Analysis of risk factors, pathogenic bacteria characteristics, and drug resistance of postoperative surgical site infection in adults with limb fractures.

PURPOSE: We carried out the study aiming to explore and analyze the risk factors, the distribution of pathogenic bacteria, and their antibiotic-resistance characteristics influencing the occurrence of surgical site infection (SSI), to provide valuable assistance for reducing the incidence of SSI after traumatic fracture surgery. METHODS: A retrospective case-control study enrolling 3978 participants from January 2015 to December 2019 receiving surgical treatment for traumatic fractures was conducted at Tangdu Hospital of Air Force Medical University. Baseline data, demographic characteristics, lifestyles, variables related to surgical treatment, and pathogen culture were harvested and analyzed. Univariate analyses and multivariate logistic regression analyses were used to reveal the independent risk factors of SSI. A bacterial distribution histogram and drug-sensitive heat map were drawn to describe the pathogenic characteristics. RESULTS: Included 3978 patients 138 of them developed SSI with an incidence rate of 3.47% postoperatively. By logistic regression analysis, we found that variables such as gender (males) (odds ratio (OR) = 2.012, 95% confidence interval (CI): 1.235 - 3.278, p = 0.005), diabetes mellitus (OR = 5.848, 95% CI: 3.513 - 9.736, p < 0.001), hypoproteinemia (OR = 3.400, 95% CI: 1.280 - 9.031, p = 0.014), underlying disease (OR = 5.398, 95% CI: 2.343 - 12.438, p < 0.001), hormonotherapy (OR = 11.718, 95% CI: 6.269 - 21.903, p < 0.001), open fracture (OR = 29.377, 95% CI: 9.944 - 86.784, p < 0.001), and intraoperative transfusion (OR = 2.664, 95% CI: 1.572 - 4.515, p < 0.001) were independent risk factors for SSI, while, aged over 59 years (OR = 0.132, 95% CI: 0.059 - 0.296, p < 0.001), prophylactic antibiotics use (OR = 0.082, 95% CI: 0.042 - 0.164, p < 0.001) and vacuum sealing drainage use (OR = 0.036, 95% CI: 0.010 - 0.129, p < 0.001) were protective factors. Pathogens results showed that 301 strains of 38 species of bacteria were harvested, among which 178 (59.1%) strains were Gram-positive bacteria, and 123 (40.9%) strains were Gram-negative bacteria. Staphylococcus aureus (108, 60.7%) and Enterobacter cloacae (38, 30.9%) accounted for the largest proportion. The susceptibility of Gram-positive bacteria to Vancomycin and Linezolid was almost 100%. The susceptibility of Gram-negative bacteria to Imipenem, Amikacin, and Meropenem exceeded 73%. CONCLUSION: Orthopedic surgeons need to develop appropriate surgical plans based on the risk factors and protective factors associated with postoperative SSI to reduce its occurrence. Meanwhile, it is recommended to strengthen blood glucose control in the early stage of admission and for surgeons to be cautious and scientific when choosing antibiotic therapy in clinical practice.

Tube-based model predictive control for linear systems with bounded disturbances and input delay.

This paper proposes a tube-based model predictive control strategy for linear systems with bounded disturbances and input delay to ensure input-to-state stability. Firstly, the actual disturbed system is decomposed into a nominal system without disturbances and an error system. For the nominal system, solving an optimization problem, where the delayed control input is set as an optimization variable, yields a nominal control law that enables the nominal state signal to approach to zero. Then, for the error system, the Razumikhin approach is used to identify a robust control invariant set. Using the set invariance theorem, an ancillary control law is developed to confine the error state signal in the invariant set. Combining the two results, we obtain a control law that enables the state signal to remain within a robustly invariant tube. Finally, the effectiveness of the developed control strategy is validated by simulations.

Synthesis, optical properties, and application of novel chalcone skeleton as pH fluorescent probe: Based AIE + ESIPT strategy.

A series of "turn off" pH fluorescence probes with chalcone skeleton for basic system have been developed. The molecules emitted bright yellow fluorescence under acidic condition, resulting AIE coupled ESIPT characteristic and ICT process. What's more, the compounds exhibited excellent sensitivity and selectivity for detecting pH as a facile "On-Off" fluorescence probe, and the fluorescence of them were quenched with the ESIPT process interrupted under alkaline condition. Theoretical calculation for the related compounds also performed to verify the electron effect on photophysical properties and confirm the rational speculation on the mechanism.

