Endocrine toxicity of atrazine and its underlying mechanisms.

Atrazine (ATR) is one of the most widely utilized herbicides globally and is prevalent in the environment due to its extensive use and long half-life. It can infiltrate the human body through drinking water, ingestion, and dermal contact, and has been recognized as an environmental endocrine disruptor. This study aims to comprehensively outline the detrimental impacts of ATR on the endocrine system. Previous research indicates that ATR is harmful to various bodily systems, including the reproductive system, nervous system, adrenal glands, and thyroi d gland. The toxic effects of ATR on the endocrine system and its underlying molecular mechanisms are summarized as follows: influencing the expression of kisspeptin in the HPG axis, consequently affecting steroid synthesis; disrupting DNA synthesis and meiosis, as well as modifying DNA methylation levels, leading to reproductive and developmental toxicity; impacting dopamine by altering Nurr1, VMAT2, and DAT expression, consequently affecting dopamine synthesis and transporter expression, and influencing other neurotransmitters, resulting in neurotoxicity; and changing adipose tissue synthesis and metabolism by reducing basal metabolism, impairing cellular oxidative phosphorylation, and inducing insulin resistance. Additionally, a compilation of natural products used to mitigate the toxic effects of ATR has been provided, encompassing melatonin, curcumin, quercetin, lycopene, flavonoids, vitamin C, vitamin E, and other natural remedies. It is important to note that existing research predominantly relies on in vitro and ex vivo experiments, with limited population-based empirical evidence available.

Impacts of shell structure on nitrate-reduction activity and air stability of nanoscale zero-valent iron.

Nanoscale zero-valent iron (nZVI) has been intensively studied for pollution control because of its high reductive activity and environmental benignity, but the poor reaction selectivity and the aging problem have limited its practical decontamination application. Here, we shed light on the impacts of nZVI shell structure on its reactivity and air stability by systematically comparing two nZVI materials with distinct iron oxide shells. The nZVI with highly crystalline and weakly hydrophilic shell exhibited ninefold higher intrinsic activity for nitrate reduction and significantly improved air stability than that with amorphous, hydrophilic iron hydroxide oxide shell. The compact-structured crystalline shell of nZVI facilitated more efficient interfacial electronic transfer for nitrate reduction and suppressed side reaction of hydrogen evolution. The protective hematite shell endowed the nZVI with significantly improved anti-aging ability, and the reducing force remained 92.6% after exposed to air for 10 days due to decreased oxygen diffusion. This work provides a better understanding of the pollutant degradation behavior of nZVI and may guide an improved synthesis and environmental application of nZVI.

Caffeine Inhibits Activation of the NLRP3 Inflammasome via Autophagy to Attenuate Microglia-Mediated Neuroinflammation in Experimental Autoimmune Encephalomyelitis.

The activation of microglia is an important cause of central nervous system (CNS) inflammatory cell infiltration and inflammatory demyelination in experimental autoimmune encephalomyelitis (EAE). Furthermore, the proinflammatory response induced by the NLR family pyrin domain containing 3 (NLRP3) inflammasome can be amplified in microglia after NLRP3 inflammasome activation. Autophagy is closely related to the inflammatory response. Caffeine exerts anti-inflammatory and autophagy-stimulating effects, but the specific mechanism remains unclear. This study examined the mechanism underlying the anti-inflammatory effect of caffeine on EAE. In this study, C57BL/6 mice were immunized to induce EAE and treated with caffeine to observe its effect on prognosis. The effects of caffeine on autophagy and inflammation were also analysed in mouse primary microglia (PM) and the BV2 cell line. The data demonstrated that caffeine reduced the clinical score, the infiltration of inflammatory cells, the demyelination level, and the activation of microglia in EAE mice. Furthermore, caffeine increased the LC3-II/LC3-I levels and decreased the NLRP3 and P62 levels in EAE mice, whereas the autophagy inhibitor 3-methylamine (3-MA) blocked these effects. In vitro, caffeine promoted autophagy by suppressing the mechanistic target of rapamycin (mTOR) pathway and inhibited activation of the NLRP3 inflammasome. However, autophagy-related gene 5 (ATG5)-specific siRNA abolished the anti-inflammatory effect of caffeine treatment in PM and BV2 cells. Taken together, these data suggest that caffeine exerts a newly discovered effect on EAE by reducing NLRP3 inflammasome activation via the induction of autophagy in microglia.

