Nobiletin inhibits breast cancer cell migration and invasion by suppressing the IL-6-induced ERK-STAT and JNK-c-JUN pathways.

BACKGROUND: Breast cancer is one of the most common cancers in women, affecting more than 2 million women worldwide annually. However, effective treatments for breast cancer are limited. Nobiletin is a flavonoid present in the dried mature pericarp of mandarin orange (Citrus reticulata Blanco), which is used to prepare Citri Renetulatae Pericarpium and can inhibit tumour growth and progression according to modern pharmacological studies. However, whether nobiletin exhibits an antimetastatic role in breast cancer and its potential mechanism need to be further investigated. PURPOSE: This study aims to evaluate the inhibitory effect of nobiletin on breast cancer and to elucidate potential mechanisms against invasion and migration. METHODS: Cell viability was determined by cell counting kit-8 and colony formation assays. Wound healing and Boyden chamber assays detected cancer cell migration and invasion capabilities. Immunoblotting and qPCR were applied to determine the protein and mRNA expression levels of extracellular signal-regulated kinases (ERK) and the c-Jun N-terminal kinase (JNK) signalling pathways. Molecular docking was used to assess the degree of nobiletin binding to phosphatidylinositol 3-kinase (PI3K). Xenografts and liver metastases were constructed in BALB/c nude mice to evaluate the anticancer effect of nobiletin in vivo. H&E staining and immunohistochemistry were used to detect proliferation and the expression of related proteins. RESULTS: Nobiletin induced cell death in a concentration- and time-dependent manner and possessed anti-invasion and anti-migration effects on MCF-7 and T47D cells by suppressing the interleukin-6-induced ERK and JNK signalling pathways. In addition, nobiletin docked with the binding site of PI3K, and the binding score was -8.0 kcal/mol. Furthermore, the inhibition of breast cancer growth and metastasis by nobiletin was demonstrated by constructing xenografts and liver metastases in vivo. CONCLUSION: Nobiletin inhibited liver metastasis of breast cancer by downregulating the ERK-STAT and JNK-c-JUN pathways, and its safety and efficacy were verified, indicating the potential of nobiletin as an anticancer agent.

The mechanism of FZXJJZ decoction suppresses colorectal liver metastasis via the VDR/TGF-ß/Snail1 signaling pathways based on network pharmacology-TCGA data-transcriptomics analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Fuzheng Xiaojijinzhan (FZXJJZF) decoction is an effective prescription for treating colorectal cancer liver metastasis (LMCRC). AIM OF THE STUDY: To elucidate the pharmacological mechanism of the FZXJJZF decoction therapy on LMCRC. MATERIALS AND METHODS: Firstly, a network pharmacological approach was used to characterize the underlying targets of FZXJJZF on LMCRC. Secondly, LMCRC-related genes are obtained from the public database TCGA, and those genes are further screened and clustered through Mfuzz, an R package tool. Then, targets of FZXJJZF predicted by network pharmacology were overlapped with LMCRC related genes screened by Mfuzz. Meanwhile, FZJZXJF intervened in LMCRC model,epithelial-to-mesenchymal transition (EMT), and migration and invasion of HCT-116 cells. Thirdly, the transcriptomics data of FZJZXJF inhibited HCT-116 cells of EMT cells were overlapped with EMT database data to narrow the possible range of targets. Based on this, the potential targets and signal pathways of FZJZXJF were speculated by combining the transcriptomics data with the targets from network pharmacology-TCGA. Finally, the anti-cancer mechanism of FZXJJZF on LMCRC was verified in vitro by Real-Time PCR and Western Blot in vitro. RESULTS: By network pharmacological analysis, 282 ingredients and 429 potential targets of FZXJJZF were predicted. The 9268 LMCRC-related genes in the TCGA database were classified into 10 clusters by the Mfuzz. The two clustering genes with the most similar clustering trends were overlapped with 429 potential targets, and 32 genes were found, such as CD34, TRPV3, PGR, VDR, etc. In vivo experiments, FZJZXJF inhibited the tumor size in LMCRC models, and the EMT, migration, and invasion of HCT-116 also be inhibited. Intersecting transcriptomics dates with 32 target genes, it is speculated that the VDR-TGF-ß signaling pathway may be an effective mechanism of FZXJJZF. Additionally, it is shown that FZXJJZF up-regulated the expression levels of VDR and E-cadherin and down-regulated the expression levels of TGF-ß and Snail1 in vitro. These results confirmed that FZXJJZF plays an effective role in LMCRC mainly by inhibiting EMT phenotype via the VDR-TGF-ß signaling pathway. CONCLUSIONS: Collectively, this study reveals the anti-LMCRC effect of FZXJJZF and its potential therapeutic mechanism from the perspective of potential targets and potential pathways.

