Publications by authors named "Liping Hou"

67 Publications

One hundred twelve cases of 46, XY DSD patients after initial gender assignment: a short-term survey of gender role and gender dysphoria.

Orphanet J Rare Dis 2021 Oct 9;16(1):416. Epub 2021 Oct 9.

Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.

Background: 46, XY disorders of sex development (46, XY DSD) are congenital disorders with 46, XY chromosomal karyotype but inconsistent gonadal/phenotypic sex. One of the biggest concerns for parents and clinicians is the gender assignment. However, there is no standard uniform of care nor consensus at present. We sought to evaluate the current treatment's rationality and provide a reference basis for the gender reassignment in 46, XY DSD patients with a specific diagnosis.

Methods: We conducted a cross-sectional survey of gender role with the Pre-school Activities Inventory (PSAI), the Children's Sex Role Inventory (CSRI) in 46, XY DSD patients and set up control groups comparison. Psychiatrist assessed gender dysphoria in patients ≥ 8-year-old with the criteria of diagnostic and statistical manual of mental disorders, 5th edition (DSM-5).

Results: A total of 112 responders of 136 patients participated in this study (82.4%, aged 2-17.8 years, median age: 4-year-old). The follow-up period was from 6 months to 10 years (median: 2 years). Twenty-five females were reassigned to the male gender after a specific diagnosis (16/25 (64%) in 5 alfa-reductase-2 deficiency (5α-RD2), 5/25 (20%) in partial androgen insensitivity syndrome (PAIS), 4/25 (16%) in NR5A1gene mutation). Male gender assignment increased from 55.3 (n = 62) to 77.7% (n = 87). The median PSAI score was similar to the control males in 5α-RD2, PAIS, and NR5A1 gene mutation groups (p > 0.05); while identical to the control females in complete androgen insensitivity syndrome (CAIS) and CYP17A1 gene mutation groups (p > 0.05). PSAI score of children raised as male was higher than those of CAIS and CYP17A1 groups raised as female (p < 0.05). CSRI scale showed no statistical differences in the consistency of gender roles and reassigned gender between 46, XY DSD patients and control groups (p > 0.05). None of the patients over 8-year-old (n = 44) had gender dysphoria.

Conclusion: The reassigned gender in 46, XY DSD patients is consistent with their gender role during early childhood. None of them had gender dysphoria. The molecular diagnosis, gonadal function, and the gender reassignment are congruent within our Chinese cohort. Long-term follow-up and more evaluation are still required.
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http://dx.doi.org/10.1186/s13023-021-02039-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501610PMC
October 2021

Integrated pharmacology reveals the mechanism of action of Bu-Shen-Tong-Du prescription against collagen-induced arthritis.

Biomed Pharmacother 2021 Nov 21;143:112160. Epub 2021 Sep 21.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address:

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Bu-Shen-Tong-Du prescription (BSP) has traditionally been used in to treat RA but its underlying mechanisms remain unclear. In this study, we explored the potential mechanisms of BSP in collagen-induced arthritis (CIA) rats, a classic animal model of RA. We employed an integrated pharmacology approach in combination with network pharmacology, H-nuclear magnetic resonance (NMR) metabolomics, and biochemical analyses to determine the mechanisms of BSP for treating RA. We found that BSP can regulate immunity and inflammation by decreasing the spleen index; inhibiting hyperplasia of the white pulp; reducing the levels of IL-1β, IL-6, IL-17A, and IFN-γ; and increasing the levels of IL-10 in the serum. Network pharmacology was utilized to predict related signal transduction pathways of BSP in RA treatment. H NMR metabolomics of the serum confirmed that BSP regulated energy metabolism and amino acid metabolism. Finally, we validated the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway using immunohistochemical methods, which demonstrated that BSP controlled RA-induced inflammation by inhibiting the TLR4/NF-κB signaling pathway. These results confirm the therapeutic effect of BSP in a CIA rat model, which is exerted via the inhibition of the inflammation and the improvement of the immune function, balancing energy metabolism and amino acid metabolism, and inhibiting the TLR4/NF-κB signaling pathway. This study provides an experimental basis for using BSP as a combinatorial drug to inhibit inflammation and regulate immunity in the treatment of RA.
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http://dx.doi.org/10.1016/j.biopha.2021.112160DOI Listing
November 2021

Discovering Cerebral Ischemic Stroke Associated Genes Based on Network Representation Learning.

Front Genet 2021 1;12:728333. Epub 2021 Sep 1.

Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Cerebral ischemic stroke (IS) is a complex disease caused by multiple factors including vascular risk factors, genetic factors, and environment factors, which accentuates the difficulty in discovering corresponding disease-related genes. Identifying the genes associated with IS is critical for understanding the biological mechanism of IS, which would be significantly beneficial to the diagnosis and clinical treatment of cerebral IS. However, existing methods to predict IS-related genes are mainly based on the hypothesis of guilt-by-association (GBA). These methods cannot capture the global structure information of the whole protein-protein interaction (PPI) network. Inspired by the success of network representation learning (NRL) in the field of network analysis, we apply NRL to the discovery of disease-related genes and launch the framework to identify the disease-related genes of cerebral IS. The utilized framework contains three main parts: capturing the topological information of the PPI network with NRL, denoising the gene feature with the participation of a stacked autoencoder (SAE), and optimizing a support vector machine (SVM) classifier to identify IS-related genes. Superior to the existing methods on IS-related gene prediction, our framework presents more accurate results. The case study also shows that the proposed method can identify IS-related genes.
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http://dx.doi.org/10.3389/fgene.2021.728333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442767PMC
September 2021

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders.

