SHARPIN contributes to sevoflurane-induced neonatal neurotoxicity through up-regulating HMGB1 to repress M2 like-macrophage polarization.

Sevoflurane exposure can result in neurotoxicity especially among children, which remains an important complication after surgery. However, its related mechanisms remain unclear. Here, we investigated the biological roles of SHARPIN in sevoflurane-induced neurotoxicity. As detected by qPCR, Western blotting and immunohistochemical staining, SHARPIN and HMGB1 expression was elevated in sevoflurane-stimulated mice as compared with the control mice. SHARPIN depletion attenuated hippocampus injury, repressed the expression of HMGB1 and M1-like macrophage markers (iNOS, TNF-α, IL-1ß, IL-6), but enhanced the expression of M2-like macrophage markers (ARG-1, IL-10). GST pull-down and Co-IP assays demonstrated that SHARPIN directly interacted with HMGB1 to enhance HMGB1 expression in SH-SY5Y cells. The inhibitory effects of SHARPIN silencing on inflammatory reaction and M1-like macrophages were counteracted by HMGB1 overexpression. Finally, SHARPIN-HMGB1 pathway affected neuroinflammation triggered by sevoflurane via modulating macrophage polarization. Collectively, our data suggested that SHARPIN stimulated sevoflurane-induced neurotoxicity via converting M2-like macrophages to M1-like macrophages by enhancing HMGB1 expression. SHARPIN intervention may be a promising therapeutic method to relieve sevoflurane-induced neurotoxicity.

The mechanisms of milder clinical symptoms of COVID-19 in children compared to adults.

In stark contrast to adult patients, children who contract Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) typically manifest milder symptoms or remain asymptomatic. However, the precise underlying mechanisms of this pathogenesis remain elusive. In this review, we primarily retrospect the clinical characteristics of SARS-CoV-2 infection in children, and explore the factors that may contribute to the typically milder clinical presentation in pediatric Coronavirus Disease 2019 (COVID-19) patients compare with adults patients with COVID-19. The pathophysiological mechanisms that mitigate lung injury in children are as follows: the expression level of ACE2 receptor in children is lower; the binding affinity between ACE2 receptors and viral spike proteins in children was weaker; children have strong pre-activated innate immune response and appropriate adaptive immune response; children have more natural lymphocytes; children with COVID-19 can produce higher levels of IgM, IgG and interferon; children infected with SARS-CoV-2 can produce lower levels of IL-6 and IL-10; children have fewer underlying diseases and the lower risk of worsening COVID-19; children are usually exposed to other respiratory viruses and have an enhanced cross-reactive immunity. Comprehending the relative contributions of these processes to the protective phenotype in the developing lungs can help in the diagnosis, treatment and research pertaining to children with COVID-19.

PD-1 inhibitors-associated myocarditis in non-small cell lung cancer patients.

Background: Immune checkpoint inhibitors (ICIs)-associated myocarditis remains a rare but fatal adverse event. The authors sought to provide a comprehensive clinical description of ICI-associated myocarditis by analyzing symptoms, laboratory indicators, imaging features, and management of ICI-associated myocarditis in patients with non-small cell lung cancer (NSCLC). Methods: A retrospective study was conducted to analyze 14 ICI-associated myocarditis cases and 45 control patients to clarify clinical features of ICI-associated myocarditis. Detailed laboratory tests and imaging examinations were performed in 14 cases, and the rescue process and follow-up after the onset of myocarditis were recorded. Results: A total of 14 (2.08%) NSCLC patients developed ICI-related myocarditis, with a median time of onset of 34 days (interquartile range, 12 to 146 days) after ICI initiation. The most common concurrent adverse events in cases were myositis (P<0.001) and peripheral neuritis (P<0.001). Among cases, cardiac troponin I (cTnI) levels were abnormally elevated in 92% of patients, and electrocardiogram (ECG) showed abnormal in all cases. Steroid therapy was used in 92.9% of patients with ICI-associated myocarditis, of which the response rate to steroids was 76.9% and the mortality rate was 7.1%. A dose of 1 g/d of glucocorticoid supplemented by immunoglobulin was observed to be effective for severe myocarditis. Conclusions: Early identification and treatment are essential for managing myocarditis caused by ICI. Routine monitoring of cTnI level and ECG is most sensitive for the early diagnosis of ICI-related myocarditis. High-dose of glucocorticoids can effectively relieve the symptoms of ICI-associated myocarditis and stabilize the condition, especially for fulminant myocarditis.

