interacts_with DB01017?
DB01017 inhibits P09917 activation and brain inflammation after focal cerebral ischemia in rats . AIM : To determine whether the anti-inflammatory effect of minocycline on postischemic brain injury is mediated by the inhibition of P09917 ( 5- P28300 ) expression and enzymatic activation in rats . METHODS : Focal cerebral ischemia was induced for 30 min with middle cerebral artery occlusion , followed by reperfusion . The ischemic injuries , endogenous IgG exudation , the accumulation of neutrophils and macrophage/microglia , and 5- P28300 mRNA expression were determined 72 h after reperfusion . 5- P28300 metabolites ( leukotriene B4 and cysteinyl leukotrienes ) were measured 3 h after reperfusion . RESULTS : DB01017 ( 22.5 and 45 mg/kg , ip , for 3 d ) attenuated ischemic injuries , IgG exudation , and the accumulation of neutrophils and macrophage/microglia 72 h after reperfusion . It also inhibited 5- P28300 expression 72 h after reperfusion and the production of leukotrienes 3 h after reperfusion . CONCLUSION : DB01017 inhibited postischemic brain inflammation , which might be partly mediated by the inhibition of 5- P28300 expression and enzymatic activation . Slow overmethylation of housekeeping genes in the body mucosa is associated with the risk for gastric cancer . Helicobacter pylori infection increases age-related diverse overmethylation in gene-control regions , which increases the risk of gastric cancer . The H. pylori-associated overmethylation changes subsequently disappear when gastric atrophy and cancer develop . To identify cancer-risk epigenotypes , we traced dynamic methylation changes in the background mucosa of the stomach depending on the extent of gastric atrophy . Paired biopsy specimens were obtained from the noncancerous antrum and body mucosa of 102 patients with cancer and 114 H. pylori-positive and 112 H. pylori-negative controls . The grade of gastric atrophy was evaluated using the endoscopic atrophic border score . The methylation-variable sites at the CpG-island margins and near the transcriptional start sites lacking CpG islands were semiquantitatively analyzed by radioisotope-labeling methylation-specific PCR . We selected eight housekeeping genes adjacent to Alu ( CDH1 , Q8NCT1 , P37231 , and Q9UL33 ) or LTR retroelements ( P08253 , CDKN2A , Q13950 , and Q13761 ) and eight stomach-specific genes ( Q03403 , P20142 , P51164 , P04155 , Q07654 , Q9UBU3 , DB00158 , and P20648 ) . Analysis of age-related methylation in the H. pylori-positive controls revealed slow overmethylation in the body and in the LTR-adjacent genes . A high-frequency overmethylation defined based on the slowly overmethylated genes was frequently observed in the body of patients with gastric cancer with open-type atrophy ( OR , 12.7 ; 95 % confidence interval , 3.2-49.8 ) . The rapidly changing methylation of Alu-adjacent genes was barely increased in the antrum of patients with gastric cancer . Among diverse methylation changes associated with H. pylori infection , an increase in slowly changing methylation could serve as a cancer-risk marker . Gefitinib ( ' DB00317 ' , ZD1839 ) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces P16035 . The effect of P01133 stimulation and its inhibition with gefitinib ( ' DB00317 ' , ZD1839 ) , an epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor , has been investigated in two P00533 -positive human bladder tumour cell lines , RT112 and RT4 . The growth of RT112 cells in a medium containing 10 % foetal bovine serum was inhibited by 50 % with 10 microM gefitinib , whereas this dose completely inhibited RT4 cell growth . Cells were more sensitive to growth inhibition in the serum-free medium . Increased growth of cells in the serum-free medium was observed with 10 or 50 ng x ml(-1) P01133 and the proliferative effect of P01133 stimulation in both cell lines was inhibited in the presence of 1 microM , but not 0.1 microM gefitinib . Zymography of the conditioned medium from RT112 cells treated with P01133 and gefitinib showed a decrease in matrix metalloproteinase 2 ( P08253 ) concentrations . Western blot analysis showed that tissue inhibitor of metalloproteinase 1( P01033 ) increased in the conditioned medium from RT112 cells treated with P01133 , and this was partially inhibited with both 1 and 5 microM gefitinib . Conversely , P16035 decreased with P01133 stimulation and this was reversed with gefitinib . Tissue inhibitor of metalloproteinase 1 had no effect on the growth of either cell line . These studies show alterations in the balance of MMPs and their inhibitors in P01133 -stimulated bladder tumour cells , which are reversed by gefitinib , suggesting gefitinib should be investigated for its effect on human bladder tumours . DB01017 protects Schwann cells from ischemia-like injury and promotes axonal outgrowth in bioartificial nerve grafts lacking Wallerian degeneration . DB01017 , a broad-spectrum antimicrobial tetracycline , acts neuroprotectively in ischemia . Recently , however , minocycline has been revealed to have ambiguous effects on nerve regeneration . Thus its effects in a rat sciatic nerve transplantation model and on cultivated Schwann cells stressed by oxygen glucose deprivation ( OGD ) were studied . The negative effect of minocycline on Wallerian degeneration , the essential initial phase of degeneration/regeneration after nerve injury , that was recently demonstrated , was excluded by using predegenerated nerve and Schwann cell-enriched muscle grafts , both free of Wallerian degeneration . They were compared with common nerve grafts . The principle findings were that in vitro minocycline provided protective effects against OGD-induced death of Schwann cells by preventing permeability of the mitochondrial membrane . It suppressed the OGD-mediated induction of HIF-1alpha and Q07812 , and stabilized/induced BCL-2 . P99999 release and cleavage of procaspase-3 were diminished ; release and translocation of O95831 and cytotoxic cleavage of actin into fractin were stopped . In common nerve grafts , minocycline , besides its direct anti-ischemic effect , hampered revascularization by down-regulation of P14780 and P15692 prolonging ischemia and impeding macrophage recruitment . In bioartificial nerve grafts that were free of Wallerian degeneration and revealed lower immunogenicity , minocycline aided the regeneration process . Here , the direct anti-ischemic effect of minocycline on Schwann cells , which are mandatory for successful peripheral nerve regeneration , dominated the systemic anti-angiogenic/pro-ischemic effects . In common nerve grafts , however , where Wallerian degeneration is a prerequisite , the anti-angiogenic and macrophage-depressing effect is an obstacle for regeneration . DB01017 increases phosphorylation and membrane insertion of neuronal GluR1 receptors . The tetracycline antibiotic minocycline beneficially affects neuronal functioning and also inhibits the enzyme P09917 ( 5- P28300 ) . We hypothesized that similar to 5- P28300 inhibitors , minocycline may increase phosphorylation and membrane insertion of the glutamate receptor GluR1 . The experiments were performed in primary cultures of mouse striatal neurons and in the prefrontal cortex and striatum of minocycline-treated mice . In vitro , low micromolar minocycline concentrations increased GluR1 phosphorylation at Ser845 and Ser831 and increased the surface content of GluR1 . DB01017 also increased GluR1 phosphorylation in vivo . Increased GluR1 phosphorylation and minocycline treatment have been associated with antidepressant and memory-enhancing activities . Direct consequences of minocycline-increased GluR1 phosphorylation are yet to be established . Splenic autonomic denervation increases inflammatory status but does not aggravate atherosclerotic lesion development . The brain plays a prominent role in the regulation of inflammation . Immune cells are under control of the so-called cholinergic anti-inflammatory reflex , mainly acting via autonomic innervation of the spleen . Activation of this reflex inhibits the secretion of proinflammatory cytokines and may reduce the development of atherosclerosis . Therefore , the aim of this study was to evaluate the effects of selective parasympathetic ( Px ) and sympathetic ( Sx ) denervation of the spleen on inflammatory status and atherosclerotic lesion development . Female P02649 *3-Leiden. P11597 mice , a well-established model for human-like lipid metabolism and atherosclerosis , were fed a cholesterol-containing Western-type diet for 4 wk after which they were subdivided into three groups receiving either splenic Px , splenic Sx , or sham surgery . The mice were subsequently challenged with the same diet for an additional 15 wk . Selective Px increased leukocyte counts ( i.e. , dendritic cells , B cells , and T cells ) in the spleen and increased gene expression of proinflammatory cytokines in the liver and peritoneal leukocytes compared with Sx and sham surgery . Both Px and Sx increased circulating proinflammatory cytokines IL-1β and P05231 . However , the increased proinflammatory status in denervated mice did not affect atherosclerotic lesion size or lesion composition . CONCLUSION : Predominantly selective Px of the spleen enhances the inflammatory status , which , however , does not aggravate diet-induced atherosclerotic lesion development . Protection of minocycline on early brain injury after subarachnoid hemorrhage in rats . DB01017 has been shown to be neuroprotective in cerebral ischemia and in other models of brain injury . Our goal is to observe the protection of minocycline on EBI after Q53FZ2 and the mechanism . 48 adult male SD rats were randomly divided into four groups : the sham-operated group , Q53FZ2 group , vehicle group ( Q53FZ2 +normal sodium ) , and minocycline group ( Q53FZ2 +minocycline ) . The Q53FZ2 model was induced by injecting 300 μl of autologous arterial blood into the prechiasmatic cistern . Expressions of P14780 in the hippocampus were examined at 24 h by western blot and zymography . Western blot and zymography showed that the expression of total and active P14780 increased dramatically at 24 h after Q53FZ2 compared with that of the sham group ( P < 0.01 ) . The clinical assessments got a lower score than that of the sham-operated group . After treated with minocycline , the expression of P14780 decreased significantly ( P < 0.01 vs. vehicle group ) , and the clinical assessments improved . We conclude that minocycline can protect EBI after Q53FZ2 , which may be related to the mechanism of inhibiting the expression of P14780 in the hippocampus . DB01017 protects PC12 cells from ischemic-like injury and inhibits P09917 activation . DB01017 protects animals against cerebral ischemia by inhibiting inflammation . To determine whether minocycline protects PC12 cells from in vitro ischemic-like injury and affects pro-inflammatory P09917 activation , the cell viability and P09917 translocation to nuclear membrane were observed after oxygen-glucose deprivation ( OGD ) . We found that OGD reduced cell viability , which was attenuated by minocycline and P09917 inhibitor caffeic acid . 