Associations of early pregnancy serum uric acid levels with risk of gestational diabetes and birth outcomes: a retrospective cohort study.

BACKGROUND: Previous evidence suggests that higher blood uric acid (UA) levels are associated with adverse cardiovascular outcomes during pregnancy and subsequent birth outcomes. However, it has been relatively unclear whether these associations persist in normotensive pregnant women. METHODS: The study was based on a retrospective analysis of 18,250 mother-infant pairs in a large obstetric center in China. Serum UA concentrations in early pregnancy (median: 17.6, IQR: 16.3, 18.6 gestational weeks) were assessed. Hyperuricemia was defined as ≥ one standard deviation (SD) of the reference value for the corresponding gestational age. Outcomes of gestational diabetes mellitus (GDM), preterm birth (PB), low birth weight (LBW), macrosomia, small for gestational age (SGA) and large for gestational age (LGA) were extracted from the medical records. RESULTS: The mean maternal UA level was 0.22 ± 0.05 mmol/L, and 2,896 (15.9%) subjects had hyperuricemia. After adjustment for several covariates, UA was associated with several adverse outcomes. The ORs (95%CI) per one SD increase in serum UA concentration were 1.250 (1.136, 1.277) for GDM, 1.137 (1.060, 1.221) for PB, 1.134 (1.051, 1.223) for LBW, and 1.077 (1.020, 1.137) for SGA, respectively. Similar adverse associations were found between hyperuricemia and GDM, PB (ORs: 1.394 and 1.385, P < 0.001), but not for LBW, macrosomia, SGA, and LGA. Adverse associations tended to be more pronounced in subjects with higher BMI for outcomes including PB, LBW, and SGA (P interaction = 0.001-0.028). CONCLUSION: Higher UA levels in early pregnancy were associated with higher risk of GDM, PB, LBW, and SGA in normotensive Chinese women.

Associations Between Maternal Thyroid Function and Birth Outcomes in Chinese Mother-Child Dyads: A Retrospective Cohort Study.

Objective: Although research suggests a close association between maternal thyroid function and birth outcomes, no clear conclusion has been reached. We aimed to explore this potential association in a retrospective cohort study. Methods: This study included 8985 mother-child dyads. The maternal serum free tetraiodothyronine (FT4), thyroid-stimulating hormone (TSH), and thyroid peroxidase antibody (TPO Ab) concentrations and birth outcome data were reviewed from medical records. Subjects with TPO Ab concentrations of >34 and ≤34 IU/ml were classified into the TPO Ab positivity (+) and TPO Ab negativity (-) groups, respectively. Results: Compared with subjects in the normal group (0.1 ≤ TSH < 2.5 mIU/L and TPO Ab-), those with TSH concentrations of 2.5-4.0 mIU/L and TPO Ab- had a 0.65-fold lower risk of low birth weight (LBW). In contrast, those with TSH concentrations of >4.0 mIU/L, regardless of the TPO Ab status, had a 2.01-fold increased risk of LBW. Subclinical hypothyroidism, regardless of the TPO Ab status, was associated with a 1.94-fold higher risk of LBW when compared with that in subjects with euthyroidism and TPO Ab-. No other significant associations were observed. Conclusion: A maternal TSH concentration of 2.5-4.0 mIU/L was associated with a lower risk of LBW when combined with TPO Ab-, whereas subjects with a TSH concentration of >4.0 mIU/L had an increased risk of LBW. Subclinical hypothyroidism appears to be associated with a higher risk of LBW.

