Infliximab alleviates memory impairment in rats with chronic pain by suppressing neuroinflammation and restoring hippocampal neurogenesis.

Patients with chronic pain commonly report impaired memory. Increasing evidence has demonstrated that inhibition of neurogenesis by neuroinflammation plays a crucial role in chronic pain-associated memory impairments. There is currently a lack of treatment strategies for this condition. An increasing number of clinical trials have reported the therapeutic potential of anti-inflammatory therapies targeting tumour necrosis factor-α (TNF-α) for inflammatory diseases. The present study investigated whether infliximab alleviates chronic pain-associated memory impairments in rats with chronic constriction injury (CCI). We demonstrated that infliximab alleviated spatial memory impairment and hyperalgesia induced by CCI. Furthermore, infliximab inhibited the activation of hippocampal astrocytes and microglia and decreased the release of proinflammatory cytokines in CCI rats. Furthermore, infliximab reversed the decrease in the numbers of newborn neurons and mature neurons in the dentate gyrus (DG) caused by chronic pain. Our data provide evidence that infliximab alleviates chronic pain-associated memory impairments, suppresses neuroinflammation and restores hippocampal neurogenesis in a CCI model. These facts indicate that infliximab may be a potential therapeutic agent for the treatment of chronic pain and associated memory impairments.

TOX3 deficiency mitigates hyperglycemia by suppressing hepatic gluconeogenesis through FoxO1.

BACKGROUND: Excessive hepatic glucose production is a hallmark that contributes to hyperglycemia in type 2 diabetes (T2D). The regulatory network governing this process remains incompletely understood. Here, we demonstrate that TOX3, a high-mobility group family member, acts as a major transcriptional driver for hepatic glucose production. METHODS: Tox3-overexpressed and knockout mice were constructed to explore its metabolic functions. Transcriptomic and chromatin-immunoprecipitation sequencing (ChIP-seq) were used to identify downstream targets of TOX3. Both FoxO1 silencing and inhibitor approaches were used to assess the contribution of FoxO1. TOX3 expression levels were examined in the livers of mice and human subjects. Finally, Tox3 was genetically manipulated in diet-induced obese mice to evaluate its therapeutic potential. RESULTS: Hepatic Tox3 overexpression activates the gluconeogenic program, resulting in hyperglycemia and insulin resistance in mice. Hepatocyte-specific Tox3 knockout suppresses gluconeogenesis and improves insulin sensitivity. Mechanistically, integrated hepatic transcriptomic and ChIP-seq analyses identify FoxO1 as a direct target of TOX3. TOX3 stimulates FoxO1 transcription by directly binding to and activating its promoter, whereas FoxO1 silencing abrogates TOX3-induced dysglycemia in mice. In human subjects, hepatic TOX3 expression shows a significant positive correlation with blood glucose levels under normoglycemic conditions, yet is repressed by high glucose during T2D. Importantly, hepatic Tox3 deficiency markedly protects against and ameliorates the hyperglycemia and glucose intolerance in diet-induced diabetic mice. CONCLUSIONS: Our findings establish TOX3 as a driver for excessive gluconeogenesis through activating hepatic FoxO1 transcription. TOX3 could serve as a promising target for preventing and treating hyperglycemia in T2D.

Lung ultrasound to evaluate pulmonary changes in patients with cardiogenic shock undergoing extracorporeal membrane oxygenation: a retrospective study.

PURPOSE: The aim of the study was to evaluate the value of lung ultrasound (LUS) in patients with cardiogenic shock treated by venoarterial extracorporeal membrane oxygenation (VA-ECMO). METHODS: A retrospective study was conducted in Xuzhou Central Hospital from September 2015 to April 2022. Patients with cardiogenic shock who received VA-ECMO treatment were enrolled in this study. The LUS score was obtained at the different time points of ECMO. RESULTS: Twenty-two patients were divided into a survival group (n = 16) and a nonsurvival group (n = 6). The intensive care unit (ICU) mortality was 27.3% (6/22). The LUS scores in the nonsurvival group were significantly higher than those in the survival group after 72 h (P < 0.05). There was a significant negative correlation between LUS scores and PaO2/FiO2 and LUS scores and pulmonary dynamic compliance(Cdyn) after 72 h of ECMO treatment (P < 0.001). ROC curve analysis showed that the area under the ROC curve (AUC) of T72-LUS was 0.964 (95% CI 0.887 ~ 1.000, P < 0.01). CONCLUSION: LUS is a promising tool for evaluating pulmonary changes in patients with cardiogenic shock undergoing VA-ECMO. TRIAL REGISTRATION: The study had been registered in the Chinese Clinical Trial Registry(NO.ChiCTR2200062130 and 24/07/2022).

