Publications by authors named "Sha Li"

788 Publications

Long non-coding RNA ADAMTS9-AS2 inhibits liver cancer cell proliferation, migration and invasion.

Exp Ther Med 2021 Jun 26;21(6):559. Epub 2021 Mar 26.

The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.

Long non-coding RNA (lncRNA) ADAM metallopeptidase with thrombospondin type 1 motif 9 antisense RNA 2 (ADAMTS9-AS2) is involved in various types of cancer, such as ovarian cancer, lung cancer and clear cell renal cell carcinoma. However, the roles of ADAMTS9-AS2 in liver cancer are not completely understood. The present study aimed to determine the functional role of ADAMTS9-AS2 in human liver cancer and investigate the potential underlying molecular mechanisms. The expression levels of ADAMTS9-AS2 and ADAMTS9 were determined following ADAMTS9-AS2 overexpression and knockdown. The results indicated that ADAMTS9-AS2 overexpression and knockdown increased and decreased ADAMTS9 mRNA and protein expression levels, respectively, indicating that alterations in ADAMTS9 expression corresponded with ADAMTS9-AS2 expression. Subsequently, the effects of ADAMTS9-AS2 on liver cancer cell proliferation, migration and invasion were analyzed by performing Cell Counting Kit-8, wound healing and Transwell assays, respectively. The results demonstrated that ADAMTS9-AS2 inhibited liver cancer cell proliferation, migration and invasion. Finally, the effect of ADAMTS9 on PI3K/AKT/mTOR signaling pathway-associated proteins [AKT, phosphorylated-AKT, phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit β (PIK3CB), mTOR and phosphorylated-mTOR], several key autophagy-related proteins [light chain 3-I/II (LC3-I/II), beclin 1 (BECN1) and sequestosome 1 (SQSTM1)] and apoptosis-related proteins (Bax and Bcl-2) was detected via western blotting. The results suggested that ADAMTS9-AS2 downregulated the phosphorylation of AKT and mTOR, the protein expression level of PIK3CB, as well as the expression levels of autophagy protein SQSTM1 and antiapoptotic protein Bcl-2. By contrast, ADAMTS9-AS2 upregulated the expression levels of autophagy proteins LC3-II and BECN1, and the proapoptotic protein Bax. Collectively, ADAMTS9-AS2 inhibited liver cancer cell proliferation, migration and invasion via inhibiting the PI3K/AKT/mTOR signaling pathway. The present study provided a novel insight into the role of ADAMTS9-AS2 in liver cancer.
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http://dx.doi.org/10.3892/etm.2021.9991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027749PMC
June 2021

Calmodulin-Binding Protein 60b is a central transcriptional activator of immunity.

Plant Physiol 2021 Apr 12. Epub 2021 Apr 12.

State Key laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Tai'an, 271018, China.

Plants use a dual defense system to cope with microbial pathogens. The first involves pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) which is conferred by membrane receptors, and the second involves effector-triggered immunity (ETI), which is conferred by disease-resistance proteins (nucleotide-binding leucine-rich repeat containing proteins; NLRs). Calmodulin-Binding Protein 60 (CBP60) family transcription factors are crucial for pathogen defense: CBP60g and Systemic Acquired Resistance Deficient 1 (SARD1) positively regulate immunity, whereas CBP60a negatively regulates immunity. The roles of other Arabidopsis (Arabidopsis thaliana) CBP60s remain unclear. We report that CBP60b positively regulates immunity, and is redundant with-yet distinct from-CBP60g and SARD1. By combining ChIP-PCRs and luciferase (LUC) reporter assays, we demonstrate that CBP60b is a transcriptional activator of immunity genes. Surprisingly, CBP60b loss-of-function results in autoimmunity, exhibiting a phenotype similar to that of CBP60b gain-of-function. Mutations at the EDS1-PAD4-dependent (ENHANCED DISEASE SUSCEPTIBILITY 1- PHYTOALEXIN DEFICIENT 4) ETI pathway fully suppressed the defects of CBP60b loss-of-function but not those of CBP60b gain-of-function, suggesting that CBP60b is monitored by NLRs. Functional loss of SUPPRESSOR OF NPR1-1, CONSTITUTIVE 1 (SNC1), an R-gene, partially rescued the phenotype of cbp60b, further supporting that CBP60b is a protein targeted by pathogen effectors, i.e., a guardee. Unlike CBP60g and SARD1, CBP60b is constitutively and highly expressed in unchallenged plants. Transcriptional and genetic studies further suggest that CBP60b plays a role redundant with CBP60g and SARD1 in pathogen-induced defense, whereas CBP60b has a distinct role in basal defense, partially via direct regulation of CBP60g and SARD1.
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http://dx.doi.org/10.1093/plphys/kiab164DOI Listing
April 2021

Noise sensitivity associated with nonrestorative sleep in Chinese adults: a cross-sectional study.

BMC Public Health 2021 Apr 1;21(1):643. Epub 2021 Apr 1.

Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, China.

Background: Nonrestorative sleep is a common sleep disorder with a prevalence ranging from 1.4 to 35%, and is associated with various psychological and physical health issues. Noise exposure and noise sensitivity have been proposed to contribute to nonrestorative sleep. This study aimed to examine the relationships among noise, noise sensitivity, nonrestorative sleep, and physiological sleep parameters in Chinese adults.

Methods: A cross-sectional household survey was conducted with randomly selected Chinese adults based on a frame stratified by geographical districts and types of quarters in Hong Kong. We administered a battery of questionnaires, including the Nonrestorative Sleep Scale, the Weinstein Noise Sensitivity Scale, the ENRICHD Social Support Instrument, the Patient Health Questionnaire, and the Perceived Stress Scale to assess nonrestorative sleep, noise sensitivity, social support, somatic symptoms and stress, respectively. Anxiety and depression were evaluated by the Hospital Anxiety and Depression Scale while sociodemographic and lifestyle characteristics were assessed with an investigator-developed sheet. Nocturnal noise level and physiological sleep parameters were measured during nighttime for a week by noise dosimetry and actigraphy, respectively. A structured multiphase linear regression was conducted to estimate associations.

