MiR‐21‐3p modulates lipopolysaccharide‐induced inflammation and apoptosis via targeting TGS4 in retinal pigment epithelial cells

Age‐related macular degeneration (AMD) is a major reason of blindness in the elderly. MicroRNAs are implicated in various pathological processes, including inflammation and apoptosis. In this study, we aim to investigate the biological functions of miR‐21‐3p in inflammation and apoptosis caused by lipopolysaccharide (LPS) in human retinal pigment epithelial (ARPE‐19) cells. The miR‐21‐3p inhibitor and mimic were transfected into ARPE‐19 cells for 48 hours, followed by exposed to LPS (10 μg/mL) for 24 hours. The mRNA and protein expression of IL‐6 and MCP‐1 were measured using real‐time PCR (RT‐PCR) and enzyme‐linked immunosorbent assays. Cell viability, apoptosis, caspase 3 activity, cleaved caspase‐3 and cleaved‐PARP protein levels were detected to evaluate the effects of miR‐21‐3p on apoptosis. Additionally, the target relationship between miR‐21‐3p and regulator of G‐protein signalling 4 (RGS4) was verified by dual luciferase reporter assay. RT‐PCR analysis demonstrated that LPS induced miR‐21‐3p expression. Inhibition of miR‐21‐3p reduced the mRNA and protein levels of IL‐6 and MCP‐1. Apoptosis, caspase‐3 activity, and cleaved‐caspase 3 and cleaved PARP protein levels were repressed by the miR‐21‐3p inhibitor. However, overexpression of miR‐21‐3p showed the opposite results. Furthermore, we identified that miR‐21‐3p directly targeted the 3′ untranslated region of RGS4. MiR‐21‐3p negatively regulated the expression of RGS4 both in mRNA and protein levels. Silencing RGS4 reduced the anti‐inflammatory and anti‐apoptotic effects of miR‐21‐3p inhibitor. Our results revealed that miR‐21‐3p inhibition targeted RGS4 to attenuate inflammatory responses and apoptosis caused by LPS in ARPE‐19 cells.     

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

β‐LAPachone (B‐LAP) is a naphthoquinone that possesses antioxidant properties. In the present investigation, the protective effect of B‐LAP against doxorubicin (DOX)‐induced cardiotoxicity was examined in mice. Thirty‐five mice were divided into 5 groups: control group, B‐LAP (5 mg/kg) group, DOX (15 mg/kg) group, DOX+B‐LAP (2.5 mg/kg) group and DOX+B‐LAP (5 mg/kg) group. B‐LAP was administered orally for 14 days of experimental period. A single dose of DOX (15 mg/kg) was injected intraperitoneally on day 3. Cardiac function, histoarchitecture, indices of oxidative stress and circulating markers of cardiac injury were examined. B‐LAP (5 mg/kg) decreased serum levels of lactate dehydrogenase (LDH), creatine kinase MB (CK‐MB) and cardiac troponin I (cTnI), and ameliorated cardiac histopathological alterations. In addition to increasing cellular NAD⁺/NADH ratio, B‐LAP up‐regulated the cardiac levels of SIRT1, beclin‐1, p‐LKB1 and p‐AMPK, and reduced the cardiac levels of p‐mTOR, interleukin (IL)‐1β, TNF (tumour necrosis factor)‐α and caspase‐3. B‐LAP also elevated the nuclear accumulation of Nrf2 and simultaneously up‐regulated the protein levels of haem oxygenase (HO‐1) and glutathione S‐transferase (GST) in the hearts of DOX mice. While B‐LAP reduced malondialdehyde concentrations in heart of DOX‐treated mice, it further promoted the activities of cardiac superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT).In accordance with increased cell survival, B‐LAP significantly improved the cardiac function of DOX mice. Collectively, these findings underline the protective potential of B‐LAP against DOX‐induced cardiotoxicity by regulating autophagy and AMPK/Nrf2 signalling pathway in mice.     

