Prioritizing the multifaceted community and species uniqueness for the conservation of lacustrine fishes in the largest subtropical floodplain, China.

Hydrological variations affect habitat characteristics and fish distribution in floodplain lakes. Assessing the contributions of the local community (i.e., LCBD, community uniqueness) and species to overall ß diversity (i.e., SCBD, species uniqueness) of fish assemblages is valuable for habitat and species conservation planning, particularly from functional and phylogenetic perspectives. We examined the changes in multifaceted LCBD and SCBD of fish across different hydrological periods in the Poyang Lake, China, and analyzed their responsive mechanisms using regression models, based on which the conservation priorities of habitats and species were evaluated. The findings revealed that taxonomic, functional, and phylogenetic LCBD and SCBD were lowest during the wet season compared to the normal and dry seasons, emphasizing the regulatory effects of hydrological regimes on fish assemblages. Taxonomic and functional LCBD were significantly impacted by the mean abundance of migratory fish, highlighting the importance of specific species combinations on community uniqueness. Taxonomic and functional SCBD exhibited positive correlations primarily with mean abundance, suggesting the potential uniqueness of certain common species. Additionally, we identified the river-lake junction (Hukou station) and natural reserve (Xingzi and Nanjishan stations) with high overall community uniqueness as critical habitats. We also emphasized the necessity for increased conservation efforts for species having high overall species uniqueness during different hydrological periods, including Coilia brachygnathus, Ctenopharyngodon idella, Coilia nasus, Saurogobio dabryi, Hypophthalmichthys molitrix, Megalobrama amblycephala, and Parabramis pekinensis. This research underscores the significance of integrating multiple ecological perspectives to manage biodiversity changes and maintain ecological conservation values effectively.

Burden evaluation and prediction of osteoarthritis and site-specific osteoarthritis coupled with attributable risk factors in China from 1990 to 2030.

OBJECTIVE: This study aimed to estimate and predict the burden of osteoarthritis (OA) and site-specific OA (hip, knee, hand, and others) from 1990 to 2030 and their attributable risk factors in China. METHOD: Data were obtained from the Global Burden of Diseases 2019. The burden was estimated by analyzing the trends of prevalence, incidence, and disability-adjusted life years (DALY). Population attributable risk (PAR) was calculated to assess the impact of high body mass index (BMI). The prediction from 2020 to 2030 was implemented by Bayesian age-period-cohort analysis. RESULTS: In China, prevalent cases, DALY, and incident cases of OA increased to 132.81 million, 4.72 million, and 10.68 million, respectively. Age-standardized rates (ASRs) of prevalence, DALYs, and incidence increased for OA and site-specific OA, especially for hip OA. Site-specific OA showed different susceptible peaking ages, and the burden for those over 50 years old became serious. Female preference existed in the trends for knee OA but not in those for hip, hand, and other OA. PARs of high BMI continued to increase, impacting knee OA more than hip OA and showing female preference. In the next decade, incident cases for OA and site-specific OA will continue to increase, despite that the ASR of OA incidence will decrease. CONCLUSIONS: OA and site-specific OA remain huge public health challenges in China. The burden of OA and site-specific OA is increasing, especially among people over 50 years old. Health education, exercise, and removing modifiable risk factors contribute to alleviate the growing burden. Key Points • In China, the burden of osteoarthritis and site-specific osteoarthritis (hip, knee, hand, and others) as well as the Risk Factor (high body mass index) increased greatly from 1990 to 2019. • It is estimated that incident cases for OA and site-specific OA will continue to increase, despite that the ASR of OA incidence will decrease.

From tissue lesions to neurotoxicity: The devastating effects of small-sized nanoplastics on red drum Sciaenops ocellatus.

