two Different Chinese Syndromes: Dampness-Heat in Large Intestine and Spleen and Kidney Yang Deficiency Syndrome” by M. Jiang et al. identified different mechanism on immune imbalance of ulcerative colitis patients with two types of TCM Zheng. D. Wang et al. identified that 26 potential biomarkers in the plasma of coronary heart disease (CHD) patients and 19 differential metabolites contributed to the classification of two main types of TCM Zheng “phlegm Zheng” and “blood stasis Zheng” in “A Metabonomics Profiling Study on Phlegm Syndrome and Blood-Stasis Syndrome in Coronary Heart Disease Patients Using Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry.”Weijing Decoction) Combined with Pharmacotherapy for the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease” by C. C. Xue's research group included 15 RCTs, 986 subjects. They concluded that Weijing decoction, a universally used herbal formula for treating chronic obstructive pulmonary disease (AECOPD), appeared to be beneficial for acute exacerbations of AECOPD and well-tolerated when taken concurrently with routine pharmacotherapy (RP).Systematic review paper “Chinese Herbal Medicine , would be valuable for the researchers for conducting TCM clinical trials. We, the editors, appeal that more proper designed clinical trials on long term major outcomes should be funded. Hopefully, this special issue will give helpful insights to scientists, physicians, and patients and will also be able to make a progress in the field of TCM clinical studies.


Cognitive impairment is the final outcome of a complex network of molecular mechanisms ultimately leading to dementia. Despite major efforts aimed at unraveling the molecular determinants of dementia of Alzheimer type (DAT), effective disease-modifying approaches are still missing. An interesting and still largely unexplored avenue is offered by nutraceutical intervention. For instance, robust epidemiological data have suggested that moderate intake of red wine may protect against several age-related pathological conditions  as well as DAT-related cognitive decline. Wine is highly enriched in many polyphenols, including resveratrol. Resveratrol is a well recognized antioxidant which may modulate metal ion deregulation outcomes as well as main features of the Alzheimer’s disease (AD) brain. The review will discuss the potentiality of resveratrol as a neuroprotectant in dementia in relation to the oxidative stress produced by amyloid and metal dysmetabolism. French paradox arises from the epidemiological fact that French people, despite their indulgence to a high fat diet, show a relative low incidence of cardiovascular diseases  extracellular deposition of misfolded β-amyloid (Aβ) in senile plaques (SPs); (2) intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs); (3) severe brain atrophy; and (4) the presence of areas of chronic inflammation  has been considered the main trigger for AD-related synaptic dysfunction. Amyloid has been therefore the major target for therapeutic intervention  can lead to direct deacetylation of acetylated tau, thereby promoting its proteasomal degradation  dependent deacetylase) which in turn sets in motion a cascade of PGC-1α-dependent events that ultimately lead to improved mitochondrial functioning and biogenesis and boost cellular ROS scavenging  by efficiently scavenging hydroxyl, superoxide, and metal-induced radicals , Amyotrophic Lateral Sclerosis (ALS), Prion Protein disease, Huntington’s disease (HD), and AD. All these neurodegenerative conditions share common pathological features that include deposition of misfolded proteins, metal ion deregulation and exposure to oxidative stress  (Shin et al., Iron deregulation has been linked to AD (Weinreb et al., Zinc dyshomeostasis has been proposed as a risk factor for AD. Accumulation of excessive zinc, or its deficiency, are both involved in the neuronal loss which leads to AD and aging related cognitive decline Brewer, . While zin vitro (Granzotto and Zatta, in vivo the downstream events of aluminum overload, namely the aluminum-related ROS production and neuroinflammatory response activation (Zaky et al., Aluminum lacks modulatory functions in biological processes; however, its accumulation in the brain has been demonstrated to be linked to several neuropathological conditions (Zatta et al., Resveratrol is a multi target compound and may represent an effective therapeutic tool in aging-related neurodegenerative