Protective Effects of Ischemic Postconditioning on Livers in Rats with Limb Ischemia-Reperfusion via Glycogen Synthase Kinase 3 beta (GSK-3ß)/Fyn/Nuclear Receptor-Erythroid-2-Related Factor (Nrf2) Pathway.

BACKGROUND Ischemia/reperfusion (I/R) injury not only exists in ischemic tissues and organs, but also can cause damage to distant tissues and organs. As the largest metabolic organ of the human body, the liver is very vulnerable to injury after limb I/R. However, the mechanism of liver injury caused by limb I/R injury has not been fully elucidated. This study investigated the effect and mechanism of ischemic postconditioning (IPO) on the liver after hindlimb I/R in rats. MATERIAL AND METHODS A rat model of hindlimb I/R was established and treated by IPO. Liver function, changes of oxidative stress index and inflammation, Bcl-2 and Bax proteins, and apoptosis were assessed. The structural changes were observed by electron microscopy. GSK-3ß/Fyn/Nrf2 levels were detected by quantitative PCR and Western blot. RESULTS IPO significantly reduced serum AST, ALP, LDH, and ALT levels induced by I/R. Compared with the I/R group, the levels of SOD, GSH-Px, and CAT in the IPO group were significantly increased, while the levels of MDA, MPO, and ROS were significantly decreased. The IPO group had significantly higher Bcl-2 level and significantly lower Bax level compared to the I/R group. Consistently, IPO decreased the apoptosis rate induced by I/R. Furthermore, IPO lowered the levels of TNF-alpha, IL-1ß, IL-10, and INF-γ and alleviated the ultrastructural changes of hepatocytes. Finally, Nrf2, Fyn, and GSK-3ß mRNA and protein levels in the IPO group were significantly higher than in the I/R group. CONCLUSIONS IPO protects against liver injury caused by I/R injury of the hindlimb, possibly via the GSK-3ß/Fyn/Nrf2 pathway.

Mid- and Short-Term Efficacy of Percutaneous Mechanical Thrombectomy in the Treatment of Acute Iliofemoral Deep Vein Thrombosis.

BACKGROUND: We aimed to evaluate the efficacy and safety of percutaneous mechanical thrombectomy (PMT) in treating acute iliofemoral deep vein thrombosis (DVT). METHODS: We retrospectively analyzed the clinical data of 82 acute iliofemoral DVT patients between November 2017 and December 2018. The therapeutic effects were evaluated based on the thrombus removal rate and circumference changes 10 cm above the affected knee. Incidence rates of pulmonary embolism were evaluated to determine the safety of the procedure. During follow-up, the incidence of postthrombotic syndrome (PTS) was evaluated using the Villalta score, whereas the patency rate of the iliac vein was evaluated via duplex ultrasonography and venography. RESULTS: The surgical success rate was 100%. We identified 48 patients with iliac vein compression syndrome (IVCS) intraoperatively: three of these underwent stent implantation and the others underwent percutaneous transluminal angioplasty (PTA). Grade II and III thrombus removal was achieved in 32.9% (27/82) and 67.1% (55/82) patients, respectively. Postoperative venography revealed that four patients had many floating thrombi under their inferior vena cava filters, which were not removed. The circumference 10 cm above the affected knee decreased from 50.3 ± 3.5 cm preoperatively to 46.3 ± 3.3 cm postoperatively (P < 0.05). During follow-up, a PTS incidence rate of 9.8% was observed. The patency rate of the iliac vein was 66.6% after stent implantation and 93.3% after PTA. CONCLUSIONS: PMT is feasible, safe, and effective for acute iliofemoral DVT. With regard to IVCS, we suggest PTA alone as a one-stage surgery, and the need of secondary stent implantation should be determined based on follow-up results.

Protective effects of polydatin on experimental testicular torsion and detorsion injury in rats.

Oxidative stress plays a critical role in the process of testicular torsion and detorsion (T/D). The purpose of the present study was to investigate the protective effect of polydatin (PD) on testicular T/D injury. Rats were randomly divided into three groups, a sham group, a group subjected to 2h torsion followed by 24h detorsion and a group subjected to T/D and injected i.p. with 20mgkg-1 PD 30min before detorsion. Unilateral orchiectomy was performed after 24h of reperfusion. Half the testes were prepared for histological examination by haematoxylin-eosin staining and the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) technique. In the remaining tissues, levels of malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) were determined, as was the expression of several apoptosis-related proteins. Compared with the T/D group, PD pretreatment significantly ameliorated the morphological damage, lowered the Cosentino histological score and increased the mean number of germ cell layers and Johnsen's testicular biopsy score. In addition, PD treatment markedly decreased MDA levels and upregulated CAT, GPx and SOD activity. Furthermore, PD decreased T/D-induced germ cell-specific apoptosis, attenuated the activation of caspase-3, caspase-8, caspase-9 and poly(ADP-ribose) polymerase and increased the Bcl-2/Bax ratio. The findings indicate that PD has a protective effect against testicular T/D injuries, especially at the histological, antioxidative stress and antiapoptotic levels.