Nanoplastic pollution typically exhibits more biotoxicity to marine organisms than microplastic pollution. Limited research exists on the toxic effects of small-sized nanoplastics on marine fish, especially regarding their post-exposure resilience. In this study, red drum (Sciaenops ocellatus) were exposed to small-sized polystyrene nanoplastics (30 nm, PS-NPs) for 7 days for the exposure experiments, followed by 14 days of recovery experiments. Histologically, hepatic lipid droplets and branchial epithelial liftings were the primary lesions induced by PS-NPs during both exposure and recovery periods. The inhibition of total superoxide dismutase activity and the accumulation of malondialdehyde content throughout the exposure and recovery periods. Transcriptional and metabolic regulation revealed that PS-NPs induced lipid metabolism disorders and DNA damage during the initial 1-2 days of exposure periods, followed by immune responses and neurotoxicity in the later stages (4-7 days). During the early recovery stages (2-7 days), lipid metabolism and cell cycle were activated, while in the later recovery stage (14 days), the emphasis shifted to lipid metabolism and energy metabolism. Persistent histological lesions, changes in antioxidant capacity, and fluctuations in gene and metabolite expression were observed even after 14 days of recovery periods, highlighting the severe biotoxicity of small-sized PS-NPs to marine fish. In summary, small-sized PS-NPs have severe biotoxicity, causing tissue lesions, oxidative damage, lipid metabolism disorders, DNA damage, immune responses, and neurotoxicity in red drum. This study offers valuable insights into the toxic effects and resilience of small-sized nanoplastics on marine fish.

Calcium sulfate-Cu2+ delivery system improves 3D-Printed calcium silicate artificial bone to repair large bone defects.

There are still limitations in artificial bone materials used in clinical practice, such as difficulty in repairing large bone defects, the mismatch between the degradation rate and tissue growth, difficulty in vascularization, an inability to address bone defects of various shapes, and risk of infection. To solve these problems, our group designed stereolithography (SLA) 3D-printed calcium silicate artificial bone improved by a calcium sulfate-Cu2+ delivery system. SLA technology endows the scaffold with a three-dimensional tunnel structure to induce cell migration to the center of the bone defect. The calcium sulfate-Cu2+ delivery system was introduced to enhance the osteogenic activity of calcium silicate. Rapid degradation of calcium sulfate (CS) induces early osteogenesis in the three-dimensional tunnel structure. Calcium silicate (CSi) which degrades slowly provides mechanical support and promotes bone formation in bone defect sites for a long time. The gradient degradation of these two components is perfectly matched to the rate of repair in large bone defects. On the other hand, the calcium sulfate delivery system can regularly release Cu2+ in the temporal and spatial dimensions, exerting a long-lasting antimicrobial effect and promoting vascular growth. This powerful 3D-printed calcium silicate artificial bone which has rich osteogenic activity is a promising material for treating large bone defects and has excellent potential for clinical application.

Loss of NSUN6 inhibits osteosarcoma progression by downregulating EEF1A2 expression and activation of Akt/mTOR signaling pathway via m5C methylation.

As an important 5-methylcytidine (m5C) methyltransferase, NOP2/Sun RNA methyltransferase family member 6 (NSUN6) has been reported to play an important role in the progression of several diseases. However, the role of NSUN6 in the progression of osteosarcoma (OS) remains unclear. This study aimed to identify the role of NSUN6 in the progression of OS and clarify the potential molecular mechanism. The present study discovered that NSUN6 was upregulated in OS and a higher NSUN6 expression was a strong indicator for poorer prognosis of patients with OS. In addition, the loss of NSUN6 led to reduced proliferation, migration and invasion of OS cells. Through bioinformatics analysis, RNA immunoprecipitation (RIP) and methylated RIP assays, eukaryotic elongation factor 1 α-2 (EEF1A2) was identified and validated as a potential target of NSUN6 in OS. Mechanistically, the expression of EEF1A2 was significantly suppressed following NSUN6 knockdown due to reduced EEF1A2 mRNA stability in an m5C-dependent manner. Meanwhile, NSUN6 deficiency inhibited m5C-dependent activation of Akt/mTOR signaling pathway. In addition, genetic overexpression of EEF1A2 or pharmacological activation of the Akt signaling pathway counteracted the suppressive effects of NSUN6 deficiency on the proliferation, invasion and migration of OS cells. The current findings suggested that NSUN6 may serve as a potential therapeutic target for OS treatment.

Species traits determined different responses to "zero-growth" policy in China's marine fisheries.