5-Lipoxygenase protein was detected in PC12 cells by immunohistochemical and Western blot analyses . OGD induced P09917 translocation to nuclear membranes , which was abolished by minocycline and caffeic acid . Thus , minocycline can protect PC12 cells from in vitro ischemic-like injury , and this effect may be partly related to the inhibition of P09917 activation . Diverse matrix metalloproteinase functions regulate cancer amoeboid migration . Rounded-amoeboid cancer cells use actomyosin contractility driven by Rho-ROCK and JAK- P40763 to migrate efficiently . It has been suggested that rounded-amoeboid cancer cells do not require matrix metalloproteinases ( MMPs ) to invade . Here we compare MMP levels in rounded-amoeboid and elongated-mesenchymal melanoma cells . Surprisingly , we find that rounded-amoeboid melanoma cells secrete higher levels of several MMPs , including collagenase P45452 and gelatinase P14780 . As a result , rounded-amoeboid melanoma cells degrade collagen I more efficiently than elongated-mesenchymal cells . Furthermore , using a non-catalytic mechanism , P14780 promotes rounded-amoeboid 3D migration through regulation of actomyosin contractility via P16070 receptor . P14780 is upregulated in a panel of rounded-amoeboid compared with elongated-mesenchymal melanoma cell lines and its levels are controlled by ROCK-JAK- P40763 signalling . P14780 expression increases during melanoma progression and it is particularly prominent in the invasive fronts of lesions , correlating with cell roundness . Therefore , rounded-amoeboid cells use both catalytic and non-catalytic activities of MMPs for invasion . DB01017 suppresses experimental autoimmune encephalomyelitis by increasing tissue inhibitors of metalloproteinases . Matrix metalloproteinases ( MMPs ) that are secreted by activated T cells play a significant role in degradation of the extracellular matrix around the blood vessels and facilitate autoimmune neuroinflammation ; however , it remains unclear how MMPs act in lesion formation and whether MMP-targeted therapies are effective in disease suppression . In the present study , we attempted to treat experimental autoimmune encephalomyelitis ( EAE ) by administration of small interfering RNAs ( siRNAs ) for P08253 , P14780 , and minocycline , all of which have MMP-inhibiting functions . DB01017 , but not siRNAs , significantly suppressed disease development . In situ zymography revealed that gelatinase activities were almost completely suppressed in the spinal cords of minocycline-treated animals , while significant gelatinase activities were measured in the EAE lesions of control animals . However , P08253 and P14780 mRNAs and proteins in the spinal cords of treated rats were unexpectedly upregulated . At the same time , mRNA for tissue inhibitors of MMPs ( P01033 ) -1 and -2 were also upregulated . The EnzChek Gelatinase/Collagenase assay using tissue containing native MMPs and TIMPs demonstrated that gelatinase activity levels in the spinal cords of treated rats were suppressed to the same level as those in normal spinal cord tissues . Finally , double immunofluorescent staining demonstrated that P14780 immunoreactivities of treated rats were almost the same as those of control rats and that P14780 and P01033 immunoreactivities were colocalized in the spinal cord . These findings suggest that minocycline administration does not suppress MMPs at mRNA and protein levels but that it suppresses gelatinase activities by upregulating TIMPs . Thus , MMP-targeted therapies should be designed after the mechanisms of candidate drugs have been considered . DB01017 inhibits angiogenesis in vitro through the translational suppression of HIF-1α . DB01017 was recently found to be effective against cancer . However , the precise molecular mechanisms of minocycline in cancer are poorly understood . Hypoxia-inducible factor-1 ( Q9BYW2 , a heterodimeric transcription factor composed of HIF-1α and β ) activates the transcription of genes that are involved in angiogenesis in cancer . In this study , we found that minocycline significantly inhibits HIF-1α protein expression and suppresses Q9BYW2 transcriptional activity . The tube formation assay showed that minocycline has anti-angiogenic activity and suppresses hypoxia-induced vascular endothelial growth factor ( P15692 ) expression . The metabolic labeling assay showed that minocycline reduces HIF-1α protein translation and global protein synthesis . In addition , minocycline suppresses P42345 signaling and increases the phosphorylation of eIF2α , which is known to be related to the translational regulation of HIF-1α expression . These findings collectively indicate that minocycline is a potential inhibitor of HIF-1α and provide new insight into the discovery of drugs for cancer treatment . Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP . Hypertensive small vessel disease is a major cause of vascular cognitive impairment ( VCI ) . Spontaneously hypertensive/stroke prone rats ( SHR/SP ) with unilateral carotid artery occlusion ( UCAO ) and a Japanese permissive diet ( JPD ) have white-matter ( WM ) damage similar to that seen in VCI . We hypothesized that WM injury was due to hypoxia-mediated , blood-brain barrier ( BBB ) disruption . Twelve-week-old SHR/SP had UCAO/JPD and were studied with immunohistochemistry , biochemistry , multimodal magnetic resonance imaging ( Q9BWK5 ) , and Morris water maze ( MWM ) testing . One week after UCAO/JPD , WM showed a significant increase in hypoxia inducible factor-1α ( HIF-1α ) , which increased further by 3 weeks . Prolyl hydroxylase-2 ( Q9GZT9 ) expression decreased at 1 and 3 weeks . Infiltrating T cells and neutrophils appeared around endothelial cells from 1 to 3 weeks after UCAO/JPD , and matrix metalloproteinase-9 ( P14780 ) colocalized with inflammatory cells . At 3 weeks , WM immunostained for IgG , indicating BBB leakage . DB01017 ( 50 mg/kg intraperitoneally ) was given every other day from weeks 12 to 20 . Multimodal Q9BWK5 showed that treatment with minocycline significantly reduced lesion size and improved cerebral blood flow . DB01017 improved performance in the MWM and prolonged survival . We propose that BBB disruption occurred secondary to hypoxia , which induced an P14780 -mediated infiltration of leukocytes . DB01017 significantly reduced WM damage , improved behavior , and prolonged life . Involvement of matrix metalloproteinases-2 and -9 in the formation of a lacuna-like cerebral cavity . We used a modified pial vessel disruption ( PVD ) protocol with adult male Wistar rats to mimic small-vessel stroke in the cerebral cortex . Within 3 weeks , this lesion develops into a single lacuna-like cavity , which is fluid-filled and encapsulated by reactive astrocytes . DB01017 treatment that commences 1 hr after lesion and continues for 6 days prevents the cavitation and causes a filling of the lesion with reactive astrocytes and no barrier . Here , we determined whether inhibition of matrix metalloproteinases-2 and -9 ( MMPs ) mediates this minocycline action . Confocal microscopy revealed increased punctate staining of MMPs inside the lesion sites after 2 days of PVD . Astrocytes lined the lesion border but showed sparse localization inside the lesion . In contrast , increased MMP levels inside the lesion coincided with increased Q92838 or OX-42 immunostaining , suggesting that MMP elevation reflected increased secretions from microglia/macrophages . Imaging analyses also revealed that minocycline administered for 2 days before animal euthanasia , significantly decreased MMP levels within the lesion . Moreover , Western blot analysis of cortical tissue extracts showed a significant 30-40 % upregulation of MMPs 2 days after lesion . DB01017 administered 2 hr before the lesion significantly inhibited both P14780 and P08253 levels by ∼40 % . In contrast , minocycline administered 1 hr after the lesion only decreased P14780 levels by ∼30 % . Because MMP inhibition with batimastat injection also prevented cavity formation at 21 days , we conclude that minocycline prevented the creation of a lacuna-like cyst in the cerebral cortex by inhibiting the MMP secretion from microglia in the affected tissue . [ DB09053 : A new drug of B-cell malignancies ] . DB09053 ( Imbruvica® ) is a first-in-class , orally administered once-daily , that inhibits B-cell antigen receptor signaling downstream of Bruton 's tyrosine kinase ( Q06187 ) . DB09053 has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed/refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed/refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression-free survival , response rate and overall survival in patients with relapsed/refractory CLL , including in those with del 17p . DB09053 had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B-cell malignancies . Experimental models of neuroprotection relevant to multiple sclerosis . Activated T cells , particularly those of the T-helper ( Th ) 1 subset , have the capacity to kill neurons . Strategies for preventing such damage may include deviation of activated T cells into the Th2 subset ( e.g. , via use of glatiramer acetate ) , alteration of functional properties of Th1 cells ( e.g. , through use of interferon [ P27352 ] -beta or IV immunoglobulin ) , and inhibition of activated cell migration into the CNS ( e.g. , by employing P27352 -beta or natalizumab ) . P14780 ( P14780 ) also causes neuron death in neurotoxicity models , and examination of medications with MMP inhibitory activity indicates that minocycline is capable of preventing such damage . DB01017 also has other properties relevant to conferring neuroprotection , such as inhibition of microglial activity and apoptosis pathways . In a small pilot study in patients with relapsing-remitting multiple sclerosis , minocycline treatment produced favorable outcomes in terms of gadolinium-enhancing lesions and clinical course . Further studies are needed to establish whether experimental neuroprotection strategies involving these mechanisms may be translated into preventing neurodegeneration in multiple sclerosis . Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke . BACKGROUND : Matrix metalloproteinases 2 and 9 ( P08253 and P14780 ) are increased in the brain after experimental ischemic stroke in rats . These two proteases are involved with the degradation of the basal lamina and loss of stability of the blood brain barrier that occurs after ischemia and that is associated with thrombolytic therapy in ischemic stroke . DB01017 is a lipophilic tetracycline and is neuroprotective in several models of brain injury . DB01017 inhibits inflammation , apoptosis and extracellular matrix degradation . In this study we investigated whether delayed minocycline inhibits brain MMPs activated by ischemia in a model of temporary occlusion in Wistar rats . RESULTS : Both P08253 and P14780 were elevated in the ischemic tissue as compared to the contra-lateral hemisphere after 3 hours occlusion and 21 hours survival ( p < 0.0001 for P14780 ) . Intraperitoneal minocycline at 45 mg/kg concentration twice a day ( first dose immediately after the onset of reperfusion ) significantly reduced gelatinolytic activity of ischemia-elevated P08253 and P14780 ( p < 0.0003 ) . Treatment also reduced protein concentration of both enzymes ( p < 0.038 for P14780 and p < 0.018 for P08253 ) . In vitro incubation of minocycline in concentrations as low as 0.1 mug/ml with recombinant P08253 and P14780 impaired enzymatic activity and P14780 was more sensitive at lower minocycline concentrations ( p < 0.05 ) . CONCLUSION : DB01017 inhibits enzymatic activity of gelatin proteases activated by ischemia after experimental stroke and is likely to be selective for P14780 at low doses . DB01017 is a potential new therapeutic agent to acute treatment of ischemic stroke . The relationship of P04141 and plasma cytokine levels to cerebral white matter injury in the premature newborn . Ischemia and systemic infection are implicated in the etiology of periventricular white matter injury , a major cause of adverse motor and cognitive outcome in preterm infants . Cytokines are signaling proteins that can be produced as part of the inflammatory response to both ischemia and infection . The aim of this study was to relate cerebrospinal fluid ( P04141 ) concentrations of P05231 , P10145 , P22301 , tumor necrosis factor alpha ( P01375 ) , and interferon gamma ( P01579 ) to magnetic resonance-defined white matter injury in preterm infants . Relationships between P04141 and plasma cytokine concentrations were also examined . Preterm infants ( < or=32 wk ) and more mature infants from The Royal Women 's Hospital , Melbourne , Australia , and Christchurch Women 's Hospital , Christchurch , New Zealand , were eligible for study if they required a clinically indicated lumbar puncture . Plasma samples were obtained in a subgroup of Christchurch infants . Preterm infants underwent advanced quantitative volumetric magnetic resonance imaging using a 1.5-Tesla scanner at term equivalent . One hundred forty-six infants were enrolled and 190 P04141 and 42 plasma samples obtained . There was no significant correlation between paired P04141 and plasma concentrations for any cytokine . In comparing plasma and P04141 concentrations , levels of P10145 were significantly higher in P04141 than plasma . Preterm infants with Q9BWK5 -defined cerebral white matter injury had higher levels of P05231 , P22301 , and P01375 in the P04141 than infants without such injury . Plasma cytokine concentrations may not reflect P04141 cytokine levels or inflammatory events within the brain . Elevated P04141 levels of cytokines in infants with white matter injury suggest an altered inflammatory balance . Inhibitors of arachidonic acid metabolism reduce DNA and nuclear fragmentation induced by P01375 plus cycloheximide in U937 cells . U937 human myeloid leukemia cells are induced to apoptosis by tumour necrosis factor ( P01375 ) plus cycloheximide ( CHX ) . We have analysed the effect of various inhibitors of the arachidonic acid ( AA ) metabolism on several features of this process . The formation of high molecular weight and oligonucleosomal DNA fragments as well as nuclear fragmentation were reduced by inhibitors of P09917 ( BWA4C and BWB70C ) , P09917 activating protein ( MK-886 ) , and cytosolic P04054 ( AACOCF3 ) . None of these agents blocked the morphological changes detected by microscopy or flow cytometry , phosphatidylserine exposure on the cell surface or Caspase 3-like activation . AA also induced nuclear fragmentation at a concentration of 1-20 microM . However , the mechanisms by which these inhibitors act , remain unexplained since there was no P09917 expression in the U937 cells and no AA release followed their stimulation with P01375 plus CHX . Differential gene expression in adipose tissue from obese human subjects during weight loss and weight maintenance . BACKGROUND : Differential gene expression in adipose tissue during diet-induced weight loss followed by a weight stability period is poorly characterized . Markers of these processes may provide a deeper understanding of underlying mechanisms . OBJECTIVE : We aimed to identify differentially expressed genes in human adipose tissue during weight loss and weight maintenance after weight loss . DESIGN : RNA from subcutaneous abdominal adipose tissue from 9 obese subjects was analyzed by using a complementary DNA microarray at baseline after weight loss on a low-calorie diet and after weight maintenance . RESULTS : Subjects lost 18.8 ± 1.8 % of weight and maintained this loss during weight maintenance ( 1.1 ± 2.1 % ; range : -9.3 to 10.6 % ) . Most differentially expressed genes exhibited a reciprocal regulation and returned to baseline after weight loss ( 2163 genes ) and weight maintenance ( 3175 genes ) . P11597 and P45844 , both of which participate in the HDL-mediated reverse cholesterol transport ( RCT ) , were among the most upregulated of the 750 genes that were differentially expressed after both processes . Several genes involved in inflammation were downregulated . The use of real-time polymerase chain reaction confirmed or partially confirmed the previously implicated genes Q9H2S6 and P14780 ( both downregulated ) , Q9NST1 ( upregulated ) , and O60543 and O00767 ( both reciprocally regulated ) . CONCLUSIONS : The beneficial effects of weight loss should be investigated after long-term weight maintenance . The processes of weight loss and weight maintenance should be viewed as biologically distinct . P11597 and P45844 may be important mediators of these effects through HDL-mediated RCT . Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells . Head and neck squamous cell carcinoma ( HNSCC ) cells exposed to cisplatin ( Q9NSE2 ) displayed a dramatic Q13315 -dependent phosphorylation of ΔNp63α that leads to the transcriptional regulation of downstream mRNAs . Here , we report that phospho (p)-ΔNp63α transcriptionally deregulates miRNA expression after Q9NSE2 treatment . Several p-ΔNp63α-dependent microRNA species ( miRNAs ) were deregulated in HNSCC cells upon Q9NSE2 exposure , including miR-181a , miR-519a , and miR-374a ( downregulated ) and miR-630 ( upregulated ) . Deregulation of miRNA expression led to subsequent modulation of mRNA expression of several targets ( P04637 -S46 , Q9H2X6 , Q13315 , P38936 and 1B , P42574 , P09874 and 2 , P24522 and 4 , P10415 and Q92843 , O15350 , P07947 , and P46937 ) that are involved in the apoptotic process . Our data support the notion that miRNAs are critical downstream targets of p-ΔNp63α and mediate key pathways implicated in the response of cancer cells to chemotherapeutic drugs . DB01017 inhibits malignant ascites of ovarian cancer through targeting multiple signaling pathways . OBJECTIVES : To evaluate the effect of minocycline on the expression of cytokines and growth factors responsible for malignant ascite formation . METHODS : In vitro , cells obtained from malignant ascites were pre-treated with minocycline ( 0-100 μmol/L ) and exposed briefly to hypoxia . In vivo , female nude mice bearing OVCAR-3 tumors were treated orally in drinking water with minocycline for 4 weeks . Plasma , ascites , and tumors were analyzed . RESULTS : DB01017 blocked hypoxia-induced surge in interleukin-6 ( P05231 ) , its soluble receptor ( sIL-6R ) and vascular endothelial growth factor ( P15692 ) levels in concentration-dependent manner . In mice , orally administered minocycline led to dramatic reduction in tumor weight and malignant ascite volume . P05231 , sIL6R and in particular P15692 levels were highly suppressed in plasma , ascite fluid and tumor tissue by minocycline . In addition , tumors from minocycline treated mice expressed profoundly lower levels of phosphorylated extracellular regulated kinases ( p-Erk1/2 ) and p-Akt . DB01017 was also effective at suppressing transforming growth factor beta ( TGF-β1 ) and increasing vascular endothelial cadherin ( P33151 ) expression thereby providing molecular confirmation for its effects on malignant ascite formation . CONCLUSION : Orally administered minocycline is highly effective in suppressing ovarian cancer-induced malignant ascites by targeting cytokines and growth factors essential for tumor growth and malignant ascite formation . DB01017 exerts multiple inhibitory effects on vascular endothelial growth factor-induced smooth muscle cell migration : the role of P27361 /2 , PI3K , and matrix metalloproteinases . Widely used tetracycline antibiotics affect many cellular functions relevant to human vascular disease including cell proliferation , migration , and matrix remodeling . We examined whether minocycline inhibited human aortic smooth muscle cell ( HASMC ) migration induced by vascular endothelial growth factor ( P15692 ) . After the establishment of an optimal dose , minocycline treated HASMC were exposed to P15692 . HASMC migration , matrix metalloproteinase ( MMP ) -2 and P14780 activities , mitogen-activated protein kinase ( MAPK ) , and phosphatidylinositol 3-kinase ( PI3K ) phosphorylation were determined by smooth muscle cell ( SMC ) invasion assay , real-time polymerase chain reaction , zymograms , and Western blot analysis , respectively . We demonstrated that P15692 and platelet-derived growth factor ( PDGF ) -induced SMC migration in a dose-dependent manner . P14780 , but not P08253 , mRNA was increased during P15692 stimulation . P14780 activity was increased from 1.5- to 2.5-fold in a dose-dependent manner ( P < 0.05 ) . Both P27361 /2 and PI3K/AKt pathways were activated during P15692 -induced HASMCs migration . We then demonstrated that minocycline can inhibit P15692 -induced HASMC migration ( P < 0.05 ) . The effects may be through the inhibition of P14780 mRNA transcription , protein activities and downregulation of P27361 /2 and PI3K/Akt pathway phosphorylation . Our results indicated that minocycline exerts multiple effects on P15692 -induced SMC migration , including inhibition of P14780 mRNA transcription and protein activities and downregulating P27361 /2 and PI3K signal pathways , suggesting minocycline may be a potentially therapeutic approach to inhibit disease process induced angiogenesis . Matrix metalloproteinase ( MMP ) -9 , but not P08253 , is involved in the development and progression of C protein-induced myocarditis and subsequent dilated cardiomyopathy . Repeated or continuous inflammation of the heart is one of the initiation factors for dilated cardiomyopathy ( DCM ) . In previous studies , we established a DCM animal model by immunizing rats with cardiac C protein . In the present study , we analyze the role of matrix metalloproteinases ( MMPs ) in experimental autoimmune carditis ( EAC ) and subsequent DCM to elucidate the pathomechanisms of this disease . In this model , inflammation begins approximately 9 days after immunization . At that time , MMP activities were detected by in situ zymography . Real-time PCR analysis revealed continuous up-regulation of P08253 mRNA from 2 wk and thereafter . P14780 mRNA , however , had only a transient increase at 2 wk . Double staining with in situ zymography and cell markers demonstrated that gelatinase ( P08253 and P14780 ) -expressing cells are infiltrating macrophages during the early stage and cardiomyocytes at later stages . DB01017 , which inhibits P14780 activities more strongly than P08253 , significantly suppressed EAC , but an P08253 -specific inhibitor , TISAM , did not affect the course of the disease . Furthermore , immunohistochemical examination revealed that minocycline treatment suppressed T cell and macrophage infiltration strongly , whereas TISAM did not . These findings indicate that P14780 , but not P08253 , is involved in the pathogenesis of the acute phase of EAC , and further suggest that P14780 inhibitors , minocycline and its derivatives , may be useful therapies for EAC and DCM . DB00338 , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . DB00338 is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P-type H+/K+ ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . DB00338 topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . DB00338 had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . DB00338 treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase . Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein-Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy/hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 -32765 , recently renamed DB09053 , has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors . Depletion of Nrf2 enhances inflammation induced by oxyhemoglobin in cultured mice astrocytes . Q16236 ( Nrf2 ) -antioxidant response element pathway has been proved to be the key regulator in reducing inflammatory damage , which is involved in subarachnoid hemorrhage ( Q53FZ2 ) . Here , in a traditional in vitro Q53FZ2 model , we investigated the effect of Nrf2 depletion on pro-inflammatory cytokines production . Primary cultured astrocytes from Nrf2 wild type ( WT ) or knockout ( KO ) mouse were exposed or not exposed to oxyhemoglobin ( OxyHb ) . Then the DNA-binding activity of transcription factor nuclear factor-κB ( NF-κB ) was detected by EMSA . The expression of P01375 -α , IL-1β , P05231 and P14780 were evaluated . The activity of P14780 was measured by Gelatin zymography . After exposure to OxyHb , NF-κB was activated and the expression of downstream pro-inflammatory cytokines was up-regulated in astrocytes . And such up-regulation was much higher in KO astrocytes than in WT astrocytes , which means more aggravated inflammation in Nrf2 deficient astrocytes . These results suggest that astrocytes participate in inflammatory process after Q53FZ2 and the absence of Nrf2 may induce more aggressive inflammation through activation of NF-κB pathway . DB01017 with aspirin : an approach to attenuate diabetic nephropathy in rats . Degradation of extracellular matrix ( Q13201 ) by enhanced production of matrix metalloproteinase-2 ( P08253 ) and matrix metalloproteinase-9 ( P14780 ) in diabetes leads to nephropathy . Cyclooxygenases ( P36551 ) further increase levels of these MMPs . The objective of present study was to inhibit P08253 and P14780 by combination of minocycline and aspirin to treat diabetic nephropathy . Diabetes was induced in male Wistar rats by streptozotocin ( Q11206 , 55 mg/kg i.p. ) . Four weeks after diabetes induction , the rats were treated with minocycline ( 50 mg/kg , p.o. ) , aspirin ( 50 mg/kg , p.o. ) , or minocycline ( 50 mg/kg , p.o. ) plus aspirin ( 50 mg/kg , p.o. ) for a period of 4 weeks . At the end of eighth week fluid input , urine output , and renal function tests were carried out for diagnosis of diabetic nephropathy . Renal hypertrophy was measured and histopathology was done to evaluate renal damage . Diabetes produced significant loss of body weight , polyuria , polydipsia , hyperglycemia , and increase in blood pressure . Serum creatinine , urea , and blood urea nitrogen levels were found to be increased significantly in the Q11206 group diabetic rats . Treatment with combination of minocycline and aspirin significantly prevented the rise in creatinine , urea , and blood urea nitrogen levels and increased creatinine clearance . Image analysis of kidneys revealed that collagen level was significantly decreased in combined treated group when compared with control . Results of present study suggest that P08253 and P14780 inhibition in presence of P36551 inhibitor prevents the development of experimental diabetic nephropathy in rats and can be a potential approach for the treatment . Guggulsterone inhibits angiogenesis by blocking P40763 and P15692 expression in colon cancer cells . The plant sterol guggulsterone has been shown to exert anti-tumor effects , making it a candidate chemotherapeutic agent . We investigated the anti-tumor effects of guggulsterone on colon cancer cells and elucidated the underlying molecular mechanisms related to angiogenesis . The apoptotic effects of guggulsterone were examined by cell survival assay . Western blot analysis was used to determine the levels of various down-stream intracellular proteins involved in angiogenesis , including signal transducer and activator of transcription 3 ( P40763 ) , vascular endothelial growth factor ( P15692 ) , hypoxia-inducible factor-1alpha ( HIF-1alpha ) and aryl hydrocarbon receptor nuclear translocator ( P27540 ) . Using chromatin immunoprecipitation assay , we tested whether guggulsterone affects the recruitment of P40763 , P27540 and HIF-1alpha to the human P15692 promoter . To investigate the effect of guggulsterone on vascular endothelial cell migration and invasion , tube formation and migration assays were conducted using human umbilical vein endothelial cells ( HUVECs ) . Matrix metalloproteinase ( MMP ) -2 and -9 activities were measured by gelatin zymography . Guggulsterone significantly reduced cell viability in colon cancer cells in a dose-dependent manner and blocked P15692 , P27540 and P40763 expression prominently in hypoxic conditions . The recruitment of P40763 and P27540 , but not HIF-1alpha , to the P15692 promoter was inhibited by guggulsterone treatment . HUVECs produced much foreshortened and severely broken tubes and showed decreased migration activity under guggulsterone effects . In addition , zymography revealed that P08253 and -9 enzyme activities were markedly lower in the presence of guggulsterone . The results of this study suggest that guggulsterone not only induces apoptosis , but also inhibits angiogenesis and metastasis in colon cancer cells by blocking P40763 and P15692 expression , suggesting its therapeutic potential in the treatment of colorectal cancer . Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first-line therapy in LDL- DB04540 ( LDL-C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL-C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin/kexin type 9 ( Q8NBP7 ) , apolipoprotein-B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and DB08827 ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease . Apigenin up-regulates transgelin and inhibits invasion and migration of colorectal cancer through decreased phosphorylation of AKT . Colorectal cancer ( CRC ) is a major cause of morbidity and mortality throughout the world . Apigenin is a flavonoid that possesses various clinically relevant properties such as anti-tumour , anti-platelet and anti-inflammatory activities . Our results showed that apigenin has anti-proliferation , anti-invasion and anti-migration effects in three kinds of colorectal adenocarcinoma cell lines , namely SW480 , DLD-1 and LS174T . Proteomic analysis with SW480 indicated that apigenin up-regulated the expression of transgelin ( Q01995 ) in mitochondria to exert its anti-tumour growth and anti-metastasis effects . Real-time quantitative polymerase chain reaction ( RQ-PCR ) and western blot confirm the up-regulation in all the three colorectal adenocarcinoma cells . An inverse correlation was observed between Q01995 expression and CRC metastasis in tissue microarray staining . Q01995 siRNA increased the viability of SW480 . Apigenin decreased the expression of P14780 in a dose-dependent manner . Transfection of three truncated forms of Q01995 and wild type has identified Q01995 as a repressor of P14780 expression . A synergetic effect was observed in overexpression of Q01995 wild type and apigenin treatment which manifested as lowered phosphorylation of AKT Ser473 and Q06187 Thr308 . In an orthotopic CRC model , apigenin inhibited tumour growth and metastasis to liver and lung . In conclusion , our research provided direct evidence that apigenin inhibited tumour growth and metastasis both in vitro and in vivo . Apigenin up-regulated Q01995 and hence down-regulated P14780 expression through decreasing phosphorylation of Akt at Ser473 and in particular Thr308 to prevent cell proliferation and migration . DB01017 inhibits P09917 expression and accelerates functional recovery in chronic phase of focal cerebral ischemia in rats . AIMS : We previously reported that minocycline attenuates acute brain injury and inflammation after focal cerebral ischemia , and this is partly mediated by inhibition of P09917 ( 5- P28300 ) expression . Here , we determined the protective effect of minocycline on chronic ischemic brain injury and its relation with the inhibition of 5- P28300 expression after focal cerebral ischemia . MAIN METHODS : Focal cerebral ischemia was induced by 90 min of middle cerebral artery occlusion followed by reperfusion for 36 days . DB01017 ( 45 mg/kg ) was administered intraperitoneally 2h and 12h after ischemia and then every 12h for 5 days . Sensorimotor function was evaluated 1-28 days after ischemia and cognitive function was determined 30-35 days after ischemia . Thereafter , infarct volume , neuron density , astrogliosis , and 5- P28300 expression in the brain were determined . KEY FINDINGS : DB01017 accelerated the recovery of sensorimotor and cognitive functions , attenuated the loss of neuron density , and inhibited astrogliosis in the boundary zone around the ischemic core , but did not affect infarct volume . DB01017 significantly inhibited the increased 5- P28300 expression in the proliferated astrocytes in the boundary zone , and in the macrophages/microglia in the ischemic core . SIGNIFICANCE : DB01017 accelerates functional recovery in the chronic phase of focal cerebral ischemia , which may be partly associated with the reduction of 5- P28300 expression . DB01017 reduces renal microvascular leakage in a rat model of ischemic renal injury . Tetracyclines exhibit significant anti-inflammatory properties , inhibit matrix metalloproteinases ( MMPs ) , and are protective in models of ischemia-reperfusion injury ( IRI ) . Both inflammatory cascades and MMP activation have been demonstrated to modulate microvascular permeability . Because increased microvascular permeability occurs during IRI in a variety of organ systems including the kidney , we hypothesized that minocycline , a semisynthetic tetracycline , would diminish microvascular leakage during renal IRI . To test this hypothesis , we used intravital 2-photon microscopy to examine leakage of fluorescent dextrans from the vasculature in a rodent model of IRI . DB01017 significantly reduced the extent of dextran ( 500 kDa ) leakage from the renal microvasculature 24 h after ischemia . Although minocycline diminished leukocyte accumulation in the kidney following ischemia , areas of leukocyte accumulation did not correlate with areas of microvascular permeability in either the saline- or minocycline-pretreated animals . DB01017 diminished the perivascular increase in P08253 and P14780 , as well as the increase in P08253 activity 24 h after ischemia . ABT-518 , a specific inhibitor of P08253 and P14780 , also significantly reduced the extent of dextran ( 500 kDa ) leakage from the renal microvasculature 24 h after ischemia . Our results indicate that