Jatrorrhizine Balances the Gut Microbiota and Reverses Learning and Memory Deficits in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is a complex disorder influenced by both genetic and environmental components and has become a major public health issue throughout the world. Oxidative stress and inflammation play important roles in the evolution of those major pathological symptoms. Jatrorrhizine (JAT), a main component of a traditional Chinese herbal, coptidis rhizome, has been shown to have neuroprotective effects and we previously showed that it is also able to clear oxygen free radicals and reduce inflammatory responses. In this study, we demonstrated that JAT administration could alleviate the learning and memory deficits in AD. Furthermore, we also found that JAT treatment reduced the levels of Aß plaques in the cortex and hippocampus of APP/PS1 double-transgenic mice. Other studies suggest that there are gut microbiome alterations in AD. In order to explore the underlying mechanisms between gut microbiota and AD, DNA sequencing for 16s rDNA V3-V4 was performed in fecal samples from APP/PS1 transgenic mice and C57BL/6 wild-type (WT) mice. Our results indicated that APP/PS1 mice showed less Operational Taxonomic Units (OTUs) abundance in gut microbiota than WT mice and with different composition. Furthermore, JAT treatment enriched OTUs abundance and alpha diversity in APP/PS1 mice compared to WT mice. High dose of JAT treatment altered the abundance of some specific gut microbiota such as the most predominant phylum Firmicutes and Bacteroidetes in APP/PS1 mice. In conclusion, APP/PS1 mice display gut dysbiosis, and JAT treatment not only improved the memory deficits, but also regulated the abundance of the microbiota. This may provide a therapeutic way to balance the gut dysbiosis in AD patients.

Multiple Signal Pathways Involved in Crocetin-Induced Apoptosis in KYSE-150 Cells.

BACKGROUND: Crocetin is a carotenoid extracted from the traditional Chinese medical herb saffron. Previous studies have demonstrated that crocetin possesses anticancer properties that are effective against various cancers. As an extension of our earlier study, the present study explored the underlying mechanisms in crocetin's anticancer effect on KYSE-150 cells. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), Mitogen-activated protein kinases (MAPK), and p53/p21 signal pathways play an important role in carcinogenesis, progression, and metastasis of carcinoma cells. Thus, we investigated crocetin's effects on the PI3K/AKT, MAPK, and p53/p21 pathways in esophageal squamous carcinoma cell line KYSE-150 cells. METHODS: KYSE-150 cells were treated with various concentrations of crocetin. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltertrazolium bromide assay, Annexin V/PI stain as well as Rh123 stain were used to evaluate the cell viability, apoptosis, and MMP. Western blot was used to detect the expression of PI3K, AKT, ERK1/2, p38, c-Jun NH-terminal kinase (JNK), P53, P21, Bcl-2, Bax, and cleaved caspase-3, which were associated with cell proliferation and apoptosis. RESULTS: Our results showed that crocetin significantly inhibited the proliferation of KYSE-150 cells in a dose- and time-dependent manner. Crocetin also markedly induced cell apoptosis. Furthermore, we have found that crocetin not only inhibited the activation of PI3K/AKT, extracellular signal-regulated kinase-1/2 (ERK1/2), and p38 but also upregulated the p53/p21 level. These regulations ultimately triggered the mitochondrial-mediated apoptosis pathway with an eventual disruption of MMP, increased levels of Bax and cleaved caspase-3, and decreased levels of Bcl-2. CONCLUSIONS: These findings suggested that crocetin interfered with multiple signal pathways in KYSE-150 cells. Therefore, this study suggested that crocetin could potentially be used as a therapeutic candidate for the treatment of esophageal cancer.

Quercetin inhibits okadaic acid-induced tau protein hyperphosphorylation through the Ca2+­calpain­p25­CDK5 pathway in HT22 cells.

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by aberrant tau protein hyperphosphorylation, which eventually leads to the formation of neurofibrillary tangles. Hyperphosphorylated tau protein is considered as a vital factor in the development of AD and is highly associated with cognitive impairment. Therefore, it is recognized to be a potential therapeutic target. Quercetin (QUE) is a naturally occurring flavonoid compound. In the present study, the inhibitory effect of QUE on okadaic acid (OA)-induced tau protein hyperphosphorylation in HT22 cells was explored. Western blotting results indicated that QUE significantly attenuated OA­induced tau protein hyperphosphorylation at the Ser396, Ser199, Thr231 and Thr205 sites. Further experiments demonstrated that QUE inhibited the activity of cyclin­dependent kinase 5 (CDK5), a key enzyme in the regulation of tau protein, and blocked the Ca2+­calpain­p25­CDK5 signaling pathway. These observations indicate the ability of QUE to decrease tau protein hyperphosphorylation and thereby attenuate the associated neuropathology. In conclusion, these results support the potential of QUE as a therapeutic agent for AD and other neurodegenerative tauopathies.

