Counteracting TGM2 by a Fibroin peptide ameliorated Adriamycin-induced nephropathy via regulation of lipid metabolism through PANX1-PPAR α/PANK1 pathway.

Peptide drug discovery for the treatment of chronic kidney disease (CKD) has attracted much attention in recent years due to the urge to find novel drugs and mechanisms to delay the progression of the disease. In this study, we identified a novel short peptide (named YR-7, primary sequence 'YEVEDYR') from the natural Fibroin protein, and demonstrated that it significantly alleviated pathological renal changes in ADR-induced nephropathy. PANX1 was identified as the most notably upregulated component by RNA-sequencing. Further analysis showed that YR-7 alleviated the accumulation of lipid droplets via regulation of the lipid metabolism-related proteins PPAR α and PANK1. Using chemical proteomics, fluorescence polarization, microscale thermophoresis, surface plasmon resonance, and molecular docking, YR-7 was proven to directly bind to ß-barrel domains of TGM2 protein to inhibit lipid accumulation. TGM2 knockdown in vivo increased the protein levels of PPAR α and PANK1 while decreased the levels of fibrotic-related proteins to alleviate nephropathy. In vitro, overexpression TGM2 reversed the protective effects of YR-7. Co-immunoprecipitation indicated that TGM2 interacted with PANX1 to promote lipid deposition, and pharmacological inhibition or knockdown of PANX1 decreased the levels of PPAR α and PANK1 induced by ADR. Taken together, our findings revealed that TGM2-PANX1 interaction in promoting lipid deposition may be a new signaling in promoting ADR-induced nephropathy. And a novel natural peptide could ameliorate renal fibrosis through TGM2-PANX1-PPAR α/PANK1 pathway, which highlight the potential of it in the treatment of CKD.

Examining the Role of GLU/GABA to GLN Metabolic Cycle in the Pathogenesis of Post-Stroke Depressive Disorder and Insomnia.

Objective: This study aims to elucidate the potential links between the GLU/GABA to GLN metabolic cycle disruptions and the onset of depressive and insomnia disorders following a stroke. We particularly focus on understanding if these disorders share a common underlying pathogenic mechanism. Methods: We examined 63 patients with post-stroke insomnia, 62 patients with post-stroke depression, and 18 healthy individuals. The study involved assessing insomnia using the Acute Insomnia Scale (AIS) and depression using the Hamilton Depression Rating Scale. We measured serum concentrations of GLN, GLU, and GABA and analyzed their correlations with AIS and HAMD scores. Results: Our results indicate no significant difference in the serum levels of GLN, GLU, and GABA between the post-stroke insomnia and depression groups. However, these levels were notably lower in both patient groups compared to the healthy control group. A negative correlation between AIS scores and GABA levels was observed in the post-stroke insomnia group, suggesting a potential link between GABAergic disturbances and insomnia. Conversely, no significant correlation was found between Hamilton Depression Rating Scale scores and the levels of GABA, GLU, or GLN in the post-stroke depression group. Conclusion: The study highlights that abnormalities in the GLU/GABA to GLN metabolic cycle, particularly the levels of GLN, GABA, and GAD, might be intricately linked to the pathogenesis of post-stroke insomnia and depression. Our findings suggest that GABAergic imbalances could be indicative of post-stroke insomnia, serving as potential biological markers for differential diagnosis in clinical settings. Further research is warranted to explore these relationships in greater depth, potentially leading to new diagnostic and therapeutic approaches for post-stroke neuropsychiatric disorders.

An investigation on the changes of serum CCK-8, substance P, and 5-HT in patients with post-stroke insomnia.