The Importance of Using Exosome-Loaded miRNA for the Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) is a major traumatic disease of the central nervous system characterized by high rates of disability and mortality. Many studies have shown that SCI can be divided into the two stages of primary and secondary injury. Primary injury leads to pathophysiological changes, while consequential injury is even more fatal, including a series of harmful reactions that expand the scope and degree of SCI. Because the pathological process of SCI is highly complex, there is still no clear and effective clinical treatment strategy. Exosomes, membrane-bound extracellular vesicles (EVs) with a diameter of 30-200 nm, have emerged as an ideal vector to deliver therapeutic molecules. At the same time, increasing numbers of studies have shown that miRNAs play a momentous role in the process of SCI. In recent studies, researchers have adopted exosomes as carriers of miRNAs with potential therapeutic effects in SCI. In this review, we summarize relevant articles describing exosomes as miRNA carriers for SCI, after which we discuss further implications and perspectives of this novel treatment modality.

Recurrent Implantation Failure May Be Identified by a Combination of Diagnostic Biomarkers: An Analysis of Peripheral Blood Lymphocyte Subsets.

Background: Recurrent implantation failure (RIF) is a challenge during assisted reproductive technology (ART). In the present study, potential diagnostic biomarkers for the immune status of peripheral blood lymphocyte subsets in patients with RIF were analyzed, with the aim of identifying novel biomarkers that may predict RIF. Methods: A total of 41 participants, including 21 women with RIF and 20 fertile controls, were included in the present study. Functional analysis was performed and the cytokine status of natural killer (NK), T, CD8+ T, T helper (Th), and γδ T cells which are lymphocyte subsets in peripheral blood was measured using flow cytometry. Binary logistic regression analysis adjusted for T follicular helper 1 (Tfh1), Tfh2, Tfh17, and early NK cells was performed to determine the relationship between the peripheral blood lymphocyte subsets and RIF. Potential diagnostic biomarkers were assessed by logistic regression analysis and receiver operating characteristic curves. Results: There were significantly more Tfh1, Tfh17, and NK cells in the RIF group compared with the control group (all P < 0.05). However, the percentage of T, regulatory T (Tregs), and Tfh2 cells, as well as early inhibitory NK cells, was significantly lower in the RIF group compared with the control group (all P < 0.05). Following logistics regression analysis, Treg, Tfh17, and early inhibitory NK cells exhibited significant differences between the two groups. Combination diagnosis using these 3 biomarkers had a higher area under the curve of 0.900 (95% confidence interval: 0.808-0.992, P < 0.001) in the RIF group compared with that in the control group. Conclusion: T, Tregs, Tfh1, Tfh2, Tfh17, NK cells, and early inhibitory NK cells may play important regulatory roles in embryo implantation. The combination of 3 molecular markers (Treg, Tfh17, and early inhibitory NK cells) could provide a high diagnostic value for women with RIF, thus providing novel potential biomarkers for RIF in ART. The present findings could provide a reference either for the clinical treatment of patients with RIF or for future large, well-designed studies.

Inhibition of TRPV4 attenuates ferroptosis against LPS-induced ALI via Ca2+ pathway.

Acute lung injury (ALI) is an inflammation of the lungs with high incidence rate and mortality. Ferroptosis is a new cell death, which has influence in body organs. Transient receptor potential vanillin-4 (TRPV4) channel is a key mediator of Ca2+, its activation induces ferroptosis. The purpose of the study is to investigate the function of TRPV4 on ferroptosis in ALI mice induced by lipopolysaccharide (LPS). In vitro, the regulation of TRPV4 on Ca2+ and ferroptosis was detected by CCK-8, fluorescent probe, and western blot in BEAS-2B cells. In vivo, the role of TRPV4 antagonists on ALI mice was analyzed by determination of pulmonary inflammation, pulmonary edema, and ferroptosis. In vitro, ferroptosis was induced in ALI. TRPV4 expression and intracellular Ca2+ concentration were up-regulated in ALI, and TRPV4 antagonist suppressed LPS-induced ferroptosis in BEAS-2B cells, including decreased MDA and ROS levels, increased GPX4 protein level and cell viability. In vivo, ALI mice showed activated ferroptosis compared with the control group, and administration of TRPV4 inhibition had protective effects on ALI mice, including improving lung pathological characteristics, and reducing the degree of pulmonary edema, inflammation, and ferroptosis. The results manifested that ferroptosis mediated lung injury in LPS-induced ALI, and TRPV4 antagonists might moderate LPS-induced damage by suppressing ferroptosis.

