Association of inactivated COVID-19 vaccination with maternal coagulation function in early pregnancy.

Reports of rare but severe thrombotic events after receiving some COVID-19 vaccines brought concerns for the possibility of vaccine-induced coagulation abnormality. However, no study has reported the impacts of COVID-19 vaccination on coagulation function in pregnant women. We aimed to explore whether vaccination with inactivated COVID-19 vaccines before pregnancy was associated with coagulation changes in pregnant women. We conducted a retrospective cohort study in a tertiary-care hospital in Shanghai, China. A total of 5166 pregnant women were included, of whom 2721 (52.7%) completed vaccination before conception. Compared with unvaccinated women, the mean serum levels of prothrombin time (PT) and fibrinogen (FIB) were lower in vaccinated women by 0.09 (ß = -0.09, 95% confidence interval [CI], -0.13, -0.05) mg/L and 0.11 (ß = -0.11, 95% CI, -0.15, -0.07) mg/L, and the mean D-Dimer (D-D) levels were higher by 0.12 (ß = 0.12, 95% CI, 0.09, 0.15) mg/L. However, no significant association was observed between COVID-19 vaccination and serum levels of activated partial thromboplastin time (APTT), fibrinogen degradation product (FDP) or thrombin time (TT). Our findings suggested that inactivated COVID-19 vaccination before conception resulted in a small change in maternal coagulation function, but this might not have clinical significance.

Association of COVID-19 vaccination before conception with maternal thyroid function during early pregnancy: A single-center study in China.

Despite the high vaccination coverage, potential COVID-19 vaccine-induced adverse effects, especially in pregnant women, have not been fully characterized. We examined the association between COVID-19 vaccination before conception and maternal thyroid function during early pregnancy. We conducted a retrospective cohort study in Shanghai, China. A total of 6979 pregnant women were included. Vaccine administration was obtained from electronic vaccination records. Serum levels of thyroid hormone were measured by fluorescence and chemiluminescence immunoassays. Among the 6979 included pregnant women, 3470 (49.7%) received at least two doses of an inactivated vaccine. COVID-19 vaccination had a statistically significant association with both maternal serum levels of free thyroxine (FT4) and thyroid stimulating hormone (TSH). Compared with unvaccinated pregnant women, the mean FT4 levels were lower in pregnant women who had been vaccinated within 3 months before the date of conception by 0.27 pmol/L (ß = -0.27, 95% confidence interval [CI], -0.42, -0.12), and the mean TSH levels were higher by 0.08 mIU/L (ß = 0.08, 95% CI, 0.00, 0.15). However, when the interval from vaccination to conception was prolonged to more than 3 months, COVID-19 vaccination was not associated with serum FT4 or TSH levels. Moreover, we found that COVID-19 vaccination did not significantly associate with maternal hypothyroidism. Our study suggested that vaccination with inactivated COVID-19 vaccines before conception might result in a small change in maternal thyroid function, but this did not reach clinically significant levels.

No association of vaccination with inactivated COVID-19 vaccines before conception with pregnancy complications and adverse birth outcomes: A cohort study of 5457 Chinese pregnant women.