BACKGROUND: At present, the pathogenesis of post-stroke insomnia (PSI) is still inconclusive. OBJECTIVE: To explore the changes and significance of serum cholecystokinin-8 (CCK-8), substance P (SP), and 5-hydroxytryptamine (5-HT) in patients with PSI. METHODS: Ninety-one patients with stroke were selected as the research subjects, and according to the score of the Athens Insomnia Scale (AIS), they were divided into the insomnia group and the non-insomnia group. The serum levels of CCK-8, SP, and 5-HT in the two groups were compared to explore their relationships with PSI. RESULTS: Among the 91 patients, 56 were in the insomnia group and 35 were in the non-insomnia group, and the incidence of insomnia was 61.5%. There was no significant difference in the serum levels of CCK-8, SP, and 5-HT between the two groups (P= 0.696, 0.980, and 0.809, respectively). One-way analysis of variance showed that there was no significant correlation between the serum levels of CCK-8, SP, 5-HT, and the AIS score (P= 0.7393, 0.9581, and 0.5952, respectively). CONCLUSION: The incidence of PSI was relatively high, but it could not be proved that CCK-8, SP, and 5-HT were involved in the pathogenesis of PSI. There might exist other neurotransmitters involved in the pathophysiological process of PSI, which should be further explored.

Deficiency of IKKα in Macrophages Mitigates Fibrosis Progression in the Kidney after Renal Ischemia-Reperfusion Injury.

Aims. Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), and macrophages play a key role in this process. The aim of this study was to discover the role of IκB kinase α (IKKα) in macrophages in the process of AKI-to-CKD transition. Main Methods. We crossed lyz2-Cre mice with IKKα-floxed mice to generate mice with IKKα ablation in macrophages (Mac IKKα-/-). A mouse renal ischemia/reperfusion injury (IRI) model was induced by clamping the renal artery for 45 minutes. Treated mice were evaluated for blood biochemistry, tissue histopathology, and fibrosis markers. Macrophages were isolated from the peritoneal cavity for coculturing with tubular epithelial cells (TECs) and flow cytometry analysis. Key Findings. We found that fibrosis and kidney function loss after IRI were significantly alleviated in Mac IKKα-/- mice compared with wild-type (WT) mice. The expression of fibrosis markers and the infiltration of M2 macrophages were decreased in the kidneys of Mac IKKα-/- mice after IRI. The in vitro experiment showed that the IRI TECs cocultured with IKKα-/- macrophages (KO MΦs) downregulated the fibrosis markers accompanied by a downregulation of Wnt/ß-catenin signaling. Significance. These data support the hypothesis that IKKα is involved in mediating macrophage polarization and increasing the expression of fibrosis-promoting inflammatory factors in macrophages. Therefore, knockdown of IKKα in macrophages may be a potential method that can be used to alleviate the AKI-to-CKD transition after IRI.

Multimodal therapy and twenty years of valid management of a patient with chronic hepatitis B in a less developed Western Region in China---case report and review of the literature.

BACKGROUND: For patients with chronic hepatitis B and cirrhosis in less developed western regions in China, due to constraints of local economic conditions, the choice of treatment measures is often limited. However if patients recieved valid management and effective treatment, they were able to maintain their health and benign prognosis. CASE PRESENTATION: This study narrates the long-term treatment and careful follow-up of a patient with chronic hepatitis B and cirrhosis in a less developed western region in China, and analyzes the prognosis of the disease and countermeasures. CONCLUSIONS: This would partly reflect the development of antiviral therapy for chronic hepatitis B and multidisciplinary comprehensive treatment for cirrhosis-related complications in remote region with limited resources in the past 20 years.

Klotho gene-modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/ß-catenin pathway in kidneys after acute injury.

Klotho is a protein primarily expressed in renal tubular epithelial cells. Studies have suggested that Klotho is an antiaging protein that reduces renal fibrosis after acute kidney injury (AKI) and inhibits stem cell senescence. Bone marrow mesenchymal stem cells (BMSCs) have consistent proliferation ability and multidirectional differentiation ability and have been used to treat tissue injury. Thus, we hypothesized that Klotho expressed in BMSCs could increase the renal protective effects of BMSCs. To verify the hypothesis, we isolated BMSCs from C57BL/6 mice, transfected them with Klotho-GFP-adenovirus and investigated the change in BMSC proliferation. We then transplanted Klotho-GFP-BMSCs into mice with AKI and investigated the therapeutic effect compared with that of sham-treated mice and GFP-BMSC-transplanted mice. Kidney fibrosis after ischemia/reperfusion injury (IRI) was relieved by BMSC transplantation, and the antifibrotic effect of BMSCs was significantly enhanced by overexpressing the Klotho gene. Mechanistic studies showed that Klotho increased pluripotency gene expression in BMSCs. Klotho produced by Klotho-GFP-BMSCs inhibited the Wnt/ß-catenin pathway in renal tubular epithelial cells (TECs). Klotho-GFP-BMSCs showed increased proliferative ability and more potent immuno-regulation ability than did GFP-BMSCs. Our findings suggested that Klotho gene-modified BMSCs may be a better choice for cell therapy after AKI.