Results: A total of 500 adults (66.4% female) with an average age of 39 years completed this study. Bivariate regressions showed that age, marital status, occupation, family income, season, exercise, cola and soda consumption, social support, somatic symptoms, stress, depression, noise sensitivity, total sleep time, and awakenings were associated with nonrestorative sleep. In the multivariable analysis, family income, season, exercise, social support, somatic symptoms, stress, and depression remained associated with nonrestorative sleep. Specifically, a one-unit increase of noise sensitivity was associated with 0.08 increase in nonrestorative sleep (95% confidence interval [CI]: 0.01, 0.15, p = 0.023). Nocturnal noise was negatively associated with time in bed (b = - 1.65, 95% CI: - 2.77, - 0.52, p = 0.004), total sleep time (b = - 1.61, 95% CI: - 2.59, - 0.62, p = 0.001), and awakenings (b = - 0.16, 95% CI: - 0.30, - 0.03, p = 0.018), but was not associated with nonrestorative sleep.

Conclusions: Nonrestorative sleep was predicted by noise sensitivity in addition to family income, season, exercise, social support, somatic symptoms, stress, and depression.
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http://dx.doi.org/10.1186/s12889-021-10667-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017893PMC
April 2021

Effect of Fluorofenidone Against Paraquat-Induced Pulmonary Fibrosis Based on Metabolomics and Network Pharmacology.

Med Sci Monit 2021 Apr 1;27:e930166. Epub 2021 Apr 1.

Department of Pharmacy, The First Hospital Affiliated with Hunan Normal University, Changsha, Hunan, China (mainland).

BACKGROUND Fluorofenidone (AKF-PD) is an anti-fibrotic small-molecule compound. Its mechanism of action on paraquat (PQ)-induced pulmonary fibrosis is still unclear. MATERIAL AND METHODS Forty-eight SD rats were divided into 4 groups: control group, PQ group, PQ+AKF-PD group, and AKF-PD group. The pathological changes of lung tissues were observed by Masson and HE staining. The UPLC-QTOF-MS analysis was performed to detect the differences in metabolites among groups, then the possible mechanisms of the anti-pulmonary fibrosis effects of fluorofenidone were further revealed by network pharmacology analysis. Biological methods were used to verify the results of the network pharmacology analysis. RESULTS The results showed that fluorofenidone treatment significantly alleviated paraquat-induced pulmonary fibrosis. Metabolomics analysis showed that 18 metabolites were disordered in the serum of paraquat-poisoned rats, of which 13 were restored following fluorofenidone treatment. Network pharmacology analysis showed that the drug screened a total of 12 targets and mainly involved multiple signaling pathways and metabolic pathways to jointly exert anti-pulmonary fibrosis effects. Autophagy is the main pathway of fluorofenidone in treatment pulmonary fibrosis. The western blot results showed that fluorofenidone upregulated the expression of LC3-II/I and E-cadherin, and downregulated the expression of p62, alpha-SMA, and TGF-ß1, which validated that fluorofenidone could inhibit the development of paraquat-induced pulmonary fibrosis by increasing autophagy. CONCLUSIONS In conclusion, metabolomics combined with network pharmacology research strategy revealed that fluorofenidone has a multi-target and multi-path mechanism of action in the treatment of pulmonary fibrosis.
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http://dx.doi.org/10.12659/MSM.930166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023277PMC
April 2021

Fluorofenidone attenuates paraquat‑induced pulmonary fibrosis by regulating the PI3K/Akt/mTOR signaling pathway and autophagy.

Mol Med Rep 2021 Jun 31;23(6). Epub 2021 Mar 31.

Department of Pharmacy, The First Hospital Affiliated with Hunan Normal University, Changsha, Hunan 410005, P.R. China.

Paraquat (PQ) is a widely used herbicide that is severely toxic to humans and animals. Pulmonary fibrosis is a disorder that can result from PQ poisoning. Fluorofenidone (AKF‑PD) is a novel small molecule pyridone drug with a widespread and clear anti‑organ fibrosis effect; however, its mechanism of action on PQ poisoning‑induced pulmonary fibrosis is not clear. The purpose of the present study was to investigate the protective effect and underlying mechanism of AKF‑PD on PQ poisoning‑induced pulmonary fibrosis. Human alveolar epithelial cells (HPAEpiC) and Sprague‑Dawley rats were treated with AKF‑PD in the presence or absence of PQ. Hematoxylin‑eosin and Masson staining were used to observe the morphological changes in lung tissue. Cell Counting Kit‑8 and lactate dehydrogenase assays were used to evaluate the viability of HPAEpiC cells. ELISA was used to detect inflammatory factors and the collagen content. Finally, the effects of AKF‑PD on pulmonary fibrosis, as well as the underlying mechanisms, were evaluated via western blotting, reverse transcription‑quantitative PCR and immunofluorescence analysis. AKF‑PD effectively alleviated PQ‑induced pulmonary fibrosis and reduced the expression of oxidative stress and inflammatory factors. Moreover, AKF‑PD treatment effectively inhibited the PI3K/Akt/mTOR signaling pathway and upregulated autophagy. Overall, these findings suggested that AKF‑PD can alleviate PQ‑induced inflammation and pulmonary fibrosis by inhibiting the PI3K/Akt/mTOR signaling pathway and by upregulating autophagy.
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http://dx.doi.org/10.3892/mmr.2021.12044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025463PMC
June 2021

Long-term impact of ambient air pollution on preterm birth in Xuzhou, China: a time series study.

Environ Sci Pollut Res Int 2021 Mar 27. Epub 2021 Mar 27.

Department of Maternal Child and Adolescent Health, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.