Cang-ai volatile oil ameliorates imiquimod-induced psoriatic skin lesions by suppressing the ILC3s.

ETHNOPHARMACOLOGICAL RELEVANCE: Cang-ai volatile oil (CAVO) is an aromatic Chinese medicine with potent antibacterial and immune regulatory properties. While CAVO has been used to treat upper respiratory tract infections, depression, otomycosis, and bacterial infections in the skin, its effect on psoriasis is unknown. AIM OF THE STUDY: This study explores the effect and mechanism of CAVO in psoriasis intervention. MATERIAL AND METHODS: The effect of CAVO on the expression of IL-6 and IL-1ß was assessed in TNF-α-induced HaCaT cells using enzyme-linked immunosorbent assay (ELISA). Mice were given imiquimod (IMQ) and administered orally with different CAVO doses (0.03 and 0.06 g/kg) for 5 days. The levels of inflammatory cytokines related to group-3 innate lymphoid cells (ILC3s) in the skin were assessed using hematoxylin and eosin (H&E) staining, ELISA, and western blotting (WB). The frequency of ILC3s in mice splenocytes and skin cells was evaluated using flow cytometry. RESULTS: The results demonstrated that CAVO decreased the expression of IL-6 and IL-1ß in TNF-α- induced HaCaT cells. CAVO significantly reduced the severity of psoriatic symptoms in IMQ-induced mice. The expression of inflammatory cytokines in the skin, such as IL-1ß, IL-6, IL-8, IL-22, IL-23, and IL-17 A were decreased, whereas IL-10 levels were increased. The mRNA expressions of TNF-α, IL-23 A, IL-23 R, IL-22, IL-17 A, and RORγt were down-regulated in skin tissues. CAVO also decreased the levels of NF-κB, STAT3, and JAK2 proteins. CONCLUSIONS: CAVO potentially inhibits ILC3s activation to relieve IMQ-induced psoriasis in mice. These effects might be attributed to inhibiting the activation of NF-κB, STAT3, and JAK2 signaling pathways.

Clinical features and prognosis of chronic natural killer cell lymphoproliferative disorders.

OBJECTIVE: To analyze the current treatment status and prognostic regression of the chronic NK cell lymphoproliferative disorder (CLPD-NK). METHODS: We retrospectively analyzed the clinical features, treatment and prognosis of 18 patients with CLPD-NK who were treated at our Hospital between September 2016 and September 2022. RESULTS: Eighteen patients were included: three patients were treated with chemotherapy, five patients underwent immune-related therapy, one patient was treated with glucocorticoids alone, five patients were administered granulocyte colony-stimulating factor, blood transfusion therapy, or anti-infection therapy, followed by observation and follow-up, and four patients were observed without treatment. Fifteen patients survived, including two patients who achieved complete remission (CR) and seven patients who achieved partial remission (PR), of whom one patient progressed to Aggressive NK-cell leukemia (ANKL) and sustained remission after multiple lines of treatment; three patients were not reviewed, of which one patient was still in active disease, three patients developed hemophagocytic syndrome during treatment and eventually died, one of them had positive Epstein-Barr virus (EBV) expression. The 5-years overall survival rate was 83%. CONCLUSION: Most patients with CLPD-NK have inert progression and a good prognosis, whereas some patients have a poor prognosis after progressing to ANKL and combined with hemophagocytic syndrome. Abnormal NK cells invading the center suggest a high possibility of ANKL development, and immunosuppressants and hormones are effective treatments for this disease.

Factors predicting depressive symptoms in parents of children with autism spectrum disorder in eastern China.