Sci Rep 2021 09 8;11(1):17823. Epub 2021 Sep 8.

Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.

Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
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http://dx.doi.org/10.1038/s41598-021-97140-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426488PMC
September 2021

Risk factors and prognosis analysis of acute myeloid leukemia in children.

J BUON 2021 Jan-Feb;26(1):166-172

Department of Hematology, Xijing Hospital, the First Affiliated Hospital of Air Force Medical University, Shaanxi 710032, China.

Purpose: To explore the efficacy and related prognostic factors of acute myeloid leukemia (AML) in children except acute promyelocytic leukemia (APL).

Methods: The clinical data of 89 non-APL children with AML treated in our hospital were retrospectively analyzed. The remission status was analyzed after chemotherapy, the long-term survival was evaluated using the Kaplan-Meier method, and the influencing factors for the prognosis were detected using univariate and multivariate Cox regression analyses.

Results: Complete remission (CR) was realized in 71 cases (79.8%) after the first course of treatment, 13 cases (14.6%) after the second course of treatment, and 5 cases (5.6%) after the third course of treatment. The 5-year event-free survival (EFS) rate and overall survival (OS) rate were 53.9% and 66.3%, respectively. The children were divided into low-risk group (n=31), middle-risk group (n=36) and high-risk group (n=22). In the three groups, the 5-year OS rate was 74.2%, 72.2% and 45.5%, respectively, while the 5-year EFS rate was 67.7%, 55.6% and 31.8%, respectively. Extramedullary infiltration at the time of initial diagnosis [HR=3.313 (95% CI: 1.748-13.664)], CD56+ [HR=1.592 (95% CI: 1.172-2.255)] and recurrence time <1 year [HR=3.040 (95% CI: 1.087-5.508)] were independent risk factors affecting the prognosis, and CR achieved after the first course [HR=0.786 (95% CI: 0.228-0.803)] was an independent factor improving the prognosis of patients.

Conclusions: The prognosis is poor in non-APL children with AML who have extramedullary infiltration at the time of initial diagnosis, CD56+ and recurrence time <1 year, and CR achieved after the first course is an independent factor improving the prognosis of patients. The long-term EFS rate is significantly lower in high-risk group than that in low- and middle-risk groups. Intensive chemotherapy or early hematopoietic stem cell transplantation should be performed for high-risk patients.
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March 2021

Norethindrone causes cellular and hepatic injury in zebrafish by compromising the metabolic processes associated with antioxidant defence: Insights from metabolomics.

Chemosphere 2021 Jul 22;275:130049. Epub 2021 Feb 22.

Faculty of Materials and Energy, Southwest University, Chongqing, 400715, China; School of Biological Sciences, The University of Adelaide, Adelaide, 5005, Australia. Electronic address:

Progestins, such as norethindrone (NET), have been increasingly detected in aquatic environments due to their extensive use for medical applications. While NET is notorious for its endocrine disrupting effects, it has been recently shown to cause cellular damage, suggesting its potential impacts on the body defence of organisms. Hence, we examined the histological features and antioxidant defence of zebrafish (Danio rerio) after exposing to NET (50 ng/L and 500 ng/L) for 72 days, followed by analysing its metabolome to explore whether NET disturbs the metabolic processes responsible for antioxidant defence. While acute mortality was not triggered, we found that antioxidant defence was substantially weakened by NET at 500 ng/L (i.e. reduced SOD and GSH levels) and hence liver injury was inflicted (i.e. elevated ALT and MDA levels), as manifested by vacuolization of liver tissues and reduced number of normal cells in the liver. Metabolomic analysis showed that the metabolic processes responsible for antioxidant defence were disrupted by NET (e.g. upregulation of nervonyl carnitine and chenodeoxycholic acid 3-sulfate; downregulation of homolanthionine and acevaltrate) and these changes can undermine antioxidant defence by suppressing Nrf2-ARE and NF-κB pathways that contribute to the synthesis of SOD and GSH. This study demonstrates how NET can compromise the body defence of aquatic organisms via metabolic disruption, suggesting that the impacts of progestins on their fitness are more detrimental than previously thought.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130049DOI Listing
July 2021

Reproductive potential of mosquitofish is reduced by the masculinizing effect of a synthetic progesterone, gestodene: Evidence from morphology, courtship behaviour, ovary histology, sex hormones and gene expressions.

Sci Total Environ 2021 May 18;769:144570. Epub 2021 Jan 18.

