The tumor necrosis factor superfamily (TNFSF) members play pivotal roles in embryonic development of lymphoid tissue and their homeostasis. RANKL  is recognized as an important player in bone homeostasis and lymphoid tissue formation. In its absence bone mass control is deregulated and lymph nodes fail to develop. While its function in bone is well described, there is still little functional insight into the action of RANKL in lymphoid tissue development and homeostasis. Here we provide an overview of the known functions of RANKL, its signaling receptor RANK and its decoy receptor OPG from the perspective of lymphoid tissue development and immune activation in the mouse. Expressed by the hematopoietic lymphoid tissue inducing (LTi) cells and the mesenchymal lymphoid tissue organizer (LTo) cells, RANKL was shown to stimulate Lymphotoxin (LT) expression and to be implicated in LTi cell accumulation. Our recent finding that RANKL also triggers proliferation of adult lymph node stroma suggests that RANKL may furthermore directly activate LTo cells. Beyond bone, the RANKL-RANK-OPG triad plays important roles in immunobiology that are waiting to be unraveled. There is now an emerging consensus to refer to the receptor as RANK and, as a consequence and for simplicity, its ligand is called RANKL. The acronym OPG has remained in use.Tumor necrosis factor (TNF) and Lymphotoxin (LT) were identified as the first members of a large family, now called the TNF-superfamily (SF). Not surprisingly, the receptors for these proteins also constitute a SF with sequence homology, named TNF Receptor (TNFR) SF. A hallmark of these ligand-receptor pairs lies in a threefold symmetry, where by the oligomeric binding arrangement amplifies their avidity and introduces flexibility. Further complexity arises through different partner affinities and generation of soluble ligand and receptor forms  cells and Vγ5+ thymocytes as well as later arising CD4+CD8− single positive thymocytes and ΓδT cells are equipped with RANKL  and cryptopatches (CPs) and abnormalities of the spleen (Dougall et al., Rankl−/− and Ltα−/− mice have lower number of LTi cells in mesenteric LNs of newborn mice (Kim et al., −/− mice display fewer LTi cells in mesenteric LNs at E 17.5 but not at E15.5 (Yoshida et al., In view of the finding that LTi cell recruitment is LT independent (Eberl et al., Rankl−/− mice. Second, mucosal LNs develop in LTβ−/− mice but not in Rankl/−− mice (Alimzhanov et al., Rankl−/− embryos cannot rescue LN genesis (Kim et al., In the current model of LN development a positive feedback loop takes place between LTi and LTo cells Figure . RANK siLTβR signaling in mTECs induces RANK expression (Mouri et al., Rankl−/− mice (Knoop et al., A number of observations support a role of RANKL in SLO growth. The LNs that developed after neutralization of RANK signaling in embryos were smaller (Eberl et al., −/− mice: it was noted that in these LNs B cells and FDCs were absent (Yoshida et al., −/−Rankl  mice and observed that most stromal cells in the B cell compartment lacked VCAM-1 and CXCL13 expression. Finally, postnatal RANKL overexpression resulted in an increase in small but clearly defined B cell follicles, which all comprised FDCs (Hess et al., B cell recruitment and organization into follicles occur in a CXCL13-dependent manner at later stages of SLO formation (Ansel et al., in vitro generated DCs and in combination with other TNFSF members (Wong et al., in vivo (Dougall et al., Activated CD4 and CD8 T cells express surface and soluble RANKL (Josien et al., Porphyromonas gingivalis (Kajiya et al., P. gingivalis-induced periodontitis and therefore reduce alveolar bone loss (Arizon et al., Th17 T cells represent an important osteoclastogenic T cell type by robust RANKL production and activation of RANKL release by mesenchymal cells (Sato et al., The RANK-RANKL-OPG axis plays a recognized role in bone homeostasis through the regulation of osteoclastogenesis. It is also implicated in SLO development and regulation of the immune response. There are many incentives to answer remaining questions. In addition to a restless curiosity of the researcher, tertiary lymphoid tissues that arise in inflamed tissue rely on similar if not identical cellular dialogs as those found in SLO development. Defining RANKL function in lymphoid tissue development will open new therapeutic avenues to treat inflammatory diseases and provide new strategies for vaccine development.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.


Burkholderia cepacia, Pseudomonas aeruginosa or Stenotrophomonas maltophilia, which cause diseases only in patients with predisposition or in hospital (Berg et al., Just like humans, plants have recently been recognized as meta-organisms, possessing a distinct microbiome and revealing close symbiotic relationships with their associated microorganisms (Berg et al., Microbiomes of humans and plants are currently intensively studied using the same methods and addressing similar scientific questions (Ramírez-Puebla et al., Despite the fact that the majority of our lifetime is spent in indoor environments such as home, work place, or public buildings, our knowledge of microbial diversity inside buildings is limited. We are not alone in these indoor environments: they provide new habitats and residence to numerous microbial communities comprising possibly hundreds of individual bacterial, archaeal and fungal species including diverse viruses. Recent studies analyzed potentially pathogenic and allergenic indoor microorganisms with mainly cultivation-based methods (Täubel et al., 6 bacteria per person-hour as measured via 16S rRNA gene quantification from aerosols (Qian et al., Indoor microbial communities are an important component of everyday human health (Arundel et al., Indoor microbiomes originate primarily from human skin, pets, or the outside air (Flores et al., Empirically the positive effects of houseplants and flowers are well-known, but there is also evidence for psychological effects such as stress reduction and creative task performance (Fjeld et al., Plant DNA as frequently detected as chloroplast 16S rRNA gene sequences in amplicon surveys is a substantial part of all indoor microbiomes, but mainly filtered out for the presentation of data (Oberauner et al., Typical and often dominant plant-associated bacteria are members of the indoor microbiome. A relationship of bacteria genera occurring on plants and indoors is given in Figure Burkholderia cepacia, Pseudomonas aeruginosa and Stenotrophomonas maltophilia (Ryan et al., At species level, no differentiation was possible for clinical and plant-associated isolates. This was studied for Interestingly, Thaumarchaeota, originally described to be associated with ammonia-oxidation in soil and the rhizosphere of plants, have been found on human skin (Probst et al., Comparing indoor with plant microbiomes, it is our opinion that both outside and inside plants are of importance for our indoor microbiome. Plants provide beneficial bacteria for indoor rooms and therefore can positively influence human health. The following facts support our opinion about the importance of plants as source for a beneficial microbial biodiversity:Based on these facts, we speculate the following:Enclosed environments and their microbiomes—like private/public buildings, hospitals, and clean rooms, which are more or less separated from outside, are especially shaped by human influence and human associated microbes (Hospodsky et al., Microbes, which live in close vicinity to human beings, are adapted to us as symbionts, commensals, or pathogens, whereas these life-styles are changeable dependent on the host-microbe balance. Indoors we share these microbes, which might get deposited on various surfaces by one person and afterwards get collected by another. Human-associated microbes e.g., skin associated, are confronted with totally new biotic and abiotic factors in the built environment. Here they have to adapt to new surface materials, compete with others for scarce nutrients and withstand stresses associated to cleaning reagents etc. However, in the case of houseplants we allow them to proliferate in a protected environment. Plant associated microbes stay on the leave or stem surface, where they have adapted to and are sheltered from cleaning procedures. Although these phyllosphere communities are confronted with an absence of direct sun light and rain as well as other changed meteorological parameters like air/dust turbulences, their rhizosphere and surrounding soil communities stay in their natural habitat. Hence, these well balanced plant communities, which we bring inside, have the potential to balance an indoor microbiome, by increasing its diversity and filter airborne microbes.Members of the plant microbiome are an important source for indoor microbiomes. Both, plants from inside and outside can contribute to the micro-flora. Plant-associated bacteria could act as counterparts against pathogens within the microbial ecosystems. They stabilize the ecosystem, enhance biodiversity and avoid outbreaks of pathogens. However, more research is necessary to understand the microbiology of indoor environments. Currently used cleaning and hygiene strategies in built environments especially in hospitals and ICUs often promote multi-resistant pathogens instead of supporting beneficials. In future, it is important to re-think our understanding of necessary sterility and our relationship to our surrounding microbiomes. This “paradigm shift in ecology” is not only required for plants, humans Jones,  but also


Spruyt et al.  report aHow can an alcohol-avoidance bias be a predictor of relapse, while alcohol-avoidance training has positive effects in alcohol-dependent patients? Consider two recent clinical alcohol-avoidance training studies. In our first study in 214 alcohol-dependent patients  interventions, such as pharmacological treatment for alcohol craving: perhaps those patients with higher risk relapse had undergone different treatments that affected their approach/avoidance associations with alcohol. These particular third-variable explanations may or may not be true for the results of Spruyt et al.; they only serve to illustrate that a correlation between avoidance associations and relapse does not imply that the relapse risk was caused by the avoidance associations; and even less that inducing an avoidance association via training would cause an increased relapse risk.r = −0.05, p = 0.37, Field, personal communication). In our own first re-training study, we also used the relevant-feature approach-avoid Implicit Association Test . Hence, measuring an approach-bias with a relevant-feature task appears to be unrelated to measuring, and perhaps changing, an approach-bias with an irrelevant-feature task. It could at least theoretically be the case that the kind of avoidance associations as measured by a relevant-feature SRC cause an increased chance of relapse, while alcohol-avoidance associations retrained and assessed by an irrelevant-feature AAT decrease the chance of relapse.Second, different tasks were used in our studies and the study by Spruyt et al. In their prediction study, Spruyt et al. used the relevant-feature R-SRC, while we used an irrelevant-feature alcohol Approach Avoidance Task to measure the approach bias (alcohol AAT; Wiers et al., In conclusion, the evidence does not support the idea that the induction of an avoidance bias is likely to be harmful in alcoholic patients: the study of Spruyt et al. does not allow conclusions regarding causality, and a recent training study in fact showed that a relative increase in avoidance mediated the beneficial effects of avoidance training. We do, however, concur with Spruyt et al. that more research is needed regarding the assessment and modification of biases in action tendencies (Watson et al.,


Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cachexia is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology. The purpose of this article was to review the current medical treatment of cancer-related cachexia, in particular focusing on combination therapy and ongoing research. Among the treatments proposed in the literature for cancer-related cachexia, some proved to be ineffective, namely, cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered the best available treatment option for cancer-related cachexia, and they are the only drugs approved in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-alpha MoAb. Several emerging drugs have shown promising results but are still under clinical investigation . To date, despite several years of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Cachexia can occur as part of many chronic or end-stage diseases such as infections, cancer, AIDS, congestive heart failure, chronic renal failure, rheumatoid arthritis, tuberculosis, and chronic obstructive pulmonary disease. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention). Anorexia, inflammation, insulin resistance, and increased muscle protein breakdown are frequently associated with cachexia. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption, and hyperthyroidism, and is associated with increased morbidity. CachexiaThe best management of cancer cachexia is to cure the cancer as this will completely reverse the cachexia syndrome. Unfortunately, this remains an infrequent achievement in adults with advanced solid tumors. A second option could be to counteract weight loss by increasing nutritional intake, but since in the majority of cachectic patients, anorexia in only a part of the problem, nutrition as a unimodal therapy was not completely able to reverse the wasting associated to cachexia. Indeed, a large number of randomized controlled trials of nutritional intervention did not show a significant benefit with regard to weight change or quality of life. These results have led to attempts to manipulate the process of cachexia with a variety of pharmacological agents, with the main purpose of providing symptomatic improvement. To date, however, despite several years of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome.Progestagens, that is, Medroxyprogesterone Acetate (MPA) and Megestrol Acetate (MA) are currently considered the best available treatment option for CACS, and they are approved in Europe for treatment of cancer- and AIDS-related cachexia. However, progestational agents are nonetheless limited in their ability to treat cancer cachexia. Fewer than 30% of patients treated with MA experience short-term appetite stimulation, and alth5in vitro study,[et al., carried out a randomized placebo-controlled study[et al.,[In a subsequent ro study, they shoro study, Simons eled study to invesled study undertooy[et al., carried Among orexigenic agents, corticosteroids are widely used. In randomized controlled studies, they have been shown to improve appetite and quality of life compared with placebo.14 MA andet al.,[et al.,[et al.,[et al.,[Drugs able to inhibit the synthesis and/or release of cytokines (i.e. eicosapentaenoic acid (EPA), melatonin, etc.), the cytokine action -12, and IL- 15), and drugs able to inhibit the proteasome activity (i.e. bortezomib) have been tested in experimental models of cachexia, with some positive results. Unfortunately, most clinical trials in humans have provided limited or disappointing results. N-3 fatty acids, especially EPA, may have anticachectic properties. The first study by Fearon[et al., comparinet al., comparedet al., conclude,[et al., and Stra,[et al., have fai,[et al., showed n,[et al., showed tet al.,[Thalidomide has multiple immunomodulatory and antiinflammatory properties; its inhibitory effect on TNF-α and IL-6 production may be responsible for its apparent anticachectic activity. Thus, thalidomide has been used for treatment of cachexia associated with acquired immunodeficiency syndrome, tuberculosis, and cancer. In the current literature, there are few studies that have assessed the anabolic effects of thalidomide in gastrointestinal cancer cachexia. Gordon et al., undertooet al.,[Research on experimental animal models has shown that non-steroidal anti-inflammatory drugs, including cyclooxygenase-2 (COX-2) inhibitors, may palliate cachexia through the suppression of systemic inflammation. Lai et al., carried Recently, much research interest has focused on ghrelin, a 28 amino acid peptide produced by the P/D1 cells of the stomach. Not only does ghrelin stimulate GH secretion (via the GH secretagogue-1a (GHS-1a) receptor) but it also promotes food intake (via the orexigenic NPY system) and decreases sympathetic nerve activity. Synthetic human ghrelin has been shown to improve muscle wasting and functional capacity in patients with cardiopulmonary-associated cachexia and to improve energy intake in anorexic cancer patients. Based on the animal studies and short-term human trials, there appears to be much promise for further studies to investigate the use of ghrelin and GHS-R agonists for the treatment of cachexia caused by multiple underlying conditions. Significant questions remain to be answered, however, before its widespread use, most prominently whether the gains produced by GHS R agonists maintain safety and efficacy with long-term use in human diseases. Clearly, more long-term research is needed.et al.,[of ghrelin to humans with cachexia has shown no univocal efficacy in increasing food intake with single dose intravenous administration.26 In a set al., 21 adultet al.,[et al.,[Neary et al., carried ,[et al., carried et al.,[Lundholm et al., carried Branched-chain amino acids are neutral amino acids with interesting and clinically relevant metabolic effects: They interfere with brain serotonergic activity and inhibit the overexpression of critical muscular proteolytic pathways. The potential role of branched-chain amino acids as antianorexia and anticachexia agents was proposed many years ago, but only recent experimental studies and clinical trials have tested their ability to stimulate food intake and counteract muscle wasting in anorectic, weight-losing patients. In experRecently, a prospective, randomized, phase III trial comparing the effects of oxandrolone (10 mg bid) and MA (800 mg q.d.) on weight, body composition, and quality of life (QOL) in 155 adult patients with solid tumors and weight loss receiving chemotherapy demonstrated that patients treated with oxandrolone experienced an increase in LBM, a reduction in fat mass, and reduced self-reported anorectic symptoms.et al.,[Olanzapine, an atypical neuroleptic with safe therapeutic window for several psychotic diseases, induces significant weight gain and positive metabolic effects. Preliminary data from a phase I pilot study by Braiteh et al., suggest et al.,[et al.,[n=12) or fish oil, 2 g tid, plus celecoxib 200 mg bid (n=10). All patients in both groups received oral food supplementation. After 6 weeks of treatment, patients receiving fish oil+placebo or fish oil + celecoxib showed significantly more appetite, less fatigue, and lower C reactive protein (C-RP) values than their respective baselines values . Additionally, patients in the fish oil+celecoxib group also improved their body weight and muscle strength compared to baseline values . Comparing both groups, patients receiving fish oil + celecoxib showed significantly lower C-RP levels  and higher muscle strength , and body weight  than patients receiving fish oil+placebo. The addition of celecoxib improved the control of the acute-phase protein response, total body weight, and muscle strength. In the context of combined approaches, one of the most intriguing ones was our open phase II trial.[L-carnitine 6 (4 g/day), (4) thalidomide (200 mg/day), or (5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 months. The sample size was 475 patients. The different single agents were selected on the basis of the following rationale. The antioxidant agents were shown to be effective in our previous studies.[4et al.,[From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. Cerchietet al., carried ,[et al., aimed toII trial.38 The ai studies.–44 The p studies. Synthetistudies.4–49 The ωstudies.4–52 Barbe[4et al., demonstr[4et al., in 200 p[4et al.,54 Patien[4et al., and the in vitro and slow muscle wasting in rats with cancer cachexia.[Current new trends include anti-IL-6 humanized monoclonal antibody which in murine models appear to inhibit cancer cachexia; IL-15, acachexia. Formotercachexia. Recentlyet al.,[A new class of nonsteroidal SARMs is being developed for use in cancer cachexia. SARMs are designed to have predominantly anabolic activity in muscle and bone with minimal androgenic effects in most other tissues. Evans et al., carried et al., Recent eet al., Predictiet al., Key defiet al.,In summary, based on current views on the cachexia syndrome in cancer patients, we put forward the following recommendations:Wasting is a predictable event in many cancer patients, readily diagnosed by assessment of weight, change in appetite, and food intake. Often these patients will also have anemia and low albumin, with a concomitant increase in C-reactive protein. The above simple assessments should form a consistent part of the record of all advanced cancer patients.Use a systematic formal guide to rule out treatable secondary causes of wasting.At the onset and throughout the course of illness, offer patients nutritional counseling , encourage them to take part in a rehabilitation program tailor made for their needs and abilities, and consider the use of specific nutraceutical and pharmacologic interventions. Follow-up visits should not only note careful evaluation of antitumor therapy and tumor volume, but also regular assessment of symptom control, weight, appetite, and function.Take careful note of the full medication profile of patients who are wasting. These might include drugs that could have a favorable effect on cachexia  and other agents that may be deleterious .Testosterone status should be established in cancer patients with the cachexia syndrome. If clearly reduced, physiologic testosterone supplementation should be considered after discussion with the patient.Patients must be assured of a reasonable intake of amino acids. Protein-containing foods are indicated and rich sources of both essential and nonessential amino acids will support any anabolic potential.Clinical researchers should be more cognizant of the work of their colleagues in sports medicine, AIDS, and geriatrics. Learning from their enterprises, further studies on creatine and supraphysiologic amounts of amino acids with a particular role in protein synthesis should be conducted. Similarly, the role of supraphysiologic doses of anabolic agents, in combination with nutrients and compounds that control muscle proteolysis, should receive high priority.There are few, if any, negative exercise trials. Patients should be encouraged to keep active or take part in tailored exercise programs, and studies on nutritional and pharmacologic agents should incorporate the potential additive effects of exercise.


Studies over the past decade have helped to decipher molecular networks dependent on Toll-like receptor (TLR) signaling, in mycobacteria-infected macrophages. Stimulation of TLRs by mycobacteria and their antigenic components rapidly induces intracellular signaling cascades involved in the activation of nuclear factor-κB and mitogen-activated protein kinase pathways, which play important roles in orchestrating proinflammatory responses and innate defense through generation of a variety of antimicrobial effector molecules. Recent studies have provided evidence that mycobacterial TLR-signaling cross talks with other intracellular antimicrobial innate pathways, the autophagy process and functional vitamin D receptor (VDR) signaling. In this article we describe recent advances in the recognition, responses, and regulation of mycobacterial signaling through TLRs. Mycobacterium tuberculosis (Mtb). In this state, healthy immune-competent individuals are able to combat infection by mounting of an effective immune response  for recognition of various molecular patterns of mycobacteria  occurs as early as 24 h post-infection. It is obvious that Mtb elicits inflammation-dampening signals in macrophages which would favor its survival.Numerous studies have revealed that TLR2 is involved in the innate recognition and responses in innate immune cells such as macrophages and dendritic cells of a variety of mycobacterial cell wall antigens including 19-kDa mycobacterial lipoprotein, glycolipids like lipoarabinomannan (LAM), LM, 38-kDa antigen, LprG lipoprotein, phosphatidylinositol mannoside (PIM), triacylated (TLR2/TLR1), or diacylated (TLR2/TLR6) lipoproteins [reviewed in Jo et al. ; KleinniMany previous studies have reported that mycobacterial components are involved in innate recognition and responses through TLR signaling , Rv0315, and Rv0577  induce dendritic cell maturation and activation leading to increased expression of costimulatory molecules  and proinflammatory cytokines , and potentiate the Th1 immune response . TDM has been reported to be tethered to several receptors, including TLR2, the class A scavenger receptor MARCO, Fc receptor-γ (FcRγ), and macrophage-inducible C-type lectin (Mincle) , TLR2 signaling activates Wnt-β-catenin signaling. The authors suggest that TLR2 integrates Wnt-β-catenin signaling to modulate a battery of genes associated with T(Reg) cell lineage commitment. At low MOIs, Mtb-triggered macrophage apoptosis depends on a TLR2 signaling cascade associated with ASK1/p38 MAPK- and c-Abl-dependent phosphorylation of c-FLIP and its degradation, leading to caspase 8 activation (Kundu et al., Recent work by Bansal et al.  suggestsTLR-dependent NF-κB signaling and MAPK pathways contribute to antimycobacterial innate immunity through secretion of antibacterial effector molecules, cytokines, and chemokines, thus recruiting various immune cells to the site of infection (Jo et al., M. bovis BCG, are linked with the increased production of Th1-type T cell cytokines through regulation of monocyte IL-10 production (Randhawa et al., M. bovis BCG infection (Davila et al., Human genetic polymorphisms of TLRs have a role in regulating innate recognition of microbes and in determining susceptibility to mycobacterial infection. The relationship between TLR polymorphisms, disease susceptibility, and innate immune activities against mycobacteria has been described in several reviews (Texereau et al., Previously, it was shown that human TLR1 deficiency is linked with impaired mycobacterial innate immune signaling and susceptibility to leprosy (Misch et al., Several other innate immune pathways are closely linked with the TLR signaling pathway, thus cooperatively defining the innate immune response which enables clearance of mycobacteria inside cells. Activation of autophagy has a critical effector role in innate immune responses such as enhancement of phagosomal maturation and coordination of the innate and adaptive immune systems Deretic, , 2012. IRecent studies have uncovered the interplay of vitamin D-dependent antimicrobial responses and autophagy pathways in the activation of host defense against mycobacterial infection (Yuk et al., in vivo and in vitro (Kim et al., The impact of host autophagy on phagosome maturation and Mtb killing gives rise to the idea that compounds that activate or modulate the autophagy pathway, could potentially enhance antimicrobial activities against Mtb infection (Gutierrez et al., Developing vaccines and chemotherapeutic agents is the cornerstone of the successful management of tuberculosis. Understanding the molecular mechanisms of specific interactions of Mtb with its host should augment efforts in both these areas. Immune modulation as a strategy to combat mycobacterial infection remains underexplored. This review brings to light how mycobacterial modulins signaling through TLRs, contribute either to an effective host immune response or to immune evasion by the pathogen. Targeting those modulins that facilitate immune evasion, or exploiting those that facilitate a robust innate and adaptive immune response, could offer new avenues for controlling infection. The review also brings forth the attractive possibility of developing therapeutics designed to augment autophagy as a means of restricting mycobacterial survival and combating infection.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.


Spatial and bodily representations are multisensory processes that imply the integration of several afferent signals into a coherent internal model of our egocentric space. Crucially, this model involves also the vestibular information from the balance organs in the inner ear (Ventre et al., CVS has been used to modulate a wide range of cognitive and sensory functions in brain-damaged patients and in healthy participants (Utz et al., specificity of these effects. Does CVS directly affect the somatosensory processing? Are the observed effects mediated by non-specific factors, such as ocular movements, spatial attention or general arousal?Various hypotheses have been suggested to explain the CVS-induced modulation on tactile perception. In particular, one of the most controversial issues in the classical and current literature concerns the Since Rubens , most ofConversely, the role of non-specific effects such as spatial attention is still a matter of debate. This hypothesis argues that CVS may induce a reorientation of spatial attention toward the hemispace ipsilateral to the stimulated ear. Strong evidence against this hypothesis derives from a recent study on brain-damaged patients (Bottini et al., More recent behavioral and electrophysiological studies, in healthy participants, have strengthened this suggestion. There are at least three main crucial observations ruling out interpretation in terms of non-specific attentional effects. First, left-cold CVS affects the perception of distinct somatosensory sub-modalities, i.e., touch and pain, for both the ipsilateral and contralateral hand (Ferrè et al., Previous studies exploring more widely CVS effects also support the idea that spatial attention does not have a pivotal role. Rorden et al.  did not specific and related to the activation of cortico-subcortical networks (Lopez et al., To conclude, this evidence suggests that in healthy volunteers the effects of CVS are


Biological Psychiatry, Levy-Gigi et al. found that a 12 weekly 90-mins cognitive behavioral therapy (CBT) treatment in individuals with posttraumatic stress disorder (PTSD) is associated with an increase in hippocampal volume and expression of glucocorticoid receptor genes, known as FKBP5 (Levy-Gigi et al., In a recent study in Interestingly, Levy-Gigi et al. found that CBT ameliorates all aspects of PTSD, including avoidance, re-experiencing, and hyperarousal symptoms. However, it is not clear from the Levy-Gigi et al. study whether changes to the hippocampal volume are associated with amelioration to which PTSD symptoms. Prior studies show that there is a trend for a negative correlation between higher re-experiencing symptoms and hippocampal volume (Shucard et al., At the neural level, several studies show that PTSD is associated with abnormalities to various brain areas, including reduced activity and volume of the hippocampus (Gilbertson et al., How can hippocampal dysfunction be related to PTSD symptoms? As noted by Levy-Gigi et al., the ventral hippocampus-amygdala pathway has been shown to be related to increased stress and anxiety (Fanselow and Dong, The Levy-Gigi et al. study also showed that CBT alters the expression of genes, including the FKBP5 gene. FKBP5 regulates glucocorticoid receptor sensitivity, and reduce the efficacy of cortisol in the brain (Mahon et al., Along these lines, Felmingham et al.  found thFuture computational modeling work is needed to explain how changes to the hippocampal volume and gene expression can ameliorate PTSD symptoms [see for example Krasne et al. ; Li et aIn summary, Levy-Gigi et al.  have ext


Recent advances in sequencing technologies have revealed extensive intratumour heterogeneity (ITH) both within individual tumours and between primary and metastatic tumours for different cancer types. Such genetic diversity may have clinical implications for both cancer diagnosis and treatment with increasing evidence linking ITH and therapeutic resistance. Nonetheless, whilst limiting the activity of targeted agents, tumour genetic heterogeneity may provide a new therapeutic opportunity through generation of neo-antigens that could be recognised and targeted by the patient's own immune system in response to immune-modulatory therapies. Longitudinal genomic studies assessing tumour clonal architecture and its correlation with the underlying immune response to cancer in each particular patient are needed to follow tumour evolutionary dynamics over time and through therapy, in order to further understand the mechanisms behind drug resistance and to inform the development of new combinatorial therapeutic strategies. Current Opinion in Pharmacology 2013, 13:497–503CancerThis review comes from a themed issue on Massimo Santoro and Francesca CarlomagnoEdited by Issue and the EditorialFor a complete overview see the Available online 7th May 20131471-4892/$ – see front matter, © 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.coph.2013.04.006The existence of distinct subpopulations of cancer cells within a tumour harbouring different behavioural phenotypes, including tumourigenicity, ability to metastasise and evolve resistance to treatment, has been recognised for many years . Recent In this article we review the clinical implications of ITH for the genetic stratification of tumours, the emerging evidence that suggests the need to investigate the changing nature of tumour subclonal architecture through therapy and the potential impact of such diversity on anti-tumour immunity. We argue that an in-depth understanding of tumour evolution over time, the mechanisms driving tumour diversity and its impact on immunity may lead to the improved management of cancer patients .Phenotypic heterogeneity observed in tumours results from both genetic and non-genetic causes of heterogeneity. Spontaneous tumours are known to arise through Darwinian-like somatic clonal evolution involving the acquisition of ‘driver’ events, such as genetic mutations or copy number variations, believed to affect cancer cell proliferation or survival, along with ‘passenger’ events, assumed to be phenotypically silent without a selective fitness advantage . Non-genRecent advances in massively parallel sequencing technologies have enabled the analysis of the complex clonal architecture of both primary and metastatic tumours . PatternHER2 predicts response to trastuzumab but its distribution can be heterogeneous in primary tumours and associated with shorter disease-free survival times compared to patients with homogenous HER2 amplification [et al. [HER2 amplification in oesophageal adenocarcinoma independently predicted worse disease-specific survival and overall survival compared to non-heterogeneous HER2 amplified tumours.The validation of predictive biomarkers may be simpler and less subject to tumour sampling bias when present in all regions of a tumour and sustained during disease progression. However, ITH for the expression of genetic and phenotypic biomarkers has been shown in several tumour types. In breast cancer, the amplification of fication . Yoon et [et al.  showed tEGFR predict response to gefitinib, but discordance for the EGFR mutation has been shown between primary and metastatic tumours [HER2 amplification and HER2 protein overexpression has been shown within the same tumour, and between diagnostic biopsies and resected tumours [HER2 amplification between primary and metastatic tumours has also been shown in breast cancer [et al. [KRAS, NRAS, BRAF, PIK3CA and TP53 genes. However, in patients with a history of more than one colorectal primary tumour and interval treatment, there was evidence for discordance in TP53. These examples demonstrate that relying on a single tumour biopsy may lead to sampling bias in some cases and risk missing potentially therapeutically relevant lesions or contribute to the allocation of a mutation as actionable without establishing clonal dominance [Primary and metastatic tumours can evolve independently and acquire different phenotypes leading to significant genetic divergence, and therefore discordance, between primary and metastatic tumours in terms of biomarkers detected in the diagnostic biopsy . In non- tumours . In prim tumours . Discordt cancer . In colo [et al.  found muominance . Furtherominance . This maT790M mutation known to confer insensitivity to gefitinib [et al. [EGFR mutations treated with EGFR TKIs, the presence of low frequency subclones harbouring T790M mutations before the onset of treatment was associated with shorter progression-free survival, and Turke et al. [MET amplification was associated with EGFR TKI resistance. In colorectal cancer, wild-type KRAS predicts sensitivity to anti-EGFR antibody therapies such as panitumumab. Diaz et al. [KRAS wild-type tumours, the emergence of mutations in KRAS could be detected during the course of therapy resulting in acquired resistance. They concluded that subclonal populations harbouring KRAS mutations existed before commencing treatment, and that under the selective pressure of anti-EGFR blockade, resistant subclones rapidly expand and repopulate the tumour. In chronic myeloid leukaemia and gastrointestinal tumours, resistance to imatinib due to mutations in the BCR-ABL fusion protein [Most advanced cancers still remain incurable despite significant progress in the fields of cancer research and therapy. Response to therapy is generally of limited duration. This may be due to the inevitable evolution and proliferation of resistant subclonal populations, which may exist before the onset of treatment, under the selective pressure of therapies ••. In NSefitinib ••. Su et [et al.  demonstre et al. • showed z et al. •• showed protein  and KIT  protein  respecti protein . These eet al. [EGFR mutant NSCLC with an EGFR TKI and EGFR-specific antibody could prevent resistance associated with the expansion of a subclone harbouring a T790M mutation. Approaches like this would require the development of biomarkers predicting likely resistance mechanisms in different patients, and such mechanisms could be targeted either in combination, or alternating, with standard treatment regimens [In light of increasing evidence in support of ITH and its role in treatment resistance, there is a need for alternative therapeutic approaches. Gillies et al.  argue thet al. ••, and tregimens . Treatmeregimens  and melaregimens . Other aregimens .post hoc analyses of data originally generated by Sjoblom et al. [in vivo ‘vaccine’ or priming effect which could be further enhanced by interference with immune-modulatory pathways. Whilst the neo-antigenic repertoire generated by ITH could be seen as non-self by the immune system, the type of tumour cell death and inflammatory environment within the tumour will define their immunogenicity and the final outcome of the immune response (i.e. tumour progression versus regression). Importantly, immunity to tumour-associated antigens can be potentiated given proper identification and manipulation of immune-regulatory checkpoints restricting T cell function [Whilst emerging evidence supports the notion that ITH limits the efficacy of conventional and targeted therapeutics, its overall effect on the immune response to cancer may still be of potential benefit for the patient since intratumoural mutational diversity can provide neo-antigens that may be perceived by the immune system as non-self, producing unique opportunities for the generation of anti-tumour immunity. The wealth of data now being generated through whole genome sequencing of tumour samples provides further support for this concept. In silico-based computer algorithms combined with high-throughput m et al.  revealedm et al. . Furtherm et al. . MSI is m et al. . One potm et al. . Based ofunction . This hafunction . In addifunction •).Although ITH may complicate diagnostic and treatment decisions, it can be clinically useful in predicting clinical outcome. In Barrett's oesophagus • and breWith the development of improved technologies allowing the interrogation of ITH, our understanding of tumours and their evolutionary trajectories may lead to better design of clinical trials in search of improved therapeutic interventions to anticipate the emergence of drug resistance mechanisms and generate improved predictive and prognostic biomarkers . Whilst None declared.None.• of special interest•• of outstanding interestPapers of particular interest, published within the period of review, have been highlighted as:


A recent study found that mosquito-transmitted (MT) lines of rodent malaria parasites elicit a more effective immune response than non-transmitted lines maintained by serial blood passage (non-MT), thereby causing lower parasite densities in the blood and less pathology to the host. The authors attribute these changes to higher diversity in expression of antigen-encoding genes in MT cf. non-MT lines. Alternative explanations that are equally parsimonious with these new data, and results from previous studies, suggest that this conclusion may be premature. Plasmodium chabaudi or other malaria species are transmitted through mosquitoes, their virulence and asexual replication rate in the blood is reduced [et al.[Many studies have shown that when parasite lines of the rodent malaria  reduced -6. This  reduced ,6-13. Spet al. [et al.’s [The family of genes that Spence et al.  found toet al.’s  observatet al. (Plasmodium chabaudi in C57/Bl6 laboratory mice) parasite lines were evolved by SBP through either immunized or naïve mice and, at the end, virulence of the evolved lines was measured, both in immunized and naïve mice, and both before and after mosquito transmission [Does this resetting render MT parasites more controllable by the immune system, or is it just that MT parasites are less intrinsically virulent? In previous experiments studying the evolution of parasite virulence in the same experimental model used by Spence smission . Before et al.[et al.[et al.’s [However, when the I-lines were compared to the N-lines in pre-immunized mice, the differences disappeared. In the light of new data from Spence et al., it is hl.[et al., these ret al.’s  interpreet al.[However, several alternative explanations that invoke changes to the parasite’s intrinsic virulence, as opposed to the immunity it provokes, are similarly parsimonious with the data of Spence et al. and fromet al.,2. Severet al. and expeet al., bottlenet al. virulencet al.[Plasmodium falciparum, the most deadly of the human malaria parasites, that certain subsets of the variable surface antigens are highly pathogenic [Although virulence attenuation in laboratory models of malaria -6 is higthogenic -20 thus The author declares that she has no competing interests.


Plants imperatively have to cope with adverse conditions owing to their lack of mobility and to the high amounts of reactive oxygen species (ROS) generated from both respiration and photosynthetic metabolism. Although thiol redox homeostasis in plants is mainly preserved by the cellular glutathione pool, specific strategies have been adopted by the plant kingdom during evolution to manage these “extra” pro-oxidative conditions. Unlike human or yeast, plants generally possess a higher number of genes coding for antioxidant proteins, including protein families responsible of dithiol/disulfide exchange reactions. During the last decades, redox-dependent post-translational modifications of proteins proved to be pivotal to many cellular functions. In particular, this is critically important under some situations of environmental constraints taking into account the alterations and fine adjustment of the cellular redox status occurring during and after any biotic or abiotic stresses.Indeed, thiol groups of cysteinyl residues are highly sensitive to oxidation which might critically perturb cellular homeostasis. Members of the thioredoxin superfamily are key proteins involved in the regulation of cysteine/protein redox state. They share two common and well-known features: (i) the presence of an active center containing at least one catalytic cysteine residue, and (ii) a highly conserved 3D-structure, the so-called thioredoxin fold, which consists of a four-stranded anti-parallel β-sheet surrounded by three α-helices. Key members of this super family are thioredoxins (TRX) and glutaredoxins (GRX). Representatives of both subgroups are distributed in most cellular compartments and contain at least one TRX motif in their structures. While TRXs are generally reduced by thioredoxin reductases (TR), the reduction of GRXs depends on reduced glutathione (GSH).The 19 reports of this Research Topic provide timely overviews and new insights into redox regulation, focusing on both TR/TRX and GSH/GRX reduction systems in plants. The biochemical characteristics of these systems as well as their target proteins and functions in metabolic and signaling pathways are discussed. Several contributions to this Research Topic deal with the role of TRX systems in plastid metabolism. Michelet et al.  summarizArabidopsis, and on the discovery of trans-thylakoid redox pathways controlling disulfide bond formation and reduction.Within the photosynthetic context, Karamoko et al.  propose in vivo approach showing the positive effect of NTRC overexpression in plant performance.In addition, the importance of NADPH thioredoxin reductase C (NTRC) in plastid redox regulation is also reported in four articles. The paper by Puerto-Galán et al.  discusseThe importance of redox regulation in plant mitochondria is also highlighted in this Research Topic by Lázaro et al. . These ah with selected target proteins using surface plasmon resonance. The presented data reveal a stronger preference of TRX h for an oxidized target, thus explaining the selective association of TRX with oxidized proteins. Zaffagnini et al. (Some aspects of the cytosolic redox regulation pathways have also been developed in this Research Topic. Hara and Hisabori  analyzedi et al.  review hgrx mutants, that GRXs are essential for stress adaptation in cyanobacteria. Finally, Knaff and Sutton (GRXs are oxidoreductases of the TRX family which display a particularly rich diversity in higher plants. Beyond classification in three main subgroups based on sequence and structural features, Couturier et al.  indicated Sutton  describeArabidopsis. The data demonstrate that cellular glutathione homeostasis influences the root architecture and the leaf area under optimal and stress conditions. Another aspect where glutathione and homoglutathione are crucial molecules is nodule development and in the context of legume-rhizobium mutualistic interactions. Indeed, these organs are peculiar due to the formation of a bacteroid in which the oxygen-sensitive nitrogenase reduces di-nitrogen to ammonia. However, the importance of other redox systems in this unique organ has been poorly documented. Frendo et al. (Glutathione is a key component in regulation and maintenance of cellular thiol redox homeostasis. It also plays key roles in different aspects of plant development. Here, Rahantaniaina et al.  provide o et al.  review to et al.  summarizThe 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.


