Heterozygous deletion of Seipin in islet beta cells of male mice has an impact on insulin synthesis and secretion through reduced PPARγ expression.

AIMS/HYPOTHESIS: Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is an autosomal recessive disorder characterised by lipodystrophy and insulin resistance. BSCL2 is caused by loss-of-function mutations in the Seipin gene (also known as Bscl2). Deletion of this gene in mice induces insulin resistance, glucose intolerance and a loss of adipose tissue. This study evaluated the effects of genetic deletion of Seipin on islet beta cell function. METHODS: We examined seipin expression in islet cells and measured glucose profiles, insulin synthesis, glucose-stimulated insulin secretion (GSIS), islet expression of peroxisome proliferator-activated receptor γ (PPARγ), levels of Pdx-1, Nkx6.1, Glut2 (also known as Slc2a2) and proinsulin mRNA, nuclear translocation of pancreatic duodenal homeobox 1 (PDX-1), islet numbers, and beta cell mass and proliferation in male and female Seipin-knockout homozygous (Seipin-/-) and heterozygous (Seipin+/-) mice. RESULTS: Male and female Seipin-/- mice displayed glucose intolerance, insulin resistance, hyperinsulinaemia and a lack of adipose tissue. By contrast, male but not female Seipin+/- mice showed glucose intolerance without adipose tissue loss or insulin resistance. Seipin was highly expressed in islet beta cells in wild-type mice. Expression of islet PPARγ was reduced in male Seipin-/- and Seipin+/- mice but not in female Seipin-/- or Seipin+/- mice. Treatment of male Seipin+/- mice with rosiglitazone corrected the glucose intolerance. Male Seipin+/- mice displayed a decrease in islet insulin concentration and GSIS with low expression of Pdx-1, Nkx6.1, Glut2 and proinsulin, and a decline in PDX-1 nuclear translocation; these changes were rescued by rosiglitazone administration. Male Seipin-/- mice showed obvious, but rosiglitazone-sensitive, increases in islet insulin concentration, islet number and beta cell mass and proliferation, with a notable decline in GSIS. Ovariectomised female Seipin+/- mice displayed glucose intolerance and deficits in insulin synthesis and secretion, with a decline in islet PPARγ level; these deleterious effects were reversed by administration of oestradiol or rosiglitazone. CONCLUSIONS/INTERPRETATION: Heterozygous deletion of Seipin in islet beta cells impacts on insulin synthesis and secretion through reduced PPARγ expression. This leads to glucose intolerance and is relieved by oestradiol, which rescues PPARγ expression.

Exposure of pregnant mice to triclosan causes hyperphagic obesity of offspring via the hypermethylation of proopiomelanocortin promoter.

Triclosan (TCS), as a broad spectrum antibacterial agent, is commonly utilized in personal care and household products. Maternal urinary TCS level has been associated with changes in birth weight of infants. We in the present study investigated whether exposure of mice to 8 mg/kg TCS from gestational day (GD) 6 to GD14 alters prenatal and postnatal growth and development, and metabolic phenotypes in male and female offspring (TCS-offspring). Compared with control offspring, body weight in postnatal day (PND) 1 male or female TCS-offspring was reduced, but body weight gain was faster within postnatal 5 days. PND30 and PND60 TCS-offspring showed overweight with increases in visceral fat and adipocyte size. PND60 TCS-offspring displayed delayed glucose clearance and insulin resistance. PND30 TCS-offspring showed an increase in food intake without the changes in the oxygen consumption and respiratory exchange ratio (RER). The expression levels of proopiomelanocortin (POMC), α-melanocyte-stimulating hormone (α-MSH) and single-minded 1 (SIM1) in hypothalamus arcuate nucleus (ARC) and paraventricular nucleus (PVN), respectively, were significantly reduced in PND30 TCS-offspring compared to controls. The hypermethylation of CpG sites at the POMC promoter was observed in PND30 TCS-offspring, while the concentration of serum leptin was elevated and the level of STAT3 phosphorylation in ARC had no significant difference from control. This study demonstrates that TCS exposure during early/mid-gestation through the hypermethylation of the POMC promoter reduces the expression of anorexigenic neuropeptides to cause the postnatal hyperphagic obesity, leading to metabolic syndrome in adulthood.

Precision therapy for intrahepatic cholangiocarcinoma: A case report on adjuvant treatment in a recurrent patient after surgery and literature review.