Accumulating evidence witnesses the negative influence of air pollution on human health, but the relationship between air pollution and premature babies has been inconsistent. In this study, the association between weekly average concentration of air pollutants and preterm birth (PTB) was conducted in Xuzhou, a heavy industry city, in China. We constructed a distributed lag non-linear model (DLNM), an ecological study, to access the associations between ambient air pollutants and PTB in this study. Totally, 5408 premature babies were included, and the weekly average levels of PM, PM, SO, NO, O, and CO were 61.24, 110.21, 22.55, 40.55, 104.45, and 1.04 mg/m, respectively. We found that PM, PM, SO, and NO significantly increased the risk of PTB, and the susceptibility windows of these contaminants were the second trimester and third trimester (from 12 to 29 weeks). Every 10 μg/m increase of PM, PM, SO, and NO, the greatest relative risk (RR) values and 95% confidence interval (CI) on PTB were 1.0075 [95% CI, 1.0019-1.0131], 1.0053 [95% CI, 1.0014-1.0092], 1.0203 [95% CI, 1.0030-1.0379], and 1.0170 [95% CI, 1.0052-1.0289] in lag 16th, 18th, 19th, and 20th gestational weeks, respectively. No significant influence of O and CO were found on preterm birth. Subgroup analysis showed that the risk of premature delivery was higher for younger pregnant women and in warm season. This finding shows that prenatal exposure to ambient air pollutants is associated with preterm birth, and there existed an exposure window period.
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http://dx.doi.org/10.1007/s11356-021-13621-2DOI Listing
March 2021

Structure characterization, antioxidant and emulsifying capacities of exopolysaccharide derived from Pantoea alhagi NX-11.

Carbohydr Polym 2021 Jun 27;261:117872. Epub 2021 Feb 27.

Hubei Sanning Chemical Industry CO., Ltd, Yichang, 443200, China.

Pantoea alhagi exopolysaccharides (PAPS) have been shown to enhance crop resistance to abiotic stress. However, physicochemical properties and structure of PAPS have not yet been analyzed. In this study, two PAPSs, named PAPS1 and PAPS2, were isolated and purified from the P. alhagi NX-11. The results showed PAPS1 and PAPS2 were composed of glucose, galactose, glucuronic acid, glucosamine and mannose with average molecular weight of 1.326 × 10 Da and 1.959 × 10 Da, respectively. Moreover, the structure of PAPS1 and PAPS2 was investigated by FT-IR and NMR analysis. PAPS1 was identified to have the backbone structure of →4)-β-D-GlcpA-(1→2)-α-D-Galp-(1→3)-β-D-Galp-(1→3)-β-D-GlcpN- (1→3)-α-D-Galp-(1→3)-β-D-Galp-(1→. PAPS2 had the backbone structure of →4)-β-D-GlcpA-(1→2)-α-D-Galp-(1→3)-β-D-Glcp-(1→3)-β-D-GlcpN-(1→3)-α-D-Galp-(1→3)-α-D-GlcpN-(1→. In addition, PAPS1 and PAPS2 had moderate antioxidant and emulsifying capacities. Overall, the structure analysis of PAPS may point out the direction for the subsequent study of PAPS-mediated microbial and plant interactions, and further exploration of the application of PAPS.
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http://dx.doi.org/10.1016/j.carbpol.2021.117872DOI Listing
June 2021

Measurement properties of the simplified Chinese version of Nonrestorative Sleep Scale in adolescents.

Health Soc Care Community 2021 Mar 23. Epub 2021 Mar 23.

School of Nursing, The University of Hong Kong, Hong Kong, China.

This study aimed to assess the measurement properties of a simplified Chinese version of the Nonrestorative Sleep Scale (NRSS) among adolescents. We obtained a simplified Chinese NRSS by the standard forward-backward translation procedures and administered it to 486 students who were attending Grade 7-11 in Nanjing, China. Furthermore, Pittsburgh Sleep Quality Index, Athens Insomnia Scale, Centre for Epidemiological Studies Depression Scale, and Toronto Hospital Alertness Test were also self-completed for measuring sleep quality, insomnia, depression and alertness respectively. The sample was randomly split into two halves, with the first half used to explore the scale structure by exploratory factor analysis (EFA), and the second half used to confirm the identified structure by confirmatory factor analysis (CFA). A total of 481 adolescents (49% male) with a mean age of 16 years (range: 13-18) completed this study. In the other half of 250 adolescents, the root mean square error of approximation (RMSEA), standardised root mean square residual, and comparative fit index (CFI) in CFA, which tested the four-factor structure obtained from EFA, were 0.062, 0.051 and 0.975, respectively. Convergent validity was demonstrated from a significant correlation of the simplified Chinese NRSS with sleep quality (r = -0.62), insomnia (r = -0.71), depression (r = -0.60) and alertness (r = 0.54). The internal consistency and test-retest reliability for the global scale were 0.83 and 0.86 respectively. Measurement invariance was established between males and females with the changes of both CFI and RMSEA < 0.01. The simplified Chinese NRSS is valid and reliable for measuring NRS among Chinese adolescents.
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http://dx.doi.org/10.1111/hsc.13354DOI Listing
March 2021

Enhancing ectoine production by recombinant Escherichia coli through step-wise fermentation optimization strategy based on kinetic analysis.

Bioprocess Biosyst Eng 2021 Mar 10. Epub 2021 Mar 10.

State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University, Nanjing, 211816, People's Republic of China.

In this study, the recombinant ectoine-producing Escherichia coli ET01 was constructed by introducing the ectABC operon from Halomonas venusta ZH. To further improve ectoine production, the regulation of the fermentation process was systematically investigated. First, the effects of the initial glucose concentrations and glucose feeding mode on ectoine production were analyzed. Using a combination of pH-feedback feeding and glucose-controlled feeding, the ectoine titer reached 25.5 g/L, representing an 8.8-fold increase over standard batch culture. Then, the effects of dissolved oxygen (DO) levels (50, 40, 30, or 20%) on ectoine production were studied, and a DO control strategy was developed based on the fermentation kinetics. When the final optimized two-stage fermentation strategy was used, the ectoine titer reached 47.8 g/L, which was the highest level of ectoine produced by E. coli fermentation. The fermentation regulation strategy developed in this study might be useful for scaling up the commercial production of ectoine.
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http://dx.doi.org/10.1007/s00449-021-02541-7DOI Listing
March 2021

Acceleration of western Arctic sea ice loss linked to the Pacific North American pattern.

Nat Commun 2021 03 9;12(1):1519. Epub 2021 Mar 9.

Department of Geology and Geophysics, University of Utah, Salt Lake City, USA.

