Application of Proteomics and Machine Learning Methods to Study the Pathogenesis of Diabetic Nephropathy and Screen Urinary Biomarkers.

Diabetic nephropathy (DN) has become the main cause of end-stage renal disease worldwide, causing significant health problems. Early diagnosis of the disease is quite inadequate. To screen urine biomarkers of DN and explore its potential mechanism, this study collected urine from 87 patients with type 2 diabetes mellitus (which will be classified into normal albuminuria, microalbuminuria, and macroalbuminuria groups) and 38 healthy subjects. Twelve individuals from each group were then randomly selected as the screening cohort for proteomics analysis and the rest as the validation cohort. The results showed that humoral immune response, complement activation, complement and coagulation cascades, renin-angiotensin system, and cell adhesion molecules were closely related to the progression of DN. Five overlapping proteins (KLK1, CSPG4, PLAU, SERPINA3, and ALB) were identified as potential biomarkers by machine learning methods. Among them, KLK1 and CSPG4 were positively correlated with the urinary albumin to creatinine ratio (UACR), and SERPINA3 was negatively correlated with the UACR, which were validated by enzyme-linked immunosorbent assay (ELISA). This study provides new insights into disease mechanisms and biomarkers for early diagnosis of DN.

Investigating metabolic dysregulation in serum of triple transgenic Alzheimer's disease male mice: implications for pathogenesis and potential biomarkers.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that lacks convenient and accessible peripheral blood diagnostic markers and effective drugs. Metabolic dysfunction is one of AD risk factors, which leaded to alterations of various metabolites in the body. Pathological changes of the brain can be reflected in blood metabolites that are expected to explain the disease mechanisms or be candidate biomarkers. The aim of this study was to investigate the changes of targeted metabolites within peripheral blood of AD mouse model, with the purpose of exploring the disease mechanism and potential biomarkers. Targeted metabolomics was used to quantify 256 metabolites in serum of triple transgenic AD (3 × Tg-AD) male mice. Compared with controls, 49 differential metabolites represented dysregulation in purine, pyrimidine, tryptophan, cysteine and methionine and glycerophospholipid metabolism. Among them, adenosine, serotonin, N-acetyl-5-hydroxytryptamine, and acetylcholine play a key role in regulating neural transmitter network. The alteration of S-adenosine-L-homocysteine, S-adenosine-L-methionine, and trimethylamine-N-oxide in AD mice serum can served as indicator of AD risk. The results revealed the changes of metabolites in serum, suggesting that metabolic dysregulation in periphery in AD mice may be related to the disturbances in neuroinhibition, the serotonergic system, sleep function, the cholinergic system, and the gut microbiota. This study provides novel insights into the dysregulation of several key metabolites and metabolic pathways in AD, presenting potential avenues for future research and the development of peripheral biomarkers.

Small Oversized Stent Graft Is Associated With Increased Patency for the Treatment of Central Venous Disease in Hemodialysis Patients.

PURPOSE: The purpose of this study was to identify the independent predictors of higher patency rates and investigate the selection of specifications of stent graft in the treatment of central venous disease. MATERIALS AND METHODS: This retrospective study included 54 patients who underwent stent-grafts' placement for the treatment of central venous disease between March 2017 and September 2022 at a tertiary hospital. The demographic data for the patients and the clinical data of the treated lesions were collected and analyzed. The patency rates of the treated lesions with different oversizing range were calculated via the Kaplan-Meier and log-rank analyses. The multivariate Cox proportional hazard models were constructed to identify the independent predictor of the target site primary patency. RESULTS: The median follow-up period was 21.5 months. The primary patency rates of the target sites were 90.7%, 72.2%, and 55.1% at 6, 12, and 24 months, respectively. The assisted primary patency rates of the lesions were 96.3%, 92.5%, and 80.3% at 6, 12, and 24 months, respectively. The log-rank analysis showed that the stent-grafts' placement with small oversizing had significantly higher primary patency rates than those with large oversizing (p=0.022). The multivariate analysis revealed that concomitant stenosis and large oversizing stent graft were the independent predictors of target site primary patency. CONCLUSIONS: Stent grafts showed reasonable primary patency for the treatment of central venous disease in hemodialysis patients. A stent graft with small oversizing is associated with better target site primary patency rates than those with large oversizing. CLINICAL IMPACT: Stent grafts showed reasonable primary patency for the treatment of central venous disease in hemodialysis patients. Few studies, however, have explored the efficiency of stent grafts to treat CVD by considering different factors such as sizing considerations, the rate of oversizing percentage, etc. A stent graft with small oversizing is associated with better target site primary patency rates than those with large oversizing. Excessive oversizing should be avoided to prevent infolding or stent collapse.