A 37-year-old female patient was diagnosed with intrahepatic cholangiocarcinoma (ICC), with the lesion located in the right lobe of the liver. Despite radical resection, postoperative adjuvant chemotherapy and a combination of adjuvant chemotherapy and immunotherapy, the patient continued to experience multiple instances of intrahepatic tumor metastases. Furthermore, the patient exhibited significant adverse reactions to systemic chemotherapy and had poor treatment tolerance. Guidance from paraffin section fluorescence in situ hybridization gene sequencing was used to select a combination of immunotherapy and targeted therapy treatments with programmed cell death 1 (PD-1)/PD-1 ligand 1 antibody durvalumab and the targeted drug pemigatinib. The patient tolerated the treatment and has continued to survive for 28 months. According to imaging evaluations, the lesions continued to decrease, with some disappearing completely. The tumor marker carbohydrate antigen 19-9 remained normal for >9 weeks during the treatment. This report described the patient's treatment process in detail and briefly reviewed relevant literature on the treatment progress of postoperative patients with ICC.

Hypoxia-Induced miR-210 Promotes Endothelial Cell Permeability and Angiogenesis via Exosomes in Pancreatic Ductal Adenocarcinoma.

Background: Exosomes have been proven to play important diagnostic, regulatory, or communication roles in tumorigenesis, tumor progression, or metastasis; in recent studies, lots of molecules, including miRNAs, were found to be aberrantly expressed in tumor exosomes and were correlated with tumor development. However, studies about the expression, relationship, or control mechanisms of miRNAs in exosomes in pancreatic ductal adenocarcinoma (PDAC) are scarce and urgently needed. The aim of this article was to identify and investigate abnormally expressed miRNAs in PDAC exosomes in vivo and in vitro. Methods: Microarray studies were used to detect aberrantly expressed miRNAs in PDAC exosomes, and miR-210 expression in cells or exosomes was further analyzed by qRT-PCR. Bioinformatics analyses, dual-luciferase assays, WB, and other assays were utilized to explore the miRNA molecular mechanisms. The living cell coculture model and immunofluorescence analysis were employed to image the communication between PDAC cells and endothelial cells. Other biological experiments in the study include a real-time intravital imaging system, EdU, transwell, xenograft models, and so on. Results: miR-210 is significantly expressed in PDAC exosomes and malignant cells. High miR-210 significantly facilitated tumor angiogenesis, cell invasion, and proliferation in PDAC cells. Further mechanistic detection revealed that miR-210 negatively regulated EFNA3 expression and participated in the PI3K/AKT/VEGFA or Wnt/Β-catenin/RHOA pathways, thus promoting tumor angiogenesis and cellular permeability. PDAC cells promote endothelial angiogenesis or permeability via miR-210 transmission by tumor exosomes. Exosomal miR-210 promotes PDAC progression in vivo. Further detection of PDAC plasma exosomal miR-210 suggests that exosomal miR-210 expression was high and significantly associated with vascular invasion and TNM stage and was an independent risk factor for PDAC overall survival. Conclusions: PDAC cell-secreted exosomes could promote angiogenesis and cellular permeability of neighboring endothelial angiogenesis or permeability via miR-210 transmission. Exosomal miR-210 may play important roles in tumor biology and may be a useful prognostic marker in PDAC.

Sol/Antisolvent Coating for High Initial Coulombic Efficiency and Ultra-stable Mechanical Integrity of Ni-Rich Cathode Materials.

The Ni-rich cathode holds great promise for high energy density lithium-ion batteries because of its high capacity and operating voltage. However, crucial problems such as cation disorder, structural degradation, side reactions, and microcracks become serious with increasing nickel content. Herein, a novel and facile sol/antisolvent coating modification of Ni-rich layered oxide LiNi0.85Co0.1Mn0.05O2 (NCM) is developed where we use ethanol to disperse the nanosized LiBO2 to form the sol and adopt tetrahydrofuran (THF) as antisolvent to prepare the cluster of nanoparticles to be coated on the surface of NCM. The coating thickness can be tuned through the THF addition amount. The LiBO2 nanorod deposition is formed as well over the crack of the NCM cathode, likely acting as a patch to repair the original defect of the intrinsic crack. The uniform LiBO2 nanospherical particle coating together with LiBO2 nanorod wrapping provides a double protection against electrolytes. Compared with the raw material, LiBO2-coated LiNi0.85Co0.1Mn0.05O2 (LiBO2-coated NCM) exhibits a high initial Coulombic efficiency of 90.3% at 0.2 C between 2.8 and 4.3 V vs Li+/Li, a superior rate capability, enhanced fast charge property at 3 C, and restricted microcrack formation. This simple in-site modification and repairing technology guarantees a good mechanical integrity of the polycrystalline Ni-rich cathode.

