Hydrocortisone, ascorbic acid, and thiamine therapy reduce sepsis-induced acute kidney injury in mice

Sepsis is a syndrome including physiological, pathological and biochemical abnormalities induced by infection. It can lead to multiple organ failure and the kidney is often an early target with severe injury. Sepsis is the most common trigger of acute kidney injury (AKI). Long term AKI often gives rise to chronic kidney injury or kidney failure eventually. AKI is also associated with extremely high mortality. Sepsis induced AKI is strongly associated with poor clinical outcomes. Sepsis induced acute kidney injury (S-AKI) is a rapid decrease in renal excretory function and with accumulation of nitrogen metabolism waste products. The decreasing renal function is due to acute tubular necrosis, which is hard to detect under histological observation. We selected kidney injury molecule 1 (KIM-1) and blood urea nitrogen (BUN) as kidney injury biomarkers to evaluate the damage in the kidney in a murine sepsis model. We also examined a combination of hydrocortisone, ascorbic acid and thiamine (HAT) as treatment for S-AKI. To accomplish this, we stratified the mice to predicted to live (p-live) and predicted to die (p-die) groups based on their heart rate six hours after septic challenge. We performed KIM-1 western blot, enzyme-linked immunosorbent assays (ELISA), hypoxyprobe staining and BUN assay to evaluate the effect and mechanism of HAT therapy on murine S-AKI. Through the experiments, we found the mean of KIM-1 levels increased around 3 times in severe S-AKI mice kidney homogenate samples and plasma samples compared to less injured mice. When we applied HAT therapy to the mice, the mean of KIM-1 level was reduced approximately 2 times compared to the vehicle-treated group. More data should be added to prove the significance. The mean of BUN level increased 2.7 times in the p-die group compared to the p-live, and the mean of BUN concentration also decreased 1.6 times in the HAT treated group than the vehicle treated group. The hypoxyprobe staining showed hypoxic injury primarily in the renal medulla area and HAT therapy significantly reduced the hypoxic injury in the p-die mice. In conclusion, HAT therapy can be a potential effective S-AKI treatment and reduce S-AKI via various mechanisms, including decreased KIM-1 and BUN concentration

Differences in Apoptosis and Cell Cycle Distribution between Human Melanoma Cell Lines UACC903 and UACC903(+6), before and after UV Irradiation

Introduction of human chromosome 6 into malignant melanoma cell line UACC903 resulted in generation of the chromosome 6-mediated suppressed cell subline UACC903(+6) that displays attenuated growth rate, anchorage-dependency, and reduced tumorigenicity. We have showed that overexpression of a chromosome 6-encoded tumor suppressor gene led to partial suppression to UACC903 cell growth. We now describe the differences in apoptosis and cell cycle between UACC903 and UACC903(+6) before and after UV irradiation. MTT assay revealed 86.92±8.24% of UACC903 cells viable, significantly (p<0.01) higher than 48.76±5.31% of UACC903(+6), at 24 hr after 254-nm UV irradiation (40 J/M2). Before UV treatment, flow cytometry analysis revealed 6.06±0.20% apoptosis in UACC903, significantly (p=0.01) lower than 6.67±0.15% in UACC903(+6). The G0/G1, S and G2/M phase cells of UACC903 were, respectively, 54.10±0.59%, 22.31±0.50% and 16.85±0.25%, all significantly (p<0.01) different from the corresponding percentages (58.82±0.35%, 20.48±0.05%, and 13.17±0.45%) of UACC903(+6). After the UV treatment, UACC903 cells in apoptosis, G0/G1, S, and G2/M became 12.59±0.17%, 38.90±0.67%, 19.74±0.70%, and 27.01±0.66%, respectively, while UACC903(+6) cells were 24.16±0.48%, 37.97±0.62%, 19.20±0.52%, and 15.69±0.14%. TUNEL assay revealed 2.31±0.62% apoptosis in UACC903, significantly (p<0.01) lower than 9.60±1.14% of UACC903(+6), and a linear and exponential increase of apoptosis, respectively, in response to the UV treatment. These results indicate that UACC903(+6) cells have a greater tendency to undergo apoptosis and are thus much more sensitive to UV irradiation. Our findings further suggest a novel mechanism for chromosome 6-mediated suppression of tumorigenesis and metastasis, i.e., through increased cell death

