MH_dev_171

Cytokine-induced human P01579 REA - secreting effector-memory Th cells in chronic autoimmune inflammation . T-helper ( Th ) cells activated by cytokines in the absence of T-cell receptor ligation are suspected to participate in inflammatory processes by production of interferon-gamma ( P01579 REA ) . Still , the relevance of such a mechanism has not been addressed in humans . Here we demonstrate that a subset of human effector-memory Th cells expressing functional interleukin - 12R ( IL - 12R ) , IL - 18Ralpha , and P51681 REA ex vivo can be induced to secrete P01579 REA by cytokines signaling via the IL - 2R common gamma-chain in combination with IL - 12 and Q14116 REA . Cytokine-driven P01579 REA production depends on P52333 REA - and p38 mitogen-activated kinase signals and is sensitive to suppression by CD25 ( + + ) regulatory T cells . Contrary to P01579 REA ( + ) Th cells induced upon antigen-specific stimulation , their cytokine-activated counterparts characteristically lack expression of costimulator 4-1 BB ( Q07011 REA ) . Strikingly , the majority of Th cells infiltrating inflamed joints of rheumatoid arthritis patients is equipped with receptors prerequisite for cytokine-induced P01579 REA secretion . Among these cells , we detected a substantial fraction that secretes P01579 REA directly ex vivo but lacks 4-1 BB expression , indicating that cytokine-induced P01579 REA ( + ) Th cells operate in autoimmune inflammation . Our data provide a rationale for how human effector-memory Thcells can participate in perpetuating inflammatory processes in autoimmunity even in the absence of T-cell receptor ligation .

Microsomal transfer protein ( P55157 REA ) inhibition-a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low-density lipoprotein receptor ( LDL-R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 REA ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 REA ) , or gain-of-function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 REA ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 REA ) system have shown a high clinical potential . P55157 REA plays a critical role in the assembly / secretion of very-low-density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 REA antagonists dramatically lower LDL-cholesterol ( LDL-C ) in animals , although a reported increase of liver fat delayed their clinical development . DB08827 MEN , the best-studied P55157 REA inhibitor , reduces LDL-C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low-fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .

DB08827 MEN : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : DB08827 MEN ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 REA ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid-lowering modalities reduced plasma concentrations of low-density lipoprotein cholesterol ( LDL-C ) by a mean of more than 50 % . DB08827 MEN is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . DB08827 MEN undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 REA substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . DB08827 MEN is contraindicated in patients with moderate-to-severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 REA inhibitors , and pregnant patients . CONCLUSION : DB08827 MEN is an oral P55157 REA inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL-C goal or can not tolerate statin therapy .

Serotonin receptor activation leads to neurite outgrowth and neuronal survival . Serotonin 5 - HT1 receptors are implicated in anxiety and depression . These receptors belong to the family A of G-protein-coupled receptors and couple to inhibitory G-proteins . Recent studies show that chronic activation of P08908 REA receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants . However , the molecular mechanisms and pathways involved are not understood . We used Neuro 2A cells transfected with P08908 REA receptors and SK-N-SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth . We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G-proteins and proteasomal degradation in this process . Interestingly , the small G-protein Rap and the transcription factor P35610 REA - 3 are also involved since reducing the levels of Rap 1 ( using small interfering RNA ) or P35610 REA - 3 ( using dominant negative P40763 REA ) significantly blocks P08908 REA - receptor-mediated neurite outgrowth . The observed increase in the phosphorylation of Src and P35610 REA - 3 , at sites leading to their activation , further supports a crucial role for these proteins in neurite outgrowth . We also find that prolonged activation of endogenous P08908 REA receptors leads to increased cell survival even under starving conditions ; this is completely blocked by co-treatment with the antagonist . Taken together , these findings indicate that activation of the P08908 REA receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long-term changes required for neurogenesis .

PSK , a novel Q9H2G2 derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization . Degenerate polymerase chain reaction against conserved kinase catalytic subdomains identified 15 tyrosine and serine-threonine kinases expressed in surgically removed prostatic carcinoma tissues , including six receptor kinases ( PDGFBR , IGF 1 - R , P35968 REA , MET , P34925 REA , and P21709 REA - A1 ) , six non-receptor kinases ( P00519 REA , P23458 REA , O60674 REA , P29597 REA , P53350 REA , and EMK ) , and three novel kinases . Several of these kinases are oncogenic , and may function in the development of prostate cancer . One of the novel kinases is a new member of the sterile 20 ( STE 20 ) family of serine-threonine kinases which we have called prostate-derived Q9H2G2 ( PSK ) and characterized functionally . PSK encodes an open reading frame of 3705 nucleotides and contains an N-terminal kinase domain . Immunoprecipitated PSK phosphorylates myelin basic protein and transfected PSK stimulates P45985 REA and O14733 REA and activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway . Microinjection of PSK into cells results in localization of PSK to a vesicular compartment and causes a marked reduction in actin stress fibers . In contrast , C-terminally truncated PSK ( 1-349 ) did not localize to this compartment or induce a decrease in stress fibers demonstrating a requirement for the C terminus . Kinase-defective PSK ( K57A ) was unable to reduce stress fibers . PSK is the first member of the STE 20 family lacking a Cdc 42 / Rac binding domain that has been shown to regulate both the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and the actin cytoskeleton .

Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : DB00734 MEN ( 1.0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 REA antagonist , WAY 100635 ( 0.2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due , at least in part , to potentiation of SSRI-induced increases in cortical DA and NE . The contributions of P08908 REA receptor stimulation and 5 - Q13049 REA and alpha 2 adrenergic receptor antagonism to this augmentation are discussed .

Kinase inhibitors : a new class of antirheumatic drugs . The outlook for patients with rheumatoid arthritis has improved significantly over the last three decades with the use of disease-modifying antirheumatic drugs . However , despite the use of methotrexate , cytokine inhibitors , and molecules targeting T and B cells , a percentage of patients do not respond or lose their response over time . The autoimmune process in rheumatoid arthritis depends on activation of immune cells , which utilize intracellular kinases to respond to external stimuli such as cytokines , immune complexes , and antigens . In the past decade , small molecules targeting several kinases , such as p38 MAPK , Syk , and JAK have been developed . Several p38 MAPK inhibitors proved ineffective in treating rheumatoid arthritis . The Syk inhibitor , fostamatinib , proved superior to placebo in Phase II trials and is currently under Phase III investigation . DB08895 SUB , a P23458 REA / 3 inhibitor , was shown to be efficacious in two Phase III trials , while VX - 509 , a P52333 REA inhibitor , showed promising results in a Phase II trial . Fostamatinib and tofacitinib were associated with increased rates of infection , elevation of liver enzymes , and neutropenia . Moreover , fostamatinib caused elevations of blood pressure and diarrhea , while tofacitinib was associated with an increase in creatinine and elevation of lipid levels .

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-B 100 ( apoB ) , Cholesteryl ester transport protein ( P11597 REA ) and microsomal triglyceride transfer protein ( P55157 REA ) . ApoB and P55157 REA inhibitors ( DB05528 and DB08827 MEN ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 REA and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .

Neonatal ghrelin programs development of hypothalamic feeding circuits . A complex neural network regulates body weight and energy balance , and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases , such as obesity . The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arcuate nucleus of the hypothalamus ( Q5SW96 ) . Here , we evaluated the physiological and neurobiological contribution of ghrelin during development by specifically blocking ghrelin action during early postnatal development in mice . Ghrelin blockade in neonatal mice resulted in enhanced Q5SW96 neural projections and long-term metabolic effects , including increased body weight , visceral fat , and blood glucose levels and decreased leptin sensitivity . In addition , chronic administration of ghrelin during postnatal life impaired the normal development of Q5SW96 projections and caused metabolic dysfunction . Consistent with these observations , direct exposure of postnatal Q5SW96 neuronal explants to ghrelin blunted axonal growth and blocked the neurotrophic effect of the adipocyte-derived hormone leptin . Moreover , chronic ghrelin exposure in neonatal mice also attenuated leptin-induced P40763 REA signaling in Q5SW96 neurons . Collectively , these data reveal that ghrelin plays an inhibitory role in the development of hypothalamic neural circuits and suggest that proper expression of ghrelin during neonatal life is pivotal for lifelong metabolic regulation .

DB08895 SUB . DB08895 SUB ( CP -690,550 ; CP - 690550 ; CP690550 ) , an orally active immunosuppressant , is being developed by Pfizer for the treatment of rheumatoid arthritis , inflammatory bowel disease , dry eyes , ankylosing spondylitis , psoriasis , psoriatic arthritis , and for the prevention of transplant rejection . DB08895 SUB specifically inhibits Janus activated kinase 3 ( P52333 REA ) , which has a pivotal role in cytokine signal transduction that governs lymphocyte survival , proliferation , differentiation , and apoptosis . This review discusses the key development milestones and therapeutic trials of this drug .

Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis . Immune / inflammatory cells act in rheumatoid arthritis ( RA ) - affected patients by synthesizing several inflammatory mediators , including cytokines that initiate intracellular signaling . Recently , small molecule inhibitors of transduction and transcription signals that influence the intracellular pathways ( such as the Janus kinase [ JAK ] family of tyrosine kinases ) have been tested for RA treatment . Four members of the JAK family are known : P23458 REA , O60674 REA , P52333 REA , and TyK 2 . P23458 REA / P52333 REA constitutively binds to the cytoplasmic portion of the cytokine receptor - the common gamma chain - that represents a common subunit of several cytokines involved in T-cell and natural killer cell development , as well as in B-cell activation . DB08895 SUB is an oral JAK inhibitor that is now available and effective in RA treatment , as shown in multiple Phase II and Phase III clinical trials . However , long-term safety data and comparisons with other disease-modifying antirheumatic drugs and small molecule inhibitors are necessary to better determine the role of tofacitinib in RA .

Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-gamma and interleukin - 10 . Serotonin ( 5 - HT ) is a neurotransmitter and an immune modulator . In vitro , antidepressants with a serotonergic mode of action have , at concentrations within the therapeutical range , negative immunoregulatory effects , i . e . , they increase the production rate of interleukin - 10 ( P22301 REA ) , a negative immunoregulatory cytokine . We have hypothesized that part of these effects may be explained by the serotonergic activities of antidepressants on immunocytes . This study was carried out to examine the effects of 5 - HT , p-chlorophenylalanine ( PCPA ) , a 5 - HT depleting agent , flesinoxan ( a P08908 REA agonist ) , m-chlorophenylpiperazine ( mCPP ; a 5 - Q13049 REA / 2C agonist ) , and ritanserin ( a 5 - Q13049 REA / 2C antagonist ) on the production rate of interferon-gamma ( IFNgamma ) , a proinflammatory cytokine , and P22301 REA by whole blood stimulated with polyclonal activators . The IFNgamma / P22301 REA production ratio was computed , since this ratio reflects the pro - versus anti-inflammatory capacity of cultured whole blood . We found that : 1 ) 5 - HT , 150 ng / mL , 1.5 microg / mL , and 15 microg / mL significantly decreased the IFNgamma / P22301 REA ratio ; 2 ) PCPA ( 5 microM ) significantly suppressed the production of IFNgamma and P22301 REA ; 3 ) flesinoxan ( 15 ng / mL ; 1.5 microg / mL ) had no significant effects on the production of the above cytokines ; and 4 ) mCPP ( 2.7 microg / mL ) and ritanserin ( 5.0 microg / mL ) suppressed the IFNgamma / P22301 REA ratio . It is concluded that intracellular 5 - HT may be necessary for an optimal synthesis of IFNgamma and P22301 REA , and that extracellular 5 - HT concentrations at or above serum values may suppress the production of the proinflammatory cytokine IFNgamma . The negative immunoregulatory effects of antidepressive drugs are probably not related to their serotonergic activities .

Autocrine / Paracrine secretion of P05231 REA family cytokines causes angiotensin II-induced delayed P40763 REA activation . We recently reported that angiotensin II ( AngII ) biphasically activates the JAK / P35610 REA pathway and induces delayed phosphorylation of P40763 REA in the late stage ( 120 min ) in cardiomyocytes . This study was designed to determine the mechanism of delayed phosphorylation of P40763 REA . Conditioned medium prepared from AngII-stimulated cardiomyocytes could reproduce the tyrosine phosphorylation of P40763 REA at 5 min . This delayed phosphorylation was almost completely inhibited by anti - P40189 REA blocking antibody RX435 , but not by TAK 044 ( P25101 REA / B-R antagonist ) , prazosin , or propranolol . AngII induced phosphorylation of P40189 REA in the late stage , which was temporally in parallel with the delayed phosphorylation of P40763 REA . AngII augmented P05231 REA , Q16619 REA , and P15018 REA mRNA expression at 30-60 min , but not P26441 REA expression . AngII increased P05231 REA protein levels by 3 - fold in the conditioned media at 2 h compared with the control . These findings indicated that AngII-induced delayed activation of P40763 REA is caused by autocrine / paracrine secreted P05231 REA family cytokines .

Ex vivo binding of flibanserin to serotonin P08908 REA and 5 - Q13049 REA receptors . DB04908 MENMAX DB04908 MEN has been reported to be an agonist at P08908 REA - receptors and an antagonist at 5 - Q13049 REA receptors , with higher affinity for P08908 REA receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 REA antagonism at doses ( 4-5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 REA receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 REA and 5 - Q13049 REA receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ]8 - OH-DPAT and [ 3H ] ketanserin to label P08908 REA and 5 - Q13049 REA receptors , respectively . DB04908 MEN was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non-selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0.5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor-mediated effects .

