Targeting ferroptosis as a promising therapeutic strategy to treat cardiomyopathy.

Cardiomyopathies are a clinically heterogeneous group of cardiac diseases characterized by heart muscle damage, resulting in myocardium disorders, diminished cardiac function, heart failure, and even sudden cardiac death. The molecular mechanisms underlying the damage to cardiomyocytes remain unclear. Emerging studies have demonstrated that ferroptosis, an iron-dependent non-apoptotic regulated form of cell death characterized by iron dyshomeostasis and lipid peroxidation, contributes to the development of ischemic cardiomyopathy, diabetic cardiomyopathy, doxorubicin-induced cardiomyopathy, and septic cardiomyopathy. Numerous compounds have exerted potential therapeutic effects on cardiomyopathies by inhibiting ferroptosis. In this review, we summarize the core mechanism by which ferroptosis leads to the development of these cardiomyopathies. We emphasize the emerging types of therapeutic compounds that can inhibit ferroptosis and delineate their beneficial effects in treating cardiomyopathies. This review suggests that inhibiting ferroptosis pharmacologically may be a potential therapeutic strategy for cardiomyopathy treatment.

The role of miR-143-3p/FNDC1 axis on the progression of non-small cell lung cancer.

The study aimed to explore the functional role of fibronectin type III domain containing 1 (FNDC1) in nonsmall cell lung cancer (NSCLC), as well as the mechanism governing its expression. The expression levels of FNDC1 and related genes in tissue and cell samples were detected by qRT-PCR. Kaplan-Meier analysis was employed to analyze the association between FNDC1 level and the overall survival of NSCLC patients. Functional experiments such as CCK-8 proliferation, colony formation, EDU staining, migration and invasion assays were conducted to investigate the functional role of FNDC1 in regulating the malignancy of NSCLC cells. Bioinformatic tools and dual-luciferase reporter assay were used to identify the miRNA regulator of FNDC1 in NSCLC cells. Our data revealed the upregulation of FNDC1 at mRNA and protein levels in NSCLC tumor tissues cancer cell lines, compared with normal counterparts. NSCLC patients with higher FNDC1 expression suffered from a poorer overall survival. FNDC1 knockdown significantly suppressed the proliferation, migration and invasion of NSCLC cells, and had an inhibitory effect on tube formation. We further demonstrated that miR-143-3p was an upstream regulator of FNDC1 and miR-143-3p expression was repressed in NSCLC samples. Similar to FNDC1 knockdown, miR-143-3p overexpression inhibited the growth, migration and invasion of NSCLC cells. FNDC1 overexpression could partially rescue the effect of miR-143-3p overexpression.  FNDC1 silencing also suppressed the tumorigenesis of NSCLC cells in mouse model. In conclusion, FNDC1 promotes the malignant prototypes of NSCLC cells. miR-143-3p is a negative regulator of FNDC1 in NSCLC cells, which may serve as a promising therapeutic target in NSCLC.

The novel bronchodilator navafenterol: a phase 2a, multicentre, randomised, double-blind, placebo-controlled crossover trial in COPD.

BACKGROUND: Navafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and ß-agonist, developed for the treatment of COPD. This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD. METHODS: This phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks' treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol (UMEC/VI); 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 15. Secondary end-points included change from baseline in peak FEV1; change from baseline in Breathlessness, Cough and Sputum Scale (BCSS); change from baseline in COPD Assessment Tool (CAT); adverse events; and pharmacokinetics. RESULTS: 73 participants were randomised. After 14 days, trough FEV1 was significantly improved with navafenterol compared with placebo (least-squares (LS) mean difference 0.202 L; p<0.0001). There was no significant difference in FEV1 between navafenterol and UMEC/VI (LS mean difference -0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p<0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period. CONCLUSION: Once-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.

In vitro fungicidal activity and in planta control efficacy of coumoxystrobin against Magnaporthe oryzae.

Rice blast, caused by Magnaporthe oryzae, is a destructive fungal disease in rice, causing serious losses in yield and quality. Coumoxystrobin is a novel methoxyacrylate strobilurin fungicide. In the current study, we determined the sensitivity of 100 M. oryzae strains to coumoxystrobin based on the mycelial growth inhibition method. The EC50 values ranged from 0.0089 to 0.0290 µg mL-1, with a mean EC50 value of 0.0163 ±â€¯0.0036 µg mL-1, indicating that coumoxystrobin exhibits an excellent inhibitory activity in the mycelial growth of M. oryzae. In addition, the EC50 values had no significant difference among four populations from the different geographical regions. After treating with coumoxystrobin, cell membrane permeability increased, respiration decreased, and the hyphal tips were contorted, with offshoot of top increasing. Protective and curative activity tests showed that coumoxystrobin exhibited better protective and curative activities against M. oryzae in detached barley leaves in comparison to the currently used fungicides tricyclazole and azoxystrobin. Also, it was found that the protective activity was better than its curative activity. Furthermore, compared with the currently used fungicides, coumoxystrobin not only exhibited excellent control efficacy on rice blast, but also markedly reduced the dosages of chemical fungicides in the field trials. Overall, these findings provide important references for revealing the pharmacological effect of coumoxystrobin against M. oryzae and managing rice blast caused by M. oryzae.

