Pinocembrin relieves hip fracture-induced pain by repressing spinal substance P signaling in aged rats.

Whether pinocembrin (PCN) could be used to alleviate hip fracture-induced pain is investigated in this research. Aged rats with hip fractures were treated with vehicle or 80 mg/kg/day PCN from week 3 to week 4. Then, hind paw mechanical allodynia, unweighting, warmth, and thickness were measured. The microglia and astrocytes activation and proliferation markers in the spinal dorsal horn were detected with real-time PCR and immunofluorescence staining. The relative expression of substance P and its receptor, tachykinin receptor 1 (Tacr1), was detected with enzyme-linked immunosorbent assay (ELISA) and Western blots. The antinociceptive effect of Tacr1 inhibitor LY303870 was also testified. PCN alleviated hip fracture-induced hind paw nociceptive (allodynia and unweighting) and vascular changes (warmth and thickness) in aged rats with diminished microglia and astrocytes activation and proliferation in the spinal dorsal horn. Upregulated substance P and Tacr1 were induced after hip fracture, which could be reversed by PCN treatment. Furthermore, LY303870 treatment partially reversed both spinal nociceptive sensitization and vascular changes after hip fracture. Substance P signaling contributes to the nociceptive and vascular changes observed in the hip fracture, which could be alleviated by PCN.NEW & NOTEWORTHY Substance P signaling contributes to the nociceptive and vascular changes observed in hip fracture, which could be alleviated by PCN.

Magnetic Resonance Imaging-Based Structural Covariance Changes of the Striatum in Lifelong Premature Ejaculation Patients.

BACKGROUND: The striatum has been reported to be implicated in various neurological diseases, including lifelong premature ejaculation (LPE). Altered striatum-related functional connectivity was investigated in LPE patients in previous studies; however, structural abnormalities in the striatum have been less studied in LPE. PURPOSE: To identify the gray matter volume (GMV) and structural covariance patterns of the striatum between LPE patients and healthy controls (HCs). STUDY TYPE: Prospective. SUBJECTS: Forty-three LPE patients and 31 male HCs. FIELD STRENGTH/SEQUENCE: 3.0 T magnetic resonance imaging (MRI) scanner; T1-weighted imaging using a spoiled gradient recalled echo sequence. ASSESSMENT: Preprocessing of structural MRI data and the striatum-seeded GMV computation were conducted using SPM12. STATISTICAL TESTS: Two sample t-test was used to compare differences in GMV of the striatum between patients and HCs. Regions showing altered between-group GMV were considered as seeds for structural covariance analysis in two groups. Additionally, correlations between GMV findings and clinical features were assessed with age and total intracranial volume (TIV) as covariates and with age, TIV, anxiety, and depression scores as covariates in the patient group, P < 0.05 was considered statistically significant. RESULTS: Compared to HCs, LPE patients had significantly decreased GMV in four regions located in the bilateral caudate and putamen. Distinct striatum-based structural covariance patterns in the two groups were mainly related to the thalamus, amygdala, insula, anterior cingulate cortex, middle cingulate cortex, medial prefrontal cortex, primary motor cortex, and precuneus/cuneus. LPE patients showed that GMV in the bilateral caudate negatively correlated with the premature ejaculation diagnostic tool (PEDT) scores (r = -0.369, r = -0.377, respectively). DATA CONCLUSION: Our findings indicated that LPE patients had altered GMV and structural covariance patterns in the striatum compared to HCs. The correlations between abnormal GMV and PEDT were also shown in the present findings. These findings may contribute to enhancing the understanding of the pathophysiology of LPE. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Altered Functional Connectivity of Hypothalamus in Lifelong Premature Ejaculation Patients.