Endothelin receptor antagonist exacerbates autoimmune myocarditis in mice . AIMS : Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults . Experimental autoimmune myocarditis ( EAM ) is a mouse model of post-infectious myocarditis and inflammatory cardiomyopathy . The pathological role of endothelin ( ET ) in myocarditis has not been elucidated . MAIN METHODS : EAM was induced by immunization of cardiac myosin peptide with complete Freund ' s adjuvant on days 0 and 7 in BALB / c mice . An P25101 REA / ETB dual receptor antagonist , SB209670 , was administered by a continuous infusion from a subcutaneous pump for 2 weeks . KEY FINDINGS : An increase in the heart-to-body weight ratio was observed in SB209670 - treated mice compared with vehicle-treated mice . Heart pathology in SB209670 - treated mice was remarkable for gross inflammatory infiltration , in contrast to the lesser inflammation in the hearts of vehicle-treated mice . We found that an ET blockade decreased the number of Foxp 3 ( + ) regulatory T cells in the heart . The ET blockade also inhibited the expression of the suppressor of cytokine signaling 3 that plays a key role in the negative regulation of both Toll-like receptor - and cytokine receptor-mediated signaling . EAM is a P01730 REA ( + ) T cell-mediated disease . P01730 REA ( + ) T cells isolated from SB209670 - treated EAM mice produced less P22301 REA and more inflammatory cytokines , P05231 REA and Q16552 REA , than those isolated from vehicle-treated mice . SIGNIFICANCE : The ET receptor antagonist exacerbated autoimmune myocarditis in mice . Our novel findings suggest that ET may play an important role in the regulation of inflammation in myocarditis .

Ca2 + - calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 REA ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 REA remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 REA ) receptor results in the formation of a signaling complex that includes activated O60674 REA ( Jak 2 ) , Ca2 + / calmodulin ( P62158 ) , and P19634 REA , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 REA as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 REA is activated through this pathway : P08908 REA receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak 2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 REA --> induction of a conformational change in P19634 REA that unmasks an obscured proton-sensing and / or proton-transporting region of P19634 REA --> activation of P19634 REA . The G ( i / o ) - coupled P08908 REA receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 REA in living cells is a dynamic process .

Population pharmacokinetics of ethionamide in patients with tuberculosis . SETTING : Three US referral hospitals . OBJECTIVE : Determine the population pharmacokinetic ( PK ) parameters of ethionamide ( P25101 REA ) following multiple oral doses . DESIGN : Fifty-five patients with tuberculosis ( TB ) participated . Patients received multiple oral doses of P25101 REA as part of their treatment . They also received other anti-tuberculosis medications based upon in vitro susceptibility data . Serum samples were collected over 12 h post-dose , and concentrations were determined using a validated high-performance liquid chromatography ( HPLC ) assay . Concentration-time data were analyzed using population methods . RESULTS : P25101 REA areas under the concentration-versus-time curve ( AUCs ) increased linearly with increasing oral doses from 250 to 1000 mg . Compared to the population pattern , delayed absorption was seen at least once in 15 % of patients . P25101 REA PK parameter estimates were independent of age , weight , height , gender , and creatinine clearance . TB patients appeared to have larger volumes of distribution ( 3.22 l / kg ) and clearance values ( 1.88 l / h / kg ) compared to previously studied healthy volunteers . This resulted in lower AUC values ( 3.95 mcg h / ml ) in the TB patients . P25101 REA displayed a short elimination half-life ( 1.94 h ) . The effect of different dosing strategies on calculated pharmacodynamic parameters was explored . Simulated doses of 250 mg P55957 REA to TID failed to achieve serum concentrations above the MIC . CONCLUSION : P25101 REA PK parameters differed between TB patients and healthy volunteers , possibly due to differences in the completeness of absorption . Doses of at least 500 mg appear to be required to achieve serum concentrations above the typical P25101 REA MIC . Additional research is needed to determine the optimal dosing of P25101 REA .

Effect of endothelin receptor antagonists on non-muscle matrix compaction in a cell culture vasospasm model . P05305 REA ( ET - 1 ) , a potent vascular smooth muscle constrictor , is one of the possible spasmogens in cerebral vasospasm . However , the role of ET - 1 in non-muscle compaction ( another aspect of the pathogenesis of cerebral vasospasm ) has not been reported . This study was undertaken to demonstrate the effect of ET - 1 , as well as erythrocyte lysate and bloody cerebrospinal fluid ( P04141 REA ) , on fibroblast populated collagen lattice ( FPCL ) compaction . Human dermal fibroblasts were used to form FPCL . The concentration-dependent effect of ET - 1 was examined in the absence and presence of an P25101 REA receptor antagonist ( BQ - 485 ) , or an ETB receptor antagonist ( BQ - 788 ) , or both . FPCL compaction was determined by measuring reduction of areas over five days following treatment . To compare the effect of ET - 1 on lattice compaction , erythrocyte lysate and bloody P04141 REA obtained from a cerebral vasospasm patient were also tested . We found that ET - 1 increased FPCL compaction in a concentration-dependent ( but not time-dependent ) manner . Erythrocyte lysate produced the strongest compaction , however , without time-dependence . Bloody P04141 REA promoted FPCL compaction in a time-dependent fashion . Compaction induced by ET - 1 was inhibited by BQ - 485 but not by BQ - 788 . We concluded that ET - 1 promotes FPCL compaction by activation of P25101 REA receptors . Other components in bloody P04141 REA or erythrocytes may also contribute to FPCL compaction .

Novel treatments with small molecules in psoriatic arthritis . Current treatment options for patients with active psoriatic arthritis ( PsA ) include synthetic disease-modifying antirheumatic drugs and biologic agents . Propelled by increased understanding of immunopathogenesis of PsA , new therapeutic agents targeting different biologic pathways have been evaluated . This article discusses novel small-molecule , orally available treatments that are currently in clinical development for the treatment of psoriasis and PsA . This includes the phosphodiesterase 4 inhibitor apremilast and Janus kinase ( JAK ) inhibitors . Apremilast has demonstrated significant improvements in patients with moderate to severe psoriasis and PsA in phase II and III clinical trials and has recently been approved for the treatment of PsA . DB08895 SUB , an oral inhibitor of P52333 REA , P23458 REA , and , to a lesser degree , O60674 REA , approved for the treatment of rheumatoid arthritis in several countries , has demonstrated positive results in psoriasis in phase II studies . Studies in PsA are ongoing . With these new developments , treatment options will continue to improve in the future .

EGCG enhances the therapeutic potential of gemcitabine and CP690550 by inhibiting P40763 REA signaling pathway in human pancreatic cancer . BACKGROUND : Signal Transducer and Activator of Transcription 3 ( P40763 REA ) is an oncogene , which promotes cell survival , proliferation , motility and progression in cancer cells . Targeting P40763 REA signaling may lead to the development of novel therapeutic approaches for human cancers . Here , we examined the effects of epigallocathechin gallate ( EGCG ) on P40763 REA signaling in pancreatic cancer cells , and assessed the therapeutic potential of EGCG with gemcitabine or P52333 REA inhibitor CP690550 ( DB08895 SUB ) for the treatment and / or prevention of pancreatic cancer . METHODOLOGY / PRINCIPAL FINDINGS : Cell viability and apoptosis were measured by XTT assay and TUNEL staining , respectively . Gene and protein expressions were measured by qRT-PCR and Western blot analysis , respectively . The results revealed that EGCG inhibited the expression of phospho and total P52333 REA and P40763 REA , P40763 REA transcription and activation , and the expression of P40763 REA - regulated genes , resulting in the inhibition of cell motility , migration and invasion , and the induction of caspase - 3 and PARP cleavage . The inhibition of P40763 REA enhanced the inhibitory effects of EGCG on cell motility and viability . Additionally , gemcitabine and CP690550 alone inhibited P40763 REA target genes and synergized with EGCG to inhibit cell viability and induce apoptosis in pancreatic cancer cells . CONCLUSIONS / SIGNIFICANCE : Overall , these results suggest that EGCG suppresses the growth , invasion and migration of pancreatic cancer cells , and induces apoptosis by interfering with the P40763 REA signaling pathway . Moreover , EGCG further enhanced the therapeutic potential of gemcitabine and CP690550 against pancreatic cancer .