Effects of dexmedetomidine on the expression profile of tsRNAs in LPS-induced acute lung injury.

BACKGROUND: Acute lung injury (ALI) is characterized by impaired alveolar function and excessive inflammation, which is commonly seen in clinical anesthesia and intensive care units. tRNA-derived small RNA (tsRNA) is a non-coding RNA that can be used as a potential disease diagnostic biomarker. The connection between ALI and tsRNA remains unknown. We aimed to explore the possible regulatory functions and mechanisms of tsRNAs in ALI treated with DEX. METHODS: Firstly, we established the ALI model by LPS injection and explored the effect of dexmedetomidine (DEX) treatment on lung damage. Then, the lung tissues were obtained from the LPS and LPS + DEX group for small RNA sequencing. RESULTS: We proved that DEX could ameliorate pulmonary injury, and decreased inflammation, pulmonary edema, and ferroptosis (MDA down-regulation and GPX4 up-regulation) in ALI. Furthermore, in the tsRNA expression profile, the top 10 down-regulated tsRNAs were tsRNA-1018, tsRNA-3045b, tsRNA-5021a, tsRNA-1020, tsRNA-5002b, tsRNA-3045b, tsRNA-1026, tsRNA-5004a, tsRNA-5005b and tsRNA-1009, and the top 10 up-regulated tsRNAs were tsRNA-3025b, tsRNA-3025a, tsRNA-5016b, tsRNA-3042b, tsRNA-3029b, tsRNA-3028b, tsRNA-5006a, tsRNA-3027b, tsRNA-3027a, and tsRNA-5009b. The enrichment analysis of GO terms and KEGG pathways pointed that target genes of DE-tsRNAs were mainly enriched in regulation of transcription-associated GO terms, NF-kappa B signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway. The RT-qPCR results of tsRNA-1020 and tsRNA-1018 were in accordance with small RNA sequencing data. CONCLUSION: DEX affected the abnormal expression of tsRNAs in ALI. These aberrantly expressed tsRNAs and enriched physiological processes provide a scientific basis for the diagnosis and treatment of ALI.

The role of the PI3K/AKT signalling pathway in bFGF/PDGF composite hydrogel promoting the repair of spinal cord injuries.

OBJECTIVE: This study aimed to explore the role of the PI3K/AKT signaling pathway in bFGF/PDGF composite hydrogel promoting the repair of spinal cord injuries. METHODS: In this study, the spinal cord injury rat model was established using Allen's punch method. Healthy male Sprague Dawley rats of the clean grade were randomly divided into four groups (n=18, each): sham operation group (group S), bFGF/PDGF composite hydrogel group (group A), bFGF/PDGF composite hydrogel + LY294002 (PI3K/AKT signaling pathway inhibitor) group (group B) and bFGF/PDGF composite hydrogel + IGF-1 (PI3K/AKT signaling pathway agonist) group (group C). After the operation, the motor function of the posterior limbs, the apoptosis of the spinal cord cells and the expression of PI3K, Akt and phosphorylated Akt (p-Akt) in the spinal cord tissues of the rats in each group were detected. RESULTS: BBB joint score were significantly higher (P<0.05). CONCLUSION: BFGF/PDGF composite hydrogel can significantly promote the repair of spinal cord injuries and the mechanism is closely correlated to the activation of the PI3K/AKT signaling pathway. KEY WORDS: BFGF, Cell apoptosis, PDGF, PI3K/Akt signaling pathway, Spinal cord injury.

Effect of dexmedetomidine and cholinergic anti-inflammatory pathways in myocardial ischemia-reperfusion injury.