Doxazosin down‐regulates sodium‐glucose cotransporter‐2 and exerts a renoprotective effect in rat models of acute renal injury

Sodium‐glucose cotransporter‐2 (SGLT2) is known to be involved in the progression of acute renal injury (ARI) and is regulated by different mediators in the kidneys including extracellular signal‐regulated kinase (ERK), hypoxia‐inducible factor 1 alpha (HIF1α) and prostaglandin E2 (PGE2). In the present study, we investigated the possible protective effect of doxazosin on renal ischaemia/reperfusion (IR) and glycerol‐induced ARI by determining its effect on SGLT2 via modifying ERK‐HIF1α pathway and/or PGE2. Rats were divided into control, sham or IR where the rats received the vehicle, doxazosin (8 mg/kg) or the SGLT2 inhibitor, dapagliflozin (10 mg/kg) for 3 days followed by 45 minutes bilateral renal ischaemia then 24 hours reperfusion. Another group of rats received the vehicle, doxazosin or dapagliflozin for three days followed by injection of 50% glycerol (8 mL/kg, IM) or saline. Kidney function tests, systolic blood pressure (SBP), oxidative stress markers (malondialdehyde [MDA] and NADPH oxidase), nitric oxide (NO), inducible nitric oxide synthase (iNOS), HIF1α, ERK phosphorylation and PGE2 levels were determined. Additionally, renal sections were used for immunological expression of SGLT2. ARI rats showed significantly increased SBP; worsened kidney function tests; increased oxidative stress, iNOS, NO, HIF1α levels; and decreased PGE2 and ERK phosphorylation along with up‐regulated SGLT2. Doxazosin treatment protected against the kidney damage and attenuated the associated biochemical changes. Doxazosin has a direct renoprotective effect possibly by down‐regulating SGLT2.     

Nitric oxide signalling is involved in diarylheptanoid‐induced increases in femoral arterial blood flow in ovariectomized rats

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Small Molecule Inhibitors of Regulator of G Protein Signalling (RGS) Proteins

Recently regulators of G protein signalling (RGS) proteins have emerged as potential therapeutic targets since they provide an alternative method of modulating the activity of GPCRs, the target of so many drugs. Inhibitors of RGS proteins must block a protein-protein interaction (RGS-Gα), but also be cell and, depending on the therapeutic target, blood brain barrier permeable. A lead compound (1a) was identified as an inhibitor of RGS4 in a screening assay and this has now been optimised for activity, selectivity and solubility. The newly developed ligands (11b, 13) display substantial selectivity over the closely related RGS8 protein, lack the off-target calcium mobilisation activity of the lead 1a and have excellent aqueous solubility. They are currently being evaluated in vivo in rodent models of depression.     

Aerobic interval training protects against myocardial infarction‐induced oxidative injury by enhancing antioxidase system and mitochondrial biosynthesis

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The CD147/MMP‐2 signaling pathway may regulate early stage cardiac remodelling in spontaneously hypertensive rats

Previous studies have reported that decreased matrix metalloproteinase‐2 (MMP‐2) is associated with early stage (age 8–16 weeks) ventricular remodelling in spontaneously hypertensive rats (SHR). We hypothesized that inhibited CD147/MMP‐2 signalling might down‐regulate MMP‐2 expression and augment remodelling in spontaneously hypertensive rats. Twenty‐nine male SHR (8 weeks) were randomly assigned to SHR, CD147, and CD147+DOX groups. The control group included eight age‐matched WKY rats. CD147 and CD147+DOX groups received recombinant human CD147 (600 ng/kg in 1.5 mL saline, weekly). The SHR and WKY groups received the vehicle. The CD147+DOX group also received doxycycline, an inhibitor of MMPs (daily, 30 mg/kg in 1.5 mL saline, iG). On day 56 echocardiography and left ventricular mass index (LVWI) measurements were collected and histological sections were stained for cell and collagen content. Myocardium MMP‐2, TIMP‐1, CD147, and collagens types I and III were estimated by western blot. CD147 and the ratio of MMP‐2/TIMP‐1 were lower in SHR than WKY rats (P<.05). Myocyte hypertrophy, partial fibre breaks, plasmolysis, necrosis and collagen content (collagen volume fraction [CVF], I and III) in SHR were above control levels (P<.05). CD147 rats showed CD147, MMP‐2 and MMP‐2/TIMP‐1 were increased (P<.05), CVF, LVWI, and collagen I and III were decreased (P<.05) and myocyte morphology was improved. CD147 levels did not differ between CD147+DOX and CD147 groups, CVF, collagens type I and III and partial fiber breaks were more abundant in CD147+DOX (P<.05). In summary, an inhibited CD147/MMP‐2 pathway was associated with early stage cardiac remodelling, and CD147 supplementation may attenuate this response.     