Data on the safety of inactivated COVID-19 vaccines in pregnant women is limited and monitoring pregnancy outcomes is required. We aimed to examine whether vaccination with inactivated COVID-19 vaccines before conception was associated with pregnancy complications or adverse birth outcomes. We conducted a birth cohort study in Shanghai, China. A total of 7000 healthy pregnant women were enrolled, of whom 5848 were followed up through delivery. Vaccine administration information was obtained from electronic vaccination records. Relative risks (RRs) of gestational diabetes mellitus (GDM), hypertensive disorders in pregnancy (HDP), intrahepatic cholestasis of pregnancy (ICP), preterm birth (PTB), low birth weight (LBW), and macrosomia associated with COVID-19 vaccination were estimated by multivariable-adjusted log-binomial analysis. After exclusion, 5457 participants were included in the final analysis, of whom 2668 (48.9%) received at least two doses of an inactivated vaccine before conception. Compared with unvaccinated women, there was no significant increase in the risks of GDM (RR = 0.80, 95% confidence interval [CI], 0.69, 0.93), HDP (RR = 0.88, 95% CI, 0.70, 1.11), or ICP (RR = 1.61, 95% CI, 0.95, 2.72) in vaccinated women. Similarly, vaccination was not significantly associated with any increased risks of PTB (RR = 0.84, 95% CI, 0.67, 1.04), LBW (RR = 0.85, 95% CI, 0.66, 1.11), or macrosomia (RR = 1.10, 95% CI, 0.86, 1.42). The observed associations remained in all sensitivity analyses. Our findings suggested that vaccination with inactivated COVID-19 vaccines was not significantly associated with an increased risk of pregnancy complications or adverse birth outcomes.

Klf5 down-regulation induces vascular senescence through eIF5a depletion and mitochondrial fission.

Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krüppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.

Wounding characteristics and treatment principles of ground anti-armored vehicle ammunition against armored crew.

The wound mechanism, injury characteristics and treatment principles of anti-armored vehicle ammunition against armored crew in the past 20 years are summarized in this paper. Shock vibration, metal jet, depleted uranium aerosol and post armor breaking effect are the main factors for wounding armored crew. Their prominent characteristics are severe injury, high incidence of bone fracture, high rate of depleted uranium injury, and high incidence of multiple/combined injuries. During the treatment, attention must be paid on that the space of armored vehicle is limited, and the casualties should be moved outside of the cabin for comprehensive treatment. Especially, the management of depleted uranium injury and burn/inhalation injury are more important than other injuries for the armored wounds.

Gestational exposure to BDE-209 induces placental injury via the endoplasmic reticulum stress-mediated PERK/ATF4/CHOP signaling pathway.

Several epidemiological studies have reported significant associations between prenatal polybrominated diphenyl ethers (PBDEs) exposure and adverse birth outcomes. Placental injury is thought to mediate these associations. However, few study has investigated the adverse effects of PBDEs exposure on placental growth and development. We examined the impacts of gestational exposure to BDE-209, the most abundant PBDE conger detected in human samples, on placental structure and function, and its model of action in vivo and in vitro. Pregnant mice were exposed to 0, 2, 20, 200 mg/kg/day of BDE-209 by gavages from gestational day (GD) 0 to GD18. Results showed that gestational BDE-209 exposure significantly reduced placental weight, impaired placental vascular development and induced placental cell apoptosis. In addition, gestational BDE-209 exposure impaired placental transport and endocrine function as demonstrated by markedly downregulated expression of Glut1, Znt1, Pgf and Igf2 in BDE-209-treated placentas. Mechanistically, gestational exposure to BDE-209 upregulated the expression of GRP78, and 3 downstream proteins (p-eIF2α, ATF4 and CHOP) of the PERK signaling, suggesting the activation of endoplasmic reticulum (ER) stress and PERK signaling pathway in mouse placentas. Further in vitro study showed that PERK siRNA pretreatment markedly reversed BDE-209-induced cell apoptosis in human JEG-3 cells. Collectively, our results suggest that the activation of the ER stress-mediated PERK/ATF4/CHOP signaling pathway played a role in BDE-209-induced placental injury. Our findings provide new insight into the mechanisms of BDE-209 induced reproductive and developmental toxicity.

The N6-Methyladenosine Regulator ALKBH5 Mediated Stromal Cell-Macrophage Interaction via VEGF Signaling to Promote Recurrent Spontaneous Abortion: A Bioinformatic and In Vitro Study.