A novel mechanism of mechanical stress-induced hypertrophy . Angiotensin II ( AII ) type 1 ( AT1 ) receptor plays a critical role in load-induced cardiac hypertrophy . We have recently found a novel mechanism of mechanical stress-induced activation of the AT1 receptor , which is independent of AII . Mechanical stretch did not activate ERKs in HEK 293 cells and COS 7 cells which had no AT1 receptor , but when AT1 receptor was overexpressed in these cells , stretch activated ERKs , Galphaq and O60674 REA . An AT1 receptor blocker , candesartan , inhibited stretch-induced activation of ERKs in these cells . Stretch also activated ERKs in COS 7 cells expressing AT1 mutant which did not bind AII and in cardiac myocytes prepared from angiotensinogen null mice . Stretch did not activate ERKs in COS 7 cells which overexpressed P25101 REA receptor and beta-adrenergic receptor . Pressure overload induced cardiac hypertrophy in angiotensinogen null mice as well as in wild-type mice , which was significantly inhibited by candesartan . These results suggest that mechanical stress activates AT1 receptor independently of AII , which is inhibited by an inverse agonist candesartan .

A common binding site on the microsomal triglyceride transfer protein for apolipoprotein B and protein disulfide isomerase . The assembly of triglyceride-rich lipoproteins requires the formation in the endoplasmic reticulum of a complex between apolipoprotein B ( apoB ) , a microsomal triglyceride transfer protein ( P55157 REA ) , and protein disulfide isomerase ( P07237 REA ) . In the P55157 REA complex , the amino-terminal region of P55157 REA ( residues 22-303 ) interacts with the amino-terminal region of apoB ( residues 1-264 ) . Here , we report the identification and characterization of a site on apoB between residues 512 and 721 , which interacts with residues 517-603 of P55157 REA . P07237 REA binds in close proximity to this apoB binding site on P55157 REA . The proximity of these binding sites on P55157 REA for P07237 REA and amino acids 512-721 of apoB was evident from studies carried out in a yeast two-hybrid system and by co-immunoprecipitation . The expression of P07237 REA with P55157 REA and apoB 16 ( residues 1-721 ) in the baculovirus expression system reduced the amount of P55157 REA co-immunoprecipitated with apoB by 73 % . The interaction of residues 512-721 of apoB with P55157 REA facilitates lipoprotein production . Mutations of apoB that markedly reduced this interaction also reduced the level of apoB-containing lipoprotein secretion .

Janus kinase inhibition with tofacitinib : changing the face of inflammatory bowel disease treatment . The advent of anti-Tumor Necrosis Factor ( P01375 REA ) therapy has changed the way of treating inflammatory bowel disease ( Q9UKU7 ) . However , primary and secondary failure are relatively frequent with all anti - P01375 REA agents , which are available only as parenteral agents . DB08895 SUB is an oral janus kinase ( JAK ) inhibitor that inhibits JAK family kinase members , in particular P23458 REA and P52333 REA , achieving a broad limitation of inflammation by interfering with several cytokine receptors . It first proved its efficacy as an immunosuppressive regimen after renal transplantation , and was recently approved by the FDA for rheumatoid arthritis . First data in Q9UKU7 are promising , especially in ulcerative colitis . Ongoing clinical trials in both UC and Crohn ' s disease ( CD ) are needed to further explore its efficacy in CD and to better assess its safety profile .

DB00559 MEN , an endothelin receptor antagonist , ameliorates collagen-induced arthritis : the role of P01375 REA - α in the induction of endothelin system genes . OBJECTIVE : Endothelins ( ETs ) are involved in several inflammatory events . The present study investigated the efficacy of DB00559 MEN , a dual P25101 REA / ETB receptor antagonist , in collagen-induced arthritis ( CIA ) in mice . TREATMENT : CIA was induced in DBA / 1J mice . Arthritic mice were treated with DB00559 MEN ( 100 mg / kg ) once a day , starting from the day when arthritis was clinically detectable . METHODS : CIA progression was assessed by measurements of visual clinical score , paw swelling and hypernociception . Histological changes , neutrophil infiltration and pro-inflammatory cytokines were evaluated in the joints . Gene expression in the lymph nodes of arthritic mice was evaluated by microarray technology . PreproET - 1 mRNA expression in the lymph nodes of mice and in peripheral blood mononuclear cells ( PBMCs ) was evaluated by real-time PCR . The differences were evaluated by one-way Q9UNW9 or Student ' s t test . RESULTS : Oral treatment with DB00559 MEN markedly ameliorated the clinical aspects of CIA ( visual clinical score , paw swelling and hyperalgesia ) . DB00559 MEN treatment also reduced joint damage , leukocyte infiltration and pro-inflammatory cytokine levels ( IL - 1β , TNFα and Q16552 REA ) in the joint tissues . Changes in gene expression in the lymph nodes of arthritic mice returned to the levels of the control mice after DB00559 MEN treatment . PreproET mRNA expression increased in PBMCs from rheumatoid arthritis ( RA ) patients but returned to basal level in PBMCs from patients under anti - P01375 REA therapy . In-vitro treatment of PBMCs with TNFα upregulated ET system genes . CONCLUSION : These findings indicate that ET receptor antagonists , such as DB00559 MEN , might be useful in controlling RA . Moreover , it seems that ET mediation of arthritis is triggered by TNFα .

Gateways to clinical trials . Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses . The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity ( R ) , the drug discovery and development portal , http://integrity.prous.com . This issue focuses on the following selection of drugs : 3,4- DAP ; DB00718 , Q16586 -10-0101 , alefacept , alemtuzumab , alosetron hydrochloride , ALT - 711 , aprepitant , atazanavir sulfate , atlizumab , atvogen ; DB00188 ; P11597 REA vaccine , clevudine , crofelemer ; P22760 REA : P0C6A0 , darbepoetin alfa , decitabine , drotrecogin alfa ( activated ) , DX - 9065a ; E - 7010 , edodekin alfa , emivirine , emtricitabine , entecavir , erlosamide , erlotinib hydrochloride , everolimus , exenatide ; DB00569 , frovatriptan , fulvestrant ; DB00056 , gestodene ; DB04865 , human insulin ; Imatinib mesylate , indiplon , indium 111 ( 111In ) ibritumomab tiuxetan , inhaled insulin , insulin detemir , insulin glargine , ivabradine hydrochloride ; DB06792 , lapatinib , O43766 REA - 34475 , levetiracetam , liraglutide , lumiracoxib ; Maxacalcitol , melagatran , micafungin sodium ; DB00108 , NSC - 640488 ; Oblimersen sodium ; DB08439 sodium , PEG-filgrastim , peginterferon alfa - 2 ( a ) , peginterferon alfa - 2b , pexelizumab , pimecrolimus , pleconaril , pramlintide acetate , pregabalin , prucalopride ; DB00025 - PFM , Ranelic acid distrontium salt , ranolazine , rDNA insulin , recombinant human soluble thrombomodulin , rhGM - P04141 REA , roxifiban acetate , RSD - 1235 , rubitecan , ruboxistaurin mesilate hydrate ; SC - 51 , squalamine ; DB01079 maleate , telbivudine , tesaglitazar , testosterone gel , tezosentan disodium , tipranavir ; DB04879 succinate ; DB04898 ; Yttrium 90 ( 90Y ) ibritumomab tiuxetan ; DB00399 monohydrate .

