Associations of Heavy Metals with Cognitive Function: An Epigenome-Wide View of DNA Methylation and Mediation Analysis.

OBJECTIVE: Exposure to heavy metals has been reported to be associated with impaired cognitive function, but the underlying mechanisms remain unclear. This pilot study aimed to identify key heavy metal elements associated with cognitive function and further explore the potential mediating role of metal-related DNA methylation. METHODS: Blood levels of arsenic, cadmium, lead, copper, manganese, and zinc and genome-wide DNA methylations were separately detected in peripheral blood in 155 older adults. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE). Least absolute shrinkage and selection operator penalized regression and Bayesian kernel machine regression were used to identify metals associated with cognitive function. An epigenome-wide association study examined the DNA methylation profile of the identified metal, and mediation analysis investigated its mediating role. RESULTS: The MMSE scores showed a significant decrease of 1.61 (95% confidence interval [CI]: -2.64, -0.59) with each 1 standard deviation increase in ln-transformed arsenic level; this association was significant in multiple-metal models and dominated the overall negative effect of 6 heavy metal mixture on cognitive function. Seventy-three differentially methylated positions were associated with blood arsenic (p < 1.0 × 10-5). The methylation levels at cg05226051 (annotated to TDRD3) and cg18886932 (annotated to GAL3ST3) mediated 24.8% and 25.5% of the association between blood arsenic and cognitive function, respectively (all p < 0.05). INTERPRETATION: Blood arsenic levels displayed a negative association with the cognitive function of older adults. This finding shows that arsenic-related DNA methylation alterations are critical partial mediators that may serve as potential biomarkers for further mechanism-related studies. ANN NEUROL 2024;96:87-98.

Effects of cadmium stress on the growth and physiological characteristics of sweet potato.

This study evaluated the responses of sweet potatoes to Cadmium (Cd) stress through pot experiments to theoretically substantiate their comprehensive applications in Cd-polluted agricultural land. The experiments included a CK treatment and three Cd stress treatments with 3, 30, and 150 mg/kg concentrations, respectively. We analyzed specified indicators of sweet potato at different growth periods, such as the individual plant growth, photosynthesis, antioxidant capacity, and carbohydrate Cd accumulation distribution. On this basis, the characteristics of the plant carbon metabolism in response to Cd stress throughout the growth cycle were explored. The results showed that T2 and T3 treatments inhibited the vine growth, leaf area expansion, stem diameter elongation, and tuberous root growth of sweet potato; notably, T3 treatment significantly increased the number of sweet potato branches. Under Cd stress, the synthesis of chlorophyll in sweet potato was significantly suppressed, and the Rubisco activity experienced significant reductions. With the increasing Cd concentration, the function of PS II was also affected. The soluble sugar content underwent no significant change in low Cd concentration treatments. In contrast, it decreased significantly under high Cd concentrations. Additionally, the tuberous root starch content decreased significantly with the increase in Cd concentration. Throughout the plant growth, the activity levels of catalase, peroxidase, and superoxide dismutase increased significantly in T2 and T3 treatments. By comparison, the superoxide dismutase activity in T1 treatment was significantly lower than that of CK. With the increasing application of Cd, its accumulation accordingly increased in various sweet potato organs. The the highest bioconcentration factor was detected in absorbing roots, while the tuberous roots had a lower bioconcentration factor and Cd accumulation. Moreover, the transfer factor from stem to petiole was the highest of the potato organs. These results demonstrated that sweet potatoes had a high Cd tolerance and a restoration potential for Cd-contaminated farmland.

Preparation of Fluorescent "on-off-on" Carbon Quantum Dots and Their Application to the Detection of Fe3+ and Ascorbic Acid and Information Encryption.