BACKGROUND: As one of the most prevalent sexual dysfunctions in men, lifelong premature ejaculation (PE) often leads to patient distress. The hypothalamus is implicated in the ejaculatory control of healthy males. However, we do not know whether the hypothalamus-related intrinsic connectivity is altered in lifelong PE patients. PURPOSE: To investigate abnormal intrinsic connectivity of the hypothalamus in lifelong PE patients compared with healthy controls (HCs). STUDY TYPE: Prospective pilot study using cross-sectional data of patients and HCs. SUBJECTS: Forty-seven lifelong PE patients and 30 HCs were included in this study. FIELD STRENGTH/SEQUENCE: 3.0T MRI scanner for T1 -weighted imaging using spoiled gradient recalled echo sequence and functional imaging using a single-shot gradient recalled echo sequence. ASSESSMENT: Preprocessing of MRI data and hypothalamus-seeded functional connectivity (FC) computation were performed using DPABI4.1. STATISTICAL TESTS: The two-sample t-test within SPM12 was adopted to examine possible alterations of intrinsic connectivity of hypothalamus in lifelong PE patients compared with HCs including anxiety and depression scores as covariates (false discovery rate-corrected, P < 0.05). The correlation analysis was then used to assess possible associations between the imaging findings and clinical features in the patient group (Bonferroni-corrected, P < 0.05). RESULTS: Compared with HCs, lifelong PE patients had decreased hypothalamus-seeded FC in the left orbitofrontal cortex, bilateral insula, superior temporal cortex, superior temporal pole, middle temporal cortex, left fusiform, right parahippocampal gyrus, and right cerebellum. The intravaginal ejaculatory latency time positively correlated with the mean z-score from the hypothalamus-insula (r = 0.45) and hypothalamus-cerebellum (r = 0.48) intrinsic connectivity, separately. DATA CONCLUSION: We have shown that hypothalamus-seeded FC alterations and the correlations between the aforementioned abnormal FC alterations and intravaginal ejaculatory latency time. The current findings may promote the understanding of the hypothalamus-related neural mechanisms involved in the abnormal ejaculatory information processing in lifelong PE patients. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:778-784.

Effects of Valsartan on Restenosis in Patients with Arteriosclerosis Obliterans of the Lower Extremities Undergoing Interventional Therapy: A Prospective, Randomized, Single-Blind Trial.

BACKGROUND The aim of this study was to further clarify the effects of valsartan on restenosis in patients with arteriosclerosis obliterans of the lower extremities. MATERIAL AND METHODS Patients with arteriosclerosis obliterans of the lower extremities undergoing continuous stent implantation in the superficial femoral artery were enrolled and randomly divided into an ARB group and a control group. Patients in the ARB group received valsartan orally in a single-blind manner and were followed up for 6 months. An evaluation was performed based on the criteria for clinical efficacies designed by the Committee of Vascular Disease, Chinese Association of Integrative Medicine. The total clinical effective rate was calculated, and ankle brachial index (ABI) of the patients was assessed. The concentrations of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) were measured using enzyme-linked immunosorbent assay. The in-stent restenosis of patients was examined by angiography. RESULTS One patient in the control group died due to acute cerebral hemorrhage 4 months after enrollment, and 1 patient was lost to follow-up due to acute myocardial infarction during follow-up 5 months after enrollment. Age, sex, Fontaine stage, and underlying diseases were comparable between the 2 groups. Hs-CRP (3.93±1.43) and IL-6 (11.26±2.29) levels were significant different in the ARB group compared with the control group. The postoperative follow-up showed that ABI was 0.98±0.20 in the ARB group and 0.62±0.48 in the control group. CONCLUSIONS Valsartan inhibited the increase in hs-CRP and IL-6 levels, improved clinical efficacies, increased ABI, and decreased the restenosis rate after the interventional therapy in patients with arteriosclerosis obliterans of the lower extremities.

Keratinocyte growth factor-2 inhibits bacterial infection with Pseudomonas aeruginosa pneumonia in a mouse model.

