Polygamous Kittlitz’s plovers travel further over larger areas and interact with more individuals than the monogamous white-fronted plover. Movement patterns and social interactions influence gene flow and thus impact on speciation, although evidence from the field is limited. Here, we show that 2 Malagasy plover species exhibit different spatial behavior and social structure, consistent with existing genetic data. These results have implications for the genetic, social, and spatial processes by which new species are formed. Charadrius spp. found strikingly different population genetic structure in Madagascar: Kittlitz’s plovers are spatially homogenous whereas white-fronted plovers have well segregated and geographically distinct populations. Here, we test the hypotheses that Kittlitz’s plovers are spatially interconnected and have extensive social interactions that facilitate gene flow, whereas white-fronted plovers are spatially discrete and have limited social interactions. By experimentally removing mates from breeding pairs and observing the movements of mate-searching plovers in both species, we compare the spatial behavior of Kittlitz’s and white-fronted plovers within a breeding season. The behavior of experimental birds was largely consistent with expectations: Kittlitz’s plovers travelled further, sought new mates in larger areas, and interacted with more individuals than white-fronted plovers, however there was no difference in breeding dispersal. These results suggest that mating strategies, through spatial behavior and social interactions, are predictors of gene flow and thus genetic differentiation and speciation. Our study highlights the importance of using social behavior to understand gene flow. However, further work is needed to investigate the relative importance of social structure, as well as intra- and inter-season dispersal, in influencing the genetic structures of populations.Mating strategy and social behavior influence gene flow and hence affect levels of genetic differentiation and potentially speciation. Previous genetic analyses of closely related plovers  How new species emerge despite homogenising gene flow is one of the most debated topics in evolutionary biology . AlthougDispersal events typically increase gene flow, including natal and breeding dispersal, migration, as well as fine-scale movements that increase demographic connectivity within populations . Many spCharadrius pecuarius and the white-fronted plover Charadrius marginatus, showed that they exhibit different population genetic structure throughout their breeding range in Madagascar: Kittlitz’s plover had a panmictic and homogenous population with no population structure detected, whereas the white-fronted plovers exhibited well-defined geographically distinct populations  and 14 white-fronted plover pairs  were captured with funnel traps placed on their nests . The difThe mate removal protocol of N = 14, we provide mean ± SD unless stated otherwise) and Kittlitz’s plovers . Although captive plovers appeared to lose a small amount of body mass during their time in captivity , many remated shortly after release indicating salubrious condition. The experiment was approved by the Malagasy authorities .Removed plovers were transported to a nearby purpose-built aviary as detailed in Both the immediately released and the captive plovers released from the aviary were searched for within the study area every day in the field, using a car and mobile hide, after release. When an experimental plover was found, the coordinates of its location were taken with a handheld GPS receiver (Garmin e-Trex H). In addition, we collected 30-min behavioral samples of one of the 2 species, the white-fronted plover, by recording the behavior of experimental plovers every 30 s , with Gaussian error structure and identity link function, were used to test whether species, sex, and their interaction predict the spatial behavior of plovers . Log transformation was used for each response variable to normalize the data. Two models were fitted for each predictor variable, one basic model with fixed factors of species, sex, and species × sex interaction; and another model with additional control variables including number of days tracked, number of relocations, and captivity . “Number of relocations” was not included in the GLM analyses of mean step length as it was used in the calculation of the variable. The models were compared using an Analysis of Deviance test, and in all cases the more complex model did not improve the fit of the basic model see , and so adehabitatHR  with the R package abitatHR , as a prabitatHR , which uabitatHR . All intabitatHR .igraph  was produced using the R package igraph . For eacigraph . Standarigraph , and 2 secodist .As overlap size is dependent on the number of conspecific experimental individuals within the study area, it is not possible to compare overlap, i.e., the UDOI value, directly between groups of differing network sizes, unlike network density. Hence sex-specific interactions 2) were investigated separately for each species; total spatial interaction between individual plovers and either conspecific males, or females, was calculated. GLMs with Gaussian error structure and identity link function were fitted with sex as a predictor variable, and response variables of total UDOI between the focal bird and all individually marked males, and then all individually marked females involved in the study. The response variables, Y, were transformed to a normal distribution by adding one and then log transforming, i.e., ln and Madagascar National Parks (No: 398-10/MEF/SG/DGF/DVRN/SGFF of 18 May 2011). Blood sampling was also covered by these research permits. The blood transport permit was approved by Service de la Gestion de la Faune et de la Flore, Direction de la Valorisation des Resources Naturelles, Ministère de l’Environnement et des Forêts Madagascar (authorization number 080N-EA06/MG11). Kittlitz’s and white-fronted plovers are common breeding birds in much of Africa and Madagascar and not considered threatened .N = 36 nests) and the white-fronted plover (N = 20 nests), respectively. Survival in these nests appeared to be higher than for unmanipulated nests .The experiment was designed to reduce adverse effects on local plover populations and all necessary precautions were taken to ensure their welfare was suitably protected. Captive plovers were monitored daily and kept under standard conditions see  to reducN = 32 plovers) than white-fronted plovers  than white-fronted plovers , and a marginally significant species * sex interaction suggests sex-difference between the 2 species , days of tracking (duration) did not explain significant variation in mean step length  was significantly higher . Additionally, the white-fronted spatial association network was significantly correlated with the observed behavioral interaction network  controlling for distance between territories.Kittlitz’s plovers were more spatially interconnected than white-fronted plovers. The density of the Kittlitz’s plover spatial association network  monogamous white-fronted plover. The smaller home ranges in white-fronted plover may be due to more restricted mate search behavior and/or to more limited movements of experimental birds once they found a mate. We believe both explanations are likely and more work is needed to disentangle the movements of unmated and mated individuals possibly by recording the movements of radio-tagged individuals. Furthermore, although field observations were carried out as consistently as possible between the 2 species, the relocations were not necessarily uniformly spaced between the 2 species.Contrary to expectation, new Kittlitz’s and white-fronted plover territories were similar distances from their previous territories, and hence the breeding dispersal distances do not seem to explain differences in gene flow within these populations of plovers. However, the other measures of spatial distribution and search effort did align with the observed genetic structure, and for future studies we recommend using territorial or social metrics alongside distance metrics where possible to understand fine-scale spatial patterns. Other studies have also found social interactions and spatial behavior explaining gene flow, in addition to or in absence of dispersal . AlthougSecond, consistent with our predictions, Kittlitz’s plovers were more spatially interconnected than white-fronted plovers. The Kittlitz’s plover spatial interaction network density was significantly higher, and therefore birds likely interact with higher numbers of conspecific experimental individuals. The spatial association network of white-fronted plover correlated with the observed social interaction network, indicating that results from the spatial interaction network may also be considered in the context of a social network.Pyrrhocorax pyrrhocorax found strongly segregated populations (and social interaction are needed to facilitate high levels of gene flow. Flocking behavior may facilitate gene flow through lower energy costs associated with mate searching due to high densities, and reduced risk of predation while searching (In Kittlitz’s plover, home ranges of both males and females overlapped with several other experimental individuals. The high levels of spatial interaction suggest flocking behavior; Kittlitz’s plovers exhibit complex gregarious social behavior where individual plovers join to flock for feeding and resting; even members of breeding pairs join flocks , but theulations , suggestearching .Kittlitz’s plover’s exhibit uni-parental brood care, whereas white-fronted plovers are biparental , and thiFicedula hypoleuca exhibit similar restricted mate searches as a consequence of competition with conspecifics for nest sites (Additionally, interactions between plovers were not sexually structured in Kittlitz’s plovers, but were in white-fronted. We found that a significant difference in spatial overlap between the sexes was only found in white-fronted plovers; overlap with the opposite sex was significantly higher than same sex overlap for both males and females. Small home range overlap with same-sex individuals, combined with the previous results of fewer interactions and less movement, suggests strong territoriality in white-fronted plovers . This fist sites .An explanation of the spatial patterns observed in white-fronted plover may be the costs of finding nest sites leading to high territoriality . Strong In conclusion, we found different spatial movements and inferred social interaction patterns in unmated individuals of closely related plover species exhibiting different breeding systems. These findings may have important implications for the role of spatial interaction in gene flow and speciation; as well as how spatial behavior and social interactions are shaped by competition, mating opportunities and territoriality. Taken together, the different spatial behavior and social structure in 2 sympatric plover populations are consistent with molecular results obtained from populations along the west coast of Madagascar . Our stuBehavioral Ecology online.Supplementary data are available at Supplementary Figure S1Click here for additional data file.Supplementary InformationClick here for additional data file.


