Surgicel, an absorbable haemostat, is widely used in cardiovascular surgery. An 81-year-old woman, who was diagnosed with ischaemic mitral regurgitation, underwent mitral valve plasty and coronary artery bypass grafting. On postoperative day two, her superior vena cava (SVC) pressure gradually rose to 38 mmHg and she developed low output syndrome. Emergent surgery revealed that the cause of SVC syndrome was external compression from a haematoma at the posterior surface of the SVC, which formed around the Surgicel. Haemostatic agents are quite useful in almost all surgeries. An absorbable haemostat is also effective in controlling oozing of suture lines or stripped surfaces. Surgicel , an absorbable sheet of oxidized cellulose polyanhydroglucuronic acid polymer, has been used in numerous cardiovascular surgeries; however, recent reports have revealed that Surgicel can disturb organ function in several contexts -4. We reAn 81-year-old Japanese woman had long been followed for chronic heart failure. She complained of dyspnoea during light exercise that was gradually worsening. Subsequent coronary angiography demonstrated three-vessel disease. Owing to chronic ischaemia, echocardiography revealed diffuse hypokinesis of the left ventricle and severe mitral regurgitation associated with the tethering of mitral leaflets due to left ventriclar dilatation. The patient underwent mitral valve plasty (MVP) and coronary artery bypass grafting (CABG) simultaneously under a standard medial sternotomy and a cardiopulmonary bypass (CPB) established by cannulation of the ascending aorta, SVC, and inferior vena cava. MVP was performed using a 24-mm Carpenter-Edwards Physio Ring  and a papillary muscle (PM) approximation, which was performed by suturing the tops of both anterolateral and posteromedial PMs using CV-4 with felt strips from the left atrium. CABG to the left ascending artery, left circumflex artery, and right coronary artery was performed using the harvested left internal thoracic artery and saphenous vein grafts. On postoperative day two, she suddenly showed a moon face appearance with an increased SVC pressure of 38 mmHg. Although echocardiography did not show evidence of tricuspid regurgitation or SVC occlusion, computed tomography (CT) revealed the possibility of a thrombus in the SVC (Figure Surgicel, an absorbable sheet of oxidized cellulose polyanhydroglucuronic acid polymer, has been used in many surgical fields. Surgicel is used at surgical oozing sites, physically promoting coagulation and producing an artificial clot ,2.Although Surgicel is often left in surgical sites for effective postoperative haemostasis, previous reports have revealed that a swollen Surgicel can compress and obstruct the function of neighbouring organs. Dogan et al. reported a case of paraplegia following left-sided thoracotomy, suggesting that Surgicel may migrate into the vertebral canal and produce haematomas that result in spinal cord compression . AnotherAs in other surgical specialties, several cases of Surgicel-related complications in cardiovascular surgery have been reported -5. A recIn most cases, SVC syndrome is associated with lung cancer, other tumours, SVC catheters, and venous thrombosis, whereas postoperative SVC syndrome in cardiovascular surgery is rare. In our case, the patient developed SVC syndrome suddenly on postoperative day two. Although her international normalized ratio 1.4 and activated partial thromboplastin time 38.2 seconds were within nornal limits, her clinical course and images on CT and angiography suggested the possibility of catheter-associated SVC thrombosis or stenosis caused by CPB cannulation; however, the emergent redo surgery revealed that the haematoma in the posterior side of the SVC was compressing the SVC externally and swollen Surgicel had enhanced compression by the haematoma. This was a finding that is clearly different from compression secondary to Surgicel granuloma formation occurring at a later stage of surgery. Furthermore, in spite of no evidence of the injury of the right pulmonary artery, a very small amount of bleeding had continued from the sternum. In the elderly, the density of the sternum is significantly low, which may promote bleeding from the bone marrow postoperatively, thus resulting in development of “Surgiceloma” [Surgicel is quite useful in many haemostatic situations, whereas the Surgicel left in surgical sites can produce a postoperative “Surgiceloma” that can be an external compressor, particularly in lower pressure systems or organs such as atriums and veins. Our experience may impress upon surgeons the importance of appropriate use of haemostatic agents.Surgeons should consider the possibility of postoperative compression by haemostatic agents swollen with blood, specially in lower pressure systems or organs.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.SVC: Superior vena cava; MVP: Mitral valve plasty; CABG: Coronary artery bypass grafting; CPB: Cardiopulmonary bypass; PM: Papillary muscle; CT: Computed tomography.The authors declare that they have no competing interests.KE wrote the manuscript and collected references. MM was the chief surgeon and commented to this manuscript. YK and RK were primarily involved in the clinical and scientific discussion of the case. All authors read and approved the final manuscript.


Left atrial intramural hematoma is a seldom cause of left atrial mass. It has been described to occur spontaneously, after interventional procedures, after blunt chest trauma, or after aortocoronary bypass surgery. We present a case of mitral valve replacement together with the removal of a large intraatrial space-occupying lesion. Intraoperative transesophageal echocardiography confirmed a successful resection of this mass. Surprisingly, upon admission to ICU, transesophageal and transthoracic echocardiography revealed a recurrence of an intramural lesion, closest matching a hematoma, which was confirmed by contrast-enhanced computed tomography. Surgical intervention was thoroughly discussed but a conservative management was favoured. 3 months after surgery, a reassessed transthoracic echocardiography and computed tomography demonstrated an almost complete resolution of the pre-existing hematoma. Atrial intramural hematomas are severe but rare complications of cardiac surgery and only few cases are described in literature. We present a case of an unexpected intramural left atrial hematoma following mitral valve replacement and concomitant left atrial thrombus resection and the beneficial role of perioperative echocardiography in detecting and monitoring this event.2, transmitral pressure gradient 9 mmHg), and the presence of a large intracavitary, space-occupying lesion attached to the left atrial roof , mitral valve stenosis , extirpation of the intracavitary mass and ligation of the left atrial appendage. Intraoperative transesophageal echocardiography revealed satisfactory valve function and confirmed the successful removal of the intracavitary lesion. Histopathological examination revealed a spherical mass which was subsequently confirmed to be a partially calcified and connective tissue-organized thrombus.Surprisingly, upon admission to ICU echocardiography revealed a reappearance of a new homogenous mass arising from the left atrial wall Figure . NeitherIn-house follow up serial echocardiography demonstrated a stable-to-improving left atrial hematoma. A transthoracic echocardiography and contrast-enhanced computed tomography 3 months after surgery revealed an almost complete resolution of the pre-existing hematoma Figures  and 5.Intramural left atrial hematomas are a very uncommon entity, but have been described to occur spontaneously -4, afterIn our case, routine postoperative transesophageal echocardiography revealed an acute 5 cm diameter intramural hematoma in the left atrium, which could have remained undetected as our patient was asymptomatic. Pre-  and intrJudging by the spontaneous regression, a conservative approach seemed justified, despite anticoagulation.A conservative approach with close-meshed serial echocardiographic examinations in a hemodynamically stable and asymptomatic patient with a left atrial intramural hematoma seems to be an appropriate strategy. This case demonstrates the usefulness and necessity of perioperative echocardiographic imaging in the detection and monitoring of this unexpected event.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.DB reviewed the case, conducted a review of the literature and drafted the manuscript. SS and MP performed the echocardiographic studies and participated in the design of the case report. RS and CS performed the operation described. BR and DC confirmed the patient's diagnosis and revised the manuscript, contributing important intellectual content. All authors read and approved the final manuscript.Preoperative transesophageal echocardiogram demonstrating a voluminous intracavitary mass attached to the left atrial roof.Click here for filePostoperative transthoracic echocardiogram showing development of an echogenic mass arising from the left atrial wall.Click here for filePostoperative axial CT images.Click here for fileTransthoracic echocardiogram three months following surgery revealing an almost complete resolution of the pre-existing hematoma.Click here for fileAxial CT images three months following surgery.Click here for file


Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy. Therefore, there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab response. Recently, several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance in breast cancer. In order to explore the predictive value of inflammation in breast cancer patients, we measured the inflammatory biomarkers serum ferritin and C-reactive protein (CRP) in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival. The elevation in pre-treatment serum ferritin (>250 ng/ml) or CRP (>7.25 mg/l) was a significant predictor of reduced progression-free survival and shorter overall survival. When patients were stratified based on their serum ferritin and CRP levels, patients with elevation in both inflammatory biomarkers had a markedly poorer response to trastuzumab-containing therapy. Therefore, the elevation in inflammatory serum biomarkers may reflect a pathological state that decreases the clinical efficacy of this therapy. Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics. Inflammation plays a critical role in breast cancer development and progression in vivo increases the efficacy of chemotherapeutic agents against primary and metastatic sites The role of the inflammatory microenvironment in modulating response to cancer therapy has only been recently appreciated Trastuzumab is a humanized monoclonal antibody targeting the HER2/neu growth factor receptor. When administered in combination with first-line chemotherapy, trastuzumab impedes tumor progression and increases survival of HER2/neu-overexpressing breast cancer patients Because inflammation within the tumor might be decreasing the efficacy of cancer therapeutics, we hypothesize that the elevation in inflammatory biomarkers is associated with a decrease in therapy response. The aim of this study is to evaluate the clinical utility of the inflammatory biomarkers serum ferritin and CRP in predicting response to trastuzumab-containing therapy in advanced breast cancer patients.Signed informed consent to participate in the present study was obtained from all patients before sample collection. This study was reviewed and approved by the institutional review boards at the Pennsylvania State University Hershey Medical Center and the University of Vienna.A comprehensive description of the eligibility criteria for this patient series was previously reported Complete response was defined as a complete disappearance of any tumor-related symptoms and all lesions in imaging studies, without appearance of any new lesions lasting for at least 4 weeks. Partial response was defined as a 50% decrease in diameter of all measurable lesions. Progression was defined as a 25% increase in the products of all measurable lesions, an unequivocal increase of nonmeasurable disease, or the appearance of new lesions. The median clinical follow-up duration was approximately 5.5 years.Ferritin and CRP levels were determined using a human ferritin or CRP ELISA .P<0.05 was considered statistically significant.Statistics for the pretreatment serum biomarkers were analyzed as dichotomous (median cutoff point) groups. Univariate analysis for progression-free survival (PFS) and overall survival (OS) was performed using the Cox proportional Hazards model. Multivariate analysis for PFS and OS was analyzed using Cox modeling. The correlation between serum ferritin and CRP was examined using Pearson's correlation coefficient. For all analyses, a In order to examine the predictive value of inflammatory biomarkers in breast cancer patients, we measured serum ferritin and CRP in HER2/neu-overexpressing patients before undergoing trastuzumab-containing therapy . We examP<0.0001, median OS 12.73 vs. 69.57 months) and PFS  compared to patients with serum ferritin values below the median.Of the 66 patients, 33 (50%) had elevated pre-treatment serum ferritin levels which were defined as being greater than the median, which at 250 ng/ml is near the upper limit of the normal range reported for serum ferritin P = 0.009, median OS 17.3 vs. 69.53 months) and reduced PFS . Therefore, both of the inflammatory biomarkers serum ferritin and CRP have strong prognostic and predictive value in advanced breast cancer patients receiving trastuzumab-containing therapy. CRP displayed a moderate linear correlation with serum ferritin .CRP also showed a wide distribution of values in HER2/neu-overexpressing patients , while the low serum ferritin/high CRP patient group was not statistically different (P = 0.186). Furthermore, multivariate analysis using estrogen receptor status, age, treatment modality, and CA 15-3 in addition to serum ferritin and CRP as covariates showed a stronger prognostic value for serum ferritin than CRP. Serum ferritin remained an independent factor for progression-free survival  and overall survival , while CRP was only an independent factor for progression-free survival  but not overall survival (P = 0.072). These observations raise the possibility that serum ferritin is an independent prognostic factor for breast cancer patients and its prognostic value is not dependent on the elevation in other inflammatory biomarkers.Interestingly, patients with high serum ferritin/low CRP had a significantly poorer outcome compared to patients with low serum ferritin/low CRP  between serum ferritin and CRP levels. These observations suggest that serum ferritin and CRP might not be produced by the same mechanism or cell type. CRP is believed to be produced exclusively by the liver in vitroin vivo studies have argued that serum ferritin is secreted primarily by macrophages and that hepatocytes do not contribute significantly to the secretion of ferritin into circulation It is still unclear what causes the elevation in some inflammatory biomarkers but not others in patients with comparable disease. In our study, we have observed that almost one third of the patients studied had elevation in either serum ferritin alone or CRP alone. As mentioned, there was also a moderate linear correlation (rPatients with low serum ferritin or low CRP had a median survival approximately six times longer than patients with high serum ferritin or CRP . More imBased on our data showing an independent prognostic value for serum ferritin , it is tIn summary, this study demonstrates that elevation in the inflammatory biomarkers serum ferritin and CRP is a common phenomenon in advanced breast cancer patients and is predictive of response to trastuzumab-containing therapy. Further investigation of the mechanisms underlying the strong association between the elevation in inflammatory biomarkers and therapy responsiveness is warranted. Moreover, the clinical utility of anti-inflammatory drugs and life-style changes that may decrease levels of inflammatory biomarkers should be explored as possible strategies to sensitize patients to trastuzumab-containing therapy.


Furtherications ,7,15. Thications , or inseications . Howeverications .rep gene encodes proteins responsible for site-specific integration, viral genome replication as well as packging. The cap gene is translated into three structural proteins building the capsid shelf. Furthermore, cap encodes a protein required for capsid assembly (AAP or assembly-activating protein) that has been described recently [rep and cap required for replication and encapsidation, as well as adenoviral helper function delivered by sequences encoding genes E1a, E1b, E2a, E4orf6 and viral associated (VA) I/II RNA [AAVs are parvoviruses whose productive infection is depending on the presence of helper viruses like e.g. adenovirus (AdV). Their single-stranded DNA genome carries two genes. The recently . The AAVI/II RNA . In a tiThe aim of the underlying study is to provide all tools necessary to generate a stable and versatile producer cell line In order to circumvent the problems triggered by toxic proteins inevitably arising during rAAV formation, one objective of the project is to establish stable producer cells where rAAV production can be induced by temperature shift at the final production scale. To begin with, we first performed some general feasability studies to investigate whether the generation of stable and inducible producer cell lines using proprietary constructs is a viable approach. For this purpose, experiments for rAAV manufacturing based on a transient packaging approach were conducted. Infection of rep, cap and rAAV vector plasmid transfected cells with wildtype Adenovirus was compared with co-tranfection of the cells with additional plasmids carrying the Adenoviral helper genes. The influence of different cultivation temperatures on Adenovirus replication kinetics and rAAV productivity in the transient packaging approaches were analyzed. Furthermore, we investigated differential gene expression in response to temperature downshifts.2/M phase, causing enhanced growth but decreased proliferation. Hence, cells exhibit enlarged size and elevated protein production, possibly supported by avoided degradation of rDNA as previously described for CHO cells [In the first experiments, a transfection-/infection-based approach was chosen to produce rAAV. For this, HeLa cells were co-transfected with three plasmids encoding the AAV vector on one side and the rep and cap genes delivered on two separate constructs on the other side . SubseqHO cells . RepressHO cells  could beE1a, the key inducer of the whole cascade required for rAAV production. Applied in stable producer cells, such a system would allow for timely-regulated induction of rAAV production. Making use of a temperature shift as primary switch for rAAV production, we would combine the inevitable induction event with conditions presumably enhancing rAAV production.Differential gene expression analysis of HeLa cells cultivated at different temperatures gave rise to the identification of three genes up-regulated up to 7-fold and 16 miRNAs likely regulated more than 2-fold at lowered temperature (Table Taken together, these first data provide the basis for a successful generation of temperature inducible stable producer cells carrying all genetic elements required for rAAV production. A versatile and high-titre rAAV production platform based on such cells will be applicable for industrial-scale manufacturing and thus has the potential to open AAV-based gene therapy to a high number of patients.


Staphylococcus aureus has emerged as a leading etiologic agent of sepsis, owing to its propensity to cause deep-seated tissue infection and bacteremia S. aureus harbors an arsenal of virulence factors to facilitate tissue adhesion, immune evasion, and host cell injury. In the bloodstream, these factors cause inflammation, impair immune cell function, alter coagulation, and compromise vascular integrity. This review will discuss key secreted and surface-anchored proteins required for S. aureus infection in the hostile host environment of the bloodstream, emphasizing mechanistic insights on virulence factor function that illustrate the complex nature of the host–pathogen interaction. While we currently lack a clear understanding of the temporal and spatial integration of these virulence factors in the bloodstream, it is apparent that S. aureus triggers pathophysiologic disturbances that are further amplified by the host inflammatory response, culminating in the severe clinical manifestations of sepsis and septic shock.Sepsis is a devastating disease process characterized by a systemic inflammatory response in the host, evoked by a known or suspected pathogen. The clinical manifestations of sepsis span a continuum of severity, in the most extreme form termed “septic shock,” in which vascular insults and systemic inflammation lead to compromised cardiac function and blood pressure, culminating in impaired oxygen delivery to the tissues and organ failure. In the United States, ∼750,000 individuals suffer from sepsis per year, with mortality rates that approach or even exceed 50% in severe disease S. aureus proteins and cell wall components are pro-inflammatory, eliciting host responses similar to gram-negative lipopolysaccharide (LPS) S. aureus lipoproteins on mononuclear phagocytes through TLR-2 pathway activation S. aureus (MRSA) strains has been described as a molecular mechanism that underlies increased disease severity observed upon infection with these isolates S. aureus mutants engineered to lack expression of even one of these toxins exhibit virulence defects in experimental infection Multiple S. aureus utilizes a number of strategies to modulate the innate host immune response and prevent bacterial clearance in the bloodstream S. aureus isolates express a polysaccharide capsule that affords protection against phagocyte-mediated clearance; furthermore, the pathogen is able to resist killing in the phagocyte. S. aureus also secretes factors that function to dampen leukocyte recruitment or prevent opsonophagocytic uptake as a predecessor to intracellular killing. Two of the best-studied of these proteins are CHemotaxis Inhibitory Protein of Staphylococci (CHIPS) and Staphylococcal Complement INhibitor (SCIN). CHIPS binds to the cellular receptors for C5a and N-formyl peptides, diminishing the ability of both bacterial peptides and complement activation to function as leukocyte chemoattractants  to preclude antibody-driven opsonophagocytic clearance. SpA binds to the Fc and Fab regions of host antibodies c-mediated effector functions. SpA also engages the B cell receptor and initiates activation-induced apoptotic death of VH3+ B cells  and von Willebrand factor binding protein (vWbp) promote the non-catalytic activation of prothrombin, yielding cleavage of soluble fibrinogen to engender fibrin clot formation in the absence of an inciting injury S. aureus in the blood promotes bacterial survival, noted by the significant virulence defect in S. aureus strains that lack expression of Coa, vWbp, and ClfA S. aureus likely contributes to the systemic inflammatory response.Coagulopathy is another hallmark of septic shock, manifest as pathologic clotting within the microvasculature and a predisposition toward systemic bleeding S. aureus and facilitating pathogen clearance  constrain the delivery of soluble virulence factors that initiate pathologic coagulation in flowing blood and (2) overcome fluid shear stress to adhere to the vascular wall and promote dissemination. Fibronectin-binding protein A (FnBPA) is a surface-displayed protein that facilitates endothelial adherence  to disrupt the endothelial barrier by promoting the untimely cleavage of vascular endothelial (VE)-cadherin, destroying the inter-cellular junction that is required for vascular integrity S. aureus sepsis. Damaged endothelium is also a potent stimulus for the rapid recruitment of platelets and activation of soluble clotting cascades. The microvascular endothelial surface may, thus, form a site wherein the pathogen, its armamentarium of virulence factors, platelets, leukocytes, and host coagulation proteins are co-localized. This “coordination” site may simultaneously trigger microvascular occlusion and increased vascular permeability—events that decrease effective blood flow to the tissues and precipitate sepsis-associated vital organ failure.A primary molecular mechanism for bacterial-induced vascular permeability is endothelial disruption due to extreme inflammation S. aureus challenge. Similarly, vaccine approaches that target isolated virulence factors do not provide complete protection against lethal sepsis S. aureus—coagulopathy, immune cell injury, microvascular occlusion, and barrier damage—collectively mirror disease endpoints in sepsis. These insults likely initiate the very pathophysiologic state that is then exacerbated by an untoward host response. While multiple blood-borne bacteria incite endothelial injury and lead to a coagulopathic state manifested as sepsis The devastating mortality of sepsis and the inability of current clinical approaches to mitigate disease testify to our limited understanding of the complex host–pathogen interaction in the bloodstream. While the virulence factors discussed herein each contributes to sepsis pathogenesis, loss of any one factor is insufficient for complete protection against experimental