To determine protective effects of concurrent administration of Keratinocyte growth factor-2 (KGF-2) with Pseudomonas aeruginosa (P. aeruginosa) inoculation on the induced pneumonia. KGF-2 (5 mg/kg) was concurrently administered into the left lobe of 55 mice with P. aeruginosa PAO1 (5 × 10(6) CFU, half-lethal dose); 55 mice in the control group were concurrently administered PBS with the PAO1. We detected and analyzed: body temperature; amount of P. aeruginosa in homogenates; count of total number of nucleated cells and of mononuclear macrophages; protein concentration in bronchoalveolar lavage fluid (BALF); lung wet-to-dry weight ratio; cytokines in BALF and blood; and lung morphology. To study survival rate, concurrent administration of KGF-2 (experimental group) versus PBS (control) with a lethal dose of PAO1 (1 × 10(7) CFU was performed, and survivorship was documented for 7 days post-inoculation. The bacterial CFU in lung homogenates was significantly decreased in the KGF-2 group compared to the control group. There were significantly more mononuclear macrophages in the BALF from the KGF-2 group than from the control group (p < 0.05). KGF-2 increased the surfactant protein and GM-CSF mRNA in lung at 6 h and 72 h after inoculation. Significant reduction of lung injury scores, protein concentrations, lung wet-to-dry weight ratio, and IL-6 and TNF-α levels was noted in the KGF-2 treated rats at 72 h after inoculation (p < 0.05). The 7-day survival rate of the KGF-2 group was significantly higher than that of the control group (p < 0.05). Concurrent administration of KGF-2 facilitates the clearance of P. aeruginosa from the lungs, attenuates P. aeruginosa-induced lung injury, and extends the 7-day survival rate in mice model with P. aeruginosa pneumonia.

Denatonium inhibits growth and induces apoptosis of airway epithelial cells through mitochondrial signaling pathways.

BACKGROUND: Denatonium, a widely used bitter agonist, activates bitter taste receptors on many cell types and plays important roles in chemical release, ciliary beating and smooth muscle relaxation through intracellular Ca(2+)-dependent pathways. However, the effects of denatonium on the proliferation of airway epithelial cells and on the integrity of cellular components such as mitochondria have not been studied. In this study, we hypothesize that denatonium might induce airway epithelial cell injury by damaging mitochondria. METHODS: Bright-field microscopy, cell counting kit-8 (CCK-8) assay and flow cytometry analysis were used to examine cellular morphology, proliferation and cell cycle, respectively. Transmission electron microscopy (TEM) was used to examine mitochondrial integrity. JC-1 dye and western blotting techniques were used to measure mitochondrial membrane potential and protein expression, respectively. RESULTS: For airway epithelial cells, we observed that denatonium significantly effects cellular morphology, decreases cell proliferation and reduces the number of cells in S phase in a dose-dependent manner. TEM analysis demonstrated that denatonium causes large amplitude swelling of mitochondria, which was confirmed by the loss of mitochondrial membrane potential, the down-regulation of Bcl-2 protein and the subsequent enhancement of the mitochondrial release of cytochrome c and Smac/DIABLO after denatonium treatment. CONCLUSIONS: In this study, we demonstrated for the first time that denatonium damages mitochondria and thus induces apoptosis in airway epithelial cells.

Characterization of 40 single nucleotide polymorphism (SNP) via Tm-shift assay in the mud crab (Scylla paramamosain).

In this study, single nucleotide polymorphism (SNP) were identified, confirmed and genotyped in the mud crab (Scylla paramamosain) using Tm-shift assay. High quality sequences (13, 311 bp long) were obtained by re-sequencing that contained 91 SNPs, with a density of one SNP every 146 bp. Of all 91 SNPs, 40 were successfully genotyped and characterized using 30 wild specimens by Tm-shift assay. The minor allele frequency per locus ranged from 0.017 to 0.500. The observed and expected heterozygosity, and polymorphism information content (PIC) ranged from 0.000 to 0.600, from 0.033 to 0.509, and from 0.033 to 0.375, respectively, with an average of 0.142, 0.239 and 0.198 per locus. Seventeen SNPs were significantly deviated from Hardy-Weinberg equilibrium. No significant linkage disequilibrium between pairs of loci was detected after sequential Bonferroni correction (P > 0.00125). Seventeen SNPs were related with known function genes. This study provided new molecular markers for investigation of population genetic diversity, construction of genetic linkage maps and molecular marker-assisted selection in this important crustacean species.

Nanoscale Metal-Organic Frameworks and Nanoscale Coordination Polymers: From Synthesis to Cancer Therapy and Biomedical Imaging.

Recently, there has been significant interest in nanoscale metal-organic frameworks (NMOFs) characterized by ordered crystal structures and nanoscale coordination polymers (NCPs) featuring amorphous structures. These structures arise from the coordination interactions between inorganic metal ions or clusters and organic ligands. Their advantages, such as the ability to tailor composition and structure, efficiently encapsulate diverse therapeutic or imaging agents within porous frameworks, inherent biodegradability, and surface functionalization capability, position them as promising carriers in the biomedical fields. This review provides an overview of the synthesis and surface modification strategies employed for NMOFs and NCPs, along with their applications in cancer treatment and biological imaging. Finally, future directions and challenges associated with the utilization of NMOFs and NCPs in cancer treatment and diagnosis are also discussed.

