The histone deacetylase inhibitor chidamide induces intermittent viraemia in HIV-infected patients on suppressive antiretroviral therapy.

OBJECTIVES: To evaluate the safety and efficacy of chidamide to reverse HIV-1 latency in vivo and to compare the effects of four clinically tested histone deacetylase (HDAC) inhibitors on non-histone proteins in vitro. METHODS: Participants received chidamide orally at 10 mg twice weekly for 4 weeks while maintaining baseline antiretroviral therapy. The primary outcome was plasma viral rebound during chidamide dosing and the secondary outcomes were safety, pharmacokinetic and pharmacodynamic profiles, changes in cell-associated HIV-1 RNA and HIV-1 DNA, and immune parameters. Western blotting was used to compare the in vitro effects of the four HDAC inhibitors on HSP90, NF-κB and AP-1. RESULTS: Seven aviraemic participants completed eight oral doses of chidamide, and only grade 1 adverse events were observed. Cyclic increases in histone acetylation were also detected. All participants showed robust and repeated plasma viral rebound (peak viraemia 147-3850 copies/mL), as well as increased cell-associated HIV-1 RNA, during chidamide treatment. Furthermore, we identified an enhanced HIV-1-specific cellular immune response and a modest 37.7% (95% CI: 12.7-62.8%, P = 0.028) reduction in cell-associated HIV-1 DNA. Compared with the other three HDAC inhibitors, chidamide had minimal cytotoxicity in vitro at clinically relevant concentrations and showed mechanistically superior effects on non-histone proteins, including HSP90, NF-κB and AP-1. CONCLUSIONS: Chidamide safely and vigorously disrupts HIV-1 latency in vivo, which makes it a promising latency-reversing agent.

Depression and anxiety in multiple system atrophy.

BACKGROUND: It has been noticed that the patients with multiple system atrophy (MSA) can accompany with depression and anxiety. This study aimed to establish the incidence and determinants of depression and anxiety symptoms in Chinese MSA patients. METHODS: A total of 237 MSA patients were enrolled in the study. Neuropsychological assessment was performed using Hamilton Depression Rating Scale-24 items and Hamilton Anxiety Rating Scale. RESULTS: We found that 62.0% and 71.7% patients had at least mild depression and anxiety symptoms, respectively. The severity of depression of MSA patients was associated with lower educational years (P=.024), longer disease duration (P<.001), and disease severity (P<.001). The severity of anxiety was associated with increased disease duration (P<.001), disease severity (P=.013), and orthostatic hypotension (P=.005). Binary logistic regression showed the determinants of depression and anxiety were female gender, longer disease duration, and disease severity. CONCLUSION: Depression and anxiety symptoms are common in patients with MSA. Neurologists should pay attention to depression and anxiety in patients with MSA, especially in female patients and those with longer disease duration and severe disease condition.

Non-motor symptoms and quality of life in tremor dominant vs postural instability gait disorder Parkinson's disease patients.

OBJECTIVES: To explore the differences in the features and impact on quality of life (QOL) of non-motor symptoms (NMS) of tremor dominant (TD) and postural instability gait disorder (PIGD) phenotypes early Parkinson's disease (PD), as well as the determinants of poor QOL for TD and PIGD phenotypes. METHODS: This cross-sectional study recruited 301 patients with early PD and 101 healthy controls. Specific assessments used for NMS included NMS scale (NMSS), the Hamilton Rating Scale for Depression (HRSD-24), the Hamilton Anxiety Scale (HAMA), the Mini-Mental state examination (MMSE), and Addenbrooke's Cognitive Exam-Revised (ACE-R). QOL was evaluated with the PD Quality of Life Questionnaire (PDQ-39). RESULTS: Tremor dominant phenotype patients were 117 (38.9%), and PIGD were 155 (51.5%). Compared with TD patients, patients with PIGD had higher frequency of NMS (9.0 ± 5.3 vs 6.7 ± 4.6, P < 0.001), NMSS total scores (39.6 ± 34.5 vs 24.4 ± 22.7, P < 0.001) and more poorly for PDQ-39 summary index (19.2 ± 14.0 vs 13.8 ± 11.5, P = 0.001). There was no difference in the impact of NMS measured with NMSS on QOL between PIGD and TD phenotypes. PIGD phenotype had little impact on poor QOL once the effect of depression was taken into account. Depression was a primary negative predictor for QOL in both TD and PIGD patients (Beta: 0.697 and 0.619, respectively, P < 0.001). CONCLUSIONS: PIGD phenotype had a higher prevalence of NMS and worse QOL than TD phenotype. Depression is related to a dramatic decline in QOL in both TD and PIGD phenotype patients with PD.