Successful conception requires the synchrony of multiple systems and organs. Dysregulation of stromal cell-immune cell interactions has been proposed to be associated with recurrent spontaneous abortion. However, the mechanism of this regulation has not been well elucidated. N6-methyladenosine is one of the most common RNA modifications, and is involved in many pathological processes. Our group has demonstrated that abnormal patterns of m6A modification inhibit trophoblast invasion and contribute to adverse pregnancy outcomes. The association between m6A regulators and stromal cell-immune cell interactions is unclear. We obtained RNA-seq profiles from a GEO dataset and identified differentially expressed m6A regulators between healthy controls and patients with a recurrent spontaneous abortion history. ROC curves, functional enrichment and subclassification analysis were applied to elucidate the role of m6A regulators in pregnancy. We verified the expression of m6A regulators and constructed an overexpression cell line in a coculture system to reveal ALKBH5 function in stromal cell-macrophage interactions. We identified 11 differentially expressed m6A regulators between healthy controls and patients with a recurrent spontaneous abortion history. Then, we identified the correlation between "eraser" genes and "writer" genes. We tested the predictive abilities of the 11 m6A regulators based on another dataset and verified their expression in primary human endometrial stromal cells. We then subclassified three distinct patterns using the 11 genes and visualized genes related to immune infiltration and macrophage function in each cluster. ALKBH5 was proven to be correlated with recurrent spontaneous abortion. To verify the role of ALKBH5 in RSA, we constructed an ALKBH5-overexpression cell line. Finally, we cocultured the overexpression cell line with THP-1 cells. A decrease in M2 differentiation was observed, and this bias could be attributed to the hyposecretion of VEGF in stromal cells. N6-methyladenosine regulators play a pivotal role in stromal cell-immune cell interactions at the maternal-fetal interface. Overexpression of the m6A "eraser" gene ALKBH5 in stromal cells resulted in the hyposecretion of VEGF. Dysregulation of VEGF might impair macrophage recruitment and M2 differentiation, which could be the potential cause of recurrent spontaneous abortion.

Decreased nitric oxide content mediated by asymmetrical dimethylarginine and protein l-arginine methyltransferase 3 in macrophages induces trophoblast apoptosis: a potential cause of recurrent miscarriage.

STUDY QUESTION: Is the protein l-arginine methyltransferase 3 (PRMT3)/asymmetrical dimethylarginine (ADMA)/nitric oxide (NO) pathway involved in the development of recurrent miscarriage (RM), and what is the potential mechanism? SUMMARY ANSWER: Elevated levels of PRMT3 and ADMA inhibit NO formation in the decidua, thereby impairing the functions of trophoblast cells at the maternal-foetal interface. WHAT IS KNOWN ALREADY: Decreased NO bioavailability is associated with RM. ADMA, an endogenous inhibitor of nitric oxide synthase (NOS), is derived from the methylation of protein arginine residues by PRMTs and serves as a predictor of mortality in critical illness. STUDY DESIGN, SIZE, DURATION: A total of 145 women with RM and 149 healthy women undergoing elective termination of an early normal pregnancy were enrolled. Ninety-six female CBA/J, 24 male DBA/2 and 24 male BALB/c mice were included. CBA/J × DBA/2 matings represent the abortion group, while CBA/J × BALB/c matings represent the normal control group. The CBA/J pregnant mice were then categorised into four groups: (i) normal + vehicle group (n = 28), (ii) abortion + vehicle group (n = 28), (iii) normal + SGC707 (a PRMT3 inhibitor) group (n = 20) and (iv) abortion + SGC707 group (n = 20). All injections were made intraperitoneally on Days 0.5, 3.5 and 6.5 of pregnancy. Decidual tissues were collected on Days 8.5, 9.5 and 10.5 of gestation. The embryo resorption rates were calculated on Day 9.5 and Day 10.5 of gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: NO concentration, ADMA content, NOS activity, expression levels of NOS and PRMTs in decidual tissues were determined using conventional assay kits or western blotting. PRMT3 expression was further analysed in decidual stromal cells, macrophages and natural killer cells. A co-culture system between decidual macrophages (DMs) and HTR-8/SVneo trophoblasts was constructed to study the roles of the PRMT3/ADMA/NO signalling pathway. Trophoblast apoptosis was analysed via Annexin V-fluorescein isothiocyanate/propidium iodide staining. CBA/J × DBA/2 mouse models were used to investigate the effects of SGC707 on embryo resorption rates. MAIN RESULTS AND THE ROLE OF CHANCE: Our results show that NO concentration and NOS activity were decreased, but ADMA content and PRMT3 expression were increased in the decidua of RM patients. Moreover, compared with the normal control subjects, PRMT3 expression was significantly up-regulated in the macrophages but not in the natural killer cells or stromal cells of the decidua from RM patients. The inhibition of PRMT3 results in a significant decrease in ADMA accumulation and an increase in NO concentration in macrophages. When co-cultured with DMs, which were treated with SGC707 and ADMA, trophoblast apoptosis was suppressed and induced, respectively. In vivo experiments revealed that the administration of SGC707 reduced the embryo resorption rate of CBA/J × DBA/2 mice. LIMITATIONS, REASONS FOR CAUTION: All sets of experiments were not performed with the same samples. The main reason is that each tissue needs to be reserved for clinical diagnosis and only a small piece of each tissue can be cut and collected for this study. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that the PRMT3/ADMA/NO pathway is a potential marker and target for the clinical diagnosis and therapy of RM. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (2017YFC1001401), National Natural Science Foundation of China (81730039, 82071653, 81671460, 81971384 and 82171657) and Shanghai Municipal Medical and Health Discipline Construction Projects (2017ZZ02015). The authors have declared no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