PAI-1 Deficiency Promotes NET-mediated Pyroptosis and Ferroptosis during Pseudomonas Aeruginosa-induced Acute Lung Injury by Regulating the PI3K/MAPK/AKT Axis.

Circulating neutrophil extracellular trap (NET) formation is an adaptive process during acute lung injury (ALI). The important role of plasminogen activator inhibitor (PAI)-1 in NET formation during ALI remains unclear. This research intends to examine the impacts of the decrease in PAI-1 levels on NET formation and the underlying mechanism. We found a relative association between the increase in plasma NET levels and thromboinflammation-induced lung damage in patients with ARDS. PAI-1 knockout (KO) mice exhibited significant increases in Pseudomonas aeruginosa (PAO1 strain)-induced ALI, inflammation, inflammatory cell accumulation, and proinflammatory cytokine secretion, and wild-type mice exhibited the opposite changes. During PAO1-induced ALI, PAI-1 KO increased NET release and the levels of prothrombotic markers in mice. PAI-1 deficiency also promoted NET formation and NET-mediated pyroptosis and ferroptosis by activating the PI3K/MAPK/AKT pathway in a PAO1-induced ALI mouse model. In conclusion, PAI-1 KO exacerbated PAO1-induced pneumonia-associated injury and contributed to NET-mediated pyroptosis and ferroptosis through PI3K/MAPK/AKT pathway activation. Thus, targeting PAI-1 and NETs may be a promising therapeutic approach for ameliorating pneumonia and thromboinflammation-associated ALI.

Antibody-Calixarene Drug Conjugate: A General Drug Delivery Platform for Tumor-Targeted Therapy.

Antibody-drug conjugates (ADCs), which combine the precise targeting capabilities of antibodies with the powerful cytotoxicity of small-molecule drugs, have evolved into a promising approach for tumor treatment. However, the traditional covalent coupling method requires the design of a specific linker tailored to the properties of the small-molecule drugs, which greatly limits the development of ADCs and the range of drugs that can be used. Herein, a novel type of antibody-calixarene drug conjugates (ACDCs) that function similarly to ADCs by delivering drugs to their targets using antibodies but without the requirement of covalent conjugation of the drugs with antibodies is presented. By replacement of conventional linkers with supramolecular linkers, the ACDCs can load various chemotherapeutic drugs through host-guest interactions. Furthermore, ACDCs are readily reduced upon reaching the hypoxic microenvironment, resulting in rapid release of the drugs. With this precise drug encapsulation and controlled release mechanism, ACDCs deliver drugs to tumor tissues effectively and achieve a significantly enhanced antitumor effect. Considering that the ACDCs can be easily prepared by combining antibody-calixarene conjugates derived from tumor-targeting antibodies with various small-molecule drugs, ACDCs may provide a promising platform technology to accelerate ADC development and thus improve the therapeutic efficacy of chemotherapy.

Critical roles of PAI-1 in lipopolysaccharide-induced acute lung injury.

PURPOSE: Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of fibrinolytic systems. The effect of PAI-1 on inflammatory response is still inconsistent. Our study was conducted to investigate its effects on inflammation to clarify the role of PAI-1 in acute lung injury (ALI) induced by lipopolysaccharide (LPS). MATERIAL AND METHODS: ALI models were established in wild-type (WT) and PAI-1 knockout (KO) mice by LPS intervention for 48 â€‹h. Lung histopathology, wet-dry ratio, total cell count and TNF-α concentration in bronchoalveolar lavage fluid (BALF), and inflammation related proteins were detected. Flow cytometry was used to sort neutrophils, macrophages, regulatory T cells (Treg) and T helper cell 17 (Th17). RNA sequencing was performed to find differentially expressed genes. Masson staining and immunohistochemistry were used to analyze pulmonary fiber deposition and proliferation. RESULTS: Compared with ALI (WT) group, the wet-dry ratio, the total number of BALF cells, the concentration of TNF-α in BALF, and the expression of pp65 in the lung tissue was increased in ALI (PAI-1 KO) group, with increased proportion of neutrophils, decreased proportion of macrophages and decreased proportion of Treg/Th17 in the lung tissue. Collagen fiber deposition and PCNA expression were lighter in ALI (PAI-1 KO) group than ALI (WT) group. PPI analysis showed that PAI-1 was closely related to TNF, IL-6, IL-1ß, Smad2/3 and mainly concentrated in the complement and coagulation system, TNF-α and IL-17 signaling pathways. CONCLUSIONS: PAI-1 KO could aggravate ALI induced by LPS at 48 â€‹h. PAI-1 may be an important target to improve the prognosis of ALI.