A 16-year-old girl inadvertently swallowed a toothbrush during attempted manual induction of emesis. The 20 cm toothbrush was successfully removed via overtube facilitated endoscopy using a retractable snare while the patient was sedated in the emergency department. Foreign body ingestion represents a common emergency department presentation. While the vast majority of ingested foreign bodies traverse the gastrointestinal tract with nil adverse sequelae , 2, few A 16-year-old female presented to our tertiary care facility two hours following ingestion of a household toothbrush. She admitted to excess alcohol intake the evening prior and have woken feeling “hung-over.” Due to ongoing nausea, she had attempted to induce emesis via manual pharyngeal stimulation with a toothbrush. However, during this process, she claimed to have “choked,” lost control of the toothbrush handle, and ingested the “white-and-orange” toothbrush whole. Clinical examination revealed a well-appearing 16-year-old female in no distress. Mild pharyngeal abrasions were apparent on examination of the oral cavity. Cardiovascular, respiratory, and abdominal examination proved unremarkable; in particular no abdominal tenderness was reported on manual palpation. Soft tissue lateral X-ray of the neck and chest X-ray revealed no evidence of ingested foreign body. Endoscopic retrieval of the toothbrush was undertaken in the emergency department. Given the dimension of the ingested foreign body and anticipated requirement for overtube utilization, airway protection was afforded with endotracheal intubation following standard rapid sequence intubation (RSI). Sedation was maintained with propofol/ketamine combination. Gastroscopy was performed with visualization of the distal (brush) end of toothbrush protruding from the gastric outlet, the proximal (handle) having already traversed the pylorus . The bruThe patient was extubated uneventfully and discharged two hours later in possession of the offending toothbrush. Future manual pharyngeal stimulation for the purposes of inducing emesis was discouraged.Inadvertent or intentional ingestion of foreign objects frequently results in emergency department attendance . In the Oesophageal foreign bodies as a group require early intervention within 24 hours) because of their potential to induce respiratory complication, oesophageal erosions, or, in the most extreme instances, aortooesophageal fistula . Ingeste4 hours bSwallowed linear foreign bodies of greater than 6–10 cm length, such as toothbrushes, present a unique problem in that, given their length, they are unable to negotiate the curvature of the duodenum with its fixed retroperitoneal attachment . DespiteToothbrush ingestion, while uncommon, presents a unique clinical challenge due to the inability of this foreign body to undergo gastrointestinal passage, spontaneously. Early endoscopic retrieval is therefore recommended to reduce morbidity associated with prolonged impaction.


Beside their role in primary metabolism, plant mitochondria also act as “signaling organelles”, able to influence processes such as nuclear gene expression. AOX activity can control the level of potential mitochondrial signaling molecules such as superoxide, nitric oxide and important redox couples. In this way, AOX also provides a degree of signaling homeostasis to the organelle. Evidence suggests that AOX function in metabolic and signaling homeostasis is particularly important during stress. These include abiotic stresses such as low temperature, drought, and nutrient deficiency, as well as biotic stresses such as bacterial infection. This review provides an introduction to the genetic and biochemical control of AOX respiration, as well as providing generalized examples of how AOX activity can provide metabolic and signaling homeostasis. This review also examines abiotic and biotic stresses in which AOX respiration has been critically evaluated, and considers the overall role of AOX in growth and stress tolerance.Alternative oxidase (AOX) is a non-energy conserving terminal oxidase in the plant mitochondrial electron transport chain. While respiratory carbon oxidation pathways, electron transport, and ATP turnover are tightly coupled processes, AOX provides a means to relax this coupling, thus providing a degree of  Respiration then uses these carbohydrates to support growth and maintenance through the provision of carbon intermediates, reducing equivalents and ATP. These processes, in turn, release CO2 and convert O2 back to H2O.Photosynthesis and respiration are the primary pathways of carbon and energy metabolism in plants. Photosynthesis uses light energy, CO2 to H2O. Importantly, electron transport at complexes I, III and IV is coupled with proton translocation from the mitochondrial matrix to inner membrane space (IMS) and the resulting proton motive force is used by complex V (ATP synthase) to generate ATP from ADP and Pi)et al..Several studies have shown that respiration and mitochondrial activity are enhanced following infection with plant pathogenic fungi –229. FurThis section highlights studies that have shown an effect of AOX respiration on plant performance  or plant tolerance to different biotic or abiotic stress.2 assimilation and/or oxygen evolution [Arabidopsis plants defective in components that contribute to control of the chloroplast redox state have increased AOX amount. These include plants defective in cyclic electron transport [Arabidopsis localizes to thylakoid membranes rather than the mitochondrion, or perhaps that it is dual-targeted to both organelles, revealing a potential unexpectedly close interaction between AOX and photosynthetic electron transport [Photosynthesis and respiration are interdependent processes. This interaction in the light depends upon a direct or indirect exchange of common metabolites between chloroplast and mitochondrion via the cytosol –237. Sinvolution ,238–241.volution ,243, AOXvolution ,222, andvolution . Furthervolution . Isotopevolution , and alsvolution . Also ofransport  or lackiransport . In thesransport .Arabidopsis plants. Microarray analyses showed that transcripts encoding chloroplast proteins, particularly those associated with the light reactions of photosynthesis and stress are amongst the most perturbed genes in plants lacking AOX [A role for AOX during photosynthesis has also been investigated in transgenic and mutant king AOX ,129,250.king AOX ,129,251.Many plants store cyanogenic glycosides in their vacuole as a defense against herbivory. If released to the cytosol by mechanical damage, these cyanogens are rapidly degraded to release CN. In the cyanogenic crop plant cassava, harvesting of the tuberous roots has been shown to result in a rapid burst of ROS that strongly curtails post-harvest shelf-life. It was recently shown that this ROS burst is dependent upon CN release, caused by the mechanical damage associated with harvesting . This suO-acetylserine(thiol)lyase C (OAS-C) can catalyze the conversion of the hydrogen sulfide and O-acetylserine back to cysteine. It has recently been shown that such a cycle in the mitochondrion is critical to managing cellular levels of CN and hydrogen sulfide. An Arabidopsis T-DNA mutant lacking the mitochondrial CAS isoform was shown to accumulate CN [2. Similarly, mutation of the mitochondrial OAS-C isoform resulted in accumulation of hydrogen sulfide and CN, accompanied again by increased AOX and higher total respiration rate [Arabidopsis were co-cultivated with CN-producing bacterial strains, plant growth was more strongly curtailed in the transgenic plants lacking AOX [In non-cyanogenic plants, the major source of CN in the cell occurs during ethylene biosynthesis. Conversion of 1-aminocyclopropane-1-carboxylic acid (ACC) to ethylene by ACC oxidase generates an equimolar amount of CN. β-cyanoalanine synthase (CAS) can catalyze the conversion of the CN and cysteine to β-cyanoalanine and hydrogen sulfide. Similar to CN, hydrogen sulfide is also a potent inhibitor of cyt oxidase. ulate CN . Interesion rate . Interesion rate , an intrking AOX .As noted earlier, ozone treatment was found to rapidly reduce cyt pathway capacity and increase AOX capacity in tobacco plants . Hence, Arabidopsis, improving growth and decreasing shoot sodium level [2O2 than the WT during stress and the authors suggested that this change may have influenced sodium transport, allowing the plants to better exclude sodium from the shoot [As discussed earlier, salt stress has been shown to disrupt mitochondrial function and increase AOX respiration. Recently, constitutive overexpression of AOX was reported to increase the salt tolerance of um level . The AOXhe shoot .versus salt) or may indicate that expression of the ROS-scavenging network in response to AOX manipulation differs between the two species. In tobacco, AOX over-expression perturbed expression of the ROS-scavenging network during the stress [Arabidopsis study did not report on the expression of the ROS-scavenging network [In summary, the ability of AOX overexpression to increase tolerance toward abiotic conditions associated with oxidative stress such as ozone or salt has met with mixed results. On the one hand, increased AOX during the stress may increase tolerance by reducing ROS generation by the respiratory chain, as suggested by the salt stress study. On the other hand, AOX overexpression might interfere with the normal signaling pathways required to engage acclimation responses to stress, as suggested by the ozone study. In this case, while the increased AOX might still dampen ROS generation by the respiratory chain, it could also paradoxically result in an increased total cellular ROS level. The different outcome in these two studies may relate to the different stresses applied  conditions.The relationship between AOX and growth has been examined in a simple tobacco suspension cell system, and with growth of the cells in macronutrient-sufficient or macronutrient (N or P) deficient conditions . Under mChlamydomonas reinhardtii[Chlamydomonas lacking AOX displayed a large increase in biomass accumulation compared to WT cultures. This was associated with a large increase in cell volume, also similar to that described for tobacco cells under P limitation [Chlamydomonas was consistent with a proteomic analysis that showed an up-regulation of proteins associated with anabolism and attendant down-regulation of catabolism-related genes [Another single cell system in which the relation between AOX and growth has been critically examined is in the green alga inhardtii. Similarmitation . The inced genes . Since cIn general, while the single cell systems discussed above have shown that removing AOX had a positive impact on growth, the relation between AOX and growth will undoubtedly be much more complex in whole plants. A recent example that illustrates this complexity comes from experiments in which AOX was overexpressed in cassava tubers . Under oArabidopsis plants growing at low temperature, AOX was reported to beneficially impact early vegetative growth since antisense knockdown of Aox1a slowed early growth while constitutive overexpression accelerated early growth [Aox1a T-DNA mutant of Arabidopsis. In this case, neither the AOX mutant nor a mutant in cyclic electron transport showed any growth defect at high light. However, the double mutant showed strongly curtailed growth [Arabidopsis leaf [et al.