Time-Dependent Solution for a Star Immersed in a Background Radiation

We study a time-dependent and spherically-symmetric solution with a star-like source. We show that this solution can be interpreted as an exterior solution of a contracting star which has a decreasing temperature and is immersed in a homogenous and isotropic background radiation. Distribution of the temperature in the fields and close-to Schwarzschild approximation of the solution are studied. By identifying the radiation with the cosmic background one, we find that the close-to-Schwarzschild approximate solution is valid in a wide range in our solar system. Possible experimental tests of the solution are discussed briefly.Comment: Latex, 7 pages, no figures, to appear in J. Math. Phys.(2002

Verbal Creativity Is Correlated With the Dynamic Reconfiguration of Brain Networks in the Resting State

Creativity is the foundation of human culture. All inventions and innovations in history rely upon us to break with the traditional thinking and create something novel. A number of neuroimaging studies have explored the neural mechanism of creativity. However, a majority of researches have focused only on the stationary functional connectivity in resting-state fMRI and task-related fMRI, neglecting the dynamic variation of brain networks. Here, we used dynamic network analysis to investigate the relation between the dynamic reorganization of brain networks and verbal creativity in 370 healthy subjects. We found that the integration of the left lingual gyrus and left middle temporal gyrus (MTG) in default mode network (DMN) and the integration of the DMN and cerebellum, frontoparietal task control network (FPTC) and auditory network (Aud) showed positive correlation with verbal creativity performance. In addition, the recruitment of the bilateral postcentral gyrus from the sensory/somatomotor network (SMN) and the recruitment of the SMN in general displayed a significant correlation with verbal creativity scores. Taken together, these results suggested that the dynamic reorganization among the brain networks involved multiple cognitive processes, such as memory retrieval, imaginative process, cognitive control – these are all important for verbal creativity. These findings provided direct evidence that verbal creativity was related to the dynamic variation of brain mechanism during resting-state, extending past research on the neural mechanism of creativity. Meanwhile, these results bought about new perspectives for verbal creative training and rehabilitation training of depression

circ-NOL10 regulated by MTDH/CASC3 inhibits breast cancer progression and metastasis via multiple miRNAs and PDCD4

Circular RNAs (circRNAs) play important roles in carcinogenesis. Here, we investigated the mechanisms and clinical significance of circ-NOL10, a highly repressed circRNA in breast cancer. Subsequently, we also identified RNA-binding proteins (RBPs) that regulate circ-NOL10. Bioinformatics analysis was utilized to predict regulatory RBPs as well as circ-NOL10 downstream microRNAs (miRNAs) and mRNA targets. RNA immunoprecipitation, luciferase assay, fluorescence in situ hybridization, cell proliferation, wound healing, Matrigel invasion, cell apoptosis assays, and a xenograft model were used to investigate the function and mechanisms of circ-NOL10 in vitro and in vivo. The clinical value of circ-NOL10 was evaluated in a large cohort of breast cancer by quantitative real-time PCR. Circ-NOL10 is downregulated in breast cancer and associated with aggressive characteristics and shorter survival time. Upregulation of circ-NOL10 promotes apoptosis, decreases proliferation, and inhibits invasion and migration. Furthermore, circ-NOL10 binds multiple miRNAs to alleviate carcinogenesis by regulating PDCD4. CASC3 and metadherin (MTDH) can bind directly to circ-NOL10 with characterized motifs. Accordingly, ectopic expression or depletion of CASC3 or MTDH leads to circ-NOL10 expression changes, suggesting that these two RBPs modulate circ-NOL10 in cancer cells. circ-NOL10 is a novel biomarker for diagnosis and prognosis in breast cancer. These results highlight the importance of therapeutic targeting of the RBP-noncoding RNA (ncRNA) regulation network

Regulatory Mechanisms of the Wnt/β-Catenin Pathway in Diabetic Cutaneous Ulcers

Skin ulcers are a serious complication of diabetes. Diabetic patients suffer from vascular lesions and complications such as peripheral neuritis, peripheral vascular lesions, and collagen abnormalities, which result in skin wounds that are refractory and often develop into chronic ulcers. The healing of skin ulcers requires an inflammatory reaction, wound proliferation, remodeling regulation, and control of stem cells. Studies investigating diabetic cutaneous ulcers have focused on cellular and molecular levels. Diabetes can cause nerve and blood vessel damage, and persistent high blood sugar levels can cause systemic multisite nerve damage based on peripheral neuropathy. The long-term hyperglycemia state enables the polyol glucose metabolism pathway to be activated, increasing the accumulation of toxic substances in the vascular injured nerve tissue cells. Sustained hyperglycemia leads to dysfunction of epithelial cells, leading to a decrease in pro-angiogenic signaling and nitric oxide production. In addition, due to impaired leukocyte function in hyperglycemia, immune function is impaired and the immune response at relevant sites is insufficient, making diabetic foot more difficult to heal. The Wnt/β-catenin pathway is a highly conserved signal transduction pathway involved in a variety of biological processes, such as cell proliferation, apoptosis, and differentiation. It is considered an important pathway involved in the healing of skin wounds. This article summarizes the mechanism of action of the Wnt/β-catenin pathway involved in the inflammatory responses to diabetic ulcers, wound proliferation, wound remodeling, and stem cells. The interactions between the Wnt signal pathway and other metabolic pathways are also discussed

