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Spermatogenesis is supported by various posttranslational modifications. There is growing evidence supporting a crosstalk between sumoylation and phosphorylation in different cell types. We have recently shown that inhibition of global sumoylation with a sumoylation inhibitor (Ginkgolic acid, GA) arrested purified mouse spermatocytes in vitro ; the spermatocytes could not condense chromatin and disassemble the synaptonemal complex. Our data have also revealed that some kinases regulating the meiotic prophase (PLK1 and AURKB) were inhibited upon the inhibition of sumoylation. Nevertheless, specific phosphorylated targets affected by the inhibition of sumoylation have not been identified. To address this gap, in this study, we performed a comparative phospho-proteome analysis of the control spermatocytes and spermatocytes treated with the GA. Our analysis has narrowed down to several proteins implicated in the regulation of cell cycle and/or meiosis. Two of these targets, NPM1 and hnRNPH1, were studied further using western blotting in both cell lines and primary cells. Decrease in sumoylaion-dependend phosphorylation of NPM1 on Ser125 regulated by AURKB can be a contributing factor to the inability of spermatocytes to condense chromatin by the end of the prophase and should be studied further. • Downregulation of sumoylation causes changes in phosphorylation of important spermatocyte proteins. • Sumoylation regulates NPM1 in GC-1 spermatogonia and mouse spermatocytes. • Sumoylation regulates hnRNPH1 in GC-1 spermatogonia mouse spermatocytes. • Phosphorylation of NPM1 on Ser125 regulated by AURKB should be studied further. [ABSTRACT FROM AUTHOR]

The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway involved in cell proliferation and survival. The three-layered MAPK signaling cascade is initiated upon RTK and RAS activation. Three RAF isoforms ARAF, BRAF and CRAF, and their downstream MEK1/2 and ERK1/2 kinases constitute a coherently orchestrated signaling module that directs a range of physiological functions. Genetic alterations in this pathway are among the most prevalent in human cancers, which consist of numerous hot-spot mutations such as BRAF V600E. Oncogenic mutations in this pathway often override otherwise tightly regulated checkpoints to open the door for uncontrolled cell growth and neoplasia. The crosstalk between the RAF-MEK-ERK axis and other signaling pathways further extends the proliferative potential of this pathway in human cancers. In this review, we summarize the molecular architecture and physiological functions of the RAF-MEK-ERK pathway with emphasis on its dysregulations in human cancers, as well as the efforts made to target the RAF-MEK-ERK module using small molecule inhibitors. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a potentially fatal chronic autoimmune disease which is underlain by complex dysfunction of the innate and adaptive immune systems. Although a series of well-defined genetic and environmental factors have been implicated in disease etiology, neither the development nor the persistence of SLE is well understood. Given that several disease susceptibility genes and environmental factors interact and influence inflammatory lineage specification through metabolism, the field of immunometabolism has become a forefront of cutting edge research. Along these lines, metabolic checkpoints of pathogenesis have been identified as targets of effective therapeutic interventions in mouse models and validated in clinical trials. Ongoing studies focus on mitochondrial oxidative stress, activation of the mechanistic target of rapamycin, calcium signaling, glucose utilization, tryptophan degradation, and metabolic cross-talk between gut microbiota and the host immune system. • Systemic Lupus Erythematosus is a potentially fatal autoimmune disease of unknown etiology. • Lupus pathogenesis is influenced by host genetic factors and the environment. • Metabolism represents a vital connection between the host genome and the environment. • This review pinpoints therapeutically targetable metabolic checkpoints of lupus pathogenesis. [ABSTRACT FROM AUTHOR]

The crosstalk between the estrogen receptor (ER) and NF-κB signalling pathways has merged in vertebrates and plays a key role in the control of genes involved in inflammation, cell proliferation and apoptosis. However, such crosstalk between the endocrine and immune systems needs to be explored in lower invertebrates. In this study, we identified a 2856-bp homologue of the estrogen receptor from Hong Kong oyster (Ch ER), containing a 5′ untranslated region (UTR) of 234 bp, a 3' UTR of 387 bp, and an open reading frame (ORF) of 2235 bp. We observed that overexpression of Ch ER suppressed Ch Rel-dependent NF-kappaB (NF-κB) activation in the HEK293T (human embryonic kidney 293T) cell line, and depletion of Ch ER in vivo resulted in upregulation of two NF-κB-responsive marker genes, namely, TNF-α and IL-17 , which confirmed its potential role in controlling NF-κB signalling. Furthermore, an EMSA (electrophoretic mobility shift assay) showed that Ch ER could negatively regulate the binding of Ch Rel to NF-κB probe-responsive elements. Serial domain requirement analysis showed that both region C (DNA-binding domain) and region E (ligand-binding domain) of Ch ER were essential for mediating the crosstalk underlying Ch ER-dependent NF-κB suppression. In conclusion, we demonstrate for the first time the negative regulatory role of the ER in NF-κB signalling in oysters, strongly indicating the presence of complex crosstalk between the endocrine and immune systems in lower marine molluscs. ● A gene from Crassostrea Hongkongensis encoding estrogen receptor (ER) was identified. ● Ch ER suppressed the Ch Rel-dependent NF-κB activation. ● Region C (DNA binding domain) and region E (ligand binding domain) of Ch ER are essential to mediate the crosstalk underlying Ch ER-dependent NF-κB suppression [ABSTRACT FROM AUTHOR]

Abstract Cytokinin (CK) signaling has been shown to play important roles in callus formation and various developmental processes by analyzing different CK-responsive mutants, including the ahk2 ahk3 (AHK , Arabidopsis histidine kinase) double mutant. Recently, an F-box protein, called MAX2 (more axillary growth 2) was identified as a key component regulating many growth and developmental processes through the strigolactone and/or karrikin pathways. However, the function of MAX2 signaling in callus formation, seed size and yield, as well as the effects of its crosstalk with CK signaling on plant growth and development remain elusive. Here, we constructed the triple mutant ahk2 ahk3 max 2 and analyzed the callus formation and various phenotypic traits of all three max2 , ahk2 ahk3 and ahk2 ahk3 max2 mutants along with wild-type (WT) during plant growth and development. We showed that MAX2 acted as a negative regulator of seed size, but positive regulator of callus formation and seed yield albeit at lower degree, as the CK receptor kinases. Importantly, our comparative analyses revealed interactive effects of CK and MAX2 pathways on primary root growth, hypocotyl elongation and shoot branching. However, these two pathways might independently regulate root hair growth, leaf development, leaf senescence, plant height, seed size, seed yield and callus formation. Our findings provide not only evidence for the involvement of MAX2 in regulating callus formation, seed size and seed yield, but also a better understanding of the relationship between CK and MAX2 signaling pathways in many key developmental processes across a plant's life. Highlights • A triple mutant was created for studying crosstalk between cytokinin (CK) and MAX2 pathways. • The two pathways interactively regulate root and hypocotyl growth and shoot branching. • The two pathways independently affect leaf and shoot growth, senescence, seed size and yield. • MAX2 was shown for the first time to act as a positive regulator in callus formation. • Callus formation is independently regulated by CK and MAX2 signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract Nitric oxide (NO) is an essential signal molecule to maintain cellular homeostasis in uni and pluricellular organisms. Conceptually, NO intervenes as much in sustaining basal metabolic processes, as in firing cellular responses to changes in internal and external conditions, and also in guiding the return to basal conditions. Behind these unusual capabilities of NO is the chemistry of this molecule, an unstable, reactive, free radical and short half-life gas. It is a lipophilic molecule that crosses all the barriers that biological membranes can impose. The extraordinary impact that the elucidation of physiological processes regulated by NO has had on plants, is comparable to the consequences of the discovery in 1986 that NO is present in animal tissues, and the following deep studies that demonstrated its biological activity regulating blood pressure. In this review, we have summarized and discuss the main discoveries that have emerged at Mar del Plata University over the past 20 years, and that have contributed to understand part of the biology of NO in plants. Besides, these findings are put in context with the progress made by other research groups, and in perspective, emphasizing that the history of NO in plants has just begun. Highlights • NO is a gaseous, redox‐active and small signal molecule in plants. • NO is a key regulator of plant growth, development and environmental interacting processes. • S-nitrosylation of Cys residues is a PTM of proteins underpinning NO functions. • NOS enzymes have been characterized in microalgae and cyanobacteria. [ABSTRACT FROM AUTHOR]

