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1.
Chaos ; 31(3): 033125, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33810711

RESUMO

With the rapid development of information technology, traditional infrastructure networks have evolved into cyber physical systems (CPSs). However, this evolution has brought along with it cyber failures, in addition to physical failures, which can affect the safe and stable operation of the whole system. In light of this, in this paper, we propose an interdependence-constrained optimization model to improve the robustness of the cyber physical system. The proposed model includes not only the realistic physical law but also the interdependence between the physical network and the cyber network. However, this model is highly nonlinear and cannot be solved directly. Therefore, we transform the model into a bi-level mixed integer linear programming problem, which can be easily and effectively solved in polynomial time. We conduct the simulation based on standard Institute of Electrical and Electronics Engineers test cases and study the impact of the disaster level and coupling strength on the robustness of the whole system. The simulation results show that our proposed model can effectively improve the robustness of the cyber physical system. Moreover, we compare the performance of the power supply in different CPSs, which have different network structures of the cyber network. Our work can provide useful instructions for system operators to improve the robustness of CPSs after extreme events happen in them.

2.
Biosci Rep ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33782696

RESUMO

BACKGROUND: Fatigue can be induced after acceleration exposure, however the mechanism of it is still unclear. The aim of the present study was to examine whether metabolites changes can decrease cognitive and physical function after acceleration. METHODS: Graybiel scale and Fatigue Self-rating scale were used to assess the seasickness and fatigue degrees of eighty-seven male seafarers respectively after sailing. To test the effect of pyruvate on cognitive and physical functions, five different doses of pyruvate were administrated into rats. Insulin can reduce the accumulation of pyruvate. To observe the insulin effect on pyruvate, and cognitive, physical functions after acceleration, insulin administration or treatment of promoting insulin secretion was used. Physical and cognitive functions were assessed using Open Field test, Morris water maze and Loaded swimming test in animals. RESULTS: Physical and cognitive abilities were decreased obviously, and Serum pyruvate level increased mostly in human and rats after acceleration. Compared to vehicle group, physical and cognitive abilities were significantly decreased after pyruvate administration. Besides, we found a significant decline in adenosine triphosphate concentration and pyruvate dehydrogenase activity in the hippocampus, prefrontal cortex, liver, and muscle of rats treated with acceleration or pyruvate injection, while insulin administration or treatment of promoting insulin secretion markedly alleviated this decline and the impairment of physical and cognitive abilities, compared to the control group. CONCLUSION: Our results indicates that pyruvate has a negative effect on physical and cognitive abilities after acceleration. Insulin can inhibit pyruvate accumulation and cognitive and physical function after acceleration exposure.

4.
Physiol Behav ; 234: 113387, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33713693

RESUMO

Chronic ethanol exposure can increase the risk of depression. The α-amino-3­hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor is a key factor in depression and its treatment. The study was conducted to investigate the depressive-like behavior induced by chronic ethanol exposure in mice and to explore the mechanism in cells. To establish the chronic ethanol exposure mouse model, male C57BL/6 N mice were administered 10% (m/V) and 20% (m/V) ethanol as the only choice for drinking for 60 days, 90 days and 180 days. Depressive-like behavior in mice was confirmed by the forced swimming test (FST). Ethanol-induced changes in the mouse hippocampus were indicated by Western blotting, qPCR and Fluoro-Jade C (FJC) staining. We confirmed that 90- and 180-day ethanol exposure can lead to depressive-like mouse behavior, cell apoptosis, neuronal degeneration, a reduction in GluA1 and brain-derived neurotrophic factor (BDNF) expression, and an increase in IL-6 and IL-1ß in the mouse hippocampus. GluA1 silencing and overexpression models of SH-SY5Y cells were established for further investigation. The cells were treated with 100 mM and 200 mM ethanol for 24 h. Ethanol exposure decreased cell viability and the expression of BDNF and increased the cell apoptosis rate and the expression of BAX, cleaved caspase-3, IL-1ß and IL-6. GluA1 silencing aggravated ethanol-induced changes in cell viability and apoptosis and the expression of BDNF, BAX and cleaved caspase-3, and GluA1 overexpression attenuated these changes. Neither the silencing nor overexpression of GluA1 had an effect on ethanol-induced increases in IL-1ß and IL-6. Our results indicated that chronic ethanol exposure induced depressive-like behavior in male C57BL/6 N mice by downregulating GluA1 expression.