A dense SNP genetic map constructed using restriction site-associated DNA sequencing enables detection of QTLs controlling apple fruit quality.

BACKGROUND: Genetic map based quantitative trait locus (QTL) analysis is an important method for studying important horticultural traits in apple. To facilitate molecular breeding studies of fruit quality traits in apple, we aim to construct a high density map which was efficient for QTL mapping and possible to search for candidate genes directly in mapped QTLs regions. METHODS: A total of 1733 F1 seedlings derived from 'Jonathan' × 'Golden Delicious' was used for the map constructionand QTL analysis. The SNP markers were developed by restriction site-associated DNA sequencing (RADseq). Phenotyping data of fruit quality traits were calculated in 2008-2011. Once QTLs were mapped, candidate genes were searched for in the corresponding regions of the apple genome sequence underlying the QTLs. Then some of the candidate genes were validated using real-time PCR. RESULTS: A high-density genetic map with 3441 SNP markers from 297 individuals was generated. Of the 3441 markers, 2017 were mapped to 'Jonathan' with a length of 1343.4 cM and the average distance between markers was 0.67 cM, 1932 were mapped to 'Golden Delicious' with a length of 1516.0 cM and the average distance between markers was 0.78 cM. Twelve significant QTLs linked to the control of fruit weight, fruit firmness, sugar content and fruit acidity were mapped to seven linkage groups. Based on gene annotation, 80, 64 and 17 genes related to fruit weight, fruit firmness and fruit acidity, respectively, were analyzed.Among the 17 candidate genes associated with control of fruit acidity, changes in the expression of MDP0000582174 (MdMYB4) were in agreement with the pattern of changes in malic acid content in apple during ripening, and the relative expression of MDP0000239624 (MdME) was significantly correlated withfruit acidity. CONCLUSIONS: We demonstrated the construction of a dense SNP genetic map in apple using next generation sequencing and that the increased resolution enabled the detection of narrow interval QTLs linked to the three fruit quality traits assessed. The candidate genes MDP0000582174 and MDP0000239624 were found to be related to fruit acidity regulation. We conclude that application of RADseq for genetic map construction improved the precision of QTL detection and should be utilized in future studies on the regulatory mechanisms of important fruit traits in apple.

