Application of Femtosecond Laser + Piggyback Multifocal Intraocular Lens Implantation in Patients with Super-High Myopia Complicated with Cataract.

OBJECTIVE: To observe the clinical effect of piggyback multifocal intraocular lens (IOL) implantation in treating patients with high myopia complicated with cataract. METHODS: This was a prospective controlled study. We compared 32 eyes of 32 patients who underwent femtosecond laser-assisted cataract surgery with piggyback IOL implantation (two IOLs were implanted into the capsule) with 32 eyes of 32 patients who also underwent the same surgery (one IOL implanted into the capsule) due to high myopia complicated with cataract at the Wuhan Aier Eye Expert Hospital between January 2019 and October 2020. All patients were followed up for three months after surgery. Uncorrected distance visual acuity (UCDVA), uncorrected intermediate visual acuity (UCIVA), uncorrected near visual acuity (UCNVA), best-corrected distance visual acuity, distance-corrected intermediate visual acuity (DCIVA), distance-corrected near visual acuity (DCNVA), postoperative spectacle independence, postoperative visual interference, equivalent spherical lens, defocus curve, and IOL tilt and eccentricity were evaluated. RESULTS: Three months after surgery, the patients' UCIVA, UCNVA, DCIVA, and DCNVA were 0.49 ± 0.07, 0.38 ± 0.15, 0.47 ± 0.09, and 0.36 ± 0.12, respectively, in the research group and 0.56 ± 0.18, 0.72 ± 0.22, 0.55 ± 0.13, and 0.69 ± 0.15, respectively, in the control group; the differences between the two groups were statistically significant (P < .05). The spectacle independence rate was higher in the research group (93%) than in the control group (13%). The overall satisfaction regarding postoperative visual quality was also higher in the research group than in the control group. The absolute mean value of the spherical equivalents was 0.48 ± 0.28 D in the research group and 0.62 ± 0.33 D in the control group; the difference between the two groups was statistically significant (P < .05). CONCLUSION: Piggyback multifocal IOL implantation can expand the multifocal IOL application range, and satisfy the desire of patients with high myopia complicated with cataract to see both near and far.

Association of high-normal albuminuria and vascular aging: Hanzhong adolescent hypertension study.

Normoalbuminuria has recently been associated with increased cardiovascular risk, and vascular aging is proposed as the early manifestation of cardiovascular disease. Here, the authors aimed to examine the association of high-normal albuminuria and vascular aging in a Chinese cohort. From our previously established cohort, 1942 participants with estimated glomerular filtration rate ≥60 mL/min/1.73 m2 or urinary albumin-creatinine ratio (UACR) <30 mg/g were enrolled. Brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s and/or carotid intima-media thickness (CIMT) ≥0.9 mm were used as indicators of vascular aging. Multivariate regression and receiving operating characteristic curve analysis were performed to examine the relationship between continuous and categorical UACR with vascular aging. We found an average UACR value of 8.08 (5.45-12.52) mg/g in this study. BaPWV and CIMT demonstrated positive correlations with lg-UACR (p < .05). High-normal albuminuria (10-29 mg/g) was significantly associated with the presence of vascular aging after adjusting for multiple cardiovascular confounders (OR = 1.540, 95% CI = 1.203-1.972, p = .001). In addition, a lg-UACR cutoff point of 0.918 lg(mg/g) (equal to UACR of 8.285 mg/g) was significantly associated with the presence of vascular aging and its components for all participants and those without hypertension or diabetes and without medication (p < .05). Briefly, high-normal albuminuria was significantly associated with vascular aging in this sample of Chinese adults. These findings implied the warning of elevated UACR even within normal range in clinical practice and the importance of UACR screening in normoalbuminuria for early detection and prevention of cardiovascular disease in otherwise healthy participants.

Associations of lipid accumulation product, visceral adiposity index, and triglyceride-glucose index with subclinical organ damage in healthy Chinese adults.