Synergistic anticancer effect of combined crocetin and cisplatin on KYSE-150 cells via p53/p21 pathway.

BACKGROUND: More than 400,000 patients die from esophageal cancer annually. Considerable efforts have been made to develop new and effective treatments, one of which is directed toward herbal medication. Crocetin is a natural carotenoid dicarboxylic acid isolated from the Chinese herb saffron. We recently reported on the anticancer effects of saffron. This study aimed to determine whether crocetin combined cisplatin has synergistic effect in KYSE-150 cells and explore the underlying mechanism. METHODS: KYSE-150 cells were treated with crocetin and/or cisplatin. The effects on cell viability, cell apoptosis, mitochondrial membrane potential (MMP), as well as the expression levels of PI3K/AKT, MAPKs, p53/p21, and apoptosis-related protein were evaluated. MTT assay, Annexin V-FITC/PI staining, Rh123 staining, and Western blot analysis were used. RESULTS: The cell proliferation significantly decreased and cell apoptosis was induced with combined crocetin and cisplatin, compared with either crocetin only or cisplatin only. The outcome suggested that crocetin combined cisplatin has synergistic effects on inhibition of cell proliferation and pro-apoptotic effect of cisplatin on KYSE-150 cells. Disruption of MMP, upregulation of cleaved caspase-3 expression, and downregulation of Bcl-2 occurred in the group treated with combined treatment. No significant differences in p-PI3K, p-AKT, and MAPKs activity were indicated between combined treatment group and the individual treatment group. However, the expression levels of p53 and p21 were markedly higher in the combined treatment group than in the individual treatment group. The wild-type p53 inhibitor, PFT-α suppressed the overexpression of p53/p21 and the synergistic effect induced by the combination of crocetin and cisplatin. CONCLUSIONS: We concluded that crocetin combined with cisplatin exerts a synergistic anticancer effect by up-regulating the p53/p21 pathway.

The Protective Effect of Jatrorrhizine Against Oxidative Stress in Primary Rat Cortical Neurons.

OBJECTIVES: This study investigated the neuroprotective effects of Jatrorrhizine in rat cortical neurons. METHOD: The effects of Jatrorrhizine on hydrogen peroxide (H2O2)-induced cell lesion, levels of lipid peroxidation and antioxidant enzyme activities were investigated in rat cortical neurons. Levels of mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) were measured by fluorescent rhodamine staining and 2',7'-dichlorfluorescein-diacetate staining, respectively. ATP content was measured by a high performance liquid chromatography. The protein levels for Bax, Bcl2 and cleaved caspase-3 were analyzed by western blot protein expression. RESULTS: There was a significant reduction in cell viability and activities of Superoxide dismutase and glutathione peroxidase for the cortical neurons after exposure to 50µM H2O2 for 12h. The hydrogen peroxide increased the production of malondialdehyde and ROS but decreased MMP and ATP in the neurons. However, pretreatment with different concentrations of Jatrorrhizine (5-20µM) inhibited H2O2-induced neurotoxicity markedly. Jatrorrhizine also attenuated the H2O2-induced Bcl-2/Bax ratio reduction and caspase-3 activation in these neurons. CONCLUSIONS: Our findings suggest that Jatrorrhizine plays a critical neuroprotective role in H2O2 - induced apoptosis through its anti-oxidative actions. This may allow Jatrorrhizine to be a novel therapeutic with its high bioavailability to treat Alzheimer's disease.

Quercetin Protects against Okadaic Acid-Induced Injury via MAPK and PI3K/Akt/GSK3ß Signaling Pathways in HT22 Hippocampal Neurons.