Outcomes and Treatment Complications of Intravenous Urokinase Thrombolysis in Acute Ischemic Stroke in China.

Background: Intravenous thrombolysis with alteplase benefits eligible patients with acute ischemic stroke. However, in some countries such as China, alteplase may be too expensive for low-income patients, and also for regions with low economic development. Urokinase is much less expensive than alteplase. This study aimed to assess the outcomes and treatment complications of urokinase in acute ischemic stroke patients, which are poorly understood. Methods: This multicenter retrospective study included acute ischemic stroke patients who received intravenous urokinase or alteplase from January 2014 to January 2018 at 21 centers in China. Outcomes and treatment complications were analyzed by univariate and multivariate analyses. Results: Among the 618 patients included in this study, 489 were treated with urokinase and 129 were treated with alteplase. Functional independence, no/minimal disability, mortality, intracranial hemorrhage (ICH), and symptomatic ICH did not significantly differ between the urokinase and alteplase groups in the univariate and multivariate analyses. However, the patients who received alteplase had a lower odds ratio (OR) of extracranial bleeding in the univariate analysis and a lower adjusted OR (aOR) in the multivariate analysis than the patients who received urokinase (OR = 0.410 [95% CI, 0.172-0.977], p = 0.038; aOR = 0.350 [95% CI, 0.144-0.854], p = 0.021). Furthermore, in patients treated with urokinase, the patients who received high-dose urokinase had a higher OR of extracranial bleeding in the univariate analysis and a higher aOR of extracranial bleeding in the multivariate analysis than patients who received low-dose urokinase (OR = 3.046 [95% CI, 1.696-5.470], p < 0.001; aOR = 3.074 [95% CI, 1.627-5.807], p = 0.001). Moreover, patients who received low-dose urokinase had similar outcomes and complications compared to patients treated with alteplase. Conclusions: Patients treated with urokinase had similar outcomes but a higher risk of extracranial bleeding compared to patients treated with alteplase. The risk of extracranial bleeding was higher in the patients treated with high-dose urokinase than in the patients treated with low-dose urokinase. Patients who received low-dose urokinase had similar outcomes and complications compared to patients treated with alteplase. In countries such as China where some acute ischemic stroke patients cannot afford alteplase, urokinase may be a good alternative to alteplase for intravenous thrombolysis.

Elevated hemoglobin is independently associated with enlarged perivascular spaces in the central semiovale.

Enlarged perivascular spaces (EPVS) are widely considered as a feature of cerebral small vessel diseases (SVD), but its underlying pathology is still under active investigation. The aim of this study was to explore the association between hemoglobin level and the severity of EPVS. Consecutive patients with acute ischemic stroke who underwent baseline MRI scan and hemoglobin testing were evaluated. EPVS in basal ganglia (BG) and central semiovale (CS) were rated with a validated 4-point semiquantitative scale (0 = none; 1 = 1-10; 2 = 11-20; 3 = 21-40; and 4 ≥ 40). Bivariate logistic regression models were used to identify the associations of hemoglobin with predefined high-degree (score > 1) CS-EPVS and BG-EPVS. Multinomial logistic regression models were used to analyze the associations between hemoglobin and CS-/BG-EPVS predominance patterns. A total of 401 patients were included in the final analysis, 94 patients (23.4%) had a high degree of CS-EPVS and 45 patients (11.2%) had a high degree of BG-EPVS. Compared with tertile 1 of hemoglobin, tertile 3 of hemoglobin was independently associated with high degree of CS-EPVS after adjusting for other features of SVD (odds ratio [OR] 2.399, 95% confidence interval [CI] 1.315-4.379, P = 0.004) and potential confounding factors (OR 2.611, 95% CI 1.346-5.066, P = 0.005). In multinomial logistic regression models, compared with tertile 1 of hemoglobin, tertile 2 (OR 2.463, 95% CI 1.195-5.075, P = 0.015) and tertile 3 (OR 2.625, 95% CI 1.102-6.251, P = 0.029) of hemoglobin were associated with higher odds of BG-EPVS = CS-EPVS pattern, and tertile 3 of hemoglobin (OR 2.576, 95% CI 1.004-6.608, P = 0.049) was associated with higher odds of BG-EPVS < CS-EPVS pattern. Elevated hemoglobin level was independently associated with high degree of CS-EPVS and higher odds of CS-EPVS predominance pattern, but not with BG-EPVS, which support that the topography of EPVS is characteristic. However, the pathogenesis linking hemoglobin and CS-EPVS is unclear and still needs further investigation.