The purpose of this review is to discuss current views regarding the acute effects of phytochemicals, exercise, and exercise plus phytochemicals on fatty acid oxidation.Data acquired from human and animal studies were comprehensively assessed to determine the single and combined effects of phytochemicals and exercise on fatty acid oxidation. In addition, underlying mechanisms associated with those conditions that may contribute to the regulation of fat metabolism are discussed.Although not all phytochemicals are effective at increasing fatty acid oxidation, some significantly improve the rate of fatty acid oxidation at rest. In addition, dietary supplementation of p-synephrine, catechins, or anthocyanins in combination with moderately intense exercise has the additive effect of increasing fatty acid oxidation, but not total energy expenditure during exercise.The data reported from current reviewed studies suggest positive outcomes regarding facilitation of fatty acid oxidation from the combined effects of certain phytochemicals with exercise. Those data provide new insight for developing a strategy to boost fat loss and control weight in obese patients. Obesity, resulting from abnormal or excessive fat accumulation, alters health and is becoming a major public health concern. Dietary supplementation with phytochemicals as anti-obesity agents can be an effective strategy for reducing body weight and adipose tissue mass in humans and animals, -Diminished body fat through increased fat burning or fatty acid oxidation is one of the most beneficial aspects of the exerciseGiven the important role of phytochemicals and exercise as anti- obesity agents or fat burners, it is imperative to determine whether the combination of phytochemicals and exercise provides an additive effect on fatty acid oxidation. To the best of our knowledge, this is the first review summarizing current perspectives available in the literature regarding the effects of phytochemicals in the form of acute dietary supplements, exercise at different intensities, and exercise plus phytochemicals on fatty acid oxidation. In this review, we also discuss potential underlying mechanisms associated with phytochemicals and exercise that may be responsible for regulating fatty acid oxidation., -Phytochemicals are bioactive chemical compounds without energy value. These compounds are derived from plants such as fruits, beans, vegetables, and grains. Emerging reports have suggested that phytochemical-based dietary supplements may reduce adipose tissue growth, differentiation of pre-adipocytes, and appetite, as well as promote lipolysis and fatty acid oxidation, thereby facilitating weight loss and preventing obesity, Phytochemicals are classified into polyphenols, terpenoids, organosulfurs, and phytosterols-Catechins, the predominant form of phenolic acid compounds, are suggested to be a major ingredient for effective fat loss and body weight control, , -Green tea catechins have been reported to increase the fat burning index using indirect calorimetry methodology, as indicated by a reduction in the respiratory exchange ratio (RER), , Anthocyanins are polyphenol flavonoids that are well-known for their antioxidant effectsCitrus aurantium-p-synephrine is primarily found in the protoalkaloid form and is widely used as an alternative to ephedra for weight controlp-synephrine enhances resting energy expenditure, lipolysis, and breakdown of fat during rest, P-synephrine intake is associated with beta-adrenergic receptor activation, resulting in thermogenic effectsp-synephrine , which did not change energy expenditure and substrate metabolism, including fatty acid oxidation at restp-synephrine treatment, along with subjects  are possible explanations. Additional, well-controlled investigations are required to define the impact of p-synephrine supplementation on fat metabolism.Synephrine is a phenolic acid polyphenol that is naturally present in bitter orange and is derived from the immature fruit of , Of all the polyphenols, resveratrol is a major stilbene compound found in red grapes, apples, peanuts, blueberries, and cranberries that has been reported to reduce adipogenesis and preadipocytes by down-regulating adipocyte- specific gene expression, Exercise intensity is a major factor that affects the fraction or rate of fatty acid oxidationRegulation of fatty acid oxidation in response to exercise intensity is highly dependent on five major systemic processes, , , , It has been demonstrated that the increased availability of plasma fatty acids during low to moderately intense exercise is primarily caused by an increase in lipolysis of triglycerides stored in adipose tissueEvidence suggests that the increment of fatty acid transport across the muscle membrane is associated with fatty acid oxidation during low to moderately intense exercise2) decreases intramuscular triglyceride content in both the soleus and tibialis anterior muscles, whereas intramuscular triglyceride content was not altered with high intensity exercise. Similarly, no changes in intramuscular triglyceride content with high intensity exercise were observed in other studies, , The contribution of intramuscular fatty acids released by hydrolysis of intramuscular triglycerides to regulate fatty acid oxidation varies depending on the intensity of exerciseIt is possible that exercise in combination with dietary phytochemical intake results in an additive effect on fatty acid oxidation because exercise boosts fatty acid oxidation and certain phytochemicals also potently stimulate fatty acid oxidation over short periods. Few studies have focused on the combined effects of exercise and phytochemicals on fatty acid oxidation.p-synephrine (3 mg/kg) and exercise on fatty acid oxidation using a randomized, double-blind, and counterbalanced experimental design. They found that p-synephrine ingestion combined with moderately intense exercise (40%~80% VO2max) significantly improved maximal fatty acid oxidation rate over that of the placebo treatment. In agreement with this finding, catechin-rich green tea extract supplementation (340 mg polyphenols and 136 mg EGCG) in combination with moderately intense steady-state exercise (30 min cycling at 60% Wmax) also had an additive effect on the rate of fatty acid oxidation and lipolysis2max). They found that 7 days of ingesting New Zealand blackcurrants (105 mg anthocyanin/day) elevated fatty acid oxidation during exercise at 65% maximal intensity only. The reasons for this discrepancy were not disclosed; however, multiple factors such as the nature of phytochemicals, bioavailability, and action on multiple molecular targets might be involved in the differing beneficial effects.Some phytochemicals have an additive effect on fat oxidation when combined with moderately intense exercise . Gutierrp-synephrine, catechins, or anthocyanins during moderately intense exercise, indicating that supplementation with those phytochemicals may modify substrate utilization at moderate exercise intensities (approximately 40%–80% VO2max), , p-synephrine, catechin, or anthocyanin contained in the supplements or a lack of other active substances such as caffeine, which is often included in that type of supplement and is well-known to be thermogenicInterestingly, total energy expenditure did not change after supplementation with One study showed an additive effect with high intensity exercise and catechins. Gahreman et al.-Molecular and cellular mechanisms responsible for the additive effects of exercise with phytochemicals on fatty acid oxidation are unknown; however, some studies have suggested possible underlying mechanisms . First, It can be concluded that, to date, clinical trials investigating an additive effect of phytochemicals and exercise on fatty acid oxidation are limited. Some studies examining phytochemicals combined with exercise, as reviewed above, show potentially promising and additive effects on fatty acid oxidation. However, for most plant-based chemical compounds and extracts, more studies are needed to determine optimal doses as well as efficacy involved with long-term use with different types of exercise to enhance fatty acid oxidation. From a practical standpoint, the additive effects of combining phytochemicals with exercise on fatty acid oxidation can provide new insights for developing strategies that facilitate fat loss and improve weight management in obese patients.


Despite being some of the most important crops globally, there has been limited research on forages when compared with cereals, fruits, and vegetables. This review summarizes the literature highlighting the significance of forage crops, the current improvements and some of future directions for improving yield and nutritional quality. We make the point that the knowledge obtained from model plant and grain crops can be applied to forage crops. The timely development of genomics and bioinformatics together with genome editing techniques offer great scope to improve forage crops. Given the social, environmental and economic importance of forage across the globe and especially in poorer countries, this opportunity has enormous potential to improve food security and political stability. Figure 1). Forage crops are usually grasses (Poaceae) or herbaceous legumes (Fabaceae). Some tree legumes such as mulga (Acacia aneura) and leadtree  are also grown in desert and tropical grasslands (Pennisetum purpureum), Brachiaria, and Panicum species. In the poorest parts of the world livestock production is critically important for smallholders’ livelihoods. Sub-Saharan Africa is an example and frequently women maintain the livestock production systems (Agrostis spp.), fescue (Festuca spp.), ryegrass (Lolium spp.) and orchard grass (Dactylis spp.) or hybrids of these. For example, Festuca and Lolium hybrids has been developed from 1970s  cultivars have been specifically bred for forage. The commonly cultivated herbaceous legumes are trefoil (Lotus corniculatus), medics (Medicago spp.), clover (Trifolium spp.) and vetches (Vicia spp.). Brassica forage species include cultivars of oilseed rape (Brassica napus) and kale (Brassica oleracea). Fodder beet (Beta vulgaris) is another temperate forage. The combination of forage crops grown in any country varies depending on climate and livestock needs, however, the perennial legume lucerne or alfalfa (Medicagosativa) is the most widely cultivated as it can be grown with both temperate and tropical grasses, or as a standalone crop. This is a huge topic to review as there are so many species grown across the world, therefore we have chosen to focus on a few examples, the tropical grasses Pennisetum and Brachiaria, and more prominently the temperate crops Lolium and alfalfa.Forage grasslands are used to feed livestock and globally it has been estimated that they represent 26% of the land area, and 70% of agricultural area . Such crasslands . In the  systems . In tempom 1970s  giving rIn an ideal world, we would all eat pulses rather than the animal products generated from them, as grain legumes are the food that offers the most sustainable future . There iMoreover, the cultural and social significance of livestock cannot be underestimated and the trend of increased global production is set to continue . LivestoLolium or a mixture of the two. This forage can be provided to animals directly through grazing pasture land or in a processed form, such as hay (where water content is >15%) or dried (pelleted) biomass. Concentrates are generally cereal, oilseed and legumes seeds, or bi-products of their preparation for human food, biofuel and textile. They can also include high energy feedstuffs such as sugar-rich crop molasses