Inactivated vaccines reduce the risk of liver function abnormality in NAFLD patients with COVID-19: a multi-center retrospective study.

BACKGROUND: Abnormal liver function was frequently observed in nonalcoholic fatty liver disease (NAFLD) patients infected with SARS-CoV-2. Our aim was to explore the effect of SARS-CoV-2 inactivated vaccines on liver function abnormality among NAFLD patients with COVID-19. METHODS: The multi-center retrospective cohort included 517 NAFLD patients with COVID-19 from 1 April to 30 June 2022. Participants who received 2 doses of the vaccine (n = 274) were propensity score matched (PSM) with 243 unvaccinated controls. The primary outcome was liver function abnormality and the secondary outcome was viral shedding duration. Logistic and Cox regression models were used to calculate the odds ratio (OR) and hazard ratio (HR) for the outcomes. Sensitivity analysis was conducted to assess robustness. FINDINGS: PSM identified 171 pairs of vaccinated and unvaccinated patients. Liver function abnormality was less frequent in the vaccinated group (adjusted OR, 0.556 [95% CI (confidence interval), 0.356-0.869], p = 0.010). Additionally, the vaccinated group demonstrated a lower incidence of abnormal bilirubin levels (total bilirubin: adjusted OR, 0.223 [95% CI, 0.072-0.690], p = 0.009; direct bilirubin: adjusted OR, 0.175 [95% CI, 0.080-0.384], p < 0.001) and shorter viral shedding duration (adjusted HR, 0.798 [95% CI, 0.641-0.994], p = 0.044) than the unvaccinated group. Further subgroup analysis revealed similar results, while the sensitivity analyses indicated consistent findings. INTERPRETATION: SARS-CoV-2 vaccination in patients with NAFLD may reduce the risk of liver dysfunction during COVID-19. Furthermore, vaccination demonstrated beneficial effects on viral shedding in the NAFLD population. FUNDING: 23XD1422700, Tszb2023-01, Zdzk2020-10, Zdxk2020-01, 2308085J27 and JLY20180124.

[The incidence and risk factors for heterogeneous vancomycin intermediate Staphylococcus aureus].

OBJECTIVES: To investigate the prevalence of heterogeneous vancomycin intermediate Staphylococcus aureus (hVISA) and the sensitivity of hVISA to novel antibiotics, and to explore the risk factors and infection attributable mortality associated with hVISA infection. METHODS: A total of 456 methicillin resistant Staphylococcus aureus (MRSA) isolates were isolated in Zhongshan Hospital from January, 2008 to November, 2010. All MRSA isolates were investigated for hVISA by two agar screening methods BHIA5T (brain-heart infusion containing teicoplanin 5 mg/L) or BHIA6V (brain-heart infusion containing vancomycin 6 mg/L), as well as macroEtest method (MET). Possible hVISA isolates were tested by modified population analysis profile-area under the curve (PAP-AUC). The minimal inhibitory concentrations (MICs) of vancomycin, teicoplanin and linezolid were determined by microbroth dilution as recommended by Clinical Laboratory Standards Institute (CLSI). The contribution difference between hVISA and vancomycin susceptible Staphylococcus aureus (VSSA) in different MIC range was compared. A retrospective case-control study of the patients with hVISA infection or VSSA infection was carried out and statistical analysis was performed using t test, Mann-Whitney test, χ(2) test and Fisher exact test. RESULTS: A total of 105 isolates of hVISA were screened by BHIA5T and BHIA6V (23.0%) with other 23 isolates by MET (5.0%) and 21 by PAP-AUC (4.6%). All isolates were 100% sensitive to vancomycin, teicoplanin and linezolid. The vancomycin MIC [(1.76 ± 0.16) mg/L] in hVISA group was significantly higher than that in VSSA group [(1.09 ± 0.07) mg/L, P < 0.01], which was a potential risk factor for hVISA infection. The retrospective study showed chronic obstructive pulmonary disease (COPD) was also a risk factor for hVISA infection of the lower respiratory tract. No significant difference in infection attributable mortality was showed between the hVISA group and the VSSA group. CONCLUSIONS: The overall prevalence of hVISA in Zhongshan Hospital is estimated as 4.6%, while the prevalence of hVISA isolated from blood is as high as 12.5%. All isolates are 100% sensitive to vancomycin and linezolid. COPD is a risk factor for hVISA infection of the lower respiratory tract.