Carbon quantum dots are a new type of fluorescent carbon-based nanomaterials, and their excellent properties have provoked a strong research interest. Herein, blue-fluorescent carbon quantum dots (k-CQDs) were successfully synthesized by a simple one-step hydrothermal method using chitosan and ethylenediaminetetraacetic acid as precursors. It was found that Fe3+ could quench the fluorescence of k-CQDs by a dynamic quenching mechanism that increased the positive charge in solution. Due to ascorbic acid (AA) can reduce Fe3+ to Fe2+, the positive charge in solution was reduced and the fluorescence of k-CQDs was restored. Based on the mechanism of the fluorescence "on-off-on", k-CQDs were used for the detection of Fe3+ and AA with strong antijamming capability. The LOD for Fe3+ concentrations in the ranges of 0 to 30 µM and 30 to 100 µM were 0.3 µM and 0.76 µM, respectively. The LOD for AA concentrations in the ranges of 0 to 82.5 µM and 82.5 to 172.5 µM were 3.93 µM and 1.63 µM, respectively. Spiking recoveries of Fe3+ in tap water, AA in orange juice and tomato juice were 87.93 ∼ 101.13%, 86.77 ∼ 105.15% and 86.43 ∼ 103.80%, respectively. Meanwhile, k-CQDs also showed good potential for anti-counterfeiting encryption.

HMGB1 accumulation in cytoplasm mediates noise-induced cochlear damage.

Damage-associated molecular pattern molecules (DAMPs) play a critical role in mediating cochlear cell death, which leads to noise-induced hearing loss (NIHL). High-mobility group box 1 (HMGB1), a prototypical DAMP released from cells, has been extensively studied in the context of various diseases. However, whether extracellular HMGB1 contributes to cochlear pathogenesis in NIHL and the potential signals initiating HMGB1 release from cochlear cells are not well understood. Here, through the transfection of the adeno-associated virus with HMGB1-HA-tag, we first investigated early cytoplasmic accumulation of HMGB1 in cochlear hair cells after noise exposure. We found that the cochlear administration of HMGB1-neutralizing antibody immediately after noise exposure significantly alleviated hearing loss and outer hair cells (OHCs) death induced by noise exposure. In addition, activation of signal transducer and activators of transcription 1 (STAT1) and cellular hyperacetylation were verified as potential canonical initiators of HMGB1 cytoplasmic accumulation. These findings reveal the adverse effects of extracellular HMGB1 on the cochlea and the potential signaling events mediating HMGB1 release in hair cells, indicating multiple potential pharmacotherapeutic targets for NIHL.

Hyperbranched Tetraphenylethylene Derivatives with Low Non-specific Aggregation-Induced Emission for Fluorescence Recognition of Proteins with Hydrophobic Pockets.

Proteins play an important role in the physiological process of many organisms, and their abnormal level often indicates the occurrence of some diseases. Therefore, protein analysis has important reference value and clinical significance for early diagnosis and therapy of disease. Using human serum albumin (HSA) as a model protein, a series of super-branched tetraphenylethylene (TPE) derivatives with different branching structures and terminal groups are reported herein for highly sensitive and specific recognition of proteins with hydrophobic cages. Benefiting from the hyperbranched structures, these probes showed much higher critical micelle concentrations (CMCs) than most linear TPE-based amphiphilic molecules since the hyperbranched structure not only improved their solubility but also amplified the steric hindrance effect and electrostatic repulsive force to prevent their aggregation. Dynamic light scattering experiments proved that these probes formed dense aggregates at CMC, and such aggregate structures would lead to a higher background fluorescence noise. Hence, a higher CMC is more conducive to the detection of the target with low backgrounds. Among them, P3-COOH with -COOH as the terminal unit and a relatively longer branch showed the highest CMC and the best signal to background ratio (S/N). Mechanism studies showed that P3-COOH was bound to HSA mainly through a hydrophobic force, resulting in a limited P3-COOH molecular movement and less attack from quenchers in solutions, thus leading to greatly enhanced fluorescence intensity. In addition, P3-COOH was also applied to the determination of HSA content in actual human serum samples.

Cadmium exposure, fasting blood glucose changes, and type 2 diabetes mellitus: A longitudinal prospective study in China.