processes. Consistently, several clinical trials are ongoing to test its effectiveness as dietary supplement to slow dementia progression (ClinicalTrials.gov, in vivo may act on other uninvestigated biological targets (Herskovits and Guarente, In summary, major effects are associated with its scavenging activity as well as in the activation of SIRT1 (see Bordone and Guarente, Resveratrol is a multi-target, simple, safe, and cost-effective dietary supplement. Nevertheless, it should be reminded that its role as therapeutic agent is not devoid of potential problems. The pro-oxidant activity in presence of labile copper, the poor bioavailability and ease degradation all represent major issue that require new sophisticated efforts (Goldberg et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This volume features state-of-the-art approaches to determining the effects of ageing on visual perception, visual cognition, and visually guided behavior. They incorporate psychophysics, eye movements, electrophysiology, and neuroimaging to determine how ageing affects vision in health and pathology.Brockmole and Logie  present 2 ingestion, they observed age-equivalent fractional cerebral blood flow (ΔCBF) in the presence of age-related increases in fractional cerebral metabolic rate of oxygen (ΔCMRO2). Reductions in ΔCBF responsiveness to increased ΔCMRO2 in elderly participants led to paradoxical age-related BOLD decreases. Age-related ΔCBF/ΔCMRO2 ratio decreases were associated with increases in behavioral reaction times, suggesting that age-related slowing resulted from less efficient neural activity. Alichniewicz et al. (Hutchison et al.  investigz et al.  used funz et al.  examinedz et al.  present Bieniek et al.  investigIt is our hope that these studies contribute to a better understanding of the effects of ageing on visual perception and visual cognition.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There are errors in the Funding section. The correct funding information is as follows: This study was funded by the FIS  co-financed by the European Union through the Fondo Europeo de Desarrollo Regional , and by the Grupo de Excelencia Investigadora URJC-Banco Santander No. 30VCPIGI03: Investigación traslacional en el proceso de salud—enfermedad (ITPSE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Plasmopara viticola, the causal agent of grapevine downy mildew, is one of the most devastating grape pathogen in Europe and North America. Although phytochemicals are used to control pathogen infections, the appearance of resistant strains and the concern for possible adverse effects on environment and human health are increasing the search for alternative strategies. In the present investigation, we successfully tested two protein hydrolysates from soybean (soy) and casein (cas) to trigger grapevine resistance against P. viticola. On Vitis vinifera cv. Marselan plants, the application of soy and cas reduced the infected leaf surface by 76 and 63%, as compared to the control, respectively. Since both hydrolysates might trigger the plant immunity, we investigated their ability to elicit grapevine defense responses. On grapevine cell suspensions, a different free cytosolic calcium signature was recorded for each hydrolysate, whereas a similar transient phosphorylation of two MAP kinases of 45 and 49 kDa was observed. These signaling events were followed by transcriptome reprogramming, including the up-regulation of defense genes encoding pathogenesis-related (PR) proteins and the stilbene synthase enzyme responsible for the biosynthesis of resveratrol, the main grapevine phytoalexin. Liquid chromatography analyses confirmed the production of resveratrol and its dimer metabolites, δ- and ε-viniferins. Overall, soy effects were more pronounced as compared to the cas ones. Both hydrolysates proved to act as elicitors to enhance grapevine immunity against pathogen attack. Vitis vinifera) has a surveillance system considered as the first defense line against invader pathogens, activated after signal molecule perception. These molecules may come from infectious agents or non-pathogenic microorganisms and therefore be designated as pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs), respectively; they may correspond also to secondary products released during pathogen invasion, called damage-associated molecular patterns (DAMPs)  into elicited cells, considered cardinal for defense response activation , proved to enhance efficiently