minocycline mitigates the renal microvascular permeability defect following IRI . This effect is spatially distinct from the effect of minocycline on leukocyte accumulation and may be related to diminished activity of MMPs on the integrity of the perivascular matrix . P01375 -α-accelerated degradation of type I collagen in human skin is associated with elevated matrix metalloproteinase ( MMP ) -1 and P08254 ex vivo . P01375 ( P01375 ) -α induces matrix metalloproteinases ( MMPs ) that may disrupt skin integrity . We have investigated the effects and mechanisms of exogenous P01375 -α on collagen degradation by incubating human skin explants in defined serum-free media with or without P01375 -α ( 10ng/ml ) in the absence or presence of the nonselective MMP inhibitor DB02255 for 8 days . The basal culture conditions promoted type I collagen catabolism that was accelerated by P01375 -α ( p < 0.005 ) and accomplished by MMPs ( p < 0.005 ) . Levels of the collagenases P22894 and P45452 were insignificant and neither P08253 nor P50281 were associated with increased collagen degradation . P01375 -α increased secretion of P03956 ( p < 0.01 ) but had no impact on P03956 quantities in the tissue . Immunohistochemical analysis confirmed similar tissue P03956 expression with or without P01375 -α with epidermis being the major source of P03956 . Increased tissue-derived collagenolytic activity with P01375 -α exposure was blocked by neutralizing P03956 monoclonal antibody and was not due to down-regulation of tissue inhibitor of metalloproteinase-1 . P01375 -α increased production ( p < 0.01 ) , tissue levels ( p < 0.005 ) and catalytic activity of the endogenous P03956 activator P08254 . Type I collagen degradation correlated with P08254 tissue levels ( rs=0.68 , p < 0.05 ) and was attenuated with selective P08254 inhibitor . Type I collagen formation was down-regulated in cultured compared with native skin explants but was not reduced further by P01375 -α . P01375 -α had no significant effect on epidermal apoptosis . Our data indicate that P01375 -α augments collagenolytic activity of P03956 , possibly through up-regulation of P08254 leading to gradual loss of type I collagen in human skin . Cytokines and growth factors stimulate hyaluronan production : role of hyaluronan in epithelial to mesenchymal-like transition in non-small cell lung cancer . In this study , we investigated the role of hyaluronan ( HA ) in non-small cell lung cancer ( NSCLC ) since close association between HA level and malignancy has been reported . HA is an abundant extracellular matrix component and its synthesis is regulated by growth factors and cytokines that include epidermal growth factor ( P01133 ) and interleukin-1beta ( IL-1beta ) . We showed that treatment with recombinant P01133 and IL-1beta , alone or in combination with TGF-beta , was able to stimulate HA production in lung adenocarcinoma cell line A549 . TGF-beta/IL-1beta treatment induced epithelial to mesenchymal-like phenotype transition ( EMT ) , changing cell morphology and expression of vimentin and P12830 . We also overexpressed hyaluronan synthase-3 ( O00219 ) in epithelial lung adenocarcinoma cell line H358 , resulting in induced HA expression , EMT phenotype , enhanced P14780 and P08253 activities and increased invasion . Furthermore , adding exogenous HA to A549 cells and inducing HA H358 cells resulted in increased resistance to epidermal growth factor receptor ( P00533 ) inhibitor , DB00317 . Together , these results suggest that elevated HA production is able to induce EMT and increase resistance to DB00317 in NSCLC . Therefore , regulation of HA level in NSCLC may be a new target for therapeutic intervention . Moving beyond chemotherapy : novel cytostatic agents for malignant mesothelioma . It is now known that vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) are autocrine growth factors in malignant mesothelioma ; epidermal growth factor receptor ( P00533 ) is also highly overexpressed . Cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma . Clinical trials have recently been initiated to evaluate the anti-tumour activity of the P15692 inhibitors SU5416 , bevacizumab and thalidomide . ZD1839 ( DB00317 , AstraZeneca ) , an inhibitor of P00533 tyrosine kinase , is also being evaluated . Two clinical trials are planned to evaluate the two PDGF inhibitors Gleevec ( Imatinib mesylate , STI-571 , Novartis Pharmaceuticals ) and PTK787 ( Novartis Pharmaceuticals ) . Glioma-associated microglial P14780 expression is upregulated by O60603 signaling and sensitive to minocycline . The invasiveness of malignant gliomas is one of the major obstacles in glioma therapy and the reason for the poor survival of patients . Glioma cells infiltrate into the brain parenchyma and thereby escape surgical resection . Glioma associated microglia/macrophages support glioma infiltration into the brain parenchyma by increased expression and activation of extracellular matrix degrading proteases such as matrix metalloprotease ( MMP ) 2 , P14780 and membrane-type 1 MMP . In this work we demonstrate that , P14780 is predominantly expressed by glioma associated microglia/macrophages in mouse and human glioma tissue but not by the glioma cells . Supernatant from glioma cells induced the expression of P14780 in cultured microglial cells . Using mice deficient for different Toll-like receptors we identified O60603 /6 as the signaling pathway for the glioma induced upregulation of microglial P14780 . Also in an experimental mouse glioma model , O60603 deficiency attenuated the upregulation of microglial P14780 . Moreover , glioma supernatant triggered an upregulation of O60603 expression in microglia . Both , the upregulation of P14780 and O60603 were attenuated by the antibiotic minocycline and a p38 mitogen-activated protein kinase antagonist in vitro . DB01017 also extended the survival rate of glioma bearing mice when given to the drinking water . Thus glioma cells change the phenotype of glioma associated microglia/macrophages in a complex fashion using O60603 as an important signaling pathway and minocycline further proved to be a potential candidate for adjuvant glioma therapy . Effect of NC-1900 , an active fragment analog of arginine vasopressin , and inhibitors of arachidonic acid metabolism on performance of a passive avoidance task in mice . In this study , we investigated the effect of administration of inhibitors of each of the arachidonic acid metabolism pathways and the effect of co-administration of these inhibitors with NC-1900 , a fragment analog of arginine vasopressin , on step-through passive avoidance task performance . All drugs were administered just after the acquisition trial in the passive avoidance task . Intracerebroventricular ( i.c.v. ) administration of nordihydroguaiaretic acid ( NDGA , 1 and 10 microg ) , a phospholipase A2 ( P04054 ) and lipoxygenase ( P28300 ) inhibitor , and of arachidonyl trifluoromethyl ketone ( Q06187 , 1 and 10 microg ) , a specific P04054 inhibitor caused reductions in latency on the retention trial . The i.c.v. administration of either of baicalein ( 0.1-10 microg ) , a P16050 inhibitor , or AA-861 ( 0.1-10 microg ) , a 5- P28300 inhibitor , did not influence the latency . Intraperitoneal administration of indomethacin ( 20 mg/kg ) , a non-specific P36551 inhibitor , or NS-398 ( 10 mg/kg ) , a specific P35354 inhibitor , impaired performance on the retention trial in the task , while piroxicam ( 20 mg/kg ) , a specific P23219 inhibitor , did not . Subcutaneous administration of NC-1900 ( 0.1 ng/kg ) ameliorated the reduction of latency caused by NDGA , Q06187 , indomethacin , or NS-398 . These results suggested that the P35354 pathway of arachidonic acid metabolism may be important for learning and/or memory in the passive avoidance task in mice , and that the ameliorating effect of NC-1900 , in part , is due to mimicking of the effects of metabolites of the P35354 pathway . DB01017 protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice . DB01017 is protective in models of transient middle cerebral artery occlusion ( MCAO ) . We studied whether minocycline and doxycycline , another tetracycline derivative , provide protection in permanent MCAO . Because minocycline inhibits matrix metalloprotease-9 ( P14780 ) , we also compared minocycline 's protective effect in wild type ( wt ) and P14780 knock-out ( ko ) mice . Wt FVB/N , Balb/C , and two lines of P14780 ko and their wt C57Bl/6 control mice were subjected to 24- or 72-hour permanent MCAO . Drug administration was started either 12 hours before or 2 hours after the onset of MCAO . Infarct size was determined by triphenyltetrazolium staining or P24752 -weighted Q9BWK5 . Zymography was used to study the expression of MMPs . In wt strains , tetracycline treatments started before MCAO reduced the infarct size by 25 % to 50 % , whereas the treatment started after MCAO was not protective . DB01017 inhibited ischemia-provoked pro- P14780 induction in wt mice , but was not protective in P14780 ko mice . Pro- P08253 was induced by MCAO in wt and P14780 ko mice . MCAO-induced pro- P08253 was downregulated by minocycline treatment in wt mice but remained in P14780 ko mice at the same level as in saline-treated wt mice . Tetracyclines are protective in permanent MCAO when the treatment is started before the insult . DB01017 may provide protection by interfering with MMPs . DB01017 accelerates hypoxia-inducible factor-1 alpha degradation and inhibits hypoxia-induced neovasculogenesis through prolyl hydroxylase , von Hippel-Lindau-dependent pathway . Hypoxia-mediated stress responses are important in tumor progression , especially when tumor growth causes the tumor to become deprived of its blood supply . The oxygen-labile transcription factor hypoxia-inducible factor-1 alpha ( HIF-1α ) plays a critical role in regulating hypoxia stress-related gene expression and is considered a novel therapeutic target . Lung adenocarcinoma cell lines were exposed to minocycline , followed by incubation at hypoxic condition for 3-6 h . Here , we show that minocycline , a second-generation tetracycline , can induce HIF-1α proteasomal degradation under hypoxia by increasing the expression prolyl hydroxylase-2 and HIF-1α/von Hippel-Lindau protein interaction , thereby overcoming hypoxia-induced HIF-1α stabilization . Neither repression of hypoxia-induced phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway nor inhibition of Hsp90 was required for minocycline-induced HIF-1α degradation . The HIF-1α degradation-enhancing effect of minocycline was evident in both cancerous and primary cells . DB01017 -pretreated , hypoxia-conditioned cells showed a clear reduction in hypoxia response element reporter expression and amelioration of vascular endothelial growth factor C/D ( P49767 /D ) , matrix metalloproteinase 2 , and glucose transporter 1 expression . By decreasing P15692 secretion of cancerous cells , minocycline could suppress endothelial cell neovasculogenesis . These findings suggest a novel application of minocycline in the treatment of tumor angiogenesis as well as hypoxia-related diseases . DB01017 with aspirin : a therapeutic approach in the treatment of diabetic neuropathy . Enhanced production of matrix metalloproteinase-2 ( P08253 ) and matrix