China remains the largest nation of marine capture fisheries in the world in the last few decades, at the cost of offshore fisheries degradation by overfishing. Although fisheries regulations have become gradually tightened, the recovering evidences are weak and the catch species compositions are far from satisfactory. To explore better and reasonable countermeasures, besides the "zero growth" policy (i.e. the national total fisheries production limitation), five targets with different ecological traits were selected for stock assessment and rebuilding by Monte Carlo Catch-Maximum Sustainable Yield method. The results showed the control of total rather than species catch could not lead to the recovery of fisheries and maintain community function. Individual species showed different responses to overfishing according to their biological characteristics. High trophic level species can be sensitive to overfishing, and difficult to rebuild stocks after collapse. Pelagic small fish resources increased first but eventually decreased under high fishing pressure. Scientific-based restocking can enhance resource recovery. Besides "zero growth" policy, fisheries management should be further refined, in particular for main economic species based on their biological traits, as well as the support of reliable fisheries statistics and regulation implementation in place. To relieve the conflict between rising fishery products demand and falling catches, aquaculture and seeking resources from the high seas and EEZs are supposed to be successful ways, on the premise of taking full account of ecological health, maritime safety, and food security.

[Ecosystem structure and function of Sanmen Bay based on Ecopath model.] / 基于Ecopath模型的三门湾生态系统结构与功能.

Ecosystem structure determines material circulation, energy flow, and system function. Based on field investigation data in the Sanmen Bay, East China Sea from 2017 to 2018, ecological channel model was constructed by Ecopath, describing energy flow routes and functional characteristics of the Sanmen Bay ecosystem. Results showed that grazing food chain was the main energy circulation channel, and the trophic level of each functional group ranged from 1 to 3.80. Energy flow of the system was mainly concentrated in the first five levels, with an average energy conversion efficiency of 13.0%. Energy conversion efficiency was 12.8% and 14.5% from primary producers and debris, respectively. Connectance index (CI) and system omnivory index (SOI) were 0.40 and 0.24 respectively. Finn's cycling index (FIC) was 0.40, and Finn's mean path length (MPL) was 2.06. The ratio of total primary productivity to total respiration was 13.59. In conclusion, Sanmen Bay ecosystem was immature in material circulation and energy flow. This work is helpful to understand the structural and functional traits of coastal ecosystems in China.

Hyperglycemia-induced accumulation of advanced glycosylation end products in fibroblast-like synoviocytes promotes knee osteoarthritis.

Osteoarthritis (OA) is significantly associated with diabetes, but how hyperglycemia induces or aggravates OA has not been shown. The synovium plays a critical role in cartilage metabolism and substance exchange. Herein, we intended to investigate whether and how hyperglycemia affects the occurrence and progression of OA by influencing the synovium. In patients with knee OA and diabetes (DM OA), we found a more severe inflammatory response, higher endoplasmic reticulum stress (ERS) levels, and more advanced glycosylation end products (AGEs) accumulation in the synovium than in patients without diabetes. Subsequently, we found similar results in the DM OA group in a rat model. In the in vitro cocultivation system, high glucose-stimulated AGEs accumulation, ERS, and inflammation in rat fibroblast-like synoviocytes (FLSs), which resulted in chondrocyte degeneration due to inflammatory factors from FLSs. Furthermore, in the synovium of the DM OA group and FLSs treated with high glucose, the expression of glucose transporter 1 (GLUT1) and its regulatory factor hypoxia-inducible factor (HIF)-1α was increased significantly. Inhibitors of HIF-1α, GLUT1 or AGEs receptors attenuated the effect of high glucose on chondrocyte degradation in the FLS-chondrocyte coculture system. In summary, we demonstrated that hyperglycemia caused AGEs accumulation in FLSs via the HIF-1α-GLUT1 pathway, which increases the release of inflammatory factors from FLSs, subsequently inducing chondrocyte degradation and promoting OA progression.

Trophic transfer of heavy metals through aquatic food web in a seagrass ecosystem of Swan Lagoon, China.