The aim of the current study was to determine the effect and mechanism underlying the cholinergic anti-inflammatory pathway of dexmedetomidine and the cholinergic anti-inflammatory pathway on myocardial ischemia-reperfusion injury by establishing a myocardial ischemia-reperfusion model in rats. Sixty healthy rats were randomly divided into 4 groups with 15 rats in each group. The first group was a sham operation group. The second group (myocardial ischemia-reperfusion model group [Ischemia-reperfusion injury (IRI)+S group]) was pre-treated with saline for 10 min before ischemia. The third group (myocardial ischemia reperfusion model with dexmedetomidine pre-treatment [IRI+Dex group]) received an intravenous injection of dexmedetomidine for 10 min before ischemia. The fourth group was the myocardial ischemia reperfusion model with dexmedetomidine pre-treatment and the disconnection of the vagus nerve group (IRI+Dex+V group). The serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels were determined. The expression of B cell lymphoma/lewkmia-2 (bcl-2), BCL2-associated X (bax), caspase-3, α7 Nicotinic acetylcholine receptor (α-7 nR), and inhibitor of nuclear factor kappa-Bα (I-κB-α) in the myocardium was measured. Dexmedetomidine can significantly reduce the myocardial tissue injury induced by myocardial ischemia-reperfusion in rats. Dexmedetomidine may relieve myocardial ischemia-reperfusion injury by activating the cholinergic anti-inflammatory pathway.

Double standards: why is pulse oximetry standard care, whereas tissue oximetry is not?

PURPOSE OF REVIEW: Why is pulse oximetry a standard monitor, whereas tissue oximeter is not? Is this a double-standard treatment? RECENT FINDINGS: There appears to be a lack of enthusiasm for a continual investigation into whether the use of pulse oximetry leads to reduced morbidity and mortality in acute care although there is no robust evidence attesting to its outcome benefits. In contrast, research investigating the outcome effectiveness of tissue oximetry-guided care is consistently ongoing. A recent randomized controlled trial involving 800 patients who underwent laparoscopic hysterectomy found that, although muscular tissue oxygen saturation-guided care did not reduce the overall occurrence of postoperative nausea and vomiting for all patients, it did reduce the occurrence of these symptoms in patients who had a body mass index ≥25. It was also observed that muscular tissue oxygen saturation increases when blood pressure falls following the administration of nicardipine. These studies highlight the persistence of interest in understanding the value of tissue oximetry in patient care. SUMMARY: Pulse oximetry and tissue oximetry are treated differently although neither monitor has robust evidence attesting to its outcome benefits. This difference may root in the difference in the physiology they monitor, the cost, the ease of use/interpretation/intervention and the relevance to patient safety and care quality. Pulse oxygen saturation represents a vital sign, whereas tissue oxygen saturation is likely a quality sign; however, further research endeavors are required to fully understand how to best use tissue oximetry.

Linc-FOXD3 knockdown enhances hippocampal NSCs activation through upregulation of the Wnt/ß-catenin pathway.

Hippocampal neural stem cells (H-NSCs) self-renewal and neurogenesis decrease with aging, but the intrinsic mechanism is unclear. In the current study, we detected the expression level of 8 conserved long intergenic noncoding RNAs (lincRNAs) in H-NSCs during aging, and investigated the function and mechanism of lincRNAs in regulating of H-NSCs. We found the proliferation and neuronal-differentiation capacities of H-NSCs reduced with aging and that this effect was accompanied by an increase in linc-FOXD3. Linc-FOXD3 knockdown improved H-NSCs proliferation and neuronal-differentiation capacities. Further mechanistic studies revealed that the effect of linc-FOXD3 knockdown on H-NSCs phenotypes was partially mediated by the up-regulation of Wnt/ß-catenin pathway. Thus, our study provides evidence that linc-FOXD3 could be a promising therapeutic target for the recovery of H-NSCs function during aging.

Prednisone may rebuild the immunologic homeostasis: Alteration of Th17 and Treg cells in the lymphocytes from rats' spleens after treated with prednisone-containing serum.