5.
Orthop Surg ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33675168

RESUMO

OBJECTIVE: To compare the clinical and radiographic outcomes between the Tri-Lock Bone Preservation Stem (BPS) and the conventional standard Corail stem in primary total hip arthroplasty (THA). METHODS: From March 2012 to May 2014, we retrospectively reviewed 84 patients (104 hips) who received Tri-Lock (BPS) and 84 patients (115 hips) who received conventional standard Corail stem in THA. Their mean ages were 53.12 ± 2.32 years and 52.00 ± 2.11 years, respectively. The clinical outcomes were assessed by Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Pain Visual Analogue Scale (VAS) and Harris Hip Score (HHS). The radiological outcomes were evaluated by the radiological examination. Accordingly, Intraoperative and postoperative complications were observed as well. RESULTS: The mean follow-up time was 48.23 ± 2.91 months in the Tri-Lock (BPS) group and 49.11 ± 2.11 months in the Corail group, respectively. The bleeding volumes in two groups were comparable (169.22 ± 58.11 mL vs 179.30 ± 59.14 mL, P = 0.003), with more bleeding volume in Corail group patients, while no statistically significance with respect to operation time was observed (65.41 ± 6.24 min vs 63.99 ± 6.33 min, P = 0.567). The rates of intraoperative fracture was 8% for the Corail group while 1% for the Tri-Lock (BPS) group (8% vs 1%, P = 0.030). At final follow-up, no statistical differences in regard to HHS, WOMAC, and Pain VAS were revealed between the two groups (P > 0.05). The rate of thigh pain was higher in Corail group than in Tri-lock (BPS) group (5% vs 0%, P = 0.043). However, incidence of stress shielding in grade 1 was higher in Tri-Lock (BPS) than in the Corail group (76% vs 23%, P < 0.01), while those in grade 2 and 3 were lower compared to the Corail stem (15% vs 28%, P < 0.01; 9% vs 16%, P = 0.008, respectively). Intriguingly, other assessments in relation to radiographic outcomes and postoperative complications were not comparable between the two groups. The Kaplan-Meier survival rate (revision surgery performed for any reason was defined as the end point) was similar between the two groups (P = 0.57), with 98.8% (95% confidence interval, 92.3%-100%) in Tri-lock (BPS) group and 97.6% (95% confidence interval, 94.6%-100%) in Corail group. CONCLUSIONS: The Tri-Lock (BPS) has similar clinic performances compared to the Corail stem. Furthermore, the Tri-lock (BPS) stem has some advantages in achieving lower incidence of thigh pain, stress shielding and intra-operative fracture. Therefore, we recommend the Tri-lock (BPS) stem as a good alternative in primary total hip arthroplasty, especially taking into account patient factors, including bone deficiency and convenience of extraction of the stem in hip revision.

6.
Vet Res ; 52(1): 37, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663572

RESUMO

Fowl cholera caused by Pasteurella multocida exerts a massive economic burden on the poultry industry. Lipopolysaccharide (LPS) is essential for the growth of P. multocida genotype L1 strains in chickens and specific truncations to the full length LPS structure can attenuate bacterial virulence. Here we further dissected the roles of the outer core transferase genes pcgD and hptE in bacterial resistance to duck serum, outer membrane permeability and virulence in ducks. Two P. multocida mutants, ΔpcgD and ΔhptE, were constructed, and silver staining confirmed that they all produced truncated LPS profiles. Inactivation of pcgD or hptE did not affect bacterial susceptibility to duck serum and outer membrane permeability but resulted in attenuated virulence in ducks to some extent. After high-dose inoculation, ΔpcgD showed remarkably reduced colonization levels in the blood and spleen but not in the lung and liver and caused decreased injuries in the spleen and liver compared with the wild-type strain. In contrast, the ΔhptE loads declined only in the blood, and ΔhptE infection caused decreased splenic lesions but also induced severe hepatic lesions. Furthermore, compared with the wild-type strain, ΔpcgD was significantly attenuated upon oral or intramuscular challenge, whereas ΔhptE exhibited reduced virulence only upon oral infection. Therefore, the pcgD deletion caused greater virulence attenuation in ducks, indicating the critical role of pcgD in P. multocida infection establishment and survival.