and fats of animal origin, for example fish by-catch discards. In industrialized countries, production of both these categories of feed can surpass the amount produced for plant-based food for human consumption; in United States over double dry matter per-capita per year (DM cap/yr.) is produced for animal feed than for foodstuffs  of each crop which along with mineral and vitamins provides the amount of energy which can be derived by the animal (ME measured in MJ/kg DM)  of carbohydrates, proteins, and lipids. The composition of these organic nutrients determines the digestibility (J/kg DM) . Such caLolium perenne, have high digestibility due to high soluble sugar content alongside low lignin content . These are degraded into simple sugars through cleavage of glycosidic bonds, either by the animal itself (non-ruminant and ruminants) or via microbial digestion and subsequent animal absorption (ruminants only). Different ratios of carbohydrates within the forage crop will have altered downstream digestibility for the animal, especially if the cell-wall structure constrains digestion by the microbial population or limits plant cell wall penetration . Althoug content .Animal digestion of simple carbohydrates produces monosaccharides which can be readily metabolized. In ruminants, only microbial digestion of structural carbohydrates produces simple sugars which are subsequently metabolized to pyruvate. Pyruvate is absorbed by the animal and is metabolized further into volatile fatty acids (VFAs) which are a major energy source, . RuminanTrifolium pratense), white clover (Trifolium repens) and lucerne (Medicago sativa) grown widely due to their high protein value (Lotus pedunculatus) and Sericea lespedeza (Lespedeza cuneata) can have levels as high as 18% DM (Nitrogen (N) availability to animals is predominantly from forage proteins and are estimated using crude total protein Kjeldahl measurements. Protein is usually abundant in the major form of Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), although relative amounts vary between species . This isin value . Again, in value . This mein value . All gras 18% DM . Other Ns 18% DM .-1 , and Festulolium hybrids of the two have been shown to vary not only between species at the beginning of their growth season, but more prominently between individual cutting regimes (Lipids in forage crops are mostly found as polyunsaturated fatty acids (PUFAs) in the range of 10 – 30 g kg-1  of which-1 ], with l-1 . These d-1 . Moreovety acids . Studiesty acids . Strikinty acids . For exa regimes .Minerals and trace elements from forages are important for maintaining livestock health. As there is a move toward using fewer antibiotics in animal production the nutritional balance of feed takes on additional importance. Zinc is particularly important for the immune system and supplements can be added to animal feed, but addition of too much results in wasteful excretion, reviewed in Probably the most important trait of any forage crop is rapid biomass production, as crops are either cut or grazed directly, and nutritional quality depends on the rate of biomass production. Intensive production with faster growth often decreases this nutritional, but this depends on the species grown and some cultivars have better recovery from defoliation. Plant height correlates well with biomass for most crops  and this factor together with ground area cover are the criteria underpinning methods to assess yields .Many plant species can be grown for forage production, but the ability of the shoot meristem to respond with increased growth after cutting is essential. In some forage species, aboveground grazing or cutting has been correlated with increased root exudation . This flMedicago spp., Trifolium spp., Lolium, and Festuca. Large scale breeding programs include testing of these crops, such as NE1010, a multistate cooperative effort of 15 institutes across 12 North-eastern states of United States and Canada , the Ugandan National Livestock Resources Research Institute (NaLIRI), the Tanzania Livestock Research Institute (TALIRI), the Institute of Agricultural Research of Mozambique (IIAM) and the Brazilian Agricultural Research Corporation (E.M.B.R.A.P.A.)   which isMedicago and Lolium. Figure 2 shows a brief historical timeline of Lolium cultivation, and includes the current breeding regimes for grasses; future breeding possibilities are also included and discussed in later sections. One of the most interesting breeding developments is the exploitation of closely related species of Lolium and Festuca  analysis or marker-assisted selection (MAS) provided from the above completed genomes. Those identified are studied in relation to biomass and growth traits; in nd vigor , plant h . Figure 3 summarizes some of the traits that can be considered for all forage crops.Despite the need to ensure optimal nutritional content especially in the end-product feed, rapid vegetative biomass accumulation is the most desirable trait of a good forage crop, especially those which undergo extensive cutting throughout the growing season. Due to this phenomenon, candidate genes for improving the crops are associated with either photosynthesis or nitrogen use efficiency (NUE). More generally for resistance to biotic and abiotic stresses there is also a huge opportunity for improving traits in forage crops using our genetic knowledge from model plants , a gene already shown to enhance abiotic stress tolerance in both Nicotiana tabacum and Festuca (MsHSP family (Ethylene Response Factor (ERF) family studies have been shown that introducing the M. sativa gene into other plants can confer enhanced resistance to salinity; MsERF9 and MsERF11 in Nicotiana and Arabidopsis, respectively , and ideally the post-harvest quality of these should be maintained. There has been considerable interest in developing organ specific proteome reference maps for stems and leaves. The dominant proteins in these tissues are photosynthetic enzymes such as RuBisCO and RuBiCO small unit (rbsS), which for in stems . As the tibility , some prtibility .Lupinus albus)   and soybs albus) , used asLathyrus sativus) seedlings under either salinity, low temperature or ABA stress gave rise to the identification of 48 stress-responsive proteins (SRPs) which include those important dominant proteins discussed above  (As protein digestion and uptake in livestock is directly related to energy availability (ME)  it is im D-value . Use of climates . The amoclimates  highlighclimates . Furthernditions . Recent ng (CAB)  has provng (CAB) . Such woM. sativa has advantages as a feed source over cereals for enhanced D-value  to confirm correlations across a range of traits, such as using three distinct alfalfa cultivars with a high-throughput genotyping-by-sequencing approach  generally has lower digestibility until it reaches the large intestine , where i D-value . One majapproach . HoweverD-value of a crop . CTs bind to protein making it unavailable to digestion for ruminants until it reaches the rumen, and thusly an important trait in increasing the f a crop , althoug promotor also delayed senescence in M. sativa with notable chlorophyll and yield increases even after 3 months of growth (Panicum virgatum NAC1 and NAC2 transcription factors in Arabidopsis atnap lines (mutants with defective senescence) to restore wild-type phenotype, predominantly measured using total chlorophyll concentrations  has yet to be applied to forage crops. For example, transporter proteins for iron and zinc storage have been identified in cereals  and theiAlthough very abundant in most soils, silicon is particularly required by grasses  and is tMost species of forage crops can form mycorrhizal associations and this type of symbiosis is important for acquisition of trace elements. For natural grazing, these symbiotic associations are particularly important, but when fertilizer is added to cultivated forage crops mycorrhiza are suppressed . EnhanciMiscanthus have low N requirements  has been attempted and validated  Presently farmers take limited samples across their growing area in the hope that this is representative of the N in the whole plot through the growing season. Nevertheless, this does not indicate a plant’s N status or provide a measure of NUE. Some research has focused on the use of spectral data to evaluate crop efficiency , but sucAs forages are grown to rear livestock which in turn becomes food products for humans it is also important to view research in plant science from a livestock study prospective, of which has been touched upon above when discussing nutritional composition of crops. At present many countries adopt large-scale, concentrate-feeding led livestock production like that of the United States, with many potential human health risks due to bacteria, antibiotic-resistant bacteria, prion, and dioxin presence in end products . DespiteArabidopsis, offers an excellent future perspective for improving the nutritional quality and yield for forage crops.In conclusion, utilizing the information obtained from the research effort to improve grain crops and the knowledge gathered from model systems like NC and AM wrote the manuscript and conceived the perspective, read, and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Psycho-physiological interaction analyses were performed using the right and left amygdala complexes as regions of interest during conscious and subconscious trauma word processing. These analyses revealed a differential, context-dependent responses by each amygdala seed during trauma processing in PTSD. Specifically, relative to controls, during subconscious processing, individuals with PTSD demonstrated increased connectivity of the CMA with the superior frontal gyrus, accompanied by a pattern of decreased connectivity between the BLA and the superior colliculus. During conscious processing, relative to controls, individuals with PTSD showed increased connectivity between the CMA and the pulvinar. These findings demonstrate alterations in amygdala subregion functional connectivity in PTSD and highlight the disruption of the innate alarm network during both conscious and subconscious trauma processing in this disorder.Post-traumatic stress disorder (PTSD) is characterized by altered functional connectivity of the amygdala complexes at rest. However, amygdala complex connectivity during conscious and subconscious threat processing remains to be elucidated. Here, we investigate specific connectivity of the centromedial amygdala (CMA) and basolateral amygdala (BLA) during conscious and subconscious processing of trauma-related words among individuals with PTSD ( Altered threat processing and alerting mechanisms are central to the pathophysiology of posttraumatic stress disorder (PTSD). Previous studies investigating the neural correlates underlying threat responses have emphasized functional connectivity alterations between the amygdala and the medial prefrontal cortex (mPFC) during symptom provocation , fear pret al. (2013) [One key limitation of the majority of previous studies examining amygdala connectivity in PTSD subjects is the limited analysis of the amygdala as whole, despite knowledge that the amygdala complex is composed of distinct subdivisions, including the centromedial amygdala (CMA) and the basolateral amygdala (BLA) nuclei that are known to have diverse functions and differential functional connectivity with other brain regions –9. The C. (2013)  showed i. (2013) . DespiteThe present study seeks to address this central gap in our understanding of threat-related processing in PTSD. PTSD patients are often triggered by stimuli of which they have no conscious awareness, where altered