BACKGROUND: Parents of children with autism spectrum disorder (ASD) are at a higher risk of depression than parents of typically developing children and those of children with other developmental disorders. Depression affects the well-being and quality of life of parents of children with ASD and has serious consequences for the long-term health outcomes of children with ASD. Therefore, this study explored the current status of depressive symptoms in parents of children with ASD in eastern China and further analyzed multiple aspects of the predictors of depressive symptoms. METHODS: A multicenter cross-sectional survey was conducted among parents of children with ASD in the rehabilitation department of a large specialized hospital and 10 rehabilitation centers for children with special needs in Lianyungang, Jiangsu Province, Eastern China. A structured questionnaire that focused on child-related factors, parent-related factors, depressive symptoms, courtesy stigma, and social support was used to obtain data. Binary logistic regression was used to identify the independent predictors of depressive symptoms in parents of children with ASD. RESULTS: A total of 409 parents of children with ASD were recruited, of whom 18.8% had depressive symptoms. Parents of children with ASD who raised a child who spoke few to no words (odds ratio [OR]: 2.747, 95% confidence interval [CI]: 1.026-7.357), claimed a high economic burden (OR: 3.215, 95% CI: 1.234-8.379), reported no change or increased severity of ASD in their children (OR: 2.518, 95% CI: 1.108-5.720), and those with a higher courtesy stigma score (OR: 1.189, 95% CI: 1.093-1.294) were more likely to have depressive symptoms. Conversely, parents of children with ASD who were employed (OR: 0.427, 95% CI: 0.201-0.907), satisfied with their current marital status (OR: 0.429, 95% CI: 0.221-0.834), and those with a higher social support score (OR: 0.973, 95% CI: 0.950-0.996) were less likely to have depressive symptoms. CONCLUSIONS: Depressive symptoms are common in parents of children with ASD in eastern China. Therefore, screening and intervention for depressive symptoms in parents of children with ASD is necessary, especially for those with high-risk factors.

Physical cleansing reduces the mindset effect in problem-solving.

The present study investigated whether physical cleansing can reduce the mindset effect in problem-solving in two experiments. Both experiments followed the same procedure. In the first stage, participants formed a mindset through the Luchins' water-jar task (Experiment 1) or the idiom maze task (Experiment 2). The second stage is cleansing manipulation. In Experiment 1, participants were asked to clean their hands with wipes (cleansing condition) or examine the packaging of the wipes (no-cleansing condition). In Experiment 2, participants were asked to watch a washing-hands video (cleansing condition) or watch an examining-pen video (no-cleansing condition). At last, all participants completed the mindset effect test problems. The results showed that the participants in the cleansing condition were less affected by the mindset than those in the no-cleansing condition, indicating that physical cleansing reduced the mindset effect. Our results provide new evidence for the clean-slate effects and support the hypothesis that physical cleansing is an embodied process of psychological separation.

Comparison of two swept-source optical coherence tomography devices, a Scheimpflug camera system and a ray-tracing aberrometer in the measurement of corneal power in patients with cataract.

PURPOSE: To assess the differences and similarities in the corneal curvature obtained by two swept-source optical coherence tomography (SS-OCT) devices, Scheimpflug imaging system and one ray tracing aberrometer in patients with cataracts. Moreover, this study aimed to compare the differences in posterior corneal (PK), total corneal (TK) and true net power (TNP) measurements among the IOLMaster 700, CASIA2, and Pentacam. METHODS: A total of 200 eyes of 200 patients (116 female, 58%) were enrolled in this study, with a mean age of 65.9 ± 9.5 years. The flattest (Kf), steepest (Ks), and mean cornal powers (Km), J0, and J45 were obtained using two SS-OCT-based biometric devices, one rotating camera system and one ray-tracing aberrometer. The PK, TK and TNP values were also measured using these devices. To evaluate the differences and similarities between the devicves, the Friedman test, Pearson correlation coefficient (r), intraclass coefficient correlation (ICC) and Bland‒Altman plots with 95% limits of agreement (LoA) were used, and boxplots and stacked histograms were generated to describe the distributions of the data. RESULTS: There were no significant differences between the IOLMaster 700 and Pentacam for any of the keratometry values. Additionally, there were no significant differences between the IOLMaster 700 and iTrace in evaluating J0 and J45. Bland‒Altman plots revealed relatively wide LoA widths, almost larger than 1 diopter for the keratometry values and almost larger than 0.5 diopter for J0 and J45 values among the four devices. In terms of PK and TK values, significant differences and low ICCs were found among the three devices. CONCLUSIONS: Although strong correlations and good agreement were found among the IOLMaster700, CASIA2, Pentacam and iTrace for Kf, Ks, Km and J0, J45, it seems that the measurements should not be used interchangeably because of the wide LoA widths and the presence of significant differences among the devices. Similarly, due to significant differences and low ICCs, the PK, TK and TNP values obtained by IOLMaster 700, CASIA2, and Pentacam should not be used interchangeably.

Courtesy stigma among primary caregivers of children with autism spectrum disorder in eastern China.

