Salvianolic Acid B Prevents Arsenic Trioxide-Induced Cardiotoxicity In Vivo and Enhances Its Anticancer Activity In Vitro

Clinical attempts to reduce the cardiotoxicity of arsenic trioxide (ATO) without compromising its anticancer activities remain to be an unresolved issue. In this study, we determined whether Sal B can protect against ATO-induced cardiac toxicity in vivo and increase the toxicity of ATO toward cancer cells. Combination treatment of Sal B and ATO was investigated using BALB/c mice and human hepatoma (HepG2) cells and human cervical cancer (HeLa) cells. The results showed that the combination treatment significantly improved the ATO-induced loss of cardiac function, attenuated damage of cardiomyocytic structure, and suppressed the ATO-induced release of cardiac enzymes into serum in BALB/c mouse models. The expression levels of Bcl-2 and p-Akt in the mice treated with ATO alone were reduced, whereas those in the mice given the combination treatment were similar to those in the control mice. Moreover, the combination treatment significantly enhanced the ATO-induced cytotoxicity and apoptosis of HepG2 cells and HeLa cells. Increases in apoptotic marker cleaved poly (ADP-ribose) polymerase and decreases in procaspase-3 expressions were observed through western blot. Taken together, these observations indicate that the combination treatment of Sal B and ATO is potentially applicable for treating cancer with reduced cardiotoxic side effects

Plumbagin inhibits fungal growth, HMGB1/LOX-1 pathway and inflammatory factors in A. fumigatus keratitis

To investigate the anti-inflammatory and antifungal effects of plumbagin (PL) in Aspergillus fumigatus (A. fumigatus) keratitis, the minimum inhibitory concentration (MIC), time-killing curve, spore adhesion, crystal violet staining, calcium fluoride white staining, and Propidium Iodide (PI) staining were employed to assess the antifungal activity of PL in vitro against A. fumigatus. The cytotoxicity of PL was assessed using the Cell Counting Kit-8 (CCK8). The impact of PL on the expression of HMGB1, LOX-1, TNF-α, IL-1β, IL-6, IL-10 and ROS in A. fumigatus keratitis was investigated using RT-PCR, ELISA, Western blot, and Reactive oxygen species (ROS) assay. The therapeutic efficacy of PL against A. fumigatus keratitis was assessed through clinical scoring, plate counting, Immunofluorescence and Hematoxylin-Eosin (HE) staining. Finally, we found that PL inhibited the growth, spore adhesion, and biofilm formation of A. fumigatus and disrupted the integrity of its cell membrane and cell wall. PL decreased IL-6, TNF-α, and IL-1β levels while increasing IL-10 expression in fungi-infected mice corneas and peritoneal macrophages. Additionally, PL significantly attenuated the HMGB1/LOX-1 pathway while reversing the promoting effect of Boxb (an HMGB1 agonist) on HMGB1/LOX-1. Moreover, PL decreased the level of ROS. In vivo, clinical scores, neutrophil recruitment, and fungal burden were all significantly reduced in infected corneas treated with PL. In summary, the inflammatory process can be inhibited by PL through the regulation of the HMGB-1/LOX-1 pathway. Simultaneously, PL can exert antifungal effects by limiting fungal spore adhesion and biofilm formation, as well as causing destruction of cell membranes and walls

Morphologic changes within the cerebellar cortex in the unilateral 6-hydroxydopamine lesioned rat model for Parkinson disease

