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All drugs have both favorable therapeutic and untoward adverse effects. Conventional opioid analgesics possess both analgesia and adverse reactions, such as nausea, vomiting, and respiratory depression. The opioid ligand binds to µ opioid receptor and non-selectively activates two intracellular signaling pathways: the G protein pathway induce analgesia, while the β-arrestin pathway is responsible for the opioid-related adverse reactions. An ideal opioid should activate the G protein pathway while deactivating the β-arrestin pathway. Oliceridine (TRV130) has a novel characteristic mechanism on the action of the µ receptor G protein pathway selective (µ-GPS) modulation. Even though adverse reactions (ADRs) are significantly attenuated, while the analgesic effect is augmented, the some residual ADRs persist. Consequently, a G protein biased µ opioid ligand, oliceridine, improves the therapeutic index owing to increased analgesia with decreased adverse events. This review article provides a brief history, mechanism of action, pharmacokinetics, pharmacodynamics, and ADRs of oliceridine.
Subject(s)
Animals , Mice , Analgesia , Analgesics, Opioid , Bias , Drug-Related Side Effects and Adverse Reactions , GTP-Binding Proteins , Intracellular Signaling Peptides and Proteins , Ligands , Mice, Knockout , Nausea , Patient Safety , Pharmacokinetics , Receptors, Opioid , Receptors, Opioid, mu , Respiratory Insufficiency , VomitingABSTRACT
Objective To explore the potential mechanisms of low density lipoprotein receptor (LDLr) in high glucose peritoneal dialysis solution (PDS)-induced peritoneal fibrosis.Methods Human peritoneal mesothelial cells (PMCs) were applied.In pre-experiment,human PMCs were cultured with 1.5％ PDS,2.5％ PDS and 4.25％ PDS for 6 h,12 h and 24 h.4.25％ mannitol was used as high osmotic pressure control.In formal experiment,PMCs were divided into the control group (treated with phosphate buffer saline) and the high glucose PDS group (treated with 4.25％ PDS for 24 h).Morphological change of PMCs was observed by inverted microscope.The mRNA and protein expressions of extracellular matrix proteins such as α-smooth muscle actin (α-SMA),fibroblast specific protein-1 (FSP-1) and collagen Ⅰ in PMCs were respectively measured by real-time PCR and Western blotting.The lipid accumulation was observed by oil red O staining and filipin staining,and the content of intracellular cholesterol ester was detected by high-performance liquid chromatography.The co-expression of the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) with golgin was observed with immunofluorescent staining.The mRNA and protein expressions of LDLr,SREBP-2 and SCAP were respectively detected by real-time PCR and Western blotting.The mRNA and protein expressions of mammalian target of rapamycin (mTOR),eukaryotic initiation factor 4E-binding protein 1 (4EBP1),and p70 S6 kinase (S6K1) were respectively detected by real-time PCR and Western blotting.Results (1) Compared with the 1.50％ PDS stimulation,4.25％ PDS for 24 h intervention significantly increased the expression of LDLr in PMCs (P ＜ 0.05),and high osmotic pressure control at 6 h,12 h and 24 h had no statistical difference (P ＞ 0.05).(2) Compared with those in the control group,in high glucose PDS group PMCs showed notable elongation consistent with the morphology of myofibroblasts,the expressions of α-SMA,FSP-1 and collagen Ⅰ were increased (all P ＜ 0.05),and the intracellular cholesterol were enhanced (P ＜ 0.05).Meanwhile,the co-expression of SCAP with golgin was enhanced,and the mRNA and protein expressions of LDLr,SREBP-2 and SCAP were up-regulated in high glucose PDS group (all P ＜ 0.05).Further,the mRNA and protein phosphorylation of mTOR,4EBP1 and S6K1 were increased (all P ＜ 0.05).Conclusions The disruption of LDLr feedback regulation is involved in high glucose PDS-mediated cholesterol accumulation in PMCs by mammalian target of rapamycin complex 1 (mTORC1) pathway,which promotes the accumulation of extracellular matrix and peritoneal fibrosis.
