CAPN2 promotes apalutamide resistance in metastatic hormone-sensitive prostate cancer by activating protective autophagy.

Apalutamide, a novel endocrine therapy agent, has been shown to significantly improve the prognosis of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, resistance to apalutamide has also been reported, and the underlying mechanism for this response has yet to be clearly elucidated. First, this study established apalutamide-resistant prostate cancer (PCa) cells, and confirmed that apalutamide activated the release of calcium ions (Ca2+) and endoplasmic reticulum stress (ERS) to enhance autophagy. Second, RNA sequencing, western blotting, and immunohistochemistry revealed significantly decreased Calpain 2 (CAPN2) expression in the apalutamide-resistant PCa cells and tissues. Furthermore, immunofluorescence and transmission electron microscopy (TEM) showed that CAPN2 promoted apalutamide resistance by activating protective autophagy. CAPN2 promoted autophagy by reducing Forkhead Box O1 (FOXO1) degradation while increasing nuclear translocation via nucleoplasmic protein isolation and immunofluorescence. In addition, FOXO1 promoted protective autophagy through the transcriptional regulation of autophagy-related gene 5 (ATG5). Furthermore, a dual-fluorescence assay confirmed that transcription factor 3 (ATF3) stimulation promoted CAPN2-mediated autophagy activation via transcriptional regulation. In summary, CAPN2 activated protective autophagy by inhibiting FOXO1 degradation and promoting its nuclear translocation via transcriptional ATG5 regulation. ATF3 activation and transcriptional CAPN2 regulation jointly promoted this bioeffect. Thus, our findings have not only revealed the mechanism underlying apalutamide resistance, but also provided a promising new target for the treatment of metastatic PCa.

Sevoflurane preconditioning protects against acute MI/R injury via enhancing AdipoR1-Cav3 interaction and alleviating endoplasmic reticulum stress.

Whether and how sevoflurane preconditioning (SevoPre) exerts protection against acute myocardial ischemia/reperfusion (MI/R) injury remains elusive. We observed significant myocardial injury, as evidenced by infarct size, cardiomyocyte apoptosis, and circulating troponin-I, at 3 h of MI/R in both wildtype and adiponectin knockout mice. The injury was significantly ameliorated by SevoPre in wildtype mice, but not in adiponectin knockout mice. In wildtype mice, we found that MI/R could increase endoplasmic reticulum stress of cardiomyocytes, and impair association of adiponectin receptor 1 and ceveolin-3, both of which processes were largely restored by SevoPre. In summary, we demonstrated that significant injury had already took place at 3 h of MI/R, which could be ameliorated by SevoPre via promoting affinity of adiponectin receptor 1 and ceveolin-3, and then attenuating endoplasmic reticulum stress of cardiomyocytes.

Minocycline and Pyrrolidine Dithiocarbamate Attenuate Hypertension via Suppressing Activation of Microglia in the Hypothalamic Paraventricular Nucleus.

Proinflammatory cytokines, reactive oxygen species and imbalance of neurotransmitters are involved in the pathophysiology of angiotensin II-induced hypertension. The hypothalamic paraventricular nucleus (PVN) plays a vital role in hypertension. Evidences show that microglia are activated and release proinflammatory cytokines in angiocardiopathy. We hypothesized that angiotensin II induces PVN microglial activation, and the activated PVN microglia release proinflammatory cytokines and cause oxidative stress through nuclear factor-kappa B (NF-κB) pathway, which contributes to sympathetic overactivity and hypertension. Male Sprague-Dawley rats (weight 275-300 g) were infused with angiotensin II to induce hypertension. Then, rats were treated with bilateral PVN infusion of microglial activation inhibitor minocycline, NF-κB activation inhibitor pyrrolidine dithiocarbamate or vehicle for 4 weeks. When compared to control groups, angiotensin II-induced hypertensive rats had higher mean arterial pressure, PVN proinflammatory cytokines, and imbalance of neurotransmitters, accompanied with PVN activated microglia. These rats also had more PVN gp91phox (source of reactive oxygen species production), and NF-κB p65. Bilateral PVN infusion of minocycline or pyrrolidine dithiocarbamate partly or completely ameliorated these changes. This study indicates that angiotensin II-induced hypertensive rats have more activated microglia in PVN, and activated PVN microglia release proinflammatory cytokines and result in oxidative stress, which contributes to sympathoexcitation and hypertensive response. Suppression of activated PVN microglia by minocycline or pyrrolidine dithiocarbamate attenuates inflammation and oxidative stress, and improves angiotensin II-induced hypertension, which indicates that activated microglia promote hypertension through activated NF-κB. The findings may offer hypertension new strategies.