8 - OH-DPAT ( P08908 REA agonist ) Attenuates 6 - Hydroxy - dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH-DPAT on 6 - OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 REA ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH-DPAT ( P08908 REA receptor agonist ; 0.25 , 0.5 and 1mg / kg , IP for 10 days ) . P04141 REA samples were collected on the tenth day of 8 - OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 REA - α , IL - 1β and P05231 REA . RESULTS : Chronic injection of 8 - OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH-DPAT . Levels of P01375 REA - α in P04141 REA increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 REA - α level of parkinsonian animals treated with 8 - OH-DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 REA decreased and increased in parkinsonian rats and in 8 - OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH-DPAT improves catalepsy in 6 - OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 REA receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .

Pyrrolo [ 1,2- f ] triazines as O60674 REA inhibitors : achieving potency and selectivity for O60674 REA over P52333 REA . SAR studies of pyrrolo [ 1,2- f ] triazines as O60674 REA inhibitors is presented . Achieving O60674 REA inhibition selectively over P52333 REA is discussed .

DB08895 SUB in kidney transplantation . INTRODUCTION : This review will discuss the mechanism of action and important kidney transplant clinical trial data for the small molecule Janus kinase ( JAK ) 3 inhibitor tofacitinib , formerly known as CP -690,550 and tasocitinib . AREAS COVERED : Successful kidney transplantation requires adequate immunosuppression . Current maintenance immunosuppressive protocols which rely on calcineurin inhibitors have long-term nephrotoxicity and negative impact on cardiometabolic risk factors . JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors , particularly members of the cytokine receptor common gamma ( cγ ) chain family . P52333 REA inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis . Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared to control . Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival . There was also a lower rate of new onset diabetes after transplant . However , there was a trend toward more infections , including cytomegalovirus and BK virus nephritis . EXPERT OPINION : DB08895 SUB may be a promising alternative to calcineurin inhibitors . The optimal therapeutic window is still being determined .

Niacin reduces plasma P11597 REA levels by diminishing liver macrophage content in P11597 REA transgenic mice . The anti-dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of P11597 REA . Since liver macrophages contribute to hepatic P11597 REA expression , we investigated the role of macrophages in the P11597 REA - lowering effect of niacin in mice . In vitro studies showed that niacin does not directly attenuate P11597 REA expression in macrophages . Treatment of normolipidemic human P11597 REA transgenic mice , fed a Western-type diet with niacin for 4 weeks , significantly reduced the hepatic cholesterol concentration ( - 20 % ) , hepatic P11597 REA gene expression ( - 20 % ) , and plasma P11597 REA mass ( - 30 % ) . Concomitantly , niacin decreased the hepatic expression of P34810 REA ( - 44 % ) and P45844 REA ( - 32 % ) , both of which are specific markers for the hepatic macrophage content . The decrease in hepatic P11597 REA expression was significantly correlated with the reduction of hepatic macrophage markers . Furthermore , niacin attenuated atherogenic diet-induced inflammation in liver , as evident from decreased expression of P01375 REA ( - 43 % ) . Niacin similarly decreased the macrophage markers and absolute macrophage content in hyperlipidemic P02649 REA * 3 - Leiden . P11597 REA transgenic mice on a Western-type diet . In conclusion , niacin decreases hepatic P11597 REA expression and plasma P11597 REA mass by attenuating liver inflammation and macrophage content in response to its primary lipid-lowering effect , rather than by attenuating the macrophage P11597 REA expression level .

Activation of the JAK / P35610 REA pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 REA , P41595 REA , and P28222 REA receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 REA and P28222 REA receptor activation of the JAK / P35610 REA pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 REA pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 ( - 6 ) M ) resulted in time-dependent activation ( approximately 2 - fold ) of O60674 REA , P23458 REA , and P42224 REA , but not P40763 REA ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 REA receptor agonist BW723C86 and the P28222 REA receptor agonist CGS 12066A ( 10 ( - 9 ) - 10 ( - 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 REA pathway . Treatment with the 5 - Q13049 REA receptor antagonist ketanserin ( 10 nM ) inhibited O60674 REA activation by 5 - HT . Treatment of streptozotocin-induced diabetic rats with ketanserin ( 5 mg.kg-1.day - 1 ) reduced activation of O60674 REA and P42224 REA but not P40763 REA in endothelium-denuded thoracic aorta in vivo . 5 - HT ( 10 ( - 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 REA inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 REA pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 REA , P23458 REA , and P42224 REA via the 5 - Q13049 REA receptors in a reactive oxygen species-independent manner under both normal and high glucose conditions .

Tofacitinab in renal transplantation . DB08895 SUB ( tositinib , CP -690,550 ) is a small molecule inhibitor of Janus associated kinases , primarily P52333 REA and O60674 REA , which inhibits cytokine signaling through the IL - 2Rγ chain . In this article , we review the mechanism of action of tofacitinib , and pre-clinical and clinical data regarding its use in solid organ transplantation thus far . It is hoped that tofacitinib may form the basis for calcineurin-free immunosuppression , improving renal function while eliminating calcineurin inhibitor renal toxicity . Current studies suggest that tofacitinib is an effective immunosuppressive agent for renal transplantation , but it ' s use in current protocols carries an increased risk of CMV , BK , and EBV viral infection , anemia and leukopenia , and post-transplant lymphoproliferative disorder .