Serum Interleukin-33 is a Novel Predictive Biomarker of Hemorrhage Transformation and Outcome in Acute Ischemic Stroke.

INTRODUCTION: Hemorrhage Transformation (HT) in acute ischemic stroke (AIS) depends on multiple factors. Some studies have shown that serum interleukin-33 (IL-33) is of central significance as a neuroprotective factor. However, the relationship between serum IL-33 and HT in AIS has not been evaluated. OBJECTIVE: To investigate the relationship between serum IL-33 concentration and HT in AIS. METHODS: We recruited 151 consecutive non-thrombolytic patients with AIS clinically diagnosed in The First Affiliated Hospital of Chongqing Medical University from December 2018 to October 2019. If the patients showed radiographic presentation of HT within two weeks following admission, they were assigned to the HT group; others were assigned to the non-HT group. There were 40 healthy control subjects recruited during the same period. Serum IL-33 concentration was detected by ELISA and the independent risk value of HT in AIS was predicted by multivariate logistic regression. The accuracy was analyzed by receiver operating characteristic (ROC) curves. In three months after admission, the functional outcome was measured by modified Rankin scale (mRS). RESULTS: ROC curve showed that the area under the curve (AUC) of serum IL-33 was 0.739 (95% CI: 0.657-0.821, P < .001) in predicting HT in AIS. When serum IL-33 concentration was ≤ 67.66 ng/L, the sensitivity and specificity of the prediction were 81.3% and 63%, respectively. Multivariate logistic regression analysis showed that serum IL-33 concentration ≤ 67.66 ng/L was an independent predictor of HT in AIS (OR = 5.773, 95% CI: 1.685-19.792, P = .005). The follow-up results of mRS showed a higher probability of an unfavorable outcome in those with HT compared to those without HT (OR = 6.520, 95% CI: 2.530-16.803, P < .001). CONCLUSIONS: HT in AIS is negatively correlated with outcome. Furthermore, serum IL-33 is an independent predictive biomarker of HT and outcome in AIS.

White matter hyperintensities and the progression from mild parkinsonian signs to parkinsonism and Parkinson's disease.

This study investigated the impact of white matter hyperintensities (WMHs) on the progression from mild parkinsonian signs (MPS) to parkinsonism and Parkinson's disease (PD). Participants with MPS completed 5 years of follow-up. WMHs were divided into periventricular WMHs and deep WMHs according to magnetic resonance imaging scans. The diagnosis of MPS, parkinsonism, and PD was based on the motor portion of the Unified Parkinson's Disease Rating Scale. Cox proportional hazard models were used to identify the association between WMHs and MPS progression. Of the 636 participants, 166 (26.1%) with MPS developed parkinsonism and PD after follow-up. After adjusting for potential factors, severe WMHs were associated with an increased risk of MPS progression, moderate and severe periventricular WMHs and severe deep WMHs were associated with the risk of MPS progression, and severe WMHs were associated with the progression of gait/balance impairment, bradykinesia, and rigidity. Additionally, participants treated for vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia had a lower risk of MPS progression.

MBNL1 reverses the proliferation defect of skeletal muscle satellite cells in myotonic dystrophy type 1 by inhibiting autophagy via the mTOR pathway.