The Swan Lagoon is a national nature reserve and an important spawning ground in China. In this study, we evaluated the concentration of heavy metals (Cd, Cr, Cu, Pb, and Zn) in different aquatic organisms (aquatic plants, crustaceans, mollusks, and fish), in order to examine their trophic transfer in food web. The results showed that the concentrations of Cd, Cu, Pb, and Zn were considerably higher in mollusks, whereas Cr concentrations were significantly higher in aquatic plants than in mollusks, crustaceans, and fish (p < 0.01). Heavy metals exhibit different patterns of trophic transfer in food web. Cd, Cr, Cu, and Pb tended to be efficiently biodiluted with increasing trophic levels in food web (trophic magnification factor, TMF < 1; p < 0.05). The concentration of Zn increased with increasing trophic level; however, it exhibited a TMF of only 1.03, and was not significantly correlated with δ15N (p > 0.05), indicating neither biomagnification or biodilution in the food web.

PYGB siRNA inhibits the cell proliferation of human osteosarcoma cell lines.

Osteosarcoma is the most common malignant bone carcinoma that primarily occurs between childhood to adolescence. It was suggested by recent research that the Brain type glycogen phosphorylase (PYGB) gene may serve an important role in various types of cancer. In the present study, the PYGB gene was knocked down in order to evaluate the cell viability, invasion and migration of the human osteosarcoma cell lines MG63 and HOS. The expression levels of PYGB in osteosarcoma and bone cyst tissue samples, as well as in the osteosarcoma cell lines were identified using reverse transcription­quantitative polymerase chain reaction and western blot assay. Subsequently, a Cell Counting kit 8 assay was employed to evaluate cell proliferation. Cell apoptosis rate and cell cycle distribution were measured by flow cytometry. In addition, cell invasion and migration were evaluated through a Transwell assay. The expression levels of the cell apoptosis and tumor metastasis associated proteins B­cell lymphoma 2 (Bcl­2), Bcl­2­associated X protein, E­cadherin, Twist, matrix metalloproteinase (MMP)­9 and MMP2 were measured via western blotting. PYGB exhibited a higher expression level in the osteosarcoma tissue samples, particularly in the human osteosarcoma cell lines MG63 and HOS. Knockdown of PYGB resulted in a decline in cell proliferation, invasion and migration, which was coupled with induced cell apoptosis and cell cycle arrest in MG63 and HOS cells. Furthermore, alterations in the expression of apoptosis and metastasis associated proteins indicated that small interfering (si)PYGB may have regulated cell viability by targeting the Bcl/Caspase and cyclin dependent kinase (CDK)­1 signaling pathway. In conclusion, PYGB siRNA exerted an inhibitory effect on the cell viability of the human osteosarcoma cells MG63 and HOS by blocking the Caspase/Bcl and CDK1 signaling pathway, highlighting novel potential therapeutic methods for treating osteosarcoma.

Prenatal food restriction induces poor-quality articular cartilage in female rat offspring fed a post-weaning high-fat diet and its intra-uterine programming mechanisms.

Epidemiological data show that osteoarthritis (OA) is significantly associated with lower birth weight, and that OA may be a type of fetal-originated adult disease. The present study aimed to investigate the prenatal food-restriction (PFR) effect on the quality of articular cartilage in female offspring to explore the underlying mechanisms of fetal-originated OA. Maternal rats were fed a restricted diet from gestational day (GD) 11 to 20 to induce intra-uterine growth retardation. Female fetuses and female adult offspring fed a post-weaning high-fat diet were killed at GD20 and postnatal week 24, respectively. Serum and knee cartilage samples from fetuses and adult female offspring were collected and examined for cholesterol metabolism and histology. Fetal serum corticosterone and insulin-like growth factor-1 (IGF-1) in the PFR group were lower than those of the control, but the serum cholesterol level was not changed. The lower expression of IGF-1 in the PFR group lasted into adulthood. The expression of extracellular matrix (ECM) genes, including type II collagen, aggrecan and cholesterol efflux genes including liver X receptor, were significantly induced, but the ATP-binding-cassette transporter A1 was unchanged. PFR could induce a reduction in ECM synthesis and impaired cholesterol efflux in female offspring, and eventually led to poor quality of articular cartilage and OA.

Increased susceptibility of prenatal food restricted offspring to high-fat diet-induced nonalcoholic fatty liver disease is intrauterine programmed.