Abstract Exocrine pancreas insufficiency is common in diabetic mellitus (DM) patients. Cellular stress is a prerequisite in the development of pancreatic pathologies such as acute pancreatitis (AP). The molecular mechanisms underlying exocrine pancreatic ER-stress in DM are largely unknown. We studied the effects of insulin and glucose (related to DM) alone and in combination with cerulein (CER)-induced stress (mimicking AP) on ER-stress unfolded protein response (UPR) in pancreatic acinar cells. Exocrine pancreas cells (AR42J) were exposed to high glucose (Glu, 25 mM) and insulin (Ins, 100 nM) levels with or without CER (10 nM). ER-stress UPR activation was analyzed at the transcript, protein, immunocytochemistry, western blotting, quantitative RT-PCR and XBP1 splicing, including; XBP1, sXBP1, ATF6, cleaved ATF6, IRE1-p, CHOP, Caspase-12 and Bax. Exocrine acinar cells exposed to high Ins or Ins+Glu concentrations (but not Glu alone) exhibited ER-stress UPR, demonstrated by significant increase of transcript and protein levels of downstream markers in the ATF6 and IRE1 transduction arms, including: sXBP1, cleaved ATF6, XBP1, CHOP, IRE1-p and caspase-12. UPR activation resulted in IRE1-p aggregation and nuclear trans-localization of cleaved activated ATF6 and sXBP1. Ins further aggravated UPR when cells were co-challenged with CER-induced stress, exacerbating the effects of CER alone. High Ins levels, typical to type-2-DM, activate the ER-stress UPR in pancreatic acinar cells, through the ATF6 and IRE1 pathways. This effect of Ins in naïve acinar cells further augments CER-induced UPR. Our data highlight molecular pathways through which DM enhances exocrine pancreas pathologies. Highlights • Exocrine pancreas insufficiency is common in diabetic mellitus (DM) patients. • Cellular stress is prerequisite in pancreatic pathologies. • DM activates the ER-stress UPR in pancreatic acinar cells (ATF6 and IRE1 arms). • High insulin levels are the main cause for the DM UPR activation in acinar cells. • In pancreatitis-induced ER-stress state insulin aggravates UPR pro-apoptosis state. [ABSTRACT FROM AUTHOR]

Abstract Alteration in the expression pattern of Nrf-2 and NFκB has been reported in ulcerative colitis (UC) in which functional crosstalk between these two critical pathways has been suggested. The ameliorative potential of the AT1R blocker olmesartan (OLM) on oxidative stress and inflammatory cytokines has received considerable attention in recent years. Acetic acid (AA)-induced UC demonstrates close resemblance to human UC regarding histopathological features and cytokine profile and is associated with local intense immune response, oxidative stress and release of inflammatory cytokines. Therefore, The effect of OLM (1, 5 and 10 mg/kg) administered orally to rats subjected to intra-rectal instillation of 2 ml of 3% AA in saline solution is investigated. The study revealed that OLM ameliorated colon injury and inflammatory signs as visualized by histopathological examination. Levels of colon IL-6, TNF-α, IL-1β, TGF-β, and serum CRP were down-regulated, while the level of colon IL-10 was up-regulated. In a dose-dependent manner, OLM suppressed AA-induced neutrophils accumulation and improved colon anti-oxidant defense machinery. Also, OLM repressed the Bax:BCL-2 ratio and caspase3 expression. The mechanism of these protective effects was found to lay behind its ability to down-regulate gene expression and inhibit phosphorylation and nuclear translocation of p65 subunits. On the other hand, OLM up-regulated gene expression of Nrf-2 and HO-1. In conclusion, our data show that OLM is an Nrf2 activator, NFkB inhibitor and apoptosis inhibitor in an experimental model of ulcerative colitis. Overall, the study indicates that OLM shows promise as a potential therapy for the treatment of human inflammatory bowel diseases. Graphical abstract Unlabelled Image Highlights • Olmesartan protected from ulcerative colitis and decreased inflammatory markers. • Olmesartan decreased NFĸB P-P65:P65 ratio and increased protein expression of IκBα. • Olmesartan decreased NFĸB p65 and increased Nrf-2 and HO-1 mRNA expression. • Olmesartan decreased Bax:BCL-2 ratio and caspase3 expression. • Olmesartan decreased MPO and increased anti-oxidant capacity. [ABSTRACT FROM AUTHOR]

Abstract The current review focuses on the significant role of nitric oxide (NO) in modulating ethylene-induced fruit ripening responses in plants. In this context, hydrogen sulfide (H 2 S) and melatonin mediated crosstalk mechanisms have been discussed with recent updates. Physiological and biochemical events associated with climacteric fruit ripening involves a plethora of effects mediated by these biomolecules. In the last few years of progress in fruit ripening physiology, the involvement of hydrogen sulfide in relation to NO remains as a nascent field of research. The importance of nitric oxide as a freely diffusible and membrane permeable biomolecule leads to its applications in post-harvest fruit storage. The process of field to market transition of edible fruits involves various intermediate stages of post-harvest storage and transport. Fruits harvested in the pre-climacteric stage are intended to be stored and transported for longer durations. However, this does not confer proper development of aroma and flavor in the post-harvest stages. Nitric oxide and ethylene crosstalk is mediated by hydrogen sulfide and melatonin activity which regulate various metabolic pathways associated with fruit ripening. A surge in the reactive nitrogen species (RNS), sugar metabolism, and plastid biogenesis are the plausible effects of NO-ethylene crosstalk. NO-mediated regulations of carbon metabolism and phytohormone levels are essential components of fruit ripening process. Melatonin by the virtue of its functional group possesses strong anti-oxidative properties. Recent updates suggest crosstalk mechanisms associated with melatonin-ethylene and nitric oxide in plants. The present review briefly summarizes the current understandings of fruit ripening physiology manifested by the effects of NO, H 2 S and melatonin signaling. The agri-horticultural applications of exogenous NO/H 2 S donors and melatonin treatment impose major benefits for delaying postharvest fruit senescence. Highlights • Nitric oxide mediated modulation of fruit ripening. • Hydrogen sulphide and nitric oxide crosstalk associated with inhibition of ethylene biosynthesis. • Melatonin induced amelioration of fruit senescence and elevated antioxidative defense. • Melatonin – nitric oxide interaction and probable formation of nitrosomelatonin during fruit ripening. • Applications of exogenous nitric oxide, hydrogen sulfide and melatonin in post-harvest management of fruits. [ABSTRACT FROM AUTHOR]