Beneficial effects of metformin supplementation in hypothalamic paraventricular nucleus and arcuate nucleus of type 2 diabetic rats.

Background Oxidative stress and inflammation play important roles in the development of diabetes. Metformin (MET) is considered as the first-line therapy for patients with type 2 diabetes (T2D). Hypothalamic paraventricular nucleus (PVN) and hypothalamic arcuate nucleus (ARC) are vital in obesity and diabetes. However, there have been few studies on the effects of MET on inflammatory reaction and oxidative stress in the PVN and ARC of T2D diabetic rats. Methods Male Sprague-Dawley (SD) rats were fed with high-fat diet (HFD), and intraperitoneally injected with low-dose streptozotocin (STZ, 30 mg/kg) at 6th week to induce T2D diabetes. After injection of STZ, they were fed with HFD continually. Starting from the 8th week of HFD feeding, T2D rats received intragastrical administration of MET (150 mg/kg/day) in addition to the HFD for another 8 weeks. At the end of the 15th week, the rats were anaesthetized to record the sympathetic nerve activity and collect blood and tissue samples. Results In comparison with control rats, T2D diabetic rats had higher levels of pro-inflammatory cytokines (PICs) and excessive oxidative stress in the PVN and ARC, accompanied with more activated astrocytes. The renal sympathetic nerve activity (RSNA) and the plasma norepinephrine (NE) increased in T2D diabetic rats. The expression of tyrosine hydroxylase (TH) increased and the expression of 67-kDa isoform of glutamate decarboxylase (GAD67) decreased in T2D diabetic rats. Supplementation of MET decreased blood glucose, suppressed RSNA, decreased PICs (TNF-α, IL-1ß and IL-6) in PVN and ARC, attenuated oxidative stress and activation of astrocytes in ARC and PVN of T2D diabetic rats, as well as restored the balance of neurotransmitter synthetase. The number of Fra-LI (chronic neuronal excitation marker) positive neurons in the ARC and PVN of T2D diabetic rats increased. Chronic supplementation of MET also decreased the number of Fra-LI positive neurons in the ARC and PVN of T2D diabetic rats. Conclusion These findings suggest that the PVN and ARC participate in the beneficial effects of MET in T2D diabetic rats, which is possibly mediated via down-regulating of inflammatory molecules, attenuating oxidative stress and restoring the balance of neurotransmitter synthetase by MET in the PVN and ARC.

What can the neurological manifestations of COVID-19 tell us: a meta-analysis.

BACKGROUND: Covid-19 became a global pandemic in 2019. Studies have shown that coronavirus can cause neurological symptoms, but clinical studies on its neurological symptoms are limited. In this meta-analysis, we aimed to summarize the various neurological manifestations that occurred in COVID-19 patients and calculate the incidence of various neurological manifestations. At the same time, we further explored the mechanism of nervous system injury and prognosis in COVID-19 patients in combination with their nervous system manifestations. This study provides a reference for early clinical identification of COVID-19 nervous system injury in the future, so as to achieve early treatment and reduce neurological sequelae. METHODS: We systematically searched all published English literature related to the neurological manifestations of COVID-19 from January 1, 2020, to April 30, 2021, in Pubmed, Embase, and Cochrane Library. The keywords used were COVID-19 and terminology related to the nervous system performance. All included studies were selected by two independent reviewers using EndNote and NoteExpress software, any disagreement was resolved by consensus or by a third reviewer, and the selected data were then collected for meta-analysis using a random-effects model. RESULTS: A total of 168 articles (n = 292,693) were included in the study, and the meta-analysis showed that the most common neurological manifestations of COVID-19 were myalgia(33%; 95%CI 0.30-0.37; I2 = 99.17%), smell impairment(33%; 95%CI 0.28-0.38; I2 = 99.40%), taste dysfunction(33%; 95%CI 0.27-0.39; I2 = 99.09%), altered mental status(32%; 95%CI 0.22-0.43; I2 = 99.06%), headache(29%; 95%CI 0.25-0.33; I2 = 99.42%), encephalopathy(26%; 95%CI 0.16-0.38; I2 = 99.31%), alteration of consciousness(13%; 95%CI 0.08-0.19; I2 = 98.10%), stroke(12%; 95%CI 0.08-0.16; I2 = 98.95%), dizziness(10%; 95%CI 0.08-0.13; I2 = 96.45%), vision impairment(6%; 95%CI 0.03-0.09; I2 = 86.82%), intracerebral haemorrhage(5%; 95%CI 0.03-0.09; I2 = 95.60%), seizure(4%; 95%CI 0.02 -0.05; I2 = 98.15%), encephalitis(2%; 95%CI 0.01-0.03; I2 = 90.36%), Guillan-Barré Syndrome (GBS) (1%; 95%CI 0.00-0.03; I2 = 89.48%). CONCLUSIONS: Neurological symptoms are common and varied in Covid-19 infections, and a growing number of reports suggest that the prevalence of neurological symptoms may be increasing. In the future, the role of COVID-19 neurological symptoms in the progression of COVID-19 should be further studied, and its pathogenesis and assessment methods should be explored, to detect and treat early neurological complications of COVID-19 and reduce mortality.