Background and aims: Obesity is an independent risk factor for cardiovascular disease development. Here, we aimed to examine and compare the predictive values of three novel obesity indices, lipid accumulation product (LAP), visceral adiposity index (VAI), and triglyceride-glucose (TyG) index, for cardiovascular subclinical organ damage. Methods: A total of 1,773 healthy individuals from the Hanzhong Adolescent Hypertension Study cohort were enrolled. Anthropometric, biochemical, urinary albumin-to-creatinine ratio (uACR), brachial-ankle pulse wave velocity (baPWV), and Cornell voltage-duration product data were collected. Furthermore, the potential risk factors for subclinical organ damage were investigated, with particular emphasis on examining the predictive value of the LAP, VAI, and TyG index for detecting subclinical organ damage. Results: LAP, VAI, and TyG index exhibited a significant positive association with baPWV and uACR. However, only LAP and VAI were found to have a positive correlation with Cornell product. While the three indices did not show an association with electrocardiographic left ventricular hypertrophy, higher values of LAP and TyG index were significantly associated with an increased risk of arterial stiffness and albuminuria. Furthermore, after dividing the population into quartiles, the fourth quartiles of LAP and TyG index showed a significant association with arterial stiffness and albuminuria when compared with the first quartiles, in both unadjusted and fully adjusted models. Additionally, the concordance index (C-index) values for LAP, VAI, and TyG index were reasonably high for arterial stiffness (0.856, 0.856, and 0.857, respectively) and albuminuria (0.739, 0.737, and 0.746, respectively). Lastly, the analyses of continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) demonstrated that the TyG index exhibited significantly higher predictive values for arterial stiffness and albuminuria compared with LAP and VAI. Conclusion: LAP, VAI, and, especially, TyG index demonstrated utility in screening cardiovascular subclinical organ damage among Chinese adults in this community-based sample. These indices have the potential to function as markers for early detection of cardiovascular disease in otherwise healthy individuals.

Lead exposure disturbs ATP7B-mediated copper export from brain barrier cells by inhibiting XIAP-regulated COMMD1 protein degradation.

The brain barrier is an important structure for metal ion homeostasis. According to studies, lead (Pb) exposure disrupts the transportation of copper (Cu) through the brain barrier, which may cause impairment of the nervous system; however, the specific mechanism is unknown. The previous studies suggested the X-linked inhibitor of apoptosis (XIAP) is a sensor for cellular Cu level which mediate the degradation of the MURR1 domain-containing 1 (COMMD1) protein. XIAP/COMMD1 axis was thought to be an important regulator in Cu metabolism maintenance. In this study, the role of XIAP-regulated COMMD1 protein degradation in Pb-induced Cu disorders in brain barrier cells was investigated. Pb exposure significantly increased Cu levels in both cell types, according to atomic absorption technology testing. Western blotting and reverse transcription PCR (RT-PCR) showed that COMMD1 protein levels were significantly increased, whereas XIAP, ATP7A, and ATP7B protein levels were significantly decreased. However, there were no significant effects at the messenger RNA (mRNA) level (XIAP, ATP7A, and ATP7B). Pb-induced Cu accumulation and ATP7B expression were reduced when COMMD1 was knocked down by transient small interfering RNA (siRNA) transfection. In addition, transient plasmid transfection of XIAP before Pb exposure reduced Pb-induced Cu accumulation, increased COMMD1 protein levels, and decreased ATP7B levels. In conclusion, Pb exposure can reduce XIAP protein expression, increase COMMD1 protein levels, and specifically decrease ATP7B protein levels, resulting in Cu accumulation in brain barrier cells.

Early-Life Cardiovascular Risk Factor Trajectories and Vascular Aging in Midlife: A 30-Year Prospective Cohort Study.