grapevine defense responses , dwarf pea (Pisum sativum), and tomato (Solanum lycopersicum)  susceptible to P. viticola, were grown in glasshouse conditions, as described by Gauthier et al. (V. vinifera cv. Gamay) were cultivated as described by Vandelle et al.  and casein (cas), produced for the pharmaceutical and food industry were supplied by “A. Costantino & C. S.p.A.” . Since the two products are not yet on the market and protected by a trademark, their physicochemical characteristics cannot be reported. Solutions at 1.6 mg/ml in sterile ultra-pure or distilled water were prepared 24 h before use, 0.20 μm filtered and stored at 4°C. This concentration was selected based on previous trials . Plants were placed for 5 h in a humid chamber , and then transferred back to the greenhouse. Five days post inoculation (dpi), plants were placed again in the humid chamber overnight to stimulate sporulation. Disease was assessed estimating the leaf surface area (%) covered by sporulation. Five plants were used per condition, evaluating three leaves per plant that were marked before treatment.Both faces of leaves of 8-weeks old grapevine plantlets were sprayed by 2+ and MAPK), cells were transferred in the M10 buffer , re-suspended at 0.1 g of fresh weight of cells (FWC) per ml and equilibrated for 1 h in light (130 rpm at 24°C) before treatments  as described in Dubreuil-Maurizi et al. (In vivo reconstitution of aequorin was performed adding 5μl of coelenterazine (5 mM stock solution in DMSO) to 5 ml of aequorin-transformed cell suspension for at least 3 h in the dark. Aequorin was quantified adding 300 μl of lysis buffer . Finally, variations in [Ca2+]cyt were calculated following the calibration equation developed by Rentel and Knight  and 50 μl of 0.3 mM luminol. Relative luminescence was recorded within a 10-s period using a luminometer  and expressed as nmol H2O2 per gram of FWC.Hr et al. . BrieflyWestern blot analyses were performed as described by Trdá et al. . AliquotDead cells were quantified according to Binet et al. . Briefly−ΔΔCt method  and reaction efficiencies were calculated.Aliquots (2 ml) of treated cells were harvested by filtration on GF/A filters following a time course , frozen and ground in liquid nitrogen. Total RNA isolation was obtained by Trizol . The RNA yield and quality were determined by NanoDrop 2000 . cDNAs were synthesized by reverse-transcribing 400 ng of total RNA using Superscript III reverse transcriptase kit . Amplifications were run in a 96 well-plates iCycler iQ thermal cycler  and quantification was performed with the iCycler iQTM associated software . Differential expression was determined according to the 22) ranging from 0.94 to 0.99  separated by filtration on GF/A filters following the same time course of qPCR analyses. The culture medium samples were directly analyzed, whereas cell samples were stirred vigorously and incubated in 2 ml absolute ethanol for 24 h at 4°C to extract stilbenes. Samples were analyzed by an Acquity UPLC system  equipped with a model 2996 photo-diode array detector, as described by Boutegrabet et al. . Each sasoy and cas), data were subjected to ANOVA . Significant differences (P ≤ 0.05) were identified by the General Linear Model (GLM) procedure with the Duncan's Multiple Range Test (DMRT). Percentage data of incidence of decay underwent arcsine-square-root transformation before ANOVA analysis. For gene expression data, since just two conditions were compared (relative expression by soy and cas), Student's t-test was applied. Data were processed using the software package Statistics for Windows .When more than two conditions were present . Thereafter, plants were sprayed by soy and cas at 1.6 mg/ml, inoculated by P. viticola sporangia 24 h later and evaluated for the leaf sporulating area at 5 dpi. A significant reduction of disease severity by 76% for soy and 63% for cas was observed as compared to the control. However, no difference was found between the two hydrolysates .Generation of Hsoy and cas hydrolysates was also evaluated by cell viability assays, in which the number of red colored grapevine cells was assessed at 24 hpt. We did not recorded any toxic effect of the two hydrolysates compared to the water control (data not shown).The toxicity of PR1), a ß-1,3-glucanase (PR2), a chitinase 4c (PR3), a protease inhibitor (PR6), a polygalacturonase-inhibiting protein (PGIP) and a stilbene synthase (STS). Overall, soy and cas induced a rapid and