The effect of Bafa Wubu of Tai Chi on college students’ anxiety and depression: A randomized, controlled pilot study

Objective: This pilot study aimed to explore the mechanism of the effects of Bafa Wubu of Tai Chi (BWTC) on anxiety and depression in college students using resting-state functional magnetic resonance imaging (RS-fMRI).Methods: Eighteen college students (5 males and 13 females) with anxiety and depression met the study criteria and were randomly divided into an experimental group (aged 24.20 ± 4.07 years) and a control group (aged 22.50 ± 5.95). The experimental group received an eight-week BWTC intervention five times/week for 60 min/session. The control group maintained normal daily life without any exercise intervention. These students were assessed using RS-fMRI scans, the self-rating anxiety scale (SAS), and the self-rating depression scale (SDS). Spearman correlation analysis was used, and statistical significance was defined as a two-sided p-value of &lt;0.05.Results: After the intervention, the SAS and SDS scores of the BWTC group significantly reduced (p = 0.002; p = 0.001). Compared with the control group, the fALFF values of the right middle frontal gyrus, orbital part (Frontal_Mid_Orb_R) (p = 0.043), right inferior occipital gyrus (Occipital_Inf_R) (p = 0.003), and right middle temporal gyrus of the temporal pole (Temporal_Pole_Mid_R) (p = 0.003) in the BWTC group increased significantly; the fALFF values of the left middle frontal gyrus (Frontal_Mid_L) (p = 0.001) and right supplementary motor area (Supp_Motor_Area_R) (p = 0.010) in BWTC group decreased significantly. The fALFF values of Frontal_Mid_Orb_R were significantly positively correlated with the SDS score (r = 0.852, p = 0.015) and the fALFF values of Frontal_Mid_L were significantly negatively correlated with the SAS score (r = −0.797, p = 0.032).Conclusion: In this pilot study with college students, BWTC alleviated anxiety and depression, potentially through modulating activity in the Frontal_Mid_L and Frontal_Mid_Orb_R, respectively

Insulin and IGF1 enhance IL-17-induced chemokine expression through a GSK3B-dependent mechanism: a new target for melatonin\u27s anti-inflammatory action.

Obesity is a chronic inflammation with increased serum levels of insulin, insulin-like growth factor 1 (IGF1), and interleukin-17 (IL-17). The objective of this study was to test a hypothesis that insulin and IGF1 enhance IL-17-induced expression of inflammatory chemokines/cytokines through a glycogen synthase kinase 3β (GSK3B)-dependent mechanism, which can be inhibited by melatonin. We found that insulin/IGF1 and lithium chloride enhanced IL-17-induced expression of C-X-C motif ligand 1 (Cxcl1) and C-C motif ligand 20 (Ccl20) in the Gsk3b(+/+) , but not in Gsk3b(-/-) mouse embryonic fibroblast (MEF) cells. IL-17 induced higher levels of Cxcl1 and Ccl20 in the Gsk3b(-/-) MEF cells, compared with the Gsk3b(+/+) MEF cells. Insulin and IGF1 activated Akt to phosphorylate GSK3B at serine 9, thus inhibiting GSK3B activity. Melatonin inhibited Akt activation, thus decreasing P-GSK3B at serine 9 (i.e., increasing GSK3B activity) and subsequently inhibiting expression of Cxcl1 and Ccl20 that was induced either by IL-17 alone or by a combination of insulin and IL-17. Melatonin\u27s inhibitory effects were only observed in the Gsk3b(+/+) , but in not Gsk3b(-/-) MEF cells. Melatonin also inhibited expression of Cxcl1, Ccl20, and Il-6 that was induced by a combination of insulin and IL-17 in the mouse prostatic tissues. Further, nighttime human blood, which contained high physiologic levels of melatonin, decreased expression of Cxcl1, Ccl20, and Il-6 in the PC3 human prostate cancer xenograft tumors. Our data support our hypothesis and suggest that melatonin may be used to dampen IL-17-mediated inflammation that is enhanced by the increased levels of insulin and IGF1 in obesity