Faculty of Materials and Energy, Southwest University, Chongqing 400715, China; School of Biological Sciences, The University of Adelaide, Adelaide 5005, Australia. Electronic address:

The ever-increasing use of synthetic hormones, especially progestins, for medical applications has drawn growing concerns due to their potential endocrine disrupting effects that may diminish the reproductive outputs of aquatic organisms. Using mosquitofish (Gambusia affinis) as a model species, we tested whether gestodene (GES), a commonly used progestin, can alter the expressions of genes associated with sex hormone synthesis and cause ensuing changes in morphological features, courtship behaviour and oocyte development. After exposing to GES at environmentally relevant concentrations (2.96, 32.9 and 354 ng L) for 40 days, we found that GES, especially at 354 ng L, induced masculinization of female fish, indicated by the reduced body weight to length ratio and development of gonopodia (i.e. anal fins of male fish). Thus, the males showed less intimacy and mating interest towards the GES-exposed females, indicated by the reduced time spent on attending, following and mating behaviours. While oocyte development was seemingly unaffected by GES, spermatogonia were developed in the ovary. All the aforementioned masculinizing effects of GES were associated with the increased testosterone level and decreased estradiol level, driven by upregulating androgen receptor genes (Arα and Arβ). Overall, our findings suggest that progestins could undermine the reproductive potential of aquatic organisms and hence their persistence in the progestin-contaminated environment.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144570DOI Listing
May 2021

Prediction of lithium response using genomic data.

Sci Rep 2021 01 13;11(1):1155. Epub 2021 Jan 13.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.
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http://dx.doi.org/10.1038/s41598-020-80814-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806976PMC
January 2021

Elevating the density and intensity of hot spots by repeated annealing for high-efficiency SERS.

Opt Express 2020 Sep;28(20):29357-29367

The simultaneous output of highly sensitive and reproducible signals for surface-enhanced Raman spectroscopy (SERS) technology remains difficult. Here, we propose a two-dimensional (2D) composite structure using the repeated annealing method with MoS film as the molecular adsorbent. This method provides enlarged Au nanoparticle (NP) density with much smaller gap spacing, and thus dramatically increases the density and intensity of hot spots. The MoS films distribute among the hot spots, which is beneficial for uniform molecular adsorption, and further increases the sensitivity of the SERS substrate. Three kinds of molecules were used to evaluate the SERS substrate. Ultra-sensitive, highly repetitive, and stable SERS signals were obtained, which would promote the application process of SERS technology in quantitative analysis and detection.
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http://dx.doi.org/10.1364/OE.403940DOI Listing
September 2020

Elevating the density and intensity of hot spots by repeated annealing for high-efficiency SERS.

Opt Express 2020 Sep;28(20):29357-29367

The simultaneous output of highly sensitive and reproducible signals for surface-enhanced Raman spectroscopy (SERS) technology remains difficult. Here, we propose a two-dimensional (2D) composite structure using the repeated annealing method with MoS film as the molecular adsorbent. This method provides enlarged Au nanoparticle (NP) density with much smaller gap spacing, and thus dramatically increases the density and intensity of hot spots. The MoS films distribute among the hot spots, which is beneficial for uniform molecular adsorption, and further increases the sensitivity of the SERS substrate. Three kinds of molecules were used to evaluate the SERS substrate. Ultra-sensitive, highly repetitive, and stable SERS signals were obtained, which would promote the application process of SERS technology in quantitative analysis and detection.
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http://dx.doi.org/10.1364/OE.403940DOI Listing
September 2020

The effects of norethindrone on the ontogeny of gene expression along the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes in zebrafish (Danio rerio).

Sci Total Environ 2020 Dec 6;747:141554. Epub 2020 Aug 6.

SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China; School of Environment, South China Normal University, University Town, Guangzhou 510006, China. Electronic address:

Little is known about the molecular effects of progestins on the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in fish prior to sexual differentiation. In this study, the effects of norethindrone (NET) on the ontogeny of HPG- and HPA-related genes in zebrafish embryo/early larvae prior to sexual differentiation were evaluated. Embryo/larvae were exposed to different concentrations (5, 50, 500 ng/L) of NET for 6 days. The levels of the transcripts of the genes closely related to the HPG and HPA axes were determined daily during 3 stages (embryo, embryo/larvae transition, and early larvae). The results showed that most genes were up-regulated and the ontogeny of genes in the HPA axis was earlier than that of HPG axis, especially for the upstream genes of both the HPG (gnrh2, gnrh3, fshb, lhb) and the HPA (crh, pomc, star) axes. In contrast, the transcriptional expressions of genes of the cortisol/stress pathway (cyp11b, mr) were inhibited and those of the progesterone pathway were not affected. More importantly, NET exposure induced the expressions of the genes (esr1, vtg1, hsd17b3, hsd11b2, ar) that are closely related to the steroid hormone pathways in the embryos/larvae stages, implying a precocious effects of NET in zebrafish. This study demonstrates that NET alters the expression of HPA- and HPG-axes related genes in zebrafish at early stages, pointing to the need for the same type of analysis during the zebrafish gonadal differentiation window.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141554DOI Listing
December 2020

CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance.

Int J Mol Med 2020 Jun 26;45(6):1661-1672. Epub 2020 Mar 26.

Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (CDK) family, CDK5 participates in numerous tumorigenic or non‑tumorigenic processes. The aim of this study is to investigate the effects of CDK5 on the viability of MM cells and bortezomib resistance using western blotting, immunohistochemistry, transient transfection, MTT assays, cell cycle analysis, apoptosis assays and a myeloma xenograft mouse model. The present study found that MM patients with high CDK5 expression in the bone marrow do not respond well to bortezomib, have higher DS stage and worse prognosis. Genetic and pharmacological (dinaciclib) inhibition of CDK5 triggers MM cell viability inhibition. Dinaciclib induces G2/M arrest and apoptosis of MM cells. In vivo experiments with myeloma xenograft mice indicate that dinaciclib significantly reduces the volume of tumors with good tolerance. Dinaciclib combined with bortezomib exerts a synergistic anti‑myeloma activity accompanied by inhibiting the activation of the nuclear factor‑κB pathway. This study demonstrates the important role of CDK5 in the pathogenesis, viability, prognosis and resistance to bortezomib of MM, laying a solid theoretical foundation for further clinical use of CDK5 inhibitors.
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http://dx.doi.org/10.3892/ijmm.2020.4553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169959PMC
June 2020

Norethindrone alters mating behaviors, ovary histology, hormone production and transcriptional expression of steroidogenic genes in zebrafish (Danio rerio).

