Discovery of novel diaryl substituted isoquinolin-1(2H)-one derivatives as hypoxia-inducible factor-1 signaling inhibitors for the treatment of rheumatoid arthritis.

Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 µM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.

Continuous positive airway pressure improved daytime sleepiness and memory function in patients with obstructive sleep apnea.

Objectives: Obstructive sleep apnea (OSA) is a sleep disorder which results in daytime sleepiness and impaired memory function. The aim of this study was to investigate the effect of continuous positive airway pressure (CPAP) on daytime sleepiness and memory function in OSA patients. We also investigated whether CPAP compliance impacted the effect of this treatment. Materials and Methods: The nonrandomized, nonblinded clinical trial enrolled 66 patients with moderate-to-severe OSA subjects. All subjects completed a polysomnographic study, daytime sleepiness questionnaires (the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index), and four memory function tests (working memory; processing speed [PS]; logical memory [LM]; face memory [FM]). Results: Before CPAP treatment, no significant differences (P < 0.05) were noted in the demographic data, daytime sleepiness, or memory function between two groups (with/without CPAP). However, OSA patients treated with CPAP for 2 months showed significant improvements in daytime sleepiness, PS, mostly of LM, and FM comparing to 2 months ago. As compared to those who did not receive CPAP treatment, CPAP can improve only parts of LM (delayed LM [DLM] and LM percentage [LMP]). In addition, compared to control group, a significant improvement of daytime sleepiness and LM (LM learning, DLM, and LMP) in good compliance with CPAP treatment group and of DLM and LMP in the low compliance with CPAP treatment group was found. Conclusion: CPAP treatment for 2 months could improve some of LM in OSA patients, especially in patients exhibiting good CPAP compliance.

The impact of obesity in cognitive and memory dysfunction in obstructive sleep apnea syndrome.

OBJECTIVE: Obstructive sleep apnea (OSA), a sleep disorder, results in decreased daytime alertness and neurocognitive dysfunction. Obesity is considered a major risk factor for the development and progression of OSA and the resulting cognitive dysfunction. However, the effect of obesity on neurocognitive dysfunction in OSA has been rarely investigated. METHODS: Eighty-three patients with moderate to severe OSA syndrome were recruited in our study. After matching for education, age, and body mass index (BMI), 40 patients were enrolled into our study with matched obese (BMI ≧ 30) and non-obese (BMI < 30) groups. All enrolled patients completed a polysomnographic study, sleepiness questionnaires, and attention, cognitive, and memory function tests. RESULTS: Compared to obese OSA patients, non-obese OSA patients had shorter reaction times in the psychomotor vigilance task but not the Flanker or Stroop cognitive tasks. Additionally, obese OSA patients had a reduced capacity for working memory relative to non-obese OSA patients. CONCLUSIONS: Obesity had a significant effect on OSA patients in our study, including delayed reaction times in the psychomotor vigilance task and a decrease in working memory.

Hypercapnia impaired cognitive and memory functions in obese patients with obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is a sleep disorder involving repeated nocturnal desaturation and sleep fragmentation. OSA can result in decreased daytime alertness and neurocognitive dysfunction. Hypercapnia status is also related to neurocognitive dysfunction in patients with pulmonary diseases. We evaluated the effects of hypercapnia on cognitive performance and memory function in a prospective case-controlled study. We enrolled thirty-nine obese patients with OSA and collected their arterial blood samples. All the participants provided arterial blood samples, and completed two questionnaires (the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale) and six cognitive tasks (the psychomotor vigilance task [PVT], the Stroop task, the Eriksen flanker task, processing speed [DSST], and verbal and visual memory [LM&FM]), which were used to evaluate daytime sleepiness, cognitive function, and memory function within one week of a polysomnographic study. When compared to the OSA without diurnal hypoventilation, the patients with stable hypercapnia (OHS) had increased reaction times in the PVT, Stroop task, and flanker task. Hypercapnic obese patients with OSA also had comparatively significantly lower scores in the processing speed and logical memory tests. OHS had increased reaction times in the attention and cognitive function assessments, and deficits in the logical memory, when compared to those with OSA without diurnal hypoventilation.