[Aox2b gene in soybean was shown to compromise both vegetative growth and seed yield under typical greenhouse growth conditions.In y growth . A benefd growth . At presd growth . Howeverd growth  and non-sis leaf . Recentlf [et al. were theArabidopsis plants with altered AOX amount, it was reported that knockdown and overexpression plants displayed similar relative growth rate as WT plants under optimal growth conditions. However, under stress (drought) conditions, plants overexpressing AOX displayed a higher relative growth rate than WT plants [In another study comparing growth of T plants . FurtherT plants . The aboStress can perturb metabolism, such as by disruption of enzymes and membrane processes. Stress likely similarly disrupts signal transduction pathways, as well as engaging signal pathways associated with stress acclimation. Over the past decade, AOX has emerged as an important mitochondrial component of the plant stress response. Such work emphasizes that numerous abiotic and biotic stresses impact on mitochondrial bioenergetics and function. Stress alters the cellular demands on mitochondrial metabolism and changes in AOX activity represent a means to rapidly meet these changing demands. AOX activity can also directly impact the level of potential important signaling molecules, thus providing an important link between mitochondrial function, signal transduction, and acclimation to stress.


Even though altered metabolism is an “old” physiological mechanism, only recently its targeting became a therapeutically interesting strategy and by now it is considered an emerging hallmark of cancer. Nevertheless, a very poor number of compounds are under investigation as potential modulators of cell metabolism. Candidate agents should display selectivity of action towards cancer cells without side effects. This ideal favorable profile would perfectly overlap the requisites of new anticancer therapies and chemopreventive strategies as well. Nature represents a still largely unexplored source of bioactive molecules with a therapeutic potential. Many of these compounds have already been characterized for their multiple anticancer activities. Many of them are absorbed with the diet and therefore possess a known profile in terms of tolerability and bioavailability compared to newly synthetized chemical compounds. The discovery of important cross-talks between mediators of the most therapeutically targeted aberrancies in cancer  and the metabolic machinery allows to predict the possibility that many anticancer activities ascribed to a number of natural compounds may be due, in part, to their ability of modulating metabolic pathways. In this review, we attempt an overview of what is currently known about the potential of natural compounds as modulators of cancer cell metabolism. Deregulated metabolism is one of the oldest mechanisms associated with cancer physiology. The actual meaning and the selective advantages induced by this deregulation remain nowadays still a matter of debate despite the pioneering work of Warburg about the impact of the alteration of the energetic metabolism in cancer cells. Certainly, several reasons have significantly contributed to delay the advancement in this area of investigation. For many years, the search for new anticancer therapeutic agents has been extremely focused on fighting the two most intuitive altered features of cancer cells, namely, their sustained and uncontrolled proliferation and their ability of evading death. Accordingly, we have assisted over the years in the development of different classes of therapeutic agents reducing cancer cell proliferation or inducing cancer cell death. The main target of these studies was the differential susceptibility of cancer versus normal cells to these treatments. Over the time, however, we have also learned about the limits of this approach considering the high incidence of therapeutic failure and the frequent development of systemic toxicity.Recently, the high level of complexity and heterogeneity of cancer allowed considering this disease as a dynamic multicellular system with complex forms of interactions and cellular communications with the own environment. It has become evident that consolidated cancer hallmarks including sustained and uncontrolled cell proliferation and resistance to cell death need to be reconsidered in a much more complex modulatory context if we want to therapeutically succeed with cancer.At the light of this new vision, the ability of cancer cells to reprogram their cellular energetic metabolism is passing through a renaissance of interest in cancer biology for these chapters of fundamental biochemistry. The discovery of unexpected cross-talks between well-known metabolic factors and mediators of unrelated processes is fuelling this renewed interest. On one side, noncanonical regulatory functions of specific metabolic enzymes or substrates are emerging; on the other side, oncogenes, tumour suppressors, as well as modulators controlling events typically altered at the very early stages of cancer progression including immune response, cell proliferation, or cell death appear in the dual role of controlled/controllers of metabolic processes. Decoding the roles of metabolic changes occurring during carcinogenesis and identifying the key nodes that differentiate pathological and healthy behavior have two important implications: novel predictive biomarkers and new drug discovery strategies. Consequently, additional knowledge may offer new tools to troubleshoot frequent chemotherapeutic failures; additionally, compounds targeting metabolic processes may also be potentially used for chemopreventive purposes. This research is only emerging, transforming the identification of metabolically active agents into an opportune challenge.Nature provides a considerable source of biologically active compounds with a diversified pharmacological potential. Remarkably, almost 80% of all anticancer compounds are isolated from plants, fungi, and microorganisms. Both natural and chemically modified molecules  are able to counteract each of the cancer hallmarks , 2 recenThe preferential switch from oxidative phosphorylation to aerobic glycolysis represents the most discussed and investigated altered metabolic feature of cancer cells and was first described by Otto Warburg in the 1920s. He already hypothesized mitochondrial dysfunctions as the causative event. Defects in the enzymatic respiratory chain exist in cancer cells ; however2) and water and leads to accumulation of precursors used by the major cellular synthesis pathways leading to amino acids, nucleotides, and lipids. Consequently, this metabolic alteration inevitably fuels these anabolic pathways. Second, cancer cells experience moderate to severely reduced oxygen tension, and the fact to preferentially exploit glycolysis to produce energy in this situation represents an interesting adaptation. Accordingly, overexpression or stabilization of the hypoxia-inducible factor (HIF) in response to low-oxygen conditions promotes the glycolytic metabolism, by inducing transcription of glucose transporters and numerous key glycolytic enzymes [Theoretically, metabolic alterations during carcinogenesis could provide multiple benefits as cancer cells need to satisfy a continuous demand in macromolecule precursors to maintain their high proliferation rate. As a matter of fact, the reduction of mitochondrial respiration prevents a complete degradation of glucose to carbon dioxide , glyceraldehyde-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH) and the isoform M2 of pyruvate kinase (PKM2) are upregulated in cancer cells and accordingly suggested as potential therapeutic targets , 9. Inte+), as part of a feedback regulatory mechanism; on the other side, it is secreted outside the cells where it promotes angiogenesis and spreading of cancer cells from their primary site. A mutual control exists between events controlling lactate production and synthesis of proangiogenic factors. For example, the extracellular acidification due to the transport of lactate coupled to H+ extrusion promotes upregulation of HIF-1 [The hyperproduction of lactate plays a dual role. On one side, it activates the glycolytic pathway, ensuring the regeneration of nicotinamide adenosine diphosphate . Suppression of ROS formation has been suggested as an important advantage for rapidly proliferating cell systems; these cells may be better protected against the risk of DNA damage during DNA synthesis . This mo+ extrusion to the intake of extracellular monocarboxylates, including pyruvate, into the cell. The group of Ganapathy has proposed an interesting model to explain the tumour suppressor activity of SLC5A8 specifically centered on the role of pyruvate [More recently, unconventional roles were ascribed to pyruvate, the end product of glycolysis, which is massively converted into lactate in cancer cells instead of being transported into mitochondria to initiate mitochondrial metabolism. The plasma membrane transporter SLC5A8 was reported to be downregulated in different human cancer cells , 26. Itspyruvate . Accordipyruvate . Therefopyruvate . Accordipyruvate . This mopyruvate . TherefoPreferential exploitation of aerobic glycolysis by cancer cells is a key issue of reprogrammed metabolism. It is becoming clear that other metabolic pathways or mediators may play a fundamental role in cancer. The availability of recent sophisticated experimental approaches to study the metabolic profile of cancer cells has allowed identification of an impressive number of alterations. They essentially concern levels of expression/accumulation or status of enzymes or intermediate substrates involved in several anabolic pathways. Despite the evident advantage of these modifications within the anabolic process in which they are mainly involved, additional noncanonical functions have emerged, including control of redox homeostasis or specific signalling events enabling the high cellular proliferation rate. In this section, we will briefly discuss two key pathways suitable for therapeutic targeting.