Ecotoxicol Environ Saf 2020 Jun 23;195:110496. Epub 2020 Mar 23.

School of Environment, South China Normal University, University Town, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou, 510006, China. Electronic address:

The impact of progestins (i.e. synthetic forms of progesterone) on aquatic organisms has drawn increasing attention due to their widespread occurrence in the aquatic environments and potential effects on the endocrine system of fish. In this study, the effects of norethindrone (NET, a progestin) on the reproductive behavior, sex hormone production and transcriptional expressions were evaluated by exposing female zebrafish to NET at 0, 3.1, 36.2 and 398.6 ng L for 60 days. Results showed that NET impaired the mating behaviors of female at 36.2 and 398.6 ng L exhibited by males and increased the frequency of atretic follicular cells in the ovary exposed to NET at 398.6 ng L. As for sex hormones, plasma testosterone concentration in zebrafish increased, while estradiol concentration decreased. Up-regulation of genes (Npr, Mpra, Mprβ, Fshβ, Lβ, Tshb, Nis and Dio2) was detected in the brain of fish exposed to NET at 398.6 ng L. The transcriptional levels of genes (Esr1, Vtg1, Ar, Cyp19a, Cyp11b and Ptgs2) were generally inhibited in the ovary of zebrafish by NET at 398.6 ng L. Moreover, the transcripts of genes (Vtg1, Esr1, Ar and Pgr) in the liver were reduced by NET at 36.2 and 398.6 ng L. Our findings suggest that NET can potentially diminish the of fish populations not only by damaging their reproductive organs, but also by altering their mating behavior through the changes in the expressions of genes responsible for the production of sex hormones.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110496DOI Listing
June 2020

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder.

Mol Psychiatry 2021 06 16;26(6):2457-2470. Epub 2020 Mar 16.

Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLiGen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
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http://dx.doi.org/10.1038/s41380-020-0689-5DOI Listing
June 2021

The progestin norethindrone alters growth, reproductive histology and gene expression in zebrafish (Danio rerio).

Chemosphere 2020 Mar 2;242:125285. Epub 2019 Nov 2.

College of Fishery, Guangdong Ocean University, Zhanjiang, 524088, PR China. Electronic address:

The aim of this study was to assess the long-term effects of synthetic progestin norethindrone (NET) on the growth, reproductive histology, and transcriptional expression profiles of genes associated with the hypothalamic-pituitary-gonadal (HPG) axis and germ cells in adult zebrafish. Adult zebrafish were exposed to 7, 84 and 810 ng/L NET for 90 days. The results showed that exposure to 810 ng/L NET caused a significant decrease in growth of females and males. The ovary weight and GSI was significantly reduced by NET at concentrations of 84 or 810 ng/L, which came along with the delay of ovary maturation in females. However, NET at all treatments resulted in acceleration of sperm maturation in males. In the ovaries of females, a strong inhibition of cyp19a1a gene was observed following exposure to NET at 810 ng/L. Similarly, NET at the highest treatment led to a significant down-regulation of cyp17, cyp19a1a, vasa, nanos1, dazl and dmc1 genes in the testes of males. Taken together, the overall results demonstrated that NET could impact growth and gonadal maturation, with significant alterations of transcriptional expression genes along HPG axis and germ cells.
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http://dx.doi.org/10.1016/j.chemosphere.2019.125285DOI Listing
March 2020

Transcriptional profiling of skeletal muscle reveals starvation response and compensatory growth in Spinibarbus hollandi.

BMC Genomics 2019 Dec 5;20(1):938. Epub 2019 Dec 5.

School of Life Science, Guangzhou University, Guangzhou, 510006, China.

Background: Spinibarbus hollandi is an economically important fish species in southern China. This fish is known to have nutritional and medicinal properties; however, its farming is limited by its slow growth rate. In the present study, we observed that a compensatory growth phenomenon could be induced by adequate refeeding following 7 days of fasting in S. hollandi. To understand the starvation response and compensatory growth mechanisms in this fish, the muscle transcriptomes of S. hollandi under control, fasting, and refeeding conditions were profiled using next-generation sequencing (NGS) techniques.

Results: More than 4.45 × 10 quality-filtered 150-base-pair Illumina reads were obtained from all nine muscle samples. De novo assemblies yielded a total of 156,735 unigenes, among which 142,918 (91.18%) could be annotated in at least one available database. After 7 days of fasting, 2422 differentially expressed genes were detected, including 1510 up-regulated genes and 912 down-regulated genes. Genes involved in fat, protein, and carbohydrate metabolism were significantly up-regulated, and genes associated with the cell cycle, DNA replication, and immune and cellular structures were inhibited during fasting. After refeeding, 84 up-regulated genes and 16 down-regulated genes were identified. Many genes encoding the components of myofibers were significantly up-regulated. Histological analysis of muscle verified the important role of muscle hypertrophy in compensatory growth.