Bioinformatics Analysis of Genes and Pathways of CD11b+/Ly6Cintermediate Macrophages after Renal Ischemia-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), which could induce the poor prognosis. The purpose of this study was to characterize the molecular mechanism of the functional changes of CDllb+/Ly6Cintermediate macrophages after renal IRI. The gene expression profiles of CDllb+/Ly6Cintermcdiate macrophages of the sham surgery mice, and the mice 4 h, 24 h and 9 days after renal IRI were downloaded from the Gene Expression Omnibus database. Analysis of mRNA expression profiles was conducted to identify differentially expressed genes (DEGs), biological processes and pathways by the series test of cluster. Protein-protein interaction network was constructed and analysed to discover the key genes. A total of 6738 DEGs were identified and assigned to 20 model profiles. DEGs in profile 13 were one of the predominant expression profiles, which are involved in immune cell chemotaxis and proliferation. Signet analysis showed that Atp5al, Atp5o, Cox4i, Cdc42, Rac2 and Nhp2 were the key genes involved in oxidation-reduction, apoptosis, migration, M1-M2 differentiation, and proliferation of macrophages. RPS18 may be an appreciate reference gene as it was stable in macrophages. The identified DEGs and their enriched pathways investigate factors that may participate in the functional changes of CD 1lb+Ly6Cintermediate macrophages after renal IRI. Moreover, the vital gene Nhp2 may involve the polarization of macrophages, which may be a new target to affect the process of AKI.

Community-acquired versus hospital-acquired acute kidney injury in patients with acute exacerbation of COPD requiring hospitalization in China.

Purpose: Previous studies have described the incidence, risk factors, and outcomes for patients with acute exacerbations of COPD (AECOPD) developing acute kidney injury (AKI). However, little is known about the differences between community-acquired AKI (CA-AKI) and hospital-acquired AKI (HA-AKI) in patients with AECOPD. Thus, in this study, we compared prevalence, risk factors, and outcomes for these patients with CA-AKI and HA-AKI. Patients and methods: This study was conducted from January 2014 to January 2017, and data from adult inpatients with AECOPD were analyzed retrospectively. A total of 1,768 patients were included, 280 patients were identified with CA-AKI and 97 patients were with HA-AKI. Results: Prevalence of CA-AKI was 15.8% and that of HA-AKI was 5.5%, giving an overall AKI prevalence of 21.3%. Patients with CA-AKI had a higher prevalence of chronic kidney disease (CKD) and lower prevalence of chronic cor pulmonale than patients with HA-AKI. Risk factors for developing HA-AKI and CA-AKI were similar, such as being elderly, requirement for mechanical ventilation, and a history of coronary artery disease and CKD. Patients with HA-AKI were more likely to have stage 3 AKI and worse short-term outcomes. In comparison with patients with CA-AKI, those with HA-AKI were more likely to require non-invasive mechanical ventilation (31.3% versus 16.8%; P = 0.003) and had a longer duration of mechanical ventilation (11 days versus 8 days; P = 0.020), longer hospitalization (14 days versus 12 days; P = 0.038), and higher inpatient mortality (32.0% versus 13.2%; P < 0.001). Patients with HA-AKI had worse (multivariate-adjusted) inpatient survival than those with CA-AKI (hazard ratio, 1.7 [95% confidence interval, 1.03-2.81; P = 0.038] for the HA-AKI group). Conclusion: AKI was common in patients with AECOPD requiring hospitalization. CA-AKI was more common than HA-AKI but otherwise demonstrated similar demographics and risk factors. Nevertheless, patients with HA-AKI had worse short-term outcomes.

Taurine enhances the protective effect of Dexmedetomidine on sepsis-induced acute lung injury via balancing the immunological system.