Proteomic analysis of the effects of Dictyophora polysaccharide on arsenic-induced hepatotoxicity in rats.

Arsenic (As) is a highly toxic environmental toxicant and a known human carcinogen. Long-term exposure to As can cause liver injury. Dictyophora polysaccharide (DIP) is a biologically active natural compound found in the Dictyophora with excellent antioxidation, anti-inflammation, and immune protection properties. In this study, the Sprague-Dawley (SD) rat model of As toxicity was established using a feeding method, followed by DIP treatment in rats with As-induced liver injury. The molecular mechanisms of As toxicity to the rat liver and the protective effect of DIP were investigated by proteomic studies. The results showed that 172, 328 and 191 differentially expressed proteins (DEPs) were identified between the As-exposed rats versus control rats (As/Ctrl), DIP treated rats versus As-exposed rats (DIP+As/As), and DIP treated rats versus control rats (DIP+As /Ctrl), respectively. Among them, the expression of 90 DEPs in the As/Ctrl groups was reversed by DIP treatment. As exposure caused dysregulation of metabolic pathways, mitochondria, oxidative stress, and apoptosis-related proteins in the rat liver. However, DIP treatment changed or restored the levels of these proteins, which attenuated the damage to the livers of rats caused by As exposure. The results provide new insights into the mechanisms of liver injury induced by As exposure and the treatment of DIP in As poisoning.

Effects of arsenic exposure on blood trace element levels in rats and sex differences.

Arsenic (As) is a widespread environmental metalloid and human carcinogen, and its exposure is associated with a wide range of toxic effects, leading to serious health hazards. As poisoning is a complex systemic multi-organ and multi-system damage disease. In this study, a rat model of As poisoning was established to investigate the levels of trace elements in the blood of rats and sex differences in the effect of As on every trace elements in rat blood. Twenty 6-week-old SD (Sprague Dawley) rats were randomly divided into the control group and the As-exposed group. After 3 months, the contents of 19 elements including As in the blood were detected in these two groups by inductively coupled plasma mass spectrometry (ICP-MS). As levels in the blood of As-exposed rats were significantly higher than those in the control group, with increased levels of Rb, Sr, Cs and Ce, and decreased levels of Pd. As showed a significant positive correlation with Rb. There were significant sex differences in blood Se, Pd, Eu, Dy, Ho, and Au levels in the As-exposed group. The results showed that As exposure can lead to an increase of As content in blood and an imbalance of some elements. There were sex differences in the concentration and the correlation between elements of some elements. Elemental imbalances may affect the toxic effects of As and play a synergistic or antagonistic role in As toxicity.

Efficacy and Safety of Sharp Recanalization with the Stiff End of a Microguidewire for Treatment of Refractory Central Venous Occlusions in Hemodialysis Patients.

BACKGROUND: Sharp recanalization is a viable procedure for some refractory central venous occlusions that cannot be recanalized with the conventional technique. The sharp recanalization procedures reported in previous studies are often rely on costly devices and with a certain proportion of complications. This study aimed to present an inexpensive and risk-controllable coaxial centrifugally sharp recanalization technique that was independent of any additional costly devices. METHODS: This retrospective study enrolled 8 patients who had received sharp recanalization of central venous occlusions, between August 2017 and May 2021. The sharp recanalization technique was performed centrifugally with the stiff end of a microguidewire after the lesions failed to be passed through with the conventional technique. Clinical data of patients on their lesions, technical success rate, procedure-related complications, and patency rates were collected and analyzed to assess the efficacy and safety of the technique. RESULTS: Technical success was achieved in all patients, with no complications were observed. All symptoms were ameliorated within 48h postsurgery. The median follow-up period was 22 months. All patients maintained patency or assisted patency at 12 month follow-up. CONCLUSIONS: Sharp recanalization performed centrifugally with the stiff end of the microguidewire could be a cost-effective and safe alternative procedure for the treatment of refractory central venous occlusion that cannot be recanalized with conventional technique.