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Objective To study the therapeutic effect of bitter gourd saponins on salt-sensitive kidney injury induced by high salt diet and its possible mechanism.Methods 50 Sprague Dawley (SD) rats were randomly divided into normal group,model group and low-dose,middle-dose and high-dose treatment group after 10 days of adaptive feeding.Each group had 10 rats.Except the normal group,the other four groups were given high salt diet (4.0％ high salt diet) to induce salt-sensitive kidney damage in rats.The normal group and the model group were given 1.0 m/(kg · d) normal saline,and the three dosage groups of total saponins of balsam pear were given 10 mg/(kg · d),20 mg/(kg · d) and 40 mg/(kg · d) respectively.After 8 weeks of treatment,rats were sacrificed and collect the 24-hour proteinuria,creatinine.Serum creatinine,serum aldosterone,serum sodium and serum potassium were measured,and renal histopathology and the expression of podocin and nephrin were detected.Results Pathological examination of model group showed obvious glomerular sclerosis and renal interstitial fibrosis,and glomerular sclerosis in the treatment group was obviously improved by bitter gourd saponins;The systolic pressure in the model group was 170 mmHg,significantly higher than that of the normal and treatment groups,the systolic blood pressure of the treatment groups were obvious decreased when treated by bitter gourd saponins (P ＜ 0.05);Compared with normal group,serum creatinine and 24 h proteinuria / urine creatinine in model group were significantly increased (P ＜ 0.05),while creatinine clearance rate and aldosterone were significantly decreased (P ＜ 0.05),and the above indexes in bitter gourd saponins treatment group were significantly improved;Compared with the model group,the protein and mRNA expression of podocin and nephrin were significantly decreased (P ＜ 0.05),while the two indexes can be revered by bitter gourd saponins in treatment group (P ＜ 0.05).Conclusions The bitter gourd saponins can significantly improve the symptoms of salt-induced hypertensive nephropathy in rats,which may be related with the expression of podocin and nephrin in renal tissue,thereby inhibiting glomerulosclerosis and improving renal interstitial fibrosis.
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Objective To investigate the effect and the underlying mechanism of miRNA (miR)-506 regulating transforming growth factor-β1 (TGF-β1)-induced endothelial-mesenchymal transition of human aortic endothelial cell lysates.Methods In this study,miR-506 and inhibitory members of the ASPP family (iASPP) were selected as the study objects.First,the expression of miR-506 in human aortic endothelial cell lysates (HAEC) lysate was detected under different concentrations of TGF-β1.The expression of platelet endothelial cell adhesion molecule-1 (CD31),endothelium-cadherin (VE-cadherin),fibroblastspecific protein-1 (FSP1),α-smooth muscle actin (α-SMA) and N-cadherin was determined after miR-506 mimics/mimic negative control (NC) transfection into HAEC treated with or without TGF-β1.Then the expression levels of iASPP in miRNA-506 mimics/mimic NC-transfected HAECs treated with or without TGF-β1 were determined.Finally,the protein expression of CD31,VE-cadherin,FSP1 and α-SMA in HAEC transfected with miR-506 mimics/mimic NC was determined after iASPP overexpression.Results TGF-β1 can induce human aortic endothelial cell mesenchymal transition,down-regulate CD31 and VE-cadherin expression while up-regulate FSP1,α-SMA and N-cadherin expression;TGF-β1 inhibited miR-506 expression,promoted iASPP expression;miR-506 transfection into HAECs up-regulated CD31 and VE-cadherin expression while up-regulate FSP1,α-SMA and N-cadherin expression;miR-506 could downregulate the expression of iASPP;the overexpression of iASPP increased the expression of FSP1,α-SMA and N-cadherin,down-regulated CD31 and VE-cadherin and promoted the transformation of human aortic endothelial cells.Conclusions The transfection of iASPP plasmid promoted the endothelial-mesenchymal transition of human aortic endothelial cell lysates.The transfection of miR-506 inhibited the expression of iASPP and inhibited the endothelial-mesenchymal transition of human aortic endothelial cell lysates induced by TGF-β1.