high transcript accumulation of most of the tested genes with different kinetics and intensities; a more pronounced effect of soy was generally observed , showed a biphasic expression profile. It peaked at 4 or 8 hpt for soy- and cas-treated cells, respectively.In this study we evaluated by qPCR in time-course experiments the expression in grapevine cell suspensions of six selected defense genes known to be activated in response to various elicitors: those encoding a pathogenesis-related protein 1 .soy and cas hydrolysates to trigger resistance against gray and green mold (Lachhab et al., in vitro of the different pathogens (Lachhab et al., 2+]cyt variations, H2O2 production, MAPK activation, defense genes expression, and phytoalexin production. Both soy and cas induced specific changes of [Ca2+]cyt, considered essential for defense response activation (Lecourieux et al., 2+]cyt, as compared to water control, similarly to other elicitors as OG, cryptogein, BcPG1, and Flg 22 (Lecourieux et al., soy and cas showed two specific signatures, characterized by different kinetics and duration, suggesting different active molecules in each hydrolysate (Blume et al., soy-treated cells, the increase in [Ca2+]cyt was more rapid than that triggered by cas, and the level of free cytosolic calcium remained higher as compared to water and cas treatments. A similar behavior was observed in [Ca2+]cyt signatures induced by the polypeptide cryptogein in tobacco cells (Lecourieux et al., soy is likely not an oligosaccharide as assumed elsewhere (Lachhab et al., soy and cas chemical composition by the manufacturer is in progress.On the bases of the effectiveness of soy-treated cells a fast, strong, and lasting MAPK activation, which is consistent with the high level of free cytosolic calcium concentration. These results are similar to those of Lecourieux et al. (2+]cyt and MAPK stimulation is more evident considering the cas- effect. Indeed, the rapid decrease of the [Ca2+]cyt level is correlated with a very low activation of MAPKs after 60 min, as previously demonstrated in cryptogein-treated tobacco cells (Lecourieux et al., Calcium signaling is known to act upstream of the MAPK pathway in some plant defense responses (Link et al., x et al.  who reco2+]cyt variations and MAPKs activation, many authors described the rapid release of H2O2 in cell suspensions as a response to various elicitors (Poinssot et al., soy- and cas-elicited cells did not show any variation in H2O2 production. Furthermore, similarly to the β–glucan derivative PS3, the two hydrolysates did not have any toxic effect on grapevine cells, supporting the hypothesis that the resistance to pathogen invasion may depend on other defense responses rapidly activated during pathogen infection (Aziz et al., 2O2 generation is not necessary for the induction of defense reactions. As shown by Galletti et al. (Arabidopsis, without affecting the expression of genes involved in defense responses effective against B. cinerea. In addition, Pauw et al. (Catharanthus roseus.In addition to [Cai et al. , a null w et al.  showed tP. viticola of some Vitis species as V. riparia, was associated to a more rapid and stronger induction of defense gene expression, as compared to susceptible cultivars, e.g., V. vinifera (Polesani et al., PR1 and PR6 (Lu et al., PR6 is in agreement with the protective effect provided by the two hydrolysates to grapevine against Botrytis attack (Lachhab et al., STS the key gene of the biosynthesis of resveratrol, known to increase resistance against pathogens (Coutos-Thévenot et al., Phomopsis viticola and B. cinerea and affecting P. viticola zoospore mobility (Adrian et al., Consistently with previous reports, the two tested hydrolysates caused an up-regulation of 6 known defense-related genes (Bézier et al., soy, induced a high and rapid accumulation of resveratrol at 4 hpt, the first time-assessment in our trials, meaning that STS gene was induced even before. This finding is in agreement with the concept that stilbene is the primary inducible response of grapevine against a number of biotic and abiotic stresses (Adrian et al., As expected, the two protein hydrolysates, in particular Interestingly, resveratrol was present at high amounts in culture medium, but showed low accumulation in cells. As suggested by Adrian et al. , part ofP. viticola (Pezet et al., soy showed pronounced efficiency in inducing defense responses, as compared to cas treatment, in particular