The altered immunological status of children conceived by assisted reproductive technology.

BACKGROUND: With the increased use of assisted reproductive technology (ART), assessing the potential health risks of children conceived on ART important to public health. Most research in this area has focused on the effects of ART on perinatal, metabolic, and oncological risks in children. Although an increased risk of immune-related diseases has been reported in children born after ART, there are no studies on the immunological status of these children. This study aimed to evaluate the impact of different embryo transfer methods and fertilization strategies on the immune status of the offspring. METHODS: A total of 69 children born to women treated with ART and a matched control group of 17 naturally conceived (NC) children, all aged from 3 to 6 years, were recruited in the reproductive hospital affiliated to Shandong University. The frequency of immune cells in the peripheral blood was assayed using flow cytometry; plasma cytokine levels were determined by multiplex cytokine immunoassay with human cytokine magnetic beads. RESULTS: Compared to children born after natural conception, children born after ART had elevated interferon-γ (IFN-γ) levels, regardless of embryo transfer and fertilization strategies. Children in the fresh-embryo transfer group had significantly higher IL-4 levels and a lower ratio of IFN-γ to IL-4 than those in the NC group ((P = 0.004, 10.41 ± 5.76 pg/mL vs 18.40 ± 7.01 pg/mL, P = 0.023, 1.00 ± 0.48 vs 0.67 ± 0.32, respectively). Similar results were shown in either the in vitro fertilization (IVF) group or the intra-cytoplasmic sperm injection (ICSI) group (P < 0.05 and P = 0.08 for IVF; P < 0.05 and P < 0.05 for ICSI, respectively). These alterations in IL-4 concentrations and the ratio of IFN-γ to IL-4 were statistically significantly correlated with supra-physical E2 (estradiol) levels on the day of hCG administration (R = 0.502, P = 0.017; R = - 0.537, P = 0.010, respectively). Consistently, the frozen embryo transfer did not result in alterations of these immune indicators in the offspring. Overall, there were no significant differences between the ART group and NC group in the frequencies of T cells, B cells, natural killer (NK) cells, CD4+T cells, CD8+T cells, T helper (TH)1 cells, TH17 cells, and regulatory T (Treg) cells and cytokine levels of IL-10 and IL-17a (all P > 0.05). CONCLUSIONS: Immunological alterations existed in children born after the use of ART. The elevated E2 levels before embryo implantation contributed to the increased IL-4 levels in children conceived by fresh embryo transfer. The assessment of immunological alteration is of importance to children conceived by ART for early monitoring and intervention.

The effect of different endometrial preparations on women with polycystic ovary syndrome undergoing initial frozen embryo transfer: A historical cohort analysis.

INTRODUCTION: Frozen embryo transfer is associated with a higher rate of live birth and a lower risk for ovarian hyperstimulation syndrome in women with polycystic ovary syndrome (PCOS) compared with fresh embryo transfer. The aim of this study is to assess the optimal endometrial preparation protocol for women with PCOS undergoing frozen embryo transfer. MATERIAL AND METHODS: We conducted a historical cohort analysis of 1720 women with PCOS who underwent the "freeze-all" strategy between August 2014 and August 2017 because of their high risk for ovarian hyperstimulation syndrome. Three endometrial preparation protocols were used: natural cycle (NC; n = 191), which relies on the dominant follicle to secrete estrogen that then promotes endometrial growth; ovarian stimulation (OS; n = 96), which induces follicle growth using low doses of human menopausal gonadotropin; and hormone replacement (HRT; n = 1433), which uses exogenous estradiol to promote endometrial growth. The primary outcome was live birth. RESULTS: For women who received a single embryo transfer, the live birth rates for the NC, OS, and HRT groups were 62.4%, 65.0%, and 52.2%, respectively. The live birth rate in the HRT group was significantly lower than that seen in the OS and NC groups (P = .009). The clinical pregnancy rates of the three groups were 72.3%, 73.8%, and 64.9%, respectively; this difference did not reach statistical significance (P = .071). CONCLUSIONS: The rate of live birth with the NC and OS regimens was higher than with the HRT protocol in women with PCOS who undergo single-blastocyst frozen embryo transfer.