BACKGROUND: Cadmium is a recognized human carcinogen, raising global concern for its ubiquitously environmental exposure on public health. Diabetogenic effects of cadmium have been suggested in previous studies, but the longitudinal associations of chronic cadmium exposure with fasting blood glucose changes and type 2 diabetes mellitus have not been fully elucidated. OBJECTIVE: To investigate the effects of long-term cadmium exposure on the fasting blood glucose changes and type 2 diabetes mellitus risk in a longitudinal prospective study of China. METHODS: A total of 3521 urban adults were included as baseline study population from the Wuhan-Zhuhai cohort, and followed up three years later. Urinary cadmium concentrations were determined repeatedly during the follow-up of a three-year period. The within-person and between-person variability of urinary cadmium concentrations over three years was estimated using multilevel random-effects mixed models. Multivariate regression models were performed to evaluate the associations of cadmium exposure with fasting blood glucose changes and type 2 diabetes mellitus risk. RESULTS: The geometric means of creatinine-corrected urinary cadmium concentration at baseline were 1.13 µg/g creatinine, which were close to the levels of follow-up (1.14 µg/g creatinine). The intra-class correlation coefficient of creatinine-corrected urinary cadmium concentrations was 0.71, achieving good reproducibility of cadmium over three years. With adjustment for potential confounders, each one-unit increase in log10-transformed cadmium was associated with a 0.11 (95%CI: 0.03 to 0.19) elevation in fasting blood glucose concentration, and was associated with a 42% (95%CI: 1.16 to 1.73) increase in risk of prevalent type 2 diabetes mellitus. Upward trends of fasting blood glucose changes and type 2 diabetes mellitus incidence were observed with increasing cadmium exposure. Individuals with the highest urinary cadmium exposure had a significant increase in fasting blood glucose change at follow-up [ß (95% CI): 0.49 (0.31-0.67)]. Risk of incident type 2 diabetes mellitus were gradually elevated across increasing quartiles of cadmium exposure, though associations did not reach statistical significance (P = 0.15). CONCLUSIONS: Our findings suggested that relatively high chronic cadmium exposure for general population adults might contribute to elevated changes of fasting blood glucose resulting in the development of type 2 diabetes mellitus.

Combined exposure to multiple metals and cognitive function in older adults.

Single toxic metal exposure has been reported to be associated with impaired cognitive function, but less is known about the effects of combined exposure to multiple metals. The aim of the study was to investigate the potential associations and interactions of multiple metals with cognitive function in older adults using multi-pollutants approach. A cross-sectional study was conducted in a total of 2879 participants aged ≥ 60 years old. We systematically measured levels of 22 blood metals and used the Mini-Mental State Examination (MMSE) to assess the cognitive function. The least absolute shrinkage and selection operator (LASSO) penalized regression was applied to identify independently main metals. Adjusted estimates of cognitive function with selected metals were investigated by generalized linear regression in the multi-metal model. We found that calcium, titanium, vanadium, copper, zinc, arsenic, selenium, rubidium, molybdenum, cadmium, barium, and lead were independently identified based on LASSO penalized regression. The multi-metal model showed a higher MMSE of 0.384 (95% CI: 0.122-0.646) for a 1-SD increment in log-transformed rubidium and a lower MMSE of 0.460 (95% CI: - 0.706 to - 0.214) for a 1-SD increment in log-transformed cadmium (P < 0.05). The significantly negative associations between cadmium and cognitive function were attenuated to null accompanying with increasing concentrations of rubidium (P interaction = 0.256). Our findings suggested that blood rubidium and cadmium were mainly associated with cognitive function when accounting for co-exposure to other metals and higher level of rubidium appeared to attenuate the toxic effects of cadmium on cognitive function in older adults.

Gene knockout or inhibition of macrophage migration inhibitory factor alleviates lipopolysaccharide-induced liver injury via inhibiting inflammatory response.

BACKGROUND: Liver injury is one of the most common complications during sepsis. Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine. This study explored the role of MIF in the lipopolysaccharide (LPS)-induced liver injury through genetically manipulated mouse strains. METHODS: The model of LPS-induced liver injury was established in wild-type and Mif-knockout C57/BL6 mice. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) were detected, and the expressions of MIF, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were measured. Liver histopathology was conducted to assess liver injury. Moreover, the inhibitions of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and 4-iodo-6-phenylpyrimidine (4-IPP) were used to evaluate their therapeutic potential of liver injury. RESULTS: Compared with wild-type mice, the liver function indices and inflammation factors presented no significant difference in the Mif-/- mice. After 72 h of the LPS-induced liver injury, serum levels of ALT, AST, and TBil as well as TNF-α and IL-1ß were significantly increased, but the knockout of Mif attenuated liver injury and inflammatory response. In liver tissue, mRNA levels of TNF-α, IL-1ß and NF-κB p65 were remarkably elevated in LPS-induced liver injury, while the knockout of Mif reduced these levels. Moreover, in LPS-induced liver injury, the inhibitions of MIF with ISO-1 and 4-IPP alleviated liver injury and slightly attenuated inflammatory response. Importantly, compared to mice with LPS-induced liver injury, Mif knockout or MIF inhibitions significantly prolonged the survival of the mice. CONCLUSIONS: In LPS-induced liver injury, the knockout of Mif or MIF inhibitions alleviated liver injury and slightly attenuated inflammatory response, thereby prolonged the survival of the mice. Targeting MIF may be an important strategy to protect the liver from injury during sepsis.

