Clinical and Experimental Pharmacology and Physiology最新文献

One of the major contributors to secondary osteoporosis is long-term glucocorticoid usage. Clinically used antidepressant agomelatine also has anti-inflammatory properties. Our research aimed to inspect the probable defensive effect of agomelatine against steroid-promoted osteoporosis. There were four groups of rats; group I had saline as a negative control; rats of group II had dexamethasone (0.6 mg/kg, s.c.), twice weekly for 12 weeks; rats of group III had agomelatine (40 mg/kg/day, orally), as a positive control, daily for 12 weeks; and rats of group IV had dexamethasone + agomelatine in the same previous doses combined for 12 weeks. Finally, biochemical as well as histopathological changes were evaluated and dexamethasone treatment caused osteoporosis, as evidenced by discontinuous thin cancellous bone trabeculae, minor fissures and fractures, irregular eroded endosteal surface with elevated alkaline phosphate, tartarate resistant acid phosphate (TRACP) and osteocalcin levels. Osteoprotegerin (OPG), calcium, and phosphorus levels decreased with disturbed receptor activator of nuclear factor κ B ligand (RANKL), forkhead box O1 (FOXO1), and silent information regulator 1 (SIRT1) protein expression. However, treatment with agomelatine restored the normal levels of biochemical parameters to a great extent, supported by SIRT activation with an improvement in histopathological changes. Here, we concluded that agomelatine ameliorates steroid-induced osteoporosis through a SIRT1/RANKL/FOXO1/OPG-dependent pathway.

Spinocerebellar ataxia 3 (SCA3) is an incurable, neurodegenerative genetic disorder that leads to progressive cerebellar ataxia and other parkinsonian-like pathologies because of loss of cerebellar neurons. The role of an expanded polyglutamine aggregate on neural progenitor cells is unknown. Here, we show that SCA3 patient-specific induced neural progenitor cells (iNPCs) exhibit proliferative defects. Moreover, SCA3 iNPCs have reduced autophagic expression compared to control. Furthermore, although SCA3 iNPCs continue to proliferate, they do not survive subsequent passages compared to control iNPCs, indicating the likelihood that SCA3 iNPCs undergo rapid senescence. Exposure to interleukin-4 (IL-4), a type 2 cytokine produced by immune cells, resulted in an observed increase in expression of autophagic programs and a reduction in the proliferation defect observed in SCA3 iNPCs. Our results indicate a previously unobserved role of SCA3 disease ontology on the neural stem cell pool and a potential therapeutic strategy using IL-4 to ameliorate or delay disease pathology in the SCA3 neural progenitor cell population.

Lu J, Chen H, He F, et al. Ginsenoside 20(S)-Rg3 upregulates HIF-1α-targeting miR-519a-5p to inhibit the Warburg effect in ovarian cancer cells. Clin Exp Pharmacol Physiol. 2020;47(8):1455-1463.

The Western blot image of β-actin in the right panel of Figure 4A had been misplaced by the Western blot image of β-actin in the right panel of Figure 7A during figure assembly.

We apologize for this error.

Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti-infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti-infective drugs. However, data from paediatric-based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti-infective drugs recommended for gene-guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children.

Bronchoscopic lung volume reduction (BLVR) is a feasible, safe, effective and minimally invasive technique to significantly improve the quality of life of advanced severe chronic obstructive pulmonary disease (COPD). In this study, three-dimensional computed tomography (3D-CT) automatic analysis software combined with pulmonary function test (PFT) was used to retrospectively evaluate the postoperative efficacy of BLVR patients. The purpose is to evaluate the improvement of lung function of local lung tissue after operation, maximize the benefits of patients, and facilitate BLVR in the treatment of patients with advanced COPD. All the reported cases of advanced COPD patients treated with BLVR with one-way valve were collected and analysed from 2017 to 2020. Three-dimensional-CT image analysis software system was used to analyse the distribution of low-density areas <950 Hounsfield units in both lungs pre- and post- BLVR. Meanwhile, all patients performed standard PFT pre- and post-operation for retrospective analysis. We reported six patients that underwent unilateral BLVR with 1 to 3 valves according to the range of emphysema. All patients showed a median increase in forced expiratory volume in 1 second (FEV1) of 34%, compared with baseline values. Hyperinflation was reduced by 16.6% (range, 4.9%-47.2%). The volumetric measurements showed a significant reduction in the treated lobe volume among these patients. Meanwhile, the targeted lobe volume changes were inversely correlated with change in FEV1/FEV1% in patients with heterogeneous emphysematous. We confirm that 3D-CT analysis can quantify the changes of lung volume, ventilation and perfusion, to accurately evaluate the distribution and improvement of emphysema and rely less on the observer.

