FTO-mediated m6A mRNA demethylation aggravates renal fibrosis by targeting RUNX1 and further enhancing PI3K/AKT pathway.

Chronic kidney disease (CKD) is a global health burden, with ineffective therapies leading to increasing morbidity and mortality. Renal interstitial fibrosis is a common pathway in advanced CKD, resulting in kidney function and structure deterioration. In this study, we investigate the role of FTO-mediated N6-methyladenosine (m6A) and its downstream targets in the pathogenesis of renal fibrosis. M6A modification, a prevalent mRNA internal modification, has been implicated in various organ fibrosis processes. We use a mouse model of unilateral ureteral obstruction (UUO) as an in vivo model and treated tubular epithelial cells (TECs) with transforming growth factor (TGF)-ß1 as in vitro models. Our findings revealed increased FTO expression in UUO mouse model and TGF-ß1-treated TECs. By modulating FTO expression through FTO heterozygous mutation mice (FTO+/- ) in vivo and small interfering RNA (siRNA) in vitro, we observed attenuation of UUO and TGF-ß1-induced epithelial-mesenchymal transition (EMT), as evidenced by decreased fibronectin and N-cadherin accumulation and increased E-cadherin levels. Silencing FTO significantly improved UUO and TGF-ß1-induced inflammation, apoptosis, and inhibition of autophagy. Further transcriptomic assays identified RUNX1 as a downstream candidate target of FTO. Inhibiting FTO was shown to counteract UUO/TGF-ß1-induced RUNX1 elevation in vivo and in vitro. We demonstrated that FTO signaling contributes to the elevation of RUNX1 by demethylating RUNX1 mRNA and improving its stability. Finally, we revealed that the PI3K/AKT pathway may be activated downstream of the FTO/RUNX1 axis in the pathogenesis of renal fibrosis. In conclusion, identifying small-molecule compounds that target this axis could offer promising therapeutic strategies for treating renal fibrosis.

Biofilm Alterations on the Stepwise Acquisition of Fluconazole-resistant Candida Albicans Isolates.

By assessing and comparing the phenotypic changes on the stepwise acquisition of fluconazole resistant Candida albicans isolates, we could find and describe the relationship between drug resistance and biofilm formation ability in a series of clonal strains. Methods: We performed antifungal susceptibility of five drugs (fluconazole, itraconazole, voriconazole, caspofungin and amphotericin B) to further verify the antifungal activity of the six isolates in vitro. Then we combined hyphal formation assay, cell surface hydrophobicity test positively related to adherence ability, and biofilm assays in vitro to observe and compare the phenotypic characteristics of our six clonal strains. Results: Biofilm capability is enhanced for four drug- intermediate strains, whereas the initial susceptible strain and the final resistant strain are both poor in adherence, hyphal growth and biofilm formation. Conclusions: It was suggested that the biofilm formation ability were not absolutely related to the degree of fluconazole resistance.

Relationship between frailty and long-term care needs in Chinese community-dwelling older adults: a cross-sectional study.

OBJECTIVES: Our study aimed to investigate the relationship between the severity of frailty and the long-term care (LTC) needs of older adults from Chinese communities. DESIGN: A cross-sectional study. SETTING: Three Chinese community health centres. All data were collected by trained researchers through face-to-face collection. PARTICIPANTS: We surveyed a total of 540 older residents who aged 60 or older from community in Guangzhou, China. MEASURES: The Chinese version of the Tilburg frailty indicator was used to assess the frailty status of participants. LTC needs was evaluated by Integrated Home Care Services Questionnaire. Using non-adjusted and multivariate adjusted logistic regression analysis to evaluate frailty and LTC needs, then smoothed plots, threshold effect analysis and P for trend were used to further investigate the relationship between them. RESULTS: The prevalence of frailty was 45.2% among the 540 older adults enrolled (aged 70.4±8.3 years; 65.7% females). 27% had higher LTC needs, which increased to 65.1% for individuals with frailty. Logistic regression analysis showed that frailty was strongly associated with LTC needs (OR 3.06, 95% CI 2.06 to 4.55, p<0.01). In the multivariate model, after adjusting for demographic characteristics, economic situation, activities of daily living and comorbidities, frailty remained significantly associated with LTC needs (OR 2.32, 95% CI 1.39 to 3.88, p<0.01). The smoothed plots showed a nearly linear relationship between frailty and LTC needs. Threshold effect analysis showed that every point increase in frailty, the score of LTC needs increased 1.3 points. The IQR to regroup individuals with frailty. Compared with the first quartile (scores ≤2), the incidence of LTC needs increased with the frailty status (p value for trend <0.01). CONCLUSION: There is a linear relationship between frailty and LTC needs. With the increasing degree of frailty, the LTC needs of older adults dramatically increases.