Influence of sagittal degenerative spondylolisthesis on anteversion of the acetabular component in total hip arthroplasty.

BACKGROUND: Degenerative lumbar spondylolisthesis (DSPL), as opposed to other degenerative spinal conditions, is disregarded in the assessment of hip stability after total hip arthroplasty (THA). This study aimed to determine whether patients with DSPL have different acetabular anteversion compared to patients with normal spine before and following THA. METHODS: Preoperative and postoperative 6­month lateral pelvic radiographs in standing and sitting positions from 91 patients who underwent primary THA were retrospectively compared for spinopelvic parameters between patients with DSPL (n = 31) and with normal spine (n = 34). RESULTS: Compared to control patients in the standing position, patients with DSPL had significantly increased preoperative pelvic tilt (24° in DSPL vs. 8° in controls; p < 0.01), pelvic-femoral angle (194° in DSPL vs. 174° in controls; p < 0.05), decreased lumbar lordosis (35° in DSPL vs. 43° in controls; p < 0.05), increased postoperative pelvic tilt (22° in DSPL vs. 7° in controls; p < 0.01), pelvic-femoral angle (187° in DSPL vs. 179° in controls; p < 0.05), and acetabular anteversion (31° in DSPL vs. 23° in controls; p < 0.05). Preoperative (p = 0.181) and postoperative (p = 0.201) sitting pelvic tilt did not differ. There were positive correlations between preoperative standing pelvic tilt and postoperative standing acetabular anteversion, pelvic-femoral angle, and combined sagittal index (CSI) in DSPL (R2 = 0.8416; R2 = 0.9180; R2 = 0.9459, respectively, p < 0.01) and in controls (R2 = 0.6872; R2 = 0.6176; R2 = 0.7129, respectively, p < 0.01). CONCLUSION: While the imbalance of seated sagittal plane is usually insignificant and compensable, the mechanism by which DSPL patients achieve a standing posture is different from control patients, with more hip extension and posterior tilt of the pelvis. Special attention should be paid to the risk of impingement caused by the increase of acetabular anteversion in the postoperative standing position.

miR-222 inhibits cardiac fibrosis in diabetic mice heart via regulating Wnt/ß-catenin-mediated endothelium to mesenchymal transition.

miR-222 participates in many cardiovascular diseases, but its effect on cardiac remodeling induced by diabetes is unclear. This study evaluated the functional role of miR-222 in cardiac fibrosis in diabetic mice. Streptozotocin (STZ) was used to establish a type 1 diabetic mouse model. After 10 weeks of STZ injection, mice were intravenously injected with Ad-miR-222 to induce the overexpression of miR-222. miR-222 overexpression reduced cardiac fibrosis and improved cardiac function in diabetic mice. Mechanistically, miR-222 inhibited the endothelium to mesenchymal transition (EndMT) in diabetic mouse hearts. Mouse heart fibroblasts and endothelial cells were isolated and cultured with high glucose (HG). An miR-222 mimic did not affect HG-induced fibroblast activation and function but did suppress the HG-induced EndMT process. The antagonism of miR-222 by antagomir inhibited HG-induced EndMT. miR-222 regulated the promoter region of ß-catenin, thus negatively regulating the Wnt/ß-catenin pathway, which was confirmed by ß-catenin siRNA. Taken together, our results indicated that miR-222 inhibited cardiac fibrosis in diabetic mice via negatively regulating Wnt/ß-catenin-mediated EndMT.

Cross-sectional and longitudinal associations between urinary zinc and lung function among urban adults in China.

