METTL3/YTHDF1 m6A axis promotes tumorigenesis by enhancing DDR2 expression in ovarian cancer.

Ovarian cancer has the highest mortality among all gynecological malignancies. Therefore, it is urgent to determine the molecular mechanism of ovarian cancer progression. As the most prevalent modification of messenger RNA (mRNA), N6-Methyladenosine (m6A) modification is recognized as a key regulatory role in the progression of various tumors. However, the specific role of m6A and its related regulatory pathways in ovarian cancer (OV) remains unclear. In this study, we demonstrated that the METTL3/YTHDF1 m6A axis plays an important role in the progression of ovarian cancer. Depletion of METTL3/YTHDF1 impaired cancer proliferation and metastasis in vitro and in vivo. Mechanistically, The METTL3/YTHDF1 m6A axis directly binds to the mRNA of DDR2, thereby promoting the expression levels of the tumor promoter DDR2 and thus contributing to the progression of ovarian cancer. Collectively, our findings on the METTL3/YTHDF1/DDR2 m6A axis provide the insight into the underlying mechanism of ovarian carcinogenesis and highlight potential therapeutic targets for cancer treatment.

Comparison of clinical characteristics between adult-onset and juvenile-onset non-radiographic axial spondyloarthritis in Chinese patients: results from the COCAS cohort.

BACKGROUND: Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease predominantly affecting the axial skeleton. We aimed to describe the clinical characteristics of patients with non-radiographic axSpA (nr-axSpA) in China and compare the differences between adult- and juvenile-onset cases. METHODS: A cross-sectional study was conducted using data from 776 patients with nr-axSpA in the Clinical Characteristic and Outcome in Chinese Axial Spondyloarthritis (COCAS) study cohort. Patients were divided into two groups including the adult-onset group (n = 662) and the juvenile-onset group (n = 114) according to age at disease onset. Baseline demographics and clinical characteristics were compared between patients with adult-onset and juvenile-onset nr-axSpA. RESULTS: Overall, the male-to-female ratio was 1.26:1, the prevalence of HLA-B27 positivity was 72.2%, and the median age at disease onset of nr-axSpA was 22 years. Nearly 75% of nr-axSpA patients had peripheral arthritis in the disease course, and the prevalence of extra-articular manifestations was 10.4%. The juvenile-onset group contained a higher proportion of men (66.7% vs. 53.9%, P = 0.011) and a longer baseline disease duration (4.0 [4.0] vs. 1.6 [3.5], P < 0.001) than the adult-onset group. A family history of spondyloarthritis was more frequent in the juvenile-onset group than in the adult-onset group (23.7% vs. 15.4%, P = 0.028), but no significant difference in the prevalence of HLA-B27 positivity was observed between the two groups (P = 0.537). Regarding initial symptoms, peripheral arthritis occurred more often in patients with juvenile-onset nr-axSpA, whereas patients with adult-onset nr-axSpA presented more frequently with axial involvement. The prevalence of inflammatory back pain (IBP) was higher in the adult-onset group than in the juvenile-onset group (85.0% vs. 75.4%, P = 0.010), whereas the juvenile-onset group showed a higher prevalence of peripheral arthritis and enthesitis than the adult-onset group (67.5% vs. 48.5%, P < 0.001; 35.1% vs. 23.3%, P = 0.007, respectively). CONCLUSIONS: Compared with adult-onset nr-axSpA, juvenile-onset nr-axSpA was more common in men and those with a family history of spondyloarthritis. Juvenile-onset nr-axSpA presents with a "peripheral predominant" mode at disease onset and a higher frequency of peripheral arthritis and enthesitis during the disease course.

Tumor Necrosis Factor-Alpha (+489 G/A) Polymorphism Can Predict the Response to Adalimumab in Chinese Han Patients With Ankylosing Spondylitis.