α-ketoglutarate in a reaction catalyzed by glutamate dehydrogenase (GDH). Exceeding substrates from the TCA cycle can be again available in the cytosol where they become the precursors of several anabolic pathways leading to biosynthesis of lipids, other aminoacids, and nucleotides. Beside its relevant role in anabolic pathways, glutamine metabolism may also promote further accumulation of lactate  and therefore exacerbate glycolysis and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) generation (glutaminolysis), the latter further buffering potential oxidative stress into the cells. Studies highlight that specific forms of cancer including glioblastoma develop an impressively high rate of glutamine metabolism, which goes beyond the real nitrogen demand, thus suggesting that glutamine consumption in cancer cells may represent a fast and preferential carbon source to replenish several biosynthetic pathways [Beside glucose, cancer cells frequently rely on glutamine metabolism. This amino acid is uptaken through specific transporters and directed to the mitochondria where it is converted first in glutamate . Glutamate then fuels the tricarboxylic acid cycle (TCA), upon further conversion to pathways . This prpathways . AltogetA growing body of evidence depicts a determinant role of altered lipid homeostasis in enabling the cancer cell phenotype. The pattern of alterations described suggests that lipid metabolism plays a multitasking role in cancer. Beyond the relevance of metabolic modifications that promote lipogenesis and therefore specific anabolic activities, lipid-related factors appear essential in controlling redox homeostasis and accumulation of specific lipid messengers, including lysophosphatidic acid and prostaglandins. Accordingly, several enzymes and transcription factors controlling lipogenesis and lipid homeostasis are overexpressed in cancer, as we will detail later. These alterations were initially identified in hormone-dependent malignancies such as those affecting breast  and prosIt is well-known that fatty acid neosynthesis is triggered by excess glucose leading to increased mitochondrial citrate concentrations. Citrate is then converted in the cytoplasm into palmitoyl-CoA, the precursor of triglycerides, and phospholipids synthesis. Accumulation of triglycerides may be reverted after starvation when a decrease of the lipogenic intermediate malonyl-CoA reactivates carnitine palmitoyltransferase-1 (CPT-1), thus leading to mitochondrial fatty acid oxidation . de novo fatty acid synthesis is sustained and several lipogenic enzymes are typically upregulated. The consequent burst in lipidogenesis confers the advantage to further exacerbate additional biosynthetic anabolic activities enabling cell growth. The enzymes ATP-citrate lyase (ACL), acetyl-CoA carboxylase (ACC), and the fatty acid synthase (FAS) are frequently overexpressed in cancer cells [in vivo procarcinogenic models of breast [In cancer cells, er cells . Especiaer cells , 48 for er cells . This duf breast  and lungf breast  tissues;f breast , 51–53, f breast . Additiof breast  and its f breast . These mf breast , 57 strof breast –60.Besides, cancer cells show a preferential synthesis of phospholipids  instead of triglyceride . This biTaking into account recent publications about the roles of lipid metabolism in cancer, we are convinced that further discoveries will further strengthen the importance of these pathways in cancer treatment and prevention.Cell death resistance and angiogenesis are two important pathways involved in tumour progression and survival –68. Thesα resulting in angiogenesis activation, cell migration, increased cell survival, and energy metabolism [α [α [Altered mitochondrial bioenergetics and functions play an important role in tumorigenesis by affecting cancer cell metabolism, decreasing mitochondria-dependent apoptosis, and contributing to angiogenesis , 70–72. tabolism , 76. Conolism [α –79. It hsm [α [α .Alterations in mitochondrial function not only influence the cellular metabolic status but also contribute to the control of the redox status of cancer cells. The large amounts of glucose available in the cells are metabolized through the pentose phosphate pathway (PPP) producing nucleosides and generating NADPH , 73.NADPH is essentially involved in redox control protecting cells against ROS. High levels of ROS, as generated in cancer cells, can promote oxidative damage-induced cell death. Therefore, cancer cells maximize their ability to produce NADPH to reduce ROS activity . The difAnother important modulator of the redox status in cancer cells is B-cell lymphoma-2 (Bcl-2) protein that is, overexpressed in a variety of cancer cells . The potAutophagy is another alternative pathway that sustains tumour cell survival. Moreover, autophagy is a major process fueling cell metabolism . It suppImpaired mitochondrial functions, oxidative stress, and autophagy are tightly correlated. Emerging evidence underlines how much autophagy may affect mitochondrial functions and accumulation of ROS . Number The logical consequence of the elucidation of the multiple roles played by altered metabolism in cancer is the exploitation of this knowledge for preventive and therapeutic purposes. The existence of specific patterns of modulations identifies also potential molecular targets for future novel classes of anticancer compounds. In this section, we suggest an overview of natural compounds regulating the most interesting metabolic pathway intermediates.+ [It is essential for a cancer cell to activate the glycolytic pathway to satisfy the anabolic demand in consistent amounts of intracellular glucose. Glucose is carried into cells via specific plasma membrane transporters that lead to glucose internalization by facilitation or active coupling to ion fluxes like the extrusion of Na+ . Annona muricata, also known as Graviola. It has been recently shown that Graviola extracts exert multiple anticancer activities on pancreatic cancer cell models [κB (NF-κB) expression levels and the inhibition of ERK (extracellular-regulated kinase) and Akt activation. Frequently, specific isoforms of glucose transporters are overexpressed in cancer cells. The facilitative glucose transporters (GLUTs) belonging to the solute carrier (SLC2) gene family are frequently overexpressed. Consistent data was published about isoforms 1, 3, 4, and 12. Therefore, targeting abnormal expression or activity of those carriers represents one promising strategy. Several natural compounds have been described as potential modulators of glucose transporters . A critil models . The extDue to the difficulties of specifically targeting glucose transporter expression without affecting many other intracellular pathways, an interesting alternative is to identify molecules that modulate the activity of glucose transporters. In this context several natural compounds deserve attention.Lechevalieria sp. bacterial strain glucopiericidin A (GPA) as a novel inhibitor of glycolysis [Following a natural product screening assay based on crude extracts of microbial origin aimed at identifying new inhibitors of filopodia protrusion , Kitagawa and colleagues have isolated and characterized in the broth of ycolysis . The autFrom plants, polyphenols are interesting bioactive anticancer molecules as several of them have been repeatedly reported to control glucose transporter activity in different cancer cell models; fisetin, myricetin, quercetin, apigenin, genistein, cyaniding, daidzein, hesperetin, naringenin, and catechin are well-known inhibitors of glucose uptake . InvestiRosmarinus officinalis L.), olive (Olea europea L.), or ginger ; it binds to HK and perturbs its association with the voltage-dependent anion channel (VDAC) in cancer cells [Hexokinase (HK) is the enzyme controlling the first enzymatic step of glycolysis, allowing intracellular transformation of glucose via phosphorylation . In cancer cells . This ever cells .bis-quinone alkaloid saframycin, a bacterial product of fermentation, exhibits antiproliferative properties in both adherent and nonadherent cancer cell models. This compound possesses activities comparable to alkylating agents. The group of Myers has shown that saframycin may form a nuclear ternary complex with GAPDH and DNA [Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme catalyzing the conversion of glyceraldehyde-3-phosphate to glycerate 1,3-biphosphate, accompanied by the generation of NADH. There is evidence that GAPDH may play multiple noncanonical functions implicated in cell growth and survival. The  and DNA  involved and DNA . Recently, the embryonic isoform M2 (PKM2) is attracting interest for diagnostic and therapeutic purposes in cancer . EnzymesArnebia sp. and Alkanna tinctoria) have been recently shown as the most potent and specific inhibitors of PKM2 [Currently two main PKM2 targeting strategies are under evaluation. The first attempt consists in identifying compounds inhibiting PKM2. High-throughput screenings based on an enzymatic LDH assay to explore a compound library including molecules approved from the Food and Drug administration (FDA) and purified natural products have led to the identification of three potential chemical structures associated with a potential inhibitory activities on PKM2 . Active  of PKM2 . These c of PKM2 . However of PKM2 , there i of PKM2 . So far Although PKM2 targeting appears a promising area for drug discovery, research remains preliminary. Identification of first chemical scaffolds may be the basis for the discovery of structurally related natural compounds.Saururus cernuus [Lonchocarpus glabrescens [There is no doubt that HIF-1 is a central molecule in the control of the expression of glucose transporters and key glycolytic enzymes as well . Accordi cernuus  and (ii)brescens . These cbrescens . They inSeveral natural compounds have been shown to be able to target mitochondrial metabolism and functions, besides affecting cell death and angiogenesis, both important pathways involved in cancer progression.Curcuma longa, widely used as a spice. Its anticarcinogenic and chemopreventive effects target mitochondrial metabolism and function inducing cell death and angiogenesis in a variety of cancer models [Curcumin is a natural compound extracted from r models . In humar models .Dimethoxycurcumin (Dimc), a synthetic analogue of curcumin, induces cell cycle arrest in S phase and apoptosis in human breast carcinoma MCF-7 cells by affecting mitochondrial dysfunction by oxidative stress. Accordingly, it was observed that DNA damage and apoptosis followed an induction of ROS generation and a reduction of glutathione levels . MitochoCurcumin-induced apoptosis in the colon cancer cell line HCT116 is significantly enhanced by the suppression of mitochondrial NADP(+)-dependent isocitrate dehydrogenase activity which plays an essential role in the cell defense against oxidative stress by supplying NADPH for the antioxidant systems .Hymenocallis littoralis exhibits potent apoptotic activity against a broad panel of cancer cells lines with modest effects on noncancerous cell lines [κB and subsequently downregulation of target genes including interleukin-2 and Bcl-2, leading to cell cycle arrest [Amaryllidaceae alkaloid pancratistatin isolated from the bulb of ll lines . Pancratll lines . In cololl lines . Converse arrest .The cross-talk between mitochondria and the autophagic machinery could be used as a therapeutic strategy. Resveratrol has several beneficial effects such as neuroprotection and cytotoxicity in glioblastoma cell lines. It has been demonstrated that resveratrol induced a crosstalk among autophagy and apoptosis to reduce glioma growth . Indeed,α. It has been published that curcumin plays a pivotal role in tumour suppression via the inhibition of HIF-1α-mediated angiogenesis in MCF-7 breast cancer cells and in HepG2 hepatocellular carcinoma cells [α activity in human KB carcinoma derived from HeLa cells [in vivo studies showed that injecting bavachinin significantly reduced tumour volume in nude mice with KB xenografts [As mentioned earlier, another important pathway in mitochondrial dysfunction involved in tumour progression is HIF-1ma cells , 120. AnLa cells . In humaLa cells . Bavachinografts .Glutamine and glucose are the main carbon sources used by cancer cells to satisfy their anabolic demand. Published data indicate a role for glutamine metabolism within the malignant cell phenotype. Accordingly, several cancer cell lines present a high rate of glutamine consumption and strategies are investigated to target enzymes implicated in this pathway. Inhibiting the activity of glutamate dehydrogenase (GDH) is an effective anticancer strategy as documented in glioblastoma cells with combinatorial treatments with agents depleting cells of glucose or inhibiting specific kinase- dependent pathways . PolypheFAS