GNRH1 and LTB4R might be novel immune-related prognostic biomarkers in clear cell renal cell carcinoma (ccRCC).

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) occupied most of renal cell carcinoma (RCC), which associated with poor prognosis. The purpose of this study is to screen novel and prognostic biomarkers for patients with ccRCC. METHODS AND RESULTS: Firstly, Gene Expression Omnibus database was used to collect microarray data for weighted gene co-expression network construction. Gene modules related to prognosis which interest us most were picked out. 90 hub genes were further chosen in the key modules, two of which including gonadotropin releasing hormone 1 (GNRH1) and leukotriene B4 receptor (LTB4R) were screened and validated as immune-related prognostic biomarkers. Based on several public databases and ccRCC tissues collected by ourselves, we performed survival analysis, spearman correlation analysis, receiver operating characteristic (ROC) analysis, quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence (IF) and immunohistochemistry (IHC) staining for the validation of immune-related prognostic biomarkers. We further explored the relationship between immune-related prognostic biomarker expressions and immunocytes. Finally, gene set enrichment analysis (GSEA) demonstrated that the two immune-related prognostic biomarkers were significantly correlated with cell cycle. CONCLUSIONS: Generally speaking, the present study has identified two novel prognostic biomarkers for patients with ccRCC, which showed strong correlation with prognosis of patients with ccRCC, could further be used as potential prognostic biomarkers in ccRCC.

Glucagon-Like Peptide-1 Analog Liraglutide Attenuates Pressure-Overload Induced Cardiac Hypertrophy and Apoptosis through Activating ATP Sensitive Potassium Channels.

PURPOSE: This study aimed to investigate whether inhibition of glucagon-like peptide-1 (GLP-1) on pressure overload induced cardiac hypertrophy and apoptosis is related to activation of ATP sensitive potassium (KATP) channels. METHODS: Male SD rats were randomly divided into five groups: sham, control (abdominal aortic constriction), GLP-1 analog liraglutide (0.3 mg/kg/twice day), KATP channel blocker glibenclamide (5 mg/kg/day), and liraglutide plus glibenclamide. RESULTS: Relative to the control on week 16, liraglutide upregulated protein and mRNA levels of KATP channel subunits Kir6.2/SUR2 and their expression in the myocardium, vascular smooth muscle, aortic endothelium, and cardiac microvasculature. Consistent with a reduction in aortic wall thickness (61.4 ± 7.6 vs. 75.0 ± 7.6 µm, p < 0.05), liraglutide enhanced maximal aortic endothelium-dependent relaxation in response to acetylcholine (71.9 ± 8.7 vs. 38.6 ± 4.8%, p < 0.05). Along with a reduction in heart to body weight ratio (2.6 ± 0.1 vs. 3.4 ± 0.4, mg/g, p < 0.05) by liraglutide, hypertrophied cardiomyocytes (371.0 ± 34.4 vs. 933.6 ± 156.6 µm2, p < 0.05) and apoptotic cells (17.5 ± 8.2 vs. 44.7 ± 7.9%, p < 0.05) were reduced. Expression of anti-apoptotic protein BCL-2 and contents of myocardial ATP were augmented, and expression of cleaved-caspase 3 and levels of serum Tn-I/-T were reduced. Echocardiography and hemodynamic measurement showed that cardiac systolic function was enhanced as evidenced by increased ejection fraction (88.4 ± 4.8 vs. 73.8 ± 5.1%, p < 0.05) and left ventricular systolic pressure (105.2 ± 10.8 vs. 82.7 ± 7.9 mmHg, p < 0.05), and diastolic function was preserved as shown by a reduction of ventricular end-diastolic pressure (-3.1 ± 2.9 vs. 6.7 ± 2.8 mmHg, p < 0.05). Furthermore, left ventricular internal diameter at end-diastole (5.8 ± 0.5 vs. 7.7 ± 0.6 mm, p < 0.05) and left ventricular internal diameter at end-systole (3.0 ± 0.6 vs. 4.7 ± 0.4 mm, p < 0.05) were improved. Dietary administration of glibenclamide alone did not alter all the parameters measured but significantly blocked liraglutide-exerted cardioprotection. CONCLUSION: Liraglutide ameliorates cardiac hypertrophy and apoptosis, potentially via activating KATP channel-mediated signaling pathway. These data suggest that liraglutide might be considered as an adjuvant therapy to treat patients with heart failure.