Pneumonia is an inflammatory disease in lower respiratory tracts and its development involves the regulation of RNAs. Circular RNAs are a class of RNA subgroups that can mediate the progression of pneumonia. However, the molecular mechanism of circ_0026579 in regulating pneumonia occurrence remains unclear. The study is designed to reveal the role of circ_0026579 in lipopolysaccharide (LPS)-induced human lung fibroblast cell injury and the underlying mechanism. The expression levels of circ_0026579, miR-370-3p and C-X-C motif chemokine receptor 1 (CXCR1) were detected by quantitative real-time polymerase chain reaction or by western blotting. The production of tumour necrosis factor-α, interleukin (IL)-1β and IL-6 was assessed by enzyme-linked immunosorbent assays. Malondialdehyde and superoxide dismutase levels were analysed using commercial kits. Cell viability, proliferation and apoptosis were analysed by cell counting kit-8 assay, 5-Ethynyl-2′-deoxyuridine assay and flow cytometry analysis, respectively. The binding relationship between miR-370-3p and circ_0026579 or CXCR1 was identified by dual-luciferase reporter assay, RNA immunoprecipitation assay and RNA pull-down assay. Circ_0026579 and CXCR1 expression were significantly upregulated, whereas miR-370-3p was downregulated in the serum of pneumonia patients. LPS treatment induced inflammatory response, oxidative stress and cell apoptosis and inhibited cell proliferation in MRC-5 cells; however, these effects were reversed after circ_0026579 depletion. In terms of the mechanism, circ_0026579 acted as a miR-370-3p sponge, and miR-370-3p combined with CXCR1. Additionally, circ_0026579 depletion ameliorated LPS-induced MRC-5 cell disorder by increasing miR-370-3p expression. CXCR1 overexpression also relieved the miR-370-3p-mediated effects in LPS-treated MRC-5 cells. Further, circ_0026579 induced CXCR1 expression by interacting with miR-370-3p. Circ_0026579 absence ameliorated MRC-5 cell dysfunction induced by LPS through the regulation of the miR-370-3p/CXCR1 axis.

Myocardial ischemia/reperfusion (I/R) injury is the primary cause of heart damage in the treatment of myocardial infarction, and the imbalance of the energy metabolism in the pathogenesis of myocardial I/R is one of the main triggers of cardiac dysfunction. Monocarboxylate transporter 4 (MCT4) is a key transporter of lactate, which plays a vital role in cellular metabolism. The present study investigated the role and underlying mechanism of MCT4 in myocardial I/R injury. The results of this study showed that MCT4 was upregulated during oxygen–glucose deprivation (OGD) and restored after reoxygenation in cardiomyocytes HL-1. Interestingly, the overexpression of MCT4 increased cell viability and decreased apoptosis of OGD/R-induced HL-1 cells. Furthermore, MCT4 boosted glucose uptake and lactate levels and promoted protein expression of glycolysis regulator LDHA, while also impeding oxidative phosphorylation (OXPHOS) regulators C-MYC and NDUFB8 in OGD/R-induced HL-1 cells. A reduction in reactive oxygen species and oxidative stress markers malonaldehyde and superoxide dismutase was also observed within the OGD/R stimulated HL-1 cells. Additionally, the in vivo exogenous application of MCT4 restored cardiac function, as demonstrated by the reduced infarct size and decreased myocardial apoptosis in I/R rats. OXPHOS and oxidative stress declined, while glycolysis was activated when the I/R mice were injected with AAV-MCT4. Our findings indicate that MCT4 could exert a cardioprotective effect after myocardial I/R injury by inducing OXPHOS/glycolysis interconversion and inhibiting oxidative stress.

RAD140 is a selective androgen receptor modulator that produces anabolic effects within skeletal muscle. Thus, RAD140 may be effective at treating sarcopenia. No long-term studies have investigated how RAD140 influences strength in ageing muscle. This study aimed to determine how 10 weeks of RAD140 supplementation impacts strength, recovery from exercise, and overall health in ageing mice. Young and adult females were assigned to receive RAD140 (5 mg/kg) or a control solution. Dorsiflexor muscles were exposed to repeated bouts of eccentric contractions, and torque was measured before and after each bout. Adaptive potential and strength gains were calculated to assess the efficacy of RAD140 in muscle, while frailty status and mortality risk were used to measure health span. Supplementation of RAD140 increased frailty status and mortality risk in the young and adult treated groups compared to the controls (p ≤ 0.042). RAD140 decreased adaptive potential in young (p = 0.040) but not adult mice (p = 0.688). Torque did not differ between groups after 2–3 weeks of recovery (p ≥ 0.135). In conclusion, long-term RAD140 supplementation reduced indices of overall health and failed to improve strength in female mice, suggesting that RAD140 (at a 5mg/kg dosage) may be more detrimental than beneficial in delaying or preventing sarcopenia.

Liver fibrosis is a chronic liver lesion caused by excessive deposition of the extracellular matrix after liver damage, resulting in fibrous scarring of liver tissue. The progression of liver fibrosis is partially influenced by the gut microbiota. Chitosan can play a therapeutic role in liver fibrosis by regulating the gut microbiota based on the ‘gut–liver axis’ theory. Salvianolic acid B can inhibit the development of liver fibrosis by inhibiting the activation of hepatic stellate cells and reducing the production of extracellular matrix. In this study, the therapeutic effect of chitosan in combination with salvianolic acid B on liver fibrosis was investigated in a mouse liver fibrosis model. The results showed that the combination of chitosan and salvianolic acid B was better than the drug alone, improving AST/ALT levels and reducing the expression of α-SAM, COL I, IL-6 and other related genes. It improved the structure of gut microbiota and increased the abundance of beneficial bacteria such as Lactobacillus. The above results could provide new ideas for the clinical treatment of liver fibrosis.