N-acetyl-beta-d-glucosaminidase), markers of inflammation  and markers of oxidative stress. Despite the promise of some of these new biomarkers, further large, multicenter prospective studies are still needed before they can be used in everyday clinical practice.Diabetes prevalence is increasing worldwide, mainly due to the increase in type 2 diabetes. Diabetic nephropathy occurs in up to 40% of people with type 1 or type 2 diabetes. It is important to identify patients at risk of diabetic nephropathy and those who will progress to end stage renal disease. In clinical practice, most commonly used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate and proteinuria or albuminuria. Unfortunately, they are all insensitive. This review summarizes the evidence regarding the prognostic value and benefits of targeting some novel risk markers for development of diabetic nephropathy and its progression. It is focused mainly on tubular biomarkers (neutrophil-gelatinase associated lipocalin, kidney injury molecule 1, liver-fatty acid-binding protein,  Chronic kidney disease (CKD) is an important public health problem and the prevalence is estimated to be 8%–16% worldwide . DiabeteAccording to the above mentioned, it is clear that new biomarkers are needed to predict patients who will develop diabetic nephropathy or are at risk of progressing to ESRD. Some of the promising new biomarkers in serum and urine will be presented in this paper.Tubulointerstitial damage is an important feature of diabetic nephropathy and is, in addition to glomerular damage, an important predictor of renal dysfunction ,5,6,7. INeutrophil gelatinase-associated lipocalin (NGAL) is small (25-kDa) protein that is released from injured renal tubular cells in acute kidney injury into the blood and urine, long before a decrease in the glomerular filtration rate can be detected ,9,10. Seet al., included 96 patients with CKD stages 2–4, among them 20% with diabetic nephropathy [et al., 74 type 2 diabetic patients were included [et al., 158 patients with CKD stage 3 and 4 were included, and 6% were patients with diabetic nephropathy [2) over one year. Adding urine NGAL-to-creatinine ratio demonstrated the greatest benefit in identifying patients with CKD progression only in group of patients with relatively low proteinuria. In the study by Nauta et al., 94 diabetic  and 45 non-diabetic control subjects were included [et al., in 63 type 1 diabetic patients with diabetic nephropathy who were followed for three years [et al., serum and urine NGAL were used in addition to albuminuria to predict the GFR decline rate in type 2 diabetic patients, but only urine albumin excretion rate was significantly associated with eGFR and the eGFR decline rate [In one of the first large studies, Bolignano hropathy . Patientincluded . They wehropathy . The basee years . Accordiine rate .According to conflicting results of previously mentioned studies, and due to the strong link with proteinuria in most of the studies, serum and urine NGAL do not offer additional prognostic information compared to already established biomarkers.Kidney injury molecule 1 (KIM-1) is a transmembrane tubular protein with unknown function, not detectable in the normal kidney, but elevated in experimental and clinical kidney damage . It is aet al., in biopsies from various renal diseases  and controls, renal KIM-1 was significantly increased in all diseases versus controls, except minimal change [versus controls and correlated positively with tissue KIM-1 and negatively with renal function, but again not with proteinuria [et al., 145 renal transplant recipients were included and were followed for four years for graft loss [In the study by von Timmeren l change . KIM-1 wl change . Renal Kl change . At the l change . Urinaryteinuria . In the aft loss . At baseaft loss . In multaft loss . Urinaryaft loss ,27,28,29Liver-fatty acid-binding protein (L-FABP) is an intracellular carrier protein that is expressed in proximal tubules of the kidney and liver. Although its precise function is unknown, it is believed to be endowed with protective functions . L-FABP et al., including 165 normoalbuminuric type 1 diabetic patients urinary L-FABP predicted the development of micro- and macro-albuminuria independent of recognized biomarkers [et al., including over 100 type 2 diabetic patients, high urinary L-FABP levels were associated with the increase in albuminuria, progression of diabetic nephropathy to ESRD or induction of haemodialysis [et al., only urine albumin excretion rate was significantly associated with eGFR and eGFR decline rate in type 2 diabetic patients and not L-FABP [In the large prospective study by Nielsen omarkers . In anotdialysis . In the t L-FABP .et al., including type 2 diabetic patients, heart fatty acid-binding protein (H-FABP), a marker of distal tubular damage, was the only tubular marker associated with eGFR after adjustment for other risk markers of progressive diabetic nephropathy [In the study by Nauta hropathy .According to published studies, members of the FABP family are emerging as the tubular markers with the greatest chance of offering added predictive value for progressive diabetic nephropathy over and above that offered by established risk markers .N-acetyl-beta-d-glucosaminidase (NAG) is a lysosomal enzyme that is constitutively expressed by the proximal tubule and a well-studied urinary marker of established proximal tubule cell injury [Urinary l injury . NAG is l injury .et al., lower urinary NAG levels were associated with the regression of microalbuminuria in type 1 diabetes mellitus [et al., including type 1 diabetic patients who participated in the Diabetes Control and Complications Trial (DCCT), baseline levels of urinary NAG independently predicted the development of micro- and macro-albuminuria during the follow up period of nine years [In the study by Vaidya mellitus . In the ne years . The lacne years . FurtherSeveral factors are involved in the development and progression of diabetic nephropathy. Growing evidence indicates that pathogenesis and progression of diabetic nephropathy is associated with the presence of a chronic subclinical low-grade inflammatory state and oxidative stress ,43. IncrCytokines are low molecular weight polypeptides and their most important function is regulation of the inflammatory process. They contribute in accelerating and maintaining chronic inflammation. The first studies suggesting the role of inflammatory cytokines in the development of diabetic nephropathy were published more than 20 years ago ,45.et al., 194 type 1 diabetic patients from multi-centre Finnish Diabetic Nephropathy Study (FinnDiane) were included [et al., including 29% of patients with diabetic nephropathy baseline IL-6 levels gradual increase from control subjects to CKD stage 3 and 4 and to CKD stage 5 patients [et al., five inflammatory markers—IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), interferon γ-inducible protein (IP-10), and macrophage inflammatory protein 1d—were measured in urine samples collected from individuals with type 1 diabetes [Interleukin-6 (IL-6) is a proinflammatory cytokine, which is produced by many cells  and is also associated with visceral obesity and insulin resistance . In the included . They weincluded . In thisincluded . In the patients . In the diabetes . Baselindiabetes . By multdiabetes .et al., 151 type 2 diabetic patients with various degrees of nephropathy, as well as 80 healthy volunteers, were included [In the study by Moriwaki included . Signifiincluded . In addiincluded .et al., serum and urinary IL-18 and serum IL-6 levels were also significantly elevated in patients with type 2 diabetes compared to control subjects [In the another study by Nakamura subjects . In uni-subjects .et al., reported in two studies direct and significant association between serum TNF-α and urinary protein excretion in diabetic patients with normal renal function and microalbuminuria, as well as in subjects with overt nephropathy and renal insufficiency [et al., where significant differences in serum levels of TNF-α were observed between the type 2 diabetic patients and control subjects [The primary source of tumour necrosis factor-α (TNF-α) are monocytes and macrophages, although intrinsic renal cells are also able to synthesize this cytokine . It was ficiency ,56. Urinficiency ,56. Multficiency ,56. Simisubjects . In patisubjects .et al., only levels of soluble forms of receptors 1 and 2 for TNF-α, and not TNF-α, were found to be associated with GFR in a multivariate analysis [et al., 410 patients with type 2 diabetes were included and were followed for 12 years [et al., 628 patients with type 1 diabetes, normal renal function and no proteinuria were included and followed for 12 years; in the follow up period, 69 patients developed eGFR less than 60 mL/min per 1.73 m2 [Interestingly, in the study by Niewczas analysis . In anot12 years . In foll12 years . In the  1.73 m2 . In this 1.73 m2 . SimilarInfiltration of leukocytes into inflammatory lesions is mediated by adhesion to endothelial cells and transmigration from vascular lumen to inflammatory sites . Adhesioet al., type 1 diabetic patients and healthy subjects were included [et al., baseline levels of ICAM-1 and VCAM-1 were measured from stored blood samples from the 1441 participants of the DCCT [et al., 30 hypertensive type 2 diabetic patients and 30 non-diabetic normotensive subjects were included; their VCAM-1, ICAM-1 and selectin levels were measured [In the study by Clausen included . In thisincluded . In the the DCCT . Only anthe DCCT . In the measured . The diameasured . Due to Growing evidence suggests that recruitment of inflammatory cells from the circulation into renal tissue plays a pivotal role in the progression of various renal diseases, including diabetic nephropathy. Infiltration of activated T cells and monocytes initiate renal damage and lead to a progressive loss of renal function ,67. Chemet al., 45 type 2 diabetic patients and 20 healthy subjects were included [et al., levels of urinary MCP-1 in type 2 diabetic patients with normal renal function were significantly higher than those in healthy adults, and urinary MCP-1 levels increased gradually from normo-, micro- to macro-albuminuria [et al., urinary levels of MCP-1 in patients with macroalbuminuria were significantly elevated compared to the levels in patients with normo- and micro-albuminuria [et al., in type 1 diabetic patients, baseline urinary MCP-1 was significantly higher in those with an early progressive kidney function decline compared with those who displayed stable kidney function [In the study by Wada included . Urinaryuminuria . Similaruminuria . In thisuminuria . In prevfunction .et al., showed that blockade of the renin–angiotensin system in patients with type 2 diabetes was associated with a reduction in urinary MCP-1 levels as well as an improvement in renal function [et al., found that aldosterone blockade by spironolactone may offer beneficial renoprotective effects through anti-inflammatory mechanisms via the modulation of MCP-1 [Two interesting studies demonstrating the effect of treatment with ACE inhibitors and spironolactone on MCP-1 in type 2 diabetic patients have been published. In the first, Amann function . In the of MCP-1 .etc., and reduced levels of antioxidant agents and enzymes, such as bilirubin, superoxide dismutase and antioxidant vitamins, thus promoting oxidative stress [Under normal physiological conditions, there is a balance in the generation of oxygen-free radicals and the antioxidant defence mechanisms used to deactivate free radical toxicity . Experime stress ,76. Mease stress ,78. 8-OHe stress ,78. Urine stress ,78.et al., 396 Japanese type 2 diabetic patients with normoalbuminuria or microalbuminuria were included and followed for five years [In the large study by Hinokio ve years . Authorset al., 52 patients with type 2 diabetes mellitus (32 with nephropathy and 20 without) and 20 healthy control subjects were included [The multivariate logistic regression analysis suggested that the urinary 8-OHdG was the strongest predictor of nephropathy among several known risk factors. In the another study by Serdar included . The conAccording to conflicting results of clinical studies, it is questionable if markers of oxidative stress add additional prognostic information in relation to the development or progression of diabetic nephropathy compared to established risk markers.etc. [Today, in clinical practice, most commonly used markers of renal disease and progression of CKD and also diabetic nephropathy are serum creatinine, eGFR and proteinuria/albuminuria but unfortunately they are all insensitive. Some new biomarkers reviewed in this paper are promising but further large, multicenter prospective studies are needed before they can be used in everyday clinical practice. The main problem is that most of the biomarkers are still at an intermediate phenotype level, which is too distant from the gene level and most of these biomarkers are deeply influenced by environment, genetics, sex differences, etc. . It is aDespite that the purpose of this paper is to present the biomarkers of renal disease and progression in patients with diabetes, it is also important and should be mentioned that, in patients with diabetic nephropathy, there is also a concomitant increase in cardiovascular morbidity and mortality . Some of