BACKGROUND: Vascular aging, as assessed by structural and functional arterial properties, is an independent predictor of cardiovascular outcomes. We aimed to explore the associations of individual cardiovascular risk factors from childhood to midlife and their accumulation over a 30-year span with vascular aging in midlife. METHODS: Using data from the ongoing cohort of Hanzhong Adolescent Hypertension study, 2180 participants aged 6 to 18 years at baseline were followed for over 30 years. Distinct trajectories of systolic blood pressure (SBP), body mass index (BMI), and heart rate from childhood to midlife were identified by group-based trajectory modeling. Vascular aging was assessed by carotid intima media thickness or brachial-ankle pulse wave velocity. RESULTS: We identified 4 distinct SBP trajectories, 3 distinct BMI trajectories, and 2 distinct heart rate trajectories from childhood to midlife. Persistently increasing SBP, high-increasing BMI, and high-stable heart rate were all shown to have a positive association with brachial-ankle pulse wave velocity in midlife. For carotid intima-media thickness, similar associations were observed for persistently increasing SBP and high-increasing body mass index. After further adjustment for SBP, body mass index and heart rate at the time of vascular assessment in 2017, associations were also observed for cardiovascular risk factor trajectories accumulation with brachial-ankle pulse wave velocity (ß, 0.656 [95% CI, 0.265-1.047]) and with carotid intima media thickness (ß, 0.045 [95% CI, 0.011-0.079]) in adulthood. CONCLUSIONS: Longitudinal exposure to individual cardiovascular risk factors from childhood to midlife and cardiovascular risk factor accumulation were associated with an increased risk of vascular aging in midlife. Our study lends support for early targeting of risk factors in order to prevent cardiovascular disease later in life.

MiR-130/SNAP-25 axis regulate presynaptic alteration in anterior cingulate cortex involved in lead induced attention deficits.

Brain volume decrease in the anterior cingulate cortex (ACC) after lead (Pb) exposure has been linked to persistent impairment of attention behavior. However, the precise structural change and molecular mechanism for the Pb-induced ACC alteration and its contribution to inattention have yet to be fully characterized. The present study determined the role of miRNA regulated synaptic structural and functional impairment in the ACC and its relationship to attention deficit disorder in Pb exposed mice. Results showed that Pb exposure induced presynaptic impairment and structural alterations in the ACC. Furthermore, we screened for critical miRNA targets responsible for the synaptic alteration. We found that miR-130, which regulates presynaptic vesicle releasing protein SNAP-25, was responsible for the presynaptic impairment in the ACC and attention deficits in mice. Blocking miR-130 function reversed the Pb-induced decrease in the expression of its presynaptic target SNAP-25, leading to the redistribution of presynaptic vesicles, as well as improved presynaptic function and attention in Pb exposed mice. We report, for the first time, that miR-130 regulating SNAP-25 mediates Pb-induced presynaptic structural and functional impairment in the ACC along with attention deficit disorder in mice.

Anti-inflammatory effect of miR-125a-5p on experimental optic neuritis by promoting the differentiation of Treg cells.

Methylprednisolone pulse treatment is currently used for optic neuritis. It can speed visual recovery, but does not improve the ultimate visual outcomes. Recent studies have reported that miR-125a-5p has immunomodulatory effects on autoimmune diseases. However, it remains unclear whether miR-125a-5p has effects on optic neuritis. In this study, we used adeno-associated virus to overexpress or silence miR-125a-5p in mice. We found that silencing miR-125a-5p increased the latency of visual evoked potential and aggravated inflammation of the optic nerve. Overexpression of miR-125a-5p suppressed inflammation of the optic nerve, protected retinal ganglion cells, and increased the percentage of Treg cells. Our findings show that miR-125a-5p exhibits anti-inflammatory effects through promoting the differentiation of Treg cells.

Comparison of the actual diameter of capsulotomy and predicted diameter of capsulotomy after femtosecond laser-assisted capsulotomy.