Tracking anti‐fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: An insight

The tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl₄ for 12 weeks. During the last 8 weeks of treatment, rats were also injected daily intraperitoneally with 20 mg/kg imatinib or 20, 10 or 5 mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti‐inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of α‐smooth muscle actin, transforming growth factor (TGF)‐β1 antibodies and platelet‐derived growth factor receptor β (PDGFRβ) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10 mg/kg) significantly (P < 0.05) decreased all serum fibrotic markers measured, but 20 mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P < 0.05) decreased the CCl₄‐induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10 mg/kg nilotinib significantly decreased TGF‐β1 levels and tissue expression of its antibody, as well expression of PDGFRβ. In conclusion, low doses (5 and 10 but not 20 mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)‐1 and IL‐6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF‐β1 levels and decreasing expression of PDGFRβ.     

Total glucosides of paeony inhibit the proliferation of fibroblast-like synoviocytes through the regulation of G proteins in rats with collagen-induced arthritis

The aim of this study was to investigate the expression of G proteins in fibroblast-like synoviocytes (FLSs) from rats with collagen-induced arthritis (CIA) and to determine the effect of total glucosides of paeony (TGP). CIA rats were induced with chicken type II collagen (CCII) in Freund's complete adjuvant. The rats with experimental arthritis were randomly separated into five groups and then treated with TGP (25, 50, and 100 mg/kg) from days 14 to 35 after immunization. The secondary inflammatory reactions were evaluated through the polyarthritis index and histopathological changes. The level of cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. The FLS proliferation response was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The toxin-catalyzed ADP-ribosylation of G proteins was performed through autoradiography. The results show that TGP (25, 50, and 100 mg/kg) significantly decreased the arthritis scores of CIA rats and improved the histopathological changes. TGP inhibited the proliferation of FLSs and increased the level of cAMP. Moreover, the FLS proliferation and the level of Gαi expression were significantly increased, but the level of Gαs expression was decreased after stimulation with IL-1β (10 ng/ml) in vitro. TGP (12.5 and 62.5 μg/ml) significantly inhibited the FLS proliferation and regulated the balance between Gαi and Gαs. These results demonstrate that TGP may exert its anti-inflammatory effects through the suppression of FLS proliferation, which may be associated with its ability to regulate the balance of G proteins. Thus, TGP may have potential as a therapeutic agent for the treatment of rheumatoid arthritis.     

Non‐Clinical Pharmacokinetics,Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody

CNTO 5825 is a human anti‐interleukin‐13 (IL‐13) monoclonal antibody (mAb) that inhibits binding of human IL‐13 to IL‐13Rα1 and IL‐13Rα2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non‐clinical PK data in order to select the right and safe doses for first‐in‐human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.98 to 11.49 ml/day/kg in rats and from 5.78 to 7.19 ml/day/kg in cynomolgus monkeys. The volume of distribution at steady‐state (Vss) in rats was large (151.52–155.64 ml/kg) compared to cynomolgus monkey (49.77–61.10 ml/kg). The terminal half‐life (T_1/2) ranged from 12.29 to 14.15 days in rats and from 6.61 to 7.73 days in cynomolgus monkeys. The PK of CNTO 5825 was linear in 1–10 mg/kg dose range in both species. The bioavailability after subcutaneous (SC) administration was 94% and 79% in rats and cynomolgus monkeys, respectively. The predicted CL and Vss based on allometric methods and PK data from rats and monkeys were within twofold of observed CL and Vss in human beings; the predicted CL and Vss in human beings (70 kg) based on time‐invariant method with combined PK data from rats and monkeys were 4.84 ± 1.13 ml/day/kg and 68.93 ± 35.55 ml/kg, respectively. The selected doses for the FIH study based on time‐invariant method and no observed adverse effect level in toxicity studies in rats and monkeys provided exposures that were subsequently shown to be well tolerated and safe in human beings.     