Origin and diversification of a Himalayan orchid genus Pleione.

Pleione is an orchid endemically distributed in high mountain areas across the Hengduan Mountains (HDM), Himalayas, Southeast Asia and South of China. The unique flower shapes, rich colors and immense medicinal importance of Pleione are valuable ornamental and economic resources. However, the phylogenetic relationships and evolutionary history of the genus have not yet been comprehensively resolved. Here, the evolutionary history of Pleione was investigated using single-copy gene single nucleotide polymorphisms and chloroplast genome datasets. The data revealed that Pleione could be divided into five clades. Discordance in topology between the two phylogenetic trees and network and D-statistic analyses indicated the occurrence of reticulate evolution in the genus. The evolution could be attributed to introgression and incomplete lineage sorting. Ancestral area reconstruction suggested that Pleione was originated from the HDM. Uplifting of the HDM drove rapid diversification by creating conditions favoring rapid speciation. This coincided with two periods of consolidation of the Asian monsoon climate, which caused the first rapid diversification of Pleione from 8.87 to 7.83 Mya, and a second rapid diversification started at around 4.05 Mya to Pleistocene. The interaction between Pleione and climate changes, especially the monsoons, led to the current distribution pattern and shaped the dormancy characteristic of the different clades. In addition to revealing the evolutionary relationship of Pleione with orogeny and climate changes, the findings of this study provide insights into the speciation and diversification mechanisms of plants in the East Asian flora.

Analysis of sagittal spinal alignment at the adolescent age: for furniture design.

Knowledge of the parameters of the human spine is essential in designing ergonomic furniture. The purpose of this study was to evaluate spinal alignment in adolescents of various ages. The lengths, curvatures, and concave-convex spacings of the spine were investigated in 268 participants aged 9-18 years. Ten ages were classified, and the rate of increase of parameters was calculated for each age and age group. The results showed that spinal parameters, except for cervical lordosis, increased with age. Adolescents were classified as 9-10, 11-12, 13-15, and 16-18 years old. A rapid increment of lengths and concave-convex spacings occurred at ages 13-15, while that of curvatures occurred at ages 16-18. Spinal parameters differed significantly among the age groups (p < 0.05). Concave-convex spacings reflected differences in the spine more clearly than the other parameters. This study suggests the necessity of designing spine-related furniture based on spinal parameters, thus providing adaptive support for the adolescent spine, particularly the lumbar spine. Practitioner summary: This study examined spinal lengths, curvatures, and concave-convex spacings in adolescents aged 9-8 years and then divided them into four age groups. Concave-convex spacings effectively reflected spinal differences between age groups, particularly the lumbar spine. These results can inform the ergonomic design of spine-related furniture.HIGHLIGHTSSpinal parameters increased progressively between 9 and 18 years. Regression analysis showed good linear correlations between TK, LL, SK, TS, and LS with age.Age classification of adolescents was Group I (9-10 years), Group II (11-12 years), Group III (13-15 years), and Group IV (16-18 years). The rapid increment of lengths and concave-convex spacings were in Group III while that of curvatures were in Group IV.Concave-convex spacings were vital parameters to evaluate the global balance of the spine.The lumbar spine is an essential segment for characterizing spinal alignment.

Deep transfer learning of structural magnetic resonance imaging fused with blood parameters improves brain age prediction.

Machine learning has been applied to neuroimaging data for estimating brain age and capturing early cognitive impairment in neurodegenerative diseases. Blood parameters like neurofilament light chain are associated with aging. In order to improve brain age predictive accuracy, we constructed a model based on both brain structural magnetic resonance imaging (sMRI) and blood parameters. Healthy subjects (n = 93; 37 males; aged 50-85 years) were recruited. A deep learning network was firstly pretrained on a large set of MRI scans (n = 1,481; 659 males; aged 50-85 years) downloaded from multiple open-source datasets, to provide weights on our recruited dataset. Evaluating the network on the recruited dataset resulted in mean absolute error (MAE) of 4.91 years and a high correlation (r = .67, p <.001) against chronological age. The sMRI data were then combined with five blood biochemical indicators including GLU, TG, TC, ApoA1 and ApoB, and 9 dementia-associated biomarkers including ApoE genotype, HCY, NFL, TREM2, Aß40, Aß42, T-tau, TIMP1, and VLDLR to construct a bilinear fusion model, which achieved a more accurate prediction of brain age (MAE, 3.96 years; r = .76, p <.001). Notably, the fusion model achieved better improvement in the group of older subjects (70-85 years). Extracted attention maps of the network showed that amygdala, pallidum, and olfactory were effective for age estimation. Mediation analysis further showed that brain structural features and blood parameters provided independent and significant impact. The constructed age prediction model may have promising potential in evaluation of brain health based on MRI and blood parameters.