BACKGROUND: Exposure to zinc was suggested to be associated with pulmonary damage, but whether zinc exposure affects lung function remains unclear. OBJECTIVES: To quantify the association between urinary zinc and lung function and explore the potential mechanisms. METHODS: Urinary zinc and lung function were measured in 3917 adults from the Wuhan-Zhuhai cohort and were repeated after 3 years of follow-up. Indicators of systemic inflammation (C reactive protein), lung epithelium integrity (club cell secretory protein-16) and oxidative damage (8-hydroxy-2'-deoxyguanosine and 8-isoprostane) were measured at baseline. Linear mixed models were used to estimate the exposure-response relationship between urinary zinc and lung function. Mediation analyses were conducted to assess mediating roles of inflammation and oxidative damage in above relationships. RESULTS: Each 1-unit increase in log-transformed urinary zinc values was associated with a 35.72 mL decrease in forced vital capacity (FVC) and a 24.89 mL decrease in forced expiratory volume in 1 s (FEV1) in the baseline analyses. In the follow-up analyses, there was a negative association between urinary zinc and FVC among participants with persistent high urinary zinc levels, with an estimated change of -93.31 mL (95% CI -178.47 to -8.14). Furthermore, urinary zinc was positively associated with restrictive ventilatory impairment. The mediation analyses suggested that C reactive protein mediated 8.62% and 8.71% of the associations of urinary zinc with FVC and FEV1, respectively. CONCLUSION: Urinary zinc was negatively associated with lung function, and the systemic inflammation may be one of the underlying mechanisms.

Oxidative damage mediates the association between polycyclic aromatic hydrocarbon exposure and lung function.

BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAHs) is related to decreased lung function. However, whether oxidative damage is involved in this relationship remains unclear. This study was aimed to explore the potential mediating role of oxidative DNA or lipid damage in the association between PAH exposure and lung function. METHODS: The urinary levels of monohydroxy polycyclic aromatic hydrocarbon metabolites (OH-PAHs) and lung function parameters were measured among 3367 participants from the baseline of the Wuhan-Zhuhai cohort. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane (8-iso-PGF2α) were determined to evaluate the individuals' oxidative DNA and lipid damage degrees, respectively. Linear mixed models were used to investigate the associations of urinary OH-PAHs, 8-OHdG and 8-iso-PGF2α with lung function parameters. Mediation analysis was further conducted to assess the potential role of oxidative damage in the association between urinary OH-PAHs and lung function. RESULTS: Each one-percentage increase in the sum of urinary OH-PAHs, high-molecular-weight or low-molecular-weight OH-PAHs (Æ©OH-PAHs, Æ©HMW OH-PAH or Æ©LMW OH-PAHs, respectively) was associated with a 0.2152-, 0.2076- or 0.1985- ml decrease in FEV1, and a 0.1891-, 0.2195- or 0.1634- ml decrease in FVC, respectively. Additionally, significantly positive dose-response relationships of Æ©OH-PAHs, Æ©HMW OH-PAH and Æ©LMW OH-PAHs with urinary 8-OHdG or 8-iso-PGF2α, as well as an inverse dose-response relationship between urinary 8-OHdG and FVC, were observed (all P for trend < 0.05). Mediation analysis indicated that urinary 8-OHdG mediated 14.22% of the association between Æ©HMW OH-PAH and FVC. CONCLUSION: Higher levels of oxidative DNA damage might be involved in the decreased levels of FVC caused by high-molecular-weight PAH exposure.

High manganese exposure decreased the risk of high triglycerides in workers: a cross-sectional study.

BACKGROUND: Manganese (Mn) participates in lipid metabolism. However, the associations between Mn exposure and dyslipidaemia is unclear. METHODS: This was a cross-sectional study. Data were collected from the 2017 the Mn-exposed workers healthy cohort (MEWHC). Finally, 803 occupationally Mn-exposed workers included in the study. The workers were divided into two groups. The grouping of this study was based on Mn-Time Weighted Averages (Mn-TWA). The high-exposure group included participants with Mn-TWA greater than 0.15 mg/m3. The low-exposure group included participants with Mn-TWA less than or equal to 0.15 mg/m3. Mn-TWA levels and dyslipidaemia were assessed. RESULTS: After adjustment for seniority, sex, cigarette consumption, alcohol consumption, high-fat diet frequency, medicine intake in the past two weeks, egg intake frequency, drinking tea, WHR, and hypertension, Mn-TWA levels was negatively correlated with high triglycerides (TG) risk in workers overall (OR = 0.51; 95% CI: 0.36, 0.73; p <  0.01). The results of males and females were consistent (OR = 0.53; 95% CI: 0.34, 0.81; p <  0.01) and (OR = 0.47; 95% CI: 0.24, 0.94; p <  0.01), respectively. By performing interactions analyses of workers overall, we observed no significant interactions among confounders. Mn-TWA levels and pack-years on high TG risk (relative excess risk for the interactions (RERI = 2.29, 95% CI: - 2.07, 6.66), (RERI) = 2.98, 95% CI: - 2.30, 8.26). Similarly, smoking status, drinking status, high-fat diet frequency, and Waist-to-Hip Ratio (WHR) showed non-significant interactions with Mn-TWA levels on high TG risk. CONCLUSIONS: This research indicates that high Mn exposure was negatively related to high TG risk in workers.