patterns of neural activity underlying subconscious processing of fearful or trauma-related material are thought to contribute to this symptom presentation –21. HereAccordingly, the present study examines the differential contribution of subdivisions to brain connectivity during conscious and subconscious processing of personalized trauma-related words in PTSD. In line with emerging reports, we expected to find differential functional connectivity between the BLA and CMA with the mPFC, parietal and insular cortex as a function of conscious and subconscious levels of awareness in PTSD. Finally, we sought to define the role of each specific amygdala subregion within the innate alarm circuit in PTSD, particularly with reference to brainstem-amygdala connectivity  during sTwenty-six civilians with a primary diagnosis of PTSD and twenty non trauma-exposed controls were recruited through community advertisement to participate in the study. This sample has been described in two previous studies ,28. All The protocol used for presenting subconscious  and conscious  stimuli during fMRI investigations followed previously published methods ,33,34. BA 3.0 Tesla whole-body MRI scanner  with a 32-channel phased array head coil was used for image acquisition. T1-weighted anatomical images were acquired with 1 mm isotropic resolution . Sixty four whole-brain, 2 mm thick imaging planes for BOLD fMRI were prescribed parallel to the AC-PC. Functional images were acquired using a gradient-echo planar imaging (EPI) sequence with an interleaved slice excitation order and a 2 mm isotropic spatial resolution .Independent sample t-tests were used to investigate between-group differences in age, CTQ score, MDI score, and reaction time during the button-press task. Pearson's chi-square tests were performed for gender and employment status.SPM8  implemented in MATLAB . Pre-processing included realignment to the first image, coregistration of the anatomical image to the mean functional image, normalization to MNI  space , and spatial smoothing with an 8 mm full width at half maximum (FWHM) isotropic Gaussian Kernel.FMRI analyses were performed using In order to investigate trauma-related effective functional connectivity, we conducted psychophysiological interactions (PPI) analyses . PPI rep3, volume right CMA = 138±28mm3). By contrast, the basolateral amygdala (BLA) encompassed the lateral nucleus, the basolateral, basomedial and paralaminar nuclei . For each seed region we extracted the first eigenvariate of the BOLD time-series in the GLM derived contrasts subliminal trauma-related > neutral words and supraliminal trauma-related > neutral words for each subject. The PPI interaction terms were obtained by multiplying the deconvolved time-series by the psychological variable  and reconvolved with the hemodynamic response function (HRF). The motion parameters were included as confounds in the design matrix. The estimated interaction term parameters were then carried forward to the second level to perform one-sample (within-group) and two-sample t-tests (between-groups) for each seed-region.To investigate effective connectivity between the amygdala and brain areas involved in threat processing, we defined four seed regions using SPM Anatomy toolbox ,43, inclWhole brain analyses (voxelwise p < .05 FWE-corrected threshold) were followed by Region of Interest (ROI) analyses. Here, three10 mm sphere radius ROIs were tested based on previous literature examining subliminal fear processing  and funcAs has been reported previously , no signWhole-brain analyses did not yield any significant results. By contrast, ROI analyses showed increased connectivity between the right CMA and the superior frontal gyrus (SFG) and decreased connectivity between the right BLA and the right superior colliculus in the PTSD as compared to the control group. ; Fig 2A.No significant results emerged from whole-brain analyses. However, ROI analyses revealed that the PTSD group showed increased connectivity between the left CMA and the left pulvinar in comparison to controls ; Fig 2B.The results of the present study demonstrate clearly the contrasting roles played by the amygdala subregions investigated (the CMA and the BLA) in threat processing. Here, we found differential patterns of functional connectivity of these regions with cortical and subcortical regions during trauma-related word processing in PTSD subjects as compared to controls. Critically, these patterns of functional connectivity appeared to be moderated by the level of awareness of the threatening cues. Moreover, subcortical and cortical regions including the innate alarm network  emerged as differentially functionally connected to the amygdala subdivisions. As this study did not include a trauma-exposed control group, it is important to bear in mind that the findings discussed below could also be interpreted as a result of trauma-exposure instead of specifically relating to the development of PTSD see also  section.During subliminal processing, the right CMA showed increased connectivity with frontal regions—specifically with the medial SFG. It is therefore probable that this pattern of right CMA connectivity underlies Bryant and colleagues' (2008)  previousIt is also noteworthy that decreased functional connectivity of the BLA with the superior colliculus (SC) was identified in PTSD subjects. Whereas the BLA is the primary site of sensory input into the amygdala, allowing for affective evaluations of sensory information ,14, the In summary, our findings highlight the differential functions of amygdala subregions in PTSD during subliminal processing of threat. Specifically, increased functional connectivity of the CMA with the SFG during subconscious threat processing suggests the involvement of the CMA in emotion regulatory processes. By contrast, the decreased connectivity of the BLA with the superior colliculus in PTSD as compared to controls may contribute to disturbances in fear learning processes, but may also represent a neural mechanism for quick defensive responses occurring independently from regulatory limbic  and cortical  regions  in PTSD.During supraliminal processing, the left CMA showed increased connectivity with the pulvinar, a subcortical region that is a key-node, in connection with the superior colliculus and the amygdala, of the innate alarm system for quick defensive responses to potential threats  and saliCertain limitations of our study must be considered. Firstly, the present findings are based on a small sample size; replication with a larger sample is therefore needed. Secondly, our study did not include a trauma-exposed group without PTSD; future research should also compare trauma-exposed and PTSD groups. Moreover, it will be important to examine potential differences between PTSD and its dissociative subtype; the present study did not afford enough power to examine different phenotypes of the disorder. Finally, the cross-sectional nature of this study precludes assumptions about whether the findings are a consequence of PTSD; future studies are warranted to consider a longitudinal approach to address this matter.These points notwithstanding, we conclude that our results provide further insight into the pathways modulated by the amygdala within the innate alarm system in PTSD. As highlighted by recent literature, the amygdala can be better understood if subdivided into distinct nuclei in order to show the differential involvement of each subregion in the alerting system for quick defensive responses. Moreover, our study design allowed us to distinguish which brain regions and hemispheres are predominant during sub- versus supraliminal threat processing. During subliminal processing, the right CMA was shown to play a major role in influencing neural activity in the prefrontal regions (SFG) as a function of threat processing. By contrast, supraliminal processing revealed that the left CMA is involved in modulating the subcortical pathway  for defensive responses to potential threats. Furthermore, our findings clarify the significance of amygdala connectivity in PTSD, specifying, for example, which amygdala subregions are involved in amygdala-prefrontal connectivity during subliminal processing and how levels of stimulus awareness differentially influence the functional connectivity of the amygdala to other brain regions. Moreover, our findings support a right lateralization of a fast subcortical route for rapid defensive responses to subliminal threat ,52. FinaS1 TableExample of personalized trauma-related (stress-related for controls) words and neutral words used for stimulus presentation during the task in the fMRI scanner. As shown in the table, trauma-related and neutral words were matched for letter/syllable length.(DOCX)Click here for additional data file.


Hormonal control of the estrous cycle that occurs in therian mammals is essential for the production of a functional egg. Supporting somatic cell types found within the ovary, such as granulosa and theca cells, respond to endocrine signals to support oocyte maturation and ovulation. Following the release of the egg, now available for fertilization, coordinated hormonal signaling between the mother and putative embryo are required for the establishment of pregnancy. If no conception occurs, both the ovary and uterus are “reset” in preparation for another cycle. The complex molecular changes that occur within cells in response to hormone signaling include a network of non-coding microRNAs (miRNAs) that posttranscriptionally regulate gene expression. They are thus able to fine-tune cellular responses to hormones and confer robustness in gene regulation. In this review, we outline the important roles established for miRNAs in regulating female reproductive hormone signaling during estrus, with a particular focus on signaling pathways in the ovary. Understanding this miRNA network can provide important insights to improving assisted reproductive technologies and may be useful in the diagnosis of female reproductive disorders. The ovary’s role in producing a fertilizable egg and in signaling to prepare for pregnancy involves complex cascades of hormonal regulation. Germ cells direct the formation of embryonic ovaries, and during this time, each primordial oocyte becomes surrounded by a layer of granulosa cells that will support its development. Cells of the follicle, the functional units of the ovary, proliferate and differentiate largely autonomously throughout early life [reviewed in Ref. ].in situ hybridization, and reverse-transcription PCR. These, along with high throughput methods like microarray hybridization and RNA sequencing, have been used to detect these small RNA molecules at all stages of ovarian development in a number of important model organisms and livestock (Studies in a number of species have demonstrated that regulation of ovary formation and early growth is driven by cellular microRNAs (miRNAs) [reviewed in Ref. ]. Naturaivestock , 7–11.via aromatization by cytochrome P450 aromatase   released by the pituitary, act on the FSH receptor (FSHR) to integrate various signaling pathways driving follicle growth. Crosstalk between granulosa cells and the oocyte drives its development to the first mitotic stage of meiosis, also known as the germinal vesicle (GV) stage. Granulosa cells ramp up their production of estrogens, specifically the essential female reproductive hormone estradiol (E2) , 13. AndA1 gene) . As an eA1 gene) ]. EndocrLHCGR gene) is expressed in granulosa and theca cells of antral follicles based on interactions between FSH and insulin-like growth factor (IGF)-1 signaling . The CL in Ref. , 24]. HiWhile the role of miRNA is minimal