The present study aims to explore the mechanisms of fetal origin of high susceptibility to adult high-fat diet induced-nonalcoholic fatty liver disease in rat offspring undergoing intrauterine growth retardation (IUGR) induced by prenatal food restriction (FR) from gestational day 11 until full-term delivery. We observed that adult IUGR offspring rats exhibited gender-dependent catch-up growth with lower serum corticosterone (CORT) but up-regulation of the insulin-like growth factor 1 (IGF1) pathway, higher hepatic Kleiner scores and lower lipid export and oxidation. Furthermore, fetal IUGR offspring rats showed lower body weights with higher serum CORT but down-regulated IGF1 pathway, which was accompanied by enhanced lipid de novo synthetic gene expression, lower lipid output and oxidation gene expression. It is suggested that a "two-programming" mechanism, which refers to the adverse intrauterine programming of hepatic lipid de novo synthesis and glucocorticoid-IGF1 axis programming associated with postnatal catch-up growth, could explain the increased susceptibility.

Mitogen-inducible gene-6 partly mediates the inhibitory effects of prenatal dexamethasone exposure on endochondral ossification in long bones of fetal rats.

BACKGROUND AND PURPOSE: Prenatal exposure to dexamethasone slows down fetal linear growth and bone mineralization but the regulatory mechanism remains unknown. Here we assessed how dexamethasone regulates bone development in the fetus. EXPERIMENTAL APPROACH: Dexamethasone (1 mg·kg(-1) ·day(-1) ) was injected subcutaneously every morning in pregnant rats from gestational day (GD)9 to GD20. Fetal femurs and tibias were harvested at GD20 for histological and gene expression analysis. Femurs of 12-week-old female offspring were harvested for microCT (µCT) measurement. Primary chondrocytes were treated with dexamethasone (10, 50, 250 and 1000 nM). KEY RESULTS: Prenatal dexamethasone exposure resulted in accumulation of hypertrophic chondrocytes and delayed formation of the primary ossification centre in fetal long bone. The retardation was accompanied by reduced maturation of hypertrophic chondrocytes, decreased osteoclast number and down-regulated expression of osteocalcin and bone sialoprotein in long bone. In addition, the mitogen-inducible gene-6 (Mig6) and osteoprotegerin (OPG) expression were stimulated, and the receptor activator of NF-κB ligand (RANKL) expression was repressed. Moreover, dexamethasone activated OPG and repressed RANKL expression in both primary chondrocytes and primary osteoblasts, and the knockdown of Mig6 abolished the effect of dexamethasone on OPG expression. Further, µCT measurement showed loss of bone mass in femur of 12-week-old offspring with prenatal dexamethasone exposure. CONCLUSIONS AND IMPLICATIONS: Prenatal dexamethasone exposure delays endochondral ossification by suppressing chondrocyte maturation and osteoclast differentiation, which may be partly mediated by Mig6 activation in bone. Bone development retardation in the fetus may be associated with reduced bone mass in later life.

Prenatal caffeine exposure-induced adrenal developmental abnormality in male offspring rats and its possible intrauterine programming mechanisms.

Glucocorticoid (GC) is a major factor for fetal tissue maturation and fate decision after birth. We previously demonstrated that prenatal caffeine exposure (PCE) suppressed fetal adrenal steroidogenesis and resulted in adrenal dysplasia. However, whether these changes play a role until adulthood and its intrauterine programming mechanisms remain unknown. In the present study, a rat model of intrauterine growth retardation (IUGR) was established by PCE, male fetuses and adult offspring were sacrificed at postnatal day (PD) 1, PD7, PD35, PD100 and PD168, respectively. Results showed that the PCE fetal weight decreased and the IUGR rate increased, while the serum corticosterone (CORT) level increased but the insulin-like growth factor 1 (IGF1) level decreased. Fetal adrenal exhibited an enhanced GC-activation system (11ß-hydroxysteroid dehydrogenases/corticoid receptors/CCAAT/enhancer binding proteins), an inhibited IGF1 pathway and steroid synthesis function. After birth, the serum CORT levels in the PCE offspring were increased in the early period followed by falling in the later stage, while the serum IGF1 level change was the opposite and was accompanied by an obvious catch-up growth. Furthermore, the adrenal GC-activation system was inhibited but the IGF1 signaling pathway was enhanced, resulting in a compensatory increase of adrenal steroidogenesis, and the expression of steroidal synthetase was consistent with that of the IGF1 signaling pathway. Based on these findings, we proposed "two-programming mechanisms" for PCE-induced adrenal abnormality: the "first programming" mechanism is a lower function of adrenal steroidogenesis, and prenatal and postnatal adrenal structural and functional abnormalities triggered by the intrauterine GC-IGF1 axis programming-mediated by the GC-activation system that acts as "the second programming" mechanism.