MiR-26b-3p regulates osteoblast differentiation via targeting estrogen receptor α.

BACKGROUND: Understanding of the molecular mechanisms of miRNAs involved in osteoblast differentiation is important for the treatment of bone-related diseases. METHODS: MC3T3-E1 cells were induced to osteogenic differentiation by culturing with bone morphogenetic protein 2 (BMP2). After transfected with miR-26b-3p mimics or inhibitors, the osteogenic differentiation of MC3T3-E1 cells was detected by ALP and ARS staining. Cell viability was analyzed by MTT. The expressions of miR-26b-3p and osteogenic related markers and signaling were examined by qPCR and western blot. Direct binding of miR-26b-3p and ER-α were determined by dual luciferase assay. RESULTS: miR-26b-3p was significantly down-regulated during osteoblast differentiation. Overexpression of miR-26b-3p inhibited osteoblast differentiation, while inhibition of miR-26b-3p enhanced osteoblast differentiation. Further studies demonstrated miR-26b-3p inhibited the expression of estrogen receptor α (ER-α) by directly targeting to the CDS region of ER-α mRNA. Overexpression of ER-α rescued the suppression effects of miR-26b-3p on osteoblast differentiation, while knockdown of ER-α reversed the upregulation of osteoblast differentiation induced by knockdown of miR-26b-3p. CONCLUSION: Our study demonstrates that miR-26b-3p suppresses osteoblast differentiation of MC3T3-E1 cells via directly targeting ER-α.

Testin protects against cardiac hypertrophy by targeting a calcineurin-dependent signalling pathway.

Multiple organs express testin (TES), including the heart. Nevertheless, current understanding of the influence of TES on cardiovascular diseases, especially on cardiac hypertrophy and its etiology, is insufficient. This study investigated the influence of TES on cardiac hypertrophy and its etiology. Murine models with excessive TES expression specific to the heart were constructed with an adeno-associated virus expression system. Cardiac hypertrophy was stimulated through aortic banding (AB). The severity of cardiac hypertrophy was evaluated through molecular, echocardiographic, pathological, and hemodynamic examination. The findings of our study revealed that TES expression was remarkably suppressed not only in failing human hearts but also in mouse hearts with cardiac hypertrophy. It was discovered that excessive TES expression driven by an adeno-associated viral vector noticeably inhibited hypertrophy triggered by angiotensin II (Ang II) in cultivated cardiomyocytes from newborn rats. It was also revealed that TES knockdown via AdshTES caused the reverse phenotype in cardiomyocytes. Furthermore, it was proved that excessive TES expression attenuated the ventricular dilation, cardiac hypertrophy, dysfunction, and fibrosis triggered by AB in mice. It was discovered that TES directly interacted with calcineurin and suppressed its downstream signalling pathway. Moreover, the inactivation of calcineurin with cyclosporin A greatly offset the exacerbated hypertrophic response triggered by AB in TES knockdown mice. Overall, the findings of our study suggest that TES serves as a crucial regulator of the hypertrophic reaction by hindering the calcineurin-dependent pathway in the heart.

The long noncoding RNA XIST regulates cardiac hypertrophy by targeting miR-101.