in the oocyte [reviewed in Ref. ], it hasEarly work to identify important miRNA players in follicle growth and ovulation took a global approach and profiled miRNA expression at important stages of the estrus cycle. Work done in rodents and livestock identified hundreds of differentially expressed miRNAs following stimulation with FSH, hCG, and during natural and induced ovarian cycling –30. GranBecause of their ease of detection, particularly compared to hormone levels in small samples  or in associated somatic cells that are routinely discarded , interest has grown in using miRNA as a non-invasive biomarker of oocyte quality. Characterization of miRNA profiles have been conducted on patients undergoing oocyte retrieval for various reproductive technologies . miRNAs in vitro and predicted to target the message for steroidogenic acute regulatory protein (STAR) (CYP11A1 gene), and was recently shown to be regulated by interactions between the miRNA let-7 and the non-coding miRNA “sponge” H19 in a human granulosa cell line  that regulates the delivery of cholesterol to cells. However, of two miRNAs shown to target these genes in adrenal cells, miR-132 and miR-214, respectively, only miR-214 showed decreased expression with cAMP treatment in granulosa cells along with a corresponding increase in SREBP-1c and LDLR protein levels  [reviewed in Ref. ]. Hormonn (STAR) . STAR isell line . Validatn levels . While avia extra- and intranuclear pathways , Bcl-2 modifying factor (BMF), Bcl-2-associated X protein (BAX), and tumor suppressor protein p53 (TP53), whose expression decreased following androgen administration , the host gene for the intronic miR-383  and SREBP as being up regulated by this miRNA, which leads to subsequent LHR degradation , the most prevalent endocrine disorder in young women, may be developed. Several studies have examined miRNA expression patterns in patients with PCOS –67. WhilAll the authors cowrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Mesenchymal stem cells (MSCs) are attracting growing interest by the scientific community due to their huge regenerative potential. Thus, the plasticity of MSCs strongly suggests the utilization of these cells for regenerative medicine applications. The main issue about the clinical use of MSCs is related to the complex way to obtain them from healthy tissues; this topic has encouraged scientists to search for novel and more advantageous sources of these cells in easily accessible tissues. The oral cavity hosts several cell populations expressing mesenchymal stem cell like-features, furthermore, the access to oral and dental tissues is simple and isolation of cells is very efficient. Thus, oral-derived stem cells are highly attractive for clinical purposes. In this context, human periapical cyst mesenchymal stem cells (hPCy-MSCs) exhibit characteristics similar to other dental-derived MSCs, including their extensive proliferative potential, cell surface marker profile and the ability to differentiate into various cell types such as osteoblasts, adipocytes and neurons. Importantly, hPCy-MSCs are easily collected from the surgically removed periapical cysts; this reusing of biological waste guarantees a smart source of stem cells without any impact on the surrounding healthy tissues. In this review, we report the most interesting research topics related to hPCy-MSCs with a newsworthy discussion about the future insights. This newly discovered cell population exhibits interesting and valuable potentialities that could be of high impact in the future regenerative medicine applications. Stem cell therapy has reached a central role in the regenerative medicine scenario with numerous examples of translational applications reported in clinical trials designed for the most various pathological conditions.The first lineage of adult stem cells was discovered in bone marrow, such bone marrow-derived cells were hematopoietic progenitors capable to reconstitute the entire blood system in immunocompromised hosts  does not imply a quite simple procedure, indeed, donors must undergo an invasive surgery to allow the proper aspiration of bone marrow from the iliac crests. Moreover, cells obtained from hBM are in a limited number, estimated to be nearly of one MSC per 34,000 nucleated cells  can be easily isolated from fresh teeth extracted because of orthodontic or periodontal reasons. The great accessibility to the oral tissues and the high abundance of MSC-like cells in such anatomical district . Such cells were also able to differentiate toward dentin/pulp-like tissues after transplantation into immunocompromised mice. Importantly, DPSCs possess the same immunophenotype of bone marrow stromal cells (BMSCs) ; these cells showed the ability to differentiate into various cell types, also promoting the formation of dentin and bone tissues Moreover, a cell population expressing mesenchymal stem cell-like markers was found in periodontal ligament (PDL). Periodontal ligament stem cells (PDLSCs) can differentiate into adipocytes, collagen-forming cells, and cementoblast-like cells. Importantly, these cells have been successfully used to regenerate both cementum and PDL in animal models . These cells were first isolated by Morsczeck et al.  in the lGingival tissues have been shown to be colonized by multipotent clonogenic stem and progenitor cells. Gingiva-derived MSCs have a clear regenerative potential comparable to BMSCs   solution containing antibiotics. Then, periapical cystic tissue samples can be minced into small pieces and subjected to enzymatic digestion with type-I collagenase and dispase. Subsequently, samples can be filtered and seeded in culture medium added with fetal bovine serum (FBS) , osteocalcin (OSC), alkaline phosphatase, and dentin matrix protein 1 (DMP-1) increased after osteogenic induction  and DMP-1 genes were increased in DPSCs with respect to hPCy-MSCs, whereas osteonectin (ON), bone sialoprotein (BSP), and runt-related transcription factor 2 (RUNX-2) were highly expressed in hPCy-MSCs compared to DPSCs , adiponectin (ADIPOQ), peroxisome proliferator-activated receptor gamma (PPARγ), and glucose transporter type 4 (GLUT4)  in hPCys-MSCs were similar to those of DPSCs. Moreover, qRT-PCR analysis under basal culturing condition revealed higher levels of transcripts for neural-related genes , neural-related transcription factors  and for dopamine-related genes (tyrosine hydroxylase and dopamine transporter) in hPCy-MSCs than in DPSCs. Importantly, the expression of neuronal markers were greatly increased under neurogenic conditions . Thus, hPCy-MSCs cultured under neurogenic medium are able to acquire the typical neuron-like morphology, characterized by the presence of dendrite and axonal structures (Marrelli et al., Mesenchymal stem cells play a key role in regenerative medicine; after their discovery, MSCs were mainly collected from bone marrow or adipose tissue, however, the surgical procedures needed to collect such cells were invasive and often painful for patients. Therefore, the scientific community is actively involved in the discovering of alternative sources of MSCs. The oral cavity is strongly populated by MSCs that could be easily isolated in a minimally invasive way (Tatullo et al., ODSCs attracted clinical interest first in the oral and maxillofacial fields, as they have been recognized to be strategic for a better regeneration of bone and dental tissues, such as cementum, dentin and periodontal ligament. Many studies supported this concept: Seo et al. showed the ability of ODSCs to produce cementum and periodontal ligament after transplantation of human PDLSCs into immunocompromised mice (Seo et al., Nanoporous and mesoporous silicon scaffolds efficiently support DPSCs proliferation, thus they could represent a fine substrate for these cells in tissue engineering procedures (Marrelli et al., In the field of bone regeneration, hydrogel-based scaffolds can be obtained from decellularized and demineralized bovine bone extracellular matrix. Recent studies emphasized how ODSCs could be easily and efficiently cultured on hydrogels (Cavalcanti et al., hPCy-MSCs have been reported to retain high proliferative rate and extensive multipotency. These key properties play a strategic role in bone and dental regeneration, even more if hPCy-MSCs are added to specific scaffolds. Furthermore, the recently discovered neural plasticity of these cells undoubtedly represents a perspective feature to be further investigated for future innovative strategies in brain repairing. In this light, stem cell therapies for some widespread neurodegenerative diseases, such as Alzheimer and Parkinson syndromes encountered many ethical issues related to the use of embryonic stem cells (Lees et al., In the last few years, researchers are carrying out pioneering studies aimed to investigate the biochemical pathways in cellular models of Parkinson's disease. In this context, the spontaneous commitment of hPCy-MSCs to differentiate toward neuron-like cells arouses exciting insights about new therapies involving hPCy-MSCs. Further investigations are needed to evaluate the neuroregenerative potential of these newly discovered ODSCs in animal models Figure .Dental periapical cysts are certainly among the most common lesions discovered after the observation of orthopanoramic radiographies; these benign formations are surgically eradicated by dentists to prevent the development of more severe pathologies, especially to the surrounding bone tissue.Although inflamed cysts are routinely discarded as biological waste, recent researches revealed a strategic role of this granulation tissue (Liao et al., The hypothesis reporting that biological wastes can be considered as resources for new unexpected biological applications have been largely discussed in the scientific literature, even in areas far from human biology, but closer to food biotechnology. For example, a recent study reported the extraction of bioactive compounds from food waste for pharmaceutical and medical purposes (Tatullo et al., in vitro experiments. Thus, the real challenge now is to translate the in vitro results to an in vivo context, and therefore future investigation should be carried out to confirm the in vivo regenerative potential of these newly discovered MSCs.Sources of abundant and highly immature MSCs, obtained from easily available and “biologically cheap” tissues, undoubtedly represent an extremely interesting and important finding. In this context, hPCy-MSCs, similarly to DPSCs, could be considered as an optimal cell source for tissue engineering applications. The use of human hPCy-MSCs is not free of criticisms since the immunomodulatory properties of these cells are not yet evaluated and most results were obtained from MT, FPad, MM, and BC: conceived and wrote the manuscript; BC, FPal, AP, and LP: generated the figures and revised the literature sources. All authors reviewed and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Insomnia and sleep disturbance are associated with declines in health functioning, alongwith increases in mortality risk. Given the prominence of reported sleep disturbance incocaine-dependent subjects and persistence into recovery, understanding the natureand severity of these disturbances in this population may help to identify relevantpathways that contribute to the increased mortality in cocaine dependence. Polysomnography provides a means of objectively characterizing sleep and, in turn, sleep disturbances. Few studies have used polysomnography to evaluate sleep incocaine-dependent persons, yet these studies have the potential to advance treatmentsthat will ultimately reduce morbidity in cocaine-dependent subjects.


