Effect of tranexamic acid in improving the lifespan of naturally aging mice Abstract An effective method to improve lifespan is not known. Therefore, in this study, we examined the lifespan-extending effect of tranexamic acid in normal mice. We bred hairless mice without exposure to ultraviolet radiation and psychical stress until they died naturally. During the study period, the mice were orally administered tranexamic acid (12 mg/kg/day) three times weekly. An increase in the lifespan of mice was observed by tranexamic acid administration. Furthermore, age-related diseases of the skin were ameliorated by tranexamic acid administration. Moreover, the blood level of tumor necrosis factor-α, interleukin-6, reactive oxygen species (ROS), and matrix metalloproteinase (MMP)-9 was decreased by tranexamic acid administration. These results indicate that tranexamic acid suppresses the secretion of inflammatory cytokines, MMP-9, and ROS induced by natural aging, ameliorating age-related diseases, and, consequently, extending the lifespan.

Neuroprotective and anti-inflammatory effects of isoliquiritigenin in kainic acid-induced epileptic rats via the TLR4/MYD88 signaling pathway Abstract Epileptogenesis is a complex pathological process that occurs after an initial brain injury and involves a series of molecular events. Isoliquiritigenin (ISL), a flavonoid in licorice, is reported to have anti-inflammatory and antioxidant effects in various experimental models, but its specific roles and molecular mechanisms in the epileptogenic process following kainic acid (KA) treatment remain unclear. The purpose of this study was to explore the effects of ISL pretreatment in KA-induced epileptic rats and the underlying mechanisms. Our findings show that ISL pretreatment significantly attenuated the KA-induced expression of ionized calcium‐binding adapter molecule 1 (IBα1)-labeled microglia (F(3, 20) = 97.29, p < 0.01, ηp2 = 0.94) and glial fibrillary acidic protein (GFAP)-positive astrocytes (F(3, 20) = 72.48, p < 0.01, ηp2 = 0.92), and the release of inflammatory mediators, such as TNF-α (F(3, 20) = 133.14, p < 0.01, ηp2 = 0.95), IL-1β, and C–C motif chemokine ligand 3 (CCL3). ISL pretreatment given before KA also significantly prevented apoptotic neuronal injury by upregulating the activities of superoxide dismutase and glutathione peroxidase. It also significantly suppressed the protein levels of Toll-like receptor 4 (TLR4) (F(3, 20) = 63.23, p < 0.01, ηp2 = 0.91) and its downstream molecules, myeloid differentiation primary response 88 (MYD88), phosphorylated (p-)IκBα, and p-NF-κB. Blocking TLR4/MYD88 signaling also attenuated KA-induced neuroinflammation and neuronal damage in the hippocampus. Overall, our study demonstrates that ISL pretreatment plays neuroprotective and anti-inflammatory roles in KA-induced epileptogenesis, which may be mediated by the TLR4/MYD88 signaling pathway.

Anti-inflammatory and renal protective effect of gingerol in high-fat diet/streptozotocin-induced diabetic rats via inflammatory mechanism Abstract P38 mitogen-activated protein kinase (p38 MAPK), a tissue inflammatory factor can be activated under oxidative stress and in conditions associated with hyperglycemia. Gingerol containing various natural herbs has been extensively studied for its pharmacological actions both in reducing the inflammation and as immunity booster. The aim of the current investigation was to examine the renal protective effect of gingerol in high-fat diet/streptozotocin-induced type II diabetes mellitus in a rat model.NRK 52E cells were divided into normal and high glucose group treated with gingerol. The methylthiazotetrazolium assay was used to establish the cell proliferation progress. Streptozotocin-inducted diabetes in rats was treated with gingerol for 16 weeks. The blood glucose, serum creatinine, body weight, food intake, biochemical, antioxidant and haematological parameters were assayed to establish the correlation. Pro-inflammatory cytokines including Il-1β, IL-6, TNF-α; inflammatory mediator COX-2, PGE2, NF-kB, p38MAPK, and TGF-β, were also determined to assess the molecular mechanism. Gingerol exhibited the protective effect on the high glucose level induced NRK 52E cells and did not show any effect on the normal cells. Gingerol significantly (P < 0.001) down-regulated the blood glucose level, creatinine and BUN level in a dose-dependent manner with further significantly (P < 0.001) alteration in pro-inflammatory cytokines, nuclear factor kappa B (N-κB) activation, renal p38MAPK, and TGF-β. From these studies it is possible to predict that gingerol plays a significant role in improving the condition of renal tissue by alteration in p38MAPK and NF-κB activity, and control inflammatory reaction and oxidative stress. Our investigation supports the clinical use of gingerol in future as an effective renal protective agent.