ACE inhibition and protection from doxorubicin-induced cardiotoxicity in the rat

The angiotensin converting enzyme inhibitor zofenopril has been shown to possess cardioprotective effects toward myocardial damage induced by chronic doxorubicin treatment in the rat. In the present study we have investigated the relationship between cardioprotection exerted by 2 angiotensin converting enzyme inhibitors (zofenopril and lisinopril) and degree of inhibition of cardiac versus serum angiotensin converting enzyme. Both zofenopril and lisinopril produced a dose-dependent inhibition of serum and cardiac angiotensin converting enzyme in rats (0.1, 1 or 10 mg/kg/day in the diet for 1 week). However, zofenopril at 0.1 mg/kg/day showed a significantly (P < 0.05) greater inhibition of angiotensin converting enzyme in the myocardium than in the serum (Δ about 20%). Using dose levels (0.1 mg/kg/day and 10 mg/kg/day) which inhibits partially (about 50%) or almost totally (about 80%) serum angiotensin converting enzyme, we evaluated the effects of zofenopril and lisinopril in preventing cardiac alterations (QαT prolongation) induced by chronic treatment with doxorubicin (1.5 mg/kg q7dx5 i.v.). Zofenopril, at a dose level (0.1 mg/kg/day) that did not affect haemodynamics and only partially inhibits serum angiotensin converting enzyme activity, almost totally prevent the QαT lengthening induced by doxorubicin, whereas lisinopril was ineffective at this dose level. At the higher dose level (10 mg/kg/day), both angiotensin converting enzyme inhibitors totally prevented the electrocardiographic alteration induced by chronic doxorubicin administration. Cardioprotection exerted by zofenopril at a dose level that partially inhibits serum angiotensin converting enzyme without affecting haemodynamics, suggests that inhibition of cardiac angiotensin converting enzyme and additional cardioprotective mechanism(s) may have a role in its ability to prevent myocardial damages in the rat subjected to chronic anthracycline treatment.     

Impact of fusion to Gα(i2) and co-expression with RGS proteins on pharmacological properties of human cannabinoid receptors CB₁R and CB₂R

Objectives G protein coupled receptor (GPCR)‐Gα fusion proteins are often employed to investigate receptor/G protein interaction. In this study, the impact of Gα fusion proteins on pharmacology of CBRs, both mediating signals through Gα_i proteins, were investigated. Gα_i2 was fused to the C‐terminus of the CBRs or co‐expressed with non‐fused Gα_i2 in Sf9 cells, always together with Gβ₁γ₂. Furthermore, the impact of RGS proteins on CBR signaling in combination with the CBR fusion approach was examined, using RGS4 and RGS19 as paradigms. Methods CBR ligands were characterized in the steady‐state GTPase assay and pharmacological properties of ligands in the different test systems were correlated. Key findings Fusion of CBRs to Gα_i2 enhanced the maximal stimulatory effects of ligands compared to the co‐expression system, especially for CB₂R. RGS4, but not RGS19, behaved as a GTPase‐activating protein at CBRs in the Gα_i2 co‐expression and fusion system. Fusion of GPCR, most prominently CB₂R, to Gα_i2, and co‐expression with RGS4 altered the pharmacological properties of ligands. Conclusions Our data suggest that fusion of CB₂R to Gα_i2 and co‐expression with RGS4 impedes with conformational changes. Moreover, our results support the concept of ligand‐specific receptor conformations. Finally, this paper describes the most sensitive CBR test system currently available.     

The role of Syk/IĸB‐α/NF‐ĸB pathway activation in the reversal effect of BAY 61‐3606, a selective Syk inhibitor,on hypotension and inflammation in a rat model of zymosan‐induced non‐septic shock

Spleen tyrosine kinase (Syk), a non‐receptor tyrosine kinase, plays an important role in allergic diseases and inflammation. Syk triggers several intracellular signalling cascades including Toll‐like receptor signalling to activate inflammatory responses following fungal infection but the role of this enzyme in zymosan (ZYM)‐induced non‐septic shock and its impacts on hypotension and inflammation in rats is not well understood. This study was conducted to determine the effects of Syk inhibition on ZYM‐induced alterations in the expression and/or activities of Syk, inhibitor ?B (I?B)‐α, and nuclear factor‐?B (NF‐?B) p65. We also examined the effect of Syk inhibition on inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)‐2, and tumour necrosis factor (TNF)‐α, and activity of myeloperoxidase (MPO) that contribute to hypotension and inflammation. Administration of ZYM (500 mg/kg, ip) to male Wistar rats decreased blood pressure and increased heart rate. These changes were associated with increased expression and/or activities of Syk, NF‐κB p65, iNOS and COX‐2 and decreased expression of IκB‐α with enhanced levels of nitrite, nitrotyrosine, 6‐keto‐PGF_1α, and TNF‐α and activity of MPO in renal, cardiac and vascular tissues. ZYM administration also elevated serum and tissue nitrite levels. The selective Syk inhibitor BAY 61‐3606 (3 mg/kg, ip) given 1 hour after ZYM injection reversed all of these changes induced by ZYM. These results suggest that Syk/I?B‐α/NF‐?B pathway activation contributes to hypotension and inflammation caused by the production of vasodilator and proinflammatory mediators in the zymosan‐induced non‐septic shock model.     