Does the need for uniqueness lead to non-suicidal self-injury? The mediation of depression and the moderation of gender.

Objective: Based on the integrated theoretical model of the development and maintenance of non-suicidal self-injury (NSSI) and gender role theory, this study investigated the longitudinal impact of the need for uniqueness on NSSI among adolescents, and the mediating role of depression and the moderating role of gender. Participants: A total of 1,166 middle school students (Mean age = 13.04, SDage = 0.78, range = 11-16) from a city in central China was recruited to complete the Need for Uniqueness Scale, Depression Scale, and Adolescent Self-Injury Questionnaire at two waves. The participants included 475 boys and 457 girls. Methods: Convenience sampling was used, and a longitudinal study (2 time points with a 6-month interval) was conducted to test our hypotheses. SPSS 25.0 was used to evaluate reliability, and to calculate descriptive statistics and Pearson correlation. PROCESS version 3 was used to test longitudinal relationships among the need for uniqueness, depression and NSSI, and construct a moderated mediation model. Results: Results revealed that T1 need for uniqueness in adolescents was significantly positively associated with T2 NSSI and T2 depression, and T2 depression was significantly positively associated with T2 NSSI. After controlling for gender, T1 need for uniqueness positively predicted T2 NSSI. Furthermore, the mediation analysis demonstrated that the pathway linking T1 need for uniqueness to T2 NSSI through T2 depression was statistically significant. Moreover, gender moderated the indirect effect from T2 depression to T2 NSSI in the association between T1 need for uniqueness and T2 NSSI. Compared to boys in the same situation, girls who are susceptible to depression were more likely to commit NSSI. Conclusion: This study demonstrated that the need for uniqueness in adolescents longitudinally predicts NSSI through the mediating role of depression and gender moderates the indirect effect from depression to NSSI. The current study not only suggests that the need for uniqueness is a risk factor for NSSI among adolescents, but also provides an empirical basis for the prevention and intervention of NSSI.

Pomalidomide enhances the maturation of dendritic cells derived from healthy donors and multiple myeloma patients.

Objective: To explore the effect of pomalidomide on the maturation of monocyte-derived dendritic cells (moDCs) from healthy donors (HDs) and multiple myeloma (MM) patients. Methods: MoDCs were generated by the incubation of monocytes from peripheral blood mononuclear cells (PBMCs) for 7 days in a medium consisting of 800 U/ml granulocyte-macrophage colony stimulating factor (GM-CSF), 500 U/ml interleukin-4 (IL-4), RPMI 1,640 medium, 5% human serum, 100 U/ml penicillin and 0.1 mg/ml streptomycin. Meanwhile, the incubation system was administrated with 10 µM pomalidomide or 1 × PBS as the control group. On the eighth day, cells were harvested and analyzed by flow cytometry. The CD80+CD86+ cell population in total cells was gated as moDCs in the FACS analyzing system. After that, the expression of CD40 and HLA-DR on moDCs was analyzed. Meanwhile, the supernatant from the incubation system was evaluated for the secretion of cytokines interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein 1α (MIP-1α) by enzyme-linked immunosorbent assay (ELISA). Results: When analyzing all the HD-moDCs together (n = 15), pomalidomide significantly increased the mean fluorescence intensity (MFI) of CD40 expression and HLA-DR expression on moDCs compared with the control group (p = 0.003, p = 0.040). Meanwhile, the proportion of CD40+ moDCs and HLA-DR+ moDCs in total moDCs was significantly higher in the pomalidomide group than in the control group (p = 0.008, p = 0.032). When analyzing all MM patient-moDCs together (n = 11), pomalidomide significantly increased the MFI of CD40 expression and HLA-DR expression on moDCs compared with the control group (p = 0.047, p = 0.006). Meanwhile, the proportion of HLA-DR+ moDCs in total DCs was significantly higher in the pomalidomide group than in the control group (p < 0.001). Moreover, HD-moDCs (n = 8) treated with pomalidomide secreted 192% IL-12, 110% TNF-α, and 112% MIP-1α of the untreated moDCs (p = 0.020, p = 0.006, p = 0.055). However, when analyzing MM patient-moDCs (n = 10) together, the secretion of IL-12, TNF-α and MIP-1α from moDCs showed no significant difference between the pomalidomide group and the control group (p = 0.458, p = 0.377, p = 0.248). Conclusion: In vitro, 10 µM pomalidomide enhances the maturation of moDCs derived from both HDs and MM patients. Pomalidomide shows potential to be applied as a DC adjuvant for DC-based immunotherapy, such as the DC vaccine and DC cell therapy in MM.