concerning stilbene accumulation. The different results may be ascribed to their different proteic origins. Indeed, soybean contains different proteins as lipid transfer proteins (Kido et al., P. viticola.The δ- and ε-viniferin dimers, considered as important markers for resistance of grapevine to pathogens (Malacarne et al., cas and particularly soy hydrolysates as enhancers of grapevine innate immunity and thus good candidates to replace or reduce fungicide applications in modern sustainable viticulture, as they are cheap, easily available and safe to humans and the environment.In conclusion, the presented data support the use of Nihed Lachhab: conducted the experiments, analyzed data and prepared the manuscript; Simona M. Sanzani: designed the experiments, analyzed the data and prepared the manuscript; Marielle Adrian: supervised phytoalexin quantification, analyzed the data and edited the manuscript; Annick Chiltz and Suzanne Balacey: helped in conducting the experiments; Maurizio Boselli: helped to design the experiments and edited the manuscript; Antonio Ippolito: helped to design the experiments and edited the manuscript; Benoit Poinssot: designed the experiments, analyzed the data and prepared the manuscript. All authors have read the manuscript and agree with its content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Recently, Bin Zhao and colleagues from the Chinese Academy of Science in Beijing and University of California, Sacramento, have published a review about identification of cardiotoxic compounds by rapid screening methods  derived cardiomyocytes have been introduced and several gene and microRNA cardiotoxicity markers have been identified . Meanwhal., 2015). Currenal., 2015, 20139]in vitro al., 2015; Grinberal., 2015), kidneyal., 2015; Bulacioal., 2015) and neual., 2015; Shinde al., 2015), which al., 2015; Vartak al., 2015; Ghallabal., 2015; Schliesal., 2015; Hoehme


Renal fibrosis represents a common pathway leading to progression of chronic kidney disease. Renal interstitial fibrosis is characterized by extensive fibroblast activation and excessive production and deposition of extracellular matrix (ECM), which leads to progressive loss of kidney function. There is no effective therapy available clinically to halt or even reverse renal fibrosis. Although activated fibroblasts/myofibroblasts are responsible for the excessive production and deposition of ECM, their origin remains controversial. Recent evidence suggests that bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. Understanding the molecular signaling mechanisms underlying the recruitment and activation of the bone marrow-derived fibroblast precursors will lead to novel therapy for the treatment of chronic kidney disease. In this review, we summarize recent advances in our understanding of the recruitment and activation of bone marrow-derived fibroblast precursors in the kidney and the development of renal fibrosis and highlights new insights that may lead to novel therapies to prevent or reverse the development of renal fibrosis. Chronic kidney disease (CKD) is a global public health problem. Worldwide, over 1 million people die from CKD yearly. It is estimated that more than 20 million Americans have CKD and more than 450,000 Americans suffer from end-stage renal disease (ESRD) requiring renal replacement therapy. CKD has become the eighth leading cause of death in the United States. Regardless of various etiologies, a common pathological feature of CKD is renal fibrosis, which is characterized by accumulation of fibroblasts/myofibroblasts with increased production and deposition of extracellular matrix (ECM) including collagen type I, III, IV, fibronectin, vimentin, and proteoglycans , macrophages, and immune cells, which suggest that interaction and communication among these cell types regulates the development of fibrotic disorders (Kisseleva and Brenner, The recruitment of circulating cells into sites of injury is mediated by locally produced chemokines. Chemokines are classified based on the relative position of cysteine residues near the NH2 terminus into four major families: CC, CXC, C, and CX3C Rollins, . Recent in vivo in a murine model of renal fibrosis induced by obstructive injury (Okamura et al., in vitro (Xia et al., in vitro and in vivo (Izquierdo et al., The chemokine CXCL16 is a recently discovered cytokine belonging to the CXC chemokine family (Matloubian et al., CXCR6 is the receptor for CXCL16. CXCR6 