Sulfur is a New High-Performance Additive toward High-Voltage LiNi0.5Co0.2Mn0.3O2 Cathode: Tiny Amount, Huge Impact.

Increasing working voltage of cathode has been identified as one of the most promising strategies to increase energy density of the lithium-ion batteries. It is of crucial importance to suppress side reactions and control the formation of a cathode electrolyte interface (CEI) on the cathode surface in a high voltage range. In this work, sulfur is utilized to increase the working voltage of LiNi0.5Co0.2Mn0.3O2(NCM 523) to 4.5 V as demonstrated by both the NCM523/Li half-cell and NCM 523/graphite full cell. When a tiny amount of sulfur (0.1 mg mL-1) is added to the blank electrolyte of ethylene carbonate (EC) and dimethyl carbonate (DMC) (3:7 by volume), the cycling stability and rate performance are greatly improved in the NCM523/Li half-cell. The capacity retention over 200 cycles at 170 mA g-1 (1.0 C) is increased from 61.2 to 82.0%. The capacity at a high current density of 850 mA g-1 (5.0 C) is increased from 92 mAh g-1 to 120 mAh g-1. Because the addition of sulfur also enhances the performance of the Li/graphite half-cell, improved performance is demonstrated by the NCM 523/graphite full cell as well. The mechanism is interpreted based on various characterizations. It is revealed that the preferential oxidation of sulfur at the cathode surface suppress decomposition of electrolyte solvent. Because only a tiny amount of sulfur is added into the electrolyte solution, excessive decomposition of sulfur is avoided, leading to improved electrochemical performance.

Stable Electrode/Electrolyte Interface for High-Voltage NCM 523 Cathode Constructed by Synergistic Positive and Passive Approaches.

Increasing the working voltage of lithium-ion batteries (LIBs) is an efficient way to increase energy density. However, high voltage triggers excessive electrolyte decomposition at the electrode-electrolyte interfaces, where the electrochemical performance such as cyclic stability and rate capability is seriously deteriorated. A new synergistic positive and passive approach is proposed in this work to construct a stable electrode-electrolyte interface at high voltage. As a positive approach, inorganic lithium sulfide salt (Li2S) is used as an electrolyte additive to build a stable cathode electrolyte interface (CEI) at the LiNi0.5Co0.2Mn0.3O2 (NCM523) cathode surface. In a passive way, acetonitrile (AN) is applied as a solvent additive to suppress oxidative decomposition of a carbonate electrolyte via preferential solvation with a lithium ion. Because of the synergistic interaction between the positive and passive approaches, the cyclic stabilities of NCM523/Li cells improved with a tiny amount of Li2S (0.01 mg mL-1) and AN (0.5 vol %). The capacity retention increased to 80.74% after 200 cycles compared to the cells with the blank electrolyte (67.98%) and AN-containing electrolyte (75.8%). What is more, the capacity retention of the NCM523/graphite full cell is increased from 65 to 81% with the addition of the same amount of Li2S and AN after 180 cycles. The mechanism is revealed on the basis of the theoretical calculations and various characterizations. The products derived from the preferential adsorption and oxidation of Li2S on the surface of NCM523 effectively increase the content of inorganic ingredients. However, the presence of AN prevents oxidation of the solvent. This study provides new principle guiding studies on a high-voltage lithium-ion battery with excellent electrochemical performance.

Exposure of adult mice to perfluorobutanesulfonate impacts ovarian functions through hypothyroxinemia leading to down-regulation of Akt-mTOR signaling.