7.
Blood ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33667305

RESUMO

We studied a subset of hematopoietic stem cells (HSCs) that are defined by elevated expression of CD41 (CD41hi) and show bias for differentiation towards megakaryocytes (Mk). Mouse models of myeloproliferative neoplasms (MPN) expressing JAK2-V617F (VF) or a JAK2 exon 12 mutation (E12) displayed increased frequencies and percentages of the CD41hi versusCD41lo HSCs compared to wildtype controls. An increase in CD41hi HSCs that correlated with JAK2-V617F mutant allele burden was also found in bone marrow from MPN patients. CD41hi HSCs produced higher numbers of Mk-colonies HSC in single cell cultures in vitro, but showed reduced long-term reconstitution potential compared to CD41lo HSCs in competitive transplantations in vivo. RNA expression profiling showed upregulated cell cycle, Myc, and oxidative phosphorylation gene signatures in CD41hi HSCs, while CD41lo HSCs showed higher gene expression of interferon, JAK/STAT and TNFα/NFkB signaling pathways. Higher cell cycle activity and elevated levels of reactive oxygen species were confirmed in CD41hi HSCs by flow cytometry. Expression of Epcr, a marker for quiescent HSCs inversely correlated with expression of CD41 in mice, but did not show such reciprocal expression pattern in MPN patients. Treatment with interferon-α further increased the frequency and percentage of CD41hi HSCs and reduced the numbers of JAK2-V617F positive HSCs in mice and patients with MPN. The shift towards the CD41hi subset of HSCs by interferon-α provides a possible mechanism of how interferon-α preferentially targets the JAK2 mutant clone.

8.
Eur J Med Chem ; 217: 113357, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33740547

RESUMO

PARP inhibitors have achieved great success in cancers with BRCA mutations, but only a small portion of patients carry BRCA mutations, which results in their narrow indication spectrum. Recently, emerging evidence has demonstrated that combinations of PARP and PI3K inhibitors could evoke unanticipated synergistic effects in various cancers, even including BRCA-proficient ones. In this work, a series of PARP/PI3K dual inhibitors were designed, synthesized, and evaluated for their biological activities. It was found that compounds 9a and 23a exhibited excellent inhibitory activities against PARP-1 (9a: IC50 = 1.57 nM, 23a: IC50 = 0.91 nM) and PI3Kα (9a: IC50 = 2.0 nM, 23a: IC50 = 1.5 nM), and showed promising antiproliferative activities against both BRCA-deficient (HCT-116, HCC-1937) and BRCA-proficient (SW620, MDA-MB-231/468) tumor cells. 9a and 23a also exhibited considerable in vivo antitumor efficacy in an MDA-MB-468 xenograft mouse model, with TGI values of 56.39% and 48.77%, respectively. Additionally, 23a possessed promising profiles including high kinase selectivity and low cardiotoxicity. Overall, this work indicates 9a and 23a might be potential PARP/PI3K dual inhibitors for cancer therapy and deserve further research.