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Objective To evaluate the effect of mild hypothermia on the expression of phosphorylated eukaryotic translation initiation factor 2α (p-eIf2αt) in the hippocampus in a mouse model of cerebral ischemia-reperfusion (I/R).Methods Sixty pathogen-free healthy male C57BL6 mice,aged 8-12 weeks,weighing 20-30 g,were divided into 3 groups (n =20 each) using a random number table:sham operation group (group S),group I/R and mild hypothermia group (group H).Cerebral I/R was induced by 15-min occlusion of bilateral common carotid arteries followed by reperfusion in chloral hydrate-anesthetized mice.Surface cooling was started immediately after reperfusion to maintain the rectal temperature at 32-34 ℃ for 3 h in group H.The neurologic deficit score was evaluated at 24 h of reperfusion.The mice were then sacrificed,brains were immediately removed,and hippocampi were isolated for examination of pathologic changes of hippocampal CA1 region and for determination of neuroapoptosis (by TUNEL) and expression of peIf2α (by Western blot).The apoptosis rate was calculated.Results Compared with group S,the neurologic deficit scores at 24 h of reperfusion and apoptosis rate of hippocampal neurons were significantly increased,and the expression of p-eIf2α was up-regulated in I/R and H groups (P＜0.05).Compared with group I/R,the neurologic deficit scores at 24 h of reperfusion and apoptosis rate of hippocampal neurons were significantly decreased,and the expression of p-eIf2α was down-regulated in group H (P＜ 0.05).Conclusion Mild hypothermia reduces endoplasmic reticulum stress and inhibits neuroapoptosis through inhibiting the expression of p-eIf2α in the hippocampus in a mouse model of cerebral I/R.
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Objective To observe the effect of adenosine monophosphate activated protein kinase (AMPK) on attenuating inflammation in fibrosis induced hy acute ischemia reperfusion injury (IRI) in mice.Methods Forty eight male C57BL/6 mice were randomly divided into four groups:sham operation group (sham group),IRI group,AMPK inhibitor+IRI group (AMPK/IRI group) and normal saline+IRI group (NS/IRI group),12 mice each group.The mice with renal IRI were occluded for 30 min through clipping bilateral renal pedicle,then released renal perfusion.Mice in sham group were performed the separation of renal pedicle without clipping.Mice in AMPK/IRI group and NS/IRI group were respectively intraperitoneal injected AMPK inhibitor and normal saline before IRI.At the 2 d after operation,6 randomly-selected mice from each group were blooded by extraction eyeball to detect BUN and Scr.The renal histopathological changes were observed through HE staining.The mRNA expression of IL-1β,IL-6 and TNF-α was detected by real time PCR,and the level of AMPK phosphorylation was detected by Western blotting.At the 14 d after operation,Collagen 1 (COL1),α-SMA and fibronectin (FN) were detected by immunofluorescence and Western blotting in 6 remained mice from each group.The degree of kidney fibrosis was observed through sirus red staining.Results Compared with those in sham group,tubular interstitial damage was aggravated (P ＜ 0.05),BUN and Scr were increased (P ＜ 0.05),the mRNA expression of IL-1β,IL-6 and TNF-α was increased at the 2 d after operation (all P ＜ 0.05),and the level of AMPK phosphorylation was activated in IRI group and NS/IRI group (all P ＜ 0.05);the degree of kidney fibrosis and the expression of COL1,α-SMA and FN were increased obviously at the 14 d (all P ＜ 0.05).Compared with those in IRI group,in AMPK/IRI group tubular interstitial damage was aggravated (P ＜ 0.05),BUN and Scr were increased (all P ＜ 0.05),the mRNA expression of IL-1β,IL-6 and TNF-α was increased at the 2 d (all P ＜ 0.05),and the level of AMPK phosphorylation was decreased (P ＜ 0.05).Moreover,the degree of kidney fibrosis and the expression of COLI,α-SMA and FN were increased obviously at the 14 d in AMPK/IRI group (all P ＜0.05).Conclusions AMPK can ameliorate the acute renal ischemia reperfusion injury induce fibrosis in mice,and the mechanism may be related to the decrease of inflammatory reaction.