Sepsis, an overwhelming systemic inflammatory disease, is the leading cause of acute lung injury (ALI). Despite plenty of researches have been done, effective drugs treating septic ALI are still eagerly needed in the clinic. Dexmedetomidine (Dex), a potent alpha-2 adrenoreceptor agonist, has been reported to possess antioxidant, anti-apoptosis and anti-inflammatory abilities. Taurine, a kind of intracellular free amino acid, has been used to treat various diseases. This study aimed to explore the combination effect of Dex and Taurine on septic ALI and the underlying mechanism in vivo. The establishment of septic ALI was set up in SD rats by cecal ligation and puncture (CLP) operation. Results indicated that Dex or Taurine could reduce septic ALI-induced cell apoptosis via decreasing caspase-3 activity. However, the combination of Dex or Taurine produced greater effect. Besides that, Dex combined with Taurine could better promote cell proliferation with remarkably elevated Ki67 expression. The combination of Dex and Taurine significantly suppressed the activation of NF-κB pathway via inhibiting P65 phosphorylation and P65 nuclear translocation, leading to the down-regulation of interleukin (IL)-6 and IL-1ß. Moreover, co-administration of Dex and Taurine alleviated the imbalance of Th1/Th2 induced by septic ALI to a great extent. All in all, our study suggested the synergistic therapeutic effect of Dex and Taurine on septic ALI.

[Compositional Characteristics of Sediment Dissolved Organic Nitrogen in Typical Lakes and Its Relationship on Water Trophic Status].

UV-Vis absorbance, fluorescence, and Gas Chromatography Mass Spectrometry (GC-MS) were applied to the comparative study on sediment dissolved organic nitrogen (DON) in five typical lakes (Erhai lake, Dianchilake, Poyang lake, Wuhan Dong lake, and Taihu lake) in different lake regions with different nutrition status, revealing the relationship between structural and compositional characteristics of sediment DON and trophic level of lakes. The obtained results showed that: ①Structure of lake sediment DON in Yungui Plateau region is more stable, compared with those in Eastern Plain region, indicating its lower bioavailability. ②In Yungui Plateau region, the source and compositional characteristics of sediment DON weremore complex in Dianchi lake (a seriously polluted lake), and its sediment DON bioavailabilitywas relatively higher. While, with respect to the less polluted Erhai lake, the source of sediment DON is more simple with a higher stability in DON structure and composition, which is beneficial for maintaining its good water quality. ③In Eastern Plain region, nutrition status of Taihu lake was similer to Donghu lake. The structure and composition of sediment DON was complex. But the lower aromaticityand fewer Aromatic ring substituents abundance made their relatively weak nutrient retention ability, posing risk to water quality. With regard to Poyang Lake, the structure and composition of sediment DON was relatively simple, but nutrient retention ability was relatively strong, which played a positive role in maintaining good water quality. ④P(Ⅲ+Ⅴ, n)/P(Ⅰ+Ⅱ, n) values(the content ratio of humic-like substanceto protein-like substances)were in sequence of Dianchi Lake (33.14)>Erhai Lake(21.49)>Taihu Lake(9.06)>Donghu Lake(7.04)>Poyang Lake(4.83), while E(4)/E(6) values (the ratio of UV-Vis absorbance at 465 and 665 nm) were in sequence of Dianchi Lake (27.00)>Donghu Lake(6.65)>Poyang Lake(5.47)>Taihu(3.50)>Erhai Lake(2.31). In addition, P(Ⅲ+Ⅴ, n)/P(Ⅰ+Ⅱ, n) and E(4)/E(6) valueswere positively correlated with thecontents of the different nitrogen (N) forms in the sediments. The above information suggested that P(Ⅲ+Ⅴ, n)/P(Ⅰ+Ⅱ, n) and E(4)/E(6) values exhibited good discrimination degree among different trophic status lakes, and they were considered to indirectly indicate the nutrition levels of lakes to a certain extent.

IKKα is involved in kidney recovery and regeneration of acute ischemia/reperfusion injury in mice through IL10-producing regulatory T cells.