9.
Stroke Vasc Neurol ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785536

RESUMO

BACKGROUND: Healthy plasma therapy reverses cognitive deficits and promotes neuroplasticity in ageing brain disease. However, whether healthy plasma therapy improve blood-brain barrier integrity after stroke remains unknown. METHODS: Here, we intravenously injected healthy female mouse plasma into adult female ischaemic stroke C57BL/6 mouse induced by 90 min transient middle cerebral artery occlusion for eight consecutive days. Infarct volume, brain atrophy and neurobehavioural tests were examined to assess the outcomes of plasma treatment. Cell apoptosis, blood-brain barrier integrity and fibroblast growth factor 21 knockout mice were used to explore the underlying mechanism. RESULTS: Plasma injection improved neurobehavioural recovery and decreased infarct volume, brain oedema and atrophy after stroke. Immunostaining showed that the number of transferase dUTP nick end labelling+/NeuN+ cells decreased in the plasma-injected group. Meanwhile, plasma injection reduced ZO-1, occluding and claudin-5 tight junction gap formation and IgG extravasation at 3 days after ischaemic stroke. Western blot results showed that the FGF21 expression increased in the plasma-injected mice. However, using FGF21 knockout mouse plasma injecting to the ischaemic wild-type mice diminished the neuroprotective effects. CONCLUSIONS: Our study demonstrated that healthy adult plasma treatment protected the structural and functional integrity of blood-brain barrier, reduced neuronal apoptosis and improved functional recovery via FGF21, opening a new avenue for ischaemic stroke therapy.

10.
Neuropharmacology ; : 108538, 2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33789118

RESUMO

Cannabinoids produce a number of central nervous system effects via the CB2 receptor (CB2R), including analgesia, antianxiety, anti-reward, hypoactivity and attenuation of opioid-induced respiratory depression. However, the cellular distributions of the CB2Rs in the brain remain unclear. We have reported that CB2Rs are expressed in midbrain dopamine (DA) neurons and functionally regulate DA-mediated behavior(s). Unexpectedly, high densities of CB2-like signaling were also found in a neighboring motor structure - the red nucleus (RN) of the midbrain. In the present study, we systematically explored CB2R expression and function in the RN. Immunohistochemistry and in situ hybridization assays showed high densities of CB2R-immunostaining and mRNA signal in RN magnocellular glutamate neurons in wildtype and CB1-knockout, but not CB2-knockout, mice. Ex vivo electrophysiological recordings in midbrain slices demonstrated that CB2R activation by JWH133 dose-dependently inhibited firing rates of RN magnocellular neurons in wildtype, but not CB2-knockout, mice, while having no effect on RN GABA neurons in transgenic GAD67-GFP reporter mice, suggesting CB2-mediated effects on glutamatergic neurons. In addition, microinjection of JWH133 into the RN produced robust ipsilateral rotations in wildtype, but not CB2-knockout mice, which was blocked by pretreatment with either a CB2 or DA D1 or D2 receptor antagonist, suggesting a DA-dependent effect. Finally, fluorescent tract tracing revealed glutamatergic projections from the RN to multiple brain areas including the ventral tegmental area, nucleus accumbens, thalamus, and cerebellum. These findings suggest that CB2Rs in RN glutamate neurons functionally modulate motor activity, and therefore, constitute a new target in cannabis-based medication development for motor disorders.

11.
Cell Cycle ; 20(5-6): 603-615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33678118

RESUMO

Retinoblastoma (RB) is commonly-seen cancer in children. The p53 pathway dysfunction, which can lead to elevated MDM2 or MDM4 (p53 antagonists) protein expression, is frequently observed in almost all human cancers, including RB. The present study attempted to investigate the underlying mechanism from the perspective of non-coding RNA regulation. Here, we demonstrated that p53 and miR-129 were positively correlated with each other in RB. miR-129 directly targeted MDM2/4 to inhibit expression, therefore counteracting MDM2/4-mediated p53 signaling suppression and modulating RB cell proliferation and apoptosis. Moreover, p53 could activate the transcription of miR-129 via binding to the miR-129 promoter region, therefore forming a regulatory loop with MDM2/4 to affect RB progression. Altogether, the p53/miR-129/MDM2/4/p53 regulatory loop can modulate RB cell growth. We provide a solid experimental basis for developing novel therapies for RB.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33693744