Effect of the Transition Metal Ions on the Single-Molecule Magnet Properties in a Family of Air-Stable 3d-4f Ion-Pair Compounds with Pentagonal Bipyramidal Ln(III) Ions.

Single-molecule magnets (SMMs) are expected to be promising candidates for the applications of high-density information storage materials and quantum information processing. Lanthanide SMMs have attracted considerable interest in recent years due to their excellent performance. It has always been interesting but not straightforward to study the relaxation and blocking mechanisms by embedding 3d ions into 4f SMMs. Here we report a family of air-stable 3d-4f ion-pair compounds, YFe (1), DyCr (2), DyFe (3), DyCo (4), and Dy0.04Y0.96Fe (5), composed of pentagonal bipyramidal (D5h) LnIII cations and transition metallocyanate anions. The ion-pair nature makes the dipole-dipole interactions almost the only component of the magnetic interactions that can be clarified and analytically resolved under proper approximation. Therefore, this family provides an intuitive opportunity to investigate the effects of 3d-4f and 4f-4f magnetic interactions on the behavior of site-resolved 4f SMMs. Dynamic magnetic measurements of 1 under a 4 kOe external field reveal slow magnetic relaxation originating from the isolated [FeIII]LS (S = 1/2) ions. Under zero dc field, compounds 2-5 show similar magnetic relaxation processes coming from the separated pentagonal bipyramidal (D5h) DyIII ions with high Orbach barriers of 592(5), 596(4), 595(3), and 606(4) K, respectively. Comparatively, both compounds 3 and 5 exhibit two distinct relaxation processes, respectively from the [FeIII]LS and DyIII [Ueff = 596(4) K for 3 and 610(7) K for 5] ions, under a 4 kOe dc field. The dipolar interactions between the neighboring TMIII (TM = transition metal, CrIII or [FeIII]LS) and DyIII ions were revealed to have little effect on the thermal relaxation in compounds 2, 3, and 5, or the coexistence of the two separate relaxation processes in compounds 3 and 5 under a 4 kOe dc field, but they significantly affect the quantum tunneling of magnetization and the magnetic hysteresis behavior of 2 and 3 at low temperatures compared to those of 4.

The comparative studies on the magnetic relaxation behaviour of the axially-elongated pentagonal-bipyramidal dysprosium and erbium ions in similar one-dimensional chain structures.

A family of cyano-bridged 3d-4f 1D chain compounds, {RE[TM(CN)6(2-PNO)5]}·(H2O)4 {RE = YIII, TM = [FeIII]LS (1); RE = DyIII, TM = CoIII (3); RE = ErIII, TM = [FeIII]LS (4), CoIII (5); 2-PNO = 2-picoline-N-oxide} and {RE[TM(CN)6(2-PNO)5]} {RE = DyIII, TM = [FeIII]LS (2)}, were synthesized and characterized. Single-crystal X-ray diffraction studies reveal that compounds 1 and 3-5 are isostructural, while compound 2 has a similar 1D chain structure with a different chain to chain arrangement. An axially-elongated pentagonal bipyramidal (D5h) coordination geometry is formed with five 2-PNO ligands in the equatorial plane and two [TM(CN)6]3- on the apical sites around the rare earth ions in these compounds. A comparison of the magnetic relaxation behaviour in detail reveals that it is more favorable for the Er (4 and 5) than the Dy analogues (2 and 3) to exhibit SIM properties in this axially-elongated D5h coordination environment. Under zero dc field, ac susceptibility measurements show that the Dy analogues have no magnetic relaxation behaviour, while the Er analogues exhibit frequency dependence despite the strong QTM effect. Under a 1 kOe dc field, the Er analogues generally show 1-2 orders of magnitude longer relaxation time at each selected temperature and a higher relaxation energy barrier than the Dy analogues. And the RECo compounds (3 and 5) show a more suppressed QTM effect than the corresponding REFe (2 and 4) compounds, which may be ascribed to the elimination of the fluctuation field from the neighbouring [FeIII]LS ions. The ab initio calculations indicate the misplacement between the orientation of the main magnetic axis and the structural axis in the Dy analogues, and the relative consistency in the Er analogues, which should be the source of the Er analogues showing better SIM properties than the Dy analogues.

