Apoptosis and Inflammation Involved with Fluoride-Induced Bone Injuries.

BACKGROUND: Excessive fluoride exposure induces skeletal fluorosis, but the specific mechanism responsible is still unclear. Therefore, this study aimed to identify the pathogenesis of fluoride-induced bone injuries. METHODS: We systematically searched fluoride-induced bone injury-related genes from five databases. Then, these genes were subjected to enrichment analyses. A TF (transcription factor)-mRNA-miRNA network and protein-protein interaction (PPI) network were constructed using Cytoscape, and the Human Protein Atlas (HPA) database was used to screen the expression of key proteins. The candidate pharmacological targets were predicted using the Drug Signature Database. RESULTS: A total of 85 studies were included in this study, and 112 osteoblast-, 35 osteoclast-, and 41 chondrocyte-related differential expression genes (DEGs) were identified. Functional enrichment analyses showed that the Atf4, Bcl2, Col1a1, Fgf21, Fgfr1 and Il6 genes were significantly enriched in the PI3K-Akt signaling pathway of osteoblasts, Mmp9 and Mmp13 genes were enriched in the IL-17 signaling pathway of osteoclasts, and Bmp2 and Bmp7 genes were enriched in the TGF-beta signaling pathway of chondrocytes. With the use of the TF-mRNA-miRNA network, the Col1a1, Bcl2, Fgfr1, Mmp9, Mmp13, Bmp2, and Bmp7 genes were identified as the key regulatory factors. Selenium methyl cysteine, CGS-27023A, and calcium phosphate were predicted to be the potential drugs for skeletal fluorosis. CONCLUSIONS: These results suggested that the PI3K-Akt signaling pathway being involved in the apoptosis of osteoblasts, with the IL-17 and the TGF-beta signaling pathways being involved in the inflammation of osteoclasts and chondrocytes in fluoride-induced bone injuries.

Preconception mitochondrial DNA copy number plays a crucial role in linking prenatal air pollution with the risk of preterm birth.

The relationship between maternal peripheral blood mitochondrial DNA and adverse pregnancy outcomes, specifically preterm birth (PTB), remains uncertain. To investigate the effects of preconception mitochondrial DNA copy number (mtDNAcn) on the association between prenatal air pollutants exposure and PTB risk, a total of 1871 expectant mothers from six regions in Henan Province were recruited. Information regarding air pollutants was obtained from 151 environmental monitoring sites, and relative mtDNAcn was evaluated using real-time PCR analysis. After adjusting for potential confounding variables, it was determined that the risk of PTB increased with elevated levels of inhalable particulate matter (PM10), fine particulate matter (PM2.5), sulfur dioxide (SO2), carbon monoxide (CO) and ozone (O3) exposure (P < 0.05) but decreased with higher nitrogen dioxide (NO2) exposure (0.05 < P < 0.10) during the entire pregnancy. Additionally, the preconception relative mtDNAcn was lower in the PTB group (0.82 ± 0.23) compared to the term group (0.92 ± 0.29). Furthermore, for each 0.1-unit increase in preconception mtDNAcn, the risk of PTB decreased by 14.8%. Stratified analyses revealed that the risk of PTB rose with increasing O3 concentrations, regardless of the relative mtDNAcn. Moreover, the study found a significant association between PTB risk and prenatal exposure to elevated PM10, PM2.5, SO2, and CO, particularly in mothers with low mtDNAcn (≤0.88) (P < 0.05). Conversely, a decrease in the PTB risk was observed with elevated NO2 exposure in mothers with high mtDNAcn (>0.88). Interaction analysis revealed that exposure to PM10, PM2.5, SO2, NO2, and CO interacted with mtDNAcn, respectively, affecting PTB risk (P-interaction<0.05). These findings indicate a noteworthy association between PTB risk and prenatal air pollutants exposure, which is influenced by the preconception mtDNAcn.