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Objective To evaluate the changes in the expression of DJ-1 protein during myocardial ischemia-reperfusion (I/R) in diabetic rats.Methods Fifty male Sprague-Dawley rats,weighing 220-280 g,were used in this study.Type 1 diabetes mellitus was induced by intraperitoneal streptozotocin 65 mg/kg and confirmed by fasting blood glucose ＞ 16.7 mmol/L.Forty animals with type 1 diabetes mellitus were randomly divided into 3 groups:diabetes group (group D,n =10),diabetic sham operation group (group DS,n =15) and diabetic I/R group (group DIR,n =15).Another 10 non-diabetic rats in which citrate buffer 6 ml/kg was injected intraperitoneally were served as control group (group C).Myocardial I/R was produced by occlusion of the anterior descending branch of left coronary artery for 30 min followed by 120 min reperfusion in group I/R.At 120 min of reperfusion,5 rats were sacrificed and myocardial specimens were c(on)tained for determination of infarct size in groups DS and DIR,and 10 rats were sacrificed and myocardial specimens were obtained for microscopic examination and for determination of cell apoptosis,malondialdehyde (MDA) content,superoxide dismutase (SOD) activity and expression of DJ-1 and phosphatase and tensin homologue (PTEN) protein.Apoptotic index (AI) was calculated.Linear correlation between the expression of DJ-1 protein and MDA content,SOD activity,AI and expression of PTEN protein was analyzed.Results Compared with group DS,the myocardial infract size was significantly increased in group DIR (P ＜ 0.05).Compared with group C,MDA content and AI were significantly increased,SOD activity was decreased,the expression of DJ-1 was down-regulated,and the expression of PTEN protein was up-regulated in groups D,DS and DIR (P ＜ 0.05).Compared with groups D and DS,MDA content and AI were significantly increased,SOD activity was decreased,the expression of DJ-1 was down-regulated,and the expression of PTEN protein was up-regulated in group DIR (P ＜ 0.05).There was no significant difference in the parameters mentioned above between groups D and DS (P ＞ 0.05).There was linear correlation between the expression of DJ-1 protein and MDA content,SOD activity,AI and expression of PTEN protein and the correlation coefficients (r) were-0.734,0.593,-0.818,and-0.812 in turn.Conclusion Down-regulation of DJ-1 protein expression is involved in myocardial I/R injury in diabetic rats via decreasing anti-oxidative stress responses and upregulating PTEN protein expression.
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Objective To evaluate the prevalence of the DJ-1 mutation in early-onset Parkinson's disease (EOPD) patients,and analyzed the association between the certain polymorphic marker g.168_185del in intron1 and Parkinson' s disease (PD).Methods We screened all 7 exons and exon-intron boundary regions of DJ-1 by PCR and direct nucleotide sequencing in 90 Chinese patients with EOPD.We also compared the allele and genotype frequencies of the g.168_185del polymorphism between EOPD patients and controls.Results We found no causative DJ-1 mutations in our cohort of Chinese EOPD patients.But we did identified 4 known polymorphic variants,including the g.168_185del in intron 1,g.5027G ＞ A (rs17523802),g.5065T ＞ C (rs226249),and g.5094C ＞ T (rs11121064) within exon 1.Del/Ins frequencies of the g.168_185 del polymorphism were 11.1％ (10/90)and 13.3％ (14/105) in EOPD group and normal group,respectively.Ins/Ins frequencies were 88.9％ (80/90) and 86.7％ (91/105),thex2 and P value of genotype frequency were 0.222 and 0.669 between EOPD patients and controls,respectively.The insert frequencies were 94.4％ (170/180)and 93.3％ (196/210) in EOPD patients and controls,the deletion frequencies were 5.6％ (10/180) and 6.7％ (14/210),thex2 and P value of allele frequency were 0.207 and 0.679 between EOPD patients and normal,respectively.Furthermore,the P value of genotype and allele frequencies were 0.736 and 0.744 between familial EOPD patients and controls,respectively;P values of genotype and allele frequencies were 0.847 and 0.852 between sporadic EOPD patients and control group,respectively.There was no statistical difference between groups.Conclusion Mutations in DJ-1 are uncommon in Chinese EOPD patients,and no association is observed between the DJ-1 intron 1 g.168_185del polymorphism and risk of PD.