Recent rapid Arctic sea-ice reduction has been well documented in observations, reconstructions and model simulations. However, the rate of sea ice loss is highly variable in both time and space. The western Arctic has seen the fastest sea-ice decline, with substantial interannual and decadal variability, but the underlying mechanism remains unclear. Here we demonstrate, through both observations and model simulations, that the Pacific North American (PNA) pattern is an important driver of western Arctic sea-ice variability, accounting for more than 25% of the interannual variance. Our results suggest that the recent persistent positive PNA pattern has led to increased heat and moisture fluxes from local processes and from advection of North Pacific airmasses into the western Arctic. These changes have increased lower-tropospheric temperature, humidity and downwelling longwave radiation in the western Arctic, accelerating sea-ice decline. Our results indicate that the PNA pattern is important for projections of Arctic climate changes, and that greenhouse warming and the resultant persistent positive PNA trend is likely to increase Arctic sea-ice loss.
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http://dx.doi.org/10.1038/s41467-021-21830-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943814PMC
March 2021

Prevalence and prediction of Lyme disease in Hainan province.

PLoS Negl Trop Dis 2021 Mar 18;15(3):e0009158. Epub 2021 Mar 18.

People's Hospital of Sanya, Hainan province, China.

Lyme disease (LD) is one of the most important vector-borne diseases worldwide. However, there is limited information on the prevalence and risk analysis using correlated factors in the tropical areas. A total of 1583 serum samples, collected from five hospitals of Hainan Province, were tested by immunofluorescence assay (IFA) and western blot (WB) analyses using anti-Borrelia burgdorferi antibodies. Then, we mapped the distribution of positive rate (by IFA) and the spread of confirmed Lyme patients (by WB). Using ArcGIS, we compiled host-vector-human interactions and correlated data as risk factor layers to predict LD risk in Hainan Province. There are three LD hotspots, designated hotspot I, which is located in central Hainan, hotspot II, which contains Sanya district, and hotspot III, which lies in the Haikou-Qiongshan area. The positive rate (16.67% by IFA) of LD in Qiongzhong, located in hotspot I, was higher than that in four other areas. Of confirmed cases of LD, 80.77% of patients (42/52) whose results had been confirmed by WB were in hotspots I and III. Hotspot II, with unknowed prevalence of LD, need to be paid more attention considering human-vector interaction. Wuzhi and Limu mountains might be the most important areas for the prevalence of LD, as the severe host-vector and human-vector interactions lead to a potential origin site for LD. Qiongzhong is the riskiest area and is located to the east of Wuzhi Mountain. In the Sanya and Haikou-Qiongshan area, intervening in the human-vector interaction would help control the prevalence of LD.
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http://dx.doi.org/10.1371/journal.pntd.0009158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009380PMC
March 2021

A Simple and Quick Method for Decalcification Using Mouse Tail as a Model for Preparation of Lymphedema Study.

Appl Immunohistochem Mol Morphol 2021 Mar 12. Epub 2021 Mar 12.

Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.

The disadvantage of 10% EDTA decalcification is a long time-consuming. It needs to identify a quick and straightforward decalcification method when the preparation of lymphedema models using mouse tail which was a sample of bone wrapped in other tissues. In the present study, mouse tail samples were decalcified in 10% EDTA at 25, 37, and 42°C, respectively, with continuous shaking (150 rpm/min). The histologic integrity of samples was evaluated by hematoxylin and eosin staining, and the preservation of antigenicity was tested by either immunohistochemistry or immunofluorescence. The decalcification was distinctly accelerated by temperature. Results of hematoxylin and eosin staining were similar among different temperature groups. Immunohistochemistry and immunofluorescence staining revealed almost no signals in samples decalcified at 42°C for 1 week. Clear signals were detected when samples were decalcified at 37 and 25°C.
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http://dx.doi.org/10.1097/PAI.0000000000000927DOI Listing
March 2021

Gut-liver axis modulation of Panax notoginseng saponins in nonalcoholic fatty liver disease.

Hepatol Int 2021 Mar 3. Epub 2021 Mar 3.

School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1/F, 10 Sassoon Road, Pokfulam, Hong Kong S.A.R., People's Republic of China.

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) is an obesity-related comorbidity, and it is characterized as a spectrum of liver abnormalities, including inflammation, steatosis, and fibrosis. The gut-liver axis is implicated in the pathogenesis and development of NAFLD. A promising drug agent targeting the gut-liver axis is expected to reverse NAFLD.

Methods: We utilized high-fat diet (HFD)-induced obese mice and obesity-prone Lep mice to examine the gut-liver regulation of the natural medicine Panax Notoginseng Saponins (PNS) on NAFLD.

Results: PNS exhibited potent anti-lipogenesis and anti-fibrotic effects in NAFLD mice, that was associated with the TLR4-induced inflammatory signalling pathway in liver. More strikingly, PNS treatment caused a deceleration of gut-to-liver translocation of microbiota-derived short chain fatty acids (SCFAs) products. PNS-induced TLR4 inhibition and restoration of Claudin-1 and ZO-1 proteins in the gut-liver axis contributed to the reverse of leaky gut, which in turn abolished by the addition of lipopolysaccharide (LPS), an agonist of TLR4. Specifically, hepatic steatosis in HFD-treated mice was attenuated by PNS through regulating AMPKα, but restored by the replenishment of LPS. Meanwhile, the anti-fibrotic effect of PNS was abolished by LPS stimulation via the overproduction of collagen I/IV and α-SMA.

Conclusion: PNS exerted hepatoprotection against NAFLD in both ob/ob and HFD-induced obese mice, primarily by mediating the gut-liver axis in a TLR4-dependent manner. Panax notoginseng saponins (PNS) ameliorated hepatic steatosis and fibrosis, and gut-liver axis-mediated pathogenesis of NAFLD is proposed to occur in a TLR4-dependent manner.
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http://dx.doi.org/10.1007/s12072-021-10138-1DOI Listing
March 2021

Lipid metabolism changes in patients with severe COVID-19.

Clin Chim Acta 2021 Feb 24;517:66-73. Epub 2021 Feb 24.

Department of Respiratory and Critical Care Medicine, Central South University, Changsha 410008, China. Electronic address:

Background: We investigated the dynamic changes in lipid profiles and their correlations with disease severity and clinical outcome in patients with severe COVID-19.