Efficacy of a Combination Treatment of Ablative Fractional Carbon Dioxide Laser Therapy and Recombinant Human Epidermal Growth Factor for Atrophic Acne Scars.

BACKGROUND: Atrophic acne scars (AAS) are disfiguring and permanent changes caused by inflammatory acne. Fractional carbon dioxide is a common ablative device used to treat this condition. However, issues such as unclear effectiveness, frequent treatments, and potential side effects exist. In recent years, recombinant human epidermal growth factor (rhEGF) has also been frequently reported for its application in the treatment of acne scars. OBJECTIVE: To explore the potential synergistic effect of fractional carbon dioxide laser combined with rhEGF in AAS treatment. METHODS: We enrolled 15 patients with AAS. They received fractional carbon dioxide laser treatment and were then randomly assigned to receive either rhEGF or a placebo on one side of the face. The procedure was repeated three times, and the results were evaluated using the échelle d'évaluation clinique des cicatrices d'acné (ECCA) score and analyzed using the CBS camera system, 3D analysis (3DMD). Reflectance confocal microscopy (RCM) examination was also conducted. RESULTS: Both sides exhibited significant improvement in the appearance of the acne scars after treatment, as confirmed by the ECCA score, 3DMD data, and CBS texture score. On the rhEGF-treated side, the pore number and epidermal pigment area significantly improved as compared to the control side, whereas no significant differences were observed in the other data. Under RCM, a significant increase in epidermal thickness and appearance of reticular collagen fibers in the dermal layer after treatment was observed. CONCLUSION: Compared to the sole use of laser, the combination of fractional carbon dioxide laser and rhEGF does not significantly enhance scar therapeutic effects. However, it does shorten the recovery period after laser treatment and improves the pore appearance.

Association between fluoride exposure and psychiatric disorders in adults.

To explore the association between fluoride exposure and depression / anxiety in adults, the 1,169 participants were recruited. The demographic information of participants was obtained through questionnaire survey and physical measurements. Morning urine samples were collected, and urinary fluoride (UF) level was determined. Changes in depression and anxiety levels were evaluated using the Patient Health Questionnaire-2 and General Anxiety Disorder-2 scales. The association between psychiatric disorders and UF levels was analyzed. In the total population, the prevalence of depression and anxiety were 3.17% and 4.19%, respectively. These results showed no significant association between depression / anxiety scale scores and UF levels. Logistic regression suggested no significant association between depression / anxiety levels, and UF levels, but there was an interaction between UF and income on depression. Our findings highlighted the interaction between fluoride exposure and monthly income, which may affect depression in adults.

Combined healthy lifestyles and risk of depressive symptoms: A baseline survey in China.

BACKGROUND: Little evidence exists about whether a combination of healthy lifestyle factors is associated with a lower risk of depressive symptoms among Chinese population. We aimed to investigate the association between combined healthy lifestyle factors and risk of depressive symptoms. METHODS: We conducted a baseline survey from July 2021 to December 2023, including 53,642 Chinese adults from general population. A healthy lifestyle score was constructed based on six lifestyle factors (physical activity, smoking status, alcohol consumption, diet, sleep duration, and body mass index). Logistic regression models were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) adjusted for confounding variables. RESULTS: Each additional healthy lifestyle score was associated with a 20 % lower risk of having depressive symptoms (OR (95 % CI): 0.80 (0.78-0.81)). Compared with individuals with ≤2 healthy lifestyle factors, individuals with all the six healthy lifestyle factors had a 58 % reduced risk of having depressive symptoms (0.42 (0.37-0.47)). After stratification by gender, education and urbanization, the significant inverse association with healthy lifestyle score was stronger in women, individuals with high education, and urban residents. Besides, the significant negative association between healthy lifestyle score and depressive symptoms remained for different severity of depressive symptoms. LIMITATIONS: Given the cross-sectional nature of data, we cannot make causal inferences. CONCLUSIONS: Our study indicated that adherence to healthy lifestyle factors was associated with a reduced risk of having depressive symptoms among Chinese adults. The observed associations were modified by gender, education and urbanization. These findings warrant further verification in interventional studies.