sustains the altered lipid metabolism in cancer cells. As discussed in Cephalosporium caerulens) acts as noncompetitive inhibitor of the β-ketoacyl synthase domain [in vitro able to affect all the three domains mentioned earlier in a competitive irreversible way [in vivo , tible way ), or stal thiols ). Currenin vitro assays of FAS enzymatic activity [β-ketoacyl reductase domain of FAS [β-ketoacyl reductase domain [in vitro FAS enzymatic activity assay confirmed their ability to inhibit FAS, however, less potently compared to ECGC [κB-mediated pathway [Hibiscus sabdariffa [In this context, the potential identification of new FAS inhibitor from natural compounds is a particularly interesting strategy, especially by investigating compounds of vegetal origin showing the double favorable profile of being regularly consumed in the diet and displaying at the same time hypolipidemic and anticancer activities. Several classes of polyphenols appear as very good candidates. Extracts from green and black tea have been repeatedly proved as lipidogenic inhibitors . Furtheractivity , 135. Thn of FAS , 135. The domain . The flae domain . An in v to ECGC . Tian an to ECGC . Possibl to ECGC  display  to ECGC . It has  to ECGC . This ab pathway . Besides pathway , 142. Gr pathway . Other p pathway ; AMPK ac pathway . The act pathway . Moreovebdariffa . Promisibdariffa . Compounbdariffa . Similarbdariffa . Howeverbdariffa . Targetibdariffa ; moreovebdariffa . These fThe targeting of altered cell metabolism in cancer cell is a promising still unexplored area in anticancer strategies. In this review, we have highlighted that many of these modifications take place at very early steps of carcinogenesis, thus at preneoplastic stages. Therefore, their targeting may be a powerful weapon for chemopreventive purposes. Besides, the literature clearly shows the crucial addiction of cancer cells to several metabolic aberrations to proliferate and survive, further underlining the importance of the targeting of some metabolic-related factors in future anticancer therapies.Identification of specific aberrantly regulated metabolic keynodes, in terms of the expression and/or activity of these factors, delineates the nature of potential pursuable molecular targets. Despite all these considerations, the effective number of agents under investigations for antimetabolic purposes is still very poor and at a very preliminary stage. Good candidates should present a favorable profile ensuring excellent differential toxicity against cancer versus healthy cells, a reduced risk of systemic toxicity, combined to a favorable profile in specific pharmacological properties including bioavailability, half-life, and stability. Many natural compounds have so far been identified as anticancer agents by affecting almost each cancer hallmark . Taking Nature represents an impressively huge “database” of different and diversified molecular scaffolds. Rapid advancement in new screening systems allowing the analysis of large libraries of isolated naturally occurring compounds offers new important and fast tools for the selection of promising antimetabolic compounds especially from dietary origins with reduced side effects. Relatively low costs for their extraction/production in large amounts make them interesting for commercial objectives and represent a good basis for chemical modifications that may further improve their anticancer activities and facilitate their pharmacological use and efficiency.


Drill holes made by predators in prey shells are widely considered to be the most unambiguous bodies of evidence of predator-prey interactions in the fossil record. However, recognition of traces of predatory origin from those formed by abiotic factors still waits for a rigorous evaluation as a prerequisite to ascertain predation intensity through geologic time and to test macroevolutionary patterns. New experimental data from tumbling various extant shells demonstrate that abrasion may leave holes strongly resembling the traces produced by drilling predators. They typically represent singular, circular to oval penetrations perpendicular to the shell surface. These data provide an alternative explanation to the drilling predation hypothesis for the origin of holes recorded in fossil shells. Although various non-morphological criteria  and morphometric studies (quantification of the drill hole shape) have been employed to separate biological from abiotic traces, these are probably insufficient to exclude abrasion artifacts, consequently leading to overestimate predation intensity. As a result, from now on, we must adopt more rigorous criteria to appropriately distinguish abrasion artifacts from drill holes, such as microstructural identification of micro-rasping traces. Predator–prey interaction is one of the key systems to understand the evolution of organisms in both modern and past ecosystems As far as a huge body of literature describe both recent and fossil drill holes In the following, we intend to reconsider the origin of holes commonly recorded in the fossil shells and provide evidence that abrasion may leave holes strongly resembling drilling-predator traces.Nassarius sp.) and brachiopods (Frenulina sanguinolenta) with smooth margins and non-abraded, intact surfaces. These shells were tumbled at 30 revolutions per minute [rpm] for 1 h, 2 h, and 4 h respectively in a barrel containing 1 kg quartz gravels (ca. 20 mm in diameter), 0.3 kg medium-size sand and 3L of artificial sea water. Given a tumbling barrel with a 27-cm-diameter and the rotation speed of 30 [rpm], the tumbling speed approximates wave-action of 0.135 m/s. One hour of tumbling is thus time equivalent to ca. 0.5 km of transport or in-place tumbling within the surf zone. After each of the three tumbling periods, shells were removed from the barrel and examined for any potential damage to the shell.To simulate shell deterioration/abrasion in seawater-agitated environment, three independent tumbling experiments using a rotating barrel LPM-20  were performed at the Faculty of Earth Sciences, Laboratory of Palaeontology & Biostratigraphy of the University of Silesia. No specific permissions were required for performing these experiments. We tested commercially available shells of extant unionid bivalves (Unionidae indet.), gastropods .After each tumbling experiment, shells were only slightly abraded and not significantly damaged. However, in some cases, tumbling induced small singular (only rarely multiple) holes that completely penetrate the shells. These holes are circular, oval or irregular and perpendicular to the shell surface . The majFurthermore, gastropod shells display non-randomly distributed holes , i.e., tWhether tumbling experiments imitate accurately the natural tumbling conditions experienced by shells in the surf zone has been argued In recent years, numerous lines of criteria have been proposed to recognize predatory drill holes. These can be separated into two groups: (i) non-morphological criteria, i.e., evaluation of holes for non-random  Predatory borings are generally defined as commonly single and unhealed perforations perpendicular to the valve surface, having circular to oval shapes, and regular outlines although irregular shapes and outlines have been also noted compare . FurtherAlthough considerable effort has been devoted to establish the reliable identification criteria for predation traces, the present data from tumbling experiments suggest that the existing methods are insufficient to exclude abrasion artifacts. Nearly all features of holes generated on shell surfaces during our tumbling experiments  provide the most promising criteria to accurately identify the drillers


In several species with external fertilization, including frogs, laid unfertilized eggs were found to die by apoptosis outside of the animal body. However, there is no apparent reason for the externally laid eggs to degrade by this process, considering that apoptosis developed as a mechanism to reduce the damaging effect of individual cell death to the whole organism.Xenopus laevis after gonadotropin-induced ovulation. The majority of these eggs exit meiotic arrest within 24 hours of hormone administration. Subsequently, post-meiotic eggs die in the frog genital tract by a well-defined apoptotic process. The hallmarks of egg degradation include prominent morphological changes, cytochrome c release, caspase activation, increase in ADP/ATP ratio, progressive intracellular acidification, egg swelling and all-out proteolysis of egg proteins. The sustained presence of post-apoptotic eggs in the genital tract of ageing frogs evidenced age-associated worsening of apoptotic clearance.Here, we demonstrate that a number of eggs are retained in the genital tract of the African clawed frog Xenopus genital tract provides a clue to the physiological relevance of frog egg apoptosis. It works to eliminate the mature unlaid eggs retained in the animal body after ovulation. Our findings establish egg apoptosis as a major physiological process accompanying ovulation in frogs.The direct observation of egg degradation in the  In vertebrates, immature fertilization incompetent oocytes are naturally arrested in the prophase of the first meiotic division with the intact nuclear envelope and partially decondensed chromatin. During the steroid hormone-induced maturation oocytes progress through the meiotic cell cycle and arrest again in the metaphase of the second meiotic division. High activities of the key meiotic regulators, maturation promoting factor  and cytostatic factor  have been established to maintain metaphase II arrest in mature eggs . FertiliUnfertilized mature eggs have been found to undergo a time-dependent quality loss in the process, which is referred to as postovulatory oocyte deterioration ,6. DelayRecently, it was found that unfertilized starfish eggs naturally deposited outside of the animal body also die by apoptosis -19. In tXenopus eggs laid outside of the frog body die by a well-defined apoptotic process ATP was obtained from Japan Radioisotope Association . Other chemicals were from Wako, Nacalai Tesque , or Sigma .Female frogs of Xenopus female frogs were maintained in dichloride tap water at the ambient temperature (21-23°C). To induce ovulation, frogs were injected hypodermically with 500 IU per animal of hCG in the dorsal lymph sac. The frogs started to lay eggs in 11-12 hours after hormonal stimulation. Eggs retained after ovulation in the genital tract were isolated by frog dissection at different times after hCG injection. Before dissection, frogs were anesthetized on ice followed by rapid decapitation. Microscopic observations of egg morphology were carried out using a stereomicroscope (Leica S8APO). Egg images were acquired with the EC3 stereomicroscope digital color camera and processed with the Leica Application Suite LAS EZ V1.8.Animal handling was carried out in accordance with the guidelines of the Kobe University Animal Experimentation Regulations. The study was approved by the Institutional Animal Care and Use Committee . The frogs were handled under strict laboratory rules. c release assay, pH measurements, immunoblotting, determination of ADP/ATP ratio, protein assay and protein kinase assay were performed as detailed elsewhere [For biochemical analyses, eggs were mildly dejellied with 1% cysteine. Caspase 3 activity assay, cytochrome lsewhere ,35.Protein SDS PAGE and gel staining with Coomassie Brilliant Blue were carried out as described previously . Egg diaCSF: cytostatic factor; GVBD: germinal vesicle breakdown; hCG: human chorionic gonadotropin; MAPK: mitogen-activated protein kinase; MPF: maturation promoting factorThe authors declare that they have no competing interests related to the manuscript.AAT designed the research, performed the experiments and wrote the paper. SI performed the experiments and analyzed data. TI and YF contributed critical comments and suggestions. All authors read and approved the final manuscript.