Proteomic Profiling of Cerebrum Mitochondria, Myelin Sheath, and Synaptosome Revealed Mitochondrial Damage and Synaptic Impairments in Association with 3 × Tg-AD Mice Model.

Alzheimer's disease (AD) is the most common age-associated dementia with complex pathological hallmarks. Mitochondrion, synaptosome, and myelin sheath appear to be vulnerable and play a key role in the pathogenesis of AD. To clarify the early mechanism associated with AD, followed by subcellular components separation, we performed iTRAQ (isobaric tags for relative and absolute quantification)-based proteomics analysis to simultaneously investigate the differentially expressed proteins (DEPs) within the mitochondria, synaptosome, and myelin sheath in the cerebrum of the 6-month-old triple transgenic AD (3 × Tg-AD) and 6-month-old wild-type (WT) mice. A large number of DEPs between the AD and WT mice were identified. Most of them are related to mitochondria and synaptic dysfunction and cytoskeletal protein change. Differential expressions of Lrpprc, Nefl, and Sirpa were verified by Western blot analysis. The results suggest that decreased energy metabolism, impaired amino acid metabolism and neurotransmitter synthesis, increase compensatory fatty acid metabolism, up-regulated cytoskeletal protein expression, and oxidative stress are the early events of AD. Among these, mitochondrial damage, synaptic dysfunction, decreased energy metabolism, and abnormal amino acid metabolism are the most significant events. The results indicate that it is feasible to separate and simultaneously perform proteomics analysis on the three subcellular components.

Ultrasensitive Detection of Exosome Using Biofunctionalized Gold Nanorods on a Silver-Island Film.

Exosomes are often a promising source of biomarkers for cancer diagnosis in the early stages. Therefore, it is important to develop a sensitive and low-cost detection method. Here, we introduce a new substrate using gold nanorods (GNRs) on a silver-island film that produces a 360-fold AF647 molecule fluorescence enhancement compared to glass. The amplified fluorescence was proven theoretically by using finite difference time-domain simulation (FDTD). Utilizing the enhanced fluorescence from the substrate, GNRs attached with the biomolecules and created a sandwich immunoassay that can significantly detect human CD63 antigen on the exosome. By applying the method, the detection limit of mouse IgG goes down to 0.3 ng/mL, which is considerably better than the existing methods. Moreover, the sensitivity and accuracy for clinical plasma from six patients confirm its diagnostic feasibility. The proposed substrate can be uniformly extended to the identification of other biomarkers by modifying the antibodies on the surfaces of the GNRs.

Investigating the Neurotoxic Impacts of Arsenic and the Neuroprotective Effects of Dictyophora Polysaccharide Using SWATH-MS-Based Proteomics.

Arsenic (As) is one of the most important toxic elements in the natural environment. Currently, although the assessment of the potential health risks of chronic arsenic poisoning has received great attention, the research on the effects of arsenic on the brain is still limited. It has been reported that dictyophora polysaccharide (DIP), a common bioactive natural compound found in dietary plants, could reduce arsenic toxicity. Following behavioral research, comparative proteomics was performed to explore the molecular mechanism of arsenic toxicity to the hippocampi of SD (Sprague Dawley) rats and the protective effect of DIP. The results showed that exposure to arsenic impaired the spatial learning and memory ability of SD rats, while DIP treatment improved both the arsenic-exposed rats. Proteomic analysis showed that arsenic exposure dysregulated the expression of energy metabolism, apoptosis, synapse, neuron, and mitochondria related proteins in the hippocampi of arsenic-exposed rats. However, DIP treatment reversed or restored the expression levels of these proteins, thereby improving the spatial learning and memory ability of arsenic-exposed rats. This study is the first to use high-throughput proteomics to reveal the mechanism of arsenic neurotoxicity in rats as well as the protective mechanism of DIP against arsenic neurotoxicity.