An association analysis of the rs1572931 polymorphism of the RAB7L1 gene in Parkinson's disease, amyotrophic lateral sclerosis and multiple system atrophy in China.

BACKGROUND AND PURPOSE: Recently, the rs1572931 single-nucleotide polymorphism (SNP) of the putative promoter of the member RAS oncogene family-like 1 (RAB7L1) gene was reported to be associated with reduced risk for Parkinson's disease (PD) in the Ashkenazi Jewish population. Ethnic-specific effects are an important consideration in genome-wide association studies. Considering that the clinical manifestations and pathological characteristics overlap between PD, amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA), the possible associations between the rs1572931 SNP and these three diseases were studied in the Chinese population. METHODS: A total of 1011 PD patients, 778 sporadic ALS (SALS) patients, 264 MSA patients and 516 healthy controls (HC) were included in this study. All subjects were genotyped for the rs1572931 SNP by using polymerase chain reaction and direct sequencing. RESULTS: Significant differences were observed in the genotype and minor allele frequency (MAF) of rs1572931 between PD and HC (P = 0.0001 and P = 1.08E-04, respectively) and between late-onset PD and matched controls (P = 0.0011 and P = 0.0002, respectively). However, no differences were observed between early-onset PD and HC. The number of minor allele carriers was significantly lower in PD patients than in HC (P = 2.96E-05, odds ratio 0.63, 95% confidence interval 0.51-0.78). No differences were observed between groups with respect to sex, onset symptoms, absence or presence of cognition impairment, anxiety or depression. In addition, no differences were found in the genotype and MAF of rs1572931 between SALS and HC or between MSA and HC. CONCLUSION: Our results suggest that rs1572931 decreases the risk for PD but not for ALS and MSA in the Chinese population. However, the polymorphism is unlikely to be a common cause of SALS and MSA in the Chinese population.

ECT2 promotes proliferation and metastasis of esophageal squamous cell carcinoma via the RhoA-ERK signaling pathway.

OBJECTIVE: In this study, the effect of epithelial cell transformation sequence 2 (ECT2) on the proliferation, invasion and migration of esophageal squamous cell carcinoma (ESCC) was investigated by interfering the expression of ECT2. PATIENTS AND METHODS: Interfering with the expression level of ECT2 in human squamous cell carcinomas KYSE140 and EC9706 cell lines, the changes of KYSE140 and EC9706 cell proliferation, invasion, and migration were measured using the CCK-8 method, transwell test, and scratch test, respectively. The effects of ECT2 on the Ras homolog gene family, member A-extracellular regulated protein kinases (RhoA-ERK) signaling pathway were also observed. RESULTS: Compared with the control group, the proliferation, migration, and invasion ability of EC9706 and KYSE140 cells after ECT2 knockout were significantly reduced (p <0.05). The knockdown of ECT2 expression in ESCC cell lines suppressed the activation of RhoA-ERK signaling pathway and protein expression of VEGF and MMP9. CONCLUSIONS: ECT2 could regulated the expression of VEGF and MMP9 to inhibit cells proliferation, invasion, migration and tumor development through RhoA-ERK signaling pathway. Therefore, ECT2 could be an available marker, and provide a new theoretical basis for the treatment of ESCC.

Circle RNA FOXP1 promotes cell proliferation in lung cancer by regulating miR-185-5p/Wnt1 signaling pathway.

OBJECTIVE: It is reported that circular RNA plays an important role in various cancers in recent years. However, there is less investigation reported in lung adenocarcinoma (LUAD) about circRNA. This study aims to explore the role and molecular mechanism of circle RNA FOXP1 in LUAD procession. PATIENTS AND METHODS: The levels of circFOXP1 and miR-185-5p in LUAD cell lines and LUAD cancer samples were examined by RT-PCR. The functions of circFOXP1 and miR-185-5p at LUAD cells were detected by cell transfection of the overexpression or repression. The A549 and H1299 cell proliferation were detected by MTT assay and colony formation assay. And the cell apoptosis was detected by TUNEL assay. The expression levels WNT1 were measured by Western blot in A549 and H1299 cells. Furthermore, the luciferase assay detected the direct interaction between circFOXP1 and miR-185-5p or miR-185-5p and WNT1. RESULTS: The circFOXP1 expression was increased in LUAD patients and LUAD cell lines. The downregulation of circFOXP1 significantly repressed LUAD cell proliferation and promoted cell apoptosis. Moreover, the luciferase assay results confirmed that circFOXP1 directly interacted with miR-185-5p. Overexpression of miR-185-5p could reverse the effect of circFOXP1 in LUAD cell. Besides, the luciferase results showed that miR-185-5p directly interacted with WNT1. miR-185-5p overexpression inhibited the WNT1 expression, while circFOXP1 repression decreased the WNT1 level in LUAD cell lines. The downregulating WNT1 could reverse the effects of miR-185-5p inhibition in LUAD cell lines. Furthermore, WNT1 was significantly upregulated in LUAD cancer tissues. In addition, circFOXP1 level was negatively correlated with miR-185-5p expression and positively correlated with WNT1 expression in LUAD cancer tissues. CONCLUSIONS: These data suggested that circFOXP1 promoted cell proliferation and repressed cell apoptosis in LUAD by regulating miR-185-5p/WNT1 signaling pathway. It provides a novel potential therapeutic agent for the treatment of LUAD.