Skeletal muscle atrophy is one of the clinical symptoms of myotonic dystrophy type 1 (DM1). A decline in skeletal muscle regeneration is an important contributor to muscle atrophy. Skeletal muscle satellite cells (SSCs) drive skeletal muscle regeneration. Increased autophagy can reduce the proliferative capacity of SSCs, which plays an important role in the early regeneration of damaged skeletal muscle in DM1. Discovering new ways to restore SSC proliferation may aid in the identification of new therapeutic targets for the treatment of skeletal muscle atrophy in DM1. In the pathogenesis of DM1, muscleblind-like 1 (MBNL1) protein is generally considered to form nuclear RNA foci and disturb the RNA-splicing function. However, the role of MBNL1 in SSC proliferation in DM1 has not been reported. In this study, we obtained SSCs differentiated from normal DM1-04-induced pluripotent stem cells (iPSCs), DM1-03 iPSCs, and DM1-13-3 iPSCs edited by transcription activator-like (TAL) effector nucleases (TALENs) targeting CTG repeats, and primary SSCs to study the pathogenesis of DM1. DM1 SSC lines and primary SSCs showed decreased MBNL1 expression and elevated autophagy levels. However, DM1 SSCs edited by TALENs showed increased cytoplasmic distribution of MBNL1, reduced levels of autophagy, increased levels of phosphorylated mammalian target of rapamycin (mTOR), and improved proliferation rates. In addition, we confirmed that after MBNL1 overexpression, the proliferative capability of DM1 SSCs and the level of phosphorylated mTOR were enhanced, while the autophagy levels were decreased. Our data also demonstrated that the proliferative capability of DM1 SSCs was enhanced after autophagy was inhibited by overexpressing mTOR. Finally, treatment with rapamycin (an mTOR inhibitor) was shown to abolish the increased proliferation capability of DM1 SSCs due to MBNL1 overexpression. Taken together, these data suggest that MBNL1 reverses the proliferation defect of SSCs in DM1 by inhibiting autophagy via the mTOR pathway.

Total Small Vessel Disease Burden Predicts Functional Outcome in Patients With Acute Ischemic Stroke.

Background: Cerebral small vessel disease (SVD) is generally considered as a cause of stroke, disability, gait disturbances, vascular cognitive impairment, and dementia. The aim of this study was to investigate whether the total SVD burden can be used to predict functional outcome in patients with acute ischemic stroke. Methods: From April 2017 to January 2018, consecutive patients with acute ischemic stroke who underwent baseline MRI scan were evaluated. The functional outcome was assessed using the modified Rankin Scale (mRS) at 90 days and defined as i) excellent outcome (mRS ≤ 1) and ii) good outcome (mRS ≤ 2). Brain MRI was performed and assessed for lacunes, white matter hyperintensities (WMH), and enlarged perivascular spaces (EPVS). The total SVD burden was calculated based on lacunes, WMH, and EPVS and then summed up to generate an ordinal "total SVD burden" (range 0-3). Bivariate logistic regression models were used to identify the association between SVD and functional outcome. Results: A total of 416 patients were included in the final analysis; 44.0, 33.4, 19.2, and 3.4% of the patients had 0, 1, 2, and 3 features of SVD, respectively. In regard to individual SVD feature, lacunes (OR: 0.48, 95% CI: 0.32-0.71; OR: 0.49, 95% CI: 0.31-0.77) and WMH (OR: 0.53, 95% CI: 0.34-0.82; OR: 0.53, 95% CI: 0.33-0.85) were negatively associated with excellent outcome and good outcome. As to the total burden of SVD, three SVD features had strongest negative associations with functional outcomes (excellent outcome, OR: 0.13, 95% CI: 0.03-0.48; good outcome, OR: 0.18, 95% CI: 0.06-0.54). After adjustment for potential confounders, a high SVD burden (3 features, OR: 0.07, 95% CI: 0.01-0.41) and the score of total SVD burden (OR: 0.64, 95% CI: 0.44-0.93) remained negatively associated with excellent outcome. Conclusion: Total SVD burden negatively associated with functional outcome at 3 months in patients with acute ischemic stroke and is superior to individual SVD feature in prediction of functional outcome. MRI-based assessment of total SVD burden is highly valuable in clinical management of stroke victims and could help guide the allocation of resources to improve outcome.

White-Matter Hyperintensities and Lacunar Infarcts Are Associated with an Increased Risk of Alzheimer's Disease in the Elderly in China.