Serum Irisin is Associated with Bone Mineral Density in Postmenopausal T2dm Patients Complicated with Osteoporosis and in Mice with Diabetic Osteoporosis.

BACKGROUND: Osteoporosis is a systemic bone disease with low bone mass, destruction of bone microstructure, and increased bone fragility. Gender and metabolic status are well-known risk factors for osteoporosis. Irisin is a newly discovered myokine that is secreted by skeletal muscle and adipose tissue. Serum Irisin was reported to be decreased in type 2 diabetes mellitus (T2DM) and/or osteoporosis patients, and it is correlated with bone mineral density (BMD) of neck bone, but its role in postmenopausal T2DM with osteoporosis remains largely unknown. METHODS: Postmenopausal T2DM patients with or without osteoporosis were recruited, and 50 agematched healthy postmenopausal women were employed as healthy control. C57BL/6J mice were intraperitoneally injected with 65 mg/kg Streptozotocin (STZ) daily for consecutive 5 days to induce diabetes, and 1 mg/kg recombinant Irisin protein was injected into diabetic mice through the tail vein once a week for 4 months. RESULTS: Compared to that of healthy control, serum Irisin levels and BMD in L1-L4 lumbar spine, femoral neck, total hip, and Wards were decreased in postmenopausal T2DM patients and further decreased in T2DM patients with osteoporosis. Moreover, serum Irisin levels were also correlated with BMD in the above body parts in T2DM patients. Furthermore, recombinant Irisin protein improved diabetic osteoporosis and inflammation in STZ-induced diabetic mice with osteoporosis. CONCLUSION: Serum Irisin levels in postmenopausal T2DM patients with osteoporosis were significantly decreased, which may be related to the decreased BMD and the occurrence of osteoporosis in postmenopausal T2DM patients. The combined measurement of serum Irisin levels and BMD in patients with T2DM in the early stage has a certain effect on the diagnosis and treatment of osteoporosis.

Prevalence and risk factors for severe linezolid-associated thrombocytopenia in pediatric patients: An analysis of a public database.

Linezolid is widely used in various clinical settings. Studies have revealed that it may cause thrombocytopenia in adults. However, the correlation between the use of linezolid and thrombocytopenia in pediatric patients is still unclear. This study aimed to identify the impact of Linezolid on the occurrence of thrombocytopenia in children. A retrospective observational study was conducted using data on patients treated with linezolid from the Pediatric Intensive Care clinical database. Univariate and multiple logistic regression analyses were performed to identify the risk factors of linezolid-related severe thrombocytopenia. A total of 134 patients were included. The prevalence of severe thrombocytopenia was 8.96% (12/134). Univariate analysis indicated that the severe thrombocytopenia group showed significantly higher proportion of concomitant carbapenem (75% vs 44.3%; P < .05) and piperacillin/tazobactam (25% vs 6.6%; P < .05) than that of the non-severe thrombocytopenia group. Multivariate analysis also revealed that the occurrence of severe thrombocytopenia was significantly associated with concurrent use of carbapenem (odd ratio = 4.058; 95% confidence interval: 1.012-16.274; P = .048) and piperacillin/tazobactam (odd ratio = 5.335; 95% confidence interval: 1.117-25.478; P = .036). 75% of patients (9/12) developed severe thrombocytopenia within the first 7 days of linezolid use. The concomitant use of carbapenem and piperacillin/tazobactam was associated with an increased probability of severe thrombocytopenia in pediatric patients undergoing linezolid treatment. Further prospective clinical studies are required, and more detailed mechanisms of blood toxicity in pediatric patients must be investigated.