Glutamine metabolism in fluorosis: Integrated metabolomics and transcriptomics analysis.

OBJECTIVE: To identify the potential metabolic biomarkers of fluorosis and the pathogenesis of fluorosis. METHODS: Sprague Dawley rats in this study were randomly divided into fluoride exposure and control groups. In the fluoride exposure group, six offspring rats without dental fluorosis were defined as group A, and six offspring rats with dental fluorosis were defined as group C. Eight offspring rats in the control group were defined as group B. The metabolites in plasma were determined using GC-MS, with differential metabolites (DMs) identified using VIP > 1, and P < 0.05. Cluster analysis, KEGG pathway enrichment analysis and Receiver Operating Characteristic (ROC) analysis were subsequently performed. The DMs which were caused by fluoride exposure in the previous study were used to verify our results. The GSE70719 from GEO database were used to support this research at the mRNA level and in vitro experiment were selected to verify above results. RESULTS: The 13 up-regulated and 4 down-regulated DMs were identified in the group A + C, the 18 up-regulated and 4 down-regulated DMs were identified in group A, and the 12 up-regulated and 2 down-regulated DMs were identified in group C. All groups showed enrichment in Aminoacyl-tRNA synthesis, D-glutamine and D-glutamate metabolism, Nitrogen metabolism, and Purine metabolism pathways. ROC analysis revealed that L-glutamine had excellent diagnostic ability for fluorosis (AUC > 0.85, P < 0.05). Changes in major DMs (L-glutamine, 4-hydroxyproline and L-alanine) were consistent with previous findings. Transcriptomic results showed the significant alteration of GLS gene in the fluoride exposure group. In vitro experiments confirmed decreased GLS and SLC1A5 genes expression. CONCLUSION: L-glutamine emerges as a potential biomarker for fluorosis. Glutamine metabolism was involved in the pathogenesis of fluorosis.

Impaired neurogenesis induced by fluoride via the Notch1 signaling and effects of carvacrol intervention.

The negative regulation on neurogenesis has been implicated in fluoride neurotoxicity, while the evidence is limited. To explore whether fluoride interferes with neurogenesis via the Notch1 signaling and the potential alleviation effects of carvacrol (CAR), we conducted in vivo and in vitro experiments, as well as epidemiological analyses in this study. The results showed that urinary fluoride levels and circulating Notch1 levels were associated with IQ levels in boys. NaF-treated rats had fewer neurons, lower densities of dendritic spines, depressed neurogenesis, and impaired learning and memory abilities. In vitro experiments using undifferentiated PC12 cells mimicking neurogenesis revealed that NaF suppressed differentiation and neurite outgrowth. Besides, Notch1 signaling activation was detected in vivo and in vitro. The latter was confirmed using an in vitro model supplemented with DAPT, a potent Notch1 inhibitor. Furthermore, CAR supplementation negatively regulated NICD1 and Hes1 expressions and promoted hippocampal neurogenesis, thereby improving neurological functions in NaF-treated rats. These findings indicated that the inhibition of neurogenesis in hippocampi induced by fluoride via Notch1 signaling activation may be one of the underlying mechanisms of its neurotoxicity, and that CAR significantly alleviated the neurotoxicity of NaF via the Notch1 signaling.

The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification.

BACKGROUND: Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification. METHODS: The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494-0.957) and 51.6% (95% CI, 0.307-0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue. CONCLUSIONS: Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration. TRIAL REGISTRATION: ChiCTR2000031608.

Mediation of mitochondrial DNA copy number and oxidative stress in fluoride-related bone mineral density alteration in Chinese farmers.