metalloproteinase-9 ( P14780 ) in diabetes leads to degradation of extracellular matrix in blood vessels and leads to complications of diabetes . In the present study , we have targeted P08253 and P14780 overactivation in diabetic neuropathy using a known P08253 and P14780 inhibitor , minocycline , with a non-selective P36551 inhibitor , aspirin . DB00428 -induced diabetic neuropathy was carried out in male Wistar rats and monitored by measuring the sensory nerve conduction velocity ( SNCV ) , motor nerve conduction velocity ( MNCV ) , tail flick latency and hot plate latency . Three weeks of treatment with a combination of minocycline and aspirin showed significant improvement in SNCV , MNCV , hot plate latency and tail flick latency when compared with diabetic control . The results of the present study suggest that P08253 and P14780 inhibition in the presence of P36551 inhibitor prevents the development of experimental diabetic neuropathy in rats and can be a potential approach for the treatment . AZD1480 blocks growth and tumorigenesis of P07949 - activated thyroid cancer cell lines . Persistent P07949 activation is a frequent event in papillary thyroid carcinoma ( PTC ) and medullary thyroid carcinoma ( P04629 ) . In these cancers , P07949 activates the P29323 /MAPK , the PI3K/AKT/ P42345 and the JAK/ P40763 pathways . Here , we tested the efficacy of a P23458 /2- inhibitor , AZD1480 , in the in vitro and in vivo growth of thyroid cancer cell lines expressing oncogenic P07949 . Thyroid cancer cell lines harboring P07949 / Q13635 ( TPC-1 ) , P07949 M918T ( MZ-CRC1 ) and P07949 C634W ( TT ) alterations , as well as TPC-1 xenografts , were treated with JAK inhibitor , AZD1480 . This inhibitor led to growth inhibition and/or apoptosis of the thyroid cancer cell lines in vitro , as well as to tumor regression of TPC-1 xenografts , where it efficiently blocked P40763 activation in tumor and stromal cells . This inhibition was associated with decreased proliferation , decreased blood vessel density , coupled with increased necrosis . However , AZD1480 repressed the growth of P40763 - deficient TPC-1 cells in vitro and in vivo , demonstrating that its effects in this cell line were independent of P40763 in the tumor cells . In all cell lines , the JAK inhibitor reduced phospho-Y1062 P07949 levels , and P42345 effector phospho-S6 , while P23458 /2 downregulation by siRNA did not affect cell growth nor P07949 and S6 activation . In conclusion , AZD1480 effectively blocks proliferation and tumor growth of activated P07949 - thyroid cancer cell lines , likely through direct P07949 inhibition in cancer cells as well as by modulation of the microenvironment ( e.g. via JAK/phospho- P40763 inhibition in endothelial cells ) . Thus , AZD1480 should be considered as a therapeutic agent for the treatment of P07949 - activated thyroid cancers . DB01017 effects on cerebral edema : relations with inflammatory and oxidative stress markers following traumatic brain injury in mice . One of the severe complications following traumatic brain injury ( TBI ) is cerebral edema and its effective treatment is of great interest to prevent further brain damage . This study investigated the effects of minocycline , known for its anti-inflammatory properties , on cerebral edema and its respective inflammatory markers by comparing different dose regimens , on oxidative stress and on neurological dysfunction following TBI . The weight drop model was used to induce TBI in mice . The brain water content was measured to evaluate cerebral edema . Inflammatory markers were detected by ELISA ( IL-1beta ) , zymography and Western blot ( P14780 ) . The oxidative stress marker ( glutathione levels ) and neurological function were measured by Griffith technique and string test , respectively . DB01017 was administered i.p. once ( 5 min ) , twice ( 5 min and 3 h ) or triple ( 5 min , 3 h and 9 h ) following TBI . The first dose of minocycline only varied ( 45 or 90 mg/kg ) , whereas the following doses were all at 45 mg/kg . The single and double administrations of minocycline reduced the increase of inflammatory markers at 6 h post-TBI . DB01017 also reduced cerebral edema at this time point , only after double administration and at the high dose regimen , although with no effect on the TBI-induced oxidized glutathione increase . The anti-edematous effect of minocycline persisted up to 24 h , upon a triple administration , and accompanied by a neurological recovery . In conclusion , we reported an anti-edematous effect of minocycline after TBI in mice according to a specific treatment regimen . These findings emphasize that the beneficial effects of minocycline depend on the treatment regimen following a brain injury . Inhibitors of P11274 signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma . Several studies provide evidences for mantle cell lymphoma ( Q8WXI8 ) cell survival relying on B-cell receptor ( P11274 ) -mediated signalling pathways , whereas the nature of this activation is unknown . Significant progress in Q8WXI8 treatment is achieved through therapies targeting P11274 -associated kinases , i.e. , DB09053 and Fostamatinib , inhibitors of Q06187 and P43405 , respectively . Our study addresses survival signals emanating from the P11274 or the tumour environment and how inhibiting P11274 signalling effectors might impact these survival signals . We found that Q06187 was constitutively activated and that P43405 phosphorylation was highly increased and sustained upon P11274 activation of primary Q8WXI8 cells . Moreover , Q8WXI8 cells from leukaemic patients secreted high amount of IL-1β , P05231 , P10145 and P13501 . Activation of the P11274 induced ( i ) cell survival , ( ii ) P40763 activation and ( iii ) increased autocrine secretion of IL-1β , P05231 , P10145 , P13501 , P22301 , TNFα and P15692 . Specific inhibition of Q06187 by DB09053 or P43405 by Fostamatinib ( R406 ) reversed these protective effects and decreased both basal and P11274 -induced autocrine cytokine secretions associated with P40763 phosphorylation . Interestingly , targeting Q06187 and P43405 prevented and inhibited P11274 -induced Q8WXI8 cell adhesion to human bone marrow stromal cells ( HMSCs ) in short- and long-term co-culture . We demonstrated that P11274 -induced survival relies on autocrine secretion of IL-1β , TNFα and P13501 that might facilitate adhesion of Q8WXI8 cells to HMSC . Treatment with DB09053 or Fostamatinib blocked the chemotactic signal thus increasing apoptosis . The impact of biological agents interfering with receptor/ligand binding in the immune system . We herein discuss the impact of biological agents based on the ability of monoclonal antibodies to target specific molecules . This approach has given to clinical immunologists a spectrum of drugs able to manipulate the immune system . In the first session , we discuss drugs targeting T-cell function by : ( 1 ) targeting P10747 mediated costimulation ( DB01281 and DB06681 ) ; ( 2 ) interfering with interleukin-2 receptor ( DB00074 and DB00111 ) ; ( 3 ) blocking cell adhesion and homing ( DB00092 , DB00095 , DB00108 ) . The second session is dedicated to drugs targeting cytokines or their receptors . The best known and largely experimented case is represented by drugs targeting tumor necrosis factor ( P01375 ) ( DB00065 , Adalilumab , Certolizumab ) or its p75 receptor ( DB00005 ) . However , newer products are now available to target other inflammatory cytokines including P05231 , P10145 , IL-12 , P40933 , Q14116 , IL-23 . These agents have the potential to become powerful tools in the control of several immune-mediated diseases , especially auto-immune and inflammatory ones . They traslate into reality the prediction that antibodies will eventually become " magic bullets which seek their own target " ( P. Ehrich , 1906 ) . DB01017 modulates cytokine and gene expression profiles in the brain after whole-body exposure to radiation . An effective countermeasure against radiation damage to normal tissues is urgently needed . The major goal of the present study was to determine if minocycline could modify the immunomodulatory effects of radiation on the brain . C57BL/6 mice were treated with minocycline intraperitoneally for 5 days beginning immediately before total-body exposure to 0 , 1 , 2 and 3 Gray ( Gy ) (60)Co γ-rays . Brains were collected on days 4 and 32 post-irradiation for cytokine and gene analyses . DB01017 treatment significantly increased the levels of interleukin ( IL ) -10 , P40933 and vascular endothelial growth factor ( P15692 ) in the brain on day 4 in one or more irradiated groups compared to radiation-alone ( p < 0.05 ) . P22301 is anti-inflammatory , P40933 can prevent apoptosis and P15692 is nuroprotective . On day 32 , the drug decreased IL-1β in the 2- Gy group ( p < 0.05 vs. 2-Gy alone ) ; this cytokine is implicated in immune-related central nervous system pathologies . Microarray analysis of brains on day 32 showed that while radiation increased expression of inflammatory genes such as Il1f10 , Il17 , Tnfrsf11b , Tnfsf12 , Il12b and Il1f8 , these were no longer up-regulated in the minocycline-treated groups . Similarly , the pro-apoptotic gene Bik and nitric oxide synthase producer ( Q8IVI9 ) were no longer up-regulated in the drug-treated groups . Pathway analysis based on gene data suggested that catenin-β1 and tumor suppressor-related transcription regulation were significantly activated by radiation and/or minocycline ( activation z-score > 2.0 ) . Overall , the data warrant further testing of minocycline as a potential neuroprotectant against radiation-induced damage . DB01017 promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model . BACKGROUND : Fragile X syndrome ( FXS ) is the most common single gene inherited form of mental retardation , with behaviours at the extreme of the autistic spectrum . Subjects with FXS and fragile X mental retardation gene knock out ( Fmr1 KO ) mice , an animal model for FXS , have been shown to exhibit defects in dendritic spine maturation that may underlie cognitive and behavioural abnormalities in FXS . DB01017 is a tetracycline analogue that has been used in clinical trials for stroke , multiple sclerosis and several neurodegenerative conditions . METHODS : We evaluated the effects of minocycline on dendritic spine development in the hippocampus of young Fmr1 KO mice , and in primary cultures of hippocampal neurons isolated from those mice . Cognitive effects of minocycline in young WT and Fmr1 KO mice were also evaluated using established behavioural tests for general cognition , activity and anxiety . RESULTS : Our studies demonstrate that minocycline promotes dendritic spine maturation both in cultures and in vivo . The beneficial effects of minocycline on dendritic spine morphology are also accompanied by changes in the behavioural performance of 3-week-old Fmr1 KO mice . DB01017 treated Fmr1 KO mice show less anxiety in the elevated plus maze and more strategic exploratory behaviour in the Y maze as compared to untreated Fmr1 KO mice . Our data suggest that these effects of minocycline may relate to its inhibitory action on P14780 expression and activity , which are higher in the hippocampus of Fmr1 KO mice . CONCLUSION : These findings establish minocycline as