The cell death mechanisms have a long history of being evaluated in diseases and pathological events. The ability of triggering cell death is considered to be a promising strategy in cancer therapy, but some mechanisms have dual functions in cancer, requiring more elucidation of underlying factors. Colorectal cancer (CRC) is a disease and malignant condition of colon and rectal that causes high mortality and morbidity. The autophagy targeting in CRC is therapeutic importance and this cell death mechanism can interact with apoptosis in inhibiting or increasing apoptosis. Autophagy has interaction with ferroptosis as another cell death pathway in CRC and can accelerate ferroptosis in suppressing growth and invasion. The dysregulation of autophagy affects the drug resistance in CRC and pro-survival autophagy can induce drug resistance. Therefore, inhibition of protective autophagy enhances chemosensitivity in CRC cells. Moreover, autophagy displays interaction with metastasis and EMT as a potent regulator of invasion in CRC cells. The same is true for ferroptosis, but the difference is that function of ferroptosis is determined and it can reduce viability. The lack of ferroptosis can cause development of chemoresistance in CRC cells and this cell death mechanism is regulated by various pathways and mechanisms that autophagy is among them. Therefore, current review paper provides a state-of-art analysis of autophagy, ferroptosis and their crosstalk in CRC. The nanoparticle-mediated regulation of cell death mechanisms in CRC causes changes in progression. The stimulation of ferroptosis and control of autophagy (induction or inhibition) by nanoparticles can impair CRC progression. The engineering part of nanoparticle synthesis to control autophagy and ferroptosis in CRC still requires more attention. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Mitochondria play essential roles in cellular bioenergetics, biosynthesis, and apoptosis. During the process of respiration and oxidative phosphorylation, mitochondria utilize oxygen to generate ATP, and at the same time, there is an inevitable generation of reactive oxygen species (ROS). As excess ROS create oxidative stress and damage cells, the proper function of the antioxidant defense system is critical for eukaryotic cell survival under aerobic conditions. Nuclear factor, erythroid 2-like 2 (Nfe2l2/Nrf2) is a master transcription factor for regulating basal as well as inducible expression of multiple antioxidant proteins. Nrf2 has been involved in maintaining mitochondrial redox homeostasis by providing reduced forms of glutathione (GSH); the reducing cofactor NADPH; and mitochondrial antioxidant enzymes such as GSH peroxidase 1, superoxide dismutase 2, and peroxiredoxin 3/5. In addition, recent research advances suggest that Nrf2 contributes to mitochondrial regulation through more divergent intermolecular linkages. Nrf2 has been positively associated with mitochondrial biogenesis through the direct upregulation of mitochondrial transcription factors and is involved in the mitochondrial quality control system through mitophagy activation. Moreover, several mitochondrial proteins participate in regulating Nrf2 to form a reciprocal regulatory loop between mitochondria and Nrf2. Additionally, Nrf2 modulation in cancer cells leads to changes in the mitochondrial respiration system and cancer bioenergetics that overall affect cancer metabolism. In this review, we describe recent experimental observations on the relationship between Nrf2 and mitochondria, and further discuss the effects of Nrf2 on cancer mitochondria and metabolism. Highlights • Nrf2 maintains mitochondrial redox homeostasis by upregulating multiple antioxidants proteins. • Nrf2 is positively associated with mitochondria biogenesis and respiration, and energy production. • Nrf2 is involved in the mitochondrial quality control system through mitophagy activation • Several mitochondrial proteins regulates Nrf2 to form a reciprocal regulatory loop. [ABSTRACT FROM AUTHOR]

Abstract The tumor microenvironment can be hypoxic, acidic, and deficient in nutrients, thus causing the metabolism of tumor cells as well as the neighboring stromal cells to be remodelled to facilitate tumor survival, proliferation, and metastasis. Abnormal tumor lipid metabolism is a fairly new field, which has received attention in the past few years. Cross-talk between tumor cells and tumor-associated stromal cells modulates the high metabolic needs of the tumor. Fatty acid turnover is high in tumor cells to meet the energy as well as synthetic requirements of the growing tumor. Lipolysis of lipids stored in lipid droplets was earlier considered to be solely carried out by cytosolic lipases. However recent studies demonstrate that lipophagy (autophagic degradation of lipids by acidic lipases) serves as an alternate pathway for the degradation of lipid droplets. Involvement of lipophagy in lipid turnover makes it a crucial player in tumorigenesis and metastasis. In this review we discuss the metabolic reprogramming of tumor cells with special focus on lipid metabolism. We also address the lipid turnover machinery in the tumor cell, especially the lipophagic pathway. Finally, we integrate the current understanding of lipophagy with tumor lipid metabolism. Highlights • Alterations in lipid metabolism modulate tumor development and progression. • Lipophagy plays a central role in regulating lipid homeostasis in tumors. • The role of lipophagy in cancer remains underappreciated. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNA) are non-coding RNAs characterized by a closed-loop structure providing increased stability and enhancing their ability to compete with messenger RNAs (mRNA) for microRNA (miRNA) binding. An important open question is if circRNA plays a physiological role in the cells regulating critical cellular functions. We address this question with a combination of theoretical modeling and experimental analysis. Theoretically, we investigated two possible scenarios, one in which circRNAs act as sponges for miRNAs but there is no other relation between the two RNAs and the other one where circRNAs are co-generated with their corresponding mRNAs. We thus compared the results with data reporting the level of circRNAs (ZEB1, CANCX, ABCC1) modulating specific miRNAs in 27 cell lines. Due to the high stability of circRNAs, we show that a miRNA mediated cross-talk between circRNA and mRNA appears for a broad range of physiological parameters. This confirms the relevance of circRNAs in cell regulation, suggesting that they could be used as biomarkers. [ABSTRACT FROM AUTHOR]

Amyloid-β is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-β (Aβο) is now believed to represent the main Amyloid-β species affecting synapse function. Yet, the exact molecular mechanism by which Aβο modifies synapse function remains to be fully elucidated. There is accumulating evidence that glucocorticoid receptors (GRs) might participate in Aβο generation and activity in the brain. Here, we provide evidence for an acute functional cross-talk between Aβ and GRs at hippocampal excitatory synapses. Using live imaging and biochemical analysis of post-synaptic densities (PSD) in cultured hippocampal neurons, we show that synthetic Aβo (100 nM) increases GR levels in spines and PSD. Also, in these cultured neurons, blocking GRs with two different GR antagonists prevents Aβo-mediated PSD95 increase within the PSD. By analyzing long-term potentiation (LTP) and long-term depression (LTD) in ex vivo hippocampal slices after pharmacologically blocking GR, we also show that GR signaling is necessary for Aβo-mediated LTP impairment, but not Aβo-mediated LTD induction. The necessity of neuronal GRs for Aβo-mediated LTP was confirmed by genetically removing GRs in vivo from CA1 neurons using conditional GR mutant mice. These results indicate a tight functional interplay between GR and Aβ activities at excitatory synapses. [ABSTRACT FROM AUTHOR]

Highlights • Molecular mechanisms behind ALI mediated cognitive deficits are not clearly known. • Induction of ALI via two hits cause persistence of lung and systemic inflammation. • Systemic inflammatory factors disrupt BBB resulting in cognitive deficits. • Anti-inflammatory agent improved the BBB disruption/cognitive deficits. • Our two hit model of ALI mimic clinical observations effectively. Abstract Acute lung injury (ALI), a pulmonary inflammatory disorder, is associated with high morbidity and mortality rates. Interestingly, ALI survivors have been reported for some neurocognitive deterioration at/after discharge. However, the molecular factors behind such extra pulmonary manifestation are not clearly known. The present work was designed to investigate lung-brain cross talk in experimental mice for deciphering primary molecular factors that may be involved in ALI-mediated cognitive impairment. ALI was induced in Balb/c mice by intra-tracheal administration of either 0.1 N HCl (2 ml/kg) or LPS (1 mg/kg) as single hits or both agents were administered successively to mimic the ‘two hit’ model. Interestingly two hit-mediated ALI resulted in exaggerated inflammatory response as reflected by increased pulmonary neutrophils and inflammatory factors (TNF-α/IL-1β/IL-6). Additionally, two hits resulted in delayed resolution of lung inflammation and was coupled with persistent decline in memory, as assessed by Morris water maze test. Further, two hits elevate serum levels of TNF-α/IL-1β which was associated with compromised blood brain barrier (BBB), as evident by decreased expression of occludin/claudin-5 and consequent Evans-blue extravasation in hippocampus 1 week post injury. Finally, dexamethasone protects against the two hit mediated cognitive impairment by lowering the pro-inflammatory factors (TNF-α/IL-1β) both in lungs and blood. Overall, we report for the first time that ‘two hit’ mediated ALI cause persistent cognitive impairment in mice partly via up-regulating systemic expression of TNF-α/IL-1β that may disrupt BBB and hence the model may be a useful tool to examine the lung-brain cross-talk at the molecular level for exploring newer therapeutics. [ABSTRACT FROM AUTHOR]