was first cloned as an orphan receptor by three independent groups and was termed STRL33, BONZO, or TYMSTR (Alkhatib et al., In these studies, we have observed that genetic deficiency of CXCL16 or CXCR6 does not completely block bone marrow-derived fibroblast precursor infiltration into the kidney and renal fibrosis development, suggesting that other chemokine/receptor pairs may be involved in the process of recruiting bone marrow-derived fibroblast precursors into the kidney. Consistent with this notion, CCR2 and CCL21/CCR7 have been reported to play a role in the recruitment of bone marrow-derived fibroblast precursors into the kidney and the development of renal fibrosis (Sakai et al., in vitro and in vivo (Chen et al., in vitro. Smad3-knockout mice accumulate significantly fewer bone marrow-derived fibroblasts in the kidney after obstructive injury, exhibit less myofibroblast activation, and express less α-SMA in the obstructed kidney. Furthermore, genetic deletion of Smad3 reduces total collagen deposition and suppresses expression of extracellular matrix proteins. Additionally, wild-type mice engrafted with Smad3−∕− bone marrow cells displayed fewer bone marrow-derived fibroblasts in the kidney with obstructive injury and showed less severe renal fibrosis compared with wild-type mice engrafted with Smad3+∕+ bone marrow cells. These results indicate that Smad3 of bone marrow-derived cells plays an important role in bone marrow-derived fibroblast activation. However, Samd3 deficiency does not completely abolish bone marrow-derived fibroblast activation, collagen deposition, and ECM protein expression in vivo. These results suggest that other factors may be involved in bone marrow-derived fibroblast activation.The activation of bone marrow derived fibroblast precursors plays a crucial role in the pathogenesis of renal fibrosis (Yang et al., + T cells can differentiate into two major distinct phenotypes, Th1 and Th2 cells, which are characterized by specific cytokine expression patterns (Wynn, in vitro. Furthermore, CP690550 treatment or STAT6 deficiency inhibits bone marrow-derived fibroblast activation and ECM protein production in the kidney in response to obstructive nephropathy. To further confirm the role of bone marrow STAT6 signaling in myeloid fibroblast activation, we performed bone marrow chimeric experiments. Wild-type mice transplanted with STAT6 null bone marrow cells exhibit fewer bone marrow-derived fibroblasts and develop a lesser degree of renal fibrosis. These results suggest that inhibition of JAK3/STAT6 signaling may serve as a novel therapeutic target for fibrotic kidney disease.The activation of bone marrow-derived fibroblasts is modulated by inflammatory cells in the microenvironment. T cells plays an important role in the pathogenesis of renal fibrosis (Tapmeier et al., ns Wynn, . Th2 celns Wynn, . Howeverns Wynn, . SpecifiAdiponectin is a multifunctional cytokine and an important regulator of lipid and carbohydrate metabolism. Emerging evidence suggests that circulating adiponectin levels are elevated in patients with CKD, and a high level of adiponectin is linked to increased cardiovascular mortality (Zoccali et al., It is generally thought that macrophages do not produce ECM proteins. These cells promote fibrosis indirectly by producing profibrotic cytokines that activate fibroblasts (Wynn and Barron, Recent studies have shown that renin angiotensin system plays an important role in the development of fibrotic kidney disease (Mezzano et al., Recent studies have demonstrated that bone marrow derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. Recruitment and activation of bone marrow-derived fibroblasts are mediated through the interaction between chemokines/cytokines and their receptors Figure . TherefoAlthough chemokines are involved in recruiting bone marrow-derived fibroblasts into the kidney in response to injury, the molecular signaling mechanisms underlying chemokines-induced bone marrow-derived fibroblast recruitment remains to be defined. Ras proteins are members of a family of small GTPase that control signaling pathways involved in cell migration, proliferation, differentiation, and survival (Rodríguez-Pena et al., JY drafted the manuscript. ZZ, LJ, and YW reviewed and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Ginsenoside-Rb1 is a chemically pure steroid glycoside from the root of Panax ginseng, which has a 3000-year history of medicinal use in the Orient.Betts