Conclusion: In the present work, we reported the transcriptome profiles of S. hollandi muscle under different conditions. During fasting, the genes involved in the mobilization of stored energy were up-regulated, while the genes associated with growth were down-regulated. After refeeding, muscle hypertrophy contributed to the recovery of growth. The results of this study may help to elucidate the mechanisms underlying the starvation response and compensatory growth.
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http://dx.doi.org/10.1186/s12864-019-6345-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896686PMC
December 2019

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice.

Environ Toxicol 2020 Apr 26;35(4):443-456. Epub 2019 Nov 26.

School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.

Titanium dioxide nanoparticles (TiO NPs) are authorized food additives, and children have the highest exposure. Therefore, children are likely more susceptible to the adverse effects of TiO NPs than adults. Previous study showed that oral administration of 50 mg/kg body weight (bw) TiO NPs increase plasma glucose in mice. However, few studies have directly compared the adverse effects of exposure to TiO NPs on plasma glucose metabolism of different age groups. In this study, the developing (age 3 weeks) and adult mice (age 10 weeks) were orally administered with 50 mg/kg bw TiO NPs per day. The TiO NPs induced hyperglycemia earlier in the developing mice than in the adult mice. Then mechanisms were analyzed after mice were oral administration of TiO2 NPs for 8 weeks and 26 weeks, respectively. Results showed that the treatment with TiO NPs activated xenobiotic biodegradation in livers of both developing and adult mice at the early stage. However, only in the developing mice, TiO NPs induced endoplasmic reticulum (ER) stress in livers and increased reactive oxygen species in livers and sera in the early stage. The ER stress and ROS activated an inflammation response and mitogen-activated protein kinase pathways, thereby inducing insulin resistance in the livers of developing mice at the early stage. The response of the adult mice was delayed, and these changes were observed in the late stage of the study. The results of this study all suggest that children are more susceptible than adults to the toxicity of orally administered TiO NPs.
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http://dx.doi.org/10.1002/tox.22880DOI Listing
April 2020

Silicon dioxide nanoparticles induce insulin resistance through endoplasmic reticulum stress and generation of reactive oxygen species.

Part Fibre Toxicol 2019 11 7;16(1):41. Epub 2019 Nov 7.

School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, No. 92 West Da-zhi Street, Harbin, Heilongjiang, 150001, China.

Background: Silicon dioxide nanoparticles (SiO NPs) are one of the most widely utilized NPs in various food sectors. However, the potential endocrine toxicity of SiO NPs has not been characterized.

Results: In the present study, mice were orally administered a series of doses of SiO NPs. All doses of SiO NPs were absorbed into the blood, liver, and pancreas of the mice. Administration of 100 mg/kg bw (body weight) of SiO NPs significantly increased blood glucose levels in mice. However, the same dose of SiO fine-particles (FPs) did not result in altered blood glucose. Whole-genome analysis showed that SiO NPs affected the expression of genes associated with reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress. In addition, we showed that SiO NPs activated xenobiotic metabolism, resulting in ER stress. Endoplasmic reticulum stress resulted in increased ROS production, which activated the NF-κB pathway leading to expression of inflammatory cytokines. Increased inflammatory cytokine expression resulted in serine phosphorylation of IRS1, which induced insulin resistance (IR). Furthermore these inflammatory cytokines activated the MAPK pathway, which further promoted the serine phosphorylation of IRS1. Insulin resistance resulted in elevated blood glucose. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) inhibited SiO NP-induced ROS production. The ROS scavenger N-acetylcysteine (NAC) did not affect SiO NP-induced ER stress, but inhibited SiO NP-induced activation of the NF-κB and MAPK pathways, expression of inflammatory cytokines, SiO NP-induced serine phosphorylation of IRS1, and SiO2 NP-induced elevations of blood glucose.

Conclusion: Silicon dioxide NPs induced IR through ER stress and generation of ROS, but SiO FPs did not. Therefore, lifelong exposure of humans to SiO NPs may result in detrimental effects on blood glucose. The results of this study strongly suggested that non-nanoformed SiO should be used as food additives.
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http://dx.doi.org/10.1186/s12989-019-0327-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836410PMC
November 2019

Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGFβ1.

Sci Transl Med 2019 09;11(510)

Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.

Transforming growth factor-β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFβ1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the promoter and identified Yin Yang 1 (YY1) as a potent repressor of YY1 bound directly to promoter regions and repressed transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFβ1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.
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http://dx.doi.org/10.1126/scitranslmed.aaw2050DOI Listing
September 2019

Molecular mechanisms underlying zinc oxide nanoparticle induced insulin resistance in mice.

Nanotoxicology 2020 02 13;14(1):59-76. Epub 2019 Sep 13.

School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.