Introduction: The experience and perception of stigma is a common problem among primary caregivers of children with autism spectrum disorder (ASD), and has a profound adverse impact on primary caregivers and children with ASD; however, few studies have explored courtesy stigma among primary caregivers of children with ASD in the Chinese context. The aim of this study was to explore the status of courtesy stigma among primary caregivers of children with ASD in Lianyungang, Jiangsu Province, Eastern China, and to conduct in-depth analysis of its predictors from multiple perspectives. Methods: An institution-based multi-center cross-sectional survey was conducted in the rehabilitation department of a large specialized hospital and 10 rehabilitation centers for children with special needs in Lianyungang, Jiangsu Province, Eastern China, from October 2022 to February 2023. A structured questionnaire to assess child-related factors, primary caregiver-related factors, courtesy stigma, general self-efficacy, and social support, was used to collect data. Predictors of courtesy stigma among primary caregivers of children with ASD were identified by linear regression. Results: A total of 428 primary caregivers of children with ASD were recruited. The mean ± standard deviation (SD) score for courtesy stigma was 7.49 ± 4.13. Multiple linear regression analysis revealed that primary caregivers of children with ASD who were not too satisfied with their current marital status (ß = 1.21, 95% CI: 0.34-2.08, p < 0.05) were more likely to have a high courtesy stigma; however, significantly lower courtesy stigma was observed in primary caregivers of children with ASD who were not picky eaters (ß = -1.33, 95% CI: -2.08 - -0.58, p < 0.05), and who reported low level challenge in caring for children with ASD (ß = -1.16, 95% CI: -2.20 - -0.12, p < 0.05), good general self-efficacy (ß = -0.16, 95% CI: -0.25 - -0.06, p < 0.05), and good social support (ß = -0.04, 95% CI: -0.08 - -0.01, p < 0.05). Conclusion: There is a high level of courtesy stigma among primary caregivers of children with ASD in eastern China, and it is affected by numerous factors. More resources should be directed to groups that are more likely to experience stigma.

Nogo-B mediates endothelial oxidative stress and inflammation to promote coronary atherosclerosis in pressure-overloaded mouse hearts.

AIMS: Endothelial dysfunction plays a pivotal role in atherosclerosis, but the detailed mechanism remains incomplete understood. Nogo-B is an endoplasmic reticulum (ER)-localized protein mediating ER-mitochondrial morphology. We previously showed endothelial Nogo-B as a key regulator of endothelial function in the setting of hypertension. Here, we aim to further assess the role of Nogo-B in coronary atherosclerosis in ApoE-/- mice with pressure overload. METHODS AND RESULTS: We generated double knockout (DKO) mouse models of systemically or endothelium-specifically excising Nogo-A/B gene on an ApoE-/- background. After 7 weeks of transverse aortic constriction (TAC) surgery, compared to ApoE-/- mice DKO mice were resistant to the development of coronary atherosclerotic lesions and plaque rapture. Sustained elevation of Nogo-B and adhesion molecules (VCAM-1/ICAM-1), early markers of atherosclerosis, was identified in heart tissues and endothelial cells (ECs) isolated from TAC ApoE-/- mice, changes that were significantly repressed by Nogo-B deficiency. In cultured human umbilical vein endothelial cells (HUVECs) exposure to inflammatory cytokines (TNF-α, IL-1ß), Nogo-B was upregulated and activated reactive oxide species (ROS)-p38-p65 signaling axis. Mitofusin 2 (Mfn2) is a key protein tethering ER to mitochondria in ECs, and we showed that Nogo-B expression positively correlated with Mfn2 protein level. And Nogo-B deletion in ECs or in ApoE-/- mice reduced Mfn2 protein content and increased ER-mitochondria distance, reduced ER-mitochondrial Ca2+ transport and mitochondrial ROS generation, and prevented VCAM-1/ICAM-1 upregulation and EC dysfunction, eventually restrained atherosclerotic lesions development. CONCLUSION: Our study revealed that Nogo-B is a critical modulator in promoting endothelial dysfunction and consequent pathogenesis of coronary atherosclerosis in pressure overloaded hearts of ApoE-/- mice. Nogo-B may hold the promise to be a common therapeutic target in the setting of hypertension.

Virtual screening-molecular docking-activity evaluation of Ailanthus altissima (Mill.) swingle bark in the treatment of ulcerative colitis.