BACKGROUND: This study aimed to investigate alterations of T helper 17 (Th17), regulatory T (Treg) cells and relative cytokines after treating with prednisone-contained serum. Lymphocytes were isolated from female rats' spleens. METHODS: The splenic lymphocytes were divided into four groups: which were treated with normal rats' serum (control); prednisone-containing rats' serum (PDN); normal rats' serum and cytokines (CTK); cytokines and prednisone-containing rats' serum (PDN + CTK). The mRNA expression level of RORC, Foxp3 and interleukin-17 (IL-17) was examined by reverse transcription-polymerase chain reaction. The quantities of Th17 and Treg cells were tested by flow cytometry, and the concentrations of IL-17 and IL-10 were detected by enzyme-linked immunosorbent assay. RESULTS: Higher mRNA expression level of Foxp3, percentages of Treg/CD4+ , and concentrations of IL-10, lower mRNA expressions of RORC and IL-17, concentrations of IL-17 and percentages of Th17/CD4+ in PDN group were detected, compared with control group (all p < 0.01). Similar trend was detected in PDN + CTK group, compared with CTK group (all p < 0.01). CONCLUSION: Our results suggest that prednisone may rebuild the immunologic homeostasis and may be used in human diseases with changes in the imbalance immune system such as unexplained recurrent spontaneous abortion (URSA), hepatitis B infection, or other autoimmune diseases.

Systematic Analysis of Gene Expression Alteration and Co-Expression Network of Eukaryotic Initiation Factor 4A-3 in Cancer.

Purpose: Eukaryotic initiation factor 4A-3 (EIF4A3) is an RNA-binding protein (RBP) that is a core component of the exon junction complex (EJC). It has been identified as an important player in post-transcriptional regulation processes. Recently, investigations have focused on EIF4A3 dysfunction in carcinogenesis. The present study aims to determine whether EIF4A3 can serve as a prognostic marker and potential regulatory mechanism in human cancers. Materials and methods: EIF4A3 expression in various cancers was assessed using Oncomine. The Correlation between EIF4A3 expression and patient survival was evaluated using PrognoScan. EIF4A3 mutations in various cancers were investigated using cBioPortal. EIF4A3 co-expression networks in various cancers were established using Coexpedia. Finally, we analyzed potential functional roles of EIF4A3 using Gene Ontology and pathway enrichment analyses by FunRich V3. Results: EIF4A3 was overexpressed in common malignancies at the transcription levels. High incidences of the breast, lung, and urinary cancers were closely related to the prognostic index for survival. The most prevalent mutation in EIF4A3 was E59K/Q. The tumor necrosis factor-α (TNF-α)/nuclear factor-κB (NF-κB) signaling pathway was affected by these mutations. Co-expression networks showed that EIF4A3 regulates apoptosis and cell cycle via several cancer-related signal pathways, and promotes tumor cell migration, invasion and drug resistance. Conclusion: Our results suggest the potential role for EIF4A3 to serve as a diagnostic marker or therapeutic target for certain types of cancers.

Effect and mechanism of hyaluronic acid on the neurotoxic injury of lidocaine.

Hyaluronic acid (HA) is used to aid tissue repair and is a characterized inhibitor of TRPV1 channels. In this study, we investigated the effects of HA on lidocaine induced neurotoxicity and its mechanism of action. U87-MG cells with low (U87-MG-shTRPV1) or high (U87-MG-TRPV1) TRPV1 expression were studied. The control group was treated with lidocaine. The experimental group was treated with lidocaine and HA. Flow cytometry was used to assess the intracellular calcium concentration ([Ca2+] i) and cell apoptosis. Cell viability was detected by MTT assays. Compared to the control group, [Ca2+]i of U87-MG-TRPV1 and U87-MG cells were lower at T3, T4 and T5 (p < 0.05), apoptosis rates of U87-MG and U87-MG-TRPV1 cells were lower (p<0.05), and the cell viability of U87-MG and U87-MG-TRPV1 cells were higher in the experimental group (p<0.05). HA reduces the toxic damage of lidocaine through blocking Ca2+ influx through TRPV1 channels, preventing Ca2+ overload, leading to nerve cell protection.

Prednisone may induce immunologic tolerance by activating the functions of decidual immune cells in early pregnancy.