The recovery phase after kidney ischemia/reperfusion (IR) injury is often associated with the suppression of inflammation and the proliferation of tubular epithelial cells (TECs). The duration of this phase is often determined by the suppression of inflammation and the proliferation of TECs. Several lines of evidence suggest that IκB kinase α (IKKα) not only promotes the production of anti-inflammatory factors and/or prevents the production of inflammatory factors, but also induces the accompanying cell differentiation and regeneration, and suppresses inflammation. We therefore hypothesized that IKKα could participate in the kidney repair after IR injury and have used a mouse model of acute kidney injury (AKI) to test this. We found that IKKα mediated the repair of the kidney via infiltrated regulatory T (Treg) cells, which can produce anti-inflammatory cytokine IL10, and that IKKα also increased the proliferation of the surviving TECs and suppressed of inflammation. In addition, the expression of indoleamine 2,3-dioxygenase (IDO) in TECs is consistent with the infiltration of IL10-producing Treg cells. We conclude that IKKα is involved in kidney recovery and regeneration through the Treg cells that can produce IL10, which might be a potential therapeutic target that can be used to promote kidney repair after IR injury.

IL-10 deficiency increases renal ischemia-reperfusion injury.

BACKGROUND: Renal ischemia-reperfusion (IR) injury is a frequent cause of acute kidney injury, which results in high morbidity and mortality. Inflammation is an important factor that is involved in kidney repair after renal IR injury. IL-10 is a potent anti-inflammatory cytokine that inhibits inflammatory pathways, but the role of IL-10 in repairing renal IR injury is not known. Here, we investigated the role of IL-10 in kidney repair after renal IR injury. METHODS: We used an IL-10(-/-) mouse model and examined the serologic and histomorphology of kidney after IR injury. We also measured ki67, TNF-α, IL-6, and macrophages with immunohistochemistry or Western blotting. RESULTS: There was a greater increase in serum creatinine in IL-10(-/-) mice than in wild-type (WT) mice. And compared with WT mice, IL-10(-/-) mice had increased histologic renal injury and decreased proliferation. Moreover, the expression of TNF-α, IL-6 and macrophages was clearly increased in IL-10(-/-) mice compared with the WT mice. CONCLUSION: These data reveal an important role for IL-10 in the improvement of renal IR injury, acting through suppression of inflammatory mediators, and that IL-10 would be a crucial target for the treatment of IR injury.

Ischemic preconditioning attenuates brain injury induced by ischemia/reperfusion during moderate hypothermia low-flow procedures.

OBJECTIVE: We determined the effects of ischemic preconditioning (IP) on apoptosis in a rat model of brain injury induced by cerebral ischemia/reperfusion following a moderate hypothermic low-flow (MHLF) procedure. METHODS: A total of 180 rats were randomly divided into three groups. The surgery group was subjected to body temperature reduction and bilateral common carotid artery occlusion for 120 min at 25 ± 0.5°C, followed by artery reopening and rewarming. The sham-surgery group underwent the same procedure, but common carotid arteries were not occluded. The ischemic preconditioning-treated surgery group was pretreated with four cycles of 2 min occlusion of bilateral common carotid arteries and 5 min reperfusion, before 120 min of cerebral ischemia. Regional cerebral blood flow was measured continuously in 10 rats per group using laser Doppler flowmetry. We investigated brain cell apoptosis levels and mitochondrial apoptosis signaling pathway components at various time points following reperfusion. RESULTS: The ischemic preconditioning-treated surgery group displayed decreases in apoptotic cell numbers and apoptotic protein expression levels after the procedure at 6 h, 24 h, 72 h, and 7 d. Ischemic preconditioning inhibited cytochrome c release, caspase-3 activation, and mitochondrial apoptosis signaling pathway activation. CONCLUSION: The protective effects of ischemic preconditioning were associated with a reduction of DNA fragmentation, and inhibition of mitochondrial cytochrome c release and caspase-3 activation, which alleviated cerebral ischemia/reperfusion injury after moderate hypothermic low flow in rats. These findings highlight the potential of ischemic preconditioning as a neuroprotective therapy for surgery involving MHLF.

Berberine ameliorates chronic kidney injury caused by atherosclerotic renovascular disease through the suppression of NFκB signaling pathway in rats.