Cardiac hypertrophy and its resultant heart failure are among the most common causes of mortality, worldwide. Long noncoding RNAs (lncRNAs) are involved in diverse biological processes, and their vital role in the regulation of cardiac hypertrophy is increasingly being discovered. Nevertheless, the biological roles of lncRNA X-inactive specific transcript (XIST) in cardiac hypertrophy are scarcely reported, and the current study was designed to determine whether cardiac hypertrophy can be regulated by XIST and to elucidate the related mechanism. The animals were randomized to receive either an adeno-associated virus expressing XIST or control plasmid via a single bolus-tail vein injection. Two weeks later, hypertrophy was established by transverse aortic constriction (TAC) surgery. In vitro, H9c2 cells were used to explore the potential molecular mechanism of XIST in the regulation of phenylephrine (PE)-induced cardiomyocyte hypertrophy. A luciferase reporter assay and RNA immunoprecipitation were performed to explore the relationships among XIST, microRNA (miR)-101, and toll-like receptor 2 (TLR2). In this study, we demonstrated that the expression of XIST was significantly upregulated in hypertrophic mouse hearts and PE-treated cardiomyocytes. Then, we observed that knockdown of XIST attenuated PE-induced cardiomyocyte hypertrophy. Conversely, overexpression of XIST aggravated TAC-induced cardiac hypertrophy. Finally, we demonstrated that miR-101 was a direct target of XIST, whereas TLR2 was a target of miR-101. Rescue assays further confirmed that XIST promoted the progression of cardiac hypertrophy through competitively binding with miR-101 to enhance the expression of TLR2. Collectively, these in vivo and in vitro findings identify XIST as a necessary regulator of cardiac hypertrophy due to its regulation of the miR-101/TLR2 axis, suggesting that XIST might act as a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

LncRNA HOTAIR functions as a competing endogenous RNA to upregulate SIRT1 by sponging miR-34a in diabetic cardiomyopathy.

The HOX transcript antisense RNA (HOTAIR) long noncoding RNA (lncRNA), a highly abundant and conserved imprinted gene, has been implicated in many essential biological processes and diseases. However, to date, the significance of HOTAIR in diabetic cardiomyopathy (DCM) has never been investigated. The current study was designed to determine whether DCM can be regulated by HOTAIR and to elucidate the related mechanism. In vivo, streptozotocin (STZ) was injected intraperitoneally to induce type 1 diabetes in mice. Cardiomyocyte specific HOTAIR overexpression was achieved using an adeno-associated virus system 12 weeks after STZ injection. In vitro, H9c2 were used to explore the potential molecular mechanism of HOTAIR in the regulation of high-glucose-induced cardiomyocyte injury. Luciferase reporter assay and RNA immunoprecipitation (RIP) were performed to explore the relationship between HOTAIR, microRNA-34a (miR-34a), and Sirtuin 1 (SIRT1). HOTAIR expression was significantly decreased in diabetic mice hearts. Knockdown of HOTAIR in high glucose-induced H9c2 resulted in increased oxidative injury, inflammation, and apoptosis in vitro. Cardiomyocyte-specific overexpression of HOTAIR improved cardiac function, decreased oxidative stress and inflammation, and attenuated myocyte death in mice treated with STZ. Mechanistically, the expression of SIRT1/forkhead box protein O1 was significantly increased in the HOTAIR-overexpressing hearts compared with the control hearts treated with STZ. Moreover, we found HOTAIR functioned as a molecular sponge of miR-34a in H9c2 and SIRT1 was identified as a target of miR-34a. Furthermore, the protective effects of HOTAIR on DCM was abolished in SIRT1 deficiency mice in vivo. HOTAIR protected against DCM via activation of the SIRT1 expression by sponging miR-34a.

Association of plasma soluble CD14 level with asthma severity in adults: a case control study in China.