The differential magnetic relaxation behaviours of slightly distorted triangular dodecahedral dysprosium analogues in a type of cyano-bridged 3d-4f zig-zag chain compounds.

A class of cyano-bridged 3d-4f zig-zag chain compounds, {RE[TM(CN)6] (PNO)2(H2O)4}·(H2O) {RE = YIII, TM = [FeIII]LS (1); RE = DyIII, TM = [FeIII]LS (2), CoIII (3)}, have been synthesized and characterized by single-crystal X-ray diffraction. The rare earth ions in these compounds are situated in a slightly distorted triangular dodecahedral (D2d) coordination environment. The magnetic properties of compounds 1-3 have been comparatively studied in detail. Under a zero dc field, the temperature dependence of ac susceptibility measurements for YFe (1) indicates the absence of magnetic relaxation stemming from the single anisotropic [FeIII]LS ion. The dysprosium analogue DyFe (2) shows only magnetic relaxation behavior with a prominent QTM effect, while DyCo (3) exhibits SIM properties not completely covered by QTM, with an extracted energy barrier of 73 K under a zero dc field. The ab initio calculations indicate that both compounds 2 and 3 are SMMs with well-behaved magnetic relaxation properties primarily from the individual DyIII ion. Therefore, the different magnetic behaviors exhibited by compound 2 compared to 3 may be ascribed to the stronger QTM effect caused by the extra weak interaction of [FeIII]LS ions in 2 as a fluctuating transverse field around the DyIII ion. The QTM effect for both 2 and 3 is suppressed under an applied dc field with an effective energy barrier of 134 and 150 K, respectively. Compared with compound 2, the higher extracted Ueff/kB and χ''(T) peak temperature for 3 should be further attributed to its slightly higher single-ion axiality as calculated and the elimination of the transverse field from the [FeIII]LS ion.

Myasthenia gravis and specific immunotherapy: monoclonal antibodies.

Myasthenia gravis (MG) is an acquired autoimmune disease affecting the postsynaptic membrane of neuromuscular junctions and characterized by antibody-mediated T cell dependence and complement involvement. Cholinesterase inhibitors (e.g., pyridostigmine bromide), glucocorticoids, and azathioprine are currently recommended as first-line treatments for MG, though they have limitations, including potential toxicity and ineffectiveness in patients with refractory MG. In recent years, owing to an increasing understanding of MG pathogenesis the development and execution of clinical trials with novel biologics, including monoclonal antibodies (mAbs) that have demonstrated higher safety and more specificity, provide new opportunities for the treatment of MG. In this article, we review recent advances in MG pathogenesis and the mAbs that have been used for target-specific MG therapy.

Inhibition of ROCK activity regulates the balance of Th1, Th17 and Treg cells in myasthenia gravis.