Preclinical to clinical translation of tofacitinib , a Janus kinase inhibitor , in rheumatoid arthritis . A critical piece in the translation of preclinical studies to clinical trials is the determination of dosing regimens that allow maximum therapeutic benefit with minimum toxicity . The preclinical pharmacokinetic ( PK ) / pharmacodynamic ( PD ) profile of tofacitinib , an oral Janus kinase ( JAK ) inhibitor , in a mouse collagen-induced arthritis ( mCIA ) model was compared with clinical PK / PD data from patients with rheumatoid arthritis ( RA ) . Preclinical evaluations included target modulation and PK / PD modeling based on continuous subcutaneous infusion or oral once - or twice-daily ( P55957 REA ) dosing paradigms in mice . The human PK / PD profile was obtained from pooled data from four phase 2 studies in patients with RA , and maximal effect models were used to evaluate efficacy after 12 weeks of tofacitinib treatment ( 1-15 mg P55957 REA ) . In mCIA , the main driver of efficacy was inhibition of cytokine receptor signaling mediated by P23458 REA heterodimers , but not O60674 REA homodimers , and continuous daily inhibition was not required to maintain efficacy . Projected efficacy could be predicted from total daily exposure irrespective of the oral dosing paradigm , with a total steady-state plasma concentration achieving 50 % of the maximal response ( Cave 50 ) of ~ 100 nM . DB08895 SUB potency ( ED50 ) in clinical studies was ~ 3.5 mg P55957 REA ( 90 % confidence interval : 2.3 , 5.5 ) or total Cave 50 of ~ 40 nM , derived using Disease Activity Scores from patients with RA . The collective clinical and preclinical data indicated the importance of Cave as a driver of efficacy , rather than maximum or minimum plasma concentration ( Cmax or Cmin ) , where Cave 50 values were within ~ 2 - fold of each other .

Expression of the adaptor protein Lnk in leukemia cells . OBJECTIVE : Tyrosine kinases are involved in cytokine signaling and are frequently aberrantly activated in hematological malignancies . Lnk , a negative regulator of cytokine signaling , plays critical nonredundant roles in hematopoiesis . By binding to phosphorylated tyrosine kinases , Lnk inhibits major cytokine receptor signaling , including c - P10721 REA ; erythropoietin receptor - O60674 REA ( O60674 REA ) ; and P40238 REA - O60674 REA . In the present study , we investigated Lnk expression and possible function in transformed hematopoietic cells . MATERIALS AND METHODS : Coimmunoprecipitations were performed to identify binding between Lnk and mutant tyrosine kinases . Proliferation assays were done to examine the affect of Lnk overexpression on cancer cell growth . Real-time polymerase chain reaction analysis was used to determine Lnk expression in patient samples . RESULTS : We show that , in parallel to binding wild-type O60674 REA and c - P10721 REA , Lnk associates with and is phosphorylated by mutant alleles of O60674 REA and c - P10721 REA . In contrast , Lnk does not bind to and is not phosphorylated by P11274 REA - P00519 REA fusion protein . Ectopic expression of Lnk strongly attenuates growth of some leukemia cell lines , while others as well as most solid tumor cancer cell lines are either moderately inhibited or completely insensitive to Lnk . Furthermore , Lnk-mediated growth inhibition is associated with differential downregulation of phosphatidylinositol 3 kinase / Akt / mammalian target of rapamycin and mitogen-activated protein kinase / extracellular signal-regulated kinase signaling in leukemia cell lines . Surprisingly , analysis of Lnk in a large panel of myelodysplastic syndrome and acute myeloid leukemia patient samples revealed high levels of Lnk in nearly half of the samples . CONCLUSION : Although how leukemic cells overcome the antiproliferative effects of Lnk is not yet clear , our data highlight the multifaceted role negative feedback mechanisms play in malignant transformation .

Targeting P52333 REA in kidney transplantation : current status and future options . PURPOSE OF REVIEW : This review will discuss the mechanism of action and important clinical trial data in renal transplantation for the small molecule Janus kinase ( JAK ) 3 inhibitor tofacitinib , formerly known as CP -690,550 and tasocitinib . RECENT FINDINGS : JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors , particularly members of the cytokine receptor common gamma ( cγ ) chain family . P52333 REA inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as psoriasis and rheumatoid arthritis . Nonhuman primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared with vehicle control . Renal transplant clinical trials in humans have demonstrated tofacitinib to be noninferior to cyclosporine in terms of rejection rates and graft survival . There was also a lower rate of new-onset diabetes after transplant . However , there was a trend toward more infections , including cytomegalovirus and BK virus nephritis . SUMMARY : DB08895 SUB may be a promising alternative to calcineurin inhibitors . The optimal therapeutic window is still being determined .

Selective JAK / P40763 REA signalling regulates transcription of colony stimulating factor - 2 and - 3 in Concanavalin-A-activated mesenchymal stromal cells . Human bone marrow-derived mesenchymal stromal cells ( MSCs ) express Toll-like receptors ( TLRs ) and produce cytokines and chemokines , all of which contribute to these cells ' immunomodulatory and proangiogenic properties . Among the secreted cytokines , colony-stimulating factors ( CSFs ) regulate angiogenesis through activation of endothelial cell proliferation and migration . Since O60682 are recruited within hypoxic tumors where they signal paracrine-regulated angiogenesis , the aim of this study was to evaluate which P04141 REA members are expressed and are inducible in activated O60682 . Furthermore , we investigated the JAK / P35610 REA signal transducing pathway that may impact on P04141 REA transcription . O60682 were activated with Concanavalin-A ( ConA ) , a TLR -2/6 agonist as well as a membrane type - 1 matrix metalloproteinase ( P50281 REA ) inducer , and we found increased transcription of granulocyte macrophage - P04141 REA ( GM - P04141 REA , P04141 REA - 2 ) , granulocyte P04141 REA ( DB00099 , P04141 REA - 3 ) , and P50281 REA . Gene silencing of either P40763 REA or P50281 REA prevented ConA-induced phosphorylation of P40763 REA , and reversed ConA effects on P04141 REA - 2 and P04141 REA - 3 . Treatment with the Janus Kinase ( JAK ) 2 inhibitor AG490 antagonized the ConA induction of P50281 REA and P04141 REA - 2 , while the pan-JAK inhibitor DB08895 SUB reversed ConA-induced P04141 REA - 2 and - 3 gene expression . Silencing of O60674 REA prevented the ConA-mediated increase of P04141 REA - 2 , while silencing of P23458 REA , P52333 REA and P29597 REA prevented the increase in P04141 REA - 3 . Given that combined TLR-activation and locally-produced P04141 REA - 2 and P04141 REA - 3 could regulate immunomodulation and neovascularization , pharmacological targeting of TLR -2/6- induced P50281 REA / JAK / P40763 REA signalling pathway may prevent O60682 contribution to tumor development .

The JAK inhibitor , tofacitinib , reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells . OBJECTIVE : DB08895 SUB , which is a Janus kinase ( JAK ) inhibitor , has shown clinical effects in the treatment of rheumatoid arthritis . JAKs are important kinases in lymphocyte differentiation ; however , their function in dendritic cells ( DCs ) is unknown . In this study , the function of JAKs in DCs was investigated with tofacitinib . METHODS : The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide ( LPS ) stimulation were investigated . In addition , its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA - positive T cells . RESULTS : DB08895 SUB decreased expression of P33681 REA / P42081 REA in a concentration-dependent manner in LPS-stimulated DCs ; however , it did not affect HLA-DR expression . DB08895 SUB suppressed tumour necrosis factor , interleukin ( IL ) - 6 and IL - 1β production without affecting transforming growth factor ( TGF ) - β and P22301 REA production . Meanwhile , P33681 REA / P42081 REA expression in DCs was enhanced by type I interferon ( IFN ) stimulation , and the LPS-induced P33681 REA / P42081 REA expression was inhibited by an antibody to type I IFN receptor . Furthermore , tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor ( Q969Q1 REA ) - 7 , which is a transcription factor involved in P33681 REA / P42081 REA and type I IFN expression . DB08895 SUB also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3- dioxygenase ( P14902 REA ) - 1 and Q6ZQW0 . CONCLUSIONS : DB08895 SUB , a P23458 REA / P52333 REA inhibitor , affected the activities of human DCs . It decreased P33681 REA / P42081 REA expression and T cell stimulatory capability through suppression of type I IFN signalling . These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs .

Blood flow alterations in TNBS-induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 REA ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist DB00559 MEN ( 30 mg / kg / day ) , P25101 REA receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 REA receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1-5 . Tissue P05164 REA activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with DB00559 MEN or P25101 REA receptor antagonist largely prevented the colitis-induced reduction in blood flow and tissue injury whereas P24530 REA receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time-dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 REA receptors but not P24530 REA receptors play an important role in the colonic inflammation following TNBS administration .

Transforming properties of chimeric P41212 REA - JAK proteins in Ba / P13726 REA cells . The involvement of the cytokine signaling pathway in oncogenesis has long been postulated . Recently , rearrangements of the gene encoding the tyrosine O60674 REA ( O60674 REA ) have been reported in human leukemias indicating a direct JAK-signal transduction and activator of transcription ( P35610 REA ) - mediated leukemic process . The leukemia-associated P41212 REA - O60674 REA fusion protein is formed by the oligomerization domain of the translocated ets leukemia ( P41212 REA ) protein fused to the catalytic domain of O60674 REA . P41212 REA - mediated oligomerization results in a constitutive tyrosine kinase activity that , in turn , is able to confer growth factor independence to the murine hematopoietic interleukin - 3 ( P08700 REA ) - dependent Ba / P13726 REA cell line . Results of the present study indicate that fusion proteins containing the oligomerization domain of P41212 REA and the tyrosine kinase domains of Jak 1 , Jak 2 , P52333 REA , or P29597 REA share similar properties and are able to efficiently substitute for the survival and mitogenic signals controlled by P08700 REA , without concomitant activation of the P08700 REA receptor . Electrophoretic mobility shift assays demonstrated Stat 5 as the only activated Stat factor in P41212 REA - Jak 2 - and P41212 REA - Jak 1 - expressing cells , whereas other Stats , namely Stat 1 and Stat 3 , could be detected in P41212 REA - P52333 REA - , P41212 REA - P29597 REA - , and also in P41212 REA - P00519 REA - expressing Ba / P13726 REA cells . High levels of expression of the Stat 5 - target genes pim - 1 , osm , and Cis were observed in all the cytokine-independent cell lines . Furthermore , the expression of a dominant negative form of Stat 5A markedly interfered with the growth factor independence process mediated by P41212 REA - Jak 2 in Ba / P13726 REA cells . Because the P11274 REA - P00519 REA and P41212 REA - PDGFbetaR oncoproteins also activate Stat 5 , activation of this factor should be a crucial step in activated tyrosine kinase-mediated leukemogenesis . ( Blood . 2000 ; 95:2076- 2083 )

Effects of nasal immunization of multi-target preventive vaccines on atherosclerosis . Previous investigations have demonstrated that anti-inflammatory or lipid-lowering treatments could be useful for alleviating morbidity and mortality of atherosclerotic cardiovascular diseases . However , whether a vaccine designed to target inflammation and lipid simultaneously is more powerful to control the process of atherosclerosis remain to be unknown . Here , a vaccine was designed to target heat shock protein - 65 ( Hsp 65 ) and cholesteryl ester transfer protein ( P11597 REA ) simultaneously and the effects of nasal immunization of multi-target vaccine on high-cholesterol-diet-driven rabbit atherosclerosis lesions were evaluated . Sera , nasal lavages and lung washes were used to ELISA assay for the analysis of IgG and IgA against Hsp 65 and P11597 REA . Sera were also used to the analysis of the avidity of combination of anti-Hsp 65 and anti - P11597 REA IgG antibodies with corresponding antigen , cytokines P22301 REA and IFN-γ , and lipoproteins . In addition , aortas were harvested for analysis of atherosclerotic lesions . The results showed that lower and lasting specific anti-Hsp 65 IgG and high anti - P11597 REA IgG in sera and protective anti-Hsp 65 and anti - P11597 REA IgA in nasal cavity and lung were induced , the avidity of combination of anti-Hsp 65 and anti - P11597 REA IgG with antigen were higher , and more protective P22301 REA and less adverse IFN-γ were produced . In addition , sera TC , and LDL-C were decreased . As a result , the size of aorta atherosclerotic plaques was significantly reduced . We conclude that multifaceted vaccine combining lipid-regulating with anti-inflammation was a potential remedy , especially for atherosclerosis with complicated etiology .

Role of Q14116 REA in overt pain-like behaviour in mice . There are evidences that targeting Q14116 REA might be beneficial to inhibit inflammatory symptoms , including hypernociception ( decrease in nociceptive threshold ) . The mechanism of Q14116 REA mechanical hypernociception depends on endothelin in rats and mice . However , the role of Q14116 REA in overt pain-like behaviour remains undetermined . Therefore , we addressed the role of Q14116 REA in writhing response induced by intraperitoneal ( i . p . ) injection of phenyl-p-benzoquinone ( PBQ ) and acetic acid in mice . Firstly , it was detected that PBQ and acetic acid i . p . injection induced a dose-dependent number of writhes in Balb / c mice . Subsequently , it was observed that the PBQ - but not the acetic acid-induced writhes were diminished in Q14116 REA deficient ( ( - / - ) ) mice . Therefore , considering that P01579 REA , endothelin and prostanoids mediate Q14116 REA - induced mechanical hypernociception , we also investigated the role of these mediators in the same model of writhing response in which Q14116 REA participates . It was noticed that PBQ-induced writhes were diminished in P01579 REA ( - / - ) mice and by the treatment with DB00559 MEN ( mixed endothelin P25101 REA / ETB receptor antagonist ) , BQ 123 ( cyclo [ DTrp-DAsp-Pro-DVal - DB00149 ] , selective endothelin P25101 REA receptor antagonist ) , BQ 788 ( N-cys -2,6 dimethylpiperidinocarbonyl-l-methylleucyl-d - 1 - methoxycarboyl-d-norleucine , selective endothelin ETB receptor antagonist ) or indomethacin ( cycloxigenase inhibitor ) . Thus , Q14116 REA , P01579 REA , endothelin acting on endothelin P25101 REA and ETB receptors , and prostanoids mediate PBQ-induced writhing response in mice . To conclude , these results further advance the understanding of the physiopathology of overt pain-like behaviour , and suggest for the first time a role for Q14116 REA in writhing response in mice .