RESUMO

CONTEXT: Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. OBJECTIVE: We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri-/post-menopausal women. DESIGN AND METHODS: We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares (PLS) regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. RESULTS: Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module, causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. DA treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (e.g.,10, 100µM). CONCLUSIONS: This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

13.
Front Cell Infect Microbiol ; 11: 631960, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33718281

RESUMO

Enterocytozoon hepatopenaei (EHP) infection has become a significant threat in shrimp farming industry in recent years, causing major economic losses in Asian countries. As there are a lack of effective therapeutics, prevention of the infection with rapid and reliable pathogen detection methods is fundamental. Molecular detection methods based on polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP) have been developed, but improvements on detection speed and convenience are still in demand. The isothermal recombinase polymerase amplification (RPA) assay derived from the recombination-dependent DNA replication (RDR) mechanism of bacteriophage T4 is promising, but the previously developed RPA assay for EHP detection read the signal by gel electrophoresis, which restricted this application to laboratory conditions and hampered the sensitivity. The present study combined fluorescence analysis with the RPA system and developed a real-time RPA assay for the detection of EHP. The detection procedure was completed in 3-7 min at 39°C and showed good specificity. The sensitivity of 13 gene copies per reaction was comparable to the current PCR- and LAMP-based methods, and was much improved than the RPA assay analyzed by gel electrophoresis. For real clinical samples, detection results of the real-time RPA assay were 100% consistent with the industrial standard nested PCR assay. Because of the rapid detection speed and the simple procedure, the real-time RPA assay developed in this study can be easily assembled as an efficient and reliable on-site detection tool to help control EHP infection in shrimp farms.

14.
BMC Cardiovasc Disord ; 21(1): 141, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731001

RESUMO

BACKGROUND: The predictive importance of visit-to-visit blood pressure variability (VVV) for high blood pressure (HBP) in a pediatric population has been largely unsettled. We aimed to evaluate it based on Health Promotion Program for Children and Adolescents (HPPCA), a school-based surveillance conducted from 2012 to 2018 in Suzhou, China. METHODS: A total of 330,618 participants had BP measurement in 2018 and ≥ 3 BP records during 2012-2017, were recruited from HPPCA. Absolute BP values (in mmHg) were converted into age-, sex- and height- normalized z-scores. VVV was expressed as standard deviation (SD), coefficient of variation (CV) or average real variability (ARV) of BP z-scores during 2012-2017. Logistic regression models were used to assess the associations between VVV and HBP in 2018. RESULTS: In 2018, 42,554 (12.87%) subjects were defined as HBP. VVV, except for SBP-CV and DBP-CV, was significantly higher in the HBP group than normotensives group. After adjusting for covariates including mean BP values from 2012 to 2017, SBP-SD, SBP-ARV, DBP-SD and DBP-ARV, increased the risk of HBP by 5.70 [95% confidence interval (95% CI) 5.54-5.87], 4.10 (95% CI 4.01-4.20), 4.70 (95% CI 4.50-4.90) and 3.39 (95% CI 3.28-3.50) times, respectively. Notably, SBP-SD significantly improved risk discrimination of HBP based on other risk variables (c-statistics, net reclassification index and integrated discrimination improvement significantly increased). CONCLUSIONS: Higher SD or ARV of BP, was independently related with higher probability of HBP in Chinese pediatric population. SBP-SD could be potentially helpful for detecting HBP. Future researches investigating the predictive value of VVV are warrant.