Pterodontic acid isolated from Laggera pterodonta suppressed RIG-I/NF-KB/STAT1/Type I interferon and programmed death-ligand 1/2 activation induced by influenza A virus in vitro Abstract Influenza viruses can bring about acute respiratory diseases and are a potential hazard to human health. Antiviral drugs are the main ways to control the influenza virus infection except the vaccine. In this study, the immune regulation activity of pterodontic acid isolated from Laggera pterodonta induced by influenza A virus in vitro was evaluated. In studies on anti-influenza activity, our results showed that it maybe target the influenza protein of polymerase basic 1 (PB1), polymerase basic 2 (PB2), polymerase acid (PA), nuclear protein (NP), non-structural protein (NS), and matrix protein (M) but not hemagglutinin (HA) and neuraminidase (NA). In studies on immune regulation, our results demonstrated that pterodontic acid can inhibit the Retinoic acid inducible gene-I (RIG-I) expression in mRNA and protein level at 100 μg/ml, then further to clarify its action on the signalling pathway, The results indicated that pterodontic acid can inhibit the Tumor Necrosis Factor-related Apoptosis-inducing Ligand/Fas Ligand (TRAIL/Fasl) expression in mRNA level at 100 μg/ml; the cleaved caspase 3/7, p-NF-KB, and p-ERK were all suppressed in protein level by pterodontic acid at 100 μg/ml. This confirmed its mechanism that restrained the nuclear export of viral RNPs. The interferon system was also affected, the STAT1, IFN-α, IFN-β expression were also inhibited by pterodontic acid at 25–100 μg/ml and also, the important programmed death-ligand of PD-L1 and PD-L2 was inhibited at 50–100 μg/ml. The mechanisms of pterodontic acid against influenza virus infection may be a cascade inhibition and it has the anti-inflammatory activity, which has no side effect, and can be as a supplement drug in clinical influenza virus infection.

The citrus flavanone naringenin attenuates zymosan-induced mouse joint inflammation: induction of Nrf2 expression in recruited CD45 + hematopoietic cells Abstract Background Naringenin is a biologically active analgesic, anti-inflammatory, and antioxidant flavonoid. Naringenin targets in inflammation-induced articular pain remain poorly explored. Methods The present study investigated the cellular and molecular mechanisms involved in the analgesic/anti-inflammatory effects of naringenin in zymosan-induced arthritis. Mice were pre-treated orally with naringenin (16.7–150 mg/kg), followed by intra-articular injection of zymosan. Articular mechanical hyperalgesia and oedema, leucocyte recruitment to synovial cavity, histopathology, expression/production of pro- and anti-inflammatory mediators and NFκB activation, inflammasome component expression, and oxidative stress were evaluated. Results Naringenin inhibited articular pain and oedema in a dose-dependent manner. The dose of 50 mg/kg inhibited leucocyte recruitment, histopathological alterations, NFκB activation, and NFκB-dependent pro-inflammatory cytokines (TNF-α, IL-1β, and IL-33), and preproET-1 mRNA expression, but increased anti-inflammatory IL-10. Naringenin also inhibited inflammasome upregulation (reduced Nlrp3, ASC, caspase-1, and pro-IL-1β mRNA expression) and oxidative stress (reduced gp91phox mRNA expression and superoxide anion production, increased GSH levels, induced Nrf2 protein in CD45+ hematopoietic recruited cells, and induced Nrf2 and HO-1 mRNA expression). Conclusions Naringenin presents analgesic and anti-inflammatory effects in zymosan-induced arthritis by targeting its main physiopathological mechanisms. These data highlight this flavonoid as an interesting therapeutic compound to treat joint inflammation, deserving additional pre-clinical and clinical studies.