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Objective To establish an animal model of rapid eye movement (REM) sleep deprivation (SD) and an animal model for perifornical nucleus microdialysis and investigate the change of cognition, hypocretinergic system and GABAergic system in rats' hypothalamus after various degrees of REM sleep deprivation and sleep revival and two GABAergic drugs intervention. Methods The modified multiple platform method (MMPM)was used to establish sleep deprivation model and the cognitive function was assessed by Morris' water maze. Immunofluorescence technique was used to analyze the number of Hypocretin (Hcrt) immunoreactive neurons, total Fos immunoreactive neurons, Hcrt and Fos colabeled neurons, and the integrated optical density ( IA ) of GABAA Rαl immunoreactive area in rats' hypothalamus.High performance liquid chromatograph (HPLC) was used to quantitatively analyze the level of GABA and Gluin in the rats' hypothalamus. Two GABAergic drugs, a selective GABAA R antagonist, SR-95531, and a selective blocker of type 1 GABA transporter (uptake blocker), NO-711, were used for perifornical nucleus microdialysis. Results There was no statistically significant difference in tests between CC and TC ( Define CC and TC). There was a significant decrease (P ＜ 0. 05 ) of cognitive function measured by Morris maze test in SD 3 d, SD 5 d and RS 6 h of SD groups compared with CC and TC groups. Number of Fos immunoreactive, F+ &H+ immunoreactive neuronsand IA of GABAA Rαl immunoreactive area were all significantly increased ( P ＜ 0. 05 ). Content of GABA measured by HPLC was also increased ( P ＜ 0. 05 ). However, all these changes were partly reversed by sleep revival SR-95531 and NO-711 had different effect on these changes. Conclusions Sleep deprivation, no matter mild or severe, has adverse effects on cognitive function. Activities of both GABAergic and Hcrtergic system are increased during REMSD. These two neurons system could be regulated by each other and the relationship between them is positive correlation. GABAergic system also had self-regulation during REMSD, but microdialysision of either SR-95531 or NO-711 acquired adverse effects on cognitive function of rats. So GABAergic system is not an optimal therapeutic target. Because GABAergic and Hcrtergic system has inhibitory effect on each other,suppressing activity of Hcrtergic system might be a promising therapeutic target.
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Objective: To investigate the anti-tumor effects of tanshinone II A (TS II A) and its nanoparticles (TS-NP) against hepatoma in mice and possible mechanism. Methods: TS-NP was prepared by emulsion-solvent evaporation method. Hepatoma model was established in mice. The cell apoptotic index was tested by TUNEL staining, and expression of p33 mitogen activated protein kinase (p38 MAPK) and tumor growth factor β1 (TGFβ1) were detected by immunohistochemistry (SP method). Results: The weight of tumor in TS II A and TS-NP groups at different dosages was significantly lower than that in NS group (P < 0.01), and the survival time of mice in TS II A and TS-NP groups was significantly longer than that in NS group (P < 0.01). The apoptotic index of hepatoma cells in TS II A and TS-NP groups was increased compared with NS group (P < 0.01). The therapeutic outcome was more superior in TS-NP group than TS II A group at the same dosage. After treatment with TS II A and TS-NP, the expression of p38 MAPK was increased, but the expression of TGFβ1 was decreased (P < 0.01). The expression of p38 MAPK negatively correlated with TGFβ1 (r = -0.873, P < 0.001). Conclusion: TS II A and TS-NP could inhibit the growth of hepatoma and prolong the survival time of mice. The therapeutic outcome of TS-NP-treated group is better than that of TS II A-treated group at the same dosage. The anti-hepatoma mechanism may be associated with upregulation of the expression of p38 MAPK and downregulation of the expression of TGFβ1 which further inhibites cell proliferation and induces apoptosis.