et al 2011) reported that Rb1 inhibits vascular endothelial growth factor (VEGF) release by retinal pigment epithelial cells, which is a major source of VEGF in the eye  of ginsenosides and their derivatives. By simple acylation of the panaxadiol, an analog of ginsenoside, its anti-tumor activity was significantly enhanced, compared with the non-acylated parent  (Using a different cancer cell line (lung fibroblast), Dong et al. (2011) noted that the removal of the sugar moiety (by hydrolysis) significantly increased its cytotoxic potency, based on MTT assays, to measure viable cell numbers . Du et aSuch SAR reports are not limited to chemical modification of ginsenosides leading to inhibition of cancer cell proliferation only. Wei et al (2009) reported that oxidation of panxadiol leads to triperpene derivatives with a significant increase in the ability to inhibit the HIV-1 protease enzyme, which is required for maturation and infectivity of the HIV virus . FinallyRecently, there has been an increased interest in SAR in medicinal chemistry. These reports provide further evidence for the need of exploring how chemically modified ginsenosides may enhance inhibition of VEGF in ocular and other cell types. Such discoveries will provide new knowledge for novel intervention methods to treat angiogenic diseases such as diabetic retinopathy, AMD and cancer.


Stem cell research is of high interest, because precursor cells can be directed to differentiate into practically all mature cell types. This represents a potential perspective for therapeutics of severely damaged organs and also an alternative to animal drug and toxicity testing. Nonetheless, an essential question still remains: How similar are differentiated stem cells to the desired mature cells, e.g. liver cells? This highlight report focusses on a study recently published in the Journal of Hepatology  where tThe liver has a spectacular ability to regenerate  developThe authors applied biostatistical techniques to compare gene clusters using real liver cells (primary human hepatocytes), stem cells and six different stem cell-derived hepatocyte-like cells . The coin vitro systems play a major role in testing of neurotoxicity  represe represe5al., 2014; Krug etal., 2014), nephroal., 2014; Yang etal., 2014) and hepal., 2014; Godoy eal., 2014; Godoy 2al., 2014; Godoy aal., 2014; Grinberal., 2014; HengstlThis is the first time that such a systematic genome wide comparison of stem cell derived and genuine hepatocytes has been performed. The recent published study in the Journal of Hepatology  offers


Progression of solid tumors is characterized by an evolutive growing cellular mass containing variable proportions of a complex network of tumor stroma cell populations  surrounding cancer cell (CC) foci. This cellular intricacy determines mechanical, molecular and functional interactions involved in multiple mechanisms driving reciprocal aspects of paracrine and justacrine crosstalks between TSC and adjacent CC. There is increasing evidence that tumor stroma is a multicellular organ containing vascular structures and a large variety of cellular populations, including resident carcinoma-associated fibroblasts (CAF), myofibroblasts (MF), leucocytes and macrophages, bone marrow-derived mesenchymal stem cells, and in breast cancer, adipose progenitor cells. This cellular heterogeneity sustains tumor growth and angiogenesis, deregulated cancer cell proliferation, survival, chemoresistance, epithelial-to-mesenchymal transitions (EMT), invasion and tumor metastasis.In primary tumors and their metastases, these intercommunications between cancer cells and their surrounding TSC are organized in part by the convergent secretion of various ECM components building the architectural formation of ECM interfaces between these two critical cellular populations. ECM remodeling during cancer progression is regulated by the concomitant secretion of CC and TSC soluble factors and cytokines as well as subcellular exosomes involved in genetic tranfer between cancer cells and their stromal microenvironment (reviewed in ref. ). PlastiSeveral studies pointed the critical roles played by the ECM, CAF and MF in tumor progression. Decorin is a member of the Small Leucine-rich Repeat Proteoglycan (SLRP) family expressed and secreted in the interstitial ECM in breast stroma (reviewed in ref. ). In ECMIn this context, decorin was shown to sequester latent form of TGFβ1 (L-TGFβ1) in the ECM and