a promising therapeutic for the treatment of fragile X mental retardation . DB01017 prevents dynorphin-induced neurotoxicity during neuropathic pain in rats . Despite many advances , our understanding of the involvement of prodynorphin systems in the development of neuropathic pain is not fully understood . Recent studies suggest an important role of neuro-glial interactions in the dynorphin effects associated with neuropathic pain conditions . Our studies show that minocycline reduced prodynorphin mRNA levels that were previously elevated in the spinal and/or dorsal root ganglia ( Q86YR7 ) following sciatic nerve injury . The repeated intrathecal administration of minocycline enhanced the analgesic effects of low-dose dynorphin ( 0.15 nmol ) and U50,488H ( 25-100 nmol ) and prevented the development of flaccid paralysis following high-dose dynorphin administration ( 15 nmol ) , suggesting a neuroprotective effect . DB01017 reverts the expression of IL-1β and P05231 mRNA within the spinal cord and IL-1β mRNA in Q86YR7 , which was elevated following intrathecal administration of dynorphin ( 15 nmol ) . These results suggest an important role of these proinflammatory cytokines in the development of the neurotoxic effects of dynorphin . Similar to minocycline , a selective inhibitor of P14780 ( P14780 levels are reduced by minocycline ) exerts an analgesic effect in behavioral studies , and its administration prevents the occurrence of flaccid paralysis caused by high-dose dynorphin administration ( 15 nmol ) . In conclusion , our results underline the importance of neuro-glial interactions as evidenced by the involvement of IL-1β and P05231 and the minocycline effect in dynorphin-induced toxicity , which suggests that drugs that alter the prodynorphin system could be used to better control neuropathic pain . Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC-4047 ( Actimid , DB08910 ) have been used as anti-inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha ( P01375 ) , interleukins ( IL ) 1-beta , 6 , 12 , and granulocyte macrophage-colony stimulating factor ( GM- P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti-angiogenic , anti-proliferative , and pro-apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies . DB01017 attenuates hypoxia-inducible factor-1α expression correlated with modulation of p53 and AKT/ P42345 /p70S6K/ Q13541 pathway in ovarian cancer : in vitro and in vivo studies . Hypoxia-inducible factor ( HIF ) -1α is the key cellular survival protein under hypoxia , and is associated with tumor progression and angiogenesis . We have recently shown the inhibitory effects of minocycline on ovarian tumor growth correlated with attenuation of vascular endothelial growth factor ( P15692 ) and herein report a companion laboratory study to test if these effects were the result of HIF-1α inhibition . In vitro , human ovarian carcinoma cell lines ( A2780 , OVCAR-3 and SKOV-3 ) were utilized to examine the effect of minocycline on Q9BYW2 and its upstream pathway components to elucidate the underlying mechanism of action of minocycline . Mice harboring OVCAR-3 xenografts were treated with minocycline to assess the in vivo efficacy of minocycline in the context of Q9BYW2 . DB01017 negatively regulated HIF-1α protein levels in a concentration-dependent manner and induced its degradation by a mechanism that is independent of prolyl-hydroxylation . The inhibition of HIF-1α was found to be associated with up-regulation of endogenous p53 , a tumor suppressor with confirmed role in HIF-1α degradation . Further studies demonstrated that the effect of minocycline was not restricted to proteasomal degradation and that it also caused down-regulation of HIF-1α translation by suppressing the AKT/ P42345 /p70S6K/ Q13541 signaling pathway . DB01017 treatment of mice bearing established ovarian tumors , led to suppression of HIF-1α accompanied by up-regulation of p53 protein levels and inactivation of AKT/ P42345 /p70S6K/ Q13541 pathway . These data reveal the therapeutic potential of minocycline in ovarian cancer as an agent that targets the pro-oncogenic factor HIF-1α through multiple mechanisms . DB01017 improves functional outcomes , memory deficits , and histopathology after endovascular perforation-induced subarachnoid hemorrhage in rats . Subarachnoid hemorrhage ( Q53FZ2 ) results in significant long-lasting cognitive dysfunction . Therefore , evaluating acute and long-term outcomes after therapeutic intervention is important for clinical translation . The aim of this study was to use minocycline , a known neuroprotectant agent , to evaluate the long-term benefits in terms of neurobehavior and neuropathology after experimental Q53FZ2 in rats , and to determine which neurobehavioral test would be effective for long-term evaluation . Q53FZ2 was induced by endovascular perforation in adult male Sprague-Dawley rats ( n=118 ) . The animals were treated with intraperitoneal injection of minocycline ( 45 mg/kg or 135 mg/kg ) or vehicle 1 h after Q53FZ2 induction . In the short-term , animals were euthanized at 24 and 72 h for evaluation of neurobehavior , brain water content , and matrix metalloproteinase ( MMP ) activity . In the long-term , neurobehavior was evaluated at days 21-28 post- Q53FZ2 , and histopathological analysis was done at day 28 . High-dose but not low-dose minocycline reduced brain water content at 24 h , and therefore only the high-dose regimen was used for further evaluation , which reduced P14780 activity at 24 h . Further , high-dose minocycline improved spatial memory and attenuated neuronal loss in the hippocampus and cortex . The rotarod , T-maze , and water maze tests , but not the inclined plane test , detected neurobehavioral deficits in Q53FZ2 rats at days 21-28 . This study demonstrates that minocycline attenuates long-term functional and morphological outcomes after endovascular perforation-induced Q53FZ2 . Long-term neurobehavioral assessments using the rotarod , T-maze , and water maze tests could be useful to evaluate the efficacy of therapeutic intervention after experimental Q53FZ2 . P14780 in an exploratory trial of intravenous minocycline for acute ischemic stroke . BACKGROUND AND PURPOSE : Plasma matrix metalloproteinase-9 levels predict posttissue plasminogen activator ( tPA ) hemorrhage . METHODS : The authors investigated the effect of minocycline on plasma matrix metalloproteinase-9 in acute ischemic stroke in the DB01017 to Improve Neurological Outcome in Stroke ( MINOS ) trial and a comparison group . RESULTS : P14780 level decreased at 72 hours compared with baseline in MINOS ( tPA , P=0.0022 ; non-tPA , P=0.0066 ) and was lower than in the non-MINOS comparison group at 24 hours ( tPA , P < 0.0001 ; non-tPA , P=0.0019 ) . CONCLUSIONS : Lower plasma matrix metalloproteinase-9 was seen among tPA-treated subjects in the MINOS trial . Combining minocycline with tPA may prevent the adverse consequences of thrombolytic therapy through suppression of matrix metalloproteinase-9 activity . Q9Y6X2 negatively regulates O14788 -mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor ( NF ) -kappaB ligand ( O14788 ) -mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction . Protein inhibitor of activated P40763 ( Q9Y6X2 ) was initially identified as a molecule that inhibits DNA binding of P40763 and regulates many transcription factors through distinct mechanisms . To analyze Q9Y6X2 function in osteoclasts in vivo , we have generated transgenic mice in which Q9Y6X2 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase ( TRAP ) gene promoter . Q9Y6X2 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation . Overexpression of Q9Y6X2 in RAW264.7 cells suppressed O14788 -induced osteoclastogenesis by inhibiting the expression of c-Fos and O95644 . Interestingly , Q9Y6X2 inhibits the transcriptional activity of microphthalmia-associated transcription factor ( O75030 ) independent of sumoylation . Down-regulation of Q9Y6X2 markedly enhances O14788 -mediated osteoclastogenesis in RAW264.7 cells . Furthermore , overexpression of Q9Y6X2 in mouse primary osteoblast ( DB00925 ) , down-regulates O14788 expression induced by interleukin-6 ( P05231 ) cytokine family , and inhibits osteoclast formation from bone marrow macrophages ( BMMs ) in vitro coculture system . Down-regulation of Q9Y6X2 leads to the accelerated expression of O14788 in DB00925 stimulated with P05231 and soluble P05231 receptor ( sIL-6R ) . Taken together , our results clearly indicate that Q9Y6X2 negatively regulates O14788 -mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts . PEG minocycline-liposomes ameliorate CNS autoimmune disease . BACKGROUND : DB01017 is an oral tetracycline derivative with good bioavailability in the central nervous system ( CNS ) . DB01017 , a potent inhibitor of matrix metalloproteinase ( MMP ) -9 , attenuates disease activity in experimental autoimmune encephalomyelitis ( EAE ) , an animal model of multiple sclerosis ( MS ) . Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning . Here , we investigated whether less frequent treatment with long-circulating polyethylene glycol ( PEG ) minocycline liposomes are effective in treating EAE . FINDINGS : Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells ( PBMCs ) , we determined that PEG minocycline-liposome preparations stabilized with CaCl(2) are effective in diminishing P14780 activity . Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline . Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes , and the overall expression of P14780 in the CNS . There was also a significant suppression of P14780 expression and proteolytic activity in splenocytes of treated animals , but not in CNS-infiltrating leukocytes . Thus , leukocytes gaining access to the brain and spinal cord require the same absolute amount of P14780 in all treatment groups , but minocycline decreases the absolute cell number . CONCLUSIONS : Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases . Also , inhibition of P14780 remains a promising treatment target in EAE and patients with MS . JTT-705 blocks cell proliferation and angiogenesis through p38 kinase/p27(kip1) and Ras/ P38936 (waf1) pathways . The excessive proliferation and migration of vascular smooth muscle cells ( SMCs ) participate in the growth and instability of atherosclerotic plaque . We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein , JTT-705 , on SMC proliferation and angiogenesis in endothelial cells ( ECs ) . JTT-705 inhibited human coronary artery SMC proliferation . JTT-705 induced the phosphorylation of p38 mitogen-activated protein kinase ( MAPK ) and extracellular-signal-regulated kinases ( P29323 ) in SMCs . In addition , the anti-proliferative effects of JTT-705 in SMCs were blocked by p38 MAPK inhibitor . JTT-705 induced the upregulation of p- P38936 (waf1) , and this effect was blocked by dominant-negative Ras ( N17 ) , but not by inhibitors of p38 MAPK or P29323 . In addition , JTT-705 also induced the upregulation of p27(kip1) , and this effect was blocked by p38 MAPK inhibitor . Interestingly , culture medium from JTT-705-treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor ( P15692 ) from SMCs and directly via an anti-proliferative effect in ECs . JTT-705 blocked the proliferation of SMCs through