PURPOSE: To compare the consistency between the actual diameter of capsulotomy (ADC) and the predicted diameter of capsulotomy (PDC) in femtosecond laser-assisted cataract surgery (FLACS) and analyze the factors that influence the deviation of the diameter of capsulotomy (DDC) between the actual and predicted. SETTING: Aier Eye Hospital of Wuhan University, China. DESIGN: Retrospective observational case series. METHODS: Patients who underwent FLACS from March 2020 to March 2021 were reviewed. The ADC in FLACS was measured and compared with the PDC. The effects of age, sex, and biometrics on DDC were analyzed. RESULTS: 412 eyes of 336 patients were included. The mean age was 53.0 ± 0.91 years (range 3 to 91 years). When the PDC was set to 4.50 mm, the results showed that the ADC was 5.21 ± 0.21 mm with a significant difference between them ( P &lt; .05). However, when the PDC was set to 5.2 mm, the ADC was 5.10 ± 0.38 mm without a significant difference between them ( P &gt; .05). No correlation ( P &gt; .05) was found between the DDC and the axial length, the DDC and the anterior chamber depth (ACD), and the DDC and the mean keratometry (Km), but a negative correlation was found between the DDC and the lens thickness (LT) ( r = -0.21; P &lt; .05) and the DDC with age ( r = -0.70; P &lt; .05). Using curvilinear regression analysis, a development of an age-depending correction formula was predicted: ADC = PDC + 1.23 - 0.30 ln (x) (x = age ≥3) ( R2 = 0.65; F = 752.39; P = .00). CONCLUSIONS: The consistency of the ADC and PDC was influenced by age and LT. For patients aged 40 years or younger, the younger the patient, the wider the DDC; for patients older than 40 years, the DDC was small. The thicker the LT, the smaller the DDC.

Early life body mass index trajectories and albuminuria in midlife: A 30-year prospective cohort study.

Background: Albuminuria is a marker of vascular dysfunction and is associated with chronic renal and cardiovascular diseases. Data on the association between the longitudinal patterns of weight change early in life and albuminuria later in life are limited. We aimed to identify the body mass index (BMI) trajectory across a 30-year span and evaluate its association with middle-age albuminuria. Methods: Of the 4623 participants aged 6-18-year-old recruited by Hanzhong Adolescent Hypertension Study cohort in northern China from March 10, 1987 to June 3, 2017, a total of 1,825 participants followed up with 6 visits over 30 years were enrolled. Group-based trajectory modeling was used to identify distinct BMI trajectories in longitudinal analyses. Albuminuria was defined as a urinary albumin-to-creatinine ratio (uACR) ≥ 30 mg/g. Findings: Three distinct BMI trajectories were identified: low-increasing (n = 671, 36.8%), moderate-increasing (n = 940, 51.5%), and high-increasing (n = 214, 11.7%); male participants exhibited a steeper increase in BMI than females. The uACR was increased linearly from the low- to high-increasing group. A total of 201 individuals developed albuminuria, with an incidence of 11.0%. Compared with the low-increasing group, the odds ratio (OR) of albuminuria in middle age was 2.13(95% confidence interval [CI]: 1.26 to 3.61) for the high-increasing group after full adjustment for age, sex, smoking, alcohol consumption, marital status, systolic blood pressure, diabetes, and hyperlipidemia. The unadjusted ORs of the high-increasing BMI group were 5.08 (2.76-9.37) for males and 3.45 (1.78-6.69) for females, and the association remained significant in males in the fully adjusted models. Interpretation: Higher BMI trajectories are associated with higher uACR and an increased risk of albuminuria in middle age, especially in males. Identifying long-term BMI trajectories from an early age may assist in predicting the risk of renal diseases and cardiovascular disease later in life. Funding: This work was supported by the National Natural Science Foundation of China (81600327, 82070437, 81870319, 82070549, and 82170437), Natural Science Basic Research Program of Shaanxi Province (2021JM-257 and 2021JM-588), Institutional Foundation of the First Affiliated Hospital of Xi'an Jiaotong University (2019QN-06 and 2021ZXY-14), the Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University of China (XJTU1AF-CRF-2019-004, XJTU1AF2021CRF-021, and XJTU1AFCRF-2017-021), Research Incubation Fund of Xi'an People's Hospital (FZ-61), Grants from the Major Chronic Non-communicable Disease Prevention and Control Research Key Project of the Ministry of Science and Technology of China (2017YFC1307604 and 2016YFC1300104).