JAK inhibitors : treatment efficacy and safety profile in patients with psoriasis . Janus kinase ( JAK ) pathways are key mediators in the immunopathogenesis of psoriasis . Psoriasis treatment has evolved with the advent of targeted therapies , which inhibit specific components of the psoriasis proinflammatory cascade . JAK inhibitors have been studied in early phase trials for psoriasis patients , and the data are promising for these agents as potential treatment options . DB08895 SUB , an oral or topically administered P23458 REA and P52333 REA inhibitor , and ruxolitinib , a topical P23458 REA and O60674 REA inhibitor , have been most extensively studied in psoriasis , and both improved clinical symptoms of psoriasis . Additional P23458 REA or P52333 REA inhibitors are being studied in clinical trials . In phase III trials for rheumatoid arthritis , tofacitinib was efficacious in patients with inadequate responses to tumor necrosis factor inhibitors , methotrexate monotherapy , or disease-modifying antirheumatic drugs . The results of phase III trials are pending for these therapies in psoriasis , and these agents may represent important alternatives for patients with inadequate responses to currently available agents . Further investigations with long-term clinical trials are necessary to verify their utility in psoriasis treatment and assess their safety in this patient population .

Antiapoptotic effect of endothelin - 1 in rat cardiomyocytes in vitro . Apoptosis of cardiac myocytes is thought to be a feature of many pathological disorders , including congestive heart failure ( CHF ) and ischemic heart disease ( IHD ) . Because recent investigations indicate that endothelin - 1 ( ET - 1 ) plays an important role in CHF and IHD , we investigated the effect of ET - 1 on cardiomyocyte apoptosis . The presence of apoptosis in rat cardiomyocytes ( H9c2 and neonatal ) was evaluated by morphological criteria , electrophoresis of DNA fragments , 4 ' , 6 ' - diamidine - 2 ' - phenylindole staining , and TUNEL analysis . ET - 1 , but not angiotensin II , prevented apoptosis induced by serum deprivation via P25101 REA receptors in a dose-dependent manner ( 1 to 100 nmol / L ) . ET - 1 also prevented cytochrome c release from mitochondria to the cytosol . The use of specific pharmacological inhibitors demonstrated that the antiapoptotic effect of ET - 1 was mediated through a tyrosine kinase pathway ( genistein and AG490 ) but not through protein kinase C ( PKC ; calphostin C ) , mitogen-activated protein kinases ( PD98059 and SB203580 ) , or PKA ( KT5270 ) pathways . Adenovirus-mediated gene transfer of kinase-inactive ( KI ) c-Src reversed the antiapoptotic effect of ET - 1 . We further investigated whether Bcl-xL , an antiapoptotic molecule , would be upregulated by using a luciferase-based reporter system . ET - 1 upregulated Bcl-xL , and this upregulation was inhibited by genistein or AG490 but not by calphostin C . The experiments with KI mutants for various tyrosine kinases revealed that c-Src and Pyk 2 ( but not P23458 REA , Jak 2 , Syk , and Tec ) are involved in ET - 1 - induced upregulation of Bcl-xL expression . These findings suggest that ET - 1 prevents apoptosis in cardiac myocytes through the P25101 REA receptor and the subsequent c-Src / Bcl-xL-dependent pathway .

Quality of life in plaque psoriasis patients treated with voclosporin : a Canadian phase III , randomized , multicenter , double-blind , placebo-controlled study . BACKGROUND : Quality of life assessments are important in the evaluation of new therapies for psoriasis . OBJECTIVE : To determine the effect of voclosporin ( VCS ) treatment on quality of life in patients with psoriasis . PATIENTS AND METHODS : 451 plaque psoriasis patients with ≥ 10 % body surface area involvement were randomly assigned in a double-blind fashion to 1 of 4 treatment groups ( placebo , VCS 0.2 mg kg ( - 1 ) P55957 REA , VCS 0.3 mg kg ( - 1 ) P55957 REA , and VCS 0.4 mg kg ( - 1 ) P55957 REA ) for up to 12 weeks of treatment . Quality of life was assessed using the Dermatology Life Quality Index ( DLQI ) and the Psoriasis Disability Index ( P07237 REA ) . RESULTS : At 12 weeks , patients treated with VCS 0.4 mg kg ( - 1 ) P55957 REA had statistically significantly more favourable assessments than placebo-treated patients in all domains of the DLQI and the P07237 REA . Patients treated with VCS 0.3 mg kg ( - 1 ) P55957 REA had statistically significant improvements in 5 of 10 domains of the DLQI and all domains of the P07237 REA . Patients treated with VCS 0.2 mg kg ( - 1 ) P55957 REA had statistically significant improvements in 4 of 10 domains of the DLQI and 2 of 4 domains of the P07237 REA . CONCLUSION : Treatment with VCS 0.4 mg kg ( - 1 ) P55957 REA significantly improves the quality of life of patients with psoriasis .

Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 REA ) cause abetalipoproteinemia ( P00519 REA ) , characterized by the absence of plasma apoB-containing lipoproteins . In this study , we characterized the effects of various P55157 REA missense mutations found in P00519 REA patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 REA ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 REA . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 REA is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 REA .

A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis . INTRODUCTION : Rheumatoid arthritis ( RA ) is a chronic painful and debilitating autoimmune disease . Although the outcome for patients with RA has improved markedly in the past decades , driven largely by the advent of biological disease-modifying antirheumatic drugs ( DMARDs ) and updated management strategies , adequate disease control can not be achieved in a substantial proportion of patients . Since RA is a syndrome with different biological subsets , DMARDs , with a novel mechanism of action , may represent a valuable addition to the current armamentarium . DB08895 SUB is a novel synthetic DMARD that selectively inhibits Janus kinases ( JAKs ) , particularly P23458 REA and P52333 REA . AREAS COVERED : This review describes the pharmacokinetics of tofacitinib . Furthermore , the article summarizes and comments the drug ' s efficacy and safety profile in RA patients . The authors furthermore assess data derived from the FDA ' s RA development program . EXPERT OPINION : DB08895 SUB is an oral synthetic DMARD displaying linear pharmacokinetics . Metabolism , primarily mediated by P08684 REA , accounts for 70 % of the total clearance of the drug ; the remaining 30 % are renally excreted . DB08895 SUB monotherapy , or in combination with traditional DMARDs , has demonstrated its efficacy while having an acceptable safety profile in RA patients who have responded inadequately to current DMARDs , including P01375 REA antagonists . In view of its undetermined benefit to risk ratio , in the real-world population , tofacitinib should , for now , only be prescribed to selected patients .

Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis . DB08895 SUB is the first in a new class of nonbiologic disease-modifying antirheumatic drugs ( DMARDs ) , a targeted , synthetic DMARD , approved for the treatment of rheumatoid arthritis ( RA ) as monotherapy or in combination with methotrexate or other non-biologic DMARD . DB08895 SUB , an orally administered Janus kinase ( JAK ) inhibitor , decreases T-cell activation , pro-inflammatory cytokine production , and cytokine signaling by inhibiting binding of type I cytokine receptors family and γ-chain cytokines to paired P23458 REA / P52333 REA receptors . The net effect of tofacitinb ' s mechanism of action is decreased synovial inflammation and structural joint damage in RA patients . To date , six phase 3 trials have been conducted to evaluate the safety and efficacy of tofacitinib under the oral rheumatoid arthritis triaLs ( ORAL ) series . This review describes the pharmacology of the novel agent , tofacitinib , and details the safety and efficacy data of the ORAL trials .