BACKGROUND: Studies investigating the association between single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNFα) and the efficacy of adalimumab (ADA) in ankylosing spondylitis (AS) therapy have reported conflicting results. We aimed to investigate the value of SNP typing of TNFα in predicting the efficacy of ADA in AS. MATERIALS AND METHODS: Eighty patients with active AS who received ADA treatment were followed up for 24 weeks. Six known SNPs of TNFα (+489G/A, -238G/A, -308G/A, -857C/T, -863C/A, and -1031C/T) were subjected to the SNaPshot SNP typing method, which has been proven to be a reliable, efficient, and cost-effective method for detecting SNPs. The relationship between each SNP genotype and the therapeutic efficacy of ADA was analyzed. RESULTS: At the end of the 24-week follow-up, 58.8% of the patients with AS achieved Assessment of SpondyloArthritis International Society (ASAS) partial remission (PR), 67.5% of the patients achieved the criteria of an ASAS40 response (40% improvement on indices), and 53.8% of the patients achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement (MI). The univariate analysis showed that patients with AS carrying the TNFα +489 A allele were more likely to achieve ASAS-PR, ASAS40 response criteria, and ASDAS-MI after ADA treatment. In the multivariate regression analysis, the TNFα +489 A allele was an independent factor influencing the efficacy of ADA in treating AS (ASAS-PR odds ratio (OR) = 2.66, 95% confidence interval (CI) = 1.01-7.01; ASAS40 OR = 4.56, 95% CI = 1.39-15.00; ASDAS-MI OR = 3.31, 95% CI = 1.02-10.69). CONCLUSIONS: The patients carrying the TNFα +489 A allele may be more likely to experience better therapeutic efficacy and achieve the treatment target (ASAS-PR, ASAS40 response, or ASDAS-MI) after receiving ADA treatment. Detection of TNFα +489 G/A may predict the therapeutic efficacy of ADA, which can be used in clinical practice to tailor treatment for individual patients with AS. Further studies with larger sample sizes and longer follow-up periods with imaging evaluation are needed to verify our findings.

Risk factors for progression of juvenile-onset non-radiographic axial spondyloarthritis to juvenile-onset ankylosing spondylitis: a nested case-control study.

OBJECTIVE: To evaluate the clinical characteristics of juvenile-onset non-radiographic axial spondyloarthritis (nr-axSpA) and to investigate risk factors associated with progression to juvenile-onset ankylosing spondylitis (JoAS). METHODS: A nested case-control study was conducted using the retrospectively collected data of 106 patients with juvenile-onset nr-axSpA (age at disease onset, <16 years) in the Clinical characteristic and Outcome in Chinese Axial Spondyloarthritis study cohort. Baseline demographic and clinical characteristics and prognosis were reviewed. Logistic regression analyses were performed to investigate risk factors associated with progression to JoAS. RESULTS: Overall, 58.5% of patients with juvenile-onset nr-axSpA presented with peripheral symptoms at disease onset. In 82.1% of these patients, axial with peripheral involvement occurred during the disease course. The rate of disease onset at >12 years and disease duration of ≤10 years were significantly higher in those with progression to JoAS than in those without progression to JoAS (83.0% vs 52.8%, p=0.001; 92.5% vs 56.6%, p<0.001, respectively). Multivariable logistic regression analysis revealed that inflammatory back pain (IBP) (OR 13.359 (95% CI 2.549 to 70.013)), buttock pain (OR 10.171 (95% CI 2.197 to 47.085)), enthesitis (OR 7.113 (95% CI 1.670 to 30.305)), elevated baseline C reactive protein (CRP) levels (OR 7.295 (95% CI 1.984 to 26.820)) and sacroiliac joint-MRI (SIJ-MRI) positivity (OR 53.821 (95% CI 9.705 to 298.475)) were significantly associated with progression to JoAS. CONCLUSION: Peripheral involvement was prevalent in juvenile-onset nr-axSpA. IBP, buttock pain, enthesitis, elevated baseline CRP levels and SIJ-MRI positivity in patients with the disease are associated with higher risk of progression to JoAS.

hERG1 is involved in the pathophysiological process and inhibited by berberine in SKOV3 cells.