Zinc oxide nanoparticles (ZnO NPs) represent an important class of commercially applied materials. Recently, adverse effects of ZnO NPs were found in humans and animals following ingestion, although the effects on endocrine system disease remain unclear. In this study, ZnO NPs were orally administered to mice, and at doses of 25 mg/kg bw (body weight) ZnO NPs and above, plasma glucose increased significantly. The genome-wide effects of ZnO NPs were then investigated using RNA-sequencing technology. In the cluster analysis, the most significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways concerned membranes and their close association with endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation. Biochemical and gene and protein expression analyses revealed that ZnO NPs activated a xenobiotic biodegradation response and increased the expression of cytochrome P450 (CYP) enzymes in mice livers, leading to ER stress. The ER stress increased ROS generation. The high levels of ROS activated the MAPK and NF-κB pathways and induced an inflammation response, resulting in the phosphorylation of insulin receptor substrate 1. Thus, the insulin resistance that developed was the primary mechanism for the increase in the plasma glucose of mice treated orally with ZnO NPs.
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http://dx.doi.org/10.1080/17435390.2019.1663288DOI Listing
February 2020

The role of the freshwater oligochaete Limnodrilus hoffmeisteri in the distribution of Se in a water/sediment microcosm.

Sci Total Environ 2019 Oct 14;687:1098-1106. Epub 2019 Jun 14.

SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Environmental Theoretical Chemistry, South China Normal University, Guangzhou 510006, China. Electronic address:

Selenite(IV) and selenate(VI) are the major species of Se in the seleniferous aquatic ecosystem. The redistribution of Se in the water/sediment microcosm by bioturbation remains largely unknown. In this study, the redistribution of Se in the water/sediment microcosm by the benthic oligochaete Limnodrilus hoffmeisteri was assessed. The worms were exposed to 2-40 μg/g dry weight of Se(IV) or Se(VI) in the sediment (diet) for 2 months. The changes in the Se levels in different compartments of the microcosm (sediment, overlying water, and worms) were quantified after 2 weeks and 2 months. The subcellular distribution of Se in the worms were also evaluated. Finally, the volatilization of Se from the two Se sources was estimated. The results showed that Se concentration in the overlying water and Se bioaccumulation in the worms were increased with Se levels in the sediments. Approximately 1.6-9.8% of Se was volatilized in the absence of the worms and was intensified in the presence of the worms (2.1-25.7%). The subcellular distribution witnessed high levels of Se in the cell debris (>60%). Se(IV) and Se(VI) differ in their bioaccumulation, redistribution and the effects on the growth of the worms. Our results suggest that the bioturbation by benthos play an essential role in the redistribution of Se in the water/sediment microcosm.
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http://dx.doi.org/10.1016/j.scitotenv.2019.06.170DOI Listing
October 2019

Mechanisms of titanium dioxide nanoparticle-induced oxidative stress and modulation of plasma glucose in mice.

Environ Toxicol 2019 Nov 12;34(11):1221-1235. Epub 2019 Jul 12.

School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.

Titanium dioxide nanoparticles (TiO NPs) are reported to increase plasma glucose levels in mice at specific doses. The production and accumulation of reactive oxygen species (ROS) is potentially the most important factor underlying the biological toxicity of TiO NPs but the underlying mechanisms are unclear at present. Data from genome-wide analyses showed that TiO NPs induce endoplasmic reticulum (ER) stress and ROS generation, leading to the inference that TiO NP-induced ER stress contributes to enhancement of ROS in mice. Resveratrol (Res) effectively relieved TiO NP-induced ER stress and ROS generation by ameliorating expression of a common set of activated genes for both processes, signifying that ER stress and ROS are closely related. TiO NP-induced ER stress occurred earlier than ROS generation. Upon treatment with 4-phenylbutyric acid to relieve ER stress, plasma glucose levels tended toward normal and TiO NP increased ROS production was inhibited. These results suggest that TiO2 NP-induced ER stress promotes the generation of ROS, in turn, triggering increased plasma glucose levels in mice. In addition, Res that displays the ability to reduce ER stress presents a dietary polyphenol antioxidant that can effectively prevent the toxicological effects of TiO NPs on plasma glucose metabolism.
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http://dx.doi.org/10.1002/tox.22823DOI Listing
November 2019

The effects of binary mixtures of estradiol and progesterone on transcriptional expression profiles of genes involved in hypothalamic-pituitary-gonadal axis and circadian rhythm signaling in embryonic zebrafish (Danio rerio).

Ecotoxicol Environ Saf 2019 Jun 10;174:540-548. Epub 2019 Mar 10.

The Environmental Research Institute, MOE Key Laboratory of Environmental Theoretical Chemistry, South China Normal University, Guangzhou 510006, PR China. Electronic address:

Natural and synthetic estrogens and progestins are present in the various aquatic environments, leading to potential exposure of aquatic organisms to their mixtures. However, very little is known about their combined effects in aquatic organisms. The aim of this study was to analyze the effects of binary mixtures of estradiol (E2) and progesterone (P4) by measuring transcriptional changes of up to 42 selected target genes related to hypothalamic-pituitary-gonadal axis and circadian rhythm signaling in zebrafish (Danio rerio) eleuthero-embryos. Zebrafish embryos were exposed to E2 and P4 alone or in combination at concentrations between 45 and 5217 ng L for 96 h post fertilization (hpf). The results showed that P4 led to slight up-regulation of the cyp11a1, hsd17b3 and fshb transcripts, while a strong induction of cyp19a1b and lhb mRNA by E2 was observed. Also, cyp19a1b and lhb mRNAs expression were strongly up-regulated in the mixtures, which were the same to E2 alone. This finding suggests the mixture activity of E2 and P4 followed the independent action in zebrafish eleuthero-embryos. These transcriptional alterations may translate to adverse effects on sex differentiation and reproduction in fish.
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http://dx.doi.org/10.1016/j.ecoenv.2019.03.021DOI Listing
June 2019

Response of microbial communities and interactions to thallium in contaminated sediments near a pyrite mining area.