Targeted metabolomics study of early pathological features in hippocampus of triple transgenic Alzheimer's disease male mice.

Alzheimer's disease (AD) is a serious neurodegenerative disease in people of age 65 or above. The detailed etiology and pathogenesis of AD have not been elucidated yet. In this study, the hippocampi of 2- and 6-month-old triple transgenic Alzheimer's disease male mice and age-sex-matched wild-type (WT) mice were analyzed by using targeted metabolomics approach. Compared with WT mice, 24 and 60 metabolites were found with significant differences in 2- and 6-month-old AD mice. Among these, 14 metabolites were found common while 10 metabolites showed consistent variable trends in both groups. These differential metabolites are found associated with amino acid, lipid, vitamin, nucleotide-related base, neurotransmitter and energy metabolisms, and oxidative stress. The results suggest that these differential metabolites might play a critical role in AD pathophysiology, and may serve as potential biomarkers for AD. Moreover, the results highlight the involvement of abnormal purine, pyrimidine, arginine, and proline metabolism, along with glycerophospholipid metabolism in early pathology of AD. For the first time, several differential metabolites are found to be associated with AD in this study. Targeted metabolomics can be used for rapid and accurate quantitative analysis of specific target metabolites associated with AD.

Metabolic characteristics of plasma bile acids in patients with intrahepatic cholestasis of pregnancy-mass spectrometric study.

INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is one of the more common complications in the middle and late stages of pregnancy, which requires early detection and intervention. OBJECTIVE: The aim of the study is to investigate the changes in the metabolic profile of bile acids (BAs) in plasma of pregnant women with ICP and to look biomarkers for the diagnosis and grading of ICP, and to explore the disease mechanism. METHODS: The targeted metabolomics based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze plasma BAs. RESULTS: Twenty-seven BAs can be quantified in all participants. Among them, 22 BAs were identified as differential BAs between ICP and control groups. Five BAs include 3ß-CA, 3ß-DCA, CDCA-3Gln, NCA, and Tß-MCA, were found to be associated with ICP for the first time. Nine BAs include NCA, GCA, GCDCA, GHCA, GUDCA, HCA, TCA, TCDCA and THCA, can be used as possible ICP diagnostic biomarkers. Four BAs, i.e., GLCA, THCA, GHCA and TLCA-3S may be used as potential biomarkers for ICP grading. CONCLUSION: There were significant differences in plasma BA profiles between ICP patients and the control. The BA profiles of mild ICP group and severe ICP group partially overlapped. Potential diagnostic and grading BA markers were identified. A significant characteristic of ICP group was the increase of conjugated BAs. A mechanism to sustain the equilibrium of BA metabolism and adaptive response has been developed in ICP patients to accelerate excretion and detoxification.

Potential biomarkers identified in plasma of patients with gestational diabetes mellitus.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common complication during pregnancy. Looking for reliable diagnostic markers for early diagnosis can reduce the impact of the disease on the fetus OBJECTIVE: The present study is designed to find plasma metabolites that can be used as potential biomarkers for GDM, and to clarify GDM-related mechanisms METHODS: By non-target metabolomics analysis, compared with their respective controls, the plasma metabolites of GDM pregnant women at 12-16 weeks and 24-28 weeks of pregnancy were analyzed. Multiple reaction monitoring (MRM) analysis was performed to verify the potential marker RESULTS: One hundred and seventy-two (172) and 478 metabolites were identified as differential metabolites in the plasma of GDM pregnant women at 12-16 weeks and 24-28 weeks of pregnancy, respectively. Among these, 40 metabolites were overlapped. Most of them are associated with the mechanism of diabetes, and related to short-term and long-term complications in the perinatal period. Among them, 7 and 10 differential metabolites may serve as potential biomarkers at the 12-16 weeks and 24-28 weeks of pregnancy, respectively. By MRM analysis, compared with controls, increased levels of 17(S)-HDoHE and sebacic acid may serve as early prediction biomarkers of GDM. At 24-28 weeks of pregnancy, elevated levels of 17(S)-HDoHE and L-Serine may be used as auxiliary diagnostic markers for GDM CONCLUSION: Abnormal amino acid metabolism and lipid metabolism in patients with GDM may be related to GDM pathogenesis. Several differential metabolites identified in this study may serve as potential biomarkers for GDM prediction and diagnosis.