Analysis of differential effects of host plants on the gut microbes of Rhoptroceros cyatheae.

As an indispensable part of insects, intestinal symbiotic bacteria play a vital role in the growth and development of insects and their adaptability. Rhoptroceros cyatheae, the main pest of the relict plant Alsophila spinulosa, poses a serious threat to the development of the A. spinulosa population. In the present study, 16S rDNA and internal transcribed spacer high-throughput sequencing techniques were used to analyze the structure of intestinal microbes and the diversity of the insect feeding on two different plants, as well as the similarities between the intestinal microorganisms of R. cyatheae. The dominant bacteria of leaf endophytes were also compared based on the sequencing data. The results showed that Proteobacteria, Firmicutes, and Actinobacteria were the dominant phyla of intestinal bacteria, and Ascomycota was the dominant phylum of intestinal fungi. Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, Methylobacterium-Methylorubrum, and Enterococcus were the dominant genera in the intestine of R. cyatheae feeding on two plants, and the relative abundance was significantly different between the two groups. Candida was the common dominant genus of intestinal fungi in the two groups, and no significant difference was observed in its abundance between the two groups. This showed that compared with the intestinal fungi of R. cyatheae, the abundance of the intestinal bacteria was greatly affected by food. The common core microbiota between the microorganisms in A. spinulosa leaves and the insect gut indicated the presence of a microbial exchange between the two. The network correlation diagram showed that the gut microbes of R. cyatheae feeding on Gymnosphaera metteniana were more closely related to each other, which could help the host to better cope with the adverse external environment. This study provides a theoretical basis for the adaptation mechanism of R. cyatheae and a new direction for the effective prevention and control of R. cyatheae.

Forsythiaside A suppresses renal fibrosis and partial epithelial-mesenchymal transition by targeting THBS1 through the PI3K/AKT signaling pathway.

Renal fibrosis is a key feature of chronic kidney disease (CKD) progression, whereas no proven effective anti-fibrotic treatments. Forsythiaside A (FTA), derived from Forsythia suspense, has been found to possess nephroprotective properties. However, there is limited research on its anti-fibrotic effects, and its mechanism of action remains unknown. This study aimed to investigate the suppressive effects of FTA on renal fibrosis and explore the underlying mechanisms. In vitro, we established a HK2 cell model induced by transforming growth factor ß1 (TGF-ß1), and in vivo, we used a mice model induced by unilateral ureteral obstruction (UUO). CCK-8 assay, qRT-PCR, Western blotting, immunofluorescence, flow cytometry, histological staining, immunohistochemistry, TUNEL assay, RNA transcriptome sequencing, and molecular docking were performed. The results showed that FTA (40 µM or 80 µM) treatment improved cell viability and suppressed TGF-ß1-induced fibrotic changes and partial epithelial-mesenchymal transition (EMT). Furthermore, FTA treatment reversed the activation of the PI3K/AKT signaling pathway, and THBS1 was identified as the target gene. We found that THBS1 knockdown suppressed the activation of the PI3K/AKT signaling pathway and reduced the fibrosis and partial EMT-related protein level. Conversely, THBS1 overexpression activated the PI3K/AKT signaling pathway and exacerbated renal fibrosis and partial EMT. In vivo, mice were administered FTA (30 or 60 mg/kg) for 2 weeks, and the results demonstrated that FTA administration significantly mitigated tubular injury, tubulointerstitial fibrosis, partial EMT, and apoptosis. In conclusion, FTA inhibited renal fibrosis and partial EMT by targeting THBS1 and inhibiting activation of the PI3K/AKT pathway.