Environ Pollut 2019 May 1;248:916-928. Epub 2019 Mar 1.

School of Life Sciences, Guangzhou University, Guangzhou, 510655, China. Electronic address:

Thallium (Tl) is a well-recognized hazardous heavy metal with very high toxicity. It is usually concentrated in sulfide minerals, such as pyrite (FeS), sphalerite (ZnS), chalcopyrite (CuS) and galena (PbS). Here, this study was carried out to investigate the indigenous microbial communities via 16S rRNA gene sequence analysis in typical surface sediments with various levels of Tl pollution (1.8-16.1 mg/kg) due to acid mine drainage from an active Tl-containing pyrite mining site in South China. It was found with more than 50 phyla from the domain Bacteria and 1 phyla from the domain Archaea. Sequences assigned to the genera Ferroplasma, Leptospirillum, Ferrovum, Metallibacterium, Acidithiobacillus, and Sulfuriferula manifested high relative abundances in all sequencing libraries from the relatively high Tl contamination. Canonical correspondence analysis further uncovered that the overall microbial community in this area was dominantly structured by the geochemical fractionation of Tl and geochemical parameters such as pH and Eh. Spearman's rank correlation analysis indicated a strong positive correlation between acidophilic Fe-metabolizing species and Tl, Tl, and Tl The findings clarify potential roles of such phylotypes in the biogeochemical cycling of Tl, which may facilitate the development of in-situ bioremediation technology for Tl-contaminated sediments.
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http://dx.doi.org/10.1016/j.envpol.2019.02.089DOI Listing
May 2019

Thallium contamination in farmlands and common vegetables in a pyrite mining city and potential health risks.

Environ Pollut 2019 May 28;248:906-915. Epub 2019 Feb 28.

School of Earth and Environmental Sciences, The University of Queensland, QLD, 4072, Australia.

Thallium (Tl) is a trace metal of severe toxicity. Its health concerns via consumption of contaminated vegetables have often been overlooked or underestimated. This study was designed to gain insight into the actual level and distribution characteristics of Tl and metal (loid)s (Pb, Cd, Cr, Sb, Mn, Cu, Zn, Ni, and Co) in agricultural soils and common vegetables cultivated in different zones (upstream, midstream, and downstream) of a densely populated residential area in a typical mine city, which has been open-pit exploiting Tl-bearing pyrite minerals since 1960s. The results show that most of the agricultural soils exhibit contaminated levels of Tl, with Tl contents (upstream: 1.35-4.31 mg/kg, midstream: 2.43-5.19 mg/kg, and downstream: 0.65-2.33 mg/kg) mostly exceeding the maximum permissible level (MPL) for agricultural land use (1 mg/kg). Sequential extraction procedure indicates that even Tl is predominantly retained in the residual fraction, significant levels of Tl are still present in the geochemically mobile fractions. Besides, metals like Cu, Cd, Mn, and Co are mostly distributed in the labile fractions. Almost all metal (loid)s in edible parts of the vegetables exceed their corresponding MPL for consumption. The chronic daily intake (CDI) and hazard quotient (HQ) values calculated for inhabitants at different ages indicate non-negligible Tl risks via consumption of local vegetables, especially for children. Therefore, it is critical to establish effective measures for hazardous waste management and enforceable regulations in Tl-polluted area to mitigate potential severe impacts of Tl on human health through food chain.
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http://dx.doi.org/10.1016/j.envpol.2019.02.092DOI Listing
May 2019

Transcriptomic and physiological changes in western mosquitofish (Gambusia affinis) after exposure to norgestrel.

Ecotoxicol Environ Saf 2019 Apr 15;171:579-586. Epub 2019 Jan 15.

School of Life Sciences, Guangzhou University, Guangzhou 510655, China. Electronic address:

Norgestrel (NGT) is a synthetic progestin used in human and veterinary medicine. Adult female mosquitofish were exposed to NGT for 42 d at 377 ng L. The fin morphology and the liver transcriptome were assessed. NGT exposure increased ray 4:6 length ratio. As compared to the control, NGT treatment affected the expression of 11,772 annotated transcripts in female mosquitofish. Specifically, we found 5780 were repressed while 5992 were significantly induced. Gene ontology (GO) analysis showed that 53 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and 158 GO terms were significantly over expressed. Genes showing the largest magnitude of expression changes were related to fin development, androgen biosynthesis, and lipid and fatty acid metabolisms, suggesting the involvement of these biological processes in response to NGT exposure in G. affinis. This first comprehensive study on the transcriptomic alterations by NGT in G. affinis not only provides valuable information on the development of molecular markers but also opens new avenues for studies on the molecular mechanisms of effects of NGT in particular and possibly other progestins in G. affinis.
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http://dx.doi.org/10.1016/j.ecoenv.2018.12.053DOI Listing
April 2019

Rapid masculinization and effects on the liver of female western mosquitofish (Gambusia affinis) by norethindrone.

Chemosphere 2019 Feb 18;216:94-102. Epub 2018 Oct 18.