BACKGROUND: The dried bark of Ailanthus altissima (Mill.) Swingle is widely used in traditional Chinese medicine for the treatment of ulcerative colitis. The objective of this study was to explore the therapeutic basis of the dried bark of Ailanthus altissima (Mill.) Swingle for the treatment of ulcerative colitis based on Virtual Screening-Molecular Docking-Activity Evaluation technology. METHODS: By searching the Traditional Chinese Medicine Systems Pharmacology TCMSP Database and Analysis Platform, 89 compounds were obtained from the chemical components of the dried bark of Ailanthus altissima (Mill.) Swingle. Then, after preliminarily screening the compounds based on Lipinski's rule of five and other relevant conditions, the AutoDock Vina molecular docking software was used to evaluate the affinity of the compounds to ulcerative colitis-related target proteins and their binding modes through use of the scoring function to identify the best candidate compounds. Further verification of the compound's properties was achieved through in vitro experiments. RESULTS: Twenty-two compounds obtained from the secondary screening were molecularly docked with ulcerative colitis-related target proteins (IL-1R, TLR, EGFR, TGFR, and Wnt) using AutoDock Vina. The free energies of the highest scoring compounds binding to the active cavity of human IL-1R, TLR, EGFR, TGFR, and Wnt proteins were - 8.7, - 8.0, - 9.2, - 7.7, and - 8.5 kcal/mol, respectively. The potential compounds, dehydrocrebanine, ailanthone, and kaempferol, were obtained through scoring function and docking mode analysis. Furthermore, the potential compound ailanthone (1, 3, and 10 µM) was found to have no significant effect on cell proliferation, though at 10 µM it reduced the level of pro-inflammatory factors caused by lipopolysaccharide. CONCLUSION: Among the active components of the dried bark of Ailanthus altissima (Mill.) Swingle, ailanthone plays a major role in its anti-inflammatory properties. The present study shows that ailanthone has advantages in cell proliferation and in inhibiting of inflammation, but further animal research is needed to confirm its pharmaceutical potential.

The promising application of hydrogel microneedles in medical application.

OBJECTIVES: Hydrogel microneedles are emerging, and promising microneedles mainly composed of swelling polymers. This review is intended to summarize the preparation materials, formation mechanisms, applications and existing problems of hydrogel microneedles. METHODS: We collected the literature on the materials, preparation and application of hydrogel microneedles in recent years, and summarized their mechanism and application in drugs delivery. KEY FINDINGS: Hydrogel microneedles have higher safety and capabilities of controlled drug release, and have been mainly used in tumour and diabetes treatment, as well as clinical monitoring. In recent years, hydrogel microneedles have shown great potential in drug delivery, and have played the role of whitening, anti-inflammatory and promoting healing. CONCLUSIONS: As an emerging drug delivery idea, hydrogel microneedles for drug delivery has gradually become a research hotspot. This review will provide a systematic vision for the favourable development of hydrogel microneedles and their promising application in medicine, especially drug delivery.

AGEs-RAGE-KCa3.1 pathway mediates palmitic acid-induced migration of PBMCs from patients with type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade systemic inflammation. Tissue infiltration by monocyte migration contributes to the pathogenesis of vascular complications in T2DM. We studied the role of intermediate-conductance Ca2+-activated K+ (KCa3.1) channels in the palmitic acid (PA)-induced migration of peripheral blood mononuclear cells (PBMCs) from T2DM patients and the influence of advanced glycation endproducts (AGEs). A total of 49 T2DM patients and 33 healthy subjects was recruited into this study. Using flow cytometry and Western blotting analysis as well as cell migration assay, we found that there was a significant decrease in frequency of T lymphocytes and monocytes in CD45+ leukocyte population. PA at 100 µM stimulated migration of PBMCs from T2DM individuals, which was inhibited by the specific KCa3.1 channel blocker TRAM-34 (1 µM). The PBMC migration was positively correlated with glycosylated hemoglobin A1 chain (HbA1c) level of T2DM patients, an indicator of AGEs, and PBMCs with higher level of HbA1c showed upregulated expression of toll-like receptor (TLR) 2/4 and KCa3.1 channels. In THP-1 cells, AGEs at 200 µg/ml increased protein expression of TLR 2/4 and KCa3.1 channels, and were synergistically involved in PA-induced migration through receptors of AGEs (RAGE)-mediated KCa3.1 upregulation. In conclusion, in PBMCs of T2DM patients, AGEs promotes PA-induced migration via upregulation of TLR2/4 and KCa3.1 channels.