Excessive fluoride can adversely affect bone mineral density (BMD). Oxidative stress and mitochondrial dysfunction are crucial mechanisms of health damage induced by fluoride. Here, a cross-sectional survey involving 907 Chinese farmers (aged 18-60) was carried out in Tongxu County in 2017, aiming to investigate the significance of mitochondrial DNA copy number (mtDNAcn) and oxidative stress in fluoride-related BMD change. Concentrations of urinary fluoride (UF), serum oxidative stress biomarkers, including total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), as well as relative mtDNAcn in peripheral blood were determined. The multivariable linear model and mediation analysis were performed to assess associations between UF, oxidative stress, and relative mtDNAcn with BMD. Results showed that GSH-Px levels increased by 6.98 U/mL [95% confidence interval (CI) 3.41-10.56)] with each 1.0 mg/L increment of UF. After stratification, the T-AOC, relative mtDNAcn, and BMD decreased by 0.04 mmol/L (-0.08 ~ -0.01), 0.29-unit (-0.55 ~ -0.04), and 0.18-unit (-0.33 ~ -0.03) with every 1.0 mg/L elevation of UF in the excessive fluoride group (EFG, adults with UF > 1.6 mg/L), respectively. Furthermore, T-AOC and relative mtDNAcn were favorably related to the BMD in the EFG (ß = 0.82, 95%CI 0.16-1.48 for T-AOC; ß = 0.11, 95%CI 0.02-0.19 for relative mtDNAcn). Mediation analysis showed that relative mtDNAcn and T-AOC mediated 15.4% and 17.1% of the connection between excessive fluoride and reduced BMD, respectively. Findings suggested that excessive fluoride was related to lower BMD in adults, and the decrement of T-AOC and relative mtDNAcn partially mediate this relationship.

Risk of heavy metal(loid) compositions in fine particulate matter on acute cardiovascular mortality: a poisson analysis in Anyang, China.

Fine particulate matter (PM2.5) is a risk factor of cardiovascular disease. Associations between PM2.5 compositions and cardiovascular disease are a point of special interest but inconsistent. This study aimed to explore the cardiovascular effects of heavy metal(loid) compositions in PM2.5. Data for mortality, air pollutants and meteorological factors in Anyang, China from 2017 to 2021 were collected. Heavy metal(loid) in PM2.5 were monitored and examined monthly. A Case-crossover design was applied to the estimated data set. The interquartile range increase in cadmium (Cd), antimony (Sb) and arsenic (As) at lag 1 was associated with increment of 8.1% (95% CI: 3.3, 13.2), 4.8% (95% CI: 0.2, 9.5) and 3.5% (95% CI: 1.1, 6.0) cardiovascular mortality. Selenium in lag 2 was inversely associated with cerebrovascular mortality (RR = 0.920 95% CI: 0.862, 0.983). Current-day exposure of aluminum was positively associated with mortality from ischemic heart disease (RR = 1.083 95% CI: 1.001, 1.172). Stratified analysis indicated sex, age and season modified the cardiovascular effects of As (P < 0.05). Our study reveals that heavy metal(loid) play key roles in adverse effects of PM2.5. Cd, Sb and As were significant risk factors of cardiovascular mortality. These findings have potential implications for accurate air pollutants control and management to improve public health benefits.

Network analysis of smoking-related sleep characteristics in Chinese adults.

The associations between multiple sleep characteristics and smoking behavior are inconsistent, and it is unclear which sleep characteristics are most crucial for tobacco prevention. This study aimed to explore the associations between smoking status/intensity and multiple sleep characteristics and to identify the potential core domain of smoking-related sleep using network analysis. Data were obtained from a survey of cancer-related risk factors among Chinese adults. Logistic regression models were used to quantify the associations between sleep characteristics and smoking status/intensity. Network analyses were employed to identify the core sleep characteristics. A total of 5,228 participants with a median age of 44 years old were included in the study. Current smoking was significantly positively associated with long nap time, difficulty falling asleep, late bedtime, getting up after 7 am, and waking up earlier than expected. There was significant positive association between current smoking and short sleep duration in young adults under 45 years old. Late bedtime and getting up after 7 am were only associated with current heavy smoking, but not current light smoking. Network analyses showed that multiple smoking-related sleep characteristics were interconnected, with difficulty falling asleep and late bedtime as central characteristics in the network. The study found that the associations between sleep characteristics and smoking varied by age and smoking intensity and highlights the potential benefits of sleep health promotion in smoking cessation, with a particular focus on difficulty falling asleep and late bedtime.