Rec8, and acquire fewer Spo11-catalyzed DNA double-strand breaks. Given that crossovers too near or too far from centromeres are detrimental to homolog disjunction and increase the incidence of aneuploidy, our data suggest that chromosome size may have a direct role in regulating the fidelity of chromosome segregation during meiosis.Synthetic genetic array (SGA) analysis automates yeast genetics, enabling high-throughput construction of ordered arrays of double mutants. Quantitative colony sizes derived from SGA analysis can be used to measure cellular fitness and score for genetic interactions, such as synthetic lethality. Here we show that SGA colony sizes also can be used to obtain global maps of meiotic recombination because recombination frequency affects double-mutant formation for gene pairs located on the same chromosome and therefore influences the size of the resultant double-mutant colony. We obtained quantitative colony size data for ~1.2 million double mutants located on the same chromosome and constructed a genome-scale genetic linkage map at ~5 kb resolution. We found that our linkage map is reproducible and consistent with previous global studies of meiotic recombination. In particular, we confirmed that the total number of crossovers per chromosome tends to follow a simple linear model that depends on chromosome size. In addition, we observed a previously unappreciated relationship between the size of linkage regions surrounding each centromere and chromosome size, suggesting that crossovers tend to occur farther away from the centromere on larger chromosomes. The pericentric regions of larger chromosomes also appeared to load larger clusters of meiotic cohesin  Synthetic genetic array (SGA) analysis provides an automated method for constructing yeast double mutants and mapping genetic interaction networks  tend to occur farther away from the centromere on larger chromosomes, which may influence chromosome segregation and aneuploidy events.Supporting Information, File S1, containing the SGA-based genetic distances (SGA-GD), is available at http://boonelab.ccbr.utoronto.ca/data/baryshnikova_2013/. A set of 16 files, one for each chromosome, contains the SGA-GD between the indicated loci. Rows and columns correspond to query and array mutants, respectively. Multiple experiments, involving the same query locus, appear as duplicated rows in each file.SGA experiments were conducted as described in The recombination rate between two loci often is expressed in terms of their genetic distance, which is measured in centimorgans (cM) and refers to the average number of CO events occurring between the loci in a single meiosis . Any difference between the observed (ijf) and the expected (if × jf) double mutant colony size must be due to either genetic interactions or genetic linkage. Because genetic interactions are rare and do not normally depend on physical distance between loci, the average colony size of double mutants involving genes located in close proximity to one another should only reflect genetic linkage, whereas the contribution of genetic interactions can be considered negligible (ijf = if × jf).Using SGA data, we estimated the relative fraction of recombinant progeny for each double mutant as:gligible . A similRecombinant fraction R counts the number of recombinant spores relative to all spores generated by meiosis and can be used as a measure of recombination among genomic loci. However, R often underestimates the true recombination rate because it does not account for recombination events that do not produce double mutants. For example, multiple CO events produce a parental arrangement of alleles and the resulting meiotic products do not contribute to recombinant frequency.i recombination events follows the Poisson distribution:m is the mean number of recombination events in the region per meiosis. Haldane’s mapping function assumes that multiple CO events occur independently from each other and do not experience interference . A genetic linkage map G for chromosome C was generated as a n × n matrix, where n is the total number of bins in C, and the value Gij corresponds to the average of SGA-based genetic distances for query-array gene pairs where queries belong to bin i and arrays belong to bin j. The consolidated genetic linkage map G′  was calculated by averaging query-array and array-query genetic linkage maps for the same positions:Figure S3). In addition, the left arms of chromosomes V and XIV, harbor two of the markers used during the SGA double mutant selection: YEL063C (CAN1) and YNL268W (LYP1). As a result, all SGA screens show linkage in the corresponding areas of chromosomes V and XIV and gene-specific linkages cannot be reported .Each chromosome was split into a set of consecutive nonoverlapping bins of 5 kb each. Query and array genes were assigned to bins based on their chromosomal position, as reported by the We estimated the recombination frequency at each position x along the chromosome by computing the average SGA-based genetic distance within the interval , corresponding to a 25-kb interval centered on position x (5 bins × 5 kb/bin). The resulting profile of recombination frequency was smoothed using a moving average filter over five consecutive positions.HIS2, HIS4, ARG4, CYS3, DED81, ARE1-IMG1, CDC19, and THR4; data not shown).We identified 347 putative recombination hotspots defined as local maxima of recombination frequency, measured in SGA-GD per kilobase, that were greater than the average genome recombination frequency. The distribution of these peaks coincided well with known genomic loci associated with high levels of meiotic recombination . For exaSpo11 DNA binding . For example, 65% and 77% of hotspots reported by Figure S4).Our data showed good precision and sensitivity in detecting recombination hotspots reported in other studies (cis-pairs (located on the same side of the centromere) and trans-pairs (located on opposite sides on the centromere). Gene pairs in each group were then distributed into discrete 5-kb bins according to their physical distance. Within each bin, genetic distances were averaged. The extent of centromere linkage was computed as the physical distance of smallest (closest to the centromere) bin of trans-pairs where the genetic distance between loci was on average equal or greater than 50 SGA-GD.All gene pairs located on the same chromosome were divided into Table S1. Linkage around the centromere was defined as the shortest physical distance between two hotspots located on opposite sides of the centromere. As a control for centromere-unrelated linkage, we calculated the average physical distance between any pair of consecutive hotspots.Data relative to the location of recombination hotspots were downloaded from the supplementary websites of the respective publications, as indicated in Saccharomyces Genome Database . Linkage around the centromere was defined as the shortest physical distance between two genetically independent loci (50 cM) located on opposite sides of the centromere. As a control for centromere-unrelated linkage, we calculated the expected physical distance between two unlinked loci by using the average number of centimorgans per kilobase reported for each chromosome at http://www.yeastgenome.org/pgMaps/pgMap.shtml.In addition, a genetic map was downloaded from the p-values between chromosome size and the estimated extent of centromere-related and centromere-unrelated linkage . Given that a number of published studies reported an overall increase in meiotic recombination rates for the four smallest chromosomes . In contrast, centromere-related linkage was generally unaffected .We computed Pearson correlation coefficients and the associated significance Table S1). Profiles were smoothed using a moving average filter applied across 25 consecutive positions. The extent of centromere-bound cohesin clustering was measured as the width of the centromere-centered peak of cohesin binding. Peak width was defined as the distance between the two farthest chromosomal positions, on either side of the centromere, where cohesin binding was greater than global genomic average .We obtained quantitative profiles of meiotic cohesin binding from two recent genome-wide studies  and double-mutant fitness . While double-mutant fitness defects generally are rare and independent from chromosomal position .In SGA analysis, double-mutant colony size reflects both the efficiency of double mutant formation (position . For linFile S1). Colony sizes were measured in pixel units from digital images of double-mutant plates . Using this frequency, we calculated the genetic distance between the corresponding loci, which is referred to as SGA-based genetic distance, or SGA-GD. A unit of SGA-GD is comparable with a centimorgan, a widely used measure of genetic linkage and recombination frequency. A genetic distance of 50 SGA-GD corresponds to a recombinant frequency of 50% and thus is indicative of genomic loci that segregate independently .From a collective set of ~3800 genome-wide SGA experiments, we obtained quantitative double mutant colony sizes for ~1.2 million gene pairs co-localized on the same chromosome . This map revealed large blocks of linkage, where recombination is rare and neighboring loci are inherited jointly . Linkage blocks were separated by relatively shorter stretches of loci that appeared to be genetically unlinked and thus likely to harbor recombination hotspots . Our genetic linkage data were reproducible  and consistent with previous studies of meiotic recombination . In particular, we confirmed the relationship, previously observed in yeast and in other organisms, between recombination events and chromosome size whereby the total number of COs per chromosome follows a simple linear model aL + b, where L is chromosome size, while a and b are constants , consistent with centromeric suppression of meiotic recombination (cis) or on opposite sides (trans) of the centromere . The shortest distance between cis-pairs of unlinked loci generally was constant for all chromosomes and matched the global genomic average of 35 kb, with the exception of the four smallest chromosomes , whose average recombination rate is greater, as documented previously , including large-scale mapping of individual CO events  (Spo11-bound oligonucleotides (Spo11-oligos), a byproduct of an early step in meiotic DSB repair and an established readout for the occurrence of a DSB  by of a DSB . For insFigure S1), consistent with the fact that not all meiotic DSBs are repaired via the CO-generating inter-homolog repair pathway . In contrast, for mitotic cohesion, the centromere association of Mcd1/Scc1 does not show size dependent variation  sister chromatids remain associated with one another, whereas homologs segregate to opposite poles. The accuracy of this process depends on the persistent centromeric cohesion and the formation of interhomolog COs, which facilitate homolog alignment, orientation and bipolar attachment to the meiotic spindle .Frequency and positioning of COs impact chromosome segregation because COs that are too distal from centromeres are not as effective in facilitating bipolar attachment , whereasRec8 association.Here, we show that colony size data associated with linked gene pairs can be used to build accurate maps of meiotic recombination throughout the yeast genome. Our study differs from previous genomic analysis of meiotic recombination in that we obtained our data from an isogenic strain, rather than a hybrid carrying alleles of two divergent genetic backgrounds  , causing the total number of CO events to depend directly on chromosome size; the other CO type occurs at a constant rate per chromosome (parameter b) and thus is chromosome-size independent. Although the relative contribution of each type of CO events is still unclear, this model implies that, because of their small size, the shortest chromosomes would be relatively enriched for the b-type CO events and present a greater total recombination rate per kilobase, a trend that was indeed observed by earlier studies . Regardless of the mechanism, our data points to the evolution of a balanced system, where the need to exclude COs from centromeres to ensure sister centromere cohesion and homolog centromere pairing creates a tendency for incorrect kinetochore-spindle attachment that is subsequently corrected by the spindle checkpoint (There is a precedent for size-dependent loading of chromosomal-bound proteins: the extent of eckpoint .