BACKGROUND AND OBJECTIVES: Impaired renal function in atherosclerotic renovascular disease (ARD) may be the result of crosstalk between atherosclerotic renovascular stenosis and amplified oxidative stress, inflammation and fibrosis. Berberine (BBR) regulates cholesterol metabolism and exerts antioxidant effects. Accordingly, we hypothesized that BBR treatment may ameliorate ARD-induced kidney injury through its cholesterol-lowering effect and also suppression of the pathways involved in oxidative stress, inflammation and NFκB activation. METHODS: Male rats were subjected to unilateral renal artery stenosis with silver-irritant coil, and then fed with 12-week hypercholesterolemic diet. Rats with renal artery stenosis were randomly assigned to two groups (n = 6 each) - ARD, or ARD+BBR - according to diet alone or in combination with BBR. Similarly, age-matched rats underwent sham operation and were also fed with hypercholesterolemic diet alone or in combination with BBR as two corresponding controls. Single-kidney hemodynamic metrics were measured in vivo with Doppler ultrasound to determine renal artery flow. The metrics reflecting hyperlipidemia, oxidative stress, renal structure and function, inflammation and NFκB activation were measured, respectively. RESULTS: Compared with control rats, ARD rats had a significant increase in urinary albumin, plasma cholesterol, LDL and thiobarbituric acid reactive substances (TBARS) and a significant decrease in SOD activity. When exposed to 12-week BBR, ARD rats had significantly lower levels in blood pressure, LDL, urinary albumin, and TBARS. In addition, there were significantly lower expression levels of iNOS and TGF-ß in the ARD+BBR group than in the ARD group, with attenuated NFκB-DNA binding activity and down-regulated protein levels of subunits p65 and p50 as well as IKKß. CONCLUSIONS: We conclude that BBR can improve hypercholesterolemia and redox status in the kidney, eventually ameliorating chronic renal injury in rats with ARD, and that BBR can act against proinflammatory and profibrotic responses through suppression of the NFκB signaling pathway.

Qualified kidney biomarkers and their potential significance in drug safety evaluation and prediction.

The kidney is one of the major organs drug toxicity may target. Some renal safety biomarkers have been proposed to measure kidney injury and function accordingly. Despite the widespread use for diagnosis and monitoring of renal injury and function for decades, serum creatinine and blood urea nitrogen are nonspecific biomarkers with insensitive and delayed response in the clinical setting. There is an urgent need to identify and qualify novel kidney safety biomarkers that would be used to detect and predict drug-induced nephrotoxicity in preclinical toxicological studies, clinical trials and patient care in sequence. To do that, eight novel renal safety biomarkers have been well characterized and qualified for preclinical drug safety screening, and their clinical bridging validation is underway as well. Of them, some are used to detect or predict proximal tubular injury, and others are used to diagnose and monitor glomerular damage. Thus, measurement of a panel of kidney safety biomarkers in parallel would help maximally capture all potential safety signals for a more informative decision to be made in drug research and development as well as for optimal selection of the drug and its dose in clinical practice.

Bidirectional regulation of neurogenesis by neuronal nitric oxide synthase derived from neurons and neural stem cells.

It has been demonstrated that neuronal nitric oxide synthase (nNOS) negatively regulates adult neurogenesis. However, the cellular and molecular mechanisms underlying are poorly understood. Here, we show that nNOS from neural stem cells (NSCs) and from neurons play opposite role in regulating neurogenesis. The NSCs treated with nNOS inhibitor N(5)-(1-imino-3-butenyl)-L- ornithine (L-VNIO) or nNOS gene deletion exhibited significantly decreased proliferation and neuronal differentiation, indicating that NSCs-derived nNOS is essential for neurogenesis. The NSCs cocultured with neurons displayed a significantly decreased proliferation, and deleting nNOS gene in neurons or scavenging extracellular nitric oxide (NO) abolished the effects of coculture, suggesting that neurons-derived nNOS, a source of exogenous NO for NSCs, exerts a negative control on neurogenesis. Indeed, the NSCs exposed to NO donor DETA/NONOate displayed decreased proliferation and neuronal differentiation. The bidirectional regulation of neurogenesis by NSCs- and neurons-derived nNOS is probably related to their distinct subcellular localizations, mainly in nuclei for NSCs and in cytoplasm for neurons. Both L-VNIO and DETA/NONOate inhibited telomerase activity and proliferation in wild-type (WT) but not in nNOS(-/-) NSCs, suggesting a nNOS-telomerase signaling in neurogenesis. The NSCs exposed to DETA/NONOate exhibited reduced cAMP response element binding protein (CREB) phosphorylation, nNOS expression, and proliferation. The effects of DETA/NONOate were reversed by forskolin, an activator of CREB signaling. Moreover, disrupting CREB phosphorylation by H-89 or LV-CREB133-GFP simulated the effects of DETA/NONOate, and inhibited telomerase activity. Thus, we conclude that NSCs-derived nNOS stimulates neurogenesis via activating telomerase, whereas neurons-derived nNOS represses neurogenesis by supplying exogenous NO that hinders CREB activation, in turn, reduces nNOS expression in NSCs.