[Risk prediction for deep venous thrombosis after total knee arthroplasty based on modified Caprini risk assessment model:a confirmatory study].

OBJECTIVE: To investigate the effectiveness of modified Caprini risk assessment model(Caprini MRAM) in predicting the risk of deep venous thrombosis (DVT) after total knee arthroplasty (TKA). METHODS: A case-control study was used to collect 43 patients with DVT after TKA in lower limb department of Sichuan Orthopedic Hospital from January 2016 to November 2020 in the positive group, and 172 patients without DVT after TKA in the same period according to the 1∶4 ratio between positive and control group were selected in the control group. Caprini MRAM was used to score and grade the risk of DVT. The clinical data, score and risk classification of the two groups were compared. The relationship between the risk of DVT in the patients after TKA and the risk factors in the risk ckassification and assessment of Caprini MRAM was analyzed by multivariate logistic regression model. RESULTS: The average score of caprini in DVT group was significantly higher than that in control group[(8.11±2.91) vs(4.07±2.12), P<0.001];DVT group was mainly at medium and high risk group(66.67%), while the control group was mainly at low risk (77.33%). There was a significant difference between the two groups in risk classification composition (P<0.001). BMI≥30 kg/m2, lower extremity edema (<1 month), severe pulmonary disease (<1 month), acute myocardial infarction (<1 month), bed rest (> 2 h), history of superficial or deep vein or pulmonary embolism and family history of thrombosis were the main risk factors for DVT in patients after TKA(all P<0.05). Preoperative D-dimer elevation (OR=4.380), BMI≥30 kg/m2(OR=2.518), lower extremity edema(<1 month)(OR=7.652), acute myocardial infarction (<1 month) (OR=1.994), bed rest (> 72 h)(OR=3.897), history of superficial or deep vein or pulmonary embolism (OR=13.517) and family history of blood embolism (OR=6.551) were independent risk factors for DVT in patients after TKA (all P<0.05). The risk of DVT was 13.457 and 2.739 times higher in high and moderate risk TKA patients with Caprini MRAM classification, respectively. CONCLUSION: Caprini MRAM can be used to predict the risk of DVT in patients after TKA, especially for patients with high risk.

Adaptability Protects University Students From Anxiety, Depression, and Insomnia During Remote Learning: A Three-Wave Longitudinal Study From China.

The longitudinal relationship between students' pre-existing adaptability and subsequent sleep and mental health during the COVID-19 pandemic has not been studied. The present study examines the relationship between adaptability and students' anxiety, depression, and insomnia during and after the lockdown related to COVID-19. 5,235 university students participated in a longitudinal study with three time points. Students completed the Adaptability Scale before the outbreak (October 2019; Time 1), the Insomnia Severity Index (ISI) both during (April 2020; Time 2) and after lockdown (March 2021; Time 3), the Anxiety and Depression subscales of the SCL-90 (at Time 1 and 3), and the SAS/SDS (at Time 2). The results showed that self-reported adaptability is significantly negatively correlated with anxiety and depression, and that anxiety and depression are positively correlated with insomnia. Furthermore, adaptability protects from insomnia both directly and through its negative relationship with anxiety and depression. This study sheds light on the internal mechanisms mediating the relationship between students' adaptability and experience of insomnia in challenging circumstances. Implications for curtailing the negative effects of stressful events on students' sleep health by improving their adaptability and reducing their anxiety and depression are discussed.

PA1 participates in the maintenance of blood-testis barrier integrity via cooperation with JUN in the Sertoli cells of mice.