Although motor imagery could improve motor rehabilitation, the detailed neural mechanisms of motor imagery cognitive process of stroke patients, particularly from functional network perspective, remain unclear. This study investigated functional brain network properties in each cognitive sub-stage of motor imagery of stroke patients with ischemic lesion in left hemisphere to reveal the impact of stroke on the cognition of motor imagery. Both stroke patients and control subjects participated in mental rotation task, which includes three cognitive sub-stages: visual stimulus perception, mental rotation and response cognitive process. Event-related electroencephalograph was recorded and interdependence between two different cortical areas was assessed by phase synchronization. Both global and nodal properties of functional networks in three sub-stages were statistically analyzed. Phase synchronization of stroke patients significantly reduced in mental rotation sub-stage. Longer characteristic path length and smaller global clustering coefficient of functional network were observed in patients in mental rotation sub-stage which implied the impaired segregation and integration. Larger nodal clustering coefficient and betweenness in contralesional occipitoparietal and frontal area respectively were observed in patients in all sub-stages. In addition, patients also showed smaller betweenness in ipsilesional central-parietal area in response sub-stage. The compensatory effects on local connectedness and centrality indicated the neuroplasticity in contralesional hemisphere. The functional brain networks of stroke patients demonstrated significant alterations and compensatory effects during motor imagery. Motor imagery has been employed in neurological rehabilitation to improve the overall behavior performance after stroke Until now, the detailed neural mechanisms of motor imagery of stroke patients remain unclear since few studies focused on its cognitive process. Our previous study, to the best of our knowledge, was the only report on the cognitive process of motor imagery of stroke Eleven stroke patients  with ischemic stroke lesion in left hemisphere  from 32 Ag-AgCl electrodes  at a sampling rate of 1000 Hz and impedance below 5 kΩ at each electrode. The electrode FCz served as the default reference, and EEG signals were further offline re-referenced to the average of the electrodes at the left and right mastoids. Horizontal and vertical electrooculograms (EOGs) were also recorded for rejecting artifacts due to eye movements. EOG contaminations in EEG were removed by independent component analysis implemented in Brain Vision Analyzer  EEG preprocessing was performed offline using Brain Vision Analyzer . Only EEG signals for correctly responded stimuli were included in subsequent analysis. Artifact-free EEG signals were segmented into trials of 1200 ms each starting from the onset of stimulus picture. All trials were further filtered into beta band (13–30 Hz), which was reported to be relevant to motor cognition Phase synchronization (PS) analysis has been commonly used to quantify the association between neural oscillations and examine the large-scale integration of neural activity L), which was the average of all the interactions within the left hemisphere; (2) the right intra-hemispheric PSI (denoted by PSIR), which was the average of all the interactions within the right hemisphere; and (3) the inter-hemispheric PSI (denoted by PSII), which was the average of all the interactions between two hemispheres.In each cognitive sub-stage, a 28-by-28 averaged associate matrix With a preset threshold For weighted network with In analysis of weighted brain network, the path length between node The characteristic path length  of brain network after stroke, the clustering coefficient  were used to test the statistical significance in this study. GROUP (Controls vs. Patients) was between-subjects factor for all statistical analysis. For ANOVA analysis of PSIs in each cognitive sub-stage, HEMISPHERE (Left-Hemisphere vs. Right-Hemisphere vs. Inter-Hemisphere), ANGLE  and HAND (Left Hand vs. Right Hand) were within-subjects factors. For ANOVA analysis of global network parameters (I) were significantly smaller than intra-hemispheric PSIs (PSIL and PSIR) during visually encoding the stimulus  = 88.057, p<0.001)  = 16.333, p = 0.001) . Furtherp<0.001) . Signifip<0.001) . In addip<0.001) . No signI were significantly smaller than PSIL and PSIR  = 85.797, p<0.001), which was also because PSIand PSIR . In addiand PSIR . Other fIn short, phase synchronizations in stroke patients were significantly impaired particularly when patients mentally rotated the hand pictures. During response cognitive process, patients showed larger phase synchronization for affected hand than unaffected hand.Statistical t-test of overall global network properties  . In addificantly . All theMain effects of factors on clustering coefficient  . Main efb-stages , indicatb-stages . Stroke b-stages . In End b-stages .ANOVA results of nodal betweenness  Neural synchrony was impaired in stroke patients in mental rotation sub-stage. (ii) Functional brain networks of stroke patients demonstrated smaller global clustering coefficient and longer characteristic path length compared with control subjects in mental rotation sub-stage. (iii) Stroke patients had larger nodal clustering coefficient and betweenness in contralesional parietal and frontal area respectively in all sub-stages. In addition, lower betweenness of stroke patients in ipsilesional central area was observed in response sub-stage. In summary, network of stroke patients showed the reduction of neural synchrony and the alterations in both global and nodal properties of the cortical connectivity. The influence of stroke on functional network of motor imagery cognition would be discussed from these three perspectives.The larger angle that the visual stimulus was rotated, the larger PSI was found across the cortex, indicating higher synchronization level for more difficult task, i.e., “angle effect” in mental rotation sub-stage. Neural synchrony reduced significantly in stroke patients when they mentally rotated the hand pictures. Previous studies on different lesion locations also showed significant synchronization reduction in stroke patients, and strongly suggested that functional outcome after stroke could be predicated by how brain areas were coupled Previous studies showed that the functional network after stroke had lower network efficiency or local connectedness during both resting-state and movement execution et al. found both skilled and unskilled movement elicited more activations in patients than control subjects in the contralesional primary sensorimotor cortex, ventral premotor cortex, supplementary motor area and occipitoparietal cortex, which implied a similar neuroplastic reorganization in contralesional hemisphere et al. also observed increase of contralesional activity, from both focal activation and connectivity perspectives by EEG, and they considered the increase of contralesional activities might facilitate the control of recovered motor function at a higher-order processing level Nodal clustering coefficient represented the density that a node’s neighbors were connected, representing the functional segregation property of network. In this study, neuroplastic reorganization in contralesional hemisphere of stroke patients, i.e., compensatory effect of contralesional occipitoparietal cortex on the functional segregation, was observed. In a fMRI study of chronic stroke patients, Schaechter et al. also investigated the “communicability” of stroke patients, which indicated the ability of information transfer across network. They found reduced ipsilesional communicability in regions surrounding the lesions Nodal betweenness reflected the importance and centrality of a node in the information transfer over whole network. Larger betweenness meant more shortest paths passed through the corresponding node and greater centrality in global information transfer over the whole network In this study, only 28-channel EEG data from eleven patients were used to investigate stroke lesion impact on functional network during MRT. Besides, no neuropsychological test was administered to investigate putative impairments in body representation. Although all patients were selected with stroke in left hemisphere, the lesion locations were not at exactly the same location, otherwise, the number of the subjects would be too few to have statistical analysis. To understand the role of a specific region of brain on the cortical functional network for motor imagery cognitive process, a larger sample size and more stringent restrictions of lesion locations should be considered, which would be our next step study.This study provided the details of functional brain network alterations after ischemic stroke in each cognitive sub-stage during motor imagery. In summary, neural synchrony during motor imagery task was impaired after stroke. Stroke patients reflected a lower capability to integrate the communication between widely separated brain regions and lower tendency to have dense local connectedness in brain networks. Stroke patients also showed neuroplastic reorganization in contralesional hemisphere.