Recently, Christoph Thiel and colleagues from Aachen University published an improved physiologically based pharmacokinetik modeling (PBPK) technique for mouse to human extrapolation . This pThe translation of preclinical knowledge often generated in mice to first-in-human studies represents a critical step . More tspecies-specific physiology, such as differences in organ size, perfusion, etc. the species-specific non-protein bound fraction of the test compound, max and KM for the primary route of excretion, and kinetic parameters, such as Vtissue-specific gene expression of the metabolizing key enzymes and transporters.The authors start with a naïve extrapolation where humans are considered as 'large mice' where the same dose per body weight was administered . This nInterspecies differences represent a major problem in toxicology (Dohnal et al., 2014; BernauePBPK modeling has been used since long to predict absorption, distribution, metabolism and excretion (Sterner et al., 2013; Lee et


G-nitro-L-arginine methyl ester  was performed throughout fructose intake. L-NAME treatment itself induces increase in blood pressure and relative heart weight as well as impairment in arterial relaxation and contractility. However, in these rats, fructose administration did not cause further elevation of blood pressure and other abnormalities observed in rats receiving fructose without L-NAME. Our results showed that in the state of NO deficiency (induced by L-NAME administration) fructose does not induce cardiovascular and metabolic alterations which develop in rats with a functional NO system. This indicates that impairment of the NO system may participate in many of the adverse effects induced by high-fructose intake.The aim of this study was to evaluate the involvement of nitric oxide (NO) system damage in the deleterious effects of high-fructose intake in rats. Fructose was administered as 10% solution in drinking water to twelve-week-old male Wistar rats for the period of 8 weeks. Blood pressure was measured by tail-cuff plethysmography. After sacrificing the rats at the end of the treatment, relative weights of heart and liver and biochemical parameters in blood plasma were determined. Reactivity of isolated conduit arteries was measured using a force-displacement transducer for recording isometric tension. Fructose drinking rats had increased blood pressure and impaired acetylcholine-induced relaxation of the thoracic aorta in comparison with control rats drinking just tap water. Relative liver weight and plasma concentrations of glucose and triglycerides were also elevated after fructose administration. In a further group of Wistar rats, inhibition of NO production by administration of N NG-nitro-L-arginine methyl ester – L-NAME) causes NO deficiency and impaired vascular relaxation leading to sustained blood pressure increase  plays a critical role as a molecular mediator in a variety of biological processes, including vasodilatation, neurotransmission and macrophage-mediated immunity. In spite of its pleiotropic effects in organisms, its role has been most extensively studied in physiology and pathology of the cardiovascular system. It is its prominent role in endothelium-dependent relaxation of vessels thanks to which the function of NO in the cardiovascular system was discovered and identified , fructose drinking rats (receiving 10% solution of fructose for 8 weeks), L-NAME treated rats (receiving 40 mg/kg/day of L-NAME in drinking water for 8 weeks), L-NAME treated fructose drinking rats (receiving 40 mg/kg/day of L-NAME in 10% solution of fructose for 8 weeks). The animal protocols used in this study were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health, and approved by the Animal Health and Welfare Division of the State Veterinary and Food Administration of the Slovak Republic.Twelve-week-old male Wistar rats were housed at 22–24°C on a 12:12-h dark-light cycle (06.00–18.00 h lights on) and maintained on a standard laboratory rat chow th week of life), all rats were fasted overnight  and then they were sacrificed under CO2 anesthesia. Samples of their blood were collected immediately and used for measurement of plasma glucose, cholesterol and triglyceride concentration. Wet weight of the left heart ventricle and of the liver and the length of the tibia were determined for calculation of the ratio of left heart ventricle weight to tibia length and of liver weight to tibia length. The thoracic aorta and superior mesenteric artery were carefully removed and prepared for functional studies performed by isometric tension recording.Systolic blood pressure and heart rate were measured in conscious rats by the non-invasive tail-cuff method. At the end of the experiment (in the 202 + 5% CO2) modified Krebs solution maintained at 37°C. The Krebs solution had the following composition (in mmol/l): NaCl 118, KCl 5, CaCl2 2.5, MgSO4 1.2, NaHCO3 25, KH2PO4 1.2, glucose 11, CaNa2.EDTA 0.03. The arterial rings were set up for isometric tension recording using a force-displacement transducer Sanborn FT 10 . The preparations were equilibrated under a resting tension of 10mN for 60–90 min and the solution was changed every 15 min.The arteries were cut into rings (3.0–3.5 mm in width) and suspended in 20 ml organ baths filled with oxygenated (95% O–6 mol/l). When the contraction reached a plateau, increasing concentrations of acetylcholine were applied in a cumulative manner (10–9–10–5 mol/l).To examine the endothelium-dependent vasorelaxation, the preparations of the aorta were first precontracted by phenylephrine (10–10–3×10–5 mol/l).Adrenergic contractions were determined in endothelium-intact thoracic aortas and mesenteric arteries as the responses to cumulatively applied exogenous noradrenaline . Frequency-response curves to electrical stimuli were obtained using square pulses of 0.5 ms in duration, at supramaximal voltage (>30 V), applied at 1–32Hz, for a period of 20 s. In our preliminary observations we found that the contractions of rat mesenteric arteries elicited by electrical stimulation (using the described parameters of stimulation) were blocked by phentolamine or tetrodotoxin, indicating that they were induced by nerve-released (endogenous) noradrenaline.Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) were purchased from Sigma-Aldrich (Germany); other chemicals were purchased from local commercial sources.Acetylcholine chloride, L-Noradrenaline hydrochloride and The results are presented as means ± S.E.M. The arterial responses to particular pharmacological and electrical stimuli are expressed as absolute values in mN and normalized to the cross sectional area of the respective ring preparation.p<0.05.Statistical evaluation was carried out by using one-way analysis of variance (ANOVA). The results were considered to be significant when After eight weeks of treatment with fructose, the Wistar rats had significantly elevated blood pressure without change in heart rate, when compared to control untreated rats. Body weight and relative weight of the left heart ventricle did not differ between control and fructose drinking rats. However, the relative liver weight, as well as plasma glucose and triglyceride concentrations were increased due to fructose treatment .In the thoracic aorta, endothelium-dependent relaxations in response to acetylcholine were significantly decreased after fructose administration . ContracEight-week L-NAME administration to control Wistar rats caused significant increase in blood pressure, relative weight of left heart ventricle, and in plasma cholesterol level . It alsoIn this study we found that eight-week-lasting fructose administration to adult Wistar rats induced metabolic changes associated with increase in plasma glucose and lipids, enlargement of liver, mild but significant blood pressure elevation, and reduction in acetylcholine-induced arterial relaxation. We also showed that in rats made NO deficient by L-NAME treatment, the high-fructose intake did not evoke such alterations. These observations indicate that impairment of the NO system might represent an important mechanism of high-fructose induced damage.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., It was shown by other investigators that production of NO decreased after feeding normal rats with excess of fructose and that this effect may induce hypertension development in such treated individuals  which exhibit similar severity of hypertension as L-NAME-treated rats and their arteries have also diminished endothelium-dependent relaxation. However, in conduit arteries of adult SHR the NO synthase activity is markedly elevated and their resting relaxant capacity is still sufficiently NO dependent (Puzserova et al., et al., 1996; Yoneyama et al., The presented observations show that fructose administration had no effect on the magnitude of arterial contractions induced by exogenous or endogenous noradrenaline. On the other hand, treatment of rats with L-NAME alone led to diminution of arterial contractile responses. This paradoxical effect of inhibiting NO synthase was demonstrated by many authors (Dowell et al. (et al., Inhibition of NO production eliminated also the high-fructose evoked increase in liver mass and in plasma glucose and lipids. It is known that NO is implicated in a myriad of mechanisms regulating liver metabolism and its higher amount may have the potential for both protecting the liver as well as exacerbating its injury. Spruss et al.  demonstr et al.,  or in ra et al., , variousIn conclusion, in this study we demonstrated that NO deficiency abolished the abnormalities observed during fructose administration in normal rats. It may thus be supposed that impairment of the NO system may participate in many of the adverse effects induced by high-fructose intake since a functional NO system is necessary for their manifestation.