Inhibition of ryanodine binding to sarcoplasmic reticulum vesicles of cardiac muscle by Zn(2+) ions.

Using the assay of [(3)H]ryanodine binding to the sarcoplasmic reticulum, the effect of Zn(2+) on ryanodine receptors (RyRs) of cardiac muscle was investigated. There was no obvious change in the binding at [Zn(2+)](f) of less than 0.2 microM. However, a decrease of the binding became significant with raising [Zn(2+)](f) to 0.5 microM. The inhibitory effect of Zn(2+) was [Zn(2+)](f)-dependent, with IC(50/ZnI) of 2.1+/-0.4 microM (mean+/-S.D.). Scatchard analysis indicates that both an increase of K(d) and a decrease of B(max) were responsible for Zn(2+)-induced decrease of the binding. The Hill coefficient for this inhibitory effect of Zn(2+) was between 0.8 and 1.2. The interactions of the effects of Zn(2+) and various modulators of RyR indicate that the inhibitory effect of Zn(2+) was mostly mediated through inhibiting Ca(2+) activation sites (CaA) on RyR. Since the [Zn(2+)](f) dependence was not clearly changed by [Ca(2+)](f), the inhibitory effect of Zn(2+) may not be due to competition of Zn(2+) with Ca(2+) for CaA and probably is indirect. The inhibitory effect of Zn(2+) could not be antagonized by 2 mM dithiothreitol, a thiol-reducing agent, suggesting that the binding of Zn(2+) ions to RyRs of cardiac muscle is not accompanied by obvious change of redox state of the RyRs. In comparison with that seen in skeletal muscle [3], the effects of Zn(2+) on ryanodine binding to the sarcoplasmic reticulum of cardiac muscle show several distinct differences. It is indicated that the effect of Zn(2+) on RyRs may be isoform-dependent. The physiological significance of the effects of Zn(2+) is discussed.

Biphasic modulation of ryanodine binding to sarcoplasmic reticulum vesicles of skeletal muscle by Zn2+ ions.

With the use of a [(3)H]ryanodine binding assay, the modulation of skeletal muscle ryanodine receptor (RyR1) by Zn(2+) was investigated. In the presence of 100 microM free Ca(2+) concentration ([Ca(2+)](f)) as activator, the equilibrium [(3)H]ryanodine binding to heavy sarcoplasmic reticulum vesicles was biphasically modulated by Zn(2+). The binding was increased by a free Zn(2+) concentration ([Zn(2+)](f)) of less than 1 microM; a peak binding, approx. 140% of the control (without added Zn(2+)) was obtained at 0.3 microM [Zn(2+)](f). An inhibitory effect of Zn(2+) became obvious with a [Zn(2+)](f) of more than 1 microM; the [Zn(2+)](f) for producing half inhibition was 2.7+/-0.5 microM (mean+/-S.D.). Scatchard analysis indicated that the increase in the binding induced by low [Zn(2+)](f) was due to a decrease in K(d), whereas both an increase in K(d) and a possible decrease in B(max) were responsible for the decrease in binding induced by high [Zn(2+)](f). The binding in the presence of micromolar [Zn(2+)](f) showed a biphasic time course. In the presence of 3 microM [Zn(2+)](f), after reaching a peak with an increased rate of initial binding, the binding gradually declined. The decline phase could be prevented by decreasing [Zn(2+)](f) to 0.5 microM or by adding 2 mM dithiothreitol, a thiol-reducing agent. The [Ca(2+)](f) dependence of binding was changed significantly by Zn(2+), whereas Ca(2+) had no clear effect on the [Zn(2+)](f) dependence of binding. Moreover, some interactions were found in the effects between Zn(2+) and other RyR1 modulators. It is indicated that Zn(2+) can modulate the activation sites and inactivation sites for Ca(2+) on RyR1. The physiological significance of the effects of Zn(2+) on ryanodine binding is discussed.