Abstract Proper regulation of stomatal movement in response to various environmental stresses or developmental status is critical for the adaptation of many plant species to land. In plants, abscisic acid (ABA)-induced stomatal closure is a well-adapted method of regulating water status. In addition to ABA, we previously showed that plant-specific steroidal hormone, brassinosteroid (BR), also induces stomatal closure; however, BR modulates ABA-induced stomatal closure negatively at high concentrations. In this study, we further investigated the cross-talk between ABA and BR in relation to stomatal movement. In contrast to previous reports that ABA-induced stomatal closure was inhibited by brassinolide (BL), the most active BR, we showed that BL-induced stomatal closure was enhanced by ABA, indicating that the sequence of ABA or BL treatments led to different results. We found that this phenomenon occurred because the guard cells still had the capacity to be closed further by ABA, as the degree of stomatal closure by BL was always less than that by ABA. We also found that BL-induced stomatal closure required Open Stomata 1 (OST1) activity and the induced expression of OST1 was indifferent to the sequence of ABA and/or BL treatments. In addition, we examined the underlying mechanism by which inhibition of ABA-induced stomatal closure by BL occurred. We revealed that the downregulation of ABA-biosynthetic genes by BL resulted in a lower accumulation of ABA. These results suggested that the regulation of stomatal movement is finely controlled by the combined effects of plant hormones, ABA and BR. Highlights • ABA strengthened BL-induced stomatal closure. • Expression of OST1 was induced by BL, and BL-induced stomatal closure required OST1. • Inhibition of ABA-induced stomatal closure by BR was due to reduced ABA accumulation. [ABSTRACT FROM AUTHOR]

Duchenne Muscular Dystrophy (DMD) is characterized by muscle extracellular matrix disorganization due to the increased collagen deposition leading to fibrosis that significantly exacerbates disease progression. Fractal dimension analysis is a method that quantifies tissue/cellular disorganization and characterizes complex structures. The first objective of the present study was use fractal analysis to evaluate extracellular matrix disorganization in mdx mice soleus muscle. Next, we mimic a hyper-proliferation of fibrogenic cells by co-culturing NIH3T3 fibroblasts and C2C12 myoblasts to test whether fibroblasts induce disorganization in myoblast arrangement. Here, we show mdx presented high skeletal muscle disorganization as revealed by fractal analysis. Similarly, this method revealed that myoblasts co-cultured with fibroblast also presented cellular arrangement disorganization. We also reanalyzed skeletal muscle microarrays transcriptomic data from mdx and DMD patients that revealed transcripts related to extracellular matrix organization. This analysis also identified Osteoglycin, which was validated as a potential regulator of ECM organization in mdx dystrophic muscles. Our results demonstrate that fractal dimension is useful tool for the analysis of skeletal muscle disorganization in DMD and also reveal a fibroblast-myoblast cross-talk that contributes to “ in vitro ” myoblast disarrangement. [ABSTRACT FROM AUTHOR]

The Hippo signaling pathway is implicated in key aspects of cell proliferation, control of organ size, stem cell functions and tumor suppression. Its functions are primarily mediated either through direct effects on transcription factors to influence target gene expression or through crosstalk with other signaling pathways that regulate multiple physiological activities. Studies are revealing Hippo pathway involvement in diverse functions including renewal of intestinal epithelium, promotion of myocardial cell proliferation, cancer suppression, etc. In this review we discuss Hippo pathway signaling in oral-maxillofacial development and bone remodeling under normal and pathological conditions and highlight promising future research directions. [ABSTRACT FROM AUTHOR]

Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined. Interestingly, the Hh pathway is also activated in Bergmann glia, but the role of Shh signaling in these cells is unknown. In this study, we show that specific ablation of Shh signaling using the tamoxifen-inducible TNC YFP-CreER line to eliminate Shh pathway activator Smoothened in Bergmann glia is sufficient to cause severe cerebellar hypoplasia and a significant reduction in CGNP proliferation. TNC YFP-CreER ; Smo F/- ( Smo CKO ) mice demonstrate an obvious reduction in cerebellar size within two days of ablation of Shh signaling. Mutant cerebella have severely reduced proliferation and increased differentiation of CGNPs due to a significant decrease in Shh activity and concomitant activation of Wnt signaling in Smo CKO CGNPs, suggesting that this pathway is involved in cross-talk with the Shh pathway in regulating CGNP proliferation. In addition, Purkinje cells are ectopically located, their dendrites stunted, and the Bergmann glial network disorganized. Collectively, these data demonstrate a previously unappreciated role for Bergmann glial Shh signaling activity in the proliferation of CGNPs and proper maintenance of cerebellar architecture. [ABSTRACT FROM AUTHOR]

Crosstalk occurs between dyslipidemia and chronic inflammation, which are both precipitants of atherosclerosis. Sterol regulatory element binding proteins cleavage-activating protein (SCAP) plays a key role in regulating cholesterol homeostasis. The present study investigated the effects of SCAP dysfunction on the expression of inflammatory cytokines and lipid metabolism in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assays. The expression of SCAP, HMGCR, pro-IL-1β and N-SREBP2, p65(N) in the nucleus were examined by real-time quantitative RT-PCR and Western blotting. The level of secretary proteins IL-1β, TNF-α and MCP-1 in the supernatants were determined by ELISA. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. Our results demonstrated that over-expression of SCAP significantly increased the expression of HMGCR, pro-IL-1β in the cytoplasm, and mature IL-1β, TNF-α, MCP-1 in the supernatants, while knocking down SCAP dramatically decreased the expression of these molecules. Betulin effectively suppressed the accumulation of intracellular cholesterol in the SCAP over-expressed THP-1 macrophages, but did not affect the expression of inflammatory cytokines, indicating that the pro-inflammatory effect of SCAP was independent of its routine role in regulating cholesterol homeostasis. Furthermore, we investigated the molecular mechanisms mediating the crosstalk between dyslipidemia and inflammatory responses. Knocking down SCAP attenuated LPS-induced IκB phosphorylation and reduced the nuclear level of p65, while over-expression of SCAP increased the nuclear level of p65. Knocking down p65 abolished the proinflammatory effect represented by elevated expression of the inflammatory mediators in the SCAP over-expressed THP-1 macrophages, suggesting that SCAP dysfunction stimulated inflammatory responses via activating the NF-κB signaling pathway. In conclusion, the cholesterol sensor SCAP plays a role in regulating the expression of inflammatory factors such as IL-1β, TNF-α, and MCP-1 in THP-1 macrophages. SCAP mediates the inflammatory response via activating the NF-κB pathway. This new function of SCAP is independent of its role in lipid metabolism. [ABSTRACT FROM AUTHOR]

Recent studies suggest that Day-7 bovine embryo starts to communicate with the uterine epithelium through interferon-tau (IFNT) signaling. However, immune modulatory role of IFNT in the uterus just after the embryo moves from the oviduct is unclear. We aimed to examine the hypothesis that Day-7 bovine embryo secretes IFNT in the uterus, which induces anti-inflammatory response in immune cells. The uterine flush (UF) with multiple embryos was collected from Day-7 donor pregnant cows and peripheral blood mononuclear cells (PBMCs) were then cultured in UF. Transcripts detected in PBMCs revealed that UF from pregnant cows down-regulated pro-inflammatory cytokines ( TNFA, IL1B) and up-regulated anti-inflammatory cytokine ( IL10) expression, with activation of interferon-stimulated genes ( ISGs; ISG15, OAS1) as compared with UF from non-pregnant cows. An addition of specific anti-IFNT antibody to the UF inhibited the effect on PBMCs, indicating that IFNT is a major factor for such immune modulation. The observation that conditioned media from bovine uterine epithelial cells both stimulated with IFNT in vitro and supplemented with fresh IFNT induced similar PBMCs gene expression, confirming that IFNT directly acts on this immune crosstalk. This study shows that IFNT secreted from Day-7 embryo in vivo generates anti-inflammatory response in immune cells, which may provide immunological tolerance to accept the embryo. [ABSTRACT FROM AUTHOR]

Alternative splicing is an essential process in eukaryotes, as it increases the complexity of gene expression by generating multiple proteins from a single pre-mRNA. However, information on the regulatory mechanisms for alternative splicing is lacking, because splicing occurs over a short period via the transient interactions of proteins within functional complexes of the spliceosome. Here, we investigated in detail the molecular mechanisms connecting alternative splicing with epigenetic mechanisms. We identified interactions between histone proteins and splicing factors such as Rbfox2, Rbfox3, and splicing factor proline and glutamine rich protein (SFPQ) by in vivo crosslinking and immunoprecipitation. Furthermore, we confirmed that splicing factors were bound to specific modified residues of histone proteins. Additionally, changes in histone methylation due to histone methyltransferase inhibitor treatment notably affected alternative splicing in selected genes. Therefore, we suggested that there may be crosstalk mechanisms connecting histone modifications and RNA-binding proteins that increase the local concentration of RNA-binding proteins in alternative exon loci of nucleosomes by binding specific modified histone proteins, leading to alternative splicing. This crosstalk mechanism may play a major role in epigenetic processes such as histone modification and the regulation of alternative splicing. [ABSTRACT FROM AUTHOR]