Methods: We retrospectively reviewed 519 severe COVID-19 patients with confirmed outcomes (discharged or deceased), admitted to the West Court of Union Hospital in Wuhan, China, between 29 January and 8 April 2020.

Results: Altogether, 424 severe COVID-19 patients, including 34 non-survivors and 390 survivors, were included in the final analyses. During hospitalization, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) showed an increasing trend in survivors, but showed a downward trend in non-survivors. The serum concentrations of HDL-C and apoA-I were inversely correlated with C-reactive protein (CRP), length of hospital stay of survivors, and disease severity scores. For in-hospital deaths, the areas under the receiver operating characteristic curves (AUCs) of the ratios of CRP/HDL-C and CRP/apoA-I at admission were 0.84 and 0.83, respectively. Moreover, patients with high ratios of CRP/HDL-C (>77.39) or CRP/apoA-I (>72.37) had higher mortality rates during hospitalization (log-rank p < 0.001). Logistic regression analysis demonstrated that hypertension, lactate dehydrogenase, SOFA score, and High CRP/HDL-C ratio were independent predictors of in-hospital mortality.

Conclusions: During severe COVID-19, HDL-C and apoA-I concentrations are dramatically decreased in non-survivors. Moreover, High CRP/HDL-C ratio is significantly associated with an increase in mortality and a poor prognosis.
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http://dx.doi.org/10.1016/j.cca.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903909PMC
February 2021

A strategy for the synthesis of low-molecular-weight welan gum by eliminating capsule form of Sphingomonas strains.

Int J Biol Macromol 2021 Feb 24;178:11-18. Epub 2021 Feb 24.

State Key Laboratory of Materials-Oriented Chemical Engineering, College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China. Electronic address:

Welan gum is widely used in food, concrete additives, and oil recovery. Here we changed the capsule form of Sphingomonas strains by knocked out the sortase gene (srtW). The obtained welan gum was mainly composed of mannose, glucose, rhamnose, and glucuronic acid at a molar ratio of 4.0:5.8:1.6:1, respectively. Meanwhile, the molecular weight of welan gum decreased sharply (about 68 kDa). Moreover, the low molecular weight (LMW) welan gum was characterized by FT-IR and NMR spectroscopy. The rheological results revealed that the LMW welan gum solution is a pseudoplastic fluid with a lower apparent viscosity. Furthermore, the oscillation test illustrated stable dynamic viscoelasticity within the temperature range of 5-68 °C and frequency range of 0.01-15 rad/s. To the best of our knowledge, this is the first report of LMW welan gum production and characterization. These results provide references for LMW welan gum applications, and likely applicable for other biopolymers production.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.02.157DOI Listing
February 2021

Androgen Plays a Carcinogenic Role in EOC via the PI3K/AKT Signaling Pathway in an AR-Dependent Manner.

J Cancer 2021 21;12(6):1815-1825. Epub 2021 Jan 21.

Department of Anatomy, Hebei Medical University, Shijiazhuang, China.

Epithelial ovarian cancer (EOC) is one of the most common gynecological cancers with the highest mortality rate. Studies indicate that androgens contribute to initiation or progression of EOC through poorly understood mechanisms, however, in the phase II clinical studies of antiandrogen therapy for EOC, neither flutamide nor bicalutamide showed good antitumor effects. Based on the contradictions, the purpose of this study was to explore the role of androgen receptor (AR) in the androgen pathogenesis of EOC and the possible mechanism, and further to find an indicator to screen the anti-androgen therapy sensitive cases. In this study, 70 EOC biopsies and 17 para-cancerous tissues with complete medical information were collected and analyzed. The expression of the androgen receptor (AR) was detected by immunohistochemistry. In addition, ovarian cancer cell lines were used for studies to further explore the role of androgen in cell proliferation and the possible mechanisms. The results showed that the expression of AR in ovarian cancer tissues was significantly elevated compared to the para-cancerous tissues, particularly in low-grade EOC, and the presence of high AR expression often suggested a worse prognosis. The study indicated that testosterone promoted the proliferation of the AR-positive SKOV3 cell line, which could be blocked by flutamide, but not in the AR-negative A2780 cell line. Next, we showed that testosterone-promoted proliferation in SKOV3 cells was abolished after we knocked out the AR. The mechanism studies revealed that the p-AKT expression in the ovarian cancer tissue was increased compared to the para-cancerous tissues, following a pattern similar to the increase of AR expression. Furthermore, the deletion and overexpression of SKOV3 cells' ARs lead to corresponding changes in the p-AKT levels. In addition, the BEZ235, an inhibitor of the PI3K/AKT signaling pathway blocked the proliferative effect of testosterone in SKOV3 cells. We showed that testosterone was able to promote the proliferation of ovarian cancer cells through activating the PI3K/AKT signaling pathway in an AR dependent manner and AR may be a screening indicator for anti-androgen therapy sensitive cases of EOC.
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http://dx.doi.org/10.7150/jca.51099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890324PMC
January 2021

Tricyclic-Carbocyclic RORγt Inverse Agonists-Discovery of BMS-986313.

J Med Chem 2021 Mar 16;64(5):2714-2724. Epub 2021 Feb 16.

Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound (BMS-986251) led to tricyclic-carbocyclic analogues represented by - and culminated in the identification of (BMS-986313), with structural differences distinct from . The X-ray co-crystal structure of with the ligand binding domain of RORγt revealed several key interactions, which are different from . The in vitro and in vivo PK profiles of are described. In addition, we demonstrate robust efficacy of in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with in these models is comparable to the results observed with .
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http://dx.doi.org/10.1021/acs.jmedchem.0c01992DOI Listing
March 2021

High expression of heme oxygenase-1 in tumor-associated macrophages characterizes a poor-prognosis subtype in nasopharyngeal carcinoma.

Aging (Albany NY) 2021 02 11;13(4):5674-5685. Epub 2021 Feb 11.

Department of Radiation Oncology, Affiliated Hospital of Jiangnan University, Wuxi 214062, Jiangsu Province, China.

Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment, which are characterized by pro-tumor M2 phenotype and correlate with poor survival of nasopharyngeal carcinoma (NPC). Heme oxygenase-1 (HO-1) plays a crucial role in macrophage polarization toward M2 phenotype, but its prognosis significance in NPC has been rarely determined. To gain insights into the HO-1 expression profile and to determine the clinical significance of HO-1 in NPC, we performed immunohistochemistry analyses in 126 NPC specimens. CD163, a highly specific marker of M2 macrophages, was used as a surrogate for the polarization state of TAMs. Our results showed that high expression of HO-1 and CD163 were detected in TAMs for 57.9% (73/126) and 61.9% (78/126) of the studied patients, and both of them were significantly associated with worse survival. Additionally, a significant correlation between the intensities of HO-1 and CD163 was identified, and HO-1 exhibited a superior ability in predicting survival compared with CD163. Our study revealed for the first time that overexpression of HO-1 characterized a poor-prognosis subtype in NPC. Individualized therapy targeting HO-1 might serve as a promising treatment modality for NPC.
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http://dx.doi.org/10.18632/aging.202492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950251PMC
February 2021

Acute associations between air pollution on premature rupture of membranes in Hefei, China.

Environ Geochem Health 2021 Feb 8. Epub 2021 Feb 8.

Department of Maternal, Child and Adolescent Health, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.

Numerous studies had focused on the association between air pollution and health outcomes in recent years. However, little evidence is available on associations between air pollutants and premature rupture of membranes (PROM). Therefore, we performed time-series analysis to evaluate the association between PROM and air pollution. The daily average concentrations of PM, SO and NO were 54.58 μg/m, 13.06 μg/m and 46.09 μg/m, respectively, and daily maximum 8-h average O concentration was 95.67 μg/m. The strongest effects of SO, NO and O were found in lag4, lag06 and lag09, and an increase of 10 μg/m in SO, NO and O was corresponding to increase in incidence of PROM of 8.74% (95% CI 2.12-15.79%), 3.09% (95% CI 0.64-5.59%) and 1.68% (95% CI 0.28-3.09%), respectively. There were no significant effects of PM on PROM. Season-specific analyses found that the effects of PM, SO and O on PROM were more obvious in cold season, but the statistically significant effect of NO was observed in warm season. We also found the modifying effects by maternal age on PROM, and we found that the effects of SO and NO on PROM were higher among younger mothers (< 35 years) than advanced age mothers (≥ 35 years); however, ≥ 35 years group were more vulnerable to O than < 35 years group. This study indicates that air pollution exposure is an important risk factor for PROM and we wish this study could provide evidence to local government to take rigid approaches to control emissions of air pollutants.
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http://dx.doi.org/10.1007/s10653-021-00833-1DOI Listing
February 2021

Profiling gene expression reveals insights into pulmonary response to aerosolized botulinum toxin type A exposure in mice.

J Appl Toxicol 2021 Feb 2. Epub 2021 Feb 2.

State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.

Botulinum neurotoxin type A (BoNT/A) is traditional medicine and well known for its therapeutic use as an anesthetic and in cosmetic applications that work through the inhibition of acetylcholine exocytosis in neuronal cells. BoNT/A also has the potential to function as a biological weapon due to its high mortality rate and ease of dispersal. Emerging evidence suggests that BoNT/A exhibits biological effects on nonneuronal cells. In cytology experiments, BoNT/A induces global gene expression alterations. However, pulmonary effects from exposure to aerosolized BoNT/A have not been evaluated. This study investigated the global transcriptional profile of lung tissues after botulism inhalation. A mice model of inhaled botulism was established using intratracheal exposure to aerosolized BoNT/A and described through histological examination and flow cytometry. Transcriptomic analysis revealed that genes related to acute inflammatory responses were upregulated at 12-h postexposure. Increased expression of multiple anti-inflammatory marker genes and decreased expression of pro-inflammatory marker genes were observed at 48- to 72-h postexposure, underscoring a transcriptional shift toward a pro-reparative phenotype. Histological examination and cell proportions analysis mirrored these expression patterns. Accordingly, the orchestration of a quick phenotype transition prompted by BoNT/A may have the potential for promoting the resolution of the inflammatory lung. To our knowledge, this study represents the first research to investigate the pulmonary transcriptional responses of aerosolized BoNT/A exposure; the results may provide new insights in elucidating the molecular mechanism for pulmonary inhaled botulism and highlight the potential therapeutic application of BoNT/A in mitigating inflammatory conditions.
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http://dx.doi.org/10.1002/jat.4140DOI Listing
February 2021

Risk factors for thoracolumbar pain following percutaneous vertebroplasty for osteoporotic vertebral compression fractures.

J Int Med Res 2021 Jan;49(1):300060521989468

Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Objective: To explore possible risk factors for poor outcomes following percutaneous vertebroplasty (PV) for painful osteoporotic compression fractures of thoracolumbar vertebra.

Methods: This was a retrospective review of data from patients who underwent PV at our institution over a ten-year period to evaluate the association between possible risk factors and thoracolumbar pain (T11-L2). According to the difference between pre- and post-operative visual analogue scale (VAS) scores for pain, patients were separated into poor relief (PR; <4) and good relief (GR; ≥4) of pain.

Results: Of the 750 patients identified, 630 (PR group, =310; GR group,  = 320) fulfilled the eligibility criteria. Multivariate binary logistic analysis showed that bone mineral density (BMD), >2 fractured vertebral bodies, maldistribution of bone cement, <5 ml bone cement injected into a single vertebral body and thoracolumbar fascia injury prior to surgery were independent risk factors associated with thoracolumbar pain following PV.

Conclusion: Although prospective controlled studies are required to confirm our results, this review suggests that the above factors should be taken into account when selecting patients for PV.
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http://dx.doi.org/10.1177/0300060521989468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871086PMC
January 2021

A Virus-Mimicking Nucleic Acid Nanogel Reprograms Microglia and Macrophages for Glioblastoma Therapy.

Adv Mater 2021 Mar 27;33(9):e2006116. Epub 2021 Jan 27.

School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200 240, China.