Correlations between bone metabolism biomarkers and fluoride exposure in adults and children.

Increased exposure to fluoride, which notably affects bone metabolism, is a global concern. However, the correlations and sensitivity of bone metabolism to fluoride remain controversial. In this cross-sectional study, 549 children (aged 7-12 years) and 504 adults (≥ 18 years old) were recruited in the high-fluoride areas of the Henan Province. Urinary fluoride (UF) level was determined using a fluoride electrode. Fasting venous blood serum was collected to measure bone metabolism biomarkers. The selected bone metabolism biomarkers for children included bone alkaline phosphatase (BALP), serum alkaline phosphatase (ALP), osteocalcin (OCN), calcitonin (CT), parathyroid hormone (PTH), phosphorus (P5+), and calcium (Ca2+). For adults, the biomarkers included ALP, CT, PTH, ß-CrossLaps (ß-CTX), P5+, and Ca2+. The correlations between UF and bone metabolism biomarkers were analyzed using binary logistic regression, a trend test, a generalized additive model, and threshold effect analysis. Regression analysis indicated a significant correlation between serum OCN, PTH, and UF levels in children aged 7-9 years. Serum OCN, PTH, and BALP contents were significantly correlated with UF in boys (P < 0.05). Furthermore, the interaction between age and UF affected serum P5+ and PTH (P < 0.05). The generalized additive model revealed nonlinear dose-response relationships between P5+, BALP, and UF contents in children (P < 0.05). Serum OCN level was linearly correlated with the UF concentration (P < 0.05). Similarly, a significant correlation was observed between ß-CTX and UF levels in adults. In addition, significant correlations were observed between UF-age and serum Ca2+, ß-CTX, and PTH contents. There was a non-linear correlation between serum Ca2+, P5+, and ß- CTX and UF levels (P < 0.05). Overall, serum OCN, BALP, and P5+ levels can serve as sensitive bone metabolism biomarkers in children, while ß-CTX, P5+, and Ca2+ can be considered fluoride-sensitive bone metabolism biomarkers in adults.

Effect of short-term exposure to air pollution on hospital admission for cardiovascular disease: A time-series study in Xiangyang, China.

BACKGROUND: Data on the relationship between short-term exposure to air pollution and cardiovascular diseases (CVDs) and the potential modifying factors are limited and inconsistent. OBJECTIVE: To explore the relationship between short-term exposure to air pollution and CVD risk, and potential modification effect factors. METHOD: A time series study was conducted on 52,991 hospital admissions for CVD from 2015 to 2019 in Xiangyang City, China. Air pollution data from four national fixed monitoring stations were collected to estimate exposure level in Xiangyang City. A quasi-Poisson generalized additive model incorporating a distributed lag nonlinear model was applied to evaluate the association between air pollution and CVD risk. The potential modification effect of sex, age, and season on the above associations was also evaluated. RESULTS: CVD risk was positively associated with air pollution. Peak associations in single lag day structures were observed for particulate matter ≤10 µm in aerodynamic (PM10; RR: 1.040, 95 % CI: 0.996-1.087), PM2.5 (1.025, 1.004-1.045), nitrogen dioxide (NO2; 1.074, 1.039-1.111), and sulfur dioxide (SO2; 1.079, 1.019-1.141) at Lag 0 and ozone (O3; 1.018, 1.004-1.031) at Lag 4. In cumulative lag day structures, the highest RRs were 1.225 (1.079,1.392) for PM10 at Lag 06, 1.054 (1.013, 1.098) for PM2.5 at Lag 03, 1.200 (1.119, 1.287) for NO2 at Lag 04, and 1.135 (1.025, 1.257) for SO2 at Lag 02. Moreover, the association between air pollution and CVD risk was modified by sex and age (P < 0.05). Females and individuals aged ≤65 years were more vulnerable to NO2 and had a higher CVD risk. CONCLUSION: Short-term exposure to air pollution was positively associated with CVD risk. Moreover, sex and age could modify the effect of air pollution on CVD risk. Females and individuals aged ≤65 years had a higher NO2 exposure-induced CVD risk.