Chronic inflammation is a major cause of human cancer. Clinical cancer therapies against inflammatory risk factors are strategically determined. To rationally guide a novel drug development, an improved mechanistic understanding on the pathological connection between inflammation and carcinogenesis is essential. PI3K-PKB signaling axis has been extensively studied and shown to be one of the key oncogenic drivers in most types of cancer. Pharmacological inhibition of the components along this signaling axis is of great interest for developing novel therapies. Interestingly, emerging studies have shown a close association between PKB activation and inflammatory activity in the vicinity of the tumor, and either blockade of PKB or attenuation of para-tumoral inflammation reveals a mutual-interactive pattern through pathway crosstalk. In this review, we intend to discuss recent advances of PKB-regulated chronic inflammation and its potential impacts on tumor development. [ABSTRACT FROM AUTHOR]

RRM, or RNA-recognition motif, domains are the largest class of single-stranded RNA binding domains in the human proteome and play important roles in RNA processing, splicing, export, stability, packaging, and degradation. Using a current database of post-translational modifications (PTMs), ProteomeScout, we found that RRM domains are also one of the most heavily modified domains in the human proteome. Here, we present two interesting findings about RRM domain modifications, found by mapping known PTMs onto RRM domain alignments and structures. First, we find significant overlap of ubiquitination and acetylation within RRM domains, suggesting the possibility for ubiquitination-acetylation crosstalk. Additionally, an analysis of quantitative study of ubiquitination changes in response to proteasome inhibition highlights the uniqueness of RRM domain ubiquitination – RRM domain ubiquitination decreases in response to proteasome inhibition, whereas the majority of sites increase. Second, we found conservation of tyrosine phosphorylation within the RNP1 and RNP2 consensus sequences, which coordinate RNA binding – suggesting a possible role for regulation of RNA binding by tyrosine kinase signaling. These observations suggest there are unique regulatory mechanisms of RRM function that have yet to be uncovered and that the RRM domain represents a model system for further studies on understanding PTM crosstalk. [ABSTRACT FROM AUTHOR]

This review offers a contemporary history of the renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems with emphasis on how these complex systems affect the eye. It describes the types of communication (cross-talk) between the two systems and evaluates their potential role in the development of diabetic retinopathy, diabetic macular edema, age-related macular degeneration, glaucoma, and uveitis. In addition to detailing the important physiological actions of components of the RAS and KKS, possibilities are suggested for new therapeutic avenues in the treatment of common ocular diseases. Historical notes indicate the major events in this research area, marking four decades from the first publication on the discovery of renin and angiotensin converting enzyme in the eye to the present time. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a major of cause of cancer-related death and is characterized by its heterogeneity and molecular complexity. FOXO1 is a transcription factor that plays a key role in GC growth and metastasis. However, the implication of FOXO1 in GC cell stemness has been elusive. This study, for the first time, demonstrates that FOXO1 regulates GC cell stemness in association with LGR5. FOXO1 expression was significantly lower in GC tumorsphere cells than in adherent GC cells. FOXO1 silencing and overexpression promoted and inhibited the tumorsphere formation capacity of GC cells, respectively. Additionally, there was an inverse correlation between FOXO1 and GC stem cell marker LGR5 in human GC specimens. Further in vitro and in vivo experiments showed that negative crosstalk between these two molecules exists and that LGR5 silencing reversed the FOXO1 shRNA-induced tumorsphere formation even without FOXO1 restoration. Taken together, our results suggest that FOXO1 inhibits the self-renewal capacity of GC cells through interaction with LGR5. Thus, FOXO1/LGR5 signaling pathway may provide a novel targeted therapy for GC. [ABSTRACT FROM AUTHOR]

Neurons allocated to sense organs respond rapidly to mechanical signals dictating behavioral responses at the organism level. The receptors that transduce these signals, and underlie these senses, are mechanically gated channels. Research on mechanosensation over the past decade, employing in many cases Drosophila as a model, has focused in typifying these receptors and in exploring the different ways, depending on context, in which these mechanosensors are modulated. In this review, we discuss first what we have learned from Drosophila on these mechanisms and we describe the different mechanosensory organs present in the Drosophila larvae and adult. Secondly, we focus on the progress obtained by studying the fly on the characterization of the mechanosensory crosstalk underlying complex behaviors like motor coordination. Finally, turning to a cellular level, we summarize what is known on the mechanical properties and sensing capabilities of neural cells and how they may affect neural physiology and pathology. [ABSTRACT FROM AUTHOR]

Enhanced turnover of subchondral trabecular bone is a hallmark of rheumatoid arthritis (RA) and it results from an imbalance between bone resorption and bone formation activities. To investigate the formation and activation of osteoclasts which mediate bone resorption, a Fas-deficient MRL/ lpr mouse model which spontaneously develops autoimmune arthritis and exhibits decreased bone mass was studied. Various assays were performed on subchondral trabecular bone of the temporomandibular joint (TMJ) from MRL/ lpr mice and MRL+/+ mice. Initially, greater osteoclast production was observed in vitro from bone marrow macrophages obtained from MRL/ lpr mice due to enhanced phosphorylation of NF-κB, as well as Akt and MAPK, to receptor activator of nuclear factor-κB ligand (RANKL). Expression of sphingosine 1-phosphate receptor 1 (S1P 1 ) was also significantly upregulated in the condylar cartilage. S1P 1 was found to be required for S1P-induced migration of osteoclast precursor cells and downstream signaling via Rac1. When SN50, a synthetic NF-κB-inhibitory peptide, was applied to the MRL/ lpr mice, subchondral trabecular bone loss was reduced and both production of osteoclastogenesis markers and sphingosine kinase (Sphk) 1/S1P 1 signaling were reduced. Thus, the present results suggest that Fas/S1P 1 signaling via activation of NF-κB in osteoclast precursor cells is a key factor in the pathogenesis of RA in the TMJ. [ABSTRACT FROM AUTHOR]

Two decades of research into functions of the ubiquitous transcription factor HIF have revealed pervasive roles in development, oxygen homeostasis, metabolism, cancer and responses to ischemia. Unsurprisingly, HIF activities impinge on many pathologies, for which underlying molecular mechanisms are actively sought. HIF is a member of the heterodimeric bHLH/PAS family of transcription factors, a set of proteins that commonly function in developmental pathways and adaptive responses to environmental or physiological stress. Similarities in the mechanisms that regulate gene targeting by these transcription factors create opportunities for extensive crosstalk between family members. Data supporting pathway interactions between HIF1a and other bHLH/PAS factors, both collaborative and antagonistic, is beginning to surface in the areas of cancer, circadian rhythm, and immune responses. This review summarises the status of HIF1a-bHLH/PAS protein crosstalk and is dedicated to the memory of Lorenz Poellinger, a pioneer investigator into the molecular mechanisms of HIF, AHR, and ARNT bHLH/PAS factors. [ABSTRACT FROM AUTHOR]

The ability to sense and adapt to low oxygen levels (hypoxia) is central for most organisms and cell types. At the center of this process is a molecular mechanism, the cellular hypoxic response, in which the hypoxia inducible factors (HIFs) are stabilized by hypoxia, allowing the HIF proteins to act as master transcriptional regulators to adjust the cell to a low oxygen environment. In recent years, it has become increasingly appreciated that the cellular hypoxic response does not always operate in splendid isolation, but intersects with signaling mechanisms such as Notch signaling, a key regulatory signaling mechanism operating in most cell types controlling stem cell maintenance and differentiation. In this review, which is dedicated to the memory of Lorenz Poellinger, 1 1 This review article is dedicated to the memory of the late Lorenz Poellinger, who was one of the leaders in hypoxia signaling (see Refs. [2,3,11,13] ) and was instrumental for the early phases of unraveling the Notch-hypoxia cross-talk (see Refs. [15,16,20,22,32,63,85] ). He will be missed as a friend and scientist. we discuss how the intersection between Notch and the cellular hypoxic response was discovered and our current understanding of the molecular basis for the cross-talk. We also provide examples of where Notch and hypoxia intersect in various physiological and disease contexts. [ABSTRACT FROM AUTHOR]