Hypoxia inducible factor‐1α inhibition produced anti‐allodynia effect and suppressed inflammatory cytokine production in early stage of mouse complex regional pain syndrome model

Complex regional pain syndrome (CRPS) is related to microcirculation impairment associated with tissue hypoxia and peripheral cytokine overproduction in the affected limb. Previous studies suggest that the pathogenesis involves hypoxia inducible factor‐1α (HIF‐1α) and exaggerated regional inflammatory response. 1‐methylpropyl 2‐imidazolyl disulfide (PX‐12) acts as the thioredoxin‐1 (Trx‐1) inhibitor and decreases the level of HIF‐1α, and can rapidly be metabolized for Trx‐1 redox inactivation. This study hypothesized that PX‐12 can decrease the cytokine production for nociceptive sensitization in the hypoxia‐induced pain model. CD1 mice weighing around 30 g were used. The animal CRPS model was developed via the chronic post‐ischaemic pain (CPIP) model. The model was induced by using O‐rings on the ankles of the mice hind limbs to produce 3‐h ischaemia–reperfusion injury on the paw. PX‐12 (25 mg/kg, 5 mg/kg) was given through tail vein injection immediately after ischaemia. Animal behaviour was tested using the von Frey method for 7 days. Local paw skin tissue was harvest from three groups (control, 5 mg/kg, 25 mg/kg) 2 h after injection of PX‐12. The protein expression of interleukin‐1β (IL‐1β) and HIF‐1α was analysed with the Western blotting method. Mice significantly present an anti‐allodynia effect in a dose‐related manner after the PX‐12 administration. Furthermore, PX‐12 not only decreased the expression of HIF‐1α but also decreased the expression of IL‐1β over the injured palm. This study, therefore, shows the first evidence of the anti‐allodynia effect of PX‐12 in a CPIP animal model for pain behaviour. The study concluded that inhibition of HIF‐1α may produce an analgesic effect and the associated suppression of inflammatory cytokine IL‐1β in a CPIP model.     

Upregulation of C/EBPβ and TSC2 by an HDAC inhibitor CG200745 protects heart from DOCA‐induced hypertrophy

Histone deacetylases (HDACs) are a vast family divided into four major classes: class I (1, 2, 3, and 8), class II (4, 5, 6, 7, 9 and 10), class III (sirtuin family) and class IV (HDAC11). HDAC inhibition attenuates cardiac hypertrophy through suppression of the mechanistic target of rapamycin complex1 (mTORC1) signaling. HDAC inhibitors upregulate the expression of tuberous sclerosis complex 2 (TSC2), an mTORC1 inhibitor. However, the molecular mechanism underlying HDAC inhibitor‐mediated upregulation of TSC2 is unclear. We hypothesized that an HDAC inhibitor, CG200745 (CG), ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling by upregulating of the CCAAT/enhancer‐binding protein‐β (C/EBP‐β)/TSC2 pathway. To establish a cardiac hypertrophy model, deoxycorticosterone acetate (DOCA, 40 mg/kg/wk) was subcutaneously injected for 4 weeks into Sprague‐Dawley rats. All rats were unilaterally nephrectomized and had free access to drinking water containing 1% NaCl with or without CG of different concentrations. The expression level of TSC2 and C/EBP‐β was measured by quantitative real‐time PCR (qRT‐PCR) and western blot analysis. Acetylation of C/EBP‐β was analyzed by immunoprecipitation. The recruitment of C/EBP‐β and polymerase II (Pol II) on TSC2 promoter region was analyzed by chromatin immunoprecipitation (ChIP). CG treatment increased the expression of TSC2. In addition, CG treated rats showed an increased in the expression and acetylation of C/EBP‐β, owing to the increase in the recruitment of C/EBP‐β and Pol II at Tsc2 gene promoter. Thus, CG ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling via upregulation of the C/EBP‐β/TSC2 pathway in DOCA‐induced hypertensive rats.     

Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter

In the CNS, several regulators of G-protein signalling (RGS) modulate the activity of mu-opioid receptors. In pull-down assays performed on membranes from mouse periaqueductal gray matter (PAG), mu-opioid receptors co-precipitated with delta-opioid receptors, Gi/o/z/q proteins, and the regulators of G-protein signalling RGS4, RGS9-2, RGS14, RGSZ1 and RGSZ2. No RGS2, RGS7, RGS10 and RGS11 proteins were associated with the mu receptors in these PAG membranes. In mice, an intracerebroventricular dose of 10 nmol morphine produced acute tolerance at mu receptors but did not disrupt the co-precipitation of mu-delta receptor complexes. However, this opioid reduced by more than 50% the co-precipitation of G alpha i/o/z subunits with mu receptors, and altered their association with some of the RGS proteins at 30 min, 3 h and 24 h after its administration. The association of RGS9-2 with mu receptors diminished by 30-40% 24 h after the administration of morphine, while that of RGSZ2 and of RGSZ1 increased. Morphine treatment recruited RGS4 to the PAG membranes, and 30 min and 3 h after the opioid challenge its association with mu receptors had increased. However, 24 h after morphine administration, the co-precipitation of RGS4 had decreased by about 30%. The opioid produced no change in the membrane levels of RGS9-2, RGS14, RGSZ1 and RGSZ2. Thus, in PAG synaptosomal membranes, a dynamic and selective link exists between, mu-opioid receptors, Gi/o/z proteins and certain RGS proteins.     

Tropisetron ameliorates early diabetic nephropathy in streptozotocin‐induced diabetic rats

It has been well established that oxidative stress and inflammation are involved in the pathogenesis of diabetic nephropathy. It has been shown that tropisetron exerts anti‐inflammatory and immunomodulatory properties. The current study was designed to investigate protective effects of tropisetron on early diabetic nephropathy in streptozotocin‐induced diabetic rats. Rats were divided into six groups: (i) untreated diabetic (streptozotocin group); (ii) untreated control; (iii) diabetic rats treated with tropisetron (3 mg/kg); (iv) normal rats treated with tropisetron (3 mg/kg); (v) diabetic rats treated with granisetron (3 mg/kg); and (vi) normal rats treated with granisetron (3 mg/kg); rats began receiving treatment at the time of diabetes induction for 2 weeks. At the termination of the experiments, bodyweight, kidney index, urinary albumin excretion, and glomerular filtration rate were measured. The levels of oxidative stress markers and tumour necrosis factor‐α were also determined. Streptozotocin‐treated animals showed significant loss of bodyweight and renal enlargement and dysfunction. Diabetic rats also exhibited an increase in malondialdehyde along with a significant decrease in glutathione, superoxide dismutase activity, and catalase activity. Furthermore, the diabetic animals demonstrated a significant rise in renal cortical, urinary tumour necrosis factor‐α, and urinary albumin excretion. Both granisetron and tropisetron decreased blood glucose in diabetic animals, but this decrease was not significant for granisetron. Treatment with tropisetron, but not granisetron, prevented increases in oxidative stress and tumour necrosis factor‐α, decreased urinary cytokine excretion and albuminuria, and improved renal morphological damage. In conclusion, the present study suggests that tropisetron may be a protective agent in early diabetic nephropathy, and its action is mediated, at least in part, by anti‐oxidative and anti‐inflammatory mechanisms that appear to be independent of the 5‐HT₃ receptor.     

NF‐κB activation mediates LPS‐or zymosan‐induced hypotension and inflammation reversed by BAY61‐3606, a selective Syk inhibitor,in rat models of septic and non‐septic shock

We have previously demonstrated that the activation of the spleen tyrosine kinase (Syk)/inhibitory‐κB (IκB)‐α/nuclear factor‐κB (NF‐κB) p65 signalling pathway contributes to hypotension and inflammatory response in a rat models of zymosan (ZYM)‐induced non‐septic shock. The purpose of this study was to further examine the possible mechanism underlying the effect of inhibition of Syk by BAY61‐3606 via NF‐κB activity at the level of nuclear translocation regarding the production of vasodilator and proinflammatory mediators in lipopolysaccharide (LPS) (septic)‐ and ZYM (non‐septic)‐induced shock. Administration of LPS (10 mg/kg, ip) or ZYM (500 mg/kg, ip) to male Wistar rats decreased mean arterial pressure and increased heart rate that was associated with an increase in the activities of cyclooxygenase and nitric oxide synthase, tumour necrosis factor‐α, and interleukin‐8 levels, and NF‐κB activation and nuclear translocation in sera and/or cardiovascular and renal tissues. BAY61‐3606 (3 mg/kg, ip), the selective Syk inhibitor, given 1 hour after LPS‐ or ZYM injection reversed all the above‐mentioned effects. These results suggest that Syk contributes to the LPS‐ or ZYM‐induced hypotension and inflammation associated with transactivation of NF‐κB in septic and non‐septic shock.     

Endothelial and neuronal nitric oxide synthases variably modulate the oestrogen‐mediated control of blood pressure and cardiovascular autonomic control

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