MicroRNA-34a induces apoptosis in the human glioma cell line, A172, through enhanced ROS production and NOX2 expression.

BACKGROUND: MicroRNA is a type of non-coding small RNA involved in regulating genes and signaling pathways through incomplete complementation with target genes. Recent research supports key roles of miRNA in the formation and development of human glioma. METHODS: The relative quantity of miR-34a was initially determined in human glioma A172 cells and glioma tissues. Next, we analyzed the impact of miR-34a on A172 cell viability with the MTT assay. The effects of miR-34a overexpression on apoptosis were confirmed with flow cytometry and Hoechst staining experiments. We further defined the target genes of miR-34a using immunofluorescence and Western blot. RESULTS: MiR-34a expression was significantly reduced in human glioma A172 cells and glioma tissue, compared with normal glial cells and tissue samples. Our MTT data suggest that up-regulation of miR-34a inhibits cell viability while suppression of miR-34a enhances cell viability. Flow cytometry and Hoechst staining results revealed increased rates of apoptosis in A172 human glioma cells overexpressing miR-34a. Using immunofluorescence and Western blot analyses, we identified NOX2 as a target of miR-34a in A172 cells. CONCLUSION: MiR-34a serves as a tumor suppressor in human glioma mainly by decreasing NOX2 expression.

α-HBDH is a superior to LDH in predicting major adverse cardiovascular events in patients with acute aortic dissection.

Objective: Acute aortic dissection (AAD) with a high mortality and postoperative complications remains presently no effective indicators to conjunctly predict the short-term mortality and the prognosis. This study aimed to investigate the predictive role of α-HBDH on in-hospital mortality and postoperative Major adverse cardiovascular events (MACE) in patients with AAD. Methods: In this retrospective study, a total of 369 enrolled patients from 2015 to 2021 were divided into three groups (T1: low, T2: medium and T3: high) based on the tertiles of α-HBDH levels on admission. In terms of the preoperative, intraoperative and postoperative indicators among 3 groups, the relationship between α-HBDH and studying endpoints was determined by logistic regression models, along with the consolidation using Kaplan-Meier and restricted cubic spline (RCS) analysis for predicting the in-hospital death and MACE complications. Last, subgroup analysis further verified the predictive value of α-HBDH. Results: Logistic regression analysis showed that α-HBDH was independently associated with in-hospital mortality of patients with AAD [OR(95CI): 4.771(1.043-21.832), P = 0.044] and MACE [OR(95CI): 9.869(2.148-45.349), P = 0.003]. Moreover, Kaplan-Meier analysis also showed an increased α-HBDH levels associated with poor survival within 30 days (log rank test, P < 0.01), especially in acute Stanford A dissection. RCS presented that 204 U/L was the optimal cut-off value of α-HBDH for in-hospital mortality and postoperative MACE, which facilitated clinical stratification of patients with AAD. Subgroup analysis confirmed a stable correlation between α-HBDH level and hospital mortality and MACE (P > 0.05). Conclusions: α-HBDH is a predictor of the in-hospital mortality and postoperative MACE, guiding admission stratification of patients with AAD.

A new diagnostic technique for identifying Angiostrongylus spp. larvae in intermediate snail species by examining the buccal cavity.