Swarming motility is a mode of bacterial movement over a solid surface driven by rotating flagella in a coordinated manner. Bacteria can use two-component system (TCS), which typically comprises a sensor kinase and a specific cognate response regulator, to properly react to environmental changes. We previously showed that the TCS RssAB suppresses flagellar biosynthesis master regulator flhDC specifically in swarming lag phase to control surface migration timing without affecting expansion rate in Serratia marcescens swarming development. Here we demonstrate that the TCS QseBC, which has been found in several human pathogens involved in flagellar and virulence regulation, has cross-talk with RssAB. We demonstrate that the phosphorylated QseB repressed flhDC expression, reducing swarming migration rate with modest effect on migration initiation. Unexpectedly, the QseC can dephosphorylate non-cognate response regulator RssB. Deletion of qseC prolonged RssAB signaling, reduced flhDC expression, and delayed migration initiation. Our data suggest that QseC is a flagellar biosynthesis activator by de-repressing RssB ∼ P and QseB ∼ P respectively in lag and migration phases in a stage-specific manner in swarming development. [ABSTRACT FROM AUTHOR]

A variety of biochemical fractionation methods are available for the quantification of cytoskeletal components. However, each method is designed to target only one cytoskeletal network, either the microtubule (MT) or actin cytoskeleton, and non-targeted cytoskeletal networks are ignored. Considering the importance of MT–actin crosstalk, the organization of both the targeted and non-targeted cytoskeletal networks must be retained intact during fractionation for the accurate analysis of cytoskeletal organization. In this study, we reveal that existing fractionation methods, represented by the MT-sedimentation-method for MTs and the Triton X-100 solubility assay-method for actin cytoskeletons, disrupt the organizations of the non-targeted cytoskeletons. We demonstrate a novel fractionation method for the accurate analysis of the cytoskeletal organizations using a taxol-containing PEM-based permeabilization buffer, which we name “semi-retentive cytoskeletal fractionation (SERCYF)-method”. The organizations of both MTs and actin cytoskeletons were retained intact even after permeabilization with this buffer. By using the SERCYF-method, we analyzed the effects of nocodazole on the cytoskeletal organizations biochemically and showed promotion of the actin cytoskeletal organization by MT depolymerization. [ABSTRACT FROM AUTHOR]

UDP-glucuronosyltransferases (UGTs) are the primary phase II enzymes catalyzing the conjugation of glucuronic acid to the xenobiotics with polar groups for facilitating their clearance. The UGTs belong to a superfamily that consists of diverse isoforms possessing distinct but overlapping metabolic activity. The abnormality or deficiency of UGTs in vivo is highly associated with some diseases, efficacy and toxicity of drugs, and precisely therapeutic personality. Despite the great effects and fruitful results achieved, to date, the expression and functions of individual UGTs have not been well clarified, the inconsistency of UGTs is often observed in human and experimental animals, and the complex regulation factors affecting UGTs have not been systematically summarized. This article gives an overview of updated reports on UGTs involving the various regulatory factors in terms of the genetic, environmental, pathological, and physiological effects on the functioning of individual UGTs, in turn, the dysfunction of UGTs induced disease risk and endo- or xenobiotic metabolism-related toxicity. The complex cross-talk effect of UGTs with internal homeostasis is systematically summarized and discussed in detail, which would be of great importance for personalized precision medicine. [ABSTRACT FROM AUTHOR]

While tumour cells are classically known to communicate via direct cell-to-cell contact and the secretion of soluble protein-based factors such as cytokines and growth factors, alternative novel mechanisms that promote tumour progression have recently emerged. Now, new critical components of the secretome thought to be involved in tumour progression are exosomes, small vesicles of endocytic origin that carry a variety of bioactive molecules, including proteins, lipids, RNA, as well as DNA molecules. Cancer cell-derived exosomes have been shown to participate in crucial steps of metastatic spread of a primary tumour, ranging from oncogenic reprogramming of malignant cells to formation of pre-metastatic niches. These effects are achieved through the mediation of intercellular cross-talk and subsequent modification of both local and distant microenvironments in an autocrine and paracrine fashion. Here, we summarise the recent findings that implicate this non-canonical signalling within the tumour as a critical driver of metastatic disease progression, and discuss how understanding the molecular mechanisms involved in exosome-mediated metastasis is of great value for the development of new therapeutic strategies to prevent cancer progression. [ABSTRACT FROM AUTHOR]

Crosstalk between mesenchymal and epithelial cells influences organogenesis in multiple tissues, such as lung, pancreas, liver, and the nervous system. Lung mesenchyme comprises multiple cell types, however, and precise identification of the mesenchymal cell type(s) that drives early events in lung development remains unknown. Endothelial cells have been shown to be required for some aspects of lung epithelial patterning, lung stem cell differentiation, and regeneration after injury. Furthermore, endothelial cells are involved in early liver and pancreas development. From these observations we hypothesized that endothelial cells might also be required for early specification of the respiratory field and subsequent lung bud initiation. We first blocked VEGF signaling in E8.5 cultured foreguts with small molecule VEGFR inhibitors and found that lung specification and bud formation were unaltered. However, when we examined E9.5 mouse embryos carrying a mutation in the VEGFR Flk-1 , which do not develop endothelial cells, we found that respiratory progenitor specification was impeded. Because the E9.5 embryos were substantially smaller than control littermates, suggesting the possibility of developmental delay, we isolated and cultured foreguts from mutant and control embryos on E8.5, when no size differences were apparent. We found that both specification of the respiratory field and lung bud formation occurred in mutant and control explants. These observations were unaffected by the presence or absence of serum. We also observed that hepatic specification and initiation occurred in the absence of endothelial cells, and that expansion of the liver epithelium in culture did not differ between mutant and control explants. Consistent with previously published results, we also found that pancreatic buds were not maintained in cultured foreguts when endothelial cells were absent. Our observations support the conclusion that endothelial cells are not required for early specification of lung progenitors and bud initiation, and that the diminished lung specification seen in E9.5 Flk -/- embryos is likely due to developmental delay resulting from the insufficient delivery of oxygen, nutrients, and other factors in the absence of a vasculature. [ABSTRACT FROM AUTHOR]

In P. falciparum , antioxidant proteins of the glutathione and thioredoxin systems are compartmentalized. Some subcellular compartments have only a partial complement of these proteins. This lack of key anti-oxidant proteins in certain sub-cellular compartments might be compensated by functional complementation between these systems. By assessing the cross-talk between these systems, we show for the first time, that the glutathione system can reduce thioredoxins that are poor substrates for thioredoxin reductase (Thioredoxin-like protein 1 and Thioredoxin 2) and thioredoxins that lack access to thioredoxin reductase (Thioredoxin 2). Our data suggests that crosstalk between the glutathione and thioredoxin systems does exist; this could compensate for the absence of certain antioxidant proteins from key subcellular compartments. [ABSTRACT FROM AUTHOR]

The meiotic G2/M1 transition is mostly regulated by posttranslational modifications, however, the cross-talk between different posttranslational modifications is not well-understood, especially in spermatocytes. Sumoylation has emerged as a critical regulatory event in several developmental processes, including reproduction. In mouse oocytes, inhibition of sumoylation caused various meiotic defects and led to aneuploidy. However, the role of sumoylation in male reproduction has only begun to be elucidated. Given the important role of several SUMO targets (including kinases) in meiosis, in this study, the role of sumoylation was addressed by monitoring the G2/M1 transition in pachytene spermatocytes in vitro upon inhibition of sumoylation. Furthermore, to better understand the cross-talk between sumoylation and phosphorylation, the activity of several kinases implicated in meiotic progression was also assessed upon down-regulation of sumoylation. The results of the analysis demonstrate that inhibition of sumoylation with ginkgolic acid (GA) arrests the G2/M1 transition in mouse spermatocytes preventing chromosome condensation and disassembling of the synaptonemal complex. Our results revealed that the activity of PLK1 and the Aurora kinases increased during the G2/M1 meiotic transition, but was negatively regulated by the inhibition of sumoylation. In the same experiment, the activity of c-Abl, the ERKs, and AKT were not affected or increased after GA treatment. Both the AURKs and PLK1 appear to be “at the right place, at the right time” to at least, in part, explain the meiotic arrest obtained in the spermatocyte culture. [ABSTRACT FROM AUTHOR]