BACKGROUND: The blood-testis barrier (BTB) is essential to the microenvironment of spermatogenesis, and Sertoli cells provide the cellular basis for BTB construction. Numerous nuclear transcription factors have been identified to be vital for the proper functioning of Sertoli cells. PA1 has been reported to play important roles during diverse biological processes, yet its potential function in male reproduction is still unknown. RESULTS: Here, we show that PA1 was highly expressed in human and mouse testis and predominantly localized in the nuclei of Sertoli cells. Sertoli cell-specific Pa1 knockout resulted in an azoospermia-like phenotype in mice. The knockout of this gene led to multiple defects in spermatogenesis, such as the disorganization of the cytoskeleton during basal and apical ectoplasmic specialization and the disruption of the BTB. Further transcriptomic analysis, together with Cut-Tag results of PA1 in Sertoli cells, revealed that PA1 could affect the expression of a subset of genes that are essential for the normal function of Sertoli cells, including those genes associated with actin organization and cellular junctions such as Connexin43 (Cx43). We further demonstrated that the expression of Cx43 depended on the interaction between JUN, one of the AP-1 complex transcription factors, and PA1. CONCLUSION: Overall, our findings reveal that PA1 is essential for the maintenance of BTB integrity in Sertoli cells and regulates BTB construction-related gene expression via transcription factors. Thus, this newly discovered mechanism in Sertoli cells provides a potential diagnostic or even therapeutic target for some individuals with azoospermia.

[Effects of Dasatinib on the Maturation of Monocyte-Derived Dendritic Cells Derived from Healthy Donors and Chronic Myelogenous Leukemia Patients].

OBJECTIVE: To investigate the effects of dasatinib on the maturation of monocyte-derived dendritic cells (moDCs) derived from healthy donors (HDs) and chronic myelogenous leukemia (CML) patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from HDs (n=10) and CML patients (n=10) who had got the remission of MR4.5 with imatinib treatment. The generation of moDCs from PBMCs was completed after 7 days of incubation in DC I culture medium, and another 3 days of incubation in DC II culture medium with or without 25 nmol/L dasatinib. On the 10th day, cells were harvested and expression of molecules of maturation related marker were assessed by flow cytometry. The CD80+CD86+ cell population in total cells was gated as DCs in the fluorescence-activated cell storting (FACS) analyzing system, then the expression of CD83, CD40 or HLA-DR in this population was analyzed respectively. RESULTS: The proportion of CD80+CD86+ cells in total cells didn't show a statistical difference between HD group and patient group (89.46%±9.70% vs 87.39%±9.34%, P=0.690). Dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.008) and HLA-DR (P=0.028) on moDCs derived from HDs compared with the control group, while the expression of CD83 on moDCs didn't show a significant difference between dasatinib group and the control group (P=0.428). Meanwhile, dasatinib significantly enhanced the expression of the surface marker CD40 (P=0.023), CD83 (P=0.038) and HLA-DR (P=0.001) on moDCs derived from patients compared with the control group. CONCLUSION: For CML patients, the same high proportion of moDCs as HDs can be induced in vitro, which provides a basis for the application of DC-based immunotherapy strategy. Dasatinib at the concentration of 25 nmol/L can efficiently promote the maturation of moDCs derived from HDs and CML patients in vitro. Dasatinib shows potential as a DC adjuvant to be applied in DC-based immunotherapy strategies, such as DC vaccine and DC cell-therapy.

Recent Progress of Exosomes in Multiple Myeloma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological malignancy that is still incurable. The bone marrow microenvironment (BMM), with cellular and non-cellular components, can create a favorable environment for the survival, proliferation and migration of MM cells, which is the main reason for the failure of MM therapies. Many studies have demonstrated that exosomes play an important role in the tumor-supportive BMM. Exosomes are nanoscale vesicles that can be released by various cells. Some exosomes contribute to the pathogenesis and progression of MM. MM-derived exosomes act on different cells in the BMM, thereby creating an environment conducive to the survival and growth of MM cells. Owing to the important roles of exosomes in the BMM, targeting the secretion of exosomes may become an effective therapeutic strategy for MM. In addition, the abnormal expression of "cargos" in the exosomes of MM patients may be used to diagnose MM or used as part of a screen for the early prognoses of MM patients. Exosomes also have good biological properties, including safety, biocompatibility, stability and biodegradability. Therefore, the encapsulation of anti-cancer drugs in exosomes, along with surface modifications of exosomes with targeting molecules, are very promising strategies for cancer therapies-particularly for MM. In addition, DC-derived exosomes (DC-EXs) can express MHC-I, MHC-II and T cell costimulatory molecules. Therefore, DC-EXs may be used as a nanocarrier to deliver cancer vaccines in MM. This review summarizes the recent progress of exosome research regarding the pathogenesis of, diagnosis of, prognosis of and therapeutic strategies for MM.

Adaptability Promotes Student Engagement Under COVID-19: The Multiple Mediating Effects of Academic Emotion.