The human ether-a-go-go-related potassium channel 1 (hERG1) is a functional component of the voltage-gated Kv11.1 potassium channel, which is commonly described as a crucial factor in the tumorigenesis of a variety of tumors. Ovarian cancer is one of the most severe types of cancer, with an extremely poor prognosis. Advances have been made in recent years; however, drug resistance and tumor recurrence remain critical issues underlying satisfactory treatment outcomes. Therefore, more effective antitumor agents with low levels of drug resistance for ovarian cancer treatment are urgently required in clinical practice. In the present study, hERG1 mRNA expression in ovarian tumor tissues and cell lines were measured by reverse transcription-quantitative polymerase chain reaction. Immunohistochemistry and western blotting were used to assess the expression levels of hERG1 protein. Cell proliferation, migration and invasion were assessed by Cell Counting Kit-8 assay and Transwell assay. A tumor xenograft assay was used to determine the growth of tumors in vivo. It was demonstrated that the expression levels of hERG1 were significantly elevated in ovarian cancer tissues and expressed in ovarian cancer cell lines, particularly in SKOV3 cells. Abnormal hERG1 expression was significantly associated with the proliferation, migration and invasion abilities of ovarian cancer. In addition, berberine (BBR) may be used as a potential drug in the treatment of ovarian cancer, possibly due to its inhibitory effects on the hERG1 channels. In conclusion, the present study demonstrated that hERG1 may be a potential therapeutic target in the treatment of ovarian cancer and provided novel insights into the mechanism underlying the antitumor effects of BBR in ovarian cancer.

Pannus inflammation in sacroiliitis following immune pathological injury and radiological structural damage: a study of 193 patients with spondyloarthritis.

BACKGROUND: The pathogenesis of sacroiliitis is unclear; therefore, we aimed to systematically study the immunopathology of sacroiliitis in patients with axial spondyloarthritis (axSpA), and explore the relationship between pannus formation, inflammation, and the structural damage caused by sacroiliitis. METHODS: Fine needle aspiration biopsy of the sacroiliac joint (SIJ) was performed in 193 patients with axSpA. Clinical, laboratory, and imaging data were collected at baseline and during the follow up. Immunohistochemistry analysis was performed to detect CD34+ microvessels, CD68+ osteoclasts/macrophages, vascular endothelial growth factor (VEGF), metalloproteinase-3 (MMP-3), tumor necrosis factor-α (TNF-α), and caspase-3. Autopsy subjects were used as controls. RESULTS: In early sacroiliitis (grade 0-1) all pathological features could be observed, with the most common being subchondral pannus formation. Among the 193 patients, 98 were followed up for 1-13 years (mean 3.6 years); 63.3% had radiological progression at the endpoint. Multiple regression analysis showed that cartilage pannus invasion (OR 2.99, P = 0.010) and endochondral ossification (OR 3.97, P = 0.049) at baseline were risk factors for radiological structural damage. Compared to SIJ controls, the subchondral microvessel density, number of CD68+ multinuclear osteoclasts, and the levels of VEGF, caspase-3, MMP-3, and TNF-α expressed at the interface of the bone and cartilage were significantly higher in patients with sacroiliitis. CONCLUSIONS: Subchondral fibrovascular tissue formation is the most important pathological feature in early sacroiliitis. The existence of cartilage pannus invasion or endochondral ossification at baseline can predict radiological structural damage during the follow up.