BACKGROUND: Angiostrongyliasis is a zoonotic parasitic disease caused by the rat lungworm Angiostrongylus cantonensis. The intermediate hosts of A. cantonensis are gastropods, and snail species such as Pomacea canaliculata play a key role in the transmission of human angiostrongyliasis. Detecting A. cantonensis infection in snails is an important component of epidemiological surveillance and the control of angiostrongyliasis. METHODS: In this study, a new method for diagnosing A. cantonensis infection in gastropods was developed by recovering larvae from the buccal cavity of three snail species. The entire buccal cavity of a snail was extracted, and the tissue was pressed between two microscope slides to observe whether A. cantonensis larvae were present. Our new method was compared with traditional pathogenic detection methods of lung microscopy, tissue homogenization, and artificial digestion. We artificially infected 160 P. canaliculata, 160 Cipangopaludina chinensis, and 160 Bellamya aeruginosa snails with A. cantonensis. Then, the four different detection methods were used to diagnose infection in each snail species at 7, 14, 21, and 28 days post exposure. RESULTS: We found no significant difference in the percentages of infected P. canaliculata snails using the four methods to detect A. cantonensis larvae. The radula pressing method had a mean detection rate of 80%, while the lung microscopy (81.3%), tissue homogenization (83.8%), and artificial digestion (85%) methods had slightly greater detection rates. Similarly, the percentages of infected C. chinensis snails that were detected using the radula pressing (80%), tissue homogenization (82.1%), and artificial digestion (83.8%) methods were not significantly different. Finally, the percentages of infected B. aeruginosa snails that were detected using the radula pressing (81.3%), tissue homogenization (81.9%), and artificial digestion (81.4%) methods were not significantly different. These results showed that the radula pressing method had a similar detection rate to traditional lung microscopy, tissue homogenization, or artificial digestion methods. CONCLUSIONS: This study demonstrates a new method for the qualitative screening of gastropods that act as intermediate hosts of A. cantonensis (and other Angiostrongylus species), provides technical support for the control of human angiostrongyliasis, and furthers research on A. cantonensis.

Inositol-requiring protein 1α signaling pathway is activated in the temporal cortex of patients with mesial temporal lobe epilepsy.

Accumulating evidence suggests that repeated seizures could induce endoplasmic reticulum (ER) stress. Inositol-requiring protein 1α (IRE1α) is a vital pro-apoptotic molecule in ER stress, but it remains unclear whether the signaling pathway mediated by IRE1α is involved in human temporal lobe epilepsy. In this report, we investigated IRE1α-mediated ER stress pro-apoptotic signaling pathway in resected anterior temporal neocortex from 32 patients with intractable mesial temporal lobe epilepsy by immunofluorescence and western blot analysis. Our results indicate that chronic epilepsy induces ER stress, and IRE1α-mediated ER stress apoptotic signaling pathway is involved in brain damage after repeated seizures, which may provide a new therapeutic target to prevent brain damage caused by epilepsy.

Predictive value of admission CO2 combining power combined with serum sodium for the prognosis in acute Stanford type A aortic dissection patients.

Acute Stanford type A aortic dissection (ATAAD) with sudden onset and high mortality requiries a standard Bentall operation and a accurate prognosis in common, together with alteration of CO2 combining power (CO2CP) and serum sodium rase concern, hence, we evaluated the prognostic value of CO2CP combined with serum sodium in ATAAD patients. This retrospective study included 183 patients who underwent Bentall operation for ATAAD from 2015 to 2021 in the Fourth Hospital of Hebei Medical University, subsequently followed grouping by the levels of CO2CP and serum sodium. The study endpoint was 30-day all-cause mortality, and the prognostic value of CO2CP combined with serum sodium levels in ATAAD patients were evaluated with multivariate logistic regression method. The postoperative incidence of in-hospital death and adverse events in patients with ATAAD were 18% and 25.7%, respectively. Combination of CO2CP and serum sodium for predicting ATAAD death and adverse events presented a higher predictive value than each single indicator with ROC curve analysis (the AUC of CO2CP combined with serum sodium was 0.786, 95% CI 0.706-0.869, P < 0.001), along with CO2CP < 22.5 mmol/L + serum sodium > 138.5 mmol/L group had the worst prognostic. Multivariate regression analyse showed that CO2CP < 22.5 mmol/L combined with serum sodium > 138.5 mmol/L preferably predicted the prognosis of ATAAD (OR =6.073, 95% CI 2.557-14.425, P < 0.001). Consistently, the cumulative 30-day survival after surgery in ATAAD patients with the low CO2CP and high serum sodium simultaneously was the worst (log-rank P < 0.05). The combination of CO2CP and serum sodium increases the predictive value of prognosis, which is conducive to risk stratification of patients with ATAAD.