Preparation of polyethyleneimine-modified chitosan/Ce-UIO-66 composite hydrogel for the adsorption of methyl orange.

In this work, a polyethyleneimine-modified chitosan/Ce-UIO-66 composite hydrogel (PEI-CS/Ce-UIO-66) was prepared using the ex-situ blend method. The synthesized composite hydrogel was characterized by SEM, EDS, XRD, FTIR, BET, XPS, and TG techniques, while the zeta potential was recorded for sample analysis. The adsorbent performance was studied by conducting adsorption experiments using methyl orange (MO), which showed that PEI-CS/Ce-UIO-66 exhibited excellent MO adsorption properties (900.5 ± 19.09 mg/g). The adsorption kinetics of PEI-CS/Ce-UIO-66 could be explained by the pseudo-second-order kinetic model, and its isothermal adsorption followed the Langmuir model. Thermodynamics showed that the adsorption was spontaneous and exothermic at low temperatures. MO could interact with PEI-CS/Ce-UIO-66 via electrostatic interaction, π-π stacking, and hydrogen bonding. The results indicated that the PEI-CS/Ce-UIO-66 composite hydrogel could potentially be used for the adsorption of anionic dyes.

Mitochondrial damage in a Takotsubo syndrome-like mouse model mediated by activation of ß-adrenoceptor-Hippo signaling pathway.

Takotsubo syndrome (TTS) is characterized by short-term contractile dysfunction with its mechanism undefined. We showed that activation of cardiac Hippo pathway mediates mitochondrial dysfunction and that stimulation of ß-adrenoceptors (ßAR) activates Hippo pathway. Here, we investigated the role of ßAR-Hippo signaling in mediating mitochondrial dysfunction in isoproterenol (Iso)-induced TTS-like mouse model. Elderly postmenopausal female mice were administered with Iso (1.25 mg/kg/h for 23 h). Cardiac function was determined by serially echocardiography. At days 1 and 7 post-Iso exposure, mitochondrial ultrastructure and function were examined by electron microscopy and various assays. Alterations in cardiac Hippo pathway and effects of genetic inactivation of Hippo kinase (Mst1) on mitochondrial damage and dysfunction in the acute phase of TTS were investigated. Isoproterenol exposure induced acute increase in biomarkers of cardiac damage and ventricular contractile dysfunction and dilation. At day 1 post-Iso, we observed extensive abnormalities in mitochondrial ultrastructure, downregulation of mitochondrial marker proteins, and mitochondrial dysfunction evidenced by lower ATP content, increased lipid droplets, higher contents of lactate, and augmented reactive oxygen species (ROS). All changes were reversed by day 7. ßAR stimulation led to activation of cardiac Hippo pathway with enhanced expression of Hippo kinase Mst1 and inhibitory YAP phosphorylation, as well as reduced nuclear YAP-TEAD1 interaction. In mice with cardiac expression of inactive mutant Mst1 gene, acute mitochondrial damage and dysfunction were mitigated. Stimulation of cardiac ßAR activates Hippo pathway that mediates mitochondrial dysfunction with energy insufficiency and enhanced ROS, promoting acute but short-term ventricular dysfunction.NEW & NOTEWORTHY Takotsubo syndrome (TTS) is featured by activation of sympatho-ß-adrenoceptor (ßAR) system leading to acute loss of ventricular contractile performance. However, the molecular mechanism remains undefined. We demonstrated, in an isoproterenol-induced murine TTS-like model, extensive mitochondrial damage, metabolic dysfunction, and downregulated mitochondrial marker proteins, changes temporarily associated with cardiac dysfunction. Mechanistically, stimulation of ßAR activated Hippo signaling pathway and genetic inactivation of Mst1 kinase ameliorated mitochondrial damage and metabolic dysfunction at the acute phase of TTS.

The NLRP3 inflammasome is involved in resident intruder paradigm-induced aggressive behaviors in mice.