Atypical presentations of UTUC: a case report of three patients.

Background: Upper tract urothelial carcinoma (UTUC) is a rare clinical condition primarily characterized by symptoms such as gross or microscopic hematuria, flank pain, and renal colic. Although computed tomography urography (CTU) is currently the most accurate imaging modality for diagnosis, atypical presentations and physical examination findings can sometimes obscure lesions, posing diagnostic challenges. Case presentation: In this report, three patients exhibited atypical symptoms, sharing a common complaint of flank pain. Notably, the first patient, who had recently undergone laparoscopic right duplex nephrectomy, presented with microscopic hematuria, whereas the other two did not show any gross or microscopic hematuria. Computed tomography urography revealed hydronephrosis and infection without significant renal pelvic space-occupying lesions, with persistently elevated white blood cell (WBC) counts, but no fever. These atypical clinical presentations confounded clinicians, delaying the diagnosis of upper tract urothelial carcinoma until postoperative pathological examination for the first two patients and resulting in advanced-stage diagnosis for the third patient. Postoperative pathology confirmed high-grade invasive upper tract urothelial carcinoma in all three patients. Conclusion: Upper tract urothelial carcinoma can manifest atypically without hematuria and may be challenging to visualize on computed tomography urography, potentially leading to misdiagnosis. Therefore, clinicians should maintain a high level of suspicion for malignant tumors when patients exhibit hydronephrosis, infection on imaging, and persistently elevated white blood cell counts without fever, even in the absence of typical signs of upper urothelial carcinoma on computed tomography urography.

Magnetic Field-Enhanced Performance of Superparamagnetic LiMn2 O4 -Based Composite Slurry Electrode for Semisolid Flow Battery.

Semisolid flow batteries are expected to be applied to large-scale energy storage fields due to the combination of the high energy density of rechargeable batteries and the flexible design of flow batteries. However, electronic conductivity, specific capacity, and viscosity of slurry electrodes are generally mutually restrictive. Here, a new concept of semisolid flow batteries based on magnetic modification slurry electrode is proposed and the electrochemical performance of the semisolid electrode is expected to be improved by close contact and enhanced electronic conductivity between the active particles with the aid of external magnetic field. This concept is further demonstrated using superparamagnetic LiMn2 O4 -Fe3 O4 -carbon nanotube composite as semisolid cathode. It achieves a capacity of 113.7 mAh g-1 at a current density of 0.5 mA cm-2 with the aid of external magnetic field (about 0.4 T), which is about 21% higher than that without external magnetic field. Simulation study also reveals this improvement mainly resulted from the increase of the conductive paths of electrons after the rearrangement of the active particles under the external magnetic field. It is believed that this strategy gives a new and effective method for controlling the viscosity and electronic conductivity of the slurry electrodes and related flowable electrochemical energy storage systems.

Ginsenoside-Rg1 mitigates cardiac arrest-induced cognitive damage by modulating neuroinflammation and hippocampal plasticity.

Ginsenoside-Rg1 can effectively ameliorate mental disorders, but whether ginsenoside-Rg1 plays a neuroprotective role in cardiac arrest and cardiopulmonary resuscitation (CA/CPR)-induced cognitive impairment remains unclear. In this study, a 5-min asphyxia-based CA/CPR rat model was established to explore the mechanisms underlying the effects of ginsenoside-Rg1 (40 mg·kg-1·d-1, ip, 14 days) on its cognitive alterations. These CA/CPR rats displayed spatial learning and memory impairment in the Morris water maze, as reflected in the compromised basal synaptic transmission and long-term potentiation (LTP) at the Schaffer collateral of hippocampal CA1 area in vivo electrophysiology, whereas the ginsenoside-Rg1 remarkably mitigated these alterations. Next, we found that ginsenoside-Rg1 inhibited hippocampal neuroinflammation by alleviating the CA/CPR-induced hippocampal activation of microglia and astrocytes and the overexpression of related proinflammatory cytokines interleukin-1ß (IL-1ß) and tumour necrosis factor-α (TNF-α). In addition, ginsenoside-Rg1 improved CA/CPR-induced hippocampal neuronal apoptosis, dendritic spines and synaptic ultrastructure defects as associated with the upregulation of the key synaptic regulatory proteins. Furthermore, ginsenoside-Rg1 could ameliorate CA/CPR-induced aberrant expression of the key regulators of hippocampal glutamate signaling pathways, excitatory amino acid transporter 2 (EAAT2), excitatory amino acid transporter 1 (EAAT1), Glutamine Synthetase (GS), GluN2B, and glutamate. In conclusion, ginsenoside-Rg1 exerts its neuroprotective effects by ameliorating hippocampus-dependent neuroglia activation-mediated neuroinflammation and neuroplasticity deficits, shedding new light on the therapeutic intervention of CA/CPR-related cognitive disorders.

UCHL5 Promotes Proliferation and Migration of Bladder Cancer Cells by Activating c-Myc via AKT/mTOR Signaling.

Ubiquitin C-terminal hydrolase L5 (UCHL5) is a deubiquitinating enzyme (DUB) that removes ubiquitin from its substrates. Associations between UCHL5 and cancer have been reported in various tissues, but the effect of UCHL5 on bladder cancer has not been thoroughly investigated. This study investigates the expression and function of UCHL5 in bladder cancer. UCHL5 was shown to be abnormally expressed using IHC of tissue microarray and Western blotting. Several procedures were performed to assess the effect of UCHL5 overexpression or knockdown on bladder cancer, such as cell proliferation, colony formation, wound-healing, and Transwell assays. In addition, RNA-Seq and Western blotting experiments were used to verify the status of downstream signaling pathways. Finally, bladder cancers with knockdown or overexpression of UCHL5 were treated with either SC79 or LY294002 to examine the participation of the AKT/mTOR signaling pathway and the expression of downstream targets c-Myc, SLC25A19, and ICAM5. In contrast to adjacent tissue samples, we discovered that UCHL5 was substantially expressed in bladder cancer samples. We also found that UCHL5 downregulation significantly suppressed both tumor growth in vivo and cell proliferation and migration in vitro. According to RNA-Seq analyses and Western blotting experiments, the expression of c-Myc, SLC25A19, and ICAM5 was modified as a result of UCHL5 activating AKT/mTOR signaling in bladder cancer cells. All things considered, our findings show that increased UCHL5 expression stimulates AKT/mTOR signaling, subsequently triggering the expression of c-Myc, SLC25A19, and ICAM5, which in turn promotes carcinogenesis in bladder cancer. UCHL5 is therefore a potential target for therapy in bladder cancer patients.

Analysis of transcriptome characteristics of UTI therapy for cerebral injury after CA/ROSC based on RNA-seq technique.

Objectives: To study the effects and mechanisms of ulinastatin (UTI) on brain injury caused by cardiac arrest/return of spontaneous circulation (CA/ROSC). Materials and Methods: In this study, modeling of CA/ROSC was set up in 56 Sprague Dawley (SD) rats, which were randomly divided into the model group, UTI (100000U/kg) treatment group, and control group. Each group then was divided into two subgroups: 24 hr and 72 hr. The survival rates between different groups was observed during two weeks. AimPlex multiplex immunoassays technology was performed to detect the expression of inflammatory cytokines in serum, such as IL-6 and TNF-α. RNA-sequencing (RNA-seq) transcriptome, Gene Ontology (GO), and Kyoto. Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to investigate the possible mechanism of UTI. Western blot and immunohistochemistry were performed to detect the expression of C-C motif chemokine ligand 2 (CCl2) and plasminogen (plg) protein expression. Results: The survival rate of the UTI group was significantly higher than the model group during two weeks. And UTI can significantly reduce the content of IL-6 and TNF-α in serum. GO and KEGG pathway enrichment analysis revealed that differentially expressed genes mainly belonged to the IL-17 signaling pathway and neuroactive ligand-receptor interaction signaling pathway. Besides, UTI can down-regulate the expression of the CCl2 inflammatory gene and up-regulate the expression of plg in the brain tissue of CA/ROSC rats. Conclusion: UTI has neuroprotective effects on brain injury after CA/ROSC. And the key mechanisms belong to the regulation of immune-inflammatory response as well as the signaling molecules and interaction.

A novel model of urosepsis in rats developed by injection of Escherichia coli into the renal pelvis.

Despite extensive research, urosepsis remains a life-threatening, high-mortality disease. Currently, animal models of urosepsis widely accepted by investigators are very scarce. This study aimed to establish a standardized and reproducible model of urosepsis in rats. Forty adult Wistar rats were randomly divided into four groups according to the concentration of injected E. coli suspensions: Sham, Sep 3×, Sep 6×, and Sep 12×. Because the ureter is so thin and fragile, no conventional needle can be inserted into the ureter, which is probably why rats are rarely used to develop models of urosepsis. To solve this problem, the left ureter was ligated in the first procedure. After 24 hours, the left ureter above the ligation was significantly dilated, then saline or different concentrations of E. coli at 3 ml/kg were injected into the left renal pelvis using a 30G needle. The left ureter was subsequently ligated again at a distance of 1 cm from the renal hilum to maintain high pressure in the renal pelvis. Following injection of E. coli or saline for 24 h, three rats from each group were sacrificed and their organs (lung, liver, and right kidney) were collected. In contrast, the remaining seven rats continued to be observed for survival. At 10 days after E. coli injection, rats in the sep12× group had a higher mortality rate (100%) compared to the sep3× group (28.6%) or the sep6× group (71.4%). The significant changes in peripheral blood WBC count, serum IL-6 and TNF-α levels were also in the sep12× group. In addition, rats in the sepsis group showed multi-organ dysfunction, including damage to the lungs, liver, and kidneys. The establishment of a standardized rat model of urosepsis may be of great value for studying the pathophysiological of urosepsis.

Diurnal regulation of oxidative phosphorylation restricts hepatocyte proliferation and inflammation.

The principles guiding the diurnal organization of biological pathways remain to be fully elucidated. Here, we perturb the hepatic transcriptome through nutrient regulators (high-fat diet and mTOR signaling components) to identify enduring properties of pathway organization. Temporal separation and counter-regulation between pathways of energy metabolism and inflammation/proliferation emerge as persistent transcriptome features across animal models, and network analysis identifies the G0s2 and Rgs16 genes as potential mediators at the metabolism-inflammation interface. Mechanistically, G0s2 and Rgs16 are sequentially induced during the light phase, promoting amino acid oxidation and suppressing overall mitochondrial respiration. In their absence, sphingolipids and diacylglycerides accumulate, accompanied by hepatic inflammation and hepatocyte proliferation. Notably, the expression of G0s2 and Rgs16 is further induced in obese mouse livers, and silencing of their expression accentuates hepatic fibrosis. Therefore, diurnal regulation of energy metabolism alleviates inflammatory and proliferative stresses under physiological and pathological conditions.

High Performance Aqueous Li-Ion Flow Capacitor Realized Through Microstructure Design of Suspension Electrode.

Suspension electrode is the core of flowable electrochemical energy storage systems, which are considered suitable for large-scale energy storage. Nevertheless, obtaining suspension electrodes with both low viscosity and high conductivity is still a big challenge. In present work, spinel LiMn2O4 was chosen as an example to make suspension with low viscosity and high conductivity through microstructure morphology control of solid particles and the contact mode between active materials and conductive additives in suspension electrode. By coating a thin layer of polyaniline on the surface of spherical spinel LiMn2O4, the resulting suspension showed much higher electronic conductivity (about 10 times) and lower viscosity (about 4.5 times) as compared to irregular and bare spinel LiMn2O4-based suspension counterpart. As a result, the Li-ion flow capacitor based on LiMn2O4 and activated carbon suspensions exhibited a record energy density of 27.4 W h L-1 at a power density of 22.5 W L-1 under static condition to date, and can be smoothly work under an intermittent-flow mode. The strategy reported in this work is an effective way for obtaining suspension electrodes with low viscosity and high electronic conductivity simultaneously. It can not only be used in the flow capacitors, but also can be extended to other flowable electrochemical energy storage systems.

Construction and Validation of an Autophagy-Related Prognostic Signature and a Nomogram for Bladder Cancer.

OBJECTIVE: Bladder cancer (BC) is one of the top ten cancers endangering human health but we still lack accurate tools for BC patients' risk stratification. This study aimed to develop an autophagy-related signature that could predict the prognosis of BC. In order to provide clinical doctors with a visual tool that could precisely predict the survival probability of BC patients, we also attempted to establish a nomogram based on the risk signature. METHODS: We screened out autophagy-related genes (ARGs) combining weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) in BC. Based on the screened ARGs, we performed survival analysis and Cox regression analysis to identify potential prognostic biomarkers. A risk signature based on the prognostic ARGs by multivariate Cox regression analysis was established, which was validated by using seven datasets. To provide clinical doctors with a useful tool for survival possibility prediction, a nomogram assessed by the ARG-based signature and clinicopathological features was constructed, verified using four independent datasets. RESULTS: Three prognostic biomarkers including BOC (P = 0.008, HR = 1.104), FGF7(P = 0.030, HR = 1.066), and MAP1A (P = 0.001, HR = 1.173) were identified and validated. An autophagy-related risk signature was established and validated. This signature could act as an independent prognostic feature in patients with BC (P = 0.047, HR = 1.419). We then constructed two nomograms with and without ARG-based signature and subsequent analysis indicated that the nomogram with ARG signature showed high accuracy for overall survival probability prediction of patients with BC (C-index = 0.732, AUC = 0.816). These results proved that the ARG signature improved the clinical net benefit of the standard model based on clinicopathological features (age, pathologic stage). CONCLUSIONS: Three ARGs were identified as prognosis biomarkers in BC. An ARG-based signature was established for the first time, showing strong potential for prognosis prediction in BC. This signature was proven to improve the clinical net benefit of the standard model. A nomogram was established using this signature, which could lead to more effective prognosis prediction for BC patients.

Systematic Pan-Cancer Analysis of KIF23 and a Prediction Model Based on KIF23 in Clear Cell Renal Cell Carcinoma (ccRCC).

PURPOSE: This study aims to carry out a pan-cancer analysis of kinesin family member 23 (KIF23) and construct a predictive model for the prognosis of clear cell renal cell carcinoma (ccRCC) patients. METHODS: We evaluated the differential expression of KIF23 in pan-cancer by The Cancer Genome Atlas (TCGA) and Oncomine database. Then, the correlation between KIF23 with prognosis, clinical grade, stage, immune subtype, tumor mutation burden (TMB), microsatellite instability (MSI) and immune microenvironment was explored by TCGA, an integrated repository portal for tumor-immune system interactions (TISIDB) and cBioPortal. Subsequently, we screened out ferroptosis-related genes (FRGs) related to KIF23 and constructed a risk score model. Univariate Cox analysis was used to determine independent prognostic factors for ccRCC overall survival (OS), and a nomogram was established. Furthermore, gene set enrichment analysis (GSEA) was applied to study the biological functions and pathways of KIF23. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to evaluate the expression of KIF23. RESULTS: KIF23 was highly expressed in most tumors. Further, KIF23 was strongly correlated with prognosis, clinical grade, stage, immune subtype, TMB, MSI and immune microenvironment in different tumors. We found that KIF23 was significantly associated with all aspects of ccRCC. Then, 8 FRGs were identified to construct a risk score model together with KIF23. And a prognostic nomogram prediction model of OS was established. After GSEA analysis, cell cycle, condensed chromosome and other physiological processes were screened out. Finally, qRT-PCR verified the high expression of KIF23 in ccRCC cell lines than normal kidney cell line. CONCLUSION: KIF23 may act as a pivotal part in occurrence and progression of different tumors. In ccRCC, KIF23 can be a great prognostic biomarker, and the nomogram based on KIF23 may contribute to better treatment plans for ccRCC patients.

The Development of Stem Cell-Based Treatment for Acute Ischemic Cerebral Injury.

Acute ischemic brain injury is a serious disease that severely endangers the life safety of patients. Such disease is hard to predict and highly lethal with very limited effective treatments currently. Although currently, there exist treatments like drug therapy, hyperbaric oxygen therapy, rehabilitation therapy and other treatments in clinical practice, these are not significantly effective for patients when the situation is severe. Thus scientists must explore more effective treatments. Stem cells are undifferentiated cells with a strong potential of self-renewal and differentiate into various types of tissues and organs. Their emergence has brought new hopes for overcoming difficult diseases, further improving medical technology and promoting the development of modern medicine. Some combining therapies and genetically modified stem cell therapy have also been proven to produce obvious neuroprotective function for acute ischemic brain injury. This review is an introduction to the current research findings and discusses the definition, origin and classification of stem cells, as well as the future prospects of the stem cell-based treatment for acute ischemic cerebral injury.