Immunotherapy is recognized as one of the most promising approaches to treat cancers. However, its effect in glioblastoma (GBM) treatment is insufficient, which can in part be attributed to the immunosuppressive tumor microenvironment (TME). Microglia and macrophages are the main immune infiltrating cells in the TME of GBM. Unfortunately, instead of initiating the anti-tumor response, GBM-infiltrating microglia and macrophages switch to a tumor-promoting phenotype (M2), and support tumor growth, angiogenesis, and immunosuppression by the release of cytokines. In this work, a virus-mimicking membrane-coated nucleic acid nanogel Vir-Gel embedded with therapeutic miRNA is developed, which can reprogram microglia and macrophages from a pro-invasive M2 phenotype to an anti-tumor M1 phenotype. By mimicking the virus infection process, Vir-Gel significantly enhances the targetability and cell uptake efficiency of the miR155-bearing nucleic acid nanogel. In vivo evaluations demonstrate that Vir-Gel apparently prolongs the circulation lifetime of miR155 and endows it with an active tumor-targeting capability and excellent tumor inhibition efficacy. Owing to its noninvasive feature and effective delivery capability, the virus-mimicking nucleic acid nanogel provides a general and convenient platform that can successfully treat a wide range of diseases.
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http://dx.doi.org/10.1002/adma.202006116DOI Listing
March 2021

A Short Form of the Chinese Version of the Weinstein Noise Sensitivity Scale through Optimal Test Assembly.

Int J Environ Res Public Health 2021 Jan 20;18(3). Epub 2021 Jan 20.

School of Nursing, The University of Hong Kong, Hong Kong 999077, China.

This study developed a short form of the traditional Chinese version of the Weinstein Noise Sensitivity Scale (WNSS) through optimal test assembly (OTA). A total of 1069 Chinese adults (64.8% female) completed the territory-wide cross-sectional study. We first removed Items 12 and 5 which had negative factor loading and gender-related differential item functioning (DIF), respectively. The optimal length was then determined as the minimal one that reasonably resembled the reliability and validity of the scale without DIF items. OTA identified an 8-item WNSS (WNSS-8) which retained 67.2% of the test information of the original 21-item scale and had a Cronbach's alpha of 0.83. It also showed significant correlations of 0.272 and -0.115 with the neuroticism and extraversion scales of Chinese NEO-Five Factor Inventory, respectively. Adequate model fit of the WNSS-8 was demonstrated by the confirmatory factor analysis. The Chinese WNSS-8 can be used to assess noise sensitivity without compromising reliability and validity.
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http://dx.doi.org/10.3390/ijerph18030879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908225PMC
January 2021

GCSF deficiency attenuates nonalcoholic fatty liver disease through regulating GCSFR-SOCS3-JAK-STAT3 pathway and immune cells infiltration.

Am J Physiol Gastrointest Liver Physiol 2021 Apr 20;320(4):G531-G542. Epub 2021 Jan 20.

Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Granulocyte colony stimulating factor (GCSF) is a cytokine with immunomodulation effects. However, little is known about its role in metabolic diseases. In the current study, we aimed to explore the role of GCSF in nonalcoholic fatty liver disease (NAFLD). Male GCSF mice were used to investigate the function of GCSF in vivo after high-fat diet (HFD). Primary hepatocytes were used for evaluating the function of GCSF in vitro. Liver immune cells were isolated and analyzed by flow cytometry. Our results showed that GCSF administration significantly increased serum triglyceride (TG) levels in patients. Circulating GCSF was markedly elevated in HFD-fed mice. GCSF mice exhibited alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis. Extra administration of GCSF significantly aggravated palmitic acid (PA)-induced lipid accumulation in primary hepatocytes. Mechanically, GCSF could bind to granulocyte colony stimulating factor receptor (GCSFR) and regulate suppressors of cytokine signaling 3, Janus kinase, signal transducer and activator of transcription 3 (SOCS3-JAK-STAT3) pathway. GCSF also enhanced hepatic neutrophils and macrophages infiltration, thereby modulating NAFLD. These findings suggest that GCSF plays an important regulatory role in NAFLD and may be a potential therapeutic target for NAFLD. We found GCSF was involved in lipid metabolism and NAFLD development. GCSF administration increased serum triglyceride levels in patients. GCSF deficiency alleviated HFD-induced insulin resistance and hepatic steatosis in mice. GCSF could directly act on hepatocytes through GCSFR-SOCS3-JAK-STAT3 pathway, and regulate the infiltration of immune cells into the liver to indirectly modulate NAFLD. Our finding indicates that GCSF may provide new strategies for the treatment of NAFLD.
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http://dx.doi.org/10.1152/ajpgi.00342.2020DOI Listing
April 2021

The role of natural products in the prevention and treatment of pulmonary fibrosis: a review.

Food Funct 2021 Feb;12(3):990-1007

Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

Pulmonary fibrosis is an incurable end-stage lung disease and remains a global public health problem. Although there have been some breakthroughs in understanding the pathogenesis of pulmonary fibrosis, effective intervention methods are still limited. Natural products have the advantages of multiple biological activities and high levels of safety, which are important factors for preventing and treating pulmonary fibrosis. In this review, we summarized the mechanisms and health benefits of natural products against pulmonary fibrosis. These natural products target oxidative stress, inflammatory injury, epithelial-mesenchymal transition (EMT), fibroblast activation, extracellular matrix accumulation and metabolic regulation, and the mechanisms involve the NF-κB, TGF-β1/Smad, PI3K/Akt, p38 MAPK, Nrf2-Nox4, and AMPK signaling pathways. We hope to provide new ideas for pulmonary fibrosis prevention and treatment strategies.
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http://dx.doi.org/10.1039/d0fo03001eDOI Listing
February 2021

Carrier-Free Hybrid DNA Nanoparticles for Light-Induced Self-Delivery of Functional Nucleic Acid Enzymes.

ACS Nano 2021 01 15;15(1):1841-1849. Epub 2021 Jan 15.

Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore.

Herein, we developed hybrid DNAzyme nanoparticles (NPs) to achieve light-induced carrier-free self-delivery of DNAzymes with sufficient cofactor supply and lysosome escape capacity. In this system, aggregation-induced emission (AIE) photosensitizer (PS) (TBD-Br) was grafted onto a phosphorothiolated DNAzyme backbone, which automatically self-assembled to form NPs and the surface phosphorothioate group could easily coordinate with the cofactor Zn in the buffer. When the yielded hybrid DNAzyme NPs were located inside tumor cell lysosomes, the O from TBD-Br under light illumination could destroy lysosome structure and promote the Zn coordinated DNAzyme NPs escape. Both in vitro and in vivo results demonstrated that the hybrid DNAzyme NPs could downregulate the early growth response factor-1 protein (EGR-1) to inhibit tumor cell growth in addition to induce tumor cell apoptosis by AIE PS (TBD-Br) under light irradiation.
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http://dx.doi.org/10.1021/acsnano.0c10045DOI Listing
January 2021

BRD4-mediated repression of p53 is a target for combination therapy in AML.