San-Huang-Yi-Shen capsule ameliorates diabetic nephropathy in mice through inhibiting ferroptosis.

Diabetic nephropathy (DN) is one of the main complications of diabetes. However, effective therapy to block or slow down the progression of DN is still lacking. San-Huang-Yi-Shen capsule (SHYS) has been shown to significantly improve renal function and delay the progression of DN. However, the mechanism of SHYS on DN is still unclear. In this study, we established a mouse model of DN. Then, we investigated the anti-ferroptotic effects of SHYS including the reduction of iron overload and the activation of cystine/GSH/GPX4 axis. Finally, we used a GPX4 inhibitor (RSL3) and ferroptosis inhibitor (ferrostatin-1) to determine whether SHYS ameliorates DN through inhibiting ferroptosis. The results showed that SHYS treatment was effective for mice with DN in terms of improving renal function, and reducing inflammation and oxidative stress. Besides, SHYS treatment reduced iron overload and upregulated the expression of cystine/GSH/GPX4 axis-related factors in kidney. Moreover, SHYS exhibited similar therapeutic effect on DN as ferrostatin-1, RSL3 could abolish the therapeutic and anti- ferroptotic effects of SHYS on DN. In conclusion, SHYS can be used to treat mice with DN. Furthermore, SHYS could inhibit ferroptosis in DN through reducing iron overload and upregulating the expression of cystine/GSH/GPX4 axis.

Working memory processing deficit associated with a nonlinear response pattern of the anterior cingulate cortex in first-episode and drug-naïve schizophrenia.

Impaired working memory (WM) is a core neuropsychological dysfunction of schizophrenia, however complex interactions among the information storage, information processing and attentional aspects of WM tasks make it difficult to uncover the psychophysiological mechanisms of this deficit. Thirty-six first-episode and drug-naïve schizophrenia and 29 healthy controls (HCs) were enrolled in this study. Here, we modified a WM task to isolate components of WM storage and WM processing, while also varying the difficulty level (load) of the task to study regional differences in load-specific activation using mixed effects models, and its relationship to distributed gene expression. Comparing patients with HCs, we found both attentional deficits and WM deficits, with WM processing being more impaired than WM storage in patients. In patients, but not controls, a linear modulation of brain activation was observed mainly in the frontoparietal and dorsal attention networks. In controls, an inverted U-shaped response pattern was identified in the left anterior cingulate cortex. The vertex of this inverted U-shape was lower in patients than controls, and a left-shifting axis of symmetry was associated with better WM performance in patients. Both the above linear and U-shaped modulation effects were associated with the expressions of the genes enriched in the dopamine neurotransmitter system across all cortical brain regions. These findings indicate that a WM processing deficit is evident in schizophrenia from an early stage before antipsychotic treatment, and associated with a dopamine pathway related aberration in nonlinear response pattern at the cingulate cortex when processing WM load.

ZNF354C Mediated by DNMT1 Ameliorates Lung Ischemia-Reperfusion Oxidative Stress Injury by Reducing TFPI Promoter Methylation to Upregulate TFPI.

Background: Pulmonary ischemia reperfusion- (I/R-) induced dysfunction is a significant clinical problem after lung transplantation. In this study, we aim to explore the molecular mechanism of lung I/R injury (LIRI). Methods: Bioinformatic analysis of gene involved in oxidative stress. A HUVEC oxygen glucose deprivation/reoxygenation (OGD/R) model and I/R mouse model were first established via I/R. The cellular proliferation, migration, reactive oxygen species (ROS), and parameters of lung injury were assessed via CCK-8, EdU staining, Transwell, cellular ROS kit, and H&E staining. We also confirmed related gene expressions and protein levels and the interaction between the tissue factor pathway inhibitor (TFPI) promotor and ZNF354C. Results: Bioinformatic analysis results showed TFPI contributed to oxidative stress. OGD/R caused a reduction in cell viability and migration, hypermethylation of TFPI, increased ROS, and downregulation of ZNF354C, TFPI, and DNA methyltransferases (DNMTs) in HUVECs. Besides, ZNF354C could directly bind to the TFPI promoter, enhance proliferation and migration, and inhibit ROS in OGD/R-induced HUVECs by upregulating TFPI. More importantly, we discovered that 5-Aza could reduce TFPI methylation, upregulate TFPI, and enhance the binding of ZNF354C to the TFPI promoter in LIRI. Furthermore, DNMT1 silencing could induce proliferation and migration and prevent ROS in OGD/R-induced HUVECs by upregulating ZNF354C. Additionally, we verified that ZNF354C could alleviate LIRI by preventing DNA methylation in vivo. Conclusions: ZNF354C overexpression induced proliferation and migration, as well as suppressed ROS in OGD/R-induced HUVECs, and alleviated LIRI in mice by inhibiting TFPI promoter methylation to upregulate TFPI. Therefore, ZNF354C and TFPI methylation might be promising molecular markers for LIRI therapy.

The Pathogenesis and Influencing Factors of Adult Hypertension Based on Structural Equation Scanning.

Explore the pathogenesis and influencing factors of adult hypertension based on structural equation scanning. Using a multistage random sampling method, randomly select 2 community health service centers in each administrative area of a certain city and conduct a sample survey of residents in the community. According to the predetermined sample size n, multiply by 1.3 (1.3n) to draw a sample. Community doctors and medical students who have been uniformly trained form an investigation team draw up a questionnaire by consulting the literature, seek expert opinions, and then make changes based on the questions in the preinvestigation. Experiment result shows that the average systolic blood pressure of the experimental subjects was 126.13 + 15.36 mmHg and the average diastolic blood pressure was 79.52 + 8.81 mmHg; males are higher than females and increase with age. The prevalence rate of hyperemia is 26.3%, and the prevalence rate of prehypertension among the survey subjects is 55.4%; that of males (62.6%) is higher than that of females (49.2%). The prevalence of isolated systolic hypertension was 7.5%, and that of men (6.9%) was lower than that of women (7.9%). The awareness rate of hypertension was 66.5%, and the treatment rate of hypertension was 62.7%; the control rate of hypertension was 13.2%, and the control rate of hypertension treatment was 25.7%; all the abovementioned rates are higher for women than for men, and they all tend to increase with age which proved that being overweight is a risk factor for hypertension, dyslipidemia, and hypertension. Hypertension, dyslipidemia, and family history of hypertension are risk factors for hypertension. There is a positive correlation between hypertension and dyslipidemia.

Inhibition of the cGAS-STING Pathway Attenuates Lung Ischemia/Reperfusion Injury via Regulating Endoplasmic Reticulum Stress in Alveolar Epithelial Type II Cells of Rats.

Purpose: Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Cyclic GMP-AMP synthase (cGAS) is a cytosol dsDNA sensor, coupling with downstream stimulator of interferon genes (STING) located in the ER, which involves innate immune responses. The aim of our present study was to investigate the effects of cGAS on lung I/R injury via regulating ERS. Methods: We used Sprague-Dawley rats to make the lung I/R model by performing left hilum occlusion-reperfusion surgery. cGAS-specific inhibitor RU.521, STING agonist SR-717, and 4-phenylbutyric acid (4-PBA), the ERS inhibitor, were intraperitoneally administered in rats. Double immunofluorescent staining was applied to detect the colocalization of cGAS or BiP, an ERS protein, with alveolar epithelial type II cells (AECIIs) marker. We used transmission electron microscopy to examine the ultrastructure of ER and mitochondria. Apoptosis and oxidative stress in the lungs were assessed, respectively. The profiles of pulmonary edema and lung tissue injury were evaluated. And the pulmonary ventilation function was measured using a spirometer system. Results: In lung I/R rats, the cGAS-STING pathway was upregulated, which implied they were activated. After cGAS-STING pathway was inhibited or activated in lung I/R rats, the ERS was alleviated after cGAS was inhibited, while when STING was activated after lung I/R, ERS was aggravated in the AECIIs, these results suggested that cGAS-STING pathway might trigger ERS responses. Furthermore, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats. Inhibition of cGAS-STING pathway attenuated ERS, therefore attenuated lung injury and promoted pulmonary ventilation function in I/R rats. Conclusion: Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via alleviating endoplasmic reticulum stress in alveolar epithelial type II cells of rats.