Sox10 escalates vascular inflammation by mediating vascular smooth muscle cell transdifferentiation and pyroptosis in neointimal hyperplasia.

Vascular smooth muscle cells (VSMCs) can transdifferentiate into macrophage-like cells in the context of sustained inflammatory injury, which drives vascular hyperplasia and atherosclerotic complications. Using single-cell RNA sequencing, we identify that macrophage-like VSMCs are the key cell population in mouse neointimal hyperplasia. Sex-determining region Y (SRY)-related HMG-box gene 10 (Sox10) upregulation is associated with macrophage-like VSMC accumulation and pyroptosis in vitro and in the neointimal hyperplasia of mice. Tumor necrosis factor α (TNF-α)-induced Sox10 lactylation in a phosphorylation-dependent manner by PI3K/AKT signaling drives transcriptional programs of VSMC transdifferentiation, contributing to pyroptosis. The regulator of G protein signaling 5 (RGS5) interacts with AKT and blocks PI3K/AKT signaling and Sox10 phosphorylation at S24. Sox10 silencing mitigates vascular inflammation and forestalls neointimal hyperplasia in RGS5 knockout mice. Collectively, this study shows that Sox10 is a regulator of vascular inflammation and a potential control point in inflammation-related vascular disease.

Protective effect of Homer 1a on tumor necrosis factor-α with cycloheximide-induced apoptosis is mediated by mitogen-activated protein kinase pathways.

Although Homer 1, of the postsynaptic density, regulates apoptosis, the signaling mechanisms are not fully elucidated. In this study, we found that tumor necrosis factor-α (TNF-α)/cycloheximide (CHX) treatment transiently increased Homer 1a (the short variant of Homer 1), but did not affect Homer 1b/c (the long variant of Homer 1). Overexpression of Homer 1a blocked TNF-α/CHX-induced apoptotic cell death, whereas inhibition of Homer 1a induction enhanced the pro-apoptotic effect of TNF-α/CHX treatment. Moreover, brain-derived neurotrophic factor, as a potential activator of endogenous Homer 1a, inhibited apoptotic cell death after TNF-α/CHX treatment through induction of Homer 1a. Since three major mitogen-activated protein kinase (MAPK) pathways have important roles in apoptosis, we examined if Homer 1a is involved in the effects of MAPK pathways on apoptosis. It was shown that inhibition of the ERK1/2 pathway increased the expression and the protective effect of Homer 1a, but inhibition of the p38 pathway produced the opposite effect. Cross-talk among MAPK pathways was also associated with the regulation of Homer 1a during apoptotic cell death. Blocking the p38 pathway increased the activity in the ERK1/2 pathway, while inhibition of ERK1/2 pathway abolished the effect of p38 inhibitor on Homer 1a. Furthermore, Homer 1a reversely affected the activation of MAPK pathways. These findings suggest that Homer 1a plays an important role in the prevention of apoptotic cell death and contributes to distinct regulatory effects of MAPK pathways on apoptotic cell death.

Serum levels of inflammation factors and cognitive performance in amnestic mild cognitive impairment: a Chinese clinical study.