Thymol reduces acetic acid-induced inflammatory response through inhibition of NF-kB signaling pathway in rat colon tissue Abstract Aim The aim of the present study was to evaluate the anti-inflammatory effect of thymol in acetic acid-induced rat colitis through inhibiting the NF-κB signaling pathway. Methods Colitis was induced by intra-rectal administration of 2 mL of diluted acetic acid (4%) solution using a flexible plastic rubber catheter in Wistar rats. Colitis was induced on the first day and all treatments were applied 5 days after the induction of colitis. Thymol was dissolved in 0.2% tween 80 in saline and administered orally at doses of 10, 30, and 100 mg/kg per day. Macroscopic and histopathologic investigations were done. The expression of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) was determined by immunohistochemistry (IHC) assay. The protein expression level of pNF-κB p65 was measured by the Western blot technique. Results Treatment with thymol reduced mucosal and histological damages compared to the acetic acid group. Our results showed that thymol markedly inhibited the production of MPO and TNF-α in the colon tissue of the acetic acid-induced group. In addition, thymol decreased acetic acid-induced up-regulation of pNFκB p65 protein. Conclusions: The results of our study suggest that thymol exerts an anti-inflammatory effect in acetic acid-induced rat colitis by inhibiting the NF-κB signaling pathway and downregulating TNF-α and MPO expressions.

Antinociceptive effect of flavonol and a few structurally related dimethoxy flavonols in mice Abstract Previous reports suggest flavonoids as potent analgesic compounds. Based on these observations, the present study investigated the antinociceptive action of flavonol, 3′, 4′-dimethoxy flavonol, 6, 3′-dimethoxy flavonol, 7, 2′-dimethoxy flavonol, and 7, 3′-dimethoxy flavonol and the possible mechanisms involved in these effects. The antinociceptive effect of the investigated compounds in doses of 25, 50, 100, and 200 mg/kg was evaluated in male Swiss albino mice using the acetic acid test, formalin-induced nociception, and hot water tail immersion test. The role of opioid, tryptaminergic, adrenergic, dopaminergic, GABAergic, and K+ATP channels in producing the antinociceptive effect was also studied using appropriate interacting agents. Treatment with flavonol and dimethoxy flavonols resulted in a significant reduction in the number of abdominal constrictions in the acetic acid test, a significant inhibition of the paw-licking/biting response time in both the phases of formalin nociception and also a significant increase in mean reaction time in the hot water tail immersion test. These observations revealed the antinociceptive effect of dimethoxy flavonols. The role of opioid, serotonergic (5HT3), and dopaminergic system was identified in the antinociceptive effect of flavonol and all dimethoxy derivatives investigated. In addition, the role of GABAergic, K+ATP channel, and α-2 adrenergic mechanisms were also observed in the antinociceptive action of some of the investigated compounds. The present study identified the antinociceptive effect of flavonol and dimethoxy flavonols in mice acting through different neuronal pathways.

Preemptive meloxicam achieves a better effect on postoperative pain control and similar tolerance compared with postoperative meloxicam in patients receiving arthroscopic knee surgery Abstract This study aimed to compare the efficacy and safety of very early preemptive meloxicam, early preemptive meloxicam, and postoperative meloxicam administration for postoperative pain relief in patients undergoing arthroscopic knee surgery (AKS). Three hundred and six patients about to receive AKS were consecutively enrolled in this randomized, controlled study and randomly allocated into three groups: very early analgesia (VEA) group, early analgesia (EA) group, and postoperative analgesia (PA) group. Pain visual analog scale (VAS) score at rest and at flexion, patient global assessment (PGA) score, consumption of rescue pethidine, and adverse events (AEs) were assessed. Pain VAS score and severity at rest/flexion were all decreased in the VEA group compared with EA group and PA group at 4 h post-operation and were also reduced in the VEA and EA groups compared with the PA group at 8 h and 12 h post-operation. PGA score was lower in the VEA group compared with the EA group and PA group at 4 h post-operation, and was attenuated in the VEA group and the EA group compared with the PA group at 8 h, 12 h, and 24 h post-operation as well. Consumption of rescue pethidine was less in the VEA group than that in the PA group. In addition, no difference in the incidence of AEs was found among the VEA, EA, and PA groups. In conclusion, preemptive meloxicam is more effective in postoperative pain control and equally tolerated compared with postoperative meloxicam in patients receiving AKS.