Parkinson’s disease (PD) is a common neurodegenerative disorder caused by the progressive loss of dopaminergic neurons in the substantia nigra. Most investigations have focused on the cerebral regions such as the basal ganglia, thalamus, or the substantia nigra, but whether there is pathologic impairment within the cerebellum has rarely been assessed. Synapsin and neurofilament as the inner markers of neurons and synapses reflect the functional state by their distribution or expression. Significant morphologic changes at the cellular level have been demonstrated directly or indirectly in multiple neurodegenerative diseases. The purpose of this study was to determine whether the behavioral abnormalities that accompany PD are associated with the cerebellum using an in vivo 6- hydroxydopamine lesioned rat model. Forty-two rats were divided into three groups, the Parkinsonian group (N=22), sham group (N=10) and control group (N=10). The dopaminergic lesion was determined by immunohistochemical analysis for tyrosine hydroxylaseimmunopositive cells. Immunohistochemical studies showed that the density of synapsin I in the granular layer of the cerebellum on both sides of the Parkinsonian -model was not statistically significantly different compared to the control and sham groups. However, expression of neurofilament H in the cortex within bilateral paramedian lobule (PML) and Crus 2 of the ansiform lobule (C2AL) in cerebellum posterior lobe of Parkinsonian rats was decreased compared with controls (P<0.05), especially in the loss of Purkinje cells and the presence of morphologic abnormalities in the cell nucleus. The study suggested that loss of neurons and synapses may take place in the cerebellar cortex of Parkinson’s disease, and might play an important role in the pathologic mechanism of PD

Propofol Attenuates Hypoxia-Induced Inflammation in BV2 Microglia by Inhibiting Oxidative Stress and NF-κB/Hif-1α Signaling

Hypoxia-induced neuroinflammation typically causes neurological damage and can occur during stroke, neonatal hypoxic-ischemic encephalopathy, and other diseases. Propofol is widely used as an intravenous anesthetic. Studies have shown that propofol has antineuroinflammatory effect. However, the underlying mechanism remains to be fully elucidated. Thus, we aimed to investigate the beneficial effects of propofol against hypoxia-induced neuroinflammation and elucidated its potential cellular and biochemical mechanisms of action. In this study, we chose cobalt chloride (CoCl2) to establish a hypoxic model. We found that propofol decreased hypoxia-induced proinflammatory cytokines (TNFα, IL-1β, and IL-6) in BV2 microglia, significantly suppressed the excessive production of reactive oxygen species, and increased the total antioxidant capacity and superoxide dismutase activity. Furthermore, propofol attenuated the hypoxia-induced decrease in mitochondrial membrane potential andy 2 strongly inhibited protein expression of nuclear factor-kappa B (NF-κB) subunit p65 and hypoxia inducible factor-1α (Hif-1α) in hypoxic BV2 cells. To investigate the role of NF-κB p65, specific small interfering RNA (siRNA) against NF-κB p65 were transfected into BV2 cells, followed by exposure to hypoxia for 24 h. Hypoxia-induced Hif-1α production was downregulated after NF-κB p65 silencing. Further, propofol suppressed Hif-1α expression by inhibiting the upregulation of NF-κB p65 after exposure to hypoxia in BV2 microglia. In summary, propofol attenuates hypoxia-induced neuroinflammation, at least in part by inhibiting oxidative stress and NF-κB/Hif-1α signaling

Reperfusion Promotes Mitochondrial Biogenesis following Focal Cerebral Ischemia in Rats