Perfluorobutanesulfonate (PFBS), a short-chain perfluoroalkyl substance, is used in many industrial products. Preliminary evidence suggests that exposure to PFBS may increase the risk of infertility. The aim of this study was to investigate the influence of PFBS on ovarian function. Herein, we show that exposure of adult female mice to PFBS (200 mg/kg/day) (PFBS-mice) caused a decrease in the levels of serum total triiodothyronine and thyroxine, which depended on the activation of peroxisome proliferator-activated receptor α (PPARα). The numbers of secondary, early antral and antral follicles were reduced in PFBS-mice with an increase in the atretic follicles, and these changes were recovered by the replacement of L-thyroxinein or the treatment with PPARα antagonist GW6471. PFBS-induced hypothyroxinemia led to a decrease in the levels of Akt, mTOR and p70S6K phosphorylation in ovarian granular cells and cumulus cells, which suppressed the proliferation of these cells and enhanced autophagic death of granular cells and cumulus cells. The levels of serum estradiol and progesterone were reduced in PFBS-mice with a low expression of the steroidogenic genes Star and P450scc in ovarian tissues, which were sensitive to the replacement of L-thyroxinein or the blockade of PPARα. The results indicate that exposure to PFBS (≥200 mg/kg/day) through reducing thyroid hormones causes down-regulation of Akt-mTOR signaling in granular cells and cumulus cells, leading to the deficits in the development of follicles and the biosynthesis of ovarian hormones.

Reduced serotonin impairs long-term depression in basolateral amygdala complex and causes anxiety-like behaviors in a mouse model of perimenopause.

Perimenopause is characterized by a gradual depletion of ovarian follicles with increased vulnerability to anxiety. However, the underlying mechanisms remain poorly understood. Herein, we show that chronic exposure to 4-vinylcycloxene diepoxide (VCD) in adult female mice (VCD-mice) caused follicles depletion and decline of serum estradiol (E2) and progesterone levels. Serotonin (5-HT) synthesis in dorsal raphe nucleus (DRN) and serotonergic afferents to basolateral amygdala complex (BLA) were reduced in VCD-mice, which were recovered by the supplement E2. VCD-mice appeared anxiety-like behaviors, which was relieved by the treatment with E2 or the co-administration of 5-HT1Ar agonist 8-OH-DPAT and 5-HT2A/Cr agonist DOI. The bath-application of 8-OH-DPAT in the slices obtained from VCD-mice (VCD-slices) corrected the increase in presynaptic glutamate release at external capsule-BLA synaptic transmission. Threshold to induce NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) was declined in VCD-mice with elevation of CaMKII phosphorylation, which was sensitive to 8-OH-DPAT. Notably, the bath-application of 8-OH-DPAT in VCD-slices caused a decrease in the GABAergic feedback inhibition, which was restored by adding DOI. In addition, NMDAr-independent long-term depression (LTD) could not be induced in VCD-mice, which was rescued by the co-application of 8-OH-DPAT with DOI or the GABAA receptor agonist muscimol. Furthermore, the treatment of VCD-mice with E2 could prevent the facilitation of LTP and recover the LTD induction. Thus, the results indicate that the 5-HT deficiency in the BLA of VCD-mice causes the facilitation of LTP via enhanced glutamate release and impairs the LTD induction through diminished GABAergic inhibition, leading to anxiety-like behaviors.

Association of Perfluoroalkyl and Polyfluoroalkyl Substances With Premature Ovarian Insufficiency in Chinese Women.

Context: Perfluoroalkyl and polyfluoroalkyl substances (PFASs), a group of ubiquitous environmental chemicals with properties of endocrine disruption, are often detectable in humans. Objective: The current study investigated the association between exposure to PFAS and primary ovarian insufficiency (POI). Design, Patients, Interventions, and Main Outcome Measures: Levels of plasma PFAS were measured in 120 Chinese women with overt POI and 120 healthy control subjects from 2013 to 2016. Associations between PFAS levels and odds of POI, as well as hormonal profiles, were evaluated using multiple logistic regression and multiple linear regression models. Results: Levels of perfluorooctanate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexanesulfonate (PFHxS) were positively associated with the risks of POI (highest vs. lowest tertile, PFOA: OR, 3.80; 95% CI, 1.92-7.49; PFOS: OR, 2.81; 95% CI, 1.46-5.41; PFHxS: OR, 6.63; 95% CI, 3.22-13.65). In patients with POI, levels of PFOS and PFHxS exposure were positively associated with FSH (PFOS: adjusted ß, 0.26; 95% CI, 0.15 to 0.38; PFHxS: adjusted ß, 0.16; 95% CI, 0.04 to 0.28) and negatively associated with estradiol (PFOS: adjusted ß, -0.30; 95% CI, -0.47 to -0.12; PFHxS: adjusted ß, -0.19; 95% CI, -0.37 to -0.02). Exposure to PFOS and PFOA was associated with elevation of prolactin (PFOS: adjusted ß, 0.17; 95% CI, 0.06 to 0.29; PFOA: adjusted ß, 0.16; 95% CI, 0.01 to 0.30) or with a decrease of free triiodothyronine (PFOS: adjusted ß, -0.88; 95% CI, -1.64 to -0.09; PFOA: adjusted ß, -0.90; 95% CI, -1.88 to 0.09) and thyroxine (PFOS: adjusted ß, -2.99; 95% CI, -4.52 to -1.46; PFOA: adjusted ß, -3.42; 95% CI, -5.39 to -1.46). Conclusion: High exposure to PFOA, PFOS, and PFHxS is associated with increased risk of POI in humans.