Urotensin-#receptor antagonist SB-706375 protected isolated rat heart from ischaemia–reperfusion injury by attenuating myocardial necrosis via RhoA/ROCK/RIP3 signalling pathway Abstract SB-706375 is a selective receptor antagonist of human urotensin-II (hU-II), which can block the aorta contraction induced by hU-II in rats. The effect of SB-706375 on myocardial ischaemia–reperfusion (I/R) injury is unclear. The major objective of this study was to investigate whether SB-706375 has a protective effect on myocardial I/R injury in rats and explore its possible mechanisms. Isolated hearts of Adult Sprague–Dawley were perfused in a Langendorff apparatus, and haemodynamic parameters, lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB), cardiac troponin I (cTnI), RhoA, and the protein expressions of U-II receptor (UTR), receptor-interacting protein 3 (RIP3), Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) and Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) were assessed. We found that SB-706375 (1 × 10−6 and 1 × 10−5 mol/L) significantly inhibited the changes of haemodynamic parameters and reduced LDH and CK-MB activities and also cTnI level in the coronary effluents in the heart subjected to myocardial I/R injury. Further experiments studies showed that SB-706375 obviously prevented myocardial I/R increased RhoA activity and UTR, RIP3, ROCK1, and ROCK2 protein expressions. ROCK inhibition abolished the improving effect of SB-706375 on myocardial I/R-induced haemodynamic change in the isolated perfused rat heart. These findings suggested that SB-706375 provides cardio-protection against I/R injury in isolated rats by blocking UTR-RhoA/ROCK-RIP3 pathway.

Inflammatory responses bridge comorbid cardiac disorder in experimental model of IBD induced by DSS: protective effect of the trigonelline Abstract Pathogenesis of the inflammatory bowel disease (IBD) involves the combination of immunological and inflammatory factors. IBD is associated with several extra-intestinal manifestations. The exact underlying bridge between the probable cardiac diseases in IBD patients is undetermined. Trigonelline is an alkaloid with several therapeutic potential properties. In this study, we aimed to assess the probable underlying mechanisms of this comorbidity as well as protective effect of trigonelline focusing inflammatory response and oxidative state in mouse model of colitis. Dextran sodium sulfate (DSS) was used for induction of colitis in mice. Trigonelline (10, 50 and 100 mg/kg) was administrated via intraperitoneal rout (i.p.) for 14 continuous days. Heart, intestine and serum samples were taken for assessment of total antioxidant capacity, malondialdehyde (MDA), gene expressions of inflammatory markers including tumor necrosis factor alpha (Tnf-α), interleukin 1-beta (Il/1β), toll- like receptor 4 (Tlr4) as well as for evaluation of histopathological alterations. Results demonstrated that trigonelline effectively attenuated the cellular/molecular and histopathological adverse effects of colitis in the intestine and heart tissues. In this regards, we found that trigonelline decreased the MDA level, attenuated the expression of Tnf-α, Il/1β and, Tlr4 as well as modulated the histopathological alterations in the intestine. Furthermore, trigonelline increased the antioxidant capacity in the related experimental groups. We concluded that IBD (colitis) is associated with comorbid cellular/molecular modifications in the heart and for the first time, we found that trigonelline has potential therapeutic effects (at least partially) to attenuate the cardiac manifestations of the colitis.