<div><p>Background and Purpose</p><p>Reperfusion after transient cerebral ischemia causes severe damage to mitochondria; however, little is known regarding the continuous change in mitochondrial biogenesis during reperfusion. Mitochondrial biogenesis causes an increase in the individual mitochondrial mass of neurons and maintains their aerobic set-point in the face of declining function. The aim of this study was to examine mitochondrial biogenesis in the cortex during reperfusion following focal cerebral ischemia.</p><p>Methods</p><p>Male Wistar rats were subjected to transient focal cerebral ischemia. The relative amount of cortical mitochondrial DNA was analyzed using quantitative real-time PCR at 0 h, 24 h, 72 h, and 7 d after reperfusion. Three critical transcriptional regulators of mitochondrial biogenesis were measured by semi-quantitative reverse-transcription PCR. The protein expression of cytochrome C oxidase subunits I and IV was detected by Western blotting.</p><p>Results</p><p>Evidence of increased mitochondrial biogenesis was observed after reperfusion. The cortical mitochondrial DNA content increased after 24 h, peaked after 72 h, and maintained a high level for 7 d. The cortical expression of three critical genes for the transcriptional regulation of mitochondrial biogenesis, namely, peroxisome proliferator-activated receptor coactivator-1α, nuclear respiratory factor-1, and mitochondrial transcription factor A, also increased at 24 h and 72 h. The expression of peroxisome proliferator-activated receptor coactivator-1α returned to the baseline level at 7 d, but two other factors maintained higher levels compared with the controls. Moreover, the expression of cytochrome C oxidase subunits I and IV was increased in the cortex.</p><p>Conclusions</p><p>These results indicate that reperfusion increased mitochondrial biogenesis following focal cerebral ischemia, and this tendency was exacerbated as the reperfusion time was extended. Reperfusion-induced mitochondrial biogenesis was mediated through up-regulation of critical transcriptional regulators of mitochondrial biogenesis.</p></div

California Study of Ablation for Atrial Fibrillation:Re-hospitalization for Cardiac Events (CAABL-CE).

BackgroundCatheter ablation (ABL) for non-valvular (NV) atrial fibrillation (AF) improves rhythm control. Our aim was to compare re-hospitalization for heart failure (HF), acute coronary syndrome (ACS), or recurrent AF among patients with NVAF who underwent ABL versus controls.MethodsFrom the Office of Statewide Planning and Development (OSHPD) database, we identified all patients who had at least one hospitalization for AF between 2005-2013. Patients who subsequently underwent ABL were compared to controls (up to fivematched controls by age, sex and duration of AF between diagnosis and time of ABL). Cases with valve disease, open maze, other arrhythmias, or implanted cardiac devices were excluded. Pre-specified clinical outcomes including readmission for HF, ACS, severe or simple AF (severe = with HF or ACS; simple= without HF or ACS)were assessed using a weighted proportional hazard model adjusting for number of hospital admissions with AF before the ABL, calendar year of ABL, and presence of chronic comorbidities.ResultsThe study population constituted 8338 cases and controls, with mean 3.5+ 1 patient-year follow up. In the ABL cohort, there was lower risk of re-hospitalizations for HF, HR=0.55(95%CI: 0.43-0.69,); ACS,HR=0.5(95%CI: 0.35-0.72,); severe AF [HR=0.86 (CI:0.74-0.99), and higher for simple AF, HR=1.25 (CI:1.18-1.33).ConclusionsIn patients with NVAF,although ABL is associated with increased risk of re-hospitalization for simple AF, ABL was associated with a significant reduction in the risk of re-hospitalization for HF, ACS and severe AF. These findingsrequireconfirmation in a prospective clinical trial

Representative histological characteristics of the cortical brain sections assessed using HE staining.

<p>(A and B) The cortical sections from the sham group revealed normal cortical tissue. (C and D) The cortical sections from the I-R 0 h group displayed cortical tissue injury. (E and F) The cortical sections from the I-R 24 h group demonstrated aggravated cortical tissue injury. (G and H) The cortical sections from the I-R 72 h group showed improved residual neurons in the damaged cortex. (I and J) The cortical sections from the I-R 7 d group showed an increased number of cells similar to glial cells in that they appeared round or elongated (arrowheads).</p

mitochondrial DNA Sequences.

<p>mitochondrial DNA Sequences.</p

RT-PCR primer sequences.

<p>RT-PCR primer sequences.</p

Change in the number of mitochondria after I-R.

<p>(A) Transmission electron microscopy images of a section from the cortex showing the nucleus (Nu) surrounded by relatively uniform and compact mitochondria (arrowheads). Scale bars: 2 μm. (B) A histogram quantifying the number of mitochondria in the cortical cells. Magnification of the brain sections, 8200x. *P<0.05 versus the sham group.</p