Improved access to healthcare, vaccines and treatment with antibiotics has reduced global mortality from childhood community-acquired pneumonia. However, as respiratory viruses are responsible for most episodes of pneumonia, important questions remain over who should receive these agents and the length of each treatment course. Worldwide concerns with increasing antibiotic resistance in respiratory pathogens and appeals for more prudent antibiotic prescribing provide further urgency to these clinical questions. Unfortunately, guidelines for treatment duration in particular are based upon limited (and often weak) evidence, resulting in national and international guidelines recommending treatment courses for uncomplicated pneumonia ranging from 3 to 10 days. The advantages of short-course therapy include a lower risk of developing antibiotic resistance, improved adherence, fewer adverse drug effects, and reduced costs. The risks include treatment failure, leading to increased short- or long-term morbidity, or even death. The initial challenge is how to distinguish between bacterial and non-bacterial causes of pneumonia and then to undertake adequately powered randomised-controlled trials of varying antibiotic treatment durations in children who are most likely to have bacterial pneumonia. Meanwhile, healthcare workers should recognise the limitations of current pneumonia treatment guidelines and remember that antibiotic course duration is also determined by the child’s response to therapy. Streptococcus pneumoniae and Haemophilus influenzae type b [Community-acquired pneumonia is the leading global cause of childhood morbidity and mortality. Annually, there are an estimated 120–160 million clinical pneumonia episodes worldwide, causing 14 million hospitalisations and almost one million deaths in children aged <5 years [e type b . Conseque type b . A good Several factors are considered when both choosing an antibiotic to treat a suspected case of bacterial pneumonia and determining how long it should be given. These include: (i) clinical presentation and severity; (ii) assumed bacterial aetiology based upon the child’s age, vaccination status, underlying co-morbidities and the local pathogen antibiotic susceptibility profiles; and (iii) cost, availability, tolerability, and ease of administration  of the chosen agent that may influence treatment adherence.In clinical practice, the optimal duration of antibiotic treatment depends upon whether the pneumonia is straightforward or complicated (e.g. empyema or systemic infection involving other organs); if underlying medical disorders are present ; the nature of the causative pathogen, adequacy of source control, and the patient’s response to treatment.In uncomplicated pneumonia the advantages of a short-treatment course include a lower risk of developing antibiotic resistance, improved adherence, fewer adverse effects, and decreased costs , 8. The Most studies on antibiotic duration were undertaken in low- and low-to-middle-income countries where the burden of pneumonia is greatest. Unfortunately, the diagnosis of bacterial pneumonia in these settings is also the most uncertain as it relies upon healthcare workers following clinical algorithms without adequate laboratory and radiographic support. Furthermore, no diagnostic gold standard for pneumonia exists, and there are major difficulties differentiating between viral and bacterial pneumonia clinically and radiographically, let alone obtaining an accurate microbiological cause .As most childhood pneumonia deaths occur out of hospital in the low-resource settings of sub-Saharan Africa and Southern Asia, the diagnostic algorithms used by the World Health Organization (WHO) are designed to reduce mortality, sacrificing specificity for sensitivity . OtherwiIn contrast to developing countries, criteria for diagnosing childhood pneumonia in developed nations often require chest radiographic confirmation, especially for hospitalised cases . NeverthThe guidelines for the treatment duration of pneumonia are based upon limited and often weak evidence –7. The sClearly, more robust evidence for antibiotic treatment duration for pneumonia is needed. A good start would be to undertake additional RCTs in sub-Saharan Africa and Asia (where feasible sample sizes are possible), recruiting subjects with a greater probability of bacterial infection . Meanwhile, healthcare workers should recognise the limitations of current “one size fits all” pneumonia treatment guidelines and remember that the duration of antibiotic therapy is also determined by individual host and pathogen factors and how the child responds to treatment.


This article deals with these lead phytomolecules with their action mechanisms on nuclear and cellular factors involved in carcinogenesis. Additionally, druggability parameters and clinical development of anticancer phytomolecules have also been discussed.Cancer is a serious concern at present. A large number of patients die each year due to cancer illnesses in spite of several interventions available. Development of an effective and side effects lacking anticancer therapy is the trending research direction in healthcare pharmacy. Chemical entities present in plants proved to be very potential in this regard. Bioactive phytochemicals are preferential as they pretend differentially on cancer cells only, without altering normal cells. Carcinogenesis is a complex process and includes multiple signaling events. Phytochemicals are pleiotropic in their function and target these events in multiple manners; hence they are most suitable candidate for anticancer drug development. Efforts are in progress to develop lead candidates from phytochemicals those can block or retard the growth of cancer without any side effect. Several phytochemicals manifest anticancer function  Cancer, a severe metabolic syndrome, is the leading cause of mortality and morbidity worldwide and the number of cases are continuously rising  has been proved an effective anticancer drug against most of the cancer types. It was isolated in 1967 from the endophytic fungi found in Taxus brevifolia bark , mucositis (inflammation of digestive tract lining), hair loss, cardiotoxicity, neurotoxicity and immunosuppression. Additionally, rapid elimination and widespread distribution of the introduced drug to the non-targeted organs by body system requires large dose of the drug which increases above mentioned side effects and also not economic. Another limitation is the resistance of cancer cells to the available drugs. Cancer cells undergo mutations and become resistant to the introduced drugs. Therefore, given the reality of unsatisfactory chemotherapy, innovations in treating cancer with fewer side effects are the trending research direction. An ideal anticancer drug will specifically be cytotoxic toward the cancer cells only and based on the research findings, phytochemicals & derivatives present in plants are promising option for the improved and less toxic cancer therapy. Bioactive phytochemicals possess diverse therapeutic functions . These phytomedicines cover an important portion of our current pharmaceutics Table .Plants and their formulations are in medicinal uses since ancient times. Various herbal preparations with different philosophies and cultural origins are used by folk medicine practitioners to heal kinds of diseases. Ayurveda, the ancient Vedic literature of India, is the science of good health and well-being  or promote activities of antioxidant enzymes  in a transformed cell. A phytomolecule can suppress malignant transformation of an initiated pre-neoplastic cell or it can block the metabolic conversion of the pro-carcinogen. Also, they can modulate cellular and signaling events involved in growth, invasion and metastasis of cancer cell. Ellagic acid of pomegranate induces apoptosis in prostate and breast cancer cells, and inhibits metastasis processes of various cancer types. Epigallocatechin gallate (EGCG) suppresses the activity of ornithine decarboxylase, the enzyme which signals the cell to proliferate faster and bypass apoptosis. Luteolin obstructs epithelial mesenchymal transition. Flavanones, isoflavones and lignans prevent binding of the estrogen to the cancer cells and reduce their proliferation. Reduction of inflammation processes through suppression of nuclear factor- kappa B (NF-κB) family transcription factors is an additional mechanism. Curcumin, bilberries anthocyanins, EGCG, caffeic acid and derivatives and quercetin act via NF-κB signaling. Besides these mechanisms, anticancer phytomolecules targets several other signaling molecules/ pathways also to reduce the growth and metastasis of cancer cells.Curcuma longa slows down the growth of human glioblastoma cells by modulating several molecular components. It upregulates the expressions of p21, p16, p53, early growth response protein 1 (Egr-1), extracellular signal regulated kinase (Erk), c-Jun-N-terminal kinase (JNK), ElK-1 (member of ETS oncogenic family), Bcl-2 associated X protein (Bax) and Caspase- 3, 8, 9 proteins; and downregulates the levels of B cell lymphoma 2 (Bcl-2), mechanistic target of rapamycin (mTOR), p65, B cell lymphoma extra-large protein (Bcl-xL), protein kinase B (Akt), epidermal growth factor receptor (EGFR), NF-κB, cell division cycle protein 2 (cdc-2), retinoblastoma protein (pRB), cellular myelocytomatosis oncogenes (c-myc) and cyclin D1 proteins  over expressing BT-474 breast cancer cells through inhibition of signal transducer and activator of transcription 3 (STAT3) signaling , NF-κB, JAK/STAT, PI3K/Akt, Wnt, and mTOR pathways , histone deacetylases (HDACs) and histone methyl transferases (HMTs) and increase promoter demethylation in various cancer models , which vary with latitude, altitude, climate and season. Different parts of a plant may possess different level of pharmacological activity. Additive or synergistic effects of bioactive phyto-constituents might be responsible for the concerned pharmacological function rather than the purified one. These bioactive phyto-constituents can be developed in antitumor therapeutic entities but they demand intense effort. Several approaches can be used to purify these pharmacologically active phytochemicals. These include isolation and assay, combinatorial chemistry and bioassay-guided fractionation. Bioassay guided fractionation involves the separation of bioactive phytochemicals from a mixture of compounds using various analytic techniques based on biological activity testing. The process begins with the testing of natural extract with the confirmed bioactivity. The active extract is fractionated on suitable matrices, eluted fractions are tested for bioactivity and active fractions are examined by various analytic techniques, viz. thin layer chromatography (TLC), HPLC, FTIR, and Mass spectroscopy (MS). This approach can also be used to purify antimicrobial, antilipolytic and antioxidant compounds Figure . SolventBhavprakash is an important ayurvedic text for the cancer prevention. The botanic candidate can be selected on the basis of ethnomedicine uses also. These plant species can be safer than the species with no history of human use. Another challenge with plant based medicinal products is their poor bioavailability due to excessive degradation by drug metabolic enzymes. The chemical entities of plants have greater steric complexity, greater number of chiral centers, greater number of hydrogen bond donors and acceptors, diverse in aromaticity and higher molecular mass and rigidity which pose strings of challenges in their development into a clinical product.Bioactive functional leads of natural origins can be used as original or must be converted into the druggable forms. Outrageous cost and reduced number of new drug approvals are serious challenges to the new drug discovery. The major task in plant-based drug discovery is the selection of right candidate species of pharmacological activity. This identification can be achieved using several approaches, viz. random