Impaired decision-making and functional neuronal network activity in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with cognitive deficit but the exact neural mechanisms remain unclear. PURPOSE: To explore sequential brain activities using functional magnetic resonance imaging (fMRI) during the performance of a decision-making task, and to determine whether serum or clinical markers can reflect the involvement of the brain in SLE. SUBJECTS: Sixteen female SLE patients without overt clinical neuropsychiatric symptoms and 16 healthy controls were included. FIELD STRENGTH/SEQUENCE: 1.5T, T1 -weighted anatomic images, gradient-echo echo-planar imaging sequence, and 3D images. ASSESSMENT: The computer-based Iowa Gambling Task (IGT) for assessing decision-making was performed by SLE patients and 16 matched controls; brain activity was recorded via blood oxygen level-dependent (BOLD) fMRI. The amplitudes of the average BOLD responses were calculated for each individual subject, and activation data from fMRI experiments were compared between the two groups. STATISTICAL TESTS: Two-sample t-test; repeated-measures analysis of variance (ANOVA); linear regression analyses. RESULTS: Imaging revealed activity in a distributed network of brain regions in both groups, including the ventromedial prefrontal cortex (vmPFC), the orbitofrontal cortex (OFC), the dorsolateral prefrontal cortex (dlPFC), the anterior cingulate cortex (ACC), the posterior cingulate cortex (PCC), and the striatum, as well as the insular, parietal, and occipital cortices. Compared to controls, SLE patients showed lower activation in a convergence zone and the limbic system, namely, the OFC, vmPFC, ACC, and PCC, but greater activation in memory, emotion, and behavior systems involving the dlPFC, the insular cortex and the striatum. Furthermore, brain activation in the vmPFC was positively correlated with IGT scores (r = 0.63, P < 0.001), but inversely related to disease activity (r = -0.57, P < 0.01). DATA CONCLUSION: The dynamics among the aforementioned neural systems (some hyperfunctioning, others hypofunctioning) may shed some light on the pathologic mechanisms underlying SLE without overt clinical neuropsychiatric symptoms. In addition, disease activity may potentially be used as an effective biomarker reflecting cerebral involvement in SLE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;48:1508-1517.

miR-493 inhibits proliferation and invasion in pancreatic cancer cells and inversely regulated hERG1 expression.

The human ether-a-go-go-related potassium channel 1 (hERG1) is a component of the voltage-gated Kv11.1 potassium channel, which has been recently indicated to have a crucial role in the tumorigenesis of multiple tumors, including pancreatic carcinoma. Pancreatic carcinoma is one of the most malignant human cancer types, which has an extremely poor prognosis. The present study demonstrated that the expression levels of hERG1 were markedly elevated in pancreatic cancer tissues and pancreatic cancer cell lines, and that the abnormal hERG1 expression was significantly associated with the proliferation and invasion ability of pancreatic cancer. Furthermore, hERG1 was identified to be a direct target of miR-493, which is generally reduced in pancreatic cancer tissues and cell lines. These findings provide a novel insight into the regulatory mechanism of miR-493/hERG1 in pancreatic cancer cell proliferation and invasion, which may aid the development of novel diagnostic and therapeutic strategies for pancreatic cancer in the future.

Changes in the Prevalence of Rheumatic Diseases in Shantou, China, in the Past Three Decades: A COPCORD Study.

This study aimed to clarify changes in the prevalence of rheumatic diseases in Shantou, China, in the past 3 decades and validate whether stair-climbing is a risk factor for knee pain and knee osteoarthritis (KOA). The World Health Organization-International League Against Rheumatism Community Oriented Program for Control of Rheumatic Diseases (COPCORD) protocol was implemented. In all, 2337 adults living in buildings without elevators and 1719 adults living in buildings with elevators were surveyed. The prevalence of rheumatic pain at any site and in the knee was 15.7% and 10.2%, respectively; both types of pain had a significantly higher incidence in residents of buildings without elevators than was reported by people who lived in buildings with elevators (14.9% vs. 10.6% and 11.32% vs. 8.82%, respectively) (both P < 0.0001). The prevalence of rheumatic pain in the neck, lumbar spine, shoulder, elbow, and foot was 5.6%, 4.5%, 3.1%, 1.4%, and 1.8%, respectively; these findings were similar to the data from the 1987 rural survey, but were somewhat lower than data reported in the urban and suburban surveys of the 1990s, with the exception of neck and lumbar pain. The prevalence of KOA, gout, and fibromyalgia was 7.10%, 1.08%, and 0.07%, respectively, and their prevalence increased significantly compared with those in previous studies from the 20th century. There were no significant differences in the prevalence of rheumatoid arthritis (RA) (0.35%) or ankylosing spondylitis (AS) (0.31%) compared to that reported in prior surveys. The prevalence of KOA was higher in for residents of buildings without elevators than that in those who had access to elevators (16-64 years, 5.89% vs. 3.95%, P = 0.004; 16->85 years, 7.64% vs. 6.26%, P = 0.162). The prevalence of RA and AS remained stable, whereas that of KOA, gout, and fibromyalgia has increased significantly in Shantou, China, during the past 3 decades. Stair-climbing might be an important risk factor for knee pain and KOA.