Aberrant ROCK activation has been found in patients with several autoimmune diseases, but the role of ROCK in myasthenia gravis (MG) has not yet been clearly investigated. Here, we demonstrated that ROCK activity was significantly higher in peripheral blood mononuclear cells (PBMCs) from MG patients. ROCK inhibitor Fasudil down-regulated the proportions of Th1 and Th17 cells in PBMCs of MG patients in vitro. Intraperitoneal injection of Fasudil ameliorated the severity of experimental autoimmune myasthenia gravis (EAMG) rats and restored the balance of Th1/Th2/Th17/Treg subsets. Furthermore, Fasudil inhibited the proliferation of antigen-specific Th1 and Th17 cells, and inhibited CD4 + T cells differentiated into Th1 and Th17 through decreasing phosphorylated Stat1 and Stat3, but promoted Treg cell differentiation through increasing phosphorylated Stat5. We conclude that dysregulated ROCK activity may be involved in the pathogenic immune response of MG and inhibition of ROCK activity might serve as a novel treatment strategy for MG.

Investigating the relationship between 25-hydroxyvitamin D and thyroid function in second-trimester pregnant women.

This study aims to explore the correlation between serum 25-hydroxyvitamin D and thyroid hormones during the second trimester. In total, 277 pregnant women at 13-28 weeks of gestation were enrolled. According to the level of thyrotropic-stimulating hormone, they were divided into a reduced TSH group, a normal TSH group and an elevated TSH group. In this study, we found that the prevalence of vitamin D deficiency was as high as 94.58%. The 25-hydroxyvitamin D level in the reduced TSH group was lower than that in the normal thyroid function group (p = .0005), and the 25-hydroxyvitamin D level in the elevated TSH group was higher than that in normal TSH group (p=.0339). A positive correlation was observed between 25-hydroxyvitamin D and thyrotropic-stimulating hormone (r = 0.3034, p = .0000). Furthermore, 25-hydroxyvitamin D was negatively correlated with the free thyroxine level (r = -0.1286, p = .0323) as well as the free triiodothyronine level (r = 0.1247, p = .0380). These data suggest that the relationships between 25-hydroxyvitamin D and thyroid parameters were characterized during the second trimester. Pregnant women in the second-trimester who are diagnosed with transient hyperthyroidism should be evaluated for the possibility of vitamin D deficiency.

A family of one-dimensional lanthanide complexes bridged by two distinct carboxylate ligands with the Dy analogue displaying magnetic relaxation behaviour.

A series of isostructural lanthanide one-dimensional (1D) chain complexes, [Ln(INNO)(Bza)2(H2O)2]·(H2O) {INNO = isonicotinate N-oxide, Bza = benzoic acid; Nd(1), Eu(2), Gd(3), Tb(4), Dy(5), Er(6) and Y(7)}, have been successfully isolated by hydrothermal reactions utilizing two distinct carboxylates as co-ligands. Due to the similar steric hindrance of the two carboxylic ligands, the neighboring lanthanide ions are bridged simultaneously by their carboxyl groups from the opposite sides to form a 1D chain structure. The shape analysis of the eight-coordinated Dy analogue 5 highlights the coordination geometry of the distorted square antiprism (D4d). The solid-state luminescence of 2 and 4 was characterized. The static magnetic analysis of the Gd analogue 3 is indicative of the dominant weak intrachain antiferromagnetic interactions via the carboxylic ligands. Dynamic magnetic measurements for 5 revealed clear slow magnetic relaxation behaviour typical for single-molecule magnets (SMMs). Compound 5 represents a very rare example, reported as a mixed carboxylate bridged lanthanide SMM.

Nonalcoholic fatty liver was associated with asymptomatic gallstones in a Chinese population.

The aim of this study was to determine the association between nonalcoholic fatty liver disease (NAFLD) and asymptomatic gallstones in a Chinese population.The study had a cross-sectional design and enrolled 7583 subjects who visited the physical check-up center at Sir Run Run Shaw Hospital between 2009 and 2011. Colorimetric methods were used to measure the levels of cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), whereas fasting plasma glucose (FPG) level was measured using a dextrose-oxidizing enzyme method. Subjects who completed a questionnaire and underwent a medical and ultrasound examinations were included in the study.The prevalence of NAFLD was significantly higher in patients with asymptomatic gallstones than in those without asymptomatic gallstones (58.98% vs 46.58%, respectively; P < .0001). The age-adjusted odds ratio (OR) for NAFLD being accompanied by asymptomatic gallstones was 1.35 [95% confidence interval (CI), 1.13-1.61; P = .0009] in male and 1.92 (95% CI, 1.45-2.54; P < .0001) in female subjects. Asymptomatic gallstones were associated with NAFLD in subjects aged < 50 years (OR = 1.74, 95% CI, 1.44-2.12; P < .0001), but not in subjects aged > 50 years (OR = 1.17, 95% CI, 0.92-1.48; P = .2040). The OR of NAFLD for asymptomatic gallstones was 1.28 after multivariate logistic regression analysis (95% CI, 1.07-1.52; P = .006).Our results indicated that asymptomatic gallstones are strongly associated with NAFLD in the Chinese study population.