15.
Orthop Surg ; 2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33749137

RESUMO

OBJECTIVE: To investigate risk factors of cage retropulsion after posterior lumbar interbody fusion (PLIF) in China and to establish a scoring system of cage retropulsion. METHODS: The retrospective analysis was based on two hospital databases. The medical data records of posterior lumbar interbody fusion with cage retropulsion were selected from August 2009 to August 2019. Inclusion and exclusion criteria were set in advance. Risk factors including patients' baseline demographics (age, gender, operation diagnosis time difference), preoperative neurological symptoms, whether the fusion involves single or double segments, screw type, intraoperative compression, preoperative bone mineral density, whether there are neurological symptoms before surgery, whether there is urine dysfunction before surgery, disease type, complete removal of the endplate, and patient's education level. The research endpoint was the retropulsion of fusion cages. The Kaplan-Meier (K-M) method was used to analyze potential risk factors, and multivariate Cox regression was used to identify independent risk factors (P < 0.05). The Statistical Package for the Social Sciences (version 22.0; SPSS, IBM, Chicago, IL, USA) software was used for statistical analysis, and univariate analysis was used to screen out the factors related to cage retropulsion. All independent risk factors were included to predict the survival time of the retropulsion of cage. RESULTS: This study included a total of 32 patients with PLIF between 2009 to 2019. All patients were residents of China. Univariate analysis showed that there were 13 patients over 60 years old and 19 patients under 60 years old. There were 20 male patients and 12 female patients. The surgical diagnosis time was seven patients within 1 month, 17 patients within 1 to 3 months, and eight patients over 3 months. The disease type was 18 cases of lumbar disc herniation, 10 cases of lumbar spinal stenosis, four cases of lumbar spondylolisthesis. The fusion segment was 18 cases of single segment, 14 cases of double segment. The intraoperative compression was seven cases of compression, 25 cases of no compression. The preoperative bone mineral density was 10 cases of low density, 18 cases of normal, four cases of osteoporosis. The screw type was 27 cases of universal screw, five cases of one-way screw. Preoperative neurological symptoms were found in 25 cases and not in seven cases. Preoperative urination dysfunction occurred in 8 cases, whereas 24 cases did not have this dysfunction. The endplate was completely removed in 10 cases and not in 22 cases. Education level was nine cases of primary school education, 10 cases of secondary school, 13 cases of university level. Cox regression analysis showed that intraoperative pressure (hazard ratio [HR] = 4.604, P = 0.015) and complete removal of the endplate (HR = 0.205, P = 0.027) are associated with the time of cage retropulsion. According to the HR of each factor, the scoring rules were formulated, and the patients were divided into the low-risk group, moderate-risk group, and high-risk group according to the final score. The three median survival times of the three groups were 66 days in the low-risk group, 55 days in the moderate-risk group, and 45 days in the high-risk group, with statistical significance (P < 0.05). CONCLUSION: Intraoperative pressure and complete removal of the intraoperative endplate can be helpful to evaluating the expected time of cage retropulsion in patients with PLIF, and this clinical model guided the selection of postoperative prevention and follow-up treatment.

16.
Reproduction ; 161(4): 425-436, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33561006

RESUMO

The survival and development of a semi-allogeneic fetus during pregnancy require the involvement of decidual stromal cells (DSCs), a series of cytokines and immune cells. Insulin-like growth factor 1 (IGF1) is a low molecular weight peptide hormone with similar metabolic activity and structural characteristics of proinsulin, which exerts its biological effects by binding with its receptor. Emerging evidence has shown that IGF1 is expressed at the maternal-fetal interface, but its special role in establishment and maintenance of pregnancy is largely unknown. Here, we found that the expression of IGF1 in the decidua was significantly higher than that in the endometrium. Additionally, decidua from women with normal pregnancy had high levels of IGF1 compared with that from women with unexplained recurrent spontaneous miscarriage. Estrogen and progesterone led to the increase of IGF1 in DSCs through upregulating the expression of WISP2. Recombinant IGF1 or DSCs-derived IGF1 increased the survival, reduced the apoptosis of DSCs, and downregulated the cytotoxicity of decidual NK cells (dNK) through interaction with IGF1R. These data suggest that estrogen and progesterone stimulate the growth of DSCs and impair the cytotoxicity of dNK possibly by the WISP2/IGF1 signaling pathway.