selection, ethnopharmacology, codified systems of medicine, ayurvedic classical texts or zoopharmacognosy. Analysis of ayurvedic attributes of ancient healing formulations for the initial selection and bioactivity guided fractionation of the identified plant is a strategy of worth with greater success rate and reduced cost, time, and toxicity parameters. The P) for being work as a drug molecule. These rules are aimed to achieve highest bioavailability. Nonetheless some breakthrough natural products for e.g., paclitaxel would have never become a drug based on these Lipinski's conventions. So there is an essential need to develop suitable druggability standards for the compounds/formulations of natural origins. Various coating materials, micelles, liposomes, phospholipid complexes and nano-materials may be used to enhance the bioavailability of phytomedicines.Therapeutic phytomolecules and dietary supplements of natural origins are governed by Food and Drug Administration  and Dietary Supplement Health and Education Act 1994 respectively for their pharmacological effects and safety issues. Despite having desired bioactivity and ADMET profile , most of the chemical entities of natural origin do not fulfill Lipinski's “rule of five” the drug likeness criteria according to which, a candidate should have less than 500 Da molecular weight, less than 5 hydrogen bond donors, less than 10 hydrogen bond acceptors and less than 5 partition coefficient (logThe world is moving toward natural products due to their low cost and reliability over side effects resulted from existing drugs. Researchers are intensifying their efforts for the development of phytopharmaceuticals against severe metabolic syndromes including cancer. Bioactive phytochemicals/formulations are potential leads for the development of safer anticancer drugs. Several plants and their constitutive phytochemicals have been screened for this purpose but only a very few have reached up to the clinical level. Anticancer phytochemicals described in this article must be further researched in clinical trials for their effectiveness and toxicological documentation. They must be developed as druggable forms with sufficient bioavailability. Moreover, we know that a traditional herbal preparation has greater medicinal effect than the same phytochemical/molecule taken in a pure form. So therapeutic intervention based upon the combination of anticancer molecules may give potent and effective therapeutic results.India is the largest producer of medicinal plants and many of the current health care products. Substantial scientific work has been done on Indian plants and their products for the treatment of frightful diseases. They must be explored for anticancer potential. Furthermore, medicinal attributes put the medicinal plants in high demand and draw the attention of world in risking their biodiversity. Due to increasing demand and deforestation, over exploitation of the medicinal plants continues worldwide with time. Thus, some of the medicinal plants may become extinct soon. Therefore, medicinal plants need their conservation also. Germplasm preservation, viable seed preservation and cryopreservation are promising strategies for the same. In final words, this review can help healthcare pharmacy to explore values of medicinal plants to treat malignancies.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


A receptor positive allosteric modulator, and dexmedetomidine (DEX), a selective α2 adrenergic receptor agonist. By targeting hypothalamic neuromodulatory systems both drugs induce a sleep-like state, but in different ways: zolpidem primarily reduces the latency to NREM sleep, and is a controlled substance taken by many people to help them sleep; DEX produces prominent slow wave activity in the electroencephalogram (EEG) resembling stage 2 NREM sleep, but with complications of hypothermia and lowered blood pressure—it is used for long term sedation in hospital intensive care units—under DEX-induced sedation patients are arousable and responsive, and this drug reduces the risk of delirium. DEX, and another α2 adrenergic agonist xylazine, are also widely used in veterinary clinics to sedate animals. Here we review how these two different classes of sedatives, zolpidem and dexmedetomideine, can selectively interact with some nodal points of the circuitry that promote wakefulness allowing the transition to NREM sleep. Zolpidem enhances GABAergic transmission onto histamine neurons in the hypothalamic tuberomammillary nucleus (TMN) to hasten the transition to NREM sleep, and DEX interacts with neurons in the preoptic hypothalamic area that induce sleep and body cooling. This knowledge may aid the design of more precise acting sedatives, and at the same time, reveal more about the natural sleep-wake circuitry.Sedatives target just a handful of receptors and ion channels. But we have no satisfying explanation for how activating these receptors produces sedation. In particular, do sedatives act at restricted brain locations and circuitries or more widely? Two prominent sedative drugs in clinical use are zolpidem, a GABA Every year, 250 million patients worldwide are given anesthetics; millions take sleeping medications to sedate themselves, and every day, at some point in the 24-h cycle, all humans and animals require natural sleep. Anesthesia, sedation and sleep are commonplace states that involve reversible loss of consciousness, but we do not understand how these processes work at a circuit level. Research suggests that at least sedation and deep sleep are connected mechanistically. Understanding how they interlink is important for both neuroscience and medicine. Sedatives target just a handful of receptors and ion channels Franks, . But we A receptors acting on histamine neurons in the posterior hypothalamus induce a natural NREM-like sleep; whereas α2 adrenergic agonists acting in the preoptic area (POA) of the hypothalamus induce a deeper form of NREM-like sleep, akin to recovery sleep following sleep deprivation. From studying these systems, we suggest that more can be learnt about the natural sleep-wake circuitry and potentially, better sedatives can be developed.In this review article, we describe how two specific drug systems induce sleep: positive-allosteric modulators of GABAThe waking state is maintained by continual activation of aminergic , acetylcholine), hypocretin/orexinergic (peptidergic), CART (peptidergic), and selective glutamatergic and GABAergic pathways  scoring, and in the case of larger mammals also electrooculographic (EOG) scoring , an increase in slow (0.5–4.5 Hz) oscillatory δ power in the EEG, reduced breathing rate, and reduced body temperature, but still with functional respiratory and brainstem circuitry and slow cognitive responsiveness. It is usually possible to be aroused from sedation, just like from natural sleep. Chemically-induced NREM-like sleep  is not identical to natural NREM sleep. But various types of sedatives/sleeping medications do work at selective nodes of the sleep-wake circuitry to induce states partially resembling aspects of NREM sleep (see below).Beyond sedation, there is surgical general anesthesia Franks, . This isGeneral anesthesia emerges from both top down  and bottom up anesthetic-induced inhibition of many types of circuitry  become easily drowsy in novel environments  and chronic hdc gene knockouts, suggest compensations in the knockouts. In fact, selective optogenetic inhibition of histamine neurons produces an immediate transition to NREM sleep , and send their axons throughout the brain  drug is an imidazopyridine compound, zolpidem  to NREM sleep  in the GABAA receptor γ2 subunit gene contributing to the zolpidem binding site, γ2F77I knock-in mice were made. In these mice, all of their GABAA receptors are insensitive to zolpidem but still respond normally to GABA , emphasizing that these noradrenergic neurons will globally influence brain state by releasing NA simultaneously throughout the brain  actions on neurons, astrocytes, microglia and capillaries  cannot be sedated with DEX, nor can DEX induce hypothermia or block painful sensations in these animals  can be used to ascertain the necessity of neurons for a particular physiological response /clozapine-activated DREADD receptor hM3Dq or light-activated channels  to excite those neurons that were previously c-fos active, thus revealing what these physiologically activated neurons regulate. The scheme is shown in a simplified way in Figures A technique known ass Figure . The conReactivating neurons that became c-FOS-positive during DEX-induced sedation using the CNO-DREADD system caused the animals to have strong NREM-like sleep (prominent delta oscillations in the EEG) as well as pronounced hypothermia (Zhang et al., per se.As with histamine, NA contributes to the complex phenomenon of wakefulness (Arnsten et al., A state termed loss-of-righting reflex, resembling postural muscle atonia, is induced by DEX when the dose of the drug is increased beyond the minimum sedative dose. Loss-of-righting reflex in animals is often considered to be an anesthetic endpoint that correlates with loss of consciousness in humans Franks, . In the During wakefulness, descending noradrenergic axons from the LC and orexin neurons provide positive modulation of spinal motor neurons that excite the skeletal muscles (McGregor and Siegel, During normal REM sleep, the LC neurons are inhibited by GABA neurons that are, in turn, driven by REM-active glutamatergic neurons in the pontine inhibitory region (McGregor and Siegel, We are far from a consensus about what makes us fall asleep. The homeostatic drive to sleep is expressed as changed neuronal activity (Szymusiak et al., XY, NPF and WW co-wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Infectious diseases are a global health burden and remain associated with high social and economic impact. Treatment of affected patients largely relies on antimicrobial agents that act by directly targeting microbial replication. Despite the utility of host specific therapies having been assessed in previous clinical trials, such as targeting the immune response via modulating the cytokine release in sepsis, results have largely been frustrating and did not lead to the introduction of new therapeutic tools. In this article, we will discuss current evidence arguing that, by applying the concept of hormesis, already approved pharmacological agents could be used therapeutically to increase survival of patients with infectious disease via improving disease tolerance, a defense mechanism that decreases the extent of infection-associated tissue damage without directly targeting pathogenic microorganisms. Infections are among the leading causes of death, taking the life of 10 to 15 million people every year . The majDisease tolerance as an important defense mechanism has been recognized in the field of botany for over 120 years. First descriptions can be traced to an Australian study published in 1894 in which Nathan Augustus Cobb investigated rust-enduring in wheat ,16 SixtyBeneficial effects of disease tolerance to infection have been in depth revealed in the field of iron/heme infection biology. Degradation of heme and appropriate adaptive metabolism of released iron are important features that decrease tissue dysfunction/damage and enhance survival in malaria ,28,29 anDosis sola facit venenum” 500 years ago, Theophrastus Bombastus von Hohenheim, also known as Paracelsus, described a long-known phenomenon of dose dependent effects of pharmacological active substances also referred to as hormesis . Undiewed in ). While The concept of hormesis in pharmacological application for infectious disease has recently been revived due to fundamental discoveries in pharmacology and toxicology applying substances at very low doses. For example, gasotransmitters such as carbon monoxide are commonly known for their strong toxic and lethal effects, causing hypoxia via the formation of complexes with heme (carboxyhemoglobin) . The samAccording, to the concept