Background: Aggressive behaviors are one of the most important negative behaviors that seriously endangers human health. Also, the central para-inflammation of microglia triggered by stress can affect neurological function, plasticity, and behavior. NLRP3 integrates stress-related signals and is a key driver of this neural para-inflammation. However, it is unclear whether the NLRP3 inflammasome is implicated in the development of aggressive behaviors. Methods: First, aggressive behavior model mice were established using the resident intruder paradigm. Then, aggressive behaviors were determined with open-field tests (OFT), elevated plus-maze (EPM), and aggressive behavior tests (AT). Moreover, the expression of P2X7R and NLRP3 inflammasome complexes were assessed by immunofluorescence and Western blot. The levels of NLRP3 and inflammatory cytokines were evaluated using enzyme-linked immunosorbent assay (ELISA) kits. Finally, nerve plasticity damage was observed by immunofluorescence, transmission electron microscope, and BrdU staining. Results: Overall, the resident intruder paradigm induced aggressive behaviors, activated the hippocampal P2X7R and NLRP3 inflammasome, and promoted the release of proinflammatory cytokines IL-1ß in mice. Moreover, NLRP3 knockdown, administration of P2X7R antagonist (A804598), and IL-1ß blocker (IL-1Ra) prevented NLRP3 inflammasome-driven inflammatory responses and ameliorated resident intruder paradigm-induced aggressive behaviors. Also, the resident intruder paradigm promoted the activation of mouse microglia, damaging synapses in the hippocampus, and suppressing hippocampal regeneration in mice. Besides, NLRP3 knockdown, administration of A804598, and IL-1Ra inhibited the activation of microglia, improved synaptic damage, and restored hippocampal regeneration. Conclusion: The NLRP3 inflammasome-driven inflammatory response contributed to resident intruder paradigm-induced aggressive behavior, which might be related to neuroplasticity. Therefore, the NLRP3 inflammasome can be a potential target to treat aggressive behavior-related mental illnesses.

Screening of rosmarinic acid from Salvia miltiorrhizae acting on the novel target TRPC1 based on the 'homology modelling-virtual screening-molecular docking-affinity assay-activity evaluation' method.

CONTEXT: Salvia miltiorrhizae Bunge (Lamiaceae) is a traditional Chinese medicine (TCM) for the treatment of 'thoracic obstruction'. Transient receptor potential canonical channel 1 (TRPC1) is a important target for myocardial injury treatment. OBJECTIVE: This work screens the active component acting on TRPC1 from Salvia miltiorrhizae. MATERIALS AND METHODS: TCM Systems Pharmacology Database and Analysis Platform (TCMSP) was used to retrieve Salvia miltiorrhiza compounds for preliminary screening by referring to Lipinski's rule of five. Then, the compound group was comprehensively scored by AutoDock Vina based on TRPC1 protein. Surface plasmon resonance (SPR) was used to determine the affinity of the optimal compound to TRPC1 protein. Western blot assay was carried out to observe the effect of the optimal compound on TRPC1 protein expression in HL-1 cells, and Fura-2/AM detection was carried out to observe the effect of the optimal compound on calcium influx in HEK293 cells. RESULTS: Twenty compounds with relatively good characteristic parameters were determined from 202 compounds of Salvia miltiorrhiza. Rosmarinic acid (RosA) was obtained based on the molecular docking scoring function. RosA had a high binding affinity to TRPC1 protein (KD value = 1.27 µM). RosA (50 µM) could reduce the protein levels (417.1%) of TRPC1 after oxygen-glucose deprivation/reperfusion (OGD/R) in HL-1 cells and it could inhibit TRPC1-mediated Ca2+ influx injury (0.07 ΔRatio340/380) in HEK293 cells. DISCUSSION AND CONCLUSIONS: We obtained the potential active component RosA acting on TRPC1 from Salvia miltiorrhizae, and we speculate that RosA may be a promising clinical candidate for myocardial injury therapy.

Graphene oxide disruption of homeostasis and regeneration processes in freshwater planarian Dugesia japonica via intracellular redox deviation and apoptosis.