A multifunctional lanthanide metal-organic framework supported by Keggin type polyoxometalates.

A neodymium metal-organic framework with 1D nanotubular channels incorporating Keggin type [SiWWO38](3-) has been synthesized by utilizing pyridine-2,5-dicarboxylic acid as an organic ligand. It represents an unusual polyoxometalate-templated framework with the multifunctionality of magnetism, near-infrared luminescence and the selective adsorption of Rhodamine B dye molecules.

Correlation between B type natriuretic peptide and metabolic risk factors.

INTRODUCTION: It has been shown that B type natriuretic peptide (BNP) level can indicate cardiovascular disease. However, the association between BNP and metabolic risk factors is unknown. The aim of this study was to investigate the correlation between N-terminal pro-B type natriuretic peptide (NT-proBNP) and metabolic risk factors. MATERIAL AND METHODS: A total of 11,508 subjects were selected from those who underwent health examinations in our hospital. NT-proBNP, waist circumference, blood pressure, fasting plasma glucose and lipid profile were measured. The level of NT-proBNP was measured and classified into four stratifications (BNP ≥ 20 pg/ml, ≥ 40 pg/ml, ≥ 60 pg/ml, and ≥ 80 pg/ml) to analyze the relationship between BNP and metabolic risk factors. RESULTS: B type natriuretic peptide increased gradually with increasing age (p < 0.001). The BNP levels were significantly higher in women than in men (p < 0.001). Multivariate regression analysis showed a positive association between NT-proBNP levels and systolic blood pressure (p < 0.001), fasting plasma glucose (p < 0.05), and total cholesterol (p < 0.001 in women). The NT-proBNP levels were inversely associated with diastolic blood pressure, waist circumference, triglyceride, high-density lipoprotein, and LDL cholesterol. Logistic regression analysis demonstrated a close relationship between NT-proBNP and systolic blood pressure, fasting plasma glucose, and total cholesterol. In the BNP ≥ 60 pg/ml group, odds ratio (OR) values were 1.80, 1.56 and 1.54 (female) and 3.74, 1.59 and 1.51 (male), respectively. In the BNP ≥ 80 pg/ml group, OR values were 2.45, 1.65 and 1.84 (female) and 4.61, 1.66 and 1.75 (male), respectively. CONCLUSIONS: NT-proBNP was independently associated with the main metabolic risk factors (systolic blood pressure, fasting plasma glucose, and total cholesterol). These findings suggest that the combined determination of NT-proBNP and the main metabolic risk factors could be important in assessing cardiovascular morbidity.

Lanthanide dinuclear complexes constructed from mixed oxygen-donor ligands: the effect of substituent positions of the neutral ligand on the magnetic dynamics in Dy analogues.

Two series of lanthanide dinuclear complexes with the general formulae, [Ln(n-PNO)(Bza)3(H2O)] {Bza = benzoic acid; n = 3, n-PNO = 3-picoline N-oxide, Dy(1) and Er(2); and n = 4, n-PNO = 4-picoline N-oxide, Nd(3), Eu(4), Gd(5), Tb(6), Dy(7), Er(8) and Y(9)} have been successfully synthesized by the hydrothermal method. Single-crystal X-ray diffraction experiments illustrate that the two series of compounds possess similar carboxylic ligand-bridged dinuclear structure and coordination geometry around the lanthanide ions despite the different methyl-substituent positions on the neutral ligand. Comparative studies of the Dy analogues in the static-field measurements reveal only a little difference with a small butterfly-shaped opening for complex 1 and a close hysteresis loop for 7 at 2.0 K. However, systematic investigations of the alternating-current (ac) measurements indicate that the different substituent positions of the picoline N-oxide ligand have a significant effect on the magnetic relaxation dynamics. A more substantial suppression of the quantum tunnelling of magnetization (QTM) effect and pronounced slow magnetic relaxation were observed in complex 7 as compared to 1 under both zero and a 1 kOe static field.