Biphenyl-3,3',4,4'-tetra-carboxylic acid dihydrate.

The asymmetric unit of the title compound, C(16)H(10)O(8)·2H(2)O, contains one-half of the centrosymmetric organic mol-ecule and one water mol-ecule. The dihedral angles between the carboxyl-ate groups and the adjacent phenyl ring are 71.31 (3) and 16.67 (3)°, while the carboxyl-ate groups are oriented at a dihedral angle of 72.01 (3)°. In the crystal structure, inter-molecular O-H⋯O and bifurcated O-H⋯(O,O) hydrogen bonds link the mol-ecules to form a three-dimensional supra-molecular network.

[Association between urinary neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery].

OBJECTIVE: To test the hypothesis that Neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for acute kidney injury (AKI) in patients after cardiac surgery. METHODS: 33 cases undergoing cardiac surgery were divided into AKI group and Non-AKI group according to the AKI criteria. The concentration of urine NGAL at different time points were measured. RESULTS: (1) Nine of 33 cases (27%) developed postoperative AKI, but diagnosis with serum creatinine was only 12-48 hours after cardiac surgery. (2)Urinary concentrations of NGAL at 2 h after cardiac surgery in patients who did not developed AKI were significantly higher compared with those of preoperative (P < 0.001). Urinary concentrations of NGAL at 2 h and 4 h after cardiac surgery in patients who developed AKI were significantly higher compared with those of preoperative (P < 0.001). (3) The mean urinary NGAL concentrations in patients who developed AKI were significantly higher after surgery compared with patients who did not develop AKI (P < 0.01). (4) Urinary concentrations of NGAL/Ucr at 2 h and 4 h after cardiac surgery in patients who did not developed AKI were significantly higher compared with those of preoperative (P < 0.05). Urinary concentrations of NGAL/Ucr at 2 h and 4 h after cardiac surgery in patients who developed AKI were significantly higher compared with those of preoperative (P < 0.01). (The mean urinary concentrations of NGAL/Ucr in patients who developed AKI were significantly higher after surgery compared with patients who did not develop AKI (P < 0.01). (6) For concentrations in urine of NGAL at 2 h after surgery, sensitivity was 0.7125, and specificity was 0.7307 for a cutoff value of 250 microg/L. For concentrations in urine of NGAL/Ucr at 2 h after surgery, sensitivity was 0.8127, and specificity was 0.7839 for a cutoff value of 250 microg/mmol. (7) Urinary concentrations of NGAL at 2 h after cardiac surgery was significantly associated with serum creatinine 12 h postoperative (R = 0.638, P < 0.05). CONCLUSIONS: The incidence of AKI in patients after cardiac surgery is high, which accounted for 27%. The amount of NGAL and NGAL/Ucr in urine at 2 h after cardiac surgery were the powerful independent predictor of acute renal injury and urine concentrations of NGAL/Ucr is more sensitive.

[Influence of nuclear factor-kappaB decoy transfection on nuclear factor-kappaB activity and vascular endothelial growth factor/urokinase-type plasminogen activator/intercellular cell adhesion molecule-1 level of SKOV3 cells].