The Environmental Research Institute, MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China. Electronic address:

Natural and synthetic progestins in receiving streams can disrupt the normal endocrine systems of fish. Norethindrone (NET) is a widely used synthetic progestin that often appears in wastewater effluents. For this research, adult female western mosquitofish (Gambusia affinis) were exposed to NET at three concentrations. The effects of NET on the following biological factors were evaluated: the histology of the ovaries and livers, the anal fin morphology, and transcription of genes related to steroidogenesis signaling pathways in the livers. After 42 d exposure to NET at 33.0 ng L and 347.5 ng L, rapid masculinization, an increase in the number of atretic and postovulatory follicles in the ovary, enhanced vascularization, degenerated hepatocytes and irregular nuclei in the livers were observed. Exposure to NET did not affect the expression of the androgenic and estrogenic receptor genes and Cyp19a except for a significant up-regulation of Erα. However, the expression of Vtg A, Vtg B, and Vtg C were markedly inhibited in the females exposed to three concentrations of NET. Compared to the control female, exposure to NET at 33.0 ng L and 347.5 ng L caused a 4.4- and 5.8-fold increase in the expression of Hsd17β3 in the livers, respectively. The results demonstrate that NET can cause rapid masculinization of female G. affinis, hepatopathological alterations and inhibited expressions of Vtg A, Vtg B, and Vtg C. The results imply that G. affinis populations might be threatened in NET-contaminated environment.
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http://dx.doi.org/10.1016/j.chemosphere.2018.10.130DOI Listing
February 2019

Emerging Thallium Pollution in China and Source Tracing by Thallium Isotopes.

Environ Sci Technol 2018 Nov 23;52(21):11977-11979. Epub 2018 Oct 23.

College of Environmental Science and Engineering , Guangzhou University ; Innovation Center and Key Lab of Waters Safety & Protection in the Pearl River Delta, Ministry of Education, Guangzhou 510006 , China.

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http://dx.doi.org/10.1021/acs.est.8b05282DOI Listing
November 2018

Sensitivities of seven algal species to triclosan, fluoxetine and their mixtures.

Sci Rep 2018 10 18;8(1):15361. Epub 2018 Oct 18.

The Environmental Research Institute, MOE Key Laboratory of Environmental Theoretical Chemistry, South China Normal University, Guangzhou, 510006, China.

Increasing release of pharmaceuticals and personal care products (PPCPs) into aquatic ecosystems is a growing environmental concern. Triclosan and fluoxetine are two widely used PPCPs and frequently detected in aquatic ecosystems. In this study, the sensitivities of 7 algal species from 4 genera to triclosan, fluoxetine and their mixture were evaluated. The results showed that the inhibitory effect on algal growth (EC-96h) of triclosan varied with 50 times differences among the 7 algal species. Chlorella ellipsoidea was the least susceptible species and Dunaliella parva was the most sensitive species to triclosan. The inhibitory effect of fluoxetine was less variable than triclosan. Slightly higher toxicity of fluoxetine than triclosan was shown in the 7 tested algal species. No consistent pattern of the effects from mixture of triclosan and fluoxetine was observed among the 7 algal species and among the 4 genera. Additive effects of the mixture occured in 4 species and antagonistic effects in the other 3 species but no synergistic effect was detected. The algal species might show some sign of phylogenetic response to triclosan, as evidenced by the wide range of differences in their sensitivity at the genus level. This study provides important data which could be beneficial for biomonitoring programs on the ecological risk (algal species diversity) of these two chemicals.
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http://dx.doi.org/10.1038/s41598-018-33785-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193942PMC
October 2018

Convergent analysis of genome-wide genotyping and transcriptomic data suggests association of zinc finger genes with lithium response in bipolar disorder.

Am J Med Genet B Neuropsychiatr Genet 2018 10 14;177(7):658-664. Epub 2018 Oct 14.

Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.

Lithium is the mainstay treatment in bipolar disorder (BD) for its effectiveness in the acute phases of illness and in prevention of recurrences. Lithium's mechanism of action is complex, and while it modulates the function of hundreds of molecular targets, most of these effects could be unspecific and not relevant for its clinical efficacy. In this study, we applied an integrated analytical approach using genome-wide expression and genotyping data from BD patients to identify lithium-responsive genes that may serve as biomarkers of its efficacy. To this purpose, we tested the effect of treatment with lithium chloride 1 mM on the transcriptome of lymphoblasts from 10 lithium responders (LR) and 10 nonresponders (NR) patients and identified genes significantly influenced by the treatment exclusively in LR. These findings were integrated with gene-based analysis on genome-wide genotyping data from an extended sample of 205 BD patients characterized for lithium response. The expression of 29 genes was significantly changed by lithium exclusively in LR. Gene-based analysis showed that two of these genes, zinc finger protein 429 (ZNF429) and zinc finger protein 493 (ZNF493), were also significantly associated with lithium response. Validation with quantitative real-time polymerase chain reaction confirmed the lithium-induced downregulation of ZNF493 in LR (p = .036). Using convergent analyses of genome-wide expression and genotyping data, we identified ZNF493 as a potential lithium-responsive target that may be involved in modulating lithium efficacy in BD. To our knowledge, this is the first evidence supporting the involvement of zinc finger proteins in lithium response.
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http://dx.doi.org/10.1002/ajmg.b.32663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230310PMC
October 2018
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