The objective of this study was to investigate alterations in human first-trimester decidual immune cells (DICs) and relevant cytokines after treatment with prednisone. Decidual lymphocytes were treated with prednisone alone, cytokines alone or the combination of prednisone and cytokines. Levels of STAT3, STAT5, RORC and FOXP3 mRNA were assayed using quantitative real-time PCR, proportions of CD4+ T helper 17 (Th17) and CD4+ T regulatory (Treg) cells were measured using flow cytometry, and concentrations of interleukin (IL)-17A and IL-10 were determined using enzyme-linked immunosorbent assay. After treatment with prednisone alone, levels of STAT5 and FOXP3 mRNA were significantly higher than in untreated control cells (both P < 0.01), while levels of RORC mRNA were significantly lower than in controls (P < 0.05). Levels of STAT3 mRNA did not vary significantly with treatment. After treatment with prednisone alone, proportions of Th17/CD4+ cells and levels of IL-17A were significantly lower than in control cells, and proportions of Treg/CD4+ cells and levels of IL-10 significantly higher than in controls (all P < 0.01). Our results suggest that prednisone may improve pregnancy outcomes by restoring immunological homeostasis through up-regulation of STAT5 and FOXP3, induction of DIC differentiation into Treg cells, inhibition of DIC differentiation into Th17 cells, reduction of IL-17A secretion and induction of IL-10 secretion.

Effects of hyperbaric factors on lidocaine-induced apoptosis in spinal neurons and the role of p38 mitogen-activated protein kinase in rats with diabetic neuropathic pain.

The application of lidocaine can lead to nerve damage. Evidence suggests that patients with diabetic neuropathy are at a higher risk for neurotoxicity. In the present study, the successful induction of diabetic neuropathic pain (DNP) in rats via a high-sugar, high-fat diet and intraperitoneal injection of 1% streptozotocin was verified and pronounced tactile allodynia was observed. It was found that intrathecal injections of hyperbaric lidocaine produced motor blocks of longer durations in the DNP model rats than in nondiabetic rats, or in DNP model rats injected with isobaric lidocaine. Histology of the lumbar 4-5 spinal cord revealed a significant difference in neuropathology between the DNP and nondiabetic rats. Moreover, edematous neurons and TUNEL-positive cells were observed in the hyperbaric lidocaine group. It was also found that the inhibition of p38 mitogen-activated protein kinase (p38MAPK) played a neuroprotective role in response to hyperbaric lidocaine-induced apoptosis in DNP rats, which indicates that p38MAPK plays a key role in the regulation of hyperbaric lidocaine-induced apoptosis in DNP rats. These findings suggest that hyperbaric lidocaine can promote spinal cord neuronal apoptosis in rats with DNP. Furthermore, p38MAPK might play a key role in the regulation of hyperbaric lidocaine-induced apoptosis in rats with DNP.

Efficacy and safety of vitamin C for atrial fibrillation after cardiac surgery: A meta-analysis with trial sequential analysis of randomized controlled trials.

OBJECTIVES: Antioxidant supplement is an option in preventing postoperative atrial fibrillation (AF) after cardiac surgery. However, the benefits and adverse effects of vitamin C have not been well assessed. We aimed to systematically evaluate the efficacy and safety of vitamin C in preventing postoperative AF in adult patients after cardiac surgery. METHODS: PubMed, EMBASE, and the Cochrane library databases from inception to September 2016 were searched. Randomized controlled trials (RCTs) that evaluated the efficacy and safety of vitamin C in preventing postoperative AF in adult patients after cardiac surgery were identified. The primary outcome was the incidence of postoperative AF. Secondary outcomes included the length of intensive care unit (ICU) stay, length of hospital stay, and stroke events. RESULTS: Eight RCTs incorporating 1060 patients were included. Compared with placebo group, vitamin C treatment was associated with a substantial reduction in postoperative AF (OR, 0.47; 95% CI, 0.36-0.62; evidence rank: moderate), with no significant heterogeneity (I2 44%; P = 0.09). Trial sequential analysis showed that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit, establishing sufficient and conclusive evidence. In addition, vitamin C administration was not associated with any length of stay, including in the ICU (evidence rank: low) and hospital (evidence rank: low), respectively. CONCLUSIONS: Short-term treatment with vitamin C is safe, and may reduce the incidence of postoperative AF after cardiac surgery. Future studies as well as more high quality RCTs are still warranted to confirm the effects of different durations of vitamin C on cardiac surgery.

Differences in Cytokine Expression and STAT3 Activation between Healthy Controls and Patients of Unexplained Recurrent Spontaneous Abortion (URSA) during Early Pregnancy.