Prenatal ethanol exposure induces the osteoarthritis-like phenotype in female adult offspring rats with a post-weaning high-fat diet and its intrauterine programming mechanisms of cholesterol metabolism.

Osteoarthritis (OA) development is associated with hypercholesterolemia in adults. Our previous study demonstrated that offspring with intrauterine growth retardation (IUGR) due to prenatal ethanol exposure (PEE) had a high risk of developing hypercholesterolemia and metabolic syndrome when fed a post-weaning high-fat diet (HFD). In this study, we examined the changes in articular chondrocytes of IUGR offspring induced by PEE and explored its intrauterine programming mechanisms related to cholesterol metabolism. Using the PEE/IUGR model, serum and tibias from female fetuses and adult female offspring fed a post-weaning HFD were collected and examined for cholesterol metabolism and histology. The results showed that PEE adult offspring manifested significant catch-up growth. Their serum total cholesterol (TCH) and low-density lipoprotein-cholesterol increased and high-density lipoprotein-cholesterol decreased; the osteoarthritis-like phenotype and an increased TCH content were observed in articular cartilage; and the expression of insulin-like growth factor1 (IGF1) and cholesterol efflux pathway, including ATP-binding-cassette transporter A1 and liver X receptor, was reduced. The expression of IGF1 and cholesterol efflux pathway was also lower in the PEE fetuses. This study showed PEE could induce an enhanced susceptibility to HFD-induced OA in adult female IUGR offspring. The underlying mechanism related to cholesterol accumulation in cartilage mediated by intrauterine programming.

Low functional programming of renal AT2R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure.

Our previous study has indicated that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for glomerulosclerosis. However, whether PCE could induce glomerulosclerosis and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to glomerulosclerosis in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited glomerulosclerosis as well as interstitial fibrosis, accompanied by elevated levels of serum creatinine and urine protein. Renal angiotensin II receptor type 2 (AT2R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT2R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as glomerulosclerosis of adult offspring, and the low functional programming of renal AT2R might mediate the developmental origin of adult glomerulosclerosis.

Increased DNA methylation of scavenger receptor class B type I contributes to inhibitory effects of prenatal caffeine ingestion on cholesterol uptake and steroidogenesis in fetal adrenals.

Steroid hormones synthesized from cholesterol in the fetal adrenal are crucial for fetal development. We have observed the inhibited fetal adrenal corticosterone synthesis and increased intrauterine growth retardation (IUGR) rate in rats under prenatal caffeine ingestion. The aim of this study is to evaluate the effects of prenatal caffeine ingestion on cholesterol supply in fetal adrenal steroidogenesis in rats and explore the underlying epigenetic mechanisms. Pregnant Wistar rats were treated with 60 mg/kg · d caffeine from gestational day (GD) 7 to GD17. Histological changes of fetal adrenals and increased IUGR rates were observed in the caffeine group. There were significantly decreased steroid hormone contents and cholesterol supply in caffeine-treated fetal adrenals. Data from the gene expression array suggested that prenatal caffeine ingestion caused increased expression of genes related to DNA methylation and decreased expression of genes related to cholesterol uptake. The following conjoint analysis of DNA methylation array with these differentially expressed genes suggested that scavenger receptor class B type I (SR-BI) may play an important role in caffeine-induced cholesterol supply deficiency. Moreover, real-time RT-PCR and immunohistochemical detection certified the inhibitory effects of caffeine on both mRNA expression and protein expression of SR-BI in the fetal adrenal. And the increased DNA methylation frequency in the proximal promoter of SR-BI was confirmed by bisulfite-sequencing PCR. In conclusion, prenatal caffeine ingestion can induce DNA hypermethylation of the SR-BI promoter in the rat fetal adrenal. These effects may lead to decreased SR-BI expression and cholesterol uptake, which inhibits steroidogenesis in the fetal adrenal.