Medical cost and healthcare utilization of amyotrophic lateral sclerosis in China: A cohort study based on hospital data from 2015 to 2018.

Amyotrophic lateral sclerosis (ALS), a specific neurodegenerative disease, imposed increased economic and utilizations burden on the healthcare system, especially with the progress of the diseases severity. However, the economic burden on Chinese ALS patients remained unclear. This study therefore was aimed to investigate medical cost and healthcare utilization for Chinese ALS patients.Longitudinal health data of over 20 million individuals, including military personnel and civilians, was collected from all Chinese military hospitals. We identified 480 patients with a first major diagnosis for ALS from 2015 to 2018, while matched 400 controlled patients on age, gender, ethnic group, geographic region, length of stay, year of diagnosis and comorbidity. Their medical cost and healthcare utilizations were then measured 1 year before, and 1 year after ALS diagnosis.The median annual medical cost of ALS patients was about 2-fold higher, 17,087 CNY during the index year than 1 year before, 7859 CNY. The highest increase in utilizations may account for medical costs on ALS patients, which was represented by hospitalizations (Odd Ratio (OR) = 4.26, 95% confidence interval (CI) 3.52, 5.15), electromyography (OR = 4.14, 95% CI 2.37, 7.22), nerve conduction velocity (OR = 3.26, 95% CI 2.23, 4.77).This study is the first one reporting direct economic burden on Chinese ALS patients. Efforts should be made to develop cost-effective diagnostic tools in order that sources of medical cost were more effectively allocated, and this disease was detected earlier.

Structural elucidation of high-molecular-weight alkaline degradation products of hexoses.

High-molecular-weight alkaline degradation products of hexoses (HMWHADPs) are colored substances in sugar solutions formed during sugar manufacturing process. These products may be occluded within sugar crystals and impart yellow or brown color to sucrose, thereby negatively affecting the quality of white sugar. Thus, the structural properties of HMWHADPs pose a significant scientific problem in the sugar industry. In the present study, the structural properties of HMWHADPs were investigated using nuclear magnetic resonance, zeta potential analyzer, energy-dispersive X-ray spectrometry, ultraviolet-visible spectra, and Fourier transform infrared spectroscopy. Results showed that HMWHADPs mainly contain carboxyl, aldehyde, alcoholic hydroxyl, conjugated double bonds, and saturated alkanes. Possible mechanisms of HMWHADP formation were proposed on the basis of structural property investigation. This study can be used as reference for future research and practice in developing effective methods for the removal of HMWHADPs from sugar solutions and prevention of their further formation in subsequent steps.

An efficient autometallography approach to localize lead at ultra-structural levels of cultured cells.

Understanding the precise intracellular localization of lead (Pb) is a key in deciphering processes in Pb-induced toxicology. However, it is a great challenge to trace Pb in vitro, especially in cultured cells. We aimed to find an innovative and efficient approach to investigate distribution of Pb in cells and to validate it through determining the subcellular Pb content. We identified its ultra-structural distribution with autometallography under electron microscopy in a choroidal epithelial Z310 cell line. Electron microscopy in combination with energy-dispersive X-ray spectroscope (EDS) was employed to provide further evidence of Pb location. In addition, Pb content was determined in the cytosol, membrane/organelle, nucleus and cytoskeleton fractions with atomic absorption spectroscopy. Pb was found predominantly inside the nuclear membranes and some was distributed in the cytoplasm under low-concentration exposure. Nuclear existence of Pb was verified by EDS under electron microscopy. Once standardized for protein content, Pb percentage in the nucleus fraction reached the highest level (76%). Our results indicate that Pb is accumulated mainly in the nucleus of choroid plexus. This method is sensitive and precise in providing optimal means to study the ultra-structural localization of Pb for in vitro models. In addition, it offers the possibility of localization of other metals in cultured cells. Some procedures may also be adopted to detect target proteins via immunoreactions.