Background Transplant vasculopathy limits the clinical results of solid organ transplantation. Materials and methods Thirty-three arterial grafts were implanted in the abdominal aorta of Lewis rats. The animals were humanely sacrificed 4 wk after surgery. The study groups had 15 arterial isografts and 18 arterial allografts. Growth factors and inflammatory cytokines, released by the removed grafts, were studied in organ culture. The released growth factors were analyzed in vitro to assess their effect on the proliferation of endothelial, smooth muscle cells and fibroblasts. Results In arterial isogenic and allogenic grafts, platelet-derived growth factor and basic fibroblastic growth factor release was minimal ( P < 0.01). There was a significant release of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α (TNF-α; P < 0.001) in allografts. GM-CSF and TNF-α, at concentrations in the allograft organ cultures, stimulated significantly the growth of smooth muscle cells. The simultaneous action of TNF-α and GM-CSF had an exponential growth effect on endothelial cells and smooth muscle cells. Interleukin (IL)-1, IL-2, and IL-9 were released in high quantities by allografts. In vitro , IL-1, IL-2, and IL-9 facilitated the growth effect of GM-CSF and TNF-α. Conclusions Transplant vasculopathy depends on the simultaneous and complementary additive effects of several growth factors and cytokines, which have a continuous “cross talk.” [ABSTRACT FROM AUTHOR]

For decades, it has been speculated that specific loci on eukaryotic chromosomes are inherently susceptible to breakage. The advent of high-throughput genomic technologies has now paved the way to their identification. A wealth of data suggests that transcriptionally active loci are particularly fragile and that a specific DNA damage response is activated and dedicated to their repair. Here, we review current understanding of the crosstalk between transcription and double-strand break repair, from the reasons underlying the intrinsic fragility of genes to the mechanisms that restore the integrity of damaged transcription units. [ABSTRACT FROM AUTHOR]

Regulation of L-type Calcium (Ca 2+ ) Channel (LCC) gating is critical to shaping the cardiac action potential (AP) and triggering the initiation of excitation-contraction (EC) coupling in cardiac myocytes. The cyclic nucleotide (cN) cross-talk signaling network, which encompasses the β-adrenergic and the Nitric Oxide (NO)/cGMP/Protein Kinase G (PKG) pathways and their interaction (cross-talk) through distinctively-regulated phosphodiesterase isoenzymes (PDEs), regulates LCC current via Protein Kinase A- (PKA) and PKG-mediated phosphorylation. Due to the tightly-coupled and intertwined biochemical reactions involved, it remains to be clarified how LCC gating is regulated by the signaling network from receptor to end target. In addition, the large number of EC coupling-related phosphorylation targets of PKA and PKG makes it difficult to quantify and isolate changes in L-type Ca 2+ current ( I CaL ) responses regulated by the signaling network. We have developed a multi-scale, biophysically-detailed computational model of LCC regulation by the cN signaling network that is supported by experimental data. LCCs are modeled with functionally distinct PKA- and PKG-phosphorylation dependent gating modes. The model exhibits experimentally observed single channel characteristics, as well as whole-cell LCC currents upon activation of the cross-talk signaling network. Simulations show 1) redistribution of LCC gating modes explains changes in whole-cell current under various stimulation scenarios of the cN cross-talk network; 2) NO regulation occurs via potentiation of a gating mode characterized by prolonged closed times; and 3) due to compensatory actions of cross-talk and antagonizing functions of PKA- and PKG-mediated phosphorylation of LCCs, the effects of individual inhibitions of PDEs 2, 3, and 4 on I CaL are most pronounced at low levels of β-adrenergic stimulation. Simulations also delineate the contribution of the following two mechanisms to overall LCC regulation, which have otherwise been challenging to distinguish: 1) regulation of PKA and PKG activation via cN cross-talk (Mechanism 1); and 2) LCC interaction with activated PKA and PKG (Mechanism 2). These results provide insights into how cN signals transduced via the cN cross-talk signaling network are integrated via LCC regulation in the heart. [ABSTRACT FROM AUTHOR]

H 2 S and NO are two important gasotransmitters that modulate stress responses in plants. There are the contradictory data on crosstalk between NO and H 2 S in the studies. Hence, in the present study, the role of interplay between NO and H 2 S was assessed on the Pb tolerance of Sesamum indicum using pharmacological and biochemical approaches. Results revealed that Pb stress reduced the plant growth and the content of photosynthetic pigments and Fv/Fm ratio, increased the lipid peroxidation and the H 2 O 2 content, elevated the endogenous contents of nitric oxide (NO), H 2 S and enhanced the activities of antioxidant enzymes (except APX). Additionally, concentrations of most mineral ions (K, P, Mg, Fe, Mn and Zn) in both shoots and roots decreased. Pb accumulation in roots was more than it in shoots. Both sodium hydrosulfide (NaHS as a donor of H 2 S) and sodium nitroprusside (SNP as an NO donor) improved the plant growth, the chlorophyll and carotenoid contents and PSII efficiency, reduced oxidative damage, increased the activities of antioxidant enzymes and reduced the proline content in Pb-stressed plants. Furthermore, both NaHS and SNP significantly restricted the uptake and translocation of Pb, thereby minimizing antagonistic effects of Pb on essential mineral contents in sesame plants. NaHS increased the NO generation and many NaHS-induced responses were completely reversed by cPTIO, as the specific NO scavenger. Applying SNP also enhanced H 2 S release levels in roots of Pb-stressed plants and only some NO-driven effects were partially weakened by hypotuarine (HT), as the scavenger of H 2 S.These findings proposed for the first time that two-sided interplay between H 2 S and NO might confer an increased tolerance to Pb stress via activating the antioxidant systems, reducing the uptake and translocation of Pb, and harmonizing the balance of mineral nutrient. [ABSTRACT FROM AUTHOR]

In dual-task settings, one can find influences from Task 2 processing even on Task 1 performance, an effect referred to as the backward crosstalk effect (BCE). The size of the BCE has been taken as an index of how well Task 1 processing can be shielded against concurrently ongoing Task 2 processes. In the current study, we compared the size of the BCE between adults and a group of 5- and 6-year-old children. First, the BCE turned out to be larger in children than in adults. Second, both groups exhibited a comparable adjustment of behavior in response to just experienced conflict; in both groups, the BCE was smaller following conflict trials than following no-conflict trials. Third, a diffusion model analysis suggests that the source for the BCE is different in adults than in children. In particular, not parallel Task 2 response activation appears to be the source of the BCE in children. Rather, non-decisional processes appear to be responsible for the BCE in this age group. Thus, this study shows that (a) 5- and 6-year-old children can perform dual-tasks, but (b) they show slightly larger signs of between-task crosstalk, and (c) the exact reasons for this appear to be different from those responsible in adults. [ABSTRACT FROM AUTHOR]

SOX family transcription factor has emerged as a double-edged sword relating to tumorigenesis and metastasis. Multiple studies have revealed different expression patterns and contradictory roles of SOX factors in the tumor initiation and progression. The aberrant expression of SOX factors is regulated by copy number alteration, methylation modulation, microRNAs, transcription factors and post-translational modification. This review summarizes the role of SOX factors in molecular interactions and signaling pathways during different steps of carcinogenesis, such as CSCs stemness maintenance, EMT occurrence, cell invasion, cell proliferation and apoptosis. The Wnt signaling pathway is also shown to provide vital intermediate signaling transduction. We believe that SOX family proteins may be used as prognostic markers for human clinical therapy, and novel therapy strategies targeting SOX factors should be explored in future clinical applications. [ABSTRACT FROM AUTHOR]