BACKGROUND: Soluble CD14 (sCD14) shedding from CD14 could regulate T lymphocyte activation and function, which has implicated in the pathogenesis of bronchial asthma. The level of sCD14 expression is obviously increased in asthmatic patients during acute asthma attacks. The objective of this study was to investigate the association between plasma sCD14 level and asthma severity in adults. METHODS: The plasma sCD14 level in asthma patients (n = 910) and healthy controls (n = 881) was quantified by commercially available enzyme-linked immunosorbent assay (ELISA) kits. The asthma cases were subdivided into intermittent asthma (n = 537), mild (n = 246), moderate (n = 96) and severe (n = 31) persistent asthma patients. Association between plasma sCD14 level and asthma severity, lung function parameters as well as asthma symptoms and signs in adults were performed using multivariate logistic regression models. RESULTS: We observed significant relationships of plasma sCD14 level with asthma severity, lung function parameters as well as asthma symptoms and signs in adults. After adjusting for multiple potential confounders, each one-unit increase in log sCD14 was significantly associated with 67, 82, 79 and 85% reduced ORs for intermittent asthma, mild, moderate and severe persistent asthma, respectively (all P < 0.0001). Compared with the participants of FEV1/FVC ≥75%, each one-unit increase in log sCD14 was significantly associated with a 37% decreased OR of FEV1/FVC < 75% (P < 0.0001). However, the adjusted odds ratios (ORs) of severe dyspnea, wheeze and cyanosis in asthma patients were 1.88, 1.46 and 2.20 for each one-unit increase in log sCD14, respectively. In addition, compared with health controls, the adjusted area under the curve (AUC) of sCD14 was 0.814 at a cut-off points of 0.53, and the sensitivity and specificity were 71.0 and 76.8% for predicting asthma in adults. And the adjusted AUC of sCD14 reached 0.786, 0.847, 0.887 and 0.917 in predicting intermittent asthma, mild, moderate and severe persistent asthma, respectively. CONCLUSIONS: Our results indicated that plasma sCD14 level is negatively associated with asthma severity, suggesting a protective role for sCD14 in the development of asthma in adults. And plasma sCD14 level might be a potential biomarker in prediction of asthma severity in adults.

Progranulin ameliorates coxsackievirus-B3-induced viral myocarditis by downregulating Th1 and Th17 cells.

Viral myocarditis, which is caused by Coxsackievirus B3 (CVB3) infection, is a leading reason of sudden cardiac death in young adults. Progranulin (PGRN), a pleiotropic growth factor, has been shown to exert anti-inflammatory function in a variety of inflammatory diseases. However, the expression and function of PGRN in the pathogenesis of viral myocarditis remain largely unknown. In this study, we found that PGRN levels in plasma and cardiac tissues were significantly upregulated post CVB3 infection, and negative correlated with disease severity. PGRN deficiency significantly exacerbated, whereas recombinant PGRN treatment attenuated CVB3-induced myocarditis in mice. PGRN downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo, whereas its effect on viral myocarditis was Treg cell independent. Furthermore, PGRN regulated Th1 and Th17 cells differentiation through inhibition of the JAK/STAT pathway. Therefore, our findings reveal a critical role for PGRN in reducing CVB3-induced myocarditis and suggest that PGRN maybe a novel therapeutic treatment for viral myocarditis.

Hyperoside Protects Against Pressure Overload-Induced Cardiac Remodeling via the AKT Signaling Pathway.

BACKGROUND/AIMS: Cardiac hypertrophy is a major predisposing factor for heart failure and sudden cardiac death. Hyperoside (Hyp), a flavonoid isolated from Rhododendron ponticum L., is a primary component of Chinese traditional patent medicines. Numerous studies have shown that Hyp exerts marked anti-viral, anti-inflammatory, anti-oxidant, anti-cancer, anti-ischemic, and particularly cardio-protective effects. However, the effects of Hyp on cardiac hypertrophy have not been explored. The aims of this study were to determine whether Hyp could protect against cardiac remodeling and to clarify the potential molecular mechanisms. METHODS: Neonatal rat cardiac myocytes were isolated and treated with different concentrations of Hyp, then cultured with angiotensin II for 48 h. Mice were subjected to either aortic banding or sham surgery (control group). One week after surgery, the mice were treated with Hyp (20 mg/kg/day) or vehicle by oral gavage for 7 weeks. Hypertrophy was evaluated by assessing morphological changes, echocardiographic parameters, histology, and biomarkers. RESULTS: Hyp pretreatment suppressed angiotensin II-induced hypertrophy in cardiomyocytes. Hyp exerted no basal effects but attenuated cardiac hypertrophy and dysfunction, fibrosis, inflammation, and oxidative stress induced by pressure overload. Both in vivo and in vitro experiments demonstrated that the effect of Hyp on cardiac hypertrophy was mediated by blocking activation of the AKT signaling pathway. CONCLUSION: Hyp improves cardiac function and prevents the development of cardiac hypertrophy via AKT signaling. Our results suggest a protective effect of Hyp on pressure overload-induced cardiac remodeling. Taken together, Hyp may have a role in the pharmacological therapy of cardiac hypertrophy.