Low-level Gestational Lead Exposure Alters Dendritic Spine Plasticity in the Hippocampus and Reduces Learning and Memory in Rats.

Lead (Pb) is known to impair children's cognitive function. It has been previously shown that developmental Pb exposure alters dendritic spine formation in hippocampal pyramidal neurons. However, the underlying mechanism has not yet been defined. In this study, a low-level gestational Pb exposure (GLE) rat model was employed to investigate the impact of Pb on the spine density of the hippocampal pyramidal neurons and its regulatory mechanism. Pb exposure resulted in impaired performance of the rats in the Morris water maze tasks, and in decreased EPSC amplitudes in hippocampal CA3-CA1 regions. With a 3D reconstruction by the Imaris software, the results from Golgi staining showed that the spine density in the CA1 region was reduced in the Pb-exposed rats in a dose-dependent manner. Decreased spine density was also observed in cultured hippocampal neurons following the Pb treatment. Furthermore, the expression level of NLGN1, a postsynaptic protein that mediates synaptogenesis, was significantly decreased following the Pb exposure both in vivo and in vitro. Up-regulation of NLGN1 in cultured primary neurons partially attenuated the impact of Pb on the spine density. Taken together, our resultssuggest that Pb exposure alters spine plasticity in the developing hippocampus by down-regulating NLGN1 protein levels.

Adult lead exposure increases blood-retinal permeability: A risk factor for retinal vascular disease.

Low-to-moderate level developmental and adult lead exposure produces retinal dysfunction and/or degeneration in humans and experimental animals. Although high level in vivo or in vitro lead disrupts blood-brain-barrier tight junctions and increases its permeability, the blood-retinal-barrier (BRB) has not been examined. There were four overall goals. First, generate environmentally relevant dose-response models of short-term lead exposure in adult rats. Second, assess retinal histology and functional integrity of the BRB. Third, investigate the transmembrane proteins occludin and claudin-5 as targets mediating the increased BRB permeability. Fourth, examine the contribution of the PI3K-Akt signaling pathway as a mechanism underlying increased BRB permeability. Young adult rats were given water, 0.01% or 0.02% lead drinking solutions for six weeks. In control, 0.01% and 0.02% groups the six week mean blood [Pb] were 1, 12.5 and 19µg/dl, respectively. We employed histology, stereology, quantitative image analysis, immunoblots and densitometry, and pharmacology techniques. Major findings were that adult lead exposure produced dose-dependent 1) decreases in outer and inner nuclear layer thickness, 2) increases in BRB permeability, 3) decreases in occludin and claudin-5 expression, 4) increases in pAkt (Ser473), but not pAkt (Thr308), expression, and 5) wortmannin partially or completely blocked the increased BRB permeability and changes in protein expression. These results indicate that lead-induced increases in PI3K-Akt signaling partially underlie the increased BRB permeability and advance our knowledge about lead-induced retinotoxicity. Furthermore, they suggest that environmental and occupational lead exposures are risk factors for increased BRB permeability in diseases such as age-related macular degeneration, diabetes and stroke.

Cellular uptake of lead in the blood-cerebrospinal fluid barrier: Novel roles of Connexin 43 hemichannel and its down-regulations via Erk phosphorylation.