Early diagnosis of Alzheimer's disease (AD) is important for initiating timely therapy to block or slow the rate of disease progression. This study was designed to investigate the potential of inflammation-related biomarkers in peripheral blood to accurately reflect AD onset and progression. Individuals (n=150) with amnestic mild cognitive impairment (aMCI) were divided into two subgroups (low- and high-risk) based on APOEε4 allele carrier status, and administered a battery of neuropsychological tests and tested for serum levels of IL-6, IL-10, TNF-α, and IFN-γ by using specific enzyme-linked immunosorbent assays. Results were compared with those from age-matched healthy controls (n=150). The levels of IL-6 were significantly higher in the aMCI group than in controls (P<0.01). When the aMCI group was stratified by APOEε4 status, significant differences were found between the low- and high-risk groups and controls in the levels of IL-6 and IFN-γ (P<0.01 and P=0.041, respectively). Moreover, the IL-6 level in the low-risk aMCI group was higher than that in the high-risk aMCI group (P=0.028). A weak but significant negative correlation was found between IL-6 and cognitive performance. Taken together, these findings indicate that IL-6, while not useful alone, has potential in combination with other biomarkers to support early diagnosis of aMCI due to its association with the progression of cognitive impairment.

Inhibition of p38 MAPK diminishes doxorubicin-induced drug resistance associated with P-glycoprotein in human leukemia K562 cells.

BACKGROUND: Several studies have shown that multidrug transporters, such as P-glycoprotein (PGP), are involved in cell resistance to chemotherapy and refractory epilepsy. The p38 mitogen-activated protein kinase (MAPK) signaling pathway may increase PGP activity. However, p38-mediated drug resistance associated with PGP is unclear. Here, we investigated p38-mediated doxorubicin-induced drug resistance in human leukemia K562 cells. MATERIAL/METHODS: The expression of PGP was detected by RT-PCR, Western blot, and immunocytochemistry. Cell viability and half-inhibitory concentrations (IC50) were determined by CCK-8 assay. The intracellular concentration of drugs was measured by HPLC. RESULTS: A doxorubicin-induced PGP overexpression cell line, K562/Dox, was generated. The p38 inhibitor SB202190 significantly decreased MDR1 mRNA expression, as well as PGP, in K562/Dox cells. The IC50 of phenytoin sodium and doxorubicin in K562/Dox cells was significantly higher than that in wild-type K562 cells, indicating the drug resistance of K562/Dox cells. During the blocking of p38 activity in the presence of SB202190, cell number was significantly reduced after the phenytoin sodium and doxorubicin treatment, and the IC50 of phenytoin sodium and doxorubicin was decreased in K562/Dox cells. HPLC showed that the intracellular levels of phenytoin sodium and doxorubicin were significantly lower in K562/Dox cells than those in K562 cells. The decrease of the intracellular level of these drugs was significantly abolished in the presence of SB202190. CONCLUSIONS: Our study demonstrated that p38 is, at least in part, involved in doxorubicin-induced drug resistance. The mechanistic study of MAPK-mediated PGP and the action of SB202190 need further investigation.

The risk of osteopenia in premenopausal women with various sellar tumors.

OBJECTIVE: Patients with prolactinoma seem to be at high risk for osteopenia. However, whether patients with various pathological sellar tumors have risk for osteopenia remains unclear. The aim of the present study is to assess the bone mass alteration in patients with various sellar tumors and further to investigate the risk factors of bone mass alteration. MATERIALS AND METHODS: 65 premenopausal female patients with diverse sellar tumors and 325 normal controls were enrolled in this study. Bone mineral density (BMD) of lumbar spine and comprehensive endocrinological evaluations were undergone. RESULTS: Compared to the matched controls, BMD of patients with prolactinoma or craniopharyngioma significantly decreased. Patients with sellar meningioma and nonfunctioning adenoma are with a decreasing tendency and patients with growth hormone-secreting adenoma are with an increasing tendency compared to controls. Univariate and multivariate regression analysis indicated that the bone loss in prolactinomas was significantly correlated to disease duration and hypogonadism. CONCLUSION: In the premenopausal women, patients with prolactinoma or craniopharyngioma are often accompanied with osteopenia or osteoporosis, and disease duration and hypogonadism are the risk factors of bone loss in prolactinoma. Continuous surveillance of BMD is recommended in patients with meningioma or nonfunctioning adenoma.