U-shaped relationship between ozone exposure and preterm birth risk associated with preconception telomere length.

There are conflicting findings regarding the association of ozone (O3) exposure with preterm birth (PTB) occurrence. In the present study, two cohorts were combined to explore the relationship between maternal O3 exposure during pregnancy and PTB risk, and analyze the underlying mechanisms of this relationship in terms of alterations in the preconception telomere length. Cohort 1 included mothers who participated in the National Free Preconception Health Examination Project in Henan Province from 2014 to 2018 along with their newborns (n = 1,066,696). Cohort 2 comprised mothers who conceived between 2016 and 2018 and their newborns (n = 1871) from six areas in Henan Province. The telomere length was assessed in the peripheral blood of mothers at the preconception stage. Data on air pollutant concentrations were collected from environmental monitoring stations and individual exposures were assessed using an inverse distance-weighted model. O3 concentrations (100.60 ± 14.13 µg/m3) were lower in Cohort 1 than in Cohort 2 (114.09 ± 15.17 µg/m3). Linear analyses showed that PTB risk decreased with increasing O3 exposure concentrations in Cohort 1 but increased with increasing O3 exposure concentrations in Cohort 2. Nonlinear analyses revealed that PTB risk tended to decrease and then increase with increasing O3 exposure concentrations in both cohorts. Besides, PTB risk was reduced by 88% for each-unit increase in telomere length in those exposed to moderate O3 concentrations (92.4-123.7 µg/m3, P < 0.05). While no significant association was observed between telomere length and PTB at extreme O3 concentration exposure during entire pregnancy (<92.4 or >123.7 µg/m3, P > 0.05) in Cohort 2. These findings reveal a nonlinear (U-shaped) relationship between O3 exposure and PTB risk. Furthermore, telomere with elevated length was associated with decreased risk of PTB only when exposed to moderate concentrations of O3, but not when exposed to extreme concentrations of O3 during pregnancy.

The Effectiveness of 595-nm Pulsed Dye Laser for the Treatment of Bilateral Cleft-Lip Scars in Asian Patients: A 6-Month Prospective, Randomized, Self-Controlled Trial.

Objective: This study is the first prospective within-patient self-controlled research seeking to investigate the safety and efficacy of 595 nm pulsed-dye laser (PDL) for the treatment of cleft-lip scars. Approach: This prospective, randomized, self-controlled study is based on the clinical records of the patients who received laser-assisted treatment due to bilateral cleft-lip scars. The bilateral scars were randomly assigned to the 595 nm PDL group with five consecutive sessions at 2-week intervals or control group in a blinded manner of evaluators, with subsequent follow-up for 6 months after the final treatment. Clinical efficacy and safety outcomes were evaluated by Vancouver Scar Scale (VSS), Patient Scar Assessment Questionnaire (PSAQ), and other objective evaluations. Results: A total of 18 patients were included. The 595 nm PDL-treated sides showed statistically significant improvement in VSS after treatment at follow-up compared with the baseline (p < 0.05). Interestingly, the 595 nm-PDL-treated side achieved significantly better improvement in scar pigmentation and pliability (p < 0.05). Though there was statistically significant difference between two groups (p < 0.05), the gap in overall PSAQ is not obvious. And comparison by area and coloring evaluation (E/M index) also suggests that the responses of scars to treatment by PDL were slightly improved (p < 0.05). Innovation and Conclusion: It is the first time to apply the 595nm PDL for cleft-lip scars. It would be a better choice for the early treatment of red scar with proliferative tendency after cleft-lip surgery.