As the structural basis of blood-cerebrospinal fluid barrier (BCB), epithelial cells in the choroid plexus (CP) are targets for lead (Pb). Pb is known to accumulate in the CP; however, the mechanism of Pb uptake in the choroidal epithelial cells remains unknown. Recently, hemichannels of Connexin 43 (Cx43), the most ubiquitously expressed gap junction proteins in the CP, were found to be important pathways for many substances. This study was designed to investigate the roles of Cx43 in Pb uptake in the epithelial cells. Autometallography was used to outline Pb's subcellular location, and the characteristics of Pb transport into CP cells, including concentration- and time-dependence were analyzed by atomic absorption spectroscopy. Knockdown/overexpression of Cx43 with transient siRNA/plasmids transfections before Pb exposure diminished/increased the Pb accumulation. In the Z310 cell-based doxycycline-inducible Cx43 expression cell line (iZCx43), doxycycline induced a significant increase (3-fold) in Pb uptake, corresponding to the increased Cx43 levels. Activation of Cx43 hemichannels by reduced serum conditions caused an increase of Pb concentrations. Cx43-induced Pb uptake was attenuated after blockage of Cx43 hemichannels with its inhibitor, carbenoxolone. Additionally, down-regulation of Cx43 protein levels by Pb exposure paralleled cellular Pb concentrations in the time study. Concomitantly, expressions of phosphor-Src and phosphor-Erk were both significantly increased by Pb. However, inactivation of Erk, not Src pathway, reversed Pb-induced downregulation of Cx43. Taken together, these data establish that Pb can accumulate in the BCB and validate the role of Cx43 hemichannel in Pb uptake and its regulations through Erk phosphorylation.

Dietary saturated fatty acid and polyunsaturated fatty acid oppositely affect hepatic NOD-like receptor protein 3 inflammasome through regulating nuclear factor-kappa B activation.

AIM: To investigate the effect of different dietary fatty acids on hepatic inflammasome activation. METHODS: Wild-type C57BL/6 mice were fed either a high-fat diet or polyunsaturated fatty acid (PUFA)-enriched diet. Primary hepatocytes were treated with either saturated fatty acids (SFAs) or PUFAs as well as combined with lipopolysaccharide (LPS). The expression of NOD-like receptor protein 3 (NLRP3) inflammasome, peroxisome proliferator-activated receptor-γ and nuclear factor-kappa B (NF-κB) was determined by real-time PCR and Western blot. The activity of Caspase-1 and interleukine-1ß production were measured. RESULTS: High-fat diet-induced hepatic steatosis was sufficient to induce and activate hepatic NLRP3 inflammasome. SFA palmitic acid (PA) directly activated NLRP3 inflammasome and increased sensitization to LPS-induced inflammasome activation in hepatocytes. In contrast, PUFA docosahexaenoic acid (DHA) had the potential to inhibit NLRP3 inflammasome expression in hepatocytes and partly abolished LPS-induced NLRP3 inflammasome activation. Furthermore, a high-fat diet increased but PUFA-enriched diet decreased sensitization to LPS-induced hepatic NLRP3 inflammasome activation in vivo. Moreover, PA increased but DHA decreased phosphorylated NF-κB p65 protein expression in hepatocytes. CONCLUSION: Hepatic NLRP3 inflammasome activation played an important role in the development of non-alcoholic fatty liver disease. Dietary SFAs and PUFAs oppositely regulated the activity of NLRP3 inflammasome through direct activation or inhibition of NF-κB.

Lead Exposure Impairs Hippocampus Related Learning and Memory by Altering Synaptic Plasticity and Morphology During Juvenile Period.

Lead (Pb) is an environmental neurotoxic metal. Pb exposure may cause neurobehavioral changes, such as learning and memory impairment, and adolescence violence among children. Previous animal models have largely focused on the effects of Pb exposure during early development (from gestation to lactation period) on neurobehavior. In this study, we exposed Sprague-Dawley rats during the juvenile stage (from juvenile period to adult period). We investigated the synaptic function and structural changes and the relationship of these changes to neurobehavioral deficits in adult rats. Our results showed that juvenile Pb exposure caused fear-conditioned memory impairment and anxiety-like behavior, but locomotion and pain behavior were indistinguishable from the controls. Electrophysiological studies showed that long-term potentiation induction was affected in Pb-exposed rats, and this was probably due to excitatory synaptic transmission impairment in Pb-exposed rats. We found that NMDA and AMPA receptor-mediated current was inhibited, whereas the GABA synaptic transmission was normal in Pb-exposed rats. NR2A and phosphorylated GluR1 expression decreased. Moreover, morphological studies showed that density of dendritic spines declined by about 20 % in the Pb-treated group. The spine showed an immature form in Pb-exposed rats, as indicated by spine size measurements. However, the length and arborization of dendrites were unchanged. Our results suggested that juvenile Pb exposure in rats is associated with alterations in the glutamate receptor, which caused synaptic functional and morphological changes in hippocampal CA1 pyramidal neurons, thereby leading to behavioral changes.