UDP-glucose dehydrogenase modulates proteoglycan synthesis in articular chondrocytes: its possible involvement and regulation in osteoarthritis.

INTRODUCTION: The objective of this study was to investigate the possible role of UDP-glucose dehydrogenase (UGDH) in osteoarthritis (OA) and uncover whether, furthermore how interleukin-1beta (IL-1ß) affects UGDH gene expression. METHODS: UGDH specific siRNAs were applied to determine the role of UGDH in proteoglycan (PG) synthesis in human articular chondrocytes. Protein levels of UGDH and Sp1 in human and rat OA cartilage were detected. Then, human primary chondrocytes were treated with IL-1ß to find out whether and how IL-1ß could regulate the gene expression of UGDH and its trans-regulators, that is Sp1, Sp3 and c-Krox. Finally, p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 and stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) inhibitor SP600125 were used to pick out the pathway that mediated the IL-1ß-modulated PGs synthesis and gene expression of UGDH, Sp1, Sp3 and c-Krox. RESULTS: UGDH specific siRNAs markedly inhibited UGDH mRNA and protein expression, and thus led to an obvious suppression of PGs synthesis in human articular chondrocytes. UGDH protein level in human and rat OA cartilage were much lower than the corresponding controls and negatively correlated to the degree of OA. Decrease in Sp1 protein level was also observed in human and rat OA cartilage respectively. Meanwhile, IL-1ß suppressed UGDH gene expression in human articular chondrocytes in the late phase, which also modulated gene expression of Sp1, Sp3 and c-Krox and increased both Sp3/Sp1 and c-Krox/Sp1 ratio. Moreover, the inhibition of SAP/JNK and p38 MAPK pathways both resulted in an obvious attenuation of the IL-1ß-induced suppression on the UGDH gene expression. CONCLUSIONS: UGDH is essential in the PGs synthesis of articular chondrocytes, while the suppressed expression of UGDH might probably be involved in advanced OA, partly due to the modulation of p38 MAPK and SAP/JNK pathways and its trans-regulators by IL-1ß.

Angelica Sinensis polysaccharides stimulated UDP-sugar synthase genes through promoting gene expression of IGF-1 and IGF1R in chondrocytes: promoting anti-osteoarthritic activity.

BACKGROUND: Osteoarthritis (OA) is a chronic joints disease characterized by progressive degeneration of articular cartilage due to the loss of cartilage matrix. Previously, we found, for the first time, that an acidic glycan from Angelica Sinensis Polysaccharides (APSs), namely the APS-3c, could protect rat cartilage from OA due to promoting glycosaminoglycan (GAG) synthesis in chondrocytes. In the present work, we tried to further the understanding of ASP-3c's anti-OA activity. METHODOLOGY/PRINCIPAL FINDINGS: Human primary chondrocytes were treated with APS-3c or/and recombinant human interleukin 1ß (IL-1ß). It turned out that APS-3c promoted synthesis of UDP-xylose and GAG, as well as the gene expression of UDP-sugar synthases (USSs), insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), and attenuated the degenerative phenotypes, suppressed biosynthesis of UDP-sugars and GAG, and inhibited the gene expression of USSs, IGF1 and IGF1R induced by IL-1ß. Then, we induced a rat OA model with papain, and found that APS-3c also stimulated GAG synthesis and gene expression of USSs, IGF1 and IGF1R in vivo. Additionally, recombinant human IGF1 and IGF1R inhibitor NP-AEW541 were applied to figure out the correlation between stimulated gene expression of USSs, IGF1 and IGF1R induced by APS-3c. It tuned out that the promoted GAG synthesis and USSs gene expression induced by APS-3c was mediated by the stimulated IGF1 and IGF1R gene expression, but not through directly activation of IGF1R signaling pathway. CONCLUSIONS/SIGNIFICANCES: We demonstrated for the first time that APS-3c presented anti-OA activity through stimulating IGF-1 and IGF1R gene expression, but not directly activating the IGF1R signaling pathway, which consequently promoted UDP-sugars and GAG synthesis due to up-regulating gene expression of USSs. Our findings presented a better understanding of APS-3c's anti-OA activity and suggested that APS-3c could potentially be a novel therapeutic agent for OA.