Impact of Triclosan on Female Reproduction through Reducing Thyroid Hormones to Suppress Hypothalamic Kisspeptin Neurons in Mice.

Triclosan (TCS), a broad-spectrum antimicrobial agent, is widely used in clinical settings and various personal care products. The aim of this study was to evaluate the influence of TCS on reproductive endocrine and function. Here, we show that the exposure of adult female mice to 10 or 100 mg/kg/day TCS caused prolongation of diestrus, and decreases in antral follicles and corpora lutea within 2 weeks. TCS mice showed decreases in the levels of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and progesterone, and gonadotrophin-releasing hormone (GnRH) mRNA with the lack of LH surge and elevation of prolactin (PRL). TCS mice had lower kisspeptin immunoreactivity and kiss1 mRNA in anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). Moreover, the estrogen (E2)-enhanced AVPV-kisspeptin expression was reduced in TCS mice. In addition, the serum thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) in TCS mice were reduced with increases in levels of thyroid stimulating hormone (TSH) and thyroid releasing hormone (TRH). In TCS mice, the treatment with Levothyroxine (L-T4) corrected the increases in PRL, TSH and TRH; the administration of L-T4 or type-2 dopamine receptors agonist quinpirole inhibiting PRL release could rescue the decline of kisspeptin expression in AVPV and ARC; the treatment with L-T4, quinpirole or the GPR45 agonist kisspeptin-10 recovered the levels of serum LH and FSH and progesterone, and GnRH mRNA. Furthermore, TCS mice treated with L-T4 or quinpirole resumed regular estrous cycling, follicular development and ovulation. Together, these results indicate that exposing adult female mice to TCS (≥10 mg/kg) reduces thyroid hormones causing hyperprolactinemia that then suppresses hypothalamic kisspeptin expression, leading to deficits in reproductive endocrine and function.

[Release of TNF-alpha and activation of Caspase-3 during apoptosis of human mononuclear cell induced by metal ion].

OBJECTIVE: To observe the human mononuclear cell releasing TNF-alpha and the activation of Caspase-3 during apoptosis after stimulated by Co2+ and Cr3+, to discuss the mechanism of artificial joint wear production metal ion on aseptic loosening. METHODS: CoCl2 powder and CrCl3 powder were dissolved by asepsis inject water, preparing solution for 10 mg/L and 500 mg/L, respectively. Mononuclear cells were acquired from peripheral blood, 4 x 10(6)/culture dish. According to the difference of culture solution, the cells were divided into 3 groups. Group A: mononuclear cell was culture with normal saline as control; group B: mononuclear cell was cultured with CoC2 solution; group C: mononuclear cell was cultured with CrCl3 solution. The production of TNF-alpha was assessed by ELISA, the activation of Caspase-3 was measured by colorimetric assay and the apoptotic cell was detected by TUNEL assays at 12, 24 and 48 hours after co-cultured respectively. RESULTS: The concentration of TNF-alpha and the expression of Caspase-3 in groups B and C were higher than those in group A (P < 0.05), and reached the peak level at 24, 48 hours, respectively. The TUNEL positive cells were detected in the all groups, nucleus was pyknotic and darker-staining, cell body was crinkle and cell membrane was integrity. There were significant differences in the apoptosis rate between groups B, C and group A (P < 0.05). And the activation of Caspase-3 increased and had the positive correlation with the apoptosis rate (r = 0.765). CONCLUSION: Co2+ and Cr3+ ions can stimulate human mononuclear cell to release TNF-alpha and induce human mononuclear cell apoptosis, which result in periprosthetic osteolysis and related to activation of Caspase-3.