Proteomics Sequencing Reveals the Role of TGF-ß Signaling Pathway in the Peripheral Blood of Offspring Rats Exposed to Fluoride.

The underlying mechanism of fluorosis has not been fully elucidated. The purpose of this study was to explore the mechanism of fluorosis induced by sodium fluoride (NaF) using proteomics. Six offspring rats exposed to fluoride without dental fluorosis were defined as group A, 8 offspring rats without fluoride exposure were defined as control group B, and 6 offspring rats exposed to fluoride with dental fluorosis were defined as group C. Total proteins from the peripheral blood were extracted and then separated using liquid chromatography-tandem mass spectrometry. The identified criteria for differentially expressed proteins were fold change > 1.2 or < 0.83 and P < 0.05. Gene Ontology function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the oeCloud tool. The 177 upregulated and 22 downregulated proteins were identified in the A + C vs. B group. KEGG pathway enrichment analysis revealed that transforming growth factor-ß (TGF-ß) signaling pathway significantly enriched. PPI network constructed using Cytoscape confirmed RhoA may play a crucial role. The KEGG results of genes associated with fluoride and genes associated with both fluoride and inflammation in the GeneCards database also showed that TGF-ß signaling pathway was significantly enriched. The immunofluorescence in HPA database showed that the main expression sites of RhoA are plasma membrane and cytosol, while the main expression site of Fbn1 is the Golgi apparatus. In conclusion, long-term NaF intake may cause inflammatory response in the peripheral blood of rats by upregulating TGF-ß signaling pathway, in which RhoA may play a key role.

T-2 toxin induces mitochondrial dysfunction in chondrocytes via the p53-cyclophilin D pathway.

Kashin-Beck disease is an endemic joint disease characterized by deep chondrocyte necrosis, and T-2 toxin exposure has been confirmed its etiology. This study investigated mechanism of T-2 toxin inducing mitochondrial dysfunction of chondrocytes through p53-cyclophilin D (CypD) pathway. The p53 signaling pathway was significantly enriched in T-2 toxin response genes from GeneCards. We demonstrated the upregulation of the p53 protein and p53-CypD complex in rat articular cartilage and ATDC5 cells induced by T-2 toxin. Transmission electron microscopy showed the damaged mitochondrial structure of ATDC5 cells induced by T-2 toxin. Furthermore, it can lead to overopening of the mitochondrial permeability transition pore (mPTP), decreased mitochondrial membrane potential, and increased reactive oxygen species generation in ATDC5 cells. Pifithrin-α, the p53 inhibitor, alleviated the increased p53-CypD complex and mitochondrial dysfunction of chondrocytes induced by T-2 toxin, suggesting that p53 played an important role in T-2 toxin-induced mitochondrial dysfunction. Mechanistically, T-2 toxin can activate the p53 protein, which can be transferred to the mitochondrial membrane and form a complex with CypD. The increased binding of p53 and CypD mediated the excessive opening of mPTP, changed mitochondrial membrane permeability, and ultimately induced mitochondrial dysfunction and apoptosis of chondrocytes.

Effect of zinc intake on association between fluoride exposure and abnormal sex steroid hormones among US pubertal males: NHANES, 2013-2016.