17.
Addict Biol ; : e13005, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33538103

RESUMO

Despite extensive research, the rewarding effects of cannabinoids are still debated. Here, we used a newly established animal procedure called optogenetic intracranial self-stimulation (ICSS) (oICSS) to re-examine the abuse potential of cannabinoids in mice. A specific adeno-associated viral vector carrying a channelrhodopsin gene was microinjected into the ventral tegmental area (VTA) to express light-sensitive channelrhodopsin in dopamine (DA) neurons of transgenic dopamine transporter (DAT)-Cre mice. Optogenetic stimulation of VTA DA neurons was highly reinforcing and produced a classical "sigmoidal"-shaped stimulation-response curve dependent upon the laser pulse frequency. Systemic administration of cocaine dose-dependently enhanced oICSS and shifted stimulation-response curves upward, in a way similar to previously observed effects of cocaine on electrical ICSS. In contrast, Δ9 -tetrahydrocannabinol (Δ9 -THC), but not cannabidiol, dose-dependently decreased oICSS responding and shifted oICSS curves downward. WIN55,212-2 and ACEA, two synthetic cannabinoids often used in laboratory settings, also produced dose-dependent reductions in oICSS. We then examined several new synthetic cannabinoids, which are used recreationally. XLR-11 produced a cocaine-like increase, AM-2201 produced a Δ9 -THC-like reduction, while 5F-AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope in situ hybridization assays indicated that CB1 Rs are expressed mainly in VTA GABA and glutamate neurons, while CB2 Rs are expressed mainly in VTA DA neurons. Together, these findings suggest that most cannabinoids are not reward enhancing, but rather reward attenuating or aversive in mice. Activation of CB1 R and/or CB2 R in different populations of neurons in the brain may underlie the observed actions.

18.
Theranostics ; 11(7): 3512-3526, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33537101

RESUMO

Menstruation occurs in few species and involves a cyclic process of proliferation, breakdown and regeneration under the control of ovarian hormones. Knowledge of normal endometrial physiology, as it pertains to the regulation of menstruation, is essential to understand disorders of menstruation. Accumulating evidence indicates that autophagy in the endometrium, under the regulation of ovarian hormones, can result in the infiltration of immune cells, which plays an indispensable role in the endometrium shedding, tissue repair and prevention of infections during menstruation. In addition, abnormal autophagy levels, together with resulting dysregulated immune system function, are associated with the pathogenesis and progression of endometriosis. Considering its potential value of autophagy as a target for the treatment of menstrual-related and endometrium-related disorders, we review the activity and function of autophagy during menstrual cycles. The role of the estrogen/progesterone-autophagy-immunity axis in endometriosis are also discussed.

20.
Pharmacol Biochem Behav ; 202: 173104, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33444596

RESUMO

Methamphetamine (METH) is a highly addictive psychostimulant. The continuous use of METH may lead to its abuse and neurotoxicity that have been associated with METH-induced increases in release of dopamine (DA) and glutamate in the brain. METH action in DA has been shown to be mediated by redistribution of DA from vesicles into cytoplasm via vesicular monoamine transporter 2 (VMAT2) and the subsequent reversal of membrane DA transporter (DAT), while little is known about the mechanisms underlying METH-induced glutamate release. Recent studies indicate that a subpopulation of midbrain DA neurons co-expresses VMAT2 and vesicular glutamate transporter 2 (VGLUT2). Therefore, we hypothesized that METH-induced glutamate release may in part originate from such a dual phenotype of DA neurons. To test this hypothesis, we used Cre-LoxP techniques to selectively delete VGLUT2 from midbrain DA neurons, and then examined nucleus accumbens (NAc) DA and glutamate responses to METH using in vivo brain microdialysis between DA-VGLUT2-KO mice and their VGLUT2-HET littermates. We found that selective deletion of VGLUT2 from DA neurons did not significantly alter basal levels of extracellular DA and glutamate, but attenuated METH-induced increases in extracellular levels of DA and glutamate. In addition, DA-VGLUT2-KO mice also displayed lower locomotor response to METH than VGLUT2-HET control mice. These findings, for the first time, suggest that cell-type specific VGLUT2 expression in DA neurons plays an important role in the behavioral and neurochemical effects of METH. Glutamate corelease from DA neurons may in part contributes to METH-induced increase in NAc glutamate release.

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