BACKGROUND AND PURPOSE: This study investigated the contribution of white-matter hyperintensities (WMH) and lacunar infarcts (LI) to the risk of Alzheimer's disease (AD) in an elderly cohort in China. METHODS: Older adults who were initially cognitively normal were examined with MRI at baseline, and followed for 5 years. WMH were classified as mild, moderate, or severe, and LI were classified into a few LI (1 to 3) or many LI (≥4). Cognitive function was assessed using the Mini Mental State Examination and the Activities of Daily Living scale. RESULTS: Among the 2,626 subjects, 357 developed AD by the end of the 5-year follow-up period. After adjusting for age and other potential confounders, having only WMH, having only LI, and having both WMH and LI were associated with an increased risk of developing AD compared with having neither WMH nor LI. Moderate and severe WMH were associated with an increased risk of developing AD compared with no WMH. Furthermore, patients with many LI had an increased risk of developing AD compared with no LI. CONCLUSIONS: Having moderate or severe WMH and many LI were associated with an increased risk of developing AD, with this being particularly striking when both WMH and LI were present.

Metabolic syndrome contributes to cognitive impairment in patients with Parkinson's disease.

INTRODUCTION: Metabolic syndrome (MetS) increases the risk of cognitive impairment in normal aging but this has not been studied in Parkinson's Disease (PD). The purpose of this study was to investigate the impact of MetS on cognitive impairment in PD. METHODS: This study investigated subjects older than 60 years who were diagnosed with PD. They were enrolled into this study between January 2010 and December 2011, and followed for 5 years. The assessment of cognitive function in subjects with PD was based on the cognitive and neuropsychiatric tests, and MetS was diagnosed according to the National Cholesterol Education Program's Adult Treatment Panel III. The subjects were divided into three groups according to the cognitive function at the end of follow-up: PD with normal cognitive function (PD-NC), mild cognitive impairment in PD (PD-MCI) and PD dementia (PDD). RESULTS: Of the 787 subjects with PD included in our study, 255 (32.4%) were diagnosed with PD-MCI, and 105 (13.3%) were diagnosed with PDD. MetS was significantly associated with PD-MCI (odds radio [OR]: 1.45, 95% confidence interval [CI]: 1.17-1.72) and PDD (OR: 2.12, 95% CI: 1.57-2.83). The associations between MetS and the main cognition domains of PDD were statistically significant. The treatment of MetS was helpful in reducing the risk of PDD. CONCLUSIONS: We found that MetS increase the risk of cognitive impairment in patients with PD, and is significantly associated with the severity of cognitive impairment. The results suggest that the intervention against MetS is helpful in managing cognitive impairment in PD.

Clinical surrogate markers for predicting metabolic syndrome in middle-aged and elderly Chinese.

AIMS/INTRODUCTION: The present study evaluated the ability of lipid accumulation product (LAP), visceral adiposity index (VAI), and the product of triglycerides and glucose (TyG), three novel markers, in identifying metabolic syndrome (MetS) with different criteria in middle-aged and elderly Chinese. MATERIALS AND METHODS: During June 2012 to January 2013, 992 consecutive patients (age ≥40 years) were enrolled at Daping Hospital. The criteria of MetS were based on the International Diabetes Federation and the modified National Cholesterol Education Program's Adult Treatment Panel III. VAI, LAP and TyG were computed based on a published mathematical model. RESULTS: The prevalence of MetS was 42.8%. The receiver operating characteristic curve found LAP, VAI and TyG were positively related to MetS in both criteria. The optimal cut-offs of VAI, LAP and TyG for the modified National Cholesterol Education Program's Adult Treatment Panel III and International Diabetes Federation criteria were 2.015, 31.465 and 8.706, and 2.035, 37.99 and 8.697, respectively. After adjustment of potential confounding factors, VAI, LAP and TyG were significantly correlated with MetS in all criteria according to optimal cut-offs. For MetS, reliable predictive value was observed in different subgroups (age and sex). LAP showed the greatest area under the curve in MetS with the International Diabetes Federation definition (area under the curve 0.887, 95% confidence interval 0.852-0.922). CONCLUSIONS: AP, VAI and TyG were reliable surrogate markers for identifying MetS in middle-aged and elderly Chinese. LAP could be a better parameter than VAI and TyG for predicting MetS in the present study.