The endothelium is the orchestral conductor of blood vessel function. Pathological blood vessel formation  or the inability of endothelial cells (ECs) to perform their physiological function (a condition known as EC dysfunction) are defining features of various diseases. Therapeutic intervention to inhibit aberrant angiogenesis or ameliorate EC dysfunction could be beneficial in diseases such as cancer and cardiovascular disease, respectively, but current strategies have limited efficacy. Based on recent findings that pathological angiogenesis and EC dysfunction are accompanied by EC-specific metabolic alterations, targeting EC metabolism is emerging as a novel therapeutic strategy. Here, we review recent progress in our understanding of how EC metabolism is altered in disease and discuss potential metabolic targets and strategies to reverse EC dysfunction and inhibit pathological angiogenesis. Partialet al, et al, et al, et al, The hexosamine biosynthesis pathway starts with the conversion of the glycolytic intermediate fructose-6-phosphate (F6P) into glucosamine-6-phosphate (GlucN6P) Fig . GlucN6Pet al, et al, et al, et al, Other metabolic pathways are less well characterized in ECs. Fatty acid (FA) oxidation (FAO) and glutamine oxidation have been implicated in replenishing the TCA cycle to produce ATP via oxidative phosphorylation Fig   in ECs. Arginine is a metabolite in the ornithine cycle and converted into citruline and nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) Fig  , which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1)  in the rate-limiting step of glycolysis. EC-specific PFKFB3 deletion diminishes retinal and hindbrain vascularization in mice, showing that increased glycolytic flux is required for growth factor-induced angiogenesis  is metabolically demanding and mediated by adaptations in EC metabolism Fig A. While in vivo -1-(4-pyridinyl)-2-propen-1-one (3PO) or EC-specific genetic silencing of PFKFB3 inhibits tumor growth et al, et al, et al, et al, et al, in vivo and that pharmacological blockade of MCT1 inhibits angiogenesis and reduces tumor growth in mice  Fig A  is characterized by heightened pressure in pulmonary arteries caused by excessive EC proliferation and vascular dysfunction  levels are another hallmark of PAH ECs  are partly reminiscent of the metabolic profile of angiogenic ECs. It would be thus interesting to determine if reducing glycolysis by pharmacological blockade of PFKFB3 can reduce the hyperproliferative rate in PAH ECs. Alternatively, the beneficial effects of PDK inhibition in PAH to induce oxidative metabolism could also be beneficial to block angiogenesis by preventing the glycolytic switch in ECs. Indeed, PDK blockade with dichloroacetate inhibits angiogenesis in glioblastoma patients  and reactive nitrogen species (RNS), which might be mediators of EC dysfunction Fig  Blake &. High glet al, et al, et al, et al, et al, et al, et al, et al, et al, et al, Accumulation of F6P increases the flux through the hexosamine biosynthesis pathway (HBP), which produces UDP-GlcNac, an important precursor of glycosylation reactions Fig A Brownl. While get al, et al, et al, et al, et al, et al, et al, et al, in vitro and transgenic overexpression of glyoxalase-I in rats reduces vascular AGE formation and improves vasoreactivity  at the expense of NADPH, increasing ROS. Sorbitol is subsequently converted into fructose and the highly reactive 3-deoxyglucosone (3DG), which promotes the formation of AGEs  and by a salvage pathway from dihydrobiopterin (BH2) via dihydrofolate reductase (DHFR)  Fig B  metabolism centers around the ability of folate-derived co-enzymes to carry activated 1C units Fig  Tibbett. DHFR caEC metabolism is best characterized in the diseases discussed above. However, these represent only a minor fraction of the disorders in which pathological EC responses are presumably involved. Indeed, it is highly likely that EC metabolic alterations are also involved in the pathogenesis of other diseases such as ischemia, pre-eclampsia, vasculitis, vascular neoplasms and others although this has hardly been studied.et al, et al, et al, et al, in vitro, and in vivo levels of serum nitrites (an indicator of NO production) are inversely proportional to serum uric acid concentrations  is common in patients with hypertension and may even be a root cause of EC dysfunction leading to cardiovascular disease (Feig et al, et al, A broader characterization of EC metabolism in the future might reveal novel therapeutic targets in metabolic pathways that are generally not considered to be important in pathological EC function. Recent findings that endothelial cholesterol efflux to high-density lipoprotein regulates angiogenesis (Fang The findings in this review suggest that blood vessel pathology is mediated, or at least characterized, by disease-specific alterations. However, at present, there are no studies that incorporate state-of-the-art metabolomics tools to characterize EC metabolism in disease. Metabolic profiling using isotope incorporation studies and metabolic flux analysis could greatly increase our understanding of the metabolic alterations that underlie EC pathology.In vivo studies to characterize EC metabolism in animal models of human disease could provide highly relevant insight in disease-specific metabolic alterations. However, this requires isolation of ECs from diseased tissue, which at present poses technical and interpretational challenges for proper analysis of metabolism using advanced metabolomics methods.in or ex vivo models. The recent development of new protocols to isolate ECs from patient tissue offers the possibility to study metabolism in clinically relevant systems. Accordingly, such studies could greatly advance the identification of novel biomarkers and therapeutic targets in EC metabolism.Another pressing issue is the lack of studies characterizing metabolism in patient-derived tissue using either et al, et al, et al, et al, Overall, it is clear that pathological blood vessel responses are associated with metabolic alterations in ECs. These metabolic adaptations are not just innocent bystanders, but in many cases mediate important aspects of disease. Increased EC glucose metabolism is emerging as a key feature of angiogenic and hyper-proliferative ECs. Targeting EC glucose metabolism has recently been shown as a viable strategy to curb pathological angiogenesis, but is still in its infancy (Schoors


Cryptococcus species, with neoformans strains mostly isolated from individuals with impaired immunity  strain that lacks the sterylglucosidase enzyme and administered to mice preceding fungal infection confers complete protection in animals challenged with lethal doses of either C. neoformans or C. gattii , a class of immunomodulatory glycolipids, in a genetically engineered non-pathogenic C. neoformans pulmonary infection and reduced phagocytosis, which can be restored by administration of IgM (Subramaniam et al., C. neoformans infected rodents produce fungal binding IgM and depletion of these cells resulted in impaired macrophage function facilitating cryptococcal dissemination to the brain (Rohatgi and Pirofski, B cells play a critical role in protection against experimental cryptococcosis (Subramaniam et al., C. neoformans. For instance, NKT cells are increased in the lungs of mice infected with C. neoformans, associating the chemokine MCP-1 in their recruitment and accumulation (Kawakami et al., sgl1 strain (Kawakami et al., C. neoformans in the lungs correlates with macrophage polarization (Davis et al., C. neoformans.SGs have been shown to modulate cytokine production (Lee et al., sgl1 strain might provide a potential vaccination strategy against cryptococcosis. Rella et al., provide a proof of concept study that opens a novel area of research and a potential therapeutic strategy to prevent and reduce the devastating consequences of cryptococcosis.Further studies focusing on the immune responses generated by SGs and safety issues associated with delivering live-attenuated cryptococci, heat-killed fungi, or vesicle formulations containing SGs preparations are necessary. However, these findings are significant in the setting of HIV/AIDS immune deficiency suggesting that the ΔThe 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.


Ischemia-reperfusion injury represents a pathological condition characterized by an initial undersupply of blood to an area or organ followed by a restoration of perfusion and concomitant reoxygenation (= reperfusion). Ischemia typically occurs in the presence of embolism or thrombosis but can also be triggered by surgery and transplantation. Anyway, the disturbance in perfusion results in a severe imbalance between metabolic supply and demand, subsequently causing tissue hypoxia . NotablyInterestingly, restoration of blood flow and reoxygenation is commonly associated with an exacerbation of tissue injury and a profound inflammatory response (“reperfusion injury”) , 2. IschFor example, myocardial ischemia followed by reperfusion typically manifests in microvascular dysfunction, death of myocytes, and myocardial stunning or dysfunction.Ischemia-reperfusion injury (IRI) of the lung, for example, following transplantation, is characterized by nonspecific alveolar damage, edema formation, and hypoxemia. The clinical spectrum of pulmonary IRI may range from mild hypoxemia to acute respiratory distress syndrome.In contrast to other organs, the brain is particularly susceptible to ischemia and irreversible neuronal damage already occurs after only 5 minutes of complete ischemia . For braIRI of the kidney may occur in the setting of transplantation and cardiac arrest and during cardiac surgery. Here it is important to note that renal injury is usually associated with a high morbidity and mortality. The cortical-medullary region is the most susceptible region to tubular injury, inflammation, and vascular alterations.Generally, IRI of a single organ causes the release of different proinflammatory mediators, which may subsequently induce inflammation in other organs, thereby potentially contributing to multiple organ dysfunction or even failure .κB (NF-κB) [Different pathological processes contribute to tissue injury secondary to ischemia-reperfusion. During ischemia, limited oxygen availability leads to an impaired endothelial cell barrier function with a concomitant increase in vascular permeability and leakage due to decreases of intracellular cAMP levels caused by a reduced adenylate cyclase activity . Further (NF-κB) .Reperfusion of ischemic tissue activates a complex inflammatory response without the involvement of pathogenic triggers, a phenomenon also referred to as sterile inflammation. During the initiation of this inflammatory response, endogenous molecules act as alarmins or danger-associated molecular patterns (DAMPs) . The inf “The effects of remote ischemic preconditioning and N-acetylcysteine with remote ischemic preconditioning in rat hepatic ischemia-reperfusion injury model” by B. U. Togrul et al., “The effects of spinal, inhalation, and total intravenous anesthetic techniques on ischemia-reperfusion injury in arthroscopic knee surgery” by S. C. Karahan et al., “Efficacy and safety of hepatectomy performed with intermittent portal triad clamping with low central venous pressure" by D. Dohman et al., “Adalimumab ameliorates abdominal aorta cross clamping induced liver injury in rats” by Y. Demirci et al., “Evidence for the use of isoflurane as a replacement for chloral hydrate anesthesia in experimental stroke: an ethical issue” by B. Michèle et al., “The effect of dexmedetomidine on oxidative stress during pneumoperitoneum” by S. C. Karahan et al., “The comparison of the effects of sevoflurane inhalation anesthesia and intravenous propofol anesthesia on oxidative stress in one lung ventilation” by D. Dohman et al., and “Role of ethyl pyruvate on systemic inflammatory response and lung injury in an experimental model of ruptured abdominal aortic aneurysm” by G. Altun et al.This special issue is devoted to the modulation of ischemia-reperfusion injury by different measures and contains eight original papers addressing this clinically relevant topic. These papers are accompanied by two review articles dealing with the effects of anesthetics on ischemia-reperfusion injury. Papers from B. U. Togrul et al., D. Dohman et al., and Y. Demirci et al. are focusing on ischemia-reperfusion injury of the liver. In two of these three papers, different therapeutic interventions on hepatic ischemia-reperfusion injury are evaluated, whereas the third paper is a retrospective study in which the authors investigated the efficacy and safety of intermittent portal triad clamping with low central venous pressure during liver resection. In this context, it has been reported that remote ischemic preconditioning and therapeutic interventions can reduce liver damage after inducing ischemia-reperfusion injury. The studies by S. C. Karahan et al., B. Michèle et al., S. C. Karahan et al., D. Dohman et al., and G. Altun et al. elucidate the effects of different anesthetic techniques and drugs on ischemia-reperfusion injury. These eight papers are entitled as follows:Alexander ZarbockAhmet ErogluEngin ErturkCan InceMartin Westphal


Advances in medical science and technology allow people live longer lives, which results in age-related problems. Humans cannot avoid the various aged-related alterations of aging; in other words, humans cannot remain young at molecular and cellular levels. In 1956, Harman proposed the “free radical theory of aging” to explain the molecular mechanisms of aging. Telomere length, and accumulation of DNA or mitochondrial damage are also considered to be mechanisms of aging. On the other hand, stem cells are essential for maintaining tissue homeostasis by replacing parenchymal cells; therefore, the stem cell theory of aging is also used to explain the progress of aging. Importantly, the stem cell theory of aging is likely related to other theories. In addition, recent studies have started to reveal the essential roles of tissue-resident mesenchymal progenitors/stem cells/stromal cells in maintaining tissue homeostasis, and some evidence of their fundamental roles in the progression of aging has been presented. In this review, we discuss how stem cell and other theories connect to explain the progress of aging. In addition, we consider the mesenchymal progenitor theory of aging to describing the process of aging. Several theories to explain the aging-related alterations in our bodies have been proposed and accepted. The free radical theory of aging was first proposed by Harman in 1956 as one factor of aging Harman, . The numAll adult stem cells exist in a unique microenvironment, which is known as a niche. The niche is consistent with heterogeneous types of cells and extracellular matrix proteins. The blood vessel has been proposed as a niche in common. Using expression patterns of cell surface receptors of the SLAM  family in hematopoietic stem cells, Kiel et al. showed that many hematopoietic stem cells are associated with sinusoidal endothelium in the spleen and bone marrow  differentiation and self-renewal potentials. They are indispensable for renewal and regeneration of parenchymal cells after damage. In adult mammals, many but not all tissues have functional resident tissue-specific stem cells that satisfy the criteria, including hematopoietic, skeletal muscle, pigment, epithelial, sperm, adipose, intestinal, and neural stem cells. Although a subset of adult stem cells is maintained in a quiescent state  in the homeostasis of skeletal muscle and hematopoiesis , some of the reactive oxygen species (ROS), and their reactive products. ROS consist of superoxide anions (O−2), hydrogen peroxide (H202), and hydroxyl radicals (OH.), which are mainly generated in cells by the mitochondrial respiratory chain  is another molecule that regulates the ROS pathway in hematopoietic stem cells. The FOXO subfamily  is known as the downstream target of the PI3K-AKT signaling pathway. Mice conditionally depleted of C. elegans. Two genes were identified as responsible for longevity in C. elegans. One is the daf-2 gene, an equal homolog to both the mammalian insulin and IGF-1 receptors, and the other is age-1, a homolog to the worm PI3K-kinase catalytic subunit  and SKN-1 (homolog of NRF2) , which is a truncated and farnesylated form of LAMIN A. HGPS affects mesenchymal linages. Zhang et al. produced iPS cells from HGPS dermal fibroblasts and differentiated them into neural progenitors, endothelial cells, fibroblasts, vascular smooth muscle, and mesenchymal stem cells  and an increase of mitochondrial MnSOD-dependent ROS  is an inherited disorder that causes premature aging and shortens the life span. The causative gene of HGPS is s Figure . Lentiviin vivo importance of telomere length, mice with the telomerase RNA component Terc knocked out (−/−Terc) were generated by Blasco et al.  −/−Terc mice exhibited failures in highly proliferative organs including the hematopoietic and reproductive systems  knockout (−/−Atm) mice, and the offspring showed increased telomere erosion and genomic instability . Compared with mdx mice, mdx/mTR mice showed severe dystrophic phenotypes and decreased proliferative potential of muscle stem cells  is a well-known inherited X-linked disorder occurring in one in 3500 boys. The causative gene is −/−Terc and +/−Terc littermates (CD45.2). First, they observed impaired B cell lymphopoiesis and increased myeloid proliferation in −/−Terc recipient mice. Twelve-month-old −/−Terc mice showed a more severe defect of B cell lymphogenesis and accelerated myelopoiesis compared with 2-month-old −/−Terc mice. The environment of −/−Terc mice limited the engraftment of even wild-type hematopoietic stem cells. They also showed a shortened telomere length in mesenchymal progenitors  in −/−Terc mice and a decrease in their number. Taken together, these results suggest that the shortening of telomere length in both stem cells and mesenchymal progenitors are factors of the telomere theory aging in various tissues  is known to cause a photosensitive form of the brittle hair disorder trichothiodystrophy. A study of de Boer at al. showed that mice with mutated Xpd genes (TTDXpd) exhibit many aged-related symptoms including osteoporosis, kyphosis, osteosclerosis, early graying, cachexia, infertility, and a reduced life span although the mice are born with developmentally normal phenotypes , Nijnik found that impairment of the NHEJ pathway causes a progressive loss of hematopoietic stem cells during aging -deficient mice  pathway is a well known mechanism to repair DNA double-strand breaks. One of its components is DNA ligase IV. Using ice Lig4Y88C mice,Accumulating studies also demonstrated that a component of serum is altered during aging. By utilizing parabiotic pairings, Conboy et al. showed that the age-related decline of muscle stem cell activity can be modulated by systemic factors that change with age  (Janzen et al., p16INK4a expression induced senescence, and a knockdown of p16INK4a prevented the senescence of human mesenchymal stem cells (Shibata et al., Cellular senescence is a unique state generally defined as irreversible cell cycle arrest. Recent studies have shown that senescent cells exhibit a robust increase in mRNA expression and secretion of numerous proinflammatory cytokines, which work in a paracrine manner (Campisi et al., Fibroblasts can be observed in all tissues. Fibroblasts and mesenchymal progenitors show similar morphologies, but their differentiative potentials distinguish them. Sudo et al. investigated the differentiation potential of human fibroblasts derived from various tissues and found that cells originally considered fibroblasts have potential to differentiate into the mesenchymal lineage, which includes osteoblasts, chondrocytes, and adipocytes (Sudo 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.