of hormesis, low-dose preconditioning by pro-inflammatory cues, or other harmful cues, can modify a subsequent response to the same or alternative insults ,38.This notion has been investigated in detail recently in the case of adaptation of monocytes to stress. Exposing monocytes to different pathogen associated molecular patterns (PAMPs) at particularly low dosage resulted in an adaptive cytokine release after a subsequent application of bacterial lipopolysaccharide (LPS) . Low conAnother study that is described in more detail in the next section reported beneficial effects of low-dose chemotherapeutics, i.e., anthracyclines, for the treatment of murine bacterial sepsis. Sepsis is a severe condition arising from a deregulated host response to infection associated with organ failure . PharmacEscherichia coli. Subsequently, when subjected to polymicrobial infection, mortality of mice that were treated with a low dose of any of these three compounds significantly improved survival as compared to control mice that received vehicle only. These effects were not restricted to one mouse strain, as NMRI mice were equally protected, nor to one disease model, as mice subjected to pneumonia by Klebsiella pneumoniae, a clinically relevant gram-negative bacterium, were also protected. Epirubicin also protected mice against endotoxin shock induced by high doses of LPS and decreased serum concentrations of inflammatory cytokines and serology markers of organ injury. Based on the observation that the survival benefit was not associated with a decrease in pathogen load in lung, kidney, liver, or spleen of the mice 24 h after infection, the authors concluded that low-dose epirubicin exerted protection against the deleterious outcome of bacterial infection via promoting disease tolerance. Mechanistically, it was shown that protection is attributed to a systemic induction of the DNA damage response (DDR) via activation of the ATM kinase [−/−Atm), epirubicin failed to protect against polymicrobial sepsis, providing further evidence for an important role for induction of DDR as an adaptive response.Anthracyclines—a class of chemotherapeutic agents in clinical use for over 30 years —have recM kinase . This isM kinase . In miceIf activation of the DDR is a general mechanism that prevents sepsis pathology, then activation of the DDR via other means should also exert the same effects as epirubicin. In fact, whole-body γ-irradiation increased survival of mice subjected to polymicrobial sepsis associated with increased ATM activation while tissue specific deletion in the lungs using an adenovirus-mediated approach reverted the protection.This landmark study is the first to show a beneficial hormetic effect of anthracyclines for the treatment of bacterial infections. The authors suggest low-dose epirubicin as a possible new treatment of septic patients as epirubicin treatment showed an increased survival even if administered 24 h after sepsis induction, when combined with former antibiotic treatment , making Of note, the same mode of action—i.e., activation of DNA damage responses in response to DNA damage—have been proposed to prevent tumor development and enhance extension (reviewed in ). It remIn sum, the reported benefits of application of low-dose epirubicin in systemic inflammation can be perceived as a first and most promising example of the therapeutic potential of already approved drugs arising from the concept of hormesis.−/−Lc3b) mouse strain in which epirubicin treatment did not exert any protection against bacterial sepsis. Moreover, lung specific deletion of Atg7, another gene involved in autophagy similarly abolished the protective effects of epirubicin. Accordingly, using a gain-of-function adenoviral approach to overexpress Atg7 increased survival rates in the same animal model [Srbl (a scavenger receptor class B type 1) which are characterized by maladaptive autophagy, exhibit increased TNFα and IL-6 production in response to LPS [As outlined above, adaptive responses are not restricted to the DDR but encompass diverse evolutionarily conserved pathways such as the unfolded protein response, heat shock response, or organelle damage response inducing autophagy . Recent al model . Autophaal model . In addial model , macrophal model , or the al model ,51, amone to LPS . These oe to LPS ,53. While to LPS ; (ii) rae to LPS ; (iii) ie to LPS ; and (ive to LPS . Other se to LPS ,58. Conse to LPS ,60,61. AThe concept of dose dependent distinct dose responses to approved agents possesses large biomedical implications. These extent beyond infectious disease and include new treatment options for cancer, auto-immune and other chronic disorders . In thisOverall, we expect that the armory against infectious disease can be expanded significantly considering the concept of hormesis and approaching mechanisms that provide disease tolerance to infection.


Obesity-related sleep breathing disorders such as obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS) cause intermittent hypoxia (IH) during sleep, a powerful trigger of oxidative stress. Obesity also leads to dramatic increases in circulating levels of leptin, a hormone produced in adipose tissue. Leptin acts in the hypothalamus to suppress food intake and increase metabolic rate. However, obese individuals are resistant to metabolic effects of leptin. Leptin also activates the sympathetic nervous system without any evidence of resistance, possibly because these effects occur peripherally without a need to penetrate the blood-brain barrier. IH is a potent stimulator of leptin expression and release from adipose tissue. Hyperleptinemia and leptin resistance may upregulate generation of reactive oxygen species, increasing oxidative stress and promoting inflammation. The current review summarizes recent data on a possible link between leptin and oxidative stress in the pathogenesis of sleep breathing disorders. Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstructions caused by a loss of pharyngeal muscle tone during sleep. OSA is highly associated with obesity and cardiovascular and metabolic complications, increasing cardiovascular morbidity and mortality. Repetitive upper airway obstructions during sleep lead to fluctuations in blood oxygen levels. These recurrent cycles of hypoxemia and reoxygenation are termed intermittent hypoxia (IH), the most prominent feature of OSA that may contribute to increased production of reactive oxygen species (ROS) and oxidative stress . SympathLeptin, also known as a satiety hormone, is a master mediator of food intake and body energy balance. Leptin is produced by adipose tissue and plays multiple regulatory roles in metabolism, immunity, and inflammation . Also, iAccumulating evidence points to the negative effects of leptin resistance. Both oxidative stress and hyperleptinemia play a role in OSA and IH-associated cardiovascular and metabolic morbidity and mortality. However, the interaction between leptin and oxidative stress in OSA has not been previously systematically examined. The purpose of this paper is to review currently available evidence on these relationships and elucidate the role of leptin and oxidative stress in cardio-metabolic complications of OSA.Obstructive sleep apnea (OSA) is a major health problem that is characterized by recurrent collapse of the upper airway during sleep leading to intermittent inspiratory flow limitation and cessation of airflow, which results in loud snoring, IH, and hypercapnia during sleep, frequent arousals, and daytime sleepiness . The recFirst identified by Coleman in 1973, as a circulating factor involved in regulation of body weight, leptin was eventually discovered in 1994 by the group led by Zhang . Leptin In addition to metabolic regulation, leptin may elicit a variety of effects by signaling either centrally or peripherally within a target tissue. On the periphery, leptin has been involved in the regulation of various processes including modulation of inflammatory and immune functions , cardiovDespite such unusually high levels of circulating leptin, it appears that obese individuals are unresponsive to its central metabolic and respiratory effects. While in lean subjects leptin tends to circulate at low levels of approximately 5–10 ng/ml , it was Accumulating evidence in recent years indicates that leptin can be implicated in the pathogenesis of OSA through central regulation of upper airway patency and diaphragmatic control. Experimental data from animal models show that genetic forms of leptin deficiency and leptin resistance in mice are associated with a higher occurrence of flow-limited breathing and pharyngeal collapsibility , 51. Expob/ob) mice exhibit hypoventilation and hypercapnia, which were normalized by leptin replacement therapy. This attenuation in hypercapnic ventilatory sensitivity in ob/ob mice was associated with lower tidal volumes compared to weight-matched wild-type mice [ob/ob mice were also previously demonstrated by several studies, indicating that leptin treatment may have a potential to treat both OSA and obesity hypoventilation [ob/ob mice, and this effect was localized in the dorsomedial hypothalamus [Leptin is also involved in the pathogenesis of obesity-associated hypoventilation. Leptin-deficient obese , other factors such as systemic and tissue hypoxia may influence leptin expression and secretion , 57. IndThe relationship between hyperleptinemia and OSA was further investigated by interventional studies measuring leptin levels after OSA treatment with continuous positive airway pressure (CPAP). Investigators reported that leptin levels begin to decrease after just a few days of CPAP and remain decreased after a long-term CPAP therapy. It was also shown that a CPAP therapy-induced reduction in circulating leptin levels is not dependent on BMI , 61. Furα production by adipose tissue [Evidence from animal studies suggests that IH can be a possible mechanism that mediates hyperleptinemia in OSA. For instance, lean mice exposed to 5 days of IH showed an increase in serum leptin levels as compared to mice kept in normoxia , indicate tissue . Howevere tissue , wherease tissue , 75. SucMechanisms of detrimental metabolic effects of leptin and leptin resistance during IH were addressed in several studies. In wild-type and leptin-resistant rats, IH induced deleterious effects on metabolism and elevated plasma leptin levels through phosphorylation of signal transducer and activator of transcription 3 (STAT3) and expression of proopiomelanocortin (POMC) in arcuate nucleus of the hypothalamus . ActivatGrowing evidence in recent years indicates that leptin-mediated increase of ROS production and oxidative stress can be one of potential mechanisms that link OSA to an increased risk of cardiovascular morbidity and mortality , 83. Oxiob/ob mice [ob/ob mice [Accumulating evidence from multiple studies links leptin to oxidative stress. It was shown that leptin can induce ROS formation in phagocytic , 89 as w/ob mice , indicat/ob mice . The rel/ob mice . In addi/ob mice . All in Obesity has been associated with oxidative stress and increased lipid peroxidation, protein carbonylation, and oxidative changes in nucleic acids . ImbalanIn summary, IH-induced hyperleptinemia in OSA patients may play a major role in the pathogenesis of sleep apnea. Leptin is a respiratory stimulant, but higher circulating levels of leptin in obese OSA patients fail to modulate the respiratory drive, because of resistance to central effects of leptin. Leptin resistance per se can contribute to development of respiratory sleep disorders. In contrast, the proinflammatory actions of leptin and resulting oxidative tissue injury on the periphery escape central leptin resistance and exert its deleterious effects on SNA, hypertension, and cardiovascular neurologic and metabolic complications in OSA. All of the above suggest that leptin resistance is a target for treatment of sleep breathing disorders including OSA and obesity hypoventilation syndrome (OHS). These findings are illustrated in