A long-term, observational cohort study on the safety of low-dose glucocorticoids in ankylosing spondylitis: adverse events and effects on bone mineral density, blood lipid and glucose levels and body mass index.

OBJECTIVES: This study aimed to investigate the risk of adverse events and effects on bone mineral density (BMD), blood lipid and glucose levels and body mass index (BMI) of low-dose glucocorticoid (GC) treatment in ankylosing spondylitis. DESIGN: We performed a retrospective, observational cohort study. Adverse effects were compared between GC users and non-GC users, and we analysed differences in the duration of GC exposure (no GC exposure, <6 months, 6 months to 2 years and >2 years). SETTING: Outpatient clinic in a tertiary general hospital in China, rheumatology follow-up visits over the past 30 years. PARTICIPANTS: We included 830 patients with ankylosing spondylitis who were followed up for at least 6 months without a previous history or current complications of active gastrointestinal problems, hypertension, psychiatric or mental problems, diabetes mellitus, tuberculosis and hepatitis. The median follow-up time was 1.6 years (range 0.5-15 years, a total of 1801 patient-years). RESULTS: A total of 555 (66.9%) patients were treated with low-dose GCs, and the median cumulative duration of GC therapy was 1.3 years (range 0.1-8.5 years). Dermatological incidents, including acne, bruisability and cutaneous infections, were the most common adverse events, with a cumulative incidence rate of 5.4% (22.2 events per 1000 patient-years), followed by a puffy and rounded face (1.6%), symptoms of weight gain (1.1%) and serious infections (1.0%). The rates of all other types of adverse events were less than 1%. The GC groups (GC users and non-GC users) and the duration of GC therapy were not associated with the frequency of low BMD, dyslipidaemia, hyperglycaemia or obesity (p<0.05). CONCLUSIONS: Adverse events during long-term treatment of low-dose GCs are limited. Low-dose GCs do not have an adverse effect on BMD, blood lipid and glucose levels and BMI.

The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides.

As is well-known, hERG plays an essential role in phase III repolarization of cardiac action potentials. Blocking of hERG channels can lead to LQTS. Inhibition of the metabolism of CYPs activities may elevate plasma levels, to further increase accumulation of drug on cardiac. The elevated serum levels may however elicit unexpected toxicities. Therefore, the inhibition tests of hERG and CYP are central to the preclinical studies because they may lead to severe cardiac toxicity. Berberine is widely used as an antibacterial agent and often combined with macrolides to treat gastropathy. Our objective was to assess cardiac toxicity during the combined use of Berberine with macrolides. (1) Azithromycin reduced hERG currents by accelerated channel inactivation. (2) The combination of Berberine with Azithromycin reduced hERG currents, producing an inhibitive effect stronger than use of a single drug alone, due to the high binding affinity for the onset of inactivation. (3) When cells were perfused concomitantly with Berberine and Clarithromycin, they showed a stronger inhibitive effect on hERG currents by decreasing the time constant for the onset of inactivation. (4) The combined administration of Berberine with Clarithromycin had a powerful inhibitive effect on CYP3A activities than use of a single drug alone. Collectively, these results demonstrated that concomitant use of Berberine with macrolides may require close monitoring because of potential drug toxicities, especially cardiac toxicity.