Benzimidazole- and QoI-resistance in Corynespora cassiicola populations from greenhouse-cultivated cucumber: An emerging problem in China.

Target leaf spot caused by Corynespora cassiicola is an economically important foliar disease on cucumber. In recent years, this disease has caused a serious problem on greenhouse-cultivated cucumber in China. In this study, to explore the characteristics and possible causes of heavy occurrence of the disease, we monitored the resistance of C. cassiicola strains from different provinces of China to benzimidazole and quinone outside inhibitor (QoI) fungicides. The results from sequence comparison of target genes ß-tubulin and Cytb of 619C. cassiicola strains indicate that resistance frequency to benzimidazoles and QoIs is up to 100%. Furtherly, molecular resistance mechanism of C. cassiicola to benzimidazoles and QoIs was analysed. One single mutation E198A and three double mutations E198A&M163I, E198A&F167Y and E198A&F200S were observed in target gene ß-tubulin, which confers resistance to benzimidazoles. To our knowledge, this is the first report that double mutations of ß-tubulin confer resistance to benzimidazoles in filamentous fungi. Compared with single mutation E198A, three double mutations significantly decreased sensitivity to benzimidazoles. Moreover, significant difference of sensitivity to benzimidazoles was observed among three double mutations. These mutation genotypes of ß-tubulin have different geographical distribution and the mutation E198A&M163I is prevalent, occupying for 63.94%. In addition, strong cross resistance patterns between carbendazim, benomyl and thiabendazole were observed in C. cassiicola strains conferring different ß-tubulin mutations. For QoI resistance, the only mutation G143A of Cytb was detected in tested 619C. cassiicola strains. Strong positive cross resistance was observed when comparing the EC50 values of sensitive and resistant strains of C. cassiicola for six intrinsically different QoIs such as azoxystrobin, fluoxastrobin, pyraclostrobin, fenaminstrobin, picoxystrobin and coumoxystrobin. Taken together, all the results not only provide novel insights into understanding resistance mechanism to benzimidazoles and QoIs in filamentous fungi, but also provide some important references for resistance management of target leaf spot on cucumber.

A new point mutation in ß2-tubulin confers resistance to carbendazim in Fusarium asiaticum.

Resistance to benzimidazole fungicides in many phytopathogenic fungi is caused by specific point mutations in the ß-tubulin gene (ß-tubulin). However, the mutated locus and genotype of ß-tubulin differ among phytopathogenic fungi. To validate the point mutation in Fusarium asiaticum ß2-tubulin that confers resistance to carbendazim and to analyze the molecular interaction between carbendazim and F. asiaticum ß2-tubulin. In this study, a new point mutation (GAG→GCG, E198A) at codon 198 of ß2-tubulin in a wild-type F. asiaticum strain was constructed by site-directed mutagenesis followed by a split marker strategy. The site-directed mutants were verified and exhibited a high level of resistance to carbendazim. In the absence of fungicide treatment, the biological characteristics did not differ between the site-directed mutants and the wild-type strain. Molecular docking between carbendazim and ß2-tubulin was carried out using the Surflex-Dock program in Sybyl X-2.0 version and the results indicated that the E198A mutation altered the configuration of ß2-tubulin, resulting in the change of the bonding sites and docking scores. We concluded that the point mutation of F. asiaticum ß2-tubulin conferring carbendazim resistance may not always be the bonding site for carbendazim.

Onset and duration of attenuation of exercise-induced bronchoconstriction in children by single-dose of montelukast.

Single-dose montelukast attenuates exercise-induced bronchoconstriction (EIB) in adults within 2 hours postdose and lasting through 24 hours. This study evaluated the onset and duration of EIB attenuation in children after a single dose of montelukast. A randomized, double-blind, placebo-controlled, two-period crossover study was performed. Patients (n = 66) aged 4-14 years, with preexercise forced expiratory volume in 1 second of (FEV(1)) ≥70% predicted and maximum percentage fall in FEV(1) of ≥20% at two screening exercise challenges were eligible. Patients were to receive single-dose montelukast (4 or 5 mg) or placebo before performing standardized exercise challenges at 2 and 24 hours postdose. A 3- to-7-day washout separated the two crossover periods. The primary end point was maximum percentage fall in FEV(1) after exercise challenge 2 hours postdose. Secondary end points included maximum percentage fall in FEV(1) after the 24-hour postdose challenge; each of the following at 2 and 24 hours postdose-maximum percentage fall in FEV(1) categorized as <10%, 10-20%, or >20%; area under the curve (AUC) during 60 minutes postchallenge; time to recovery of FEV(1) to within 5% of preexercise baseline; and need for rescue medication. The mean maximum percentage fall in FEV(1) after the 2-hour postdose exercise challenge was significantly attenuated after single-dose montelukast compared with placebo (15.35% versus 20.00%; p = 0.020). Montelukast was also significantly more effective than placebo for maximum percentage fall after the 24-hour challenge (12.92% versus 17.25%; p = 0.005), the categorized maximum percent fall in FEV(1) at 2 hours (p = 0.034), and AUC at 2 hours (p = 0.022) and 24 hours (p = 0.013). Single-dose montelukast provided rapid and sustained EIB attenuation in children. Clinicaltrials.gov identifier: NCT00534976.