Tuning the Origin of Magnetic Relaxation by Substituting the 3d or Rare-Earth Ions into Three Isostructural Cyano-Bridged 3d-4f Heterodinuclear Compounds.

Three isostructural cyano-bridged 3d-4f compounds, [YFe(CN)6(hep)2(H2O)4] (1), [DyFe(CN)6(hep)2(H2O)4] (2), and [DyCo(CN)6(hep)2(H2O)4] (3), were successfully assembled by site-targeted substitution of the 3d or rare-earth ions. All compounds have been structurally characterized to display slightly distorted pentagonal-bipyramidal local coordination geometry around the rare-earth ions. Magnetic analyses revealed negligible magnetic coupling in compound 1, antiferromagnetic intradimer interaction in 2, and weak ferromagnetic coupling through dipolar-dipolar interaction in 3. Under an applied direct-current (dc) field, 1 (Hdc = 2.5 kOe, τ0 = 1.3 × 10(-7) s, and Ueff/kB = 23 K) and 3 (Hdc = 2.0 kOe, τ0 = 7.1 × 10(-11) s, and Ueff/kB = 63 K) respectively indicated magnetic relaxation behavior based on a single [Fe(III)]LS ion and a Dy(III) ion; nevertheless, 2 (Hdc = 2.0 kOe, τ0 = 9.7 × 10(-8) s, and Ueff/kB = 23 K) appeared to be a single-molecule magnet based on a cyano-bridged DyFe dimer. Compound 1, which can be regarded as a single-ion magnet of the [Fe(III)]LS ion linked to a diamagnetic Y(III) ion in a cyano-bridged heterodimer, represents one of the rarely investigated examples based on a single Fe(III) ion explored in magnetic relaxation behavior. It demonstrated that the introduction of intradimer magnetic interaction of 2 through a cyano bridge between Dy(III) and [Fe(III)]LS ions negatively affects the energy barrier and χ″(T) peak temperature compared to 3.

Discovery of 4-benzoylamino-N-(prop-2-yn-1-yl)benzamides as novel microRNA-21 inhibitors.

MicroRNA-21, as an oncogenic miRNA, has caught great attention for medicinal chemists to develop its novel inhibitors for cancer therapy. In the present study, we designed 4-benzoylamino-N-(prop-2-yn-1-yl)benzamides as miR-21 inhibitor candidates on the basis of scaffold hopping. Eighteen compounds were synthesized. The inhibitory activities of synthesized compounds against the expression of miR-21 were evaluated using stem loop RT-qPCR and compound 1j was discovered as the most potent compound, which displayed a time and concentration dependent inhibition manner. In addition, various functional assays such as the expression of miR-21 target gene detected by Western blotting and the cell growth and apoptosis detected by flow cytometric analysis were checked in Hela (human epithelioid cervix carcinoma) and U-87 MG (human glioblastoma) cells to confirm its activity. The results indicate that compound 1j can enhance apoptosis, retard proliferation, and up-regulate PDCD4, a target protein of miR-21. In addition, the compound 1j does not influence the expression of multiple miRNAs and the genes that participate in miRNA universal biosynthesis pathway. These results strongly support the assumption that title compounds can serve as a small molecule inhibitor of miR-21.

Correlation between non-alcoholic fatty liver with metabolic risk factors and brachial-ankle pulse wave velocity.