OBJECTIVE: To investigate the effect of nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotides (ODN) on NF-kappaB activation and expressions of vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), intercellular cell adhesion molecule-1 (ICAM-1) of SKOV3 cell. METHODS: After transfected with NF-kappaB decoy ODN, SKOV3 cells were stimulated by IL-1beta and cultured for 6, 12, 24, and 48 h, respectively. NF-kappaB DNA binding activity was measured by gel mobility shift assay and mRNA levels of ICAM-1, uPA, VEGF were analyzed by RT-PCR and VEGF level in supernatant was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: (1) SKOV3 cells expressed constitutive NF-kappaB DNA binding activity and stimulation of IL-1beta resulted in a significant increase of the binding activity. NF-kappaB decoy ODN transfection significantly decreased constitutive level and elevated level of NF-kappaB DNA binding activity by IL-1beta at 6, 12, 24, and 48 h in vitro (P < 0.05). (2) The constitutive and activated mRNA levels of uPA, VEGF, ICAM-1 and VEGF levels in the supernatant were significantly inhibited by NF-kappaB decoy ODN transfection especially at 6 h after transfection in vitro. CONCLUSIONS: Both NF-kappaB DNA binding activity and expressions of uPA, VEGF, and ICAM-1 at 48 h were upregulated by IL-1beta, and inhibited by transfection with NF-kappaB decoy ODN in SKOV3 cell line. NF-kappaB decoy ODN transfection shows promise as a novel molecular approach for ovarian cancer.

In vivo transfection of NF-kappaB decoy oligodeoxynucleotides attenuate renal ischemia/reperfusion injury in rats.

BACKGROUND: Ischemic acute renal failure (ARF) is a common and often fatal condition characterized by tubular epithelial cell necrosis and marked monocyte infiltration. Inflammatory mechanisms, including cell adhesion, cell infiltration, and cytokine production, are involved. These processes are thought to be directly or indirectly regulated by nuclear factor kappaB (NF-kappaB). Targeted of NF-kappaB might ameliorate ischemia/reperfusion (I/R) injury by inhibiting the production of genes that involved in ischemic ARF. The objective of the present study was to evaluate the effect of NF-kappaB decoy oligodeoxynucleotides (ODN) in experimental rat ischemic ARF. METHODS: Ischemic ARF was induced by left renal artery clamping for 60 minutes, while the right kidney was being removed in female Sprague-Dawley rats. The effect of cationic liposome-protamine-NF-kappaB decoy ODN was evaluated after infusion into the kidney via the renal artery before clamping. After 24 hours of reperfusion, we then assessed morphologic and functional parameters, NF-kappaB/DNA binding activity, monocyte/macrophage (M/MPhi) infiltration, and gene expression in I/R kidney. RESULTS: After 24 hours of reperfusion, compared with sham-operated animals, serum creatinine and blood urea nitrogen (BUN) levels in ischemic ARF animals were increased about 10-fold and fivefold respectively. (255.67 +/- 34.48 micromol/L vs. 25.33 +/- 2.23 micromol/L and 43.47 +/- 5.50 mmol/L vs. 8.45 +/- 0.43 mmol/L, P < 0.001), NF-kappaB/DNA binding activity was markedly elevated [median value was 1.75 vs. 0.15 relative density unit (RDU), P < 0.005]. NF-kappaB decoy ODN treatment reduced the elevation of serum creatinine level by 70% (79.17 +/- 8.64 micromol/L vs. 255.67 +/- 34.48 micromol/L, P < 0.01), BUN level by 40% (28.33 +/- 4.86 mmol/L vs. 43.47 +/- 5.50 mmol/L, P= NS), and almost abolished the NF-kappaB activation compared with levels observed in sham-operated rats (median value was 0.25 vs. 1.9 RDU, P < 0.005). Furthermore, NF-kappaB decoy ODN pretreatment prevented the occurrence of tubular necrosis and reduced the renal tubular damage scores markedly (1.85 +/- 0.06 vs. 3.63 +/- 0.06 scores, P < 0.01). In addition, M/MPhi infiltration was obviously suppressed (9.77 +/- 1.19 cells/hpf vs. 29.22 +/- 1.94 cells/hpf, P < 0.01), Moreover, results of reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry showed the up-regulation of monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) was greatly decreased, inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) expression were also reduced, approaching levels observed in sham-operated animals. The data suggest that NF-kappaB decoy ODN treatment protects renal tissue from the effects of I/R injury and thus reduces the severity of ARF. CONCLUSION: These experiments demonstrated that NF-kappaB plays a critical role in renal I/R injury by reducing a series of inflammatory genes. NF-kappaB decoy ODN treatment reduces the renal dysfunction and damage associated with ischemic ARF. Therefore, in vivo transfection of NF-kappaB decoy ODN provides a new therapeutic strategy for ischemic ARF.