Neuropathic pain-induced cognitive dysfunction and down-regulation of neuronal pentraxin 2 in the cortex and hippocampus.

Evidence from both basic and clinical science suggests that neuropathic pain can induce cognitive dysfunction. However, these results are mainly based on a series of behavioral tests, there is a lack of quantitative variables to indicate cognitive impairment. Neuronal activity-regulated pentraxin (NPTX2) is a ubiquitously expressed, secreted protein in the nervous system. NPTX2 has been implicated to be involved in a variety of neuropathic diseases including Parkinson's disease, ischemia, and Alzheimer's disease. In a mouse model of chronic pain, NPTX2 is involved in the regulation of inflammatory responses. Here, we employ a variety of behavioral approaches to demonstrate that mice with chronic neuropathic pain have cognitive impairment and exhibit an increased anxiety response. The expression of NPTX2, but not NPTX1, was down-regulated in the hippocampus and cortex after chronic neuropathic pain exposure. The modulation effect of NPTX2 on cognitive function was also verified by behavioral tests using Nptx2 knock-out mice. Above all, we conclude that downregulation of NPTX2 induced by neuropathic pain may serve as an indicator of a progressive cognitive dysfunction during the induction and maintenance of spared nerve injury.

Loss of miR-23b/27b/24-1 Cluster Impairs Glucose Tolerance via Glycolysis Pathway in Mice.

Alterations in miRNAs are associated with many metabolic disorders, such as type 2 diabetes (T2DM). The miR-23b/27b/24-1 cluster contains miR-23b, miR-27b, and miR-24-1, which are located within 881 bp on chromosome 9. Studies examining the roles of miR-23b, miR-27b, and miR-24-1 have demonstrated their multifaceted functions in variable metabolic disorders. However, their joint roles in metabolism in vivo remain elusive. To investigate this subject, we constructed miR-23b/27b/24-1 cluster knockout (KO) mice. Compared with wild-type (WT) mice, the KO mice exhibited impaired glucose tolerance, which was accompanied by a reduction in the respiratory exchange rate (RER). These alterations were more noticeable after a high-fat diet (HFD) induction. Hepatic metabolomic results showed decreased expression of reduced nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide (NAD), phosphoenolpyruvic acid (PEP), and phosphoric acid, which are involved in the glycolysis pathway. The transcriptomic results indicated that genes involved in glycolysis showed a downregulation trend. qPCR and Western blot revealed that pyruvate kinase (PKLR), the key rate-limiting enzyme in glycolysis, was significantly reduced after the deletion of the miR-23b/27b/24-1 cluster. Together, these observations suggest that the miR-23b/27b/24-1 cluster is involved in the regulation of glucose homeostasis via the glycolysis pathway.

Oxidative stress markers in the follicular fluid of patients with polycystic ovary syndrome correlate with a decrease in embryo quality.