the activation of p38 kinase/p27(kip1) and Ras/ P38936 (waf1) pathways , and simultaneously blocked EC tube formation associated with a decrease in P15692 production from SMCs and an anti-proliferative effect in ECs . Our results indicate that JTT-705 may induce a direct anti-atherogenic effect in addition to its inhibitory effect of P11597 activity . A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue-specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two-hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 's DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull-down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co-immunoprecipitation of Q9Y6X2 . Co-transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP-6 promoter-luciferase reporter demonstrated up to 94 % inhibition of O75030 -mediated transcriptional activation . Using a gel-shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development . DB01017 partially inhibits caspase-3 activation and photoreceptor degeneration after photic injury . PURPOSE : To evaluate the possible role of caspase-3 in retinal photic injury , and to investigate whether minocycline can ameliorate light-induced photoreceptor degeneration . METHODS : Retinal photic injury was induced in rats by exposure to intense light . Expression of caspase-3 was studied using Western blot analysis , immunohistochemical staining and enzyme activity assay . Apoptotic photoreceptor cells were detected by the TdT-dUTP terminal nick-end labeling ( TUNEL ) method . DB01017 ( 15 , 30 or 45 mg/kg ) was administered before or after photic injury in rats randomly assigned to pretreatment and posttreatment groups . DB01017 and vehicle-treated retinas subjected to photic injury were compared with respect to Western blotting , enzyme activity assay , quantitative counts of TUNEL stains , morphometry of the outer nuclear layer ( ONL ) thickness and histopathological examination . RESULTS : After light exposure , active caspase-3 and poly-adenosine diphosphate-ribose-polymerase were upregulated in the retinas and increased caspase-3 immunoreactivity was observed in the ONL . P42574 enzyme activity increased in the retinas that underwent photic injury , and this increase was significantly reduced in minocycline pretreated ( 30 and 45 mg/kg ) and posttreated ( 45 mg/kg ) groups . Intraperitoneal administration of minocycline before or after photic injury in rats also resulted in less TUNEL-positive photoreceptors , as assessed by the quantitative TUNEL counts . The degree of retinal degeneration , measured by the ONL thickness 14 days after photic injury , was significantly improved in minocycline pretreatment ( 45 mg/kg ) rats . CONCLUSIONS : We demonstrate that increased caspase-3 activities localize specifically within the ONL after photic injury , and that minocycline partially inhibits caspase-3 activation and photoreceptor degeneration in this animal model . DB01017 and tissue-type plasminogen activator for stroke : assessment of interaction potential . BACKGROUND AND PURPOSE : New treatment strategies for acute ischemic stroke must be evaluated in the context of effective reperfusion . DB01017 is a neuroprotective agent that inhibits proteolytic enzymes and therefore could potentially both inactivate the clot lysis effect and decrease the damaging effects of tissue-type plasminogen activator ( t-PA ) . This study aimed to determine the effect of minocycline on t-PA clot lysis and t-PA-induced hemorrhage formation after ischemia . METHODS : Fibrinolytic and amidolytic activities of t-PA were investigated in vitro over a range of clinically relevant minocycline concentrations . A suture occlusion model of 3-hour temporary cerebral ischemia in rats treated with t-PA and 2 different minocycline regimens was used . Blood-brain barrier basal lamina components , matrix metalloproteinases ( MMPs ) , hemorrhage formation , infarct size , edema , and behavior outcome were assessed . RESULTS : DB01017 did not affect t-PA fibrinolysis . However , minocycline treatment at 3 mg/kg IV decreased total protein expression of both P08253 ( P=0.0034 ) and P14780 ( P=0.001 for 92 kDa and P=0.0084 for 87 kDa ) . It also decreased the incidence of hemorrhage ( P=0.019 ) , improved neurologic outcome ( P=0.0001 for Bederson score and P=0.0391 for paw grasp test ) , and appeared to decrease mortality . MMP inhibition was associated with decreased degradation in collagen IV and laminin-alpha1 ( P=0.0001 ) . CONCLUSIONS : Combination treatment with minocycline is beneficial in t-PA-treated animals and does not compromise clot lysis . These results also suggest that neurovascular protection by minocycline after stroke may involve direct protection of the blood-brain barrier during thrombolysis with t-PA . Differential radiosensitisation by ZD1839 ( DB00317 ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( DB00317 ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0.01 microM ) and ionising radiation in the established bladder cancer cell lines MGH-U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0.001 for MGH-U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0.01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0.01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer . DB01017 protects PC12 cells against DB01221 -induced injury via inhibiting P09917 activation . Recently , we have reported that minocycline , a semi-synthetic tetracycline with neuroprotective effects , inhibits the in vitro ischemic-like injury and P09917 ( 5- P28300 ) activation in PC12 cells . In the present study , we further determined whether minocycline protects PC12 cells from excitotoxicity via inhibiting 5- P28300 activation . We used N-methyl-d-aspartate ( DB01221 , 200 microM ) to induce early ( exposure for 6 h ) and delayed ( exposure for 6 h followed by 24 h recovery ) injuries . We found that DB01221 receptor antagonist ketamine , 5- P28300 inhibitor caffeic acid and minocycline concentration dependently attenuated DB01221 -induced early and delayed cell injuries ( viability reduction and cell death ) . However , only ketamine ( 1 microM ) inhibited DB01221 -evoked elevation of intracellular calcium . In addition , immunohistochemical analysis showed that DB01221 induced 5- P28300 translocation to the nuclear membrane after 1- to 6-h exposure which was confirmed by Western blotting , indicating that 5- P28300 was activated . DB01221 , caffeic acid and minocycline ( each at 1 microM ) inhibited 5- P28300 translocation after early injury . After delayed injury , PC12 cells were shrunk , and 5- P28300 was translocated to the nuclei and nuclear membrane ; ketamine , caffeic acid and minocycline inhibited both cell shrinking and 5- P28300 translocation . As a control , P16050 inhibitor baicalein showed a weak effect on cell viability and death , but no effect on 5- P28300 translocation . Therefore , we conclude that the protective effect of minocycline on DB01221 -induced injury is partly mediated by inhibiting 5- P28300 activation . Association of polymorphisms in P36888 , P00533 , P09917 , and Q8TAT5 with glioblastoma in the Han Chinese population . Glioblastoma ( GBM ) is the highest-grade glioma in astrocytoma . Patients often have poor prognosis due to therapeutic resistance and tumor recurrence . Identification of the genetic factors of GBM could be important contribution to early prevention of this disease . We genotyped 17 tag single-nucleotide polymorphisms ( tSNPs ) from nine genes in this study , including 72 cases and 302 controls . SNP genotyping was conducted using Sequenom MassARRAY RS1000 . Statistical analysis of the association between tSNPs and GBM was performed using the χ ( 2 ) test and SNPStats software . The rs3829382 in P36888 was associated with increased odds of developing GBM using the χ ( 2 ) test . When we analyzed tSNPs under different inheritance models , we found rs9642393 in P00533 increased odds of developing GBM in the dominant model . After stratification by gender , we found that rs12645561 in Q8TAT5 and rs2291427 in P09917 were associated with developing GBM . Polymorphisms within P36888 , P00533 , Q8TAT5 , and P09917 may contribute to the occurrence of GBM in the Han Chinese population . However , the functional significance of these polymorphisms needs further investigation . Multifaceted link between cancer and inflammation . Increasing evidence from epidemiological , preclinical and clinical studies suggests that dysregulated inflammatory response plays a pivotal role in a multitude of chronic ailments including cancer . The molecular mechanism(s) by which chronic inflammation drives cancer initiation and promotion include increased production of pro-inflammatory mediators , such as cytokines , chemokines , reactive oxygen intermediates , increased expression of oncogenes , P35354 ( cyclo-oxygenase-2 ) , 5- P28300 ( P09917 ) and MMPs ( matrix metalloproteinases ) , and pro-inflammatory transcription factors such as NF-κB ( nuclear factor κB ) , P40763 ( signal transducer and activator of transcription 3 ) , AP-1 ( activator protein 1 ) and HIF-1α ( hypoxia-inducible factor 1α ) that mediate tumour cell proliferation , transformation , metastasis , survival , invasion , angiogenesis , chemoresistance and radioresistance . These inflammation-associated molecules are activated by a number of environmental and lifestyle-related factors including infectious agents , tobacco , stress , diet , obesity and alcohol , which together are thought to drive as much as 90 % of all cancers . The present review will focus primarily on the role of various inflammatory intermediates responsible for tumour initiation and progression , and discuss in detail the critical link between inflammation and cancer . [ Induction of antitumor immune response by NK-cell-sensitive target cells transfected by P33681 -1 gene ] . OBJECTIVE : To investigate whether the expression of P33681 -1 is involved in NK cell activation . METHODS : P33681 -1 gene was transfected into K562 cell line ( a sensitive target cell of NK cell , without MHC class I expression ) by electropolation . Specific cytotoxicity of NK cells to P33681 +K562 cell was assayed by 4-h Cr release assay . The proliferation of NK cells induced by P33681 +K562 cell was analysed by Flow Cytometry . Expansion of NK cells and cloning of NK cells were performed by mixed lymphocyte-tumor cultures and limiting dilution analysis . Production of P01375 -A , GM- P04141 and IFN-A was detected by ELISA tests . RESULTS : The cytotoxicity of NK cells to P33681 +K562 cell could be induced and that the number of NK cells could be increased by stimulation with P33681 +K562 cells , in particular , further enhanced with biotherapeutic agent such as OK432 and P60568 . Also , NK cell clones were established . Cytokines such as P01375 - A , P27352 - A and GM- P04141 were detected in the supernatant produced by NK cell clones . In addition , culture of lymphocytes in the presence of supernatant produced by NK cell clones and tumor antigens resulted in an increased autologous tumor killing( Q06187 ) . CONCLUSION : These findings suggest that K562 cells transfected by P33681 -1 gene may elicit a series of antitumor immunity and these cells may be used for further development of therapeutic tumor vaccine .