Modelling effects of public health educational campaigns on drinking dynamics.

This paper deals with the global property of a drinking model with public health educational campaigns. With the help of Lyapunov function, global stability of equilibria of the model is derived. The alcohol-free equilibrium is globally asymptotically stable and the alcohol problems are eliminated from population if [Formula: see text]. A unique alcohol present equilibrium is globally asymptotically stable if [Formula: see text]. Furthermore, the basic reproductive [Formula: see text] for the model is compared with the basic reproductive number [Formula: see text] for the absence of public health educational campaigns. We conclude that the public health educational campaigns of drinking individuals can slow down the drinking dynamics. Some numerical simulations are also given to explain our conclusions.

Effects of electroacupuncture at Zusanli (ST36) on inflammatory cytokines in a rat model of smoke-induced chronic obstructive pulmonary disease.

OBJECTIVE: Improvement in lung function was reported after acupuncture treatment of chronic obstructive pulmonary disease (COPD), but little is known about the underlying mechanisms. Because an immune response imbalance could be seen in COPD, we hypothesize that electroacupuncture (EA) may play a role in regulating inflammatory cytokines and contribute to lung protection in a rat model of smoke-induced COPD. METHODS: A COPD model using male Sprague-Dawley rats exposed to cigarette smoke was established. The rats were randomly divided into four groups (control, sham, COPD, and COPD plus EA), and COPD model was evaluated by measuring pulmonary pathological changes and lung function. EA was applied to the acupuncture point Zusanli (ST36) for 30 min/d for 14 d in sham and COPD rats. Bronchoalveolar lavage fluid (BALF) was used to measure levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and malonaldehyde (MDA). RESULTS: Compared with the control rats, COPD rats had significant changes in lung resistance (RL) and lung compliance (CL) (both P<0.01), bronchi and bronchiole airway obstruction (P<0.01), and levels of MDA, TNF-α, and IL-1ß (P<0.01). There were no significant differences between the control and the sham groups. Compared with the COPD rats, the COPD plus EA rats had decreased RL and increased CL (both P<0.05), and reduced bronchi and bronchiole airway obstruction (P<0.05, P<0.01, respectively), while levels of TNF-α, IL-1ß, and MDA in BALF were lowered (P<0.05 and P<0.01, respectively). However, TNF-α and IL-1ß levels of the EA group rats remained higher than those of the control group (P<0.05). CONCLUSION: EA at ST36 can reduce lung injury in a COPD rat model, and beneficial effects may be related to down-regulation of inflammatory cytokines. The anti-inflammatory and antioxidant effects may prolong the clinical benefit of EA.

Orexin-A and respiration in a rat model of smoke-induced chronic obstructive pulmonary disease.

1. Orexins are neuropeptides synthesized in the hypothalamus that regulate many physiological functions, including energy homeostasis, stress responses, sleep/wake states etc. It is now emerging that orexins may also regulate breathing, but little is known as to how they do this, particularly in chronic obstructive pulmonary disease (COPD). In the present study, we used a rat model of cigarette smoke-induced COPD to investigate orexin-A expression in the hypothalamus and medulla and its effect on respiration. 2. Sprague-Dawley rats were exposed to cigarette smoke (1 h twice daily) for 12 weeks. Lung function and pathological changes associated with inflammation and emphysema were determined to confirm the validity of the COPD model. 3. Hypothalamic and medullary orexin-A levels, as determined by radioimmunoassay, were higher in smoke-exposed than control rats. Furthermore, the expression of prepro-orexin (PPO) mRNA in the hypothalamus and orexin OX(1) receptor mRNA in the medulla, as determined by real-time quantitative polymerase chain reaction, was higher in smoke-exposed than control rats. 4. The number of orexin-A-positive neurons in the hypothalamus and OX(1) and OX(2) receptor-positive neurons in the ventrolateral medulla was higher in smoke-exposed than control rats. 5. Microinjection of orexin-A (1 µmol/L, 0.1 µL) into the pre-Bötzinger complex enhanced phrenic nerve discharge to a greater extent in smoke-exposed compared with control rats (61% vs 36%, respectively). 6. The findings of the present study demonstrate that the increased respiratory activity in smoke-exposed rats is due to an increase in orexin-A as well as upregulation of orexin receptors in the ventrolateral medulla.