Correlation between serum IGF-1 and blood lead level in short stature children and adolescent with growth hormone deficiency.

UNLABELLED: This study aimed to investigate correlation between serum insulin-like growth factor-1 (IGF-1) and blood lead level in short stature children with growth hormone deficiency (GHD), and IGF-1 signal molecules were investigated in lead exposed rats. Our findings may provide evidence for clarifying pathogenesis of lead induced short stature in children. METHODS: 880 short stature children were recruited from clinics and divided into GHD group and idiopathic short stature (ISS) group according to the GH peak in growth hormone stimulation test. The height, body weight, serum IGF-1 level and blood lead level were determined. A rat model of lead poisoning was used to establish and western blot assay was employed to detect the phosphorylation of signaling molecules (MAPK and PI3K/Akt) related to IGF-1 signaling pathway. RESULTS: In GHD group, the height, body weight and serum IGF-1 level were significantly lower, but the blood lead level was significantly higher than those in ISS group (P<0.05). Western blot assay confirmed that the protein expression of phosphorylated ERK1/2, JNK, p38, Akt473 and Akt308 increased significantly (P<0.01) in lead exposure rats. CONCLUSION: Our study suggesting that reduction in IGF-1 in children with GHD is associated with blood lead level. Lead exposure may induce expression of phosphorylated MAPK and Akt signaling molecules. The activation of these molecules may influence binding of IGF-1 and tyrosine kinase receptor IGFIR to regulate cell growth via the MAPK and Akt signaling pathways, which then interfere with growth-promoting effect of IGF-1 in short children.

Reduction of brain barrier tight junctional proteins by lead exposure: role of activation of nonreceptor tyrosine kinase Src via chaperon GRP78.

Lead (Pb) has long been recognized as a neurodevelopmental toxin. Developing blood-brain barrier (BBB) is known to be a target of Pb neurotoxicity; however, the underlying mechanisms are still unclear. Recent evidence suggests that intracellular nonreceptor protein tyrosine kinase Src regulates tight junctional proteins (TJPs). This study was designed to investigate whether Pb acted on the Src-mediated cascade event leading to an altered TJP expression at BBB. Rats aged 20-22 days were exposed to Pb in drinking water (0, 100, 200, and 300 ppm Pb) for eight weeks. Electron microscopic and Western blot analyses revealed a severe leakage of BBB and significantly decreased expressions of TJP occludin and ZO-1. When cultured brain endothelial RBE4 cells were exposed to 10µM Pb for 24 h, expressions of phosphor-Src and an upstream regulator GRP78 were significantly increased by 6.42-fold and 8.29-fold (p < 0.01), respectively. Inactivation of Src pathway by a Src-specific inhibitor reversed Pb-induced downregulation of occludin, but not ZO-1; small interfering RNA knockdown of GRP78 attenuated Pb-induced Src phosphorylation and occludin reduction. Furthermore, Pb exposure caused redistribution of GRP78 from endoplasmic reticulum to cytosol and toward cell member. However, the data from immunoneutralization studies did not show the involvement of cell-surface GRP78 in regulating Src phosphorylation upon Pb exposure, suggesting that the cytosolic GRP78, rather than cell-surface GRP78, was responsible to Pb-induced Src activation and ensuing occludin reduction. Taken together, this study provides the evidence of a novel linkage of GRP78, Src activation to downregulation of occludin, and BBB disruption during Pb exposure.