The aquatic system is a major sink for engineered nanomaterials released into the environment. Here, we assessed the toxicity of graphene oxide (GO) using the freshwater planarian Dugesia japonica, an invertebrate model that has been widely used for studying the effects of toxins on tissue regeneration and neuronal development. GO not only impaired the growth of normal (homeostatic) worms, but also inhibited the regeneration processes of regenerating (amputated) worms, with LC10 values of 9.86 mg/L and 9.32 mg/L for the 48-h acute toxicity test, respectively. High concentration (200 mg/L) of GO killed all the worms after 3 (regenerating) or 4 (homeostasis) days of exposure. Whole-mount in situ hybridization (WISH) and immunofluorescence analyses suggest GO impaired stem cell proliferation and differentiation, and subsequently caused cell apoptosis and oxidative DNA damage during planarian regeneration. Mechanistic analysis suggests that GO disturbed the antioxidative system (enzymatic and non-enzymatic) and energy metabolism in the planarian at both molecular and genetic levels, thus causing reactive oxygen species (ROS) over accumulation and oxidative damage, including oxidative DNA damage, loss of mitochondrial membrane integrity, lack of energy supply for cell differentiation and proliferation leading to retardance of neuron regeneration. The intrinsic oxidative potential of GO contributes to the GO-induced toxicity in planarians. These data suggest that GO in aquatic systems can cause oxidative stress and neurotoxicity in planarians. Overall, regenerated tissues are more sensitive to GO toxicity than homeostatic ones, suggesting that careful handling and appropriate decisions are needed in the application of GO to achieve healing and tissue regeneration.

Toxicity of ceria nanoparticles to the regeneration of freshwater planarian Dugesia japonica: The role of biotransformation.

Cerium oxide nanoparticles (n-CeO2) have wide applications ranging from industrial to consumer products, which would inevitably lead to their release into the environment. Despite the toxicity of n-CeO2 on aquatic organisms has been largely reported, research on developing organisms is still lacking. In this study, we investigate the toxic effects of n-CeO2 on the stem cells, tissue- and neuro-regeneration, using freshwater planarian Dugesia japonica as a model. Effects of bulk sized (µ-) CeO2 and ionic Ce (Ce3+) were compared with that of n-CeO2 to explore the origin of the toxic effects of n-CeO2. No overt toxicity was observed in µ-CeO2 treatment. n-CeO2 not only impaired the homeostasis of normal planarians, but also inhibited the regeneration processes of regenerated planarians, demonstrated by the inhibited blastema growth, disturbed antioxidant defense system at molecular levels, elevated DNA-damage and decreased stem cell proliferation. Regenerating organisms are more susceptible to n-CeO2 than the normal ones. Ce3+ exhibited significantly higher toxicity than n-CeO2, even though the total Ce uptake is 0.2 % less in Ce3+ than in n-CeO2 treated in planarian. X-ray absorption near edge spectroscopy (XANES) analysis revealed that 12.8 % of n-CeO2 (5.95 mg/kg Ce per planarian) was transformed to Ce3+ after interaction with planarian, suggesting that biotransformation at the nano-bio interface might play an important role in the observed toxicity. Since the biotransformation of n-CeO2 is a slow process, it may cause long-term chronic toxicity to planarians due to the slow while sustained release of toxic Ce3+ ions.

Network pharmacology study on the potential effect mechanism of Chuanzhi Tongluo Capsule in the treatment of cerebral infarction.

BACKGROUND: Chuanxiong Tongluo capsules have been widely used to treat recovered stroke and cerebral infarction, but their specific therapeutic mechanism is not well understood. METHODS: This study aims to investigate the mechanism of action for Chuanzhi Tongluo capsule on cerebral infarction based on a network pharmacology approach. The TCMSP platform collected the chemical composition of Chuanzhi Tongluo capsules. Its potential targets were predicted by Swiss target prediction and standardized using the Uniprot database for gene normalization. Meanwhile, the OMIM, Genecards, and TTD databases were used to obtain the targets related to cerebral infarction. The standard targets of Chuanzhi Tongluo capsule and cerebral infarction were uploaded to the STRING database to construct protein-protein interaction networks. Topological methods analyzed the key targets and components in the drug-component-disease-target network. Gene ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the shared targets were performed using the DAVID database. RESULTS: A total of 105 active ingredients and 427 targets were associated with Chuanzhi Tongluo capsule, and there were 3055 targets related to cerebral infarction disease and 240 common targets between the two keywords. The key targets included INS, ALB, IL-6, VEGFA, TNF, and TP53. The conduction pathways involved include the calcium signaling pathway, cAMP signaling pathway, cGMP-PKG signaling pathway, and TNF signaling pathway. CONCLUSION: The active ingredients in Chuanzhi Tongluo capsule may participate in the therapeutic process of cerebral infarction by regulating the calcium, cAMP, cGMP-PKG, and TNF signaling pathway through critical targets such as INS, ALB, IL-6, VEGFA, TNF, and TP53.