Excessive fluoride exposure can disturb the balance of sex hormones. Zinc is essential for sex hormone synthesis and spermatogenesis. But it is not clear how zinc affects the relationship of fluoride exposure with abnormal sex steroid hormones. Here, a total of 1008 pubertal males from the National Health and Nutrition Examination Survey (NHANES) in two cycles (2013-2014, 2015-2016) were enrolled. The concentrations of water fluoride and plasma fluoride and the levels of serum testosterone, estradiol, and sex hormone binding globulin (SHBG) were measured. Two 24-h dietary recall interviews were conducted to assess the dietary zinc intake. The relationships of fluoride exposure and zinc intake with sex hormones were examined using linear regression and logistic regression models, while the generalized additive model was used to evaluate their non-linear relationship. Our findings revealed that for every two-fold increase in plasma fluoride concentration, testosterone levels decreased by 7.27% (95% CI - 11.49%, - 2.86%) and estradiol levels decreased by 8.73% (95% CI - 13.61%, - 3.57%). There was also significant non-linear association observed between zinc intake and SHBG levels. Being in the first tertile of plasma fluoride had a 60% lower risk of high SHBG (OR = 0.40, 95% CI 0.18, 0.89) compared with being in the second tertile. When compared to the first tertile, being in the second tertile of zinc intake was associated with a 63% (OR = 0.37, 95% CI 0.14, 0.98) lower risk of high SHBG. Furthermore, we observed an interactive effect between the plasma fluoride and zinc intake on estradiol and SHBG, as well as the risk of high SHBG (P-interaction < 0.10). These findings suggest that fluoride exposure and zinc intake can affect sex steroid hormone levels and the risk of high SHBG. Notably, zinc intake may alleviate the increased risk of high SHBG and the abnormal changes of estradiol and SHBG caused by higher fluoride exposure.

SIRT1, a target of miR-708-3p, alleviates fluoride-induced neuronal damage via remodeling mitochondrial network dynamics.

INTRODUCTION: Neurological dysfunction induced by fluoride contamination is still one of major concern worldwide. Recently, neuroprotective roles of silent information regulator 1 (SIRT1) focusing on mitochondrial function have been highlighted. However, what roles SIRT1 exerts and the underlying regulative mechanisms, remain largely uncharacterized in such neurotoxic process of fluoride. OBJECTIVES: We aimed at evaluating the regulatory roles of SIRT1 in human neuroblastoma SH-SY5Y cells and Sprague-Dawley rats with fluoride treatment, and to further identify potential miRNA directly targeting SIRT1. METHODS: Pharmacological suppression of SIRT1 by nicotinamide (NIC) and promotion of SIRT1 by adenovirus (Ad-SIRT1) or resveratrol (RSV) were employed to assess the effects of SIRT1 in mitochondrial dysfunction induced by fluoride. Also, miRNAs profiling and bioinformatic prediction were used to screen the miRNAs which can regulate SIRT1 directly. Further, chemical mimic or inhibitor of chosen miRNA was applied to validate the modulation of chosen miRNA. RESULTS: NIC exacerbated defects in mitochondrial network dynamics and cytochrome c (Cyto C) release-driven apoptosis, contributing to fluoride-induced neuronal death. In contrast, the ameliorative effects were observed when overexpressing SIRT1 by Ad-SIRT1 in vitro or RSV in vivo. More importantly, miR-708-3p targeting SIRT1 directly was identified. And interestingly, moreover, treatment with chemically modified miR-708-3p mimic aggravated, while miR-708-3p inhibitor suppressed fluoride-caused neuronal death. Further confirmedly, overexpressing SIRT1 effectively neutralized miR-708-3p mimic-worsened fluoride neuronal death via correcting mitochondrial network dynamics. On contrary, inhibiting SIRT1 counteracted the promotive effects of miR-708-3p inhibitor against neurotoxic response by fluoride through aggravating abnormal mitochondrial network dynamics. CONCLUSION: These data underscore the functional importance of SIRT1 to mitochondrial network dynamics in neurotoxic process of fluoride and further screen a novel unreported neuronal function of miR-708-3p as an upstream regulator of targeting SIRT1, which has important theoretical implications for a potential therapeutic and preventative target for treatment of neurotoxic progression by fluoride.