Unexplained recurrent spontaneous abortion (URSA) is a common complication of pregnancy. Although tolerance of the maternal immune system is considered to be essential for a normal pregnancy, the precise mechanism underlying the pathogenesis of URSA remains to be fully elucidated, albeit it is known to involve inflammation. Here, we examine the relationship between the expression of inflammatory cytokines and the activation of downstream signaling pathways in URSA patients. Decidual and peripheral blood samples were collected from 30 URSA patients and from 30 women with normal early pregnancies. Western blot analysis was used to measure the expression levels of signal transducers and activators of transcription 3(STAT3), phosphorylated STAT3(p-STAT3), and interleukin-17 receptor(IL-17R) in the decidual samples. Enzyme-linked immunosorbent assay was used to assess the levels of IL-17, IL-10, IL-6, and IL-23 in the peripheral blood and decidual samples. In the URSA patients, the IL-10 expression levels were lower than those in the control subjects (P<0.05), whereas IL-6, IL-17, and IL-23 were all expressed at higher levels(P<0.05). Furthermore, the expression levels of IL-17R and p-STAT3 were higher in the URSA patients, exhibiting a trend similar to that of IL-23. Our finding of increased IL-23 expression in the deciduae and peripheral blood of patients with URSA suggest that this maybe a contributing factor to the pathogenesis of this disease. Likewise, STAT3 activation through its phosphorylation, which was associated with the IL-23 increase, may also be involved in URSA pathogenesis. However, the precise pathogenic mechanism requires further study.

MicroRNA-125b suppresses the epithelial-mesenchymal transition and cell invasion by targeting ITGA9 in melanoma.

Increasing evidence has shown that aberrant miRNAs contribute to the development and progression of human melanoma. Previous studies have shown that miR-125b functions as a suppressor in malignant melanoma. However, the molecular function and mechanism by which miR-125b influences melanoma growth and invasion are still unclear. In this study, we aimed to investigate the role of miR-125b in melanoma progression and metastasis. We found that miR-125b expression is significantly downregulated in primary melanoma, and an even greater downregulation was observed in metastatic invasion. Restored expression of miR-125b in melanoma suppressed cell proliferation and invasion both in vitro and in vivo. Furthermore, our findings demonstrate that upregulating miR-125b significantly inhibits malignant phenotypes by repressing the expression of integrin alpha9 (ITGA9). Finally, our data reveal that upregulated expression of ITGA9 in melanoma tissues is inversely associated with miR-125b levels. Together, our results demonstrate that upregulation of ITGA9 in response to the decrease in miR-125b in metastatic melanoma is responsible for melanoma tumor cell migration and invasion.

Interleukin 23 regulates the functions of human decidual immune cells during early pregnancy.

BACKGROUND: This study investigated the effects of interleukin 23 (IL-23) on the production of cytokines (IL-1, IL-4, IL-10, and IL-17), the differentiation of Treg/Th17 and STAT3 (i.e., signal transducer and activator of transcription 3) in human decidual immune cells (DICs) during early pregnancy. METHODS: DICs were treated with recombinant human IL-23 and an antibody against IL-23 subunit p19. The differentiation of Treg and Th17 cells was detected by flow cytometry. Levels of IL-23 receptor (IL-23R), STAT3, and phosphorylated STAT3 (pSTAT3) was examined by Western blot. The production of IL1, IL4, IL10, and IL-17 in DICs was measured by ELISA. RESULTS: Exogenous recombinant human IL-23 significantly promoted the differentiation of Th17 cells from DICs, while anti-IL-23 antibody significantly promoted the differentiation of Treg cells from DICs. Consistent with the differentiation of Th17 and Tregs cells, levels of IL-1ß and IL-17 correlated positively with IL-23 treatment, and anti-IL-23 antibody increased the secretion of IL-4 and IL-10 from DICs. Levels of pSTAT3, but not STAT3 or IL-23R, were significantly elevated by recombinant IL-23 treatment; anti-IL-23 antibody significantly decreased the levels of pSTAT3 and IL-23R in DICs. CONCLUSIONS: IL-23 mediates the differentiation of Th17 and Treg cells and the production of associated cytokines in DICs. The potential mechanism likely involves the STAT3 pathway.