Prevalence and risk factors of osteoporosis in patients with ankylosing spondylitis: a 5-year follow-up study of 504 cases.

OBJECTIVES: The objective of this study was to assess the prevalence and risk factors of osteoporosis (OP) in patients with ankylosing spondylitis (AS). METHODS: Demographic and clinical data of 504 AS patients were collected. Bone mineral density (BMD) measurements of the lumbar spine, proximal femur and forearm were performed by dual-energy x-ray absorptiometry at baseline and follow-up. 106 cases of sex- and age-matched healthy volunteers were enrolled as normal controls. RESULTS: In contrast to normal controls, AS patients displayed a higher prevalence of both OP (9.7% vs. 0%) and osteopenia (57.5% vs. 34.9%). The prevalence of OP was significantly higher and the BMD were significantly lower in patients with elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) than patients with normal ESR and CRP. Juvenile onset, morning stiffness lasting over 0.5 hours and elevated ESR levels were risk factors for bone loss at the lumbar spine; Male gender, older age, hip involvement and lack of regular treatment were risk factors for bone loss at the femur. 173 cases were followed up for 1 to 5 years, BMD changes per year at the lumbar spine, femur and forearm were 4.8%, 2.7%, and 2.6% respectively. There was no significant difference in annual BMD change between patients treated with or without low dose glucocorticoids (GCs). Hip involvement and persistent elevated ESR levels, but not GCs treatment, were associated with decreased BMD at both the lumbar spine and the femur during follow-up in longitudinal regression analysis. CONCLUSIONS: High disease activity and hip involvement are risk factors of bone loss in patients with AS. Low-dose GCs treatment in AS does not increase the risk of OP.

Arylamine N-acetyltransferase polymorphisms in Han Chinese patients with ankylosing spondylitis and their correlation to the adverse drug reactions to sulfasalazine.

BACKGROUND: Polymorphisms of Arylamine N-acetyltransferase (NAT) that contribute to diverse susceptibilities of some autoimmune diseases are also linked to the metabolism of several drugs including sulfasalazine (SSZ). The aim of this study was to investigate the distribution of NAT polymorphisms in Han Chinese patients with ankylosing spondylitis (AS) and their correlation to sulfasalazine-induced adverse drug reactions (ADRs). METHODS: Arylamine N-acetyltransferase 1 (NAT1) and arylamine N-acetyltransferase 2 (NAT2) genotypes were determined in 266 AS patients who received SSZ treatment and 280 healthy controls. The correlation between NAT polymorphisms and SSZ-induced ADRs was analyzed. RESULTS: The co-occurrence frequency of NAT2 fast acetylator genotype and NAT1*10/NAT1*10 genotype was lower in AS patients than in controls. No positive correlations were detected between NAT polymorphisms and AS clinical features. The prevalence of SSZ-induced ADRs and drug withdrawal was 9.4% and 7.1%, respectively. The frequencies of overall ADRs, dose-related ADRs, and termination of drug treatment because of intolerance were higher in the NAT2 slow acetylator genotype carriers than in the fast-type carriers and in those with co-existence of NAT1 and NAT2 slow acetylator genotypes. Furthermore, the ADRs emerged earlier in the AS cases carrying both NAT1 and NAT2 slow acetylator genotypes. CONCLUSIONS: The prevalence of co-occurring NAT2 fast acetylator genotype and NAT1*10/NAT1*10 genotype was lower in AS patients than in controls. The NAT2 slow acetylator genotype and co-existing NAT1 and NAT2 slow acetylator genotypes appear to be associated with higher risks of SSZ-induced ADRs.

Berberine induces hERG channel deficiency through trafficking inhibition.