Visceral adiposity index, lipid accumulation product and intracranial atherosclerotic stenosis in middle-aged and elderly Chinese.

We investigated the association of the newly established lipid accumulation product (LAP) and visceral adiposity index (VAI) with intracranial atherosclerotic stenosis (ICAS) in middle-aged and elderly Chinese. From June 2012 to January 2013, consecutive patients ≥40 years of age who underwent cerebral vascular imaging for various medical reasons were enrolled in this study. Multivariate logistic regression models were used to evaluate the correlation of VAI and LAP with the risk of ICAS. In total, 845 patients were included in the study. The prevalence of ICAS gradually increased in females and in all patients with advancing tertiles of VAI or LAP. After adjusting for potential risks, both the VAI and LAP were related to ICAS in females [VAI: odds ratio (OR) = 3.25, 95% confidence interval (95%CI) = 1.17-9.03, P = 0.024; LAP: OR = 4.11, 95%CI = 1.39-12.12, P = 0.011; tertiles 3 vs. 1]. The sensitivity, specificity, and positive predictive value (PPV) were 74.7%, 45.5%, and 84.4% for VAI (cut-off: 1.71) and 79.3%, 40.5%, and 84.1% for LAP (cut-off: 23.99). The same relationships in males were not significant. Both VAI and LAP were closely associated with an increased risk of ICAS in middle-aged and elderly Chinese females.

Biogenic FeS accelerates reductive dechlorination of carbon tetrachloride by Shewanella putrefaciens CN32.

Dissimilatory metal reducing bacteria (DMRB) widely exist in the subsurface environment and are involved in various contaminant degradation and element geochemical cycling processes. Recent studies suggest that DMRB can biosynthesize metal nanoparticles during metal reduction, but it is unclear yet how such biogenic nanomaterials would affect their decontamination behaviors. In this study, we found that the dechlorination rates of carbon tetrachloride (CT) by Shewanella putrefaciens CN32 was significantly increased by 8 times with the formation of biogenic ferrous sulfide (FeS) nanoparticles. The pasteurized biogenic FeS enabled 5 times faster dechlorination than abiotic FeS that had larger sizes and irregular structure, confirming a significant contribution of the biogenic FeS to CT bioreduction resulting from its good dispersion and relatively high dechlorination activity. This study highlights a potentially important role of biosynthesized nanoparticles in environmental bioremediation.

Differences between patients with unilateral and bilateral internal carotid kinking in age distribution, risk factors and clinical relevance.

BACKGROUND: Clinical differences between patients with and without internal carotid kinking (ICK) were frequently discussed in previous literatures. However, studies comparing patients with unilateral and bilateral ICK for their characteristics are scarce. The purpose of this study was to identify the differences between these patients in age distribution, risk factors and clinical relevance. METHODS: From November 1, 2013 to January 30, 2014, all the patients who underwent carotid CT angiography and skull MRI for various medical reasons in our hospital were consecutively enrolled. Patient data were assessed simultaneously according to medical records. Then, age distribution, risk factors and prevalence of subcortical ischemic change in patients with unilateral ICK (unilateral group) and those with bilateral ICK (bilateral group) were compared statistically. RESULTS: A total of 13.5% and 14.9% study patients had unilateral and bilateral ICK, respectively. Age distribution of ICK prevalence was similar between the two groups. Compared to the unilateral group, being female was the only independent risk factor related to bilateral ICK, in both univariate (χ2=11.76, P=0.001) and logistic regression (OR =1.34, 95% CI: 1.1.18-1.65, P=0.001) analyses. Moreover, the prevalence rates of leukoaraiosis (72.1 vs. 54.8%, P=0.004) and multiple lacunar infarct (62.3 vs. 42.9%, P=0.009) in the bilateral group were significantly higher compared with the values obtained for the unilateral group. CONCLUSIONS: Compared to patients with unilateral ICK, female gender is the only risk factor associated with bilateral ICK, and subcortical ischemic change is significantly more prevalent in patients with bilateral ICK.