In response to the COVID-19 pandemic, millions of students in China followed an emergency policy called "Suspending Classes without Stopping Learning" to continue their study online as schools across the country were closed. The present study examines how students adapted to learning online in these unprecedented circumstances. We aimed to explore the relationship between adaptability, academic emotion, and student engagement during COVID-19. 1,119 university students from 20 provinces participated in this longitudinal study (2 time points with a 2-week interval). The results showed that adaptability (the ability to respond to changes) and student engagement are significantly positively correlated with positive academic emotion and negatively correlated with negative academic emotion. Furthermore, adaptability not only directly predicts student engagement, but also affects student engagement through the chain mediation of positive academic emotion and negative academic emotion. The results contribute to the gap in knowledge regarding changes in students' learning in response to the outbreak. This study further explains the internal mechanisms mediating the relationship between adaptability and student engagement. It may provide references for educational researchers and universities in dampening the negative effects of COVID-19 on students' learning by improving their adaptability and developing positive academic emotions.

Recent progress of graphene oxide as a potential vaccine carrier and adjuvant.

Vaccine is one of the most effective strategies for preventing and controlling infectious diseases and some noninfectious diseases, especially cancers. Adjuvants and carriers have been appropriately added to the vaccine formulation to improve the immunogenicity of the antigen and induce long-lasting immunity. However, there is an urgent need to develop new all-purpose adjuvants because some adjuvants approved for human use have limited functionality. Graphene oxide (GO), widely employed for the delivery of biomolecules, excels in loading and delivering antigen and shows the potentiality of activating the immune system. However, GO aggregates in biological liquid and induces cell death, and it also exhibits poor biosolubility and biocompatibility. To address these limitations, various surface modification protocols have been employed to integrate aqueous compatible substances with GO to effectively improve its biocompatibility. More importantly, these modifications render functionalized-GO with superior properties as both carriers and adjuvants. Herein, the recent progress of physicochemical properties and surface modification strategies of GO for its application as both carriers and adjuvants is reviewed. STATEMENT OF SIGNIFICANCE: Due to its unique physicochemical properties, graphene oxide is widely employed in medicine for purposes of photothermal treatment of cancer, drug delivery, antibacterial therapy, and medical imaging. Our work describes the surface modification of graphene oxide and for the first time summarizes that functionalized graphene oxide serves as a vaccine carrier and shows significant adjuvant activity in activating cellular and humoral immunity. In the future, it is expected to be introduced into vaccine research to improve the efficacy of vaccines.

A hybrid electrochemical device based on a synergetic inner combination of Li ion battery and Li ion capacitor for energy storage.

Li ion battery (LIB) and electrochemical capacitor (EC) are considered as the most widely used energy storage systems (ESSs) because they can produce a high energy density or a high power density, but it is a huge challenge to achieve both the demands of a high energy density as well as a high power density on their own. A new hybrid Li ion capacitor (HyLIC), which combines the advantages of LIB and Li ion capacitor (LIC), is proposed. This device can successfully realize a potential match between LIB and LIC and can avoid the excessive depletion of electrolyte during the charge process. The galvanostatic charge-discharge cycling tests reveal that at low current, the HyLIC exhibits a high energy density, while at high current, it demonstrates a high power density. Ragone plot confirms that this device can make a synergetic balance between energy and power and achieve a highest energy density in the power density range of 80 to 300 W kg-1. The cycle life test proves that HyLIC exhibits a good cycle life and an excellent coulombic efficiency. The present study shows that HyLIC, which is capable of achieving a high energy density, a long cycle life and an excellent power density, has the potential to achieve the winning combination of a high energy and power density.

Bolus injection of hypertonic solutions for cerebral edema in rats: challenge of homeostasis of healthy brain.

Hypertonic solutions are mainstay of osmotherapy to cerebral edema. How hypertonic solutions affect healthy brain homeostasis, however, is not fully understood. Using rat model of cerebral edema induced by local cryoinjury, we found with immunohistochemistry that less microglial activation in healthy hemishere 24 h after hypertonic saline (HS, 3% NaCl) administration, compared to mannitol (20%, the same osmotic concentration of 3% NaCl) while dehydrating the brain tissue. To see whether blood-brain barrier (BBB) or aquaporin-4 (AQP4) contribute to this difference, HS or mannitol was intra-arterially injected to normal rats, and BBB opening, ultrastructure and AQP4 immunoreactivity were examined. Evans blue extravasation indicated that BBB was opened much lighter in HS group than mannitol group at the same time points. Electron microscopy also showed edema around the capillaries slightly lighter in HS than mannitol group 24 h after injection. Meanwhile, HS injection led to AQP4 down regulation in expression similarly as mannitol, compared with NS group. These data suggested that bolus injection of hypertonic agents may lead to microglia activation in healthy brain in different extent, due to BBB compromise, instead of water movement or AQP4 expression. Hence in clinical application, BBB of healthy brain should be considered in perspective to maintain the brain homeostasis.