AIMS: The human ether-a-go-go-related gene (hERG) encodes the α subunit of the IKr, which plays an essential role in repolarization of action potentials. hERG channels are targeted by various pro-arrhythmic drugs. Berberine (BBR) was previously found to acutely inhibit hERG currents and prolong action potential duration. The present study aimed to determine long-term effects of BBR on the expression of 135kDa/155kDa hERG and the mechanism. METHODS AND RESULTS: hERG expression was assessed by western blot. Mature hERG (155 kDa) was reduced, whereas ER-located hERG (135 kDa) was increased by BBR. This indicated that hERG was restricted to the ER and that BBR disrupted channel trafficking. To determine the mechanism of trafficking inhibition, we performed western blot and immunoprecipitation to test folding of hERG by assessing interaction between hERG and Hsp90/Hsp70. Both the expression of Hsp90 and its interaction with hERG were strongly decreased by BBR. These data suggest that BBR reduces channel folding to induce trafficking inhibition. Western blot and confocal imaging were used to further detect whether the unfolded protein response (UPR) was activated. Active ATF6, a marker of the UPR, was activated by BBR. Calnexin and calreticulin, chaperones that are activated by ATF6 to assist channel folding, were also elevated and increasingly colocalized with hERG. These data also demonstrate that the UPR was activated. Immunoprecipitation and western blot assays were performed after BBR treatment to examine ubiquitination and degradation, common endpoints of the UPR. We found that the ER-restricted hERG was ubiquitinized and degraded in the lysosomes and proteasomes. CONCLUSION: Our study demonstrates that BBR induces hERG channel deficiency by inhibiting channel trafficking after incubation for 24h. Trafficking inhibition activated the UPR, and the ER-restricted hERG was ubiquitinized and degraded in lysosomes and proteasomes.

Novel sinomenine derivative 1032 improves immune suppression in experimental autoimmune encephalomyelitis.

Sinomenine (SIN) is an alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating autoimmune diseases. Due to its poor efficiency, the large-dose treatment presents some side effects and limits its further applications. In this study, we used chemical modification to improve the therapeutic effect of SIN in vitro and in vivo. A new derivative of sinomenine, named 1032, demonstrates significantly improved immunosuppressive activity over that of its parent natural compound (SIN). In an experimental autoimmune encephalomyelitis (EAE) model, 1032 significantly reduced encephalitogenic T cell responses and induced amelioration of EAE, which outcome was related to its selective inhibitory effect on the production of IL-17. By contrast, SIN treatment only led to a moderate alleviation of EAE severity and the expression level of IL-17 was not significantly reduced. Furthermore, 1032 exhibited suppression of Th17, but not Treg, cell differentiation, a result probably related to its inhibitory effect on IkappaB-alpha degradation as well as on IL-6 and TNF-alpha secretion in BMDCs. We speculate that 1032 as a novel anti-inflammatory agent may target DC to block IL-6 production, which in turn would terminate Th17 cell development. Thus, SIN derivative 1032 presents considerable potential in new drug development for treating autoimmune and inflammatory disease.

[Recognition and study of susceptible gene to ankylosing spondylitis].

To study the potential correlations between variances of TNFalpha gene and onset of ankylosing spondylitis in Chinese population, We scanned and analyzed the promoters of TNFalpha genes in 75 AS patients from south of China and found -850 T mutation allele frequency rather high (39.3%).By case-control study, the distribution of TT genotype is significantly higher in AS patients than that in normal subjects (10.7% VS 2.1%,P=0.003); Mutation T allele has a remarkable difference between AS group and normal control (72.2% vs 21.4%,P=2.729 x 10(-9)). The difference in distribution of TX genotype and non -TX genotype is also significant statistically between different genders(male: P=3.42 x 10(-9);female: P=0.001). The result suggests that this variation has a strong association with AS in males and females. No similar reports about the association between AS and the T mutation allele have been acquired. Therefore, our hypothesis can be supported by our results on the whole and the -850 C-->T mutation allele in the region on promoter of TNFalpha gene is likely one of susceptible genes to AS.