Highly linear wavelength-tunable microring-assisted Mach-Zehnder modulator.

This paper proposes a wavelength-tunable microring-assisted Mach-Zehnder modulator (MRAMZM) based on the graphene structure. The integrated graphene on the racetrack microring achieves the tunability of the working wavelength and introduces the one-cycle loss of the microring corresponding to the working wavelength. Through the analysis of the modulation characteristic curve with loss, it is determined to eliminate the second- and third-order nonlinearities. The graphene-embedded asymmetric coupling structure is used to control the coupling efficiency, and finally, the linearity of the device in the range of 2 nm (1.5543 to 1.5562 µm) is improved. The simulation result shows that when the working wavelength is in this range, the spurious-free dynamic range third-order intermodulation distortion of this modulator is about 114dB⋅Hz2/3.

[Cognition function and its influencing factors among people aged 55 and above in 4 provinces of China from 2018 to 2019].

OBJECTIVE: To analyze the current situation of cognition function of people aged 55 and above in 4 provinces of China, and to explore its influencing factors of demographic characteristics. METHODS: Using the baseline data of the "Community-based Cohort Study on Nervous System Diseases", middle-aged and older populations aged ≥55 years with completed data on demographic and economic factors and the cognitive function scale were selected as study subjects. A total of 5103 subjects were included in the study(male 2294, female 2809, 55-64 years old 1875, 65-74 years old 2197, 75-94 years old 1031). Multi-stage stratified cluster random sampling was adopted, and survey subjects were selected from a total of 32 communities in Hebei, Zhejiang, Shaanxi and Hunan provinces. The baseline data obtained from a face-to-face questionnaire survey was entered using electronic tablets on the spot. Montreal cognitive assessment(MoCA) and activities of daily living scale(ADL) were used to determine mild cognitive impairment(MCI) and its subtypes. Multiple linear regression and multiple Logistic regression model were used to analyze the influencing factors of cognitive function in populations. RESULTS: Among middle-aged and elderly Chinese populations, the score of overall cognitive function and its sub-domains were 21. 79±6. 17, 11. 20±4. 18(memory), 8. 81±3. 31(execution), 5. 33±1. 76(visual-spatial ability), 4. 53±1. 40(language), 13. 32±3. 98(attention) and 5. 54±0. 95(orientation). The prevalence of MCI and its subtypes were 35. 86%, 4. 57%(amnestic MCI single domain, aMCI-SD), 3. 64%(nonamnestic MCI single domain, naMCI-SD), 6. 68%(amnestic MCI multiple domains, aMCI-MD) and 3. 94%(nonamnestic MCI multiple domains, naMCI-MD). Subjects aged ≥55 years, living in rural areas, or with per capita monthly household income less than 1000 yuan had lower score of overall cognitive function and its sub-domains(P<0. 05), and also had lower prevalence of MCI and its subtypes. The OR of MCI, naMCI-SD, aMCI-MD and naMCI-MD was 2. 38(95% CI 1. 98-2. 86), 1. 54(95% CI 1. 01-2. 34), 2. 30(95% CI 1. 65-3. 20) and 3. 11(95% CI 2. 07-4. 69) respectively in subjects aged ≥75 years versus those aged 55-64 years, and of MCI, naMCI-SD and aMCI-MD was 3. 02(95%CI 2. 48-3. 66), 4. 30(95%CI 2. 69-6. 88) and 2. 62(95%CI 1. 81-3. 79) respectively in those living in rural areas versus those living in city areas. Subjects with higher per capita monthly household income had lower ORs of MCI and its subtypes. CONCLUSION: The prevalence rate of MCI among people aged 55 and above in four provinces in China is at a relatively high level. In the studied 4 provinces of China, about 35% of Chinese middle-aged and elderly populations are affected by MCI. The status of overall cognitive function and its sub-domains of subjects aged 75 years and above, living rural areas and with lower per capita monthly household income are poor, and they may have a higher risk of MCI and its subtypes.