AIM: To assess the relationship between non-alcoholic fatty liver disease (NAFLD) with metabolic risk factors and brachial ankle pulse wave velocity (baPWV). METHODS: A total of 8603 subjects (6662 males and 1941 females) were enrolled during an annual health check-up. Fatty liver was examined using a Philips HD 11 XE multi-function color Doppler diagnostic instrument, and baPWV was determined using a novel arteriosclerosis detection device. Blood pressure (BP), fasting plasma glucose (FPG), waist circumference (WC), plasma triglycerides (TG), high-density lipoprotein (HDL), total cholesterol (TC), low-density lipoprotein (LDL) and uric acid (UA) were measured using standard methods. The relationship between fatty liver with metabolic risk factors and baPWV was analyzed using regression analysis and the χ (2) test. RESULTS: The values and abnormal rates of baPWV were significantly different between NAFLD patients and non-NAFLD subjects (P < 0.001). In addition, the values of baPWV were different by gender between NAFLD patients and non-NAFLD subjects. The OR values in females, males, and the entire population were 3.33, 1.67, and 2.13, respectively (P < 0.001). The incidence of high baPWV increased with increasing degree of NAFLD (levels 0, 1, 2, and 3) (P < 0.001), which was 45.9%, 54.5%, 60.2%, and 71.4% in males and 27.0%, 49.1%, 55.60%, and 60.0% in females (P < 0.001), respectively. Logistic regression analysis showed that the OR value for baPWV in the non-metabolic syndrome group and the metabolic syndrome group was 1.28 vs 1.14 (males) and 2.55 vs 0.98 (females). The OR values for baPWV in the non-high-BP and high-BP, non-high-WC and high-WC, non-high-FPG and high-FPG, non-high-TG and high-TG, non-high-HDL and high-HDL, non-high-TC and high-TC, non-high-LDL and high-LDL, non-high-UA and high-UA groups were 3.38 vs 1.19, 3.50 vs 1.44, 2.80 vs 2.30, 3.29 vs 1.88, 3.03 vs 3.28, 3.35 vs 2.70, 3.93 vs 1.66, and 3.20 vs 2.34, respectively, in females (P < 0.001), and were 1.37 vs 1.34, 1.56 vs 1.26, 1.51 vs 1.28, 1.49 vs 1.52, 1.71 vs 1.61, 1.59 vs 1.74, 1.76 vs 1.47, and 1.73 vs 1.54, respectively, in males (P < 0.01). The OR value for baPWV was still higher than 1.2 (1.21 in males and 1.40 in females) after adjustment for the metabolic component (0, 1, 2, 3, 4, 5, 6 and above) (P < 0.01). CONCLUSION: NAFLD is closely correlated with baPWV, particularly in females. NAFLD has a large impact on baPWV, no matter whether the metabolic index is increased or not. NAFLD may be a useful indicator for assessing early arteriosclerosis.

Novel LAMP2 mutations in Chinese patients with Danon disease cause varying degrees of clinical severity.

AIMS: Danon disease is an Xlinked dominant lysosomal glycogen storage disorder characterized by cardiomyopathy, skeletal myopathy, and mental retardation. This study described two Chinese cases of Danon disease in order to broaden the phenotypic and genetic spectrum. METHODS: Clinical data were collected and LAMP2 mutations were analyzed. RESULTS: Patient A had fluctuating limb weakness during 6 months follow-up and was diagnosed with drug-induced myopathy due to anti-hepatitis B therapy with lamivudine. However, the first muscle biopsy with large cytoplasmic vacuoles confused the diagnosis and led to the second biopsy that allowed for the final diagnosis. Patient B had severe cardiac disturbances leading to sudden death. Molecularly, patient A harbored a synonymous mutation adjacent to the exon 6-intron 6 junction; mRNA analysis provided evidence that totally abolished the donor site and caused skipping of exon 6. Patient B harbored a frame-shift deletion mutation in exon 3 (c.396delA) leading to a truncated protein. DISCUSSION: To our knowledge, this is the first report of Danon disease caused by a synonymous exon mutation that affected mRNA splicing, which indicates that a synonymous substitution may not be silent when it is in the exon sequences close to the splice sites. It is also the first description of Danon disease clinically presenting as druginduced myopathy at onset; the pathological changes might be the key point for making a differential diagnosis. *These two authors contributed equally to this work.