Increasing evidence shows that oxidative stress and the hyperphosphorylation of tau protein play essential roles in the progression of Alzheimer's disease (AD). Quercetin is a major flavonoid that has anti-oxidant, anti-cancer and anti-inflammatory properties. We investigated the neuroprotective effects of quercetin to HT22 cells (a cell line from mouse hippocampal neurons). We found that Okadaic acid (OA) induced the hyperphosphorylation of tau protein at Ser199, Ser396, Thr205, and Thr231 and produced oxidative stress to the HT22 cells. The oxidative stress suppressed the cell viability and decreased the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), mitochondria membrane potential (MMP) and Glutathione peroxidase (GSH-Px). It up-regulated malondialdehyde (MDA) production and intracellular reactive oxygen species (ROS). In addition, phosphoinositide 3 kinase/protein kinase B/Glycogen synthase kinase3ß (PI3K/Akt/GSK3ß) and mitogen activated protein kinase (MAPK) were also involved in this process. We found that pre-treatment with quercetin can inhibited OA-induced the hyperphosphorylation of tau protein and oxidative stress. Moreover, pre-treatment with quercetin not only inhibited OA-induced apoptosis via the reduction of Bax, and up-regulation of cleaved caspase 3, but also via the inhibition of PI3K/Akt/GSK3ß, MAPKs and activation of NF-κB p65. Our findings suggest the therapeutic potential of quercetin to treat AD.

Jatrorrhizine Protects Against Okadaic Acid Induced Oxidative Toxicity Through Inhibiting the Mitogen-Activated Protein Kinases Pathways in HT22 Hippocampal Neurons.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by deposit of amyloid plaques and neurofibrillary tangles and oxidative stress plays an essential role in the pathogenesis of AD. Jatrorrhizine (JAT), a Coptidis Rhizome, has multiple biological functions such as anti-oxidation and anti-inflammation. Herein, we investigated the neuroprotective effects of JAT on okadaic acid (OA)- induced cytotoxicity and apoptosis in HT22 cells. Following the exposure to 80 nmol/L OA for 12h, the reduction in cell survival, activities of superoxide dismutase, glutathione peroxidase and mitochondria membrane potential has been shown in HT22 cells. In contrast, OA increased levels of lactate dehydrogenase, malondialdehyde production and intracellular reactive oxygen species. OA also enhanced the expression of Bax but decreased the levels of Bcl-2, OA also upregulated the expression of cleaved caspase-3, phosphorylated extracellular signal-regulated kinases 1/2, phosphorylated c-Jun N-terminal kinases, phosphorylated p38 and NF-kappa B p65 subunit in HT22 cells and this up-regulation was attenuated by JAT which was pre-incubated for 12h in the cells prior to OA exposure. In conclusion, our data present the protective role of JAT in OA induced cytotoxicity, via its antioxidant and anti-apoptotic properties by inhibiting the mitogen-activated protein kinases pathways in HT22 hippocampal neurons. These results indicate that JAT may be the potential target to treat AD induced by oxidative stress and apoptosis.

Anticancer effects of crocetin in human esophageal squamous cell carcinoma KYSE-150 cells.

Crocetin is the main pharmacologically-active component of saffron and has been considered as a promising candidate for cancer chemoprevention. The purpose of the present study was to investigate the anticancer effects of crocetin and the possible mechanisms of these properties in the esophageal squamous cell carcinoma cell line KYSE-150. The KYSE-150 cells were cultured in Dulbecco's modified Eagle's medium and incubated with 0, 12.5, 25, 50, 100 or 200 µmol/l crocetin for 48 h. Cell proliferation was measured using an MTT assay. Hoechst 33258 staining and observation under fluorescent microscopy were used to analyze the proapoptotic effects of crocetin. The migration rate was assessed by a wound-healing assay. The cell cycle distribution was analyzed using flow cytometry analysis subsequent to propidium iodide staining. The expression of B-cell lymphoma-2-associated X protein (Bax) and cleaved caspase 3 was determined by western blot analysis. It was found that treatment of KYSE-150 cells with crocetin for 48 h significantly inhibited the proliferation of the cells in a concentration-dependent manner, and the inhibition of proliferation was associated with S phase arrest. Crocetin was also found to induce morphological changes and cell apoptosis in a dose-dependent manner through increased expression of proapoptotic Bax and activated caspase 3. In addition, crocetin suppressed the migration of KYSE-150 cells. The present study provides evidence that crocetin exerts a prominent chemopreventive effect against esophageal cancer through the inhibition of cell proliferation, migration and induction of apoptosis. These findings reveal that crocetin may be considered to be a promising future chemotherapeutic agent for esophageal cancer therapy.