Augmentation of miR-202 in varicose veins modulates phenotypic transition of vascular smooth muscle cells by targeting proliferator-activated receptor-γ coactivator-1α.

In varicose veins, vascular smooth muscle cells (VSMCs) often show abnormal proliferative and migratory rates and phenotypic transition. This study aimed to investigate whether microRNA (miR)-202 and its potential target, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), were involved in VSMC phenotypic transition. miR-202 expression was analyzed in varicose veins and in VSMCs conditioned with platelet-derived growth factor. The effect of miR-202 on cell proliferation and migration was assessed. Furthermore, contractile marker SM-22α, synthetic markers vimentin and collagen I, and PGC-1α were analyzed by Western blot analysis. The modulation of PGC-1α expression by miR-202 was also evaluated. In varicose veins and proliferative VSMCs, miR-202 expression was upregulated, with decreased SM-22α expression and increased vimentin and collagen I expression. Transfection with a miR-202 mimic induced VSMC proliferation and migration, whereas a miR-202 inhibitor reduced cell proliferation and migration. miR-202 mimic constrained luciferase activity in HEK293 cells that were cotransfected with the PGC-1α 3'-untranslated region (3'-UTR) but not those with mutated 3'-UTR. miR-202 suppressed PGC-1α protein expression, with no influence on its messenger RNA expression. PGC-1α mediated VSMC phenotypic transition and was correlated with reactive oxygen species production. In conclusion, miR-202 affects VSMC phenotypic transition by targeting PGC-1α expression, providing a novel target for varicose vein therapy.

Estrogen receptor variant ER-α36 promotes tamoxifen agonist activity in glioblastoma cells.

Glioblastoma (GBM) is a highly infiltrative and malignant primary brain tumor. Despite aggressive therapy, patients with GBM have a dismal prognosis with median survival of approximately 1 year. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), has been used to treat GBM for many years. ER-α36 is a novel variant of estrogen receptor-alpha66 (ER-α66) and can mediate cell proliferation through estrogen or anti-estrogen signaling in different cancer cells. Previously, we found that ER-α36 was highly expressed in GBM and was involved in the tamoxifen sensitivity of glioblastoma cells. However, the molecular mechanism responsible has not been well established. Here, we found that ER-α36 is highly expressed in glioblastoma specimens. We further found that ER-α36 knockdown increased sensitivity of glioblastoma U87 cells to TAM and decreased autophagy in these cells. However, ER-α36 overexpression decreased TAM sensitivity and induced autophagy. We also established TAM-resistant glioblastoma U251 cells by a long-term culture in TAM-containing medium and found that TAM-resistant cells showed a six-fold increase of ER-α36 mRNA expression and elevated basal autophagy. ER-α36 knockdown in these TAM-resistant cells restored TAM sensitivity. In addition, we recapitulated the physiologically relevant tumor microenvironment in an integrated microfluidic device, and U87 cells were treated with a gradient of TAM. We found that ER-α36 expression is consistent with autophagy protein P62 in a three-dimensional microenvironment. In summary, these results indicate that ER-α36 contributes to tamoxifen resistance in glioblastoma cells presumably through regulation of autophagy.

PTEN silencing enhances neuronal proliferation and differentiation by activating PI3K/Akt/GSK3ß pathway in vitro.

The failure of neuronal proliferation and differentiation is a major obstacle for neural repair and regeneration after traumatic central nervous system (CNS) injury. PTEN acts as an intrinsic brake on the neuronal cells, but its roles and mechanism still remain to be clarified. Herein, for the first time we confirmed that PTEN had a dual effect on the neuronal cells in vitro. Firstly, we found that PTEN knockdown significantly promoted cell proliferation and differentiation. Then, PTEN knockdown activated PI3K/Akt and Wnt/ß-catenin pathways in vitro. Further evidence revealed that GSK3ß as a key node involved in PTEN controlling cell proliferation and differentiation in PC12 cells. In addition, we identified that PTEN-GSK3ß pathway modulated neuronal proliferation via ß-catenin. Taken together, these results suggest that PTEN silencing enhances neuronal proliferation and differentiation by activating PI3K/Akt/GSK3ß pathway that it may be a promising therapeutic approach for CNS injury.