Nat Commun 2021 01 11;12(1):241. Epub 2021 Jan 11.

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53, encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate wild-type p53, and BET inhibitors (BETi), targeting the BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report enhanced toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETi's ability to evict an unexpected repressive form of BRD4 from p53 target genes, and hence potentiate MDM2i-induced p53 activation. These results indicate that wild-type TP53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.
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http://dx.doi.org/10.1038/s41467-020-20378-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801601PMC
January 2021

A time series analysis of ambient air pollution and low birth weight in Xuzhou, China.

Int J Environ Health Res 2021 Jan 7:1-10. Epub 2021 Jan 7.

Department of Maternal Child and Adolescent Health, School of Public Health, Anhui Medical University , Hefei, Anhui, China.

The objective of this study was to examine the relationship between weekly specific maternal air pollution exposures and low birth weight. We fitted a distributed lag nonlinear model (DLNM) to analyze the nonlinear exposure-response association and delayed effects of air pollutants on the risk for low birth weight. The model assumed that all live births have 40 gestational weeks.The 1st week lag was the 40th gestational week, and 40th lag week was the 1st gestational week.The study included 71,809 live births (from July 1, 2016, to June 30, 2019), of which 2,391 (3.33%) exhibited low birth weight. The results demonstrated that exposure of pregnant women to PM10 at lag 22-30 weeks was significantly associated with low birth weight risk, with the greatest impact at the lag 30 week. Exposure to SO2 at lag 29-37 weeks was significantly associated with low birth weight risk. The sensitive exposure window for NO2 began at lag 25-37 weeks of pregnancy. The lag 6-10 weeks constituted the susceptible exposure window for O3. Therefore we concluded that maternal exposures to PM10, SO2, NO2, and O3 were associated with increased risk for low birth weight.
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http://dx.doi.org/10.1080/09603123.2020.1867828DOI Listing
January 2021

Downregulating in Guard Cells Causes Drought Hypersensitivity by Inhibiting Stomatal Closure.

Front Plant Sci 2020 17;11:602701. Epub 2020 Dec 17.

State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Tai'an, China.

Stomata are a key land plant innovation that permit the regulation of gaseous exchanges between the plant interior and the surrounding environment. By opening or closing, stomata regulate transpiration of water though the plant; and these actions are coordinated with acquisition of CO for photosynthesis. Stomatal movement is controlled by various environmental and physiological factors and associates with multiple intracellular activities, among which the dynamic remodeling of vacuoles plays a crucial role. Phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] is critical for dynamic remodeling of vacuoles. Its production requires a PI(3,5)P-metabolizing complex consisting of FAB1/PIKfyve kinases, SAC phosphatases, and the scaffolding protein VAC14. Although genetic or pharmacological downregulation of PI(3,5)P causes hyposensitivity to ABA-induced stomatal closure, whether the effect of PI(3,5)P on stomatal movement is cell-autonomous and the physiological consequences of its reduction were unclear. We report that downregulating Arabidopsis specifically in guard cells by artificial microRNAs (amiR-VAC14) results in enlarged guard cells and hyposensitivity to ABA- and dark-induced stomatal closure. Vacuolar fission during stomatal closure is compromised by downregulating in guard cells. Exogenous application of PI(3,5)P rescued the amiR-VAC14 phenotype whereas PI(3,5)P inhibitor YM201636 caused wild-type plants to have inhibited stomatal closure. We further show that downregulating VAC14 specifically in guard cells impairs drought tolerance, suggestive of a key role of guard cell-produced PI(3,5)P in plant fitness.
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http://dx.doi.org/10.3389/fpls.2020.602701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773697PMC
December 2020

Characteristics of inflammation process in monocrotaline-induced pulmonary arterial hypertension in rats.

Biomed Pharmacother 2021 Jan 15;133:111081. Epub 2020 Dec 15.

Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, 563000, China; Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, 563000, China. Electronic address:

Objective: A growing evidence demonstrates that inflammation is a major contributor to the pathogenesis of pulmonary arterial hypertension (PAH). However, blocking inflammation has only been shown to be of minor clinical benefit due to a lack of understanding of the precise inflammation present in PAH. Thus, the present study aimed to investigate characteristics of inflammatory process in PAH induced by monocrotaline (MCT) in rats.

Methods: Adult male Sprague-Dawley rats received a single dose of MCT (50 mg/kg, ip), and the occurrence of PAH and inflammation biomarkers were measured at 3, 6, 9, 12, 15, 18, 21, 24, 27 and 30 days after MCT injection.

Results: From the 6th day after the injection of MCT, the mean pulmonary artery pressure gradually increased and doubled on the 30th day, accompanied by right ventricular hypertrophy and pulmonary arterial remodeling in a time-dependent manner. In the first 6 days after MCT treatment, only pro-inflammatory cytokines TNF-α, IL-1β increased, which was defined as acute inflammatory phase, after that, both pro-inflammatory factors TNF-α, IL-1β, IL-6, IL-12 and anti-inflammatory factors Arg1, IL-10, TGF-β increased, which was defined as chronic inflammatory phase. The M1/M2 macrophage ratios in lung and alveolar lavage fluid were elevated on the 6th and 30th day, moreover, which were higher on the 6th than 30th day, and the PI3K/Akt signaling pathway increased along with the progression of PAH and correlated with pro-inflammatory proteins, which revealed also to some extent the characteristics of inflammation of PAH induced by MCT.

Conclusion: The course of PAH induced by MCT injection is progressive with persistent inflammation, which is defined as acute inflammatory phase within 6 days after MCT treatment, after that, is defined as chronic inflammatory phase.
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http://dx.doi.org/10.1016/j.biopha.2020.111081DOI Listing
January 2021