to interact with the active TGFβ1 ligand, thus preventing its binding to TGFβ1 receptors . Most imIn the background of ductal carcinoma in situ (DCIS) of the breast, Van Bockstal et al reveal that the function of decorin is involved in breast cancer cell spreading and that both TGFβ1 and bFGF down-regulated the ECM protein decorin in CAF-associated breast tumors . In turnin vitro and in vivo will provide a rationale for new therapeutic options aimed to neutralize the oncogenic role of TGFβ1 as a repressor of the decorin tumor suppressive functions. As reported by Van Bockstal et al [These findings collected in breast cancer-associated fibroblasts  are of pal et al  this ass


The integration of information from genome to metabolome allows the establishment of associations between genetic potential and final phenotype, a feature not realizable by only considering single ‘omes’. Therefore, in our opinion, integrated omics will become the future standard for large-scale characterization of microbial consortia including those underpinning biological wastewater treatment processes. Systematically obtained time and space-resolved omic datasets will allow deconvolution of structure–function relationships by identifying key members and functions. Such knowledge will form the foundation for discovering novel genes on a much larger scale compared with previous efforts. In general, these insights will allow us to optimize microbial biotechnological processes either through better control of mixed culture processes or by use of more efficient enzymes in bioengineering applications.Biological wastewater treatment plants harbour diverse and complex microbial communities which prominently serve as models for microbial ecology and mixed culture biotechnological processes. Integrated omic analyses  are currently gaining momentum towards providing enhanced understanding of community structure, function and dynamics  Biological wastewater treatment plants host diverse and dynamic microbial communities possessing varied metabolic capabilities over changing environmental conditions, e.g. microorganisms accumulating various storage compounds of biotechnological importance. Given their structural and functional diversity, BWWT processes hold great potential for future sustainable production of various commodities from wastewater as well as from other mixed substrates  with well-defined physico-chemical boundaries and are widespread in developed and developing countries  biomolecular extractions protocols and computational analyses ineffective  yet highly active populations  minimizing errors by cancelling out noise and biases stemming from single omic analyses and (ii) optimizing/maximizing overall data usage.Following standardized and systematized biomolecular isolations, multi-omic datasets are generated in addition to the physico-chemical parameters recorded at the time of sampling Fig. ; step 2.et al., et al., et al., in silico data processing and analysis methods, which in turn will allow integrated omics to provide comprehensive multi-level snapshots of microbial population structures and functions in situ , fully integrated omic analyses should be applied routinely in the study of microbial consortia for greater effectiveness. For instance, despite this wealth of information, current metagenomic assemblies and analysis schemes, metagenomic (and metatranscriptomic) data resulting from the use of current short-read sequencing and assembly approaches do not allow the comprehensive resolution of microdiversity, e.g. genetic heterogeneity of microbial populations , coupled to carefully controlled laboratory experiments, will allow the effective elucidation of novel functions within BWWT plant microbial communities with potential biotechnological applications.Although integrated omics-based approaches are highly effective for large-scale analysis and formulation of hypotheses (including within the context of BWWT plant communities), these efforts are limited due to current high-throughput measurement methods (see previous section) and the reliance on et al., et al., et al., et al., Knowledge of gene function, regulation and physiological potential derived from integrated omic data over different spatial and temporal scales holds great promise in harnessing the biotechnological potential of microbial consortia. In particular, advancements in integrated omics followed by hypothesis testing may generate new knowledge (Muller None declared.