Mitochondria play a relevant role in Ca 2+ buffering, governing energy metabolism and neuronal function. Huntington's disease (HD) and Alzheimer's disease (AD) are two neurodegenerative disorders that, although clinically distinct, share pathological features linked to selective brain damage. These include mitochondrial dysfunction, intracellular Ca 2+ deregulation and mitochondrial Ca 2+ handling deficits. Both diseases are associated with misfolding and aggregation of specific proteins that physically interact with mitochondria and interfere with endoplasmic reticulum (ER)/mitochondria-contact sites. Cumulating evidences indicate that impairment of mitochondrial Ca 2+ homeostasis underlies the susceptibility to selective neuronal death observed in HD and AD; however data obtained with different models and experimental approaches are not always consistent. In this review, we explore the recent literature on deregulation of mitochondrial Ca 2+ handling underlying the interplay between mitochondria and ER in HD and AD-associated neurodegeneration. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is an autoimmune disorder characterized by chronic, relapsing intestinal inflammation. Autoimmune liver disease (AILD) may be involved in IBD as an extra-intestinal manifestation (EIM). Epidemiologic and anatomic evidence have demonstrated an intimate crosstalk between the gut and the liver. In this review, we briefly introduced nine groups of susceptibility loci shared by inflammatory bowel and autoimmune liver disease for the first time. The genome-wide association studies (GWAS) evidence of pathways involving crosstalk between the gut and the liver is clarified and explained. It has been found that HNF4-α , GPR35 , MST1R , CARD9 , IL2/IL21/IL2R , BACH2 , TNFRSF14 , MAdCAM-1 , and FUT2 are the genes involved in tight junction formation, macrophage function, T helper cell or T reg cell cycle and function, TNF secretion, lymphocyte homing or intestinal dysbiosis, respectively. The intimate crosstalk between the gut and liver in immunity is also highlighted and discussed in this review. [ABSTRACT FROM AUTHOR]

Background and aim Low-grade inflammation persists in patients with acute pancreatitis (AP) after hospital discharge, and is linked to metabolic disorders. Neuropeptide Y (NPY) is well recognized as an important mediator of inflammation in these patients but the role of the other two structurally similar peptides, pancreatic polypeptide (PP) and peptide YY (PYY), in inflammation has been sparsely investigated. The aim was to investigate the association between PYY, PP, NPY and circulating levels of innate cytokines in patients after AP. Methods Fasting blood samples were collected to measure PYY (ng/mL), PP (ng/mL), NPY (pg/mL), interleukin-6 (IL-6) (ng/mL), monocyte chemoattractant protein (MCP) 1 (ng/mL), and tumour necrosis factor (TNF) α (ng/mL). Modified Poisson regression analysis and linear regression analyses were conducted. Age, sex, ethnicity, obesity, diabetes, aetiology, time from 1st attack of AP, recurrence, severity, physical activity, and smoking were adjusted for in several statistical models. P < 0.05 was considered statistically significant. Results A total of 93 patients were recruited. Peptide YY was significantly associated ( p < 0.001) with IL-6, MCP-1, and TNFα in the unadjusted and all adjusted models. Pancreatic polypeptide was significantly associated ( p < 0.001) with IL-6, MCP-1, and TNFα in the unadjusted and at least one adjusted model. Peptide YY and PP together contributed 22.2%, 72.7%, and 34.6% to the variance of IL-6, MCP-1, and TNFα, respectively. Neuropeptide Y was not significantly associated with any of the three cytokines. Conclusions Peptide YY and PP are associated with circulating innate pro-inflammatory cytokines in patients after AP and cumulatively contribute to nearly half of the variance of IL-6, MCP-1, and TNFα. Future research is warranted to investigate the signaling pathways that underlie these associations. [ABSTRACT FROM AUTHOR]

The success of pregnancy depends mostly on a synchronized immune-endocrine crosstalk at the maternal–fetal interface. Hormones are important in terms of maintaining the suitable environment and sufficient nutrition for the developing fetus. They also play a major role during the process of parturition and lactation. Maternal immunomodulation is important for the tolerance of semiallogeneic fetus. This is achieved in concert with a variety of endocrine stimulation. Estrogen, progesterone, and Human Chorionic Gonadotropin play a major role in immune modulation during pregnancy. Hormones modulate B cells, dendritic cells, uterine natural killer cells, macrophages, neutrophils to adopt fetal friendly immune phenotypes. Recently the use of hormones in assisted reproductive technology has been found to improve the pregnancy outcome. The present review focuses on the pregnancy-related hormones, their role in immunomodulation for successful pregnancy outcome. This also shed light on the immune-endocrine crosstalk at maternal–fetal interface during pregnancy. [ABSTRACT FROM AUTHOR]

Mitophagy, the selective degradation of mitochondria via the autophagic pathway, is a vital mechanism of mitochondrial quality control in cells. Mitophagy is responsible for the removal of malfunctioning or damaged mitochondria, which is essential for normal cellular physiology and tissue development. Pathways involved in the regulation of mitophagy, tumorigenesis, and cell death are overlapping in many cases and may be triggered by common upstream signals, which converge at the mitochondria. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses can either stimulate or suppress tumorigenesis. Thus, the analysis of crosstalk among the processes of mitophagy, cell death and tumorigenesis is important for the identification of targets responsible for the stimulation of cell death and selective elimination of cancer cells. In the present review, we analyze the mechanisms of mitophagy regulation, the pathways underlying the utilization of damaged mitochondria, and how intervention with mitophagy can affect tumor cell resistance to treatment. [ABSTRACT FROM AUTHOR]

Most disease-related mutations that impair cAMP protein kinase A (PKA) signaling are present within the regulatory (R) PKA RI alpha-subunit (RIα). Although mutations in the PRKAR1A gene are linked to Carney complex (CNC) disease and, more recently, to acrodysostosis-1 (ACRDYS1), the two diseases show contrasting phenotypes. While CNC mutations cause increased PKA activity, ACRDYS1 mutations result in decreased PKA activity and cAMP resistant holoenzymes. Mapping the ACRDYS1 disease mutations reveals their localization to the second of two tandem cAMP-binding (CNB) domains (CNB-B), and here, we characterize a recurrent deletion mutant where the last 14 residues are missing. The crystal structure of a monomeric form of this mutant (RIα92–365) bound to the catalytic (C)-subunit reveals the dysfunctional regions of the RIα subunit. Beyond the missing residues, the entire capping motif is disordered (residues 357–379) and explains the disrupted cAMP binding. Moreover, the effects of the mutation extend far beyond the CNB-B domain and include the active site and N-lobe of the C-subunit, which is in a partially open conformation with the C-tail disordered. A key residue that contributes to this crosstalk, D267, is altered in our structure, and we confirmed its functional importance by mutagenesis. In particular, the D267 interaction with Arg241, a residue shown earlier to be important for allosteric regulation, is disrupted, thereby strengthening the interaction of D267 with the C-subunit residue Arg194 at the R:C interface. We see here how the switch between active (cAMP-bound) and inactive (holoenzyme) conformations is perturbed and how the dynamically controlled crosstalk between the helical domains of the two CNB domains is necessary for the functional regulation of PKA activity. [ABSTRACT FROM AUTHOR]

Bacterial pathogens not only stimulate innate immune receptors, but also activate the complement system. Crosstalk between complement C5a receptor (C5aR) and other innate immune receptors is known to enhance the proinflammatory cytokine response. An important determinant of the magnitude of complement activation is the activity of the alternative pathway, which serves as an amplification mechanism for complement activation. Both alternative pathway activity as well as plasma levels of factor H, a key inhibitor of the alternative pathway, show large variation within the human population. Here, we studied the effect of factor H-mediated regulation of the alternative pathway on bacterial-induced proinflammatory cytokine responses. We used the human pathogen Streptococcus pneumoniae as a model stimulus to induce proinflammatory cytokine responses in human peripheral blood mononuclear cells. Serum containing active complement enhanced pneumococcal induced proinflammatory cytokine production through C5a release and C5aR crosstalk. We found that inhibition of the alternative pathway by factor H, with a concentration equivalent to a high physiological level, strongly reduced C5a levels and decreased proinflammatory cytokine production in human peripheral blood mononuclear cells. This suggests that variation in alternative pathway activity due to variation in factor H plasma levels affects individual cytokine responses during infection. [ABSTRACT FROM AUTHOR]