PURPOSE: Elevated oxidative stress has been proposed as an important factor in the pathogenesis of polycystic ovary syndrome (PCOS)-related infertility. Our study was aimed at simultaneously exploring local and systemic oxidative stress in PCOS individuals and its relationship with embryo quality. METHODS: We recruited 86 PCOS cases and 60 controls. Five representative oxidative stress markers, namely, total oxidant capacity (TOC), total antioxidant capacity (TAC), malonaldehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD), were measured in both follicular fluid (FF) and serum. RESULTS: Women with PCOS compared to normal controls had higher levels of TOC in both FF (10.13 ± 2.68 vs.7.03 ± 2.45, P < 0.001) and serum (11.76 ± 2.92 vs. 8.82 ± 2.57, P < 0.001). The oxidative stress index (OSI, the ratio of TOC to TAC) was also higher in PCOS cases. They were still significant after BMI adjustment (Padj<0.01). In addition, the serum OSI level was much higher than the FF OSI level in both groups. Correlation analysis showed that the FF and serum TOC were negatively correlated with the high-quality embryo rate on day 3 and the later blastocyst formation rate in the PCOS group (P < 0.05). The correlation coefficient was higher in FF. Moreover, as the regression analysis data showed, the FF MDA level was significantly associated with embryo quality indicators (P < 0.05). CONCLUSIONS: PCOS was accompanied by elevated oxidative stress in both serum and FF. Even though serum oxidative stress was severe, the study suggested that FF oxidative stress contributed more to embryo quality, to which we should give more attention in the future.

Superior trichloroethylene removal from water by sulfide-modified nanoscale zero-valent iron/graphene aerogel composite.

Sulfide-modified nanoscale zero-valent iron (S-nZVI) is a promising material for removal of organic pollutants from water, but S-nZVI nanoparticles (NPs) easily agglomerate and have poor contact with organic contaminants. Herein, we propose a new S-nZVI/graphene aerogel (S-nZVI/GA) composite which exhibits superior removal capability for trichloroethylene (TCE) from water. Three-dimensional porous graphene aerogel (GA) can improve the efficiency of electron transport, enhance the adsorption of organic pollutants and restrain the agglomeration of the core-shell S-nZVI NPs. The TCE removal rates of FeS, nZVI, GA and S-nZVI were 27.8%, 42%, 63% and 75% in 2 hr, respectively. Furthermore, TCE was completely removed within 50 min by S-nZVI/GA. The TCE removal rate increased with increasing pH and temperature, and TCE removal followed the pseudo-first-order kinetic model. The results demonstrate the great potential of S-nZVI/GA composite as a low-cost, easily separated and superior monolithic adsorbent for removal of organic pollutants.

TOX3 Promotes Ovarian Estrogen Synthesis: An RNA-Sequencing and Network Study.

Background: Women who undergo chronic exposure to excessive estrogen are at a high risk of developing breast cancer. TOX3 has been reported to be highly expressed in breast tumors and is closely related to estrogen receptors. However, the effect of TOX3 on estrogen synthesis remains poorly understood. Methods: Using lentiviruses as a vector, we stably overexpressed TOX3 in the ovarian granulosa cell line KGN, the cells where estradiol is primarily produced, to investigate its role in estrogen production as well as cell viability and apoptosis. RNA-Sequencing was applied to uncover the global gene expression upon TOX3 overexpression. Results: We observed an increased level of cell viability and a reduced cell apoptosis rate after TOX3 overexpression, and the level of estradiol in the cell culture supernatant also increased significantly. Gene set enrichment analysis of the transcriptome showed that the ovarian steroidogenesis pathway was significantly enriched. Similarly, pathway mapping using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses also showed that TOX3 overexpression affects the ovarian steroidogenesis pathway. Further experiments showed that upregulated FSHR, CYP19A1, and BMP6 accounted for the enhanced estrogen synthesis. Conclusion: Our study demonstrated that TOX3 quantitatively and qualitatively stimulates estrogen synthesis by enhancing estrogen signaling pathway-related gene expression in ovarian granulosa cells. These findings suggest that TOX3 may play a vital role in the pathogenesis of breast cancer.

Incidence of bradycardia in pediatric patients receiving dexmedetomidine anesthesia: a meta-analysis.

Background Dexmedetomidine, an α2-receptor agonist, provides potent sedation, analgesia, and anxiolysis without respiratory depression and is used in a variety of surgical and procedural situations. Aim of the review The aim of this study was to estimate the incidence of bradycardia in pediatric patients who received dexmedetomidine as a sole agent for any procedural, intensive care or surgical sedation. Method Literature was searched in electronic databases and studies were selected by following pre-determined eligibility criteria. Meta-analyses were carried out by pooling the percent incidence of bradycardia to attain a weighted overall effect size. Age-wise subgroup analyses and meta-regression analyses for the identification of factors affecting the incidence were also performed. Results Data of 2835 patients from 21 studies were included. The mean age was 62.21 ± 35.68 months. Initial, maintenance and total doses of dexmedetomidine (mean ± standard deviation) were 1.63 ± 0.33 µg/kg body weight, 0.86 ± 0.68 µg/kg/h, and 26.7 ± 20.8 µg/kg. The overall incidence of bradycardia (95% confidence interval) was 3.067 (2.863, 3.270)%; P < 0.0001. However, range was wider (0-22%) with 9 studies observed 0% incidence. The mean change in the heart rate was -17.26 (-21.60, -12.92); P < 0.00001. In the meta-regression analyses, age, body weight and dexmedetomidine dose were not significantly associated with the incidence of bradycardia. The minimum heart rate observed during the dexmedetomidine treatment period was positively associated with baseline heart rate. Conclusion Incidence of bradycardia in dexmedetomidine treated pediatric patients is 3%.

Efficacy of perioperative dexmedetomidine in postoperative neurocognitive function: a meta-analysis.

Neuroprotective effects of dexmedetomidine are reported in preclinical and clinical studies but evidence regarding the postoperative neurocognitive function is not as clear. This study performed a meta-analysis on outcomes of studies which examined neurocognitive performance by using valid assessment tools before and after perioperative dexmedetomidine treatment. Literature was searched in several electronic databases and studies were selected by following précised inclusion criteria. Meta-analyses of mean differences in percent changes from baseline in neurocognitive assessment scores were carried out and subgroup analyses were performed. Eighteen studies were included. Initial dose of dexmedetomidine (mean ± SD) was 1.28 ± 0.97 µg/kg and maintenance dose was 0.41 ± 0.11 µg/kg per hour. In healthy volunteers, there was no significant difference in the neurocognitive performance between dexmedetomidine and controls/comparators (mean difference (95% confidence interval (CI)): -12.72 (-50.25, 24.80) %; P = 0.51). Perioperative dexmedetomidine treatment was associated with significantly better neurocognitive performance in comparison with saline (mean difference (95% CI): 9.10 (3.03, 15.16) %; P = 0.003) as well as with comparator anaesthetics (mean difference: 5.50 (0.15, 10.86) %; P = 0.04) treated patients. In the submeta-analyses of studies which utilized neurocognitive assessment tools other than Mini-Mental State Examination (mean difference: 6.66 (-3.42, 16.74); P = 0.20) or studies with patients under 60 years of age (mean difference: 7.48 (-3.00, 17.96); P = 0.16), the differences were not significant between dexmedetomidine- and saline-/comparator-treated patients. Perioperative dexmedetomidine treatment is associated with significantly better neurocognitive function postoperatively in comparison with both saline controls and comparator anaesthetics (predominantly midazolam).

Levo-tetrahydropalmatine attenuates oxaliplatin-induced mechanical hyperalgesia in mice.

Common chemotherapeutic agents such as oxaliplatin often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is difficult to treat and responds poorly to common analgesics, which represents a challenging clinical issue. Corydalis yanhusuo is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the potential analgesic effect of its active component, levo-tetrahydropalmatine (l-THP), has not been reported in conditions of neuropathic pain. This study found that l-THP (1-4 mg/kg, i.p.) produced a dose-dependent anti-hyperalgesic effect in a mouse model of chemotherapeutic agent oxaliplatin-induced neuropathic pain. In addition, we found that the anti-hyperalgesic effect of l-THP was significantly blocked by a dopamine D1 receptor antagonist SCH23390 (0.02 mg/kg), suggesting a dopamine D1 receptor mechanism. In contrast, l-THP did not significantly alter the general locomotor activity in mice at the dose that produced significant anti-hyperalgesic action. In summary, this study reported that l-THP possesses robust analgesic efficacy in mice with neuropathic pain and may be a useful analgesic in the management of neuropathic pain.