Anticancer activity of a thymidine quinoxaline conjugate is modulated by cytosolic thymidine pathways

Background High levels of thymidine kinase 1 (TK1) and thymidine phosphorylase (TYMP) are key molecular targets by thymidine therapeutics in cancer treatment. The dual roles of TYMP as a tumor growth factor and a key activation enzyme of anticancer metabolites resulted in a mixed outcome in cancer patients. In this study, we investigated the roles of TK1 and TYMP on a thymidine quinoxaline conjugate to evaluate an alternative to circumvent the contradictive role of TYMP. Methods TK1 and TYMP levels in multiple liver cell lines were assessed along with the cytotoxicity of the thymidine conjugate. Cellular accumulation of the thymidine conjugate was determined with organelle-specific dyes. The impacts of TK1 and TYMP were evaluated with siRNA/shRNA suppression and pseudoviral overexpression. Immunohistochemical analysis was performed on both normal and tumor tissues. In vivo study was carried out with a subcutaneous liver tumor model. Results We found that the thymidine conjugate had varied activities in liver cancer cells with different levels of TK1 and TYMP. The conjugate mainly accumulated at endothelial reticulum and was consistent with cytosolic pathways. TK1 was responsible for the cytotoxicity yet high levels of TYMP counteracted such activities. Levels of TYMP and TK1 in the liver tumor tissues were significantly higher than those of normal liver tissues. Induced TK1 overexpression decreased the selectivity of dT-QX due to the concurring cytotoxicity in normal cells. In contrast, shRNA suppression of TYMP significantly enhanced the selective of the conjugate in vitro and reduced the tumor growth in vivo. Conclusions TK1 was responsible for anticancer activity of dT-QX while levels of TYMP counteracted such an activity. The counteraction by TYMP could be overcome with RNA silencing to significantly enhance the dT-QX selectivity in cancer cells

Effects of Walking in Bamboo Forest and City Environments on Brainwave Activity in Young Adults

Background. In Japan, “Shinrin-yoku” or forest bathing (spending time in forests) is a major practice used for relaxation. However, its effects on promoting human mental health are still under consideration. The objective of this study was to investigate the physiological and psychological relaxation effects of forest walking on adults. Sixty participants (50% males; 50% females) were trained to walk 15-minute predetermined courses in a bamboo forest and a city area (control). The length of the courses was the same to allow comparison of the effects of both environments. Blood pressure and EEG results were measured to assess the physiological responses and the semantic differential method (SDM) and STAI were used to study the psychological responses. Blood pressure was significantly decreased and variation in brain activity was observed in both environments. The results of the two questionnaires indicated that walking in the bamboo forest improves mood and reduces anxiety. Moreover, the mean meditation and attention scores were significantly increased after walking in a bamboo forest. The results of the physiological and psychological measurements indicate the relaxing effects of walking in a bamboo forest on adults

Hypolipidemic effect of aqueous leaf extract of carmona microphylla G Don

Purpose: To investigate the hypolipidemic effects of the aqueous leaf extract of Carmona microphylla (Lam.) G. Don. (CAE) in vitro and in vivo.Methods: The lipid-lowering effect of CAE was investigated in oleic acid (OA)-induced steatosis in HepG2 liver cells, as well as in high-fat diet (HFD)- and triton WR-1339 (TRI)-induced hyperlipidemic mice. The levels of intracellular, serum and/or hepatic total cholesterol (TC); triglyceride (TG); low density lipoprotein-cholesterol (LDL-c); high density lipoprotein-cholesterol (HDL-c); hepatic superoxide dismutase (SOD) activity and malondialdehyde (MDA) were determined by oil-red O staining and appropriate kits.Results: Treatment with CAE inhibited lipid accumulation in HepG2 cells and reduced the elevated levels of serum TC, TG and LDL-c as well as hepatic TC and TG in hyperlipidemic mice induced by HFD. CAE administration also significantly decreased arteriosclerosis index (AI) and LDL-c/HDL-c ratio, but improved oxidative status as revealed by increased hepatic SOD activity and decreased MDA level. The lipid ameliorating and antioxidative effects of CAE (600 mg/kg) were comparable to those of the standard lipid-lowering drug, sivastatin (5 mg/kg).Conclusion: These results suggest that C. microphylla aqueous extract (CAE) protects against hyperlipidemia induced by HFD in mice and may find therapeutic application in hyperlipidemic patients.Keywords: Carmona microphylla, Hyperlipidemia, Atherosclerosis, Oxidative stress, Sivastatin, Lipidlowerin

Clinical efficacy of intra-articular infusion of cocktail combined with tranexamic acid in the treatment of middle-age and older patients with frozen shoulder following arthroscopic capsular release

ObjectiveTo investigate the clinical efficacy of arthroscopic capsular release and postoperative intra-articular infusion of cocktail combined with tranexamic acid (TXA) in the treatment of patients with frozen shoulder.MethodA total of 85 middle-aged and older patients with frozen shoulder who underwent arthroscopic capsular release and received intra-articular infusion of TXA alone (n = 28), cocktail alone (n = 26), and cocktail plus TXA (n = 31) after surgery were retrospective analyzed. The drainage volume within 24 h after surgery, postoperative length of hospital stay, postoperative complications, visual analog scale (VAS), Neer shoulder assessment scale, ASES score, and range of motion (ROM) of the shoulder joint at 1 day, 1 week, 1 month, and 3 months after surgery in all three groups were recorded and compared.ResultsPostoperative length of hospital stay was significantly shorter in the cocktail + TXA and cocktail groups than that in the TXA group. Postoperative drainage volume was significantly higher in the cocktail group compared with TXA + cocktail group (P < 0.05). At 1 day and 1 week after surgery, pain was more pronounced in the TXA group, which was significantly relieved in the cocktail and the cocktail + TXA groups (P < 0.05). Pain was significantly relieved in all the three groups at 1 and 3 months after surgery. Significant functional improvement of the shoulder was achieved in all three groups at 1 week after surgery, the improvement was apparent in the cocktail + TXA groups (P < 0.05), followed by the cocktail group. At 1 month after surgery, patients in the cocktail + TXA groups obtained excellent functional recovery of the shoulder joint. At 3 months after surgery, patients in all the three groups both obtained good recovery of the shoulder joint function, and the recovery was apparent in the cocktail + TXA groups (P < 0.05).ConclusionArthroscopic capsular release and postoperative intra-articular infusion of cocktail combined with TXA has good safety and efficacy in the treatment of middle-age and older patients with frozen shoulder, which can reduce postoperative pain and intra-articular bleeding, promote early postoperative functional exercises and accelerate early postoperative recovery

Analysis of the effect of anti-tuberculosis treatment and lung injury in patients with tuberculosis combined with underlying disease

Objective·To investigate the impact of complications on the prognosis and lung injury of patients with tuberculosis..Methods·A retrospective cohort study was used for analysis, to select a total of 450 smear-positive tuberculosis (TB) patients, 323 males (71.8%) and 127 females (28.2%), from January to December 2018 at Shanghai Pulmonary Hospital, Tongji University School of Medicine, which were divided into non-complication group and complication group (diabetes, hypertension, liver diseases, kidney diseases and gallbladder diseases). Overall treatment outcomes and lung injuries in TB patients with and without complications were analyzed by using χ2 test. Stratified analysis of the impact of each comorbidity on the prognosis and lung injury of TB patients was performed. Kaplan-Meier analysis was used to analyze the temporal correlation between complications and tuberculosis prognosis.Results·Four hundred and fifty patients with a median age of 33 years were included, 173 of whom had complications: diabetes in 49 cases, hypertension in 23 cases, liver diseases in 83 cases, kidney diseases in 35 cases, and gallbladder diseases in 17 cases. The cure rate of TB patients without complications was 80.5%, which was significantly higher than that of the group with complications (P<0.05); the significantly lower cure rate of TB patients with diabetes, hypertension and kidney diseases at diagnosis was the key cause of anti-tuberculosis treatment failure; TB patients with diabetes and liver diseases had higher lung bacterial load and larger areas of lung damage, and TB patients with diabetes and kidney diseases had higher incidence of pulmonary cavity.Conclusion·Diabetes, hypertension and kidney diseases exacerbate lung damage and lead to lower TB cure rates. Early interventions by clinicians at the time of